Efficacy of a vaccine and a direct-fed microbial against fecal shedding of Escherichia coli O157:H7 in a randomized pen-level field trial of commercial feedlot cattle.

PubMed

Cull, Charley A; Paddock, Zachary D; Nagaraja, T G; Bello, Nora M; Babcock, Abram H; Renter, David G

2012-09-21

Our primary objective was to determine the efficacy of a siderophore receptor and porin proteins-based vaccine (VAC) and a Lactobacillus acidophilus-based direct-fed microbial (DFM) against fecal shedding of Escherichia coli O157:H7 in commercial feedlot cattle fed a corn grain-based diet with 25% distiller's grains. Cattle projected to be on a finishing diet during the summer were randomly allocated into 40 study pens within ten blocks based on allocation dates. Blocks were complete; each of the four pens within a block was randomly assigned one treatment: control, VAC, DFM, or VAC+DFM. The DFM was fed (10⁶CFU/animal/day of Lactobacillus) throughout the study periods (84-88 days) and cattle were vaccinated at enrollment and again three weeks later. Fresh fecal samples (30/pen) from pen floors were collected weekly for four consecutive weeks (study days 52-77). Two concurrent culture procedures were used to enable estimates of E. coli O157:H7 shedding prevalence and prevalence of high shedders. From 4800 total samples, 1522 (31.7%) were positive for E. coli O157:H7 and 169 (3.5%) were considered high shedders. Pen-level linear mixed models were used for data analyses. There were no significant interactions among treatments and time of sampling. However, vaccinated pens had lower (P<0.01) overall prevalence of E. coli O157:H7 (model-adjusted mean ± SEM=17.4 ± 3.95%) and lower (P<0.01) prevalence of high shedders (0.95 ± 0.26%) than unvaccinated pens (37.0 ± 6.32% and 4.19 ± 0.81%, respectively). There was no evidence of a DFM effect on either measure of E. coli O157:H7 shedding. Results indicate that a two-dose regimen of the vaccine significantly reduces fecal prevalence of E. coli O157:H7 (vaccine efficacy of 53.0%) and prevalence of E. coli O157:H7 high shedders (vaccine efficacy of 77.3%) in commercial feedlot cattle reared in the summer on a finishing diet with 25% distiller's grains. Copyright © 2012 Elsevier Ltd. All rights reserved.

Recent developments in vaccination against malaria: Gamete vaccines and transmission-blocking immunity in malaria*

PubMed Central

Gwadz, Robert W.; Carter, Richard; Green, Ira

1979-01-01

We have recently proposed an approach to malaria control based on immunization of the host against extracellular malarial gametes, the stage in the mosquito guts, in order to block transmission by the mosquito vector. Our studies with avian and primate models have demonstrated that immunization of the host with extracellular gametes totally suppresses infectivity to the mosquito of a subsequent blood meal. Gametocytes within the erythrocytes are unaffected by the immunity, since resuspending the gametocytes in serum from normal nonimmune animals restores their infectivity to mosquitos. Immunity is mediated by antibodies that are ingested with the blood meal. These antibodies interact with extracellular gametes and prevent fertilization (the fusion of male and female gametes). Thus the infection in the mosquito is blocked, and in this way transmission is interrupted. PMID:317439

Surface antigens of Plasmodium falciparum gametocytes--a new class of transmission-blocking vaccine targets?

PubMed

Sutherland, Colin J

2009-08-01

The re-establishment of elimination and eradication on the malaria control agenda has led to calls for renewed effort in the development of parasite transmission-blocking interventions. Vaccines are ideally suited to this task, but progress towards an anti-gamete transmission-blocking vaccine, designed to act on parasites in blood-fed mosquitoes, has been slow. Recent work has confirmed that the surface of the gametocyte-infected erythrocyte presents antigens to the host immune system, and elicits specific humoral immune responses to these antigens, termed gametocyte surface antigens (GSAs). Likely candidate molecules, including antigens encoded by sub-telomeric multi-gene families, are discussed, and a hypothetical group of parasite molecules involved in spatial and temporal signal transduction in the human host is proposed, the tropins and circadins. The next steps for development of anti-gametocyte transmission-blocking vaccines for P. falciparum and the other human malaria species are considered.

National Vaccine Policy: ethical equity issues.

PubMed

Jayakrishnan, T

2013-01-01

The ministry of health and family welfare published the national vaccination policy in April 2011. The policy document drew severe criticism from several public health experts. A review of the print and web-based literature on the national vaccine policy was done and the issues of ethics and equity involved in introducing new vaccines under the Universal Immunisation Programme (UIP) were studied. The average coverage of the UIP vaccines at the national level is below 50%. Despite this, the policy document did not state any concrete strategy for increasing the coverage. The main stumbling block for evidence-based vaccine policy in India is the lack of reliable epidemiological data, which makes it difficult for the National Technical Advisory Group on Immunisation to offer sound technical advice to the government. No attempts have been made to prioritise diseases or the selection of vaccines. The policy suggests the introduction of the following vaccines in the UIP: Haemophilus influenzae type b, pneumococcal vaccine, rotavirus vaccines and human papillomavirus (HPV). This selection is on the grounds of the vaccines' availability, not on the basis of epidemiological evidence or proven cost-effectiveness. This is a critical review of the current vaccination policy and the move to include the rotavirus and HPV vaccines in the UIP.

On the impact of masking and blocking hypotheses for measuring the efficacy of new tuberculosis vaccines.

PubMed

Arregui, Sergio; Sanz, Joaquín; Marinova, Dessislava; Martín, Carlos; Moreno, Yamir

2016-01-01

Over the past 60 years, the Mycobacterium bovis bacille Calmette-Guérin (BCG) has been used worldwide to prevent tuberculosis (TB). However, BCG has shown a very variable efficacy in different trials, offering a wide range of protection in adults against pulmonary TB. One of the most accepted hypotheses to explain these inconsistencies points to the existence of a pre-existing immune response to antigens that are common to environmental sources of mycobacterial antigens and Mycobacterium tuberculosis. Specifically, two different mechanisms have been hypothesized to explain this phenomenon: the masking and the blocking effects. According to masking hypothesis, previous sensitization confers some level of protection against TB that masks vaccine's effects. In turn, the blocking hypothesis postulates that previous immune response prevents vaccine taking of a new TB vaccine. In this work we introduce a series of models to discriminate between masking and blocking mechanisms and address their relative likelihood. We apply our methodology to the data reported by BCG-REVAC clinical trials, which were specifically designed for studying BCG efficacy variability. Our results yield estimates that are consistent with high levels of blocking (41% in Manaus -95% CI [14-68]- and 96% in Salvador -95% CI [52-100]-). Moreover, we also show that masking does not play any relevant role in modifying vaccine's efficacy either alone or in addition to blocking. The quantification of these effects around a plausible model constitutes a relevant step towards impact evaluation of novel anti-tuberculosis vaccines, which are susceptible of being affected by similar effects, especially if applied on individuals previously exposed to mycobacterial antigens.

A Comprehensive, Model-Based Review of Vaccine and Repeat Infection Trials for Filariasis

PubMed Central

Morris, C. Paul; Evans, Holly; Larsen, Sasha E.

2013-01-01

SUMMARY Filarial worms cause highly morbid diseases such as elephantiasis and river blindness. Since the 1940s, researchers have conducted vaccine trials in 27 different animal models of filariasis. Although no vaccine trial in a permissive model of filariasis has provided sterilizing immunity, great strides have been made toward developing vaccines that could block transmission, decrease pathological sequelae, or decrease susceptibility to infection. In this review, we have organized, to the best of our ability, all published filaria vaccine trials and reviewed them in the context of the animal models used. Additionally, we provide information on the life cycle, disease phenotype, concomitant immunity, and natural immunity during primary and secondary infections for 24 different filaria models. PMID:23824365

An Oral DNA Vaccine Encoding Endoglin Eradicates Breast Tumors by Blocking Their Blood Supply

DTIC Science & Technology

2006-05-01

W81XWH-04-1-0489 TITLE: An Oral DNA Vaccine Encoding Endoglin Eradicates Breast Tumors by Blocking Their Blood Supply PRINCIPAL...Encoding Endoglin Eradicates Breast Tumors by Blocking Their Blood Supply 5b. GRANT NUMBER W81XWH-04-1-0489 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR...blocking renewal of blood vessel growth in the tumor bed, have been proposed as suitable antitumor strategies. Endoglin (CD105) is a suitable

Burrow Dusting or Oral Vaccination Prevents Plague-Associated Prairie Dog Colony Collapse.

PubMed

Tripp, Daniel W; Rocke, Tonie E; Runge, Jonathan P; Abbott, Rachel C; Miller, Michael W

2017-09-01

Plague impacts prairie dogs (Cynomys spp.), the endangered black-footed ferret (Mustela nigripes) and other sensitive wildlife species. We compared efficacy of prophylactic treatments (burrow dusting with deltamethrin or oral vaccination with recombinant "sylvatic plague vaccine" [RCN-F1/V307]) to placebo treatment in black-tailed prairie dog (C. ludovicianus) colonies. Between 2013 and 2015, we measured prairie dog apparent survival, burrow activity and flea abundance on triplicate plots ("blocks") receiving dust, vaccine or placebo treatment. Epizootic plague affected all three blocks but emerged asynchronously. Dust plots had fewer fleas per burrow (P < 0.0001), and prairie dogs captured on dust plots had fewer fleas (P < 0.0001) than those on vaccine or placebo plots. Burrow activity and prairie dog density declined sharply in placebo plots when epizootic plague emerged. Patterns in corresponding dust and vaccine plots were less consistent and appeared strongly influenced by timing of treatment applications relative to plague emergence. Deltamethrin or oral vaccination enhanced apparent survival within two blocks. Applying insecticide or vaccine prior to epizootic emergence blunted effects of plague on prairie dog survival and abundance, thereby preventing colony collapse. Successful plague mitigation will likely entail strategic combined uses of burrow dusting and oral vaccination within large colonies or colony complexes.

Lessons learned from successful human vaccines: Delineating key epitopes by dissecting the capsid proteins

PubMed Central

Zhang, Xiao; Xin, Lu; Li, Shaowei; Fang, Mujin; Zhang, Jun; Xia, Ningshao; Zhao, Qinjian

2015-01-01

Recombinant VLP-based vaccines have been successfully used against 3 diseases caused by viral infections: Hepatitis B, cervical cancer and hepatitis E. The VLP approach is attracting increasing attention in vaccine design and development for human and veterinary use. This review summarizes the clinically relevant epitopes on the VLP antigens in successful human vaccines. These virion-like epitopes, which can be delineated with molecular biology, cryo-electron microscopy and x-ray crystallographic methods, are the prerequisites for these efficacious vaccines to elicit functional antibodies. The critical epitopes and key factors influencing these epitopes are discussed for the HEV, HPV and HBV vaccines. A pentamer (for HPV) or a dimer (for HEV and HBV), rather than a monomer, is the basic building block harboring critical epitopes for the assembly of VLP antigen. The processing and formulation of VLP-based vaccines need to be developed to promote the formation and stabilization of these epitopes in the recombinant antigens. Delineating the critical epitopes is essential for antigen design in the early phase of vaccine development and for critical quality attribute analysis in the commercial phase of vaccine manufacturing. PMID:25751641

Leishmune vaccine: the newest tool for prevention and control of canine visceral leishmaniosis and its potential as a transmission-blocking vaccine.

PubMed

Dantas-Torres, Filipe

2006-10-10

Canine visceral leishmaniosis is a life-threatening disease caused by Leishmania infantum. For quite some time, specialists in leishmaniosis have tried to develop more affordable and effective control measures against this disease. In this search, the first vaccine against canine visceral leishmaniosis was recently licensed in Brazil. In the light of recent research, the Leishmune vaccine might be seen as the newest tool for prevention and control of canine visceral leishmaniosis. Moreover, the potential of the Leishmune as a transmission-blocking vaccine has recently been demonstrated, indicating its usefulness in the control of zoonotic visceral leishmaniosis.

Optimized dosing of a CCR2 antagonist for amplification of vaccine immunity.

PubMed

Mitchell, Leah A; Hansen, Ryan J; Beaupre, Adam J; Gustafson, Daniel L; Dow, Steven W

2013-02-01

We have recently discovered that inflammatory monocytes recruited to lymph nodes in response to vaccine-induced inflammation can function as potent negative regulators of both humoral and cell-mediated immune responses to vaccination. Monocyte depletion or migration blockade can significantly amplify both antibody titers and cellular immune responses to vaccination with several different antigens in mouse models. Thus, we hypothesized that the use of small molecule CCR2 inhibitors to block monocyte migration into lymph nodes may represent a broadly effective means of amplifying vaccine immunity. To address this question, the role of CCR2 in monocyte recruitment to vaccine draining lymph nodes was initially explored in CCR2-/- mice. Next, a small molecule antagonist of CCR2 (RS102895) was evaluated in mouse vaccination models. Initial studies revealed that a single intraperitoneal dose of RS102895 failed to effectively block monocyte recruitment following vaccination. Pharmacokinetic analysis of RS102895 revealed a short half-life (approximately 1h), and suggested that a multi-dose treatment regimen would be more effective. We found that administration of RS102895 every 6 h resulted in consistent plasma levels of 20 ng/ml or greater, which effectively blocked monocyte migration to lymph nodes following vaccination. Moreover, administration of RS102895 with concurrent vaccination markedly enhanced vaccine responses following immunization against the influenza antigen HA1. We concluded that administration of small molecule CCR2 antagonists such as RS102895 in the immediate post-vaccine period could be used as a novel means of significantly enhancing vaccine immunity. Copyright © 2012 Elsevier B.V. All rights reserved.

Designing a VAR2CSA-based vaccine to prevent placental malaria.

PubMed

Fried, Michal; Duffy, Patrick E

2015-12-22

Placental malaria (PM) due to Plasmodium falciparum is a major cause of maternal, fetal and infant mortality, but the mechanisms of pathogenesis and protective immunity are relatively well-understood for this condition, providing a path for vaccine development. P. falciparum parasites bind to chondroitin sulfate A (CSA) to sequester in the placenta, and women become resistant over 1-2 pregnancies as they acquire antibodies that block adhesion to CSA. The protein VAR2CSA, a member of the PfEMP1 variant surface antigen family, mediates parasite adhesion to CSA, and is the leading target for a vaccine to prevent PM. Obstacles to PM vaccine development include the large size (∼ 350 kD), high cysteine content, and sequence variation of VAR2CSA. A number of approaches have been taken to identify the combination of VAR2CSA domains and alleles that can induce broadly active antibodies that block adhesion of heterologous parasite isolates to CSA. This review summarizes these approaches, which have examined VAR2CSA fragments for binding activity, antigenicity with naturally acquired antibodies, and immunogenicity in animals for inducing anti-adhesion or surface-reactive antibodies. Two products are expected to enter human clinical studies in the near future based on N-terminal VAR2CSA fragments that have high binding affinity for CSA, and additional proteins preferentially expressed by placental parasites are also being examined for their potential contribution to a PM vaccine. Copyright © 2015. Published by Elsevier Ltd.

Algae-Produced Pfs25 Elicits Antibodies That Inhibit Malaria Transmission

PubMed Central

Gregory, James A.; Li, Fengwu; Tomosada, Lauren M.; Cox, Chesa J.; Topol, Aaron B.; Vinetz, Joseph M.; Mayfield, Stephen

2012-01-01

Subunit vaccines are significantly more expensive to produce than traditional vaccines because they are based primarily on recombinant proteins that must be purified from the expression system. Despite the increased cost, subunit vaccines are being developed because they are safe, effective, and can elicit antibodies that confer protection against diseases that are not currently vaccine-preventable. Algae are an attractive platform for producing subunit vaccines because they are relatively inexpensive to grow, genetically tractable, easily scaled to large volumes, have a short generation time, and are devoid of inflammatory, viral, or prion contaminants often present in other systems. We tested whether algal chloroplasts can produce malaria transmission blocking vaccine candidates, Plasmodium falciparum surface protein 25 (Pfs25) and 28 (Pfs28). Antibodies that recognize Pfs25 and Pfs28 disrupt the sexual development of parasites within the mosquito midgut, thus preventing transmission of malaria from one human host to the next. These proteins have been difficult to produce in traditional recombinant systems because they contain tandem repeats of structurally complex epidermal growth factor-like domains, which cannot be produced in bacterial systems, and because they are not glycosylated, so they must be modified for production in eukaryotic systems. Production in algal chloroplasts avoids these issues because chloroplasts can fold complex eukaryotic proteins and do not glycosylate proteins. Here we demonstrate that algae are the first recombinant system to successfully produce an unmodified and aglycosylated version of Pfs25 or Pfs28. These antigens are structurally similar to the native proteins and antibodies raised to these recombinant proteins recognize Pfs25 and Pfs28 from P. falciparum. Furthermore, antibodies to algae-produced Pfs25 bind the surface of in-vitro cultured P. falciparum sexual stage parasites and exhibit transmission blocking activity. Thus, algae are promising organisms for producing cysteine-disulfide-containing malaria transmission blocking vaccine candidate proteins. PMID:22615931

Vaccines against malaria-still a long way to go.

PubMed

Matuschewski, Kai

2017-08-01

Several species of Plasmodium cause a broad spectrum of human disease that range from nausea and fever to severe anemia, cerebral malaria, and multiorgan failure. In malaria-endemic countries, continuous exposure to Plasmodium sporozoite inoculations and subsequent blood infections elicit only partial and short-lived immunity, which gradually develops over many years of parasite exposure and multiple clinical episodes. The ambitious goal of malaria vaccinology over the past 70 years has been to develop an immunization strategy that mounts protection superior to naturally acquired immunity. Herein, three principal concepts in evidence-based malaria vaccine development are compared. Feasible leads are typically stand-alone subunit vaccine approaches that block Plasmodium parasite life cycle progression or parasite/host interactions, and they constitute the majority of candidates in preclinical research and early clinical testing. Integrated approaches incorporate malaria antigen(s) into licensed or emerging pediatric vaccine formulations. This strategy can complement the malaria control portfolio even if the antimalarial component is only partially effective and has led to the development of the only candidate vaccine to date, namely RTS,S-AS01. Experimental whole parasite vaccine approaches have been repeatedly shown to elicit sterile and lasting protection against identical parasite strains, but mass production, proof of broad protection against different parasite strains, and routes of vaccine delivery remain significant translational road blocks. Global access to an effective and affordable malaria vaccine will critically depend on innovative translational research that builds on a better molecular understanding of Plasmodium biology and host immunity. © 2017 Federation of European Biochemical Societies.

Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys.

PubMed

Barouch, Dan H; Liu, Jinyan; Li, Hualin; Maxfield, Lori F; Abbink, Peter; Lynch, Diana M; Iampietro, M Justin; SanMiguel, Adam; Seaman, Michael S; Ferrari, Guido; Forthal, Donald N; Ourmanov, Ilnour; Hirsch, Vanessa M; Carville, Angela; Mansfield, Keith G; Stablein, Donald; Pau, Maria G; Schuitemaker, Hanneke; Sadoff, Jerald C; Billings, Erik A; Rao, Mangala; Robb, Merlin L; Kim, Jerome H; Marovich, Mary A; Goudsmit, Jaap; Michael, Nelson L

2012-01-04

Preclinical studies of human immunodeficiency virus type 1 (HIV-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges. Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant simian immunodeficiency virus (SIV) challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus-vector-based vaccines expressing SIV(SME543) Gag, Pol and Env antigens resulted in an 80% or greater reduction in the per-exposure probability of infection against repetitive, intrarectal SIV(MAC251) challenges in rhesus monkeys. Protection against acquisition of infection showed distinct immunological correlates compared with post-infection virological control and required the inclusion of Env in the vaccine regimen. These data demonstrate the proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys.

Improving the malaria transmission-blocking activity of a Plasmodium falciparum 48/45 based vaccine antigen by SpyTag/SpyCatcher mediated virus-like display.

PubMed

Singh, Susheel K; Thrane, Susan; Janitzek, Christoph M; Nielsen, Morten A; Theander, Thor G; Theisen, Michael; Salanti, Ali; Sander, Adam F

2017-06-27

Malaria is a devastating disease caused by Plasmodium parasites, resulting in almost 0.5 million deaths per year. The Pfs48/45 protein exposed on the P. falciparum sexual stages is one of the most advanced antigen candidates for a transmission-blocking (TB) vaccine in the clinical pipeline. However, it remains essential to identify an optimal vaccine formulation that can facilitate induction of a long-lasting TB anti-Pfs48/45 response. Here we report on the development and evaluation of two Pfs48/45-based virus-like particle (VLP) vaccines generated using the AP205 SpyTag/Catcher VLP system. Two different recombinant proteins (SpyCatcher-R0.6C and SpyCatcher-6C), comprising the Pfs48/45-6C region, were covalently attached to the surface of Spy-tagged Acinetobacter phage AP205 VLPs. Resulting Pfs48/45-VLP complexes appeared as non-aggregated particles of ∼30nm, each displaying an average of 216 (R0.6C) or 291 (6C) copies of the antigens. Both R0.6C and 6C VLP conjugates were strongly reactive with a monoclonal antibody (mAb45.1) targeting a conformational TB Pfs48/45 epitope, suggesting that the TB epitope is accessible for immune recognition on the particles. To select the most suitable vaccine formulation for downstream clinical studies the two VLP vaccines were tested in CD1 mice using different adjuvant formulations. The study demonstrates that VLP-display of R0.6C and 6C significantly increases antigen immunogenicity when using Montanide ISA 720 VG as extrinsic adjuvant. Copyright © 2017 Elsevier Ltd. All rights reserved.

The effectiveness of preventative mass vaccination regimes against the incidence of highly pathogenic avian influenza on Java Island, Indonesia.

PubMed

Bett, B; McLaws, M; Jost, C; Schoonman, L; Unger, F; Poole, J; Lapar, M L; Siregar, E S; Azhar, M; Hidayat, M M; Dunkle, S E; Mariner, J

2015-04-01

We conducted an operational research study involving backyard and semicommercial farms on Java Island, Indonesia, between April 2008 and September 2009 to evaluate the effectiveness of two preventive mass vaccination strategies against highly pathogenic avian influenza (HPAI). One regimen used Legok 2003 H5N1 vaccine, while the other used both Legok 2003 H5N1 and HB1 Newcastle disease (ND) vaccine. A total of 16 districts were involved in the study. The sample size was estimated using a formal power calculation technique that assumed a detectable effect of treatment as a 50% reduction in the baseline number of HPAI-compatible outbreaks. Within each district, candidate treatment blocks with village poultry populations ranging from 80 000 to 120 000 were created along subdistrict boundary lines. Subsequently, four of these blocks were randomly selected and assigned one treatment from a list that comprised control, vaccination against HPAI, vaccination against HPAI + ND. Four rounds of vaccination were administered at quarterly intervals beginning in July 2008. A vaccination campaign involved vaccinating 100 000 birds in a treatment block, followed by another 100 000 vaccinations 3 weeks later as a booster dose. Data on disease incidence and vaccination coverage were also collected at quarterly intervals using participatory epidemiological techniques. Compared with the unvaccinated (control) group, the incidence of HPAI-compatible events declined by 32% (P = 0.24) in the HPAI-vaccinated group and by 73% (P = 0.00) in the HPAI- and ND-vaccinated group. The effect of treatment did not vary with time or district. Similarly, an analysis of secondary data from the participatory disease and response (PDSR) database revealed that the incidence of HPAI declined by 12% in the HPAI-vaccinated group and by 24% in the HPAI + ND-vaccinated group. The results suggest that the HPAI + ND vaccination significantly reduced the incidence of HPAI-compatible events in mixed populations of semicommercial and backyard poultry. © 2013 Blackwell Verlag GmbH.

Acceptability of a herd immunity-focused, transmission-blocking malaria vaccine in malaria-endemic communities in the Peruvian Amazon: an exploratory study.

PubMed

White, Sara E; Harvey, Steven A; Meza, Graciela; Llanos, Alejandro; Guzman, Mitchel; Gamboa, Dionicia; Vinetz, Joseph M

2018-04-27

A transmission-blocking vaccine (TBV) to prevent malaria-infected humans from infecting mosquitoes has been increasingly considered as a tool for malaria control and elimination. This study tested the hypothesis that a malaria TBV would be acceptable among residents of a malaria-hypoendemic region. The study was carried out in six Spanish-speaking rural villages in the Department of Loreto in the Peruvian Amazon. These villages comprise a cohort of 430 households associated with the Peru-Brazil International Centre for Excellence in Malaria Research. Individuals from one-third (143) of enrolled households in an ongoing longitudinal, prospective cohort study in 6 communities in Loreto, Peru, were randomly selected to participate by answering a pre-validated questionnaire. All 143 participants expressed desire for a malaria vaccine in general; only 1 (0.7%) expressed unwillingness to receive a transmission-blocking malaria vaccine. Injection was considered most acceptable for adults (97.2%); for children drops in the mouth were preferred (96.8%). Acceptability waned marginally with the prospect of multiple injections (83.8%) and different projected efficacies at 70 and 50% (90.1 and 71.8%, respectively). Respondents demonstrated clear understanding that the vaccine was for community, rather than personal, protection against malaria infection. In this setting of the Peruvian Amazon, a transmission-blocking malaria vaccine was found to be almost universally acceptable. This study is the first to report that residents of a malaria-endemic region have been queried regarding a malaria vaccine strategy that policy-makers in the industrialized world often dismiss as altruistic.

Modified Vaccinia virus Ankara-based vaccines in the era of personalized immunotherapy of cancer.

PubMed

Bendjama, Kaïdre; Quemeneur, Eric

2017-09-02

While interest in immunotherapies is renewed by the successful introduction of immune checkpoint blocking agent in the clinic, advances in genome sequencing are opening new possibilities in the design of increasingly personalized vaccines. Personalization of medicine can now be realistically contemplated at the single patient level. Unlike the previous generation of cancer vaccines, neoantigen directed vaccines would target truly specific tumor antigens resulting from acquired tumor genome mutations. Immune response induced by this next generation vaccine would not be subject to self-tolerance and will likely result to enhanced efficacy. Nevertheless, this new technologies can hold to their promises only if sponsors manage to meet several scientific, technical, logistical and regulatory challenges. In particular manufacturers will have to design, manufacture, and deliver to the patient a new pharmaceutical grade in a matters of weeks. In this paper, we briefly review current technologies currently tried at the translation of personalized vaccines and explore the possibilities offered by the Modified Vaccinia virus Ankara in this next wave of cancer vaccines.

Blocking herpes simplex virus 2 glycoprotein E immune evasion as an approach to enhance efficacy of a trivalent subunit antigen vaccine for genital herpes.

PubMed

Awasthi, Sita; Huang, Jialing; Shaw, Carolyn; Friedman, Harvey M

2014-08-01

Herpes simplex virus 2 (HSV-2) subunit antigen vaccines targeting virus entry molecules have failed to prevent genital herpes in human trials. Our approach is to include a virus entry molecule and add antigens that block HSV-2 immune evasion. HSV-2 glycoprotein C (gC2) is an immune evasion molecule that inhibits complement. We previously reported that adding gC2 to gD2 improved vaccine efficacy compared to the efficacy of either antigen alone in mice and guinea pigs. Here we demonstrate that HSV-2 glycoprotein E (gE2) functions as an immune evasion molecule by binding the IgG Fc domain. HSV-2 gE2 is synergistic with gC2 in protecting the virus from antibody and complement neutralization. Antibodies produced by immunization with gE2 blocked gE2-mediated IgG Fc binding and cell-to-cell spread. Mice immunized with gE2 were only partially protected against HSV-2 vaginal challenge in mice; however, when gE2 was added to gC2/gD2 to form a trivalent vaccine, neutralizing antibody titers with and without complement were significantly higher than those produced by gD2 alone. Importantly, the trivalent vaccine protected the dorsal root ganglia (DRG) of 32/33 (97%) mice between days 2 and 7 postchallenge, compared with 27/33 (82%) in the gD2 group. The HSV-2 DNA copy number was significantly lower in mice immunized with the trivalent vaccine than in those immunized with gD2 alone. The extent of DRG protection using the trivalent vaccine was better than what we previously reported for gC2/gD2 immunization. Therefore, gE2 is a candidate antigen for inclusion in a multivalent subunit vaccine that attempts to block HSV-2 immune evasion. Herpes simplex virus is the most common cause of genital ulcer disease worldwide. Infection results in emotional distress for infected individuals and their partners, is life threatening for infants exposed to herpes during childbirth, and greatly increases the risk of individuals acquiring and transmitting HIV infection. A vaccine that prevents genital herpes infection will have major public health benefits. Our vaccine approach includes strategies to prevent the virus from evading immune attack. Mice were immunized with a trivalent vaccine containing an antigen that induces antibodies to block virus entry and two antigens that induce antibodies that block immune evasion from antibody and complement. Immunized mice demonstrated no genital disease, and 32/33 (97%) animals had no evidence of infection of dorsal root ganglia, suggesting that the vaccine may prevent the establishment of latency and recurrent infections. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Epitope analysis of the malaria surface antigen pfs48/45 identifies a subdomain that elicits transmission blocking antibodies.

PubMed

Outchkourov, Nikolay; Vermunt, Adriaan; Jansen, Josephine; Kaan, Anita; Roeffen, Will; Teelen, Karina; Lasonder, Edwin; Braks, Anneke; van de Vegte-Bolmer, Marga; Qiu, Li Yan; Sauerwein, Robert; Stunnenberg, Hendrik G

2007-06-08

Pfs48/45, a member of a Plasmodium-specific protein family, displays conformation-dependent epitopes and is an important target for malaria transmission-blocking (TB) immunity. To design a recombinant Pfs48/45-based TB vaccine, we analyzed the conformational TB epitopes of Pfs48/45. The Pfs48/45 protein was found to consist of a C-terminal six-cysteine module recognized by anti-epitope I antibodies, a middle four-cysteine module recognized by anti-epitopes IIb and III, and an N-terminal module recognized by anti-epitope V antibodies. Refolding assays identified that a fragment of 10 cysteines (10C), comprising the middle four-cysteine and the C-terminal six-cysteine modules, possesses superior refolding capacity. The refolded and partially purified 10C conformer elicited antibodies in mice that targeted at least two of the TB epitopes (I and III). The induced antibodies could block the fertilization of Plasmodium falciparum gametes in vivo in a concentration-dependent manner. Our results provide important insight into the structural organization of the Pfs48/45 protein and experimental support for a Pfs48/45-based subunit vaccine.

Chimeric GII.4 norovirus virus-like-particle-based vaccines induce broadly blocking immune responses.

PubMed

Debbink, Kari; Lindesmith, Lisa C; Donaldson, Eric F; Swanstrom, Jesica; Baric, Ralph S

2014-07-01

There is currently no licensed vaccine for noroviruses, and development is hindered, in part, by an incomplete understanding of the host adaptive immune response to these highly heterogeneous viruses and rapid GII.4 norovirus molecular evolution. Emergence of a new predominant GII.4 norovirus strain occurs every 2 to 4 years. To address the problem of GII.4 antigenic variation, we tested the hypothesis that chimeric virus-like particle (VLP)-based vaccine platforms, which incorporate antigenic determinants from multiple strains into a single genetic background, will elicit a broader immune response against contemporary and emergent strains. Here, we compare the immune response generated by chimeric VLPs to that of parental strains and a multivalent VLP cocktail. Results demonstrate that chimeric VLPs induce a more broadly cross-blocking immune response than single parental VLPs and a similar response to a multivalent GII.4 VLP cocktail. Furthermore, we show that incorporating epitope site A alone from one strain into the background of another is sufficient to induce a blockade response against the strain donating epitope site A. This suggests a mechanism by which population-wide surveillance of mutations in a single epitope could be used to evaluate antigenic changes in order to identify potential emergent strains and quickly reformulate vaccines against future epidemic strains as they emerge in human populations. Noroviruses are gastrointestinal pathogens that infect an estimated 21 million people per year in the United States alone. GII.4 noroviruses account for >70% of all outbreaks, making them the most clinically important genotype. GII.4 noroviruses undergo a pattern of epochal evolution, resulting in the emergence of new strains with altered antigenicity over time, complicating vaccine design. This work is relevant to norovirus vaccine design as it demonstrates the potential for development of a chimeric VLP-based vaccine platform that may broaden the protective response against multiple GII.4 strains and proposes a potential reformulation strategy to control newly emergent strains in the human population. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Evaluation of a Plasmodium-Specific Carrier Protein To Enhance Production of Recombinant Pfs25, a Leading Transmission-Blocking Vaccine Candidate.

PubMed

Parzych, Elizabeth M; Miura, Kazutoyo; Ramanathan, Aarti; Long, Carole A; Burns, James M

2018-01-01

Challenges with the production and suboptimal immunogenicity of malaria vaccine candidates have slowed the development of a Plasmodium falciparum multiantigen vaccine. Attempting to resolve these issues, we focused on the use of highly immunogenic merozoite surface protein 8 (MSP8) as a vaccine carrier protein. Previously, we showed that a genetic fusion of the C-terminal 19-kDa fragment of merozoite surface protein 1 (MSP1 19 ) to P. falciparum MSP8 ( Pf MSP8) facilitated antigen production and folding and the induction of neutralizing antibodies to conformational B cell epitopes of MSP1 19 Here, using the Pf MSP1/8 construct, we further optimized the recombinant Pf MSP8 (r Pf MSP8) carrier by the introduction of two cysteine-to-serine substitutions (CΔS) to improve the yield of the monomeric product. We then sought to test the broad applicability of this approach using the transmission-blocking vaccine candidate Pf s25. The production of r Pf s25-based vaccines has presented challenges. Antibodies directed against the four highly constrained epidermal growth factor (EGF)-like domains of Pf s25 block sexual-stage development in mosquitoes. The sequence encoding mature Pf s25 was codon harmonized for expression in Escherichia coli We produced a r Pf s25- Pf MSP8 fusion protein [r Pf s25/8(CΔS)] as well as unfused, mature r Pf s25. r Pf s25 was purified with a modest yield but required the incorporation of refolding protocols to obtain a proper conformation. In comparison, chimeric r Pf s25/8(CΔS) was expressed and easily purified, with the Pf s25 domain bearing the proper conformation without renaturation. Both antigens were immunogenic in rabbits, inducing IgG that bound native Pf s25 and exhibited potent transmission-reducing activity. These data further demonstrate the utility of Pf MSP8 as a parasite-specific carrier protein to enhance the production of complex malaria vaccine targets. Copyright © 2017 American Society for Microbiology.

The role of attitudes about vaccine safety, efficacy, and value in explaining parents' reported vaccination behavior.

PubMed

Lavail, Katherine Hart; Kennedy, Allison Michelle

2013-10-01

To explain vaccine confidence as it related to parents' decisions to vaccinate their children with recommended vaccines, and to develop a confidence measure to efficiently and effectively predict parents' self-reported vaccine behaviors. A sample of parents with at least one child younger than 6 years (n = 376) was analyzed using data from the HealthStyles 2010 survey. Questions were grouped into block variables to create three confidence constructs: value, safety, and efficacy. Regression equations controlling for demographic characteristics were used to identify the confidence construct(s) that best predicted parents' self-reported vaccination decisions (accept all, some, or none of the recommended childhood vaccines). Among the three constructs evaluated, confidence in the value of vaccines, that is the belief that vaccines are important and vaccinating one's children is the right thing to do, was the best predictor of parents' vaccine decisions, F(2, 351) = 119.199, p < .001. When combined into a block variable for analysis, two survey items measuring confidence in the value of vaccines accounted for 40% of the variance in parents' self-reported vaccine decisions. Confidence in the safety or efficacy of vaccines failed to account for additional significant variance in parent-reported vaccination behavior. Confidence in the value of vaccines is a helpful predictor of parent-reported vaccination behavior. Attitudinal constructs of confidence in the safety and efficacy of vaccines failed to account for additional significant variance in parents' vaccination behaviors. Future research should assess the role of vaccine knowledge and tangible barriers, such as access and cost, to further explain parents' vaccination behaviors.

Transmission blocking malaria vaccines: Assays and candidates in clinical development.

PubMed

Sauerwein, R W; Bousema, T

2015-12-22

Stimulated by recent advances in malaria control and increased funding, the elimination of malaria is now considered to be an attainable goal for an increasing number of malaria-endemic regions. This has boosted the interest in transmission-reducing interventions including vaccines that target sexual, sporogenic, and/or mosquito-stage antigens to interrupt malaria transmission (SSM-VIMT). SSM-VIMT aim to prevent human malaria infection in vaccinated communities by inhibiting parasite development within the mosquito after a blood meal taken from a gametocyte carrier. Only a handful of target antigens are in clinical development and progress has been slow over the years. Major stumbling blocks include (i) the expression of appropriately folded target proteins and their downstream purification, (ii) insufficient induction of sustained functional blocking antibody titers by candidate vaccines in humans, and (iii) validation of a number of (bio)-assays as correlate for blocking activity in the field. Here we discuss clinical manufacturing and testing of current SSM-VIMT candidates and the latest bio-assay development for clinical evaluation. New testing strategies are discussed that may accelerate the evaluation and application of SSM-VIMT. Copyright © 2015. Published by Elsevier Ltd.

Engineering synthetic vaccines using cues from natural immunity.

PubMed

Irvine, Darrell J; Swartz, Melody A; Szeto, Gregory L

2013-11-01

Vaccines aim to protect against or treat diseases through manipulation of the immune response, promoting either immunity or tolerance. In the former case, vaccines generate antibodies and T cells poised to protect against future pathogen encounter or attack diseased cells such as tumours; in the latter case, which is far less developed, vaccines block pathogenic autoreactive T cells and autoantibodies that target self tissue. Enormous challenges remain, however, as a consequence of our incomplete understanding of human immunity. A rapidly growing field of research is the design of vaccines based on synthetic materials to target organs, tissues, cells or intracellular compartments; to co-deliver immunomodulatory signals that control the quality of the immune response; or to act directly as immune regulators. There exists great potential for well-defined materials to further our understanding of immunity. Here we describe recent advances in the design of synthetic materials to direct immune responses, highlighting successes and challenges in prophylactic, therapeutic and tolerance-inducing vaccines.

Engineering synthetic vaccines using cues from natural immunity

NASA Astrophysics Data System (ADS)

Irvine, Darrell J.; Swartz, Melody A.; Szeto, Gregory L.

2013-11-01

Vaccines aim to protect against or treat diseases through manipulation of the immune response, promoting either immunity or tolerance. In the former case, vaccines generate antibodies and T cells poised to protect against future pathogen encounter or attack diseased cells such as tumours; in the latter case, which is far less developed, vaccines block pathogenic autoreactive T cells and autoantibodies that target self tissue. Enormous challenges remain, however, as a consequence of our incomplete understanding of human immunity. A rapidly growing field of research is the design of vaccines based on synthetic materials to target organs, tissues, cells or intracellular compartments; to co-deliver immunomodulatory signals that control the quality of the immune response; or to act directly as immune regulators. There exists great potential for well-defined materials to further our understanding of immunity. Here we describe recent advances in the design of synthetic materials to direct immune responses, highlighting successes and challenges in prophylactic, therapeutic and tolerance-inducing vaccines.

Substance abuse vaccines.

PubMed

Orson, Frank M; Kinsey, Berma M; Singh, Rana A K; Wu, Yan; Gardner, Tracie; Kosten, Thomas R

2008-10-01

Conventional substance-abuse treatments have only had limited success for drugs such as cocaine, nicotine, methamphetamine, and phencyclidine. New approaches, including vaccination to block the effects of these drugs on the brain, are in advanced stages of development. Although several potential mechanisms for the effects of antidrug vaccines have been suggested, the most straightforward and intuitive mechanism involves binding of the drug by antibodies in the bloodstream, thereby blocking entry and/or reducing the rate of entry of the drug into the central nervous system. The benefits of such antibodies on drug pharmacodynamics will be influenced by both the quantitative and the qualitative properties of the antibodies. The sum of these effects will determine the success of the clinical applications of antidrug vaccines in addiction medicine. This review will discuss these issues and present the current status of vaccine development for nicotine, cocaine, methamphetamine, phencyclidine, and morphine.

Blocking pathogen transmission at the source: reservoir targeted OspA-based vaccines against Borrelia burgdorferi.

PubMed

Gomes-Solecki, Maria

2014-01-01

Control strategies are especially challenging for microbial diseases caused by pathogens that persist in wildlife reservoirs and use arthropod vectors to cycle amongst those species. One of the most relevant illnesses that pose a direct human health risk is Lyme disease; in the US, the Centers for Disease Control and Prevention recently revised the probable number of cases by 10-fold, to 300,000 cases per year. Caused by Borrelia burgdorferi, Lyme disease can affect the nervous system, joints and heart. No human vaccine is approved by the Food and Drug Administration. In addition to novel human vaccines, new strategies for prevention of Lyme disease consist of pest management interventions, vector-targeted vaccines and reservoir-targeted vaccines. However, even human vaccines can not prevent Lyme disease expansion into other geographical areas. The other strategies aim at reducing tick density and at disrupting the transmission of B. burgdorferi by targeting one or more key elements that maintain the enzootic cycle: the reservoir host and/or the tick vector. Here, I provide a brief overview of the application of an OspA-based wildlife reservoir targeted vaccine aimed at reducing transmission of B. burgdorferi and present it as a strategy for reducing Lyme disease risk to humans.

Blocking pathogen transmission at the source: reservoir targeted OspA-based vaccines against Borrelia burgdorferi

PubMed Central

Gomes-Solecki, Maria

2014-01-01

Control strategies are especially challenging for microbial diseases caused by pathogens that persist in wildlife reservoirs and use arthropod vectors to cycle amongst those species. One of the most relevant illnesses that pose a direct human health risk is Lyme disease; in the US, the Centers for Disease Control and Prevention recently revised the probable number of cases by 10-fold, to 300,000 cases per year. Caused by Borrelia burgdorferi, Lyme disease can affect the nervous system, joints and heart. No human vaccine is approved by the Food and Drug Administration. In addition to novel human vaccines, new strategies for prevention of Lyme disease consist of pest management interventions, vector-targeted vaccines and reservoir-targeted vaccines. However, even human vaccines can not prevent Lyme disease expansion into other geographical areas. The other strategies aim at reducing tick density and at disrupting the transmission of B. burgdorferi by targeting one or more key elements that maintain the enzootic cycle: the reservoir host and/or the tick vector. Here, I provide a brief overview of the application of an OspA-based wildlife reservoir targeted vaccine aimed at reducing transmission of B. burgdorferi and present it as a strategy for reducing Lyme disease risk to humans. PMID:25309883

The future for blood-stage vaccines against malaria.

PubMed

Richards, Jack S; Beeson, James G

2009-07-01

Malaria is a leading cause of mortality and morbidity globally, and effective vaccines are urgently needed. Malaria vaccine approaches can be broadly grouped as pre-erythrocytic, blood stage and transmission blocking. This review focuses on blood-stage vaccines, and considers the evidence supporting the development of blood-stage vaccines, the advantages and challenges of this approach, potential targets, human vaccine studies and future directions. There is a strong rationale for the development of vaccines based on antigens of blood-stage parasites. Symptomatic malaria is caused by blood-stage parasitemia and acquired immunity in humans largely targets blood-stage antigens. Several candidate vaccines have proved efficacious in animal models and at least one vaccine showed partial efficacy in a clinical trial. At present, all leading candidate blood-stage antigens are merozoite proteins, located on the merozoite surface or within the apical organelles. Major challenges and priorities include overcoming antigenic diversity, identification of protective epitopes, understanding the nature and targets of protective immune responses, and defining antigen combinations that give the greatest efficacy. Additionally, objective criteria and approaches are needed to prioritize the large number of candidate antigens, and strong candidates need to be tested in clinical trials as quickly as possible.

Assessment of cold-chain maintenance in vaccine carriers during Pulse Polio National Immunization Day in a rural block of India.

PubMed

Pakhare, Abhijit P; Bali, Surya; Pawar, Radhakishan B; Lokhande, Ganesh S

2014-01-01

India was certified polio free on 27 March 2014. Supplementary immunization activities, in the form of national immunization days, is one of the core strategies for eradication, where oral polio vaccine is administered to children aged under 5 years throughout the country. Oral polio vaccine is heat sensitive and requires maintenance of a stringent cold chain. Therefore, vaccine carriers with ice packs are used in the Pulse Polio Immunization (PPI) programme. This study assessed whether the cold chain is maintained during National Immunization Day in Beed district. A cross-sectional study was conducted at six randomly selected booths, one each from six primary health centres in Georai block of Beed district in Maharashtra. Electronic data loggers, configured to measure half-hourly temperatures, were kept in vaccine carriers throughout the day of PPI. The vaccine carrier temperature was below 8 °C at all six booths; minimum temperature recorded was -9.5 °C, while the maximum was 4.5 °C. The vaccine vial monitor did not reach discard point in any booth. A vaccine carrier with four ice packs very effectively maintains the cold chain required for oral polio vaccine.

Structural and Immunological Characterization of Recombinant 6-Cysteine Domains of the Plasmodium falciparum Sexual Stage Protein Pfs230*

PubMed Central

MacDonald, Nicholas J.; Nguyen, Vu; Shimp, Richard; Reiter, Karine; Herrera, Raul; Burkhardt, Martin; Muratova, Olga; Kumar, Krishan; Aebig, Joan; Rausch, Kelly; Lambert, Lynn; Dawson, Nikiah; Sattabongkot, Jetsumon; Ambroggio, Xavier; Duffy, Patrick E.; Wu, Yimin; Narum, David L.

2016-01-01

Development of a Plasmodium falciparum (Pf) transmission blocking vaccine (TBV) has the potential to significantly impact malaria control. Antibodies elicited against sexual stage proteins in the human bloodstream are taken up with the blood meal of the mosquitoes and inactivate parasite development in the mosquito. In a phase 1 trial, a leading TBV identified as Pfs25-EPA/Alhydrogel® appeared safe and immunogenic, however, the level of Pfs25-specific antibodies were likely too low for an effective vaccine. Pfs230, a 230-kDa sexual stage protein expressed in gametocytes is an alternative vaccine candidate. A unique 6-cysteine-rich domain structure within Pfs230 have thwarted its recombinant expression and characterization for clinical evaluation for nearly a quarter of a century. Here, we report on the identification, biochemical, biophysical, and immunological characterization of recombinant Pfs230 domains. Rabbit antibodies generated against recombinant Pfs230 domains blocked mosquito transmission of a laboratory strain and two field isolates using an ex vivo assay. A planned clinical trial of the Pfs230 vaccine is a significant step toward the potential development of a transmission blocking vaccine to eliminate malaria. PMID:27432885

Saccharomyces cerevisiae-Secreted Fusion Proteins Pfs25 and Pfs28 Elicit Potent Plasmodium falciparum Transmission-Blocking Antibodies in Mice

PubMed Central

Gozar, Mary Margaret G.; Price, Virginia L.; Kaslow, David C.

1998-01-01

Transmission-blocking vaccines based on sexual-stage surface antigens of Plasmodium falciparum may assist in the control of this lethal form of human malaria. Two vaccine candidates, Pfs25 and Pfs28, were produced as single recombinant fusion proteins. The 39-kDa chimeric proteins, having a C-terminal His6 tag, were secreted by Saccharomyces cerevisiae, using the prepro-α-factor leader sequence. Pfs25-28 fusion proteins were significantly more potent than either Pfs25 or Pfs28 alone in eliciting antibodies in mice that blocked oocyst development in Anopheles freeborni mosquitoes: complete inhibition of oocyst development in the mosquito midgut was achieved with fewer vaccinations, at a lower dose, and for a longer duration than with either Pfs25 or Pfs28 alone. Increased antigen-specific immunoglobulin G titers and highly significant lymphoproliferative stimulation by Pfs28-containing antigens suggest the presence of an immunodominant helper T-cell epitope in the Pfs28 portion of the fusion proteins. This epitope may be responsible for the enhanced humoral response to both Pfs25 and Pfs28 antigens. Protein production of the fusion protein was improved 12-fold by converting Pfs28 codons to yeast-preferred codons (TBV28), using a modified ADH2 promoter and incorporating a (Glu-Ala)2 repeat after the Kex2 cleavage site. PMID:9423839

Antibacterials: A sweet vaccine

NASA Astrophysics Data System (ADS)

Bundle, David

2016-03-01

Vaccination with a synthetic glycoconjugate, in combination with the administration of an inhibitor that blocks capsular polysaccharide synthesis in bacteria, could offer an alternative route to combat bacterial infections.

Mucosal delivery of a transmission-blocking DNA vaccine encoding Giardia lamblia CWP2 by Salmonella typhimurium bactofection vehicle.

PubMed

Abdul-Wahid, Aws; Faubert, Gaétan

2007-12-05

In this study, we investigated the use of Salmonella typhimurium (STM1 strain) as a bactofection vehicle to deliver a transmission-blocking DNA vaccine (TBDV) plasmid to the intestinal immune system. The gene encoding the full length cyst wall protein-2 (CWP2) from Giardia lamblia was subcloned into the pCDNA3 mammalian expression vector and stably introduced into S. typhimurium STM1. Eight-week-old female BALB/c mice were orally immunized every 2 weeks, for a total of three immunizations. Vaccinated and control mice were sacrificed 1 week following the last injection. Administration of the DNA vaccine led to the production of CWP2-specific cellular immune responses characterized by a mixed Th1/Th2 response. Using ELISA, antigen-specific IgA and IgG antibodies were detected in intestinal secretions. Moreover, analysis of sera demonstrated that the DNA immunization also stimulated the production of CWP2-specific IgG antibodies that were mainly of the IgG2a isotype. Finally, challenge infection with live Giardia muris cysts revealed that mice receiving the CWP2-encoding DNA vaccine were able to reduce cyst shedding by approximately 60% compared to control mice. These results demonstrate, for the first time, the development of parasite transmission-blocking immunity at the intestinal level following the administration of a mucosal DNA vaccine delivered by S. typhimurium STM1.

Computational design of hepatitis C vaccines using empirical fitness landscapes and population dynamics

NASA Astrophysics Data System (ADS)

Hart, Gregory; Ferguson, Andrew

Hepatitis C virus (HCV) afflicts 170 million people and kills 350,000 annually. Vaccination offers the most realistic and cost effective hope of controlling this epidemic. Despite 25 years of research, no vaccine is available. A major obstacle is the virus' extreme genetic variability and rapid mutational escape from immune pressure. Improvements in the vaccine design process are urgently needed. Coupling data mining and maximum entropy inference, we have developed a computational approach to translate sequence databases into empirical fitness landscapes. These landscapes explicitly connect viral genotype to phenotypic fitness and reveal vulnerable targets that can be exploited to rationally design vaccines. These landscapes represent the mutational ''playing field'' over which the virus evolves. We have integrated them with agent-based models of the viral mutational and host immune response, establishing a data-driven multi-scale immune simulator. We have used this simulator to perform in silico screening of HCV immunogens to rationally design vaccines to both cripple viral fitness and block escape. By systematically identifying a small number of promising vaccine candidates, these models can accelerate the search for a vaccine by massively reducing the experimental search space.

Engineering of a hybrid nanoparticle-based nicotine nanovaccine as a next-generation immunotherapeutic strategy against nicotine addiction: A focus on hapten density.

PubMed

Zhao, Zongmin; Powers, Kristen; Hu, Yun; Raleigh, Michael; Pentel, Paul; Zhang, Chenming

2017-04-01

Although vaccination is a promising way to combat nicotine addiction, most traditional hapten-protein conjugate nicotine vaccines only show limited efficacy due to their poor recognition and uptake by immune cells. This study aimed to develop a hybrid nanoparticle-based nicotine vaccine with improved efficacy. The focus was to study the impact of hapten density on the immunological efficacy of the proposed hybrid nanovaccine. It was shown that the nanovaccine nanoparticles were taken up by the dendritic cells more efficiently than the conjugate vaccine, regardless of the hapten density on the nanoparticles. At a similar hapten density, the nanovaccine induced a significantly stronger immune response against nicotine than the conjugate vaccine in mice. Moreover, the high- and medium-density nanovaccines resulted in significantly higher anti-nicotine antibody titers than their low-density counterpart. Specifically, the high-density nanovaccine exhibited better immunogenic efficacy, resulting in higher anti-nicotine antibody titers and lower anti-carrier protein antibody titers than the medium- and low-density versions. The high-density nanovaccine also had the best ability to retain nicotine in serum and to block nicotine from entering the brain. These results suggest that the hybrid nanoparticle-based nicotine vaccine can elicit strong immunogenicity by modulating the hapten density, thereby providing a promising next-generation immunotherapeutic strategy against nicotine addiction. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Novel Malaria Vaccine Candidate Antigen Expressed in Tetrahymena thermophila

PubMed Central

Eleni-Muus, Janna; Aldag, Ingo; Samuel, Kay; Creasey, Alison M.; Hartmann, Marcus W. W.; Cavanagh, David R.

2014-01-01

Development of effective malaria vaccines is hampered by the problem of producing correctly folded Plasmodium proteins for use as vaccine components. We have investigated the use of a novel ciliate expression system, Tetrahymena thermophila, as a P. falciparum vaccine antigen platform. A synthetic vaccine antigen composed of N-terminal and C-terminal regions of merozoite surface protein-1 (MSP-1) was expressed in Tetrahymena thermophila. The recombinant antigen was secreted into the culture medium and purified by monoclonal antibody (mAb) affinity chromatography. The vaccine was immunogenic in MF1 mice, eliciting high antibody titers against both N- and C-terminal components. Sera from immunized animals reacted strongly with P. falciparum parasites from three antigenically different strains by immunofluorescence assays, confirming that the antibodies produced are able to recognize parasite antigens in their native form. Epitope mapping of serum reactivity with a peptide library derived from all three MSP-1 Block 2 serotypes confirmed that the MSP-1 Block 2 hybrid component of the vaccine had effectively targeted all three serotypes of this polymorphic region of MSP-1. This study has successfully demonstrated the use of Tetrahymena thermophila as a recombinant protein expression platform for the production of malaria vaccine antigens. PMID:24489871

Vaccine approaches to malaria control and elimination: Insights from mathematical models.

PubMed

White, Michael T; Verity, Robert; Churcher, Thomas S; Ghani, Azra C

2015-12-22

A licensed malaria vaccine would provide a valuable new tool for malaria control and elimination efforts. Several candidate vaccines targeting different stages of the malaria parasite's lifecycle are currently under development, with one candidate, RTS,S/AS01 for the prevention of Plasmodium falciparum infection, having recently completed Phase III trials. Predicting the public health impact of a candidate malaria vaccine requires using clinical trial data to estimate the vaccine's efficacy profile--the initial efficacy following vaccination and the pattern of waning of efficacy over time. With an estimated vaccine efficacy profile, the effects of vaccination on malaria transmission can be simulated with the aid of mathematical models. Here, we provide an overview of methods for estimating the vaccine efficacy profiles of pre-erythrocytic vaccines and transmission-blocking vaccines from clinical trial data. In the case of RTS,S/AS01, model estimates from Phase II clinical trial data indicate a bi-phasic exponential profile of efficacy against infection, with efficacy waning rapidly in the first 6 months after vaccination followed by a slower rate of waning over the next 4 years. Transmission-blocking vaccines have yet to be tested in large-scale Phase II or Phase III clinical trials so we review ongoing work investigating how a clinical trial might be designed to ensure that vaccine efficacy can be estimated with sufficient statistical power. Finally, we demonstrate how parameters estimated from clinical trials can be used to predict the impact of vaccination campaigns on malaria using a mathematical model of malaria transmission. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cross-species malaria immunity induced by chemically attenuated parasites

PubMed Central

Good, Michael F.; Reiman, Jennifer M.; Rodriguez, I. Bibiana; Ito, Koichi; Yanow, Stephanie K.; El-Deeb, Ibrahim M.; Batzloff, Michael R.; Stanisic, Danielle I.; Engwerda, Christian; Spithill, Terry; Hoffman, Stephen L.; Lee, Moses; McPhun, Virginia

2013-01-01

Vaccine development for the blood stages of malaria has focused on the induction of antibodies to parasite surface antigens, most of which are highly polymorphic. An alternate strategy has evolved from observations that low-density infections can induce antibody-independent immunity to different strains. To test this strategy, we treated parasitized red blood cells from the rodent parasite Plasmodium chabaudi with seco-cyclopropyl pyrrolo indole analogs. These drugs irreversibly alkylate parasite DNA, blocking their ability to replicate. After administration in mice, DNA from the vaccine could be detected in the blood for over 110 days and a single vaccination induced profound immunity to different malaria parasite species. Immunity was mediated by CD4+ T cells and was dependent on the red blood cell membrane remaining intact. The human parasite, Plasmodium falciparum, could also be attenuated by treatment with seco-cyclopropyl pyrrolo indole analogs. These data demonstrate that vaccination with chemically attenuated parasites induces protective immunity and provide a compelling rationale for testing a blood-stage parasite-based vaccine targeting human Plasmodium species. PMID:23863622

Development of a blocking ELISA based on a monoclonal antibody against a predominant epitope in non-structural protein 3B2 of foot-and-mouth disease virus for differentiating infected from vaccinated animals.

PubMed

Fu, Yuanfang; Lu, Zengjun; Li, Pinghua; Cao, Yimei; Sun, Pu; Tian, Meina; Wang, Na; Bao, Huifang; Bai, Xingwen; Li, Dong; Chen, Yingli; Liu, Zaixin

2014-01-01

A monoclonal antibody (McAb) against non-structural protein (NSP) 3B of foot-mouth-disease virus (FMDV) (3B4B1) was generated and shown to recognize a conserved epitope spanning amino acids 24-32 of 3B (GPYAGPMER) by peptide screening ELISA. This epitope was further shown to be a unique and predominant B cell epitope in 3B2, as sera from animals infected with different serotypes of FMDV blocked the ability of McAb 3B4B1 to bind to NSP 2C3AB. Also, a polyclonal antibody against NSP 2C was produced in a rabbit vaccinated with 2C epitope regions expressed in E. coli. Using McAb 3B4B1 and the 2C polyclonal antibody, a solid-phase blocking ELISA (SPB-ELISA) was developed for the detection of antibodies against NSP 2C3AB to distinguish FMDV-infected from vaccinated animals (DIVA test). The parameters for this SPB-ELISA were established by screening panels of sera of different origins. Serum samples with a percent inhibition (PI) greater than or equal to 46% were considered to be from infected animals, and a PI lower than 46% was considered to indicate a non-infected animal. This test showed a similar performance as the commercially available PrioCHECK NS ELISA. This is the first description of the conserved and predominant GPYAGPMER epitope of 3B and also the first report of a DIVA test for FMDV NSP 3B based on a McAb against this epitope.

Local immunization program for susceptible-infected-recovered network epidemic model

NASA Astrophysics Data System (ADS)

Wu, Qingchu; Lou, Yijun

2016-02-01

The immunization strategies through contact tracing on the susceptible-infected-recovered framework in social networks are modelled to evaluate the cost-effectiveness of information-based vaccination programs with particular focus on the scenario where individuals belonging to a specific set can get vaccinated due to the vaccine shortages and other economic or humanity constraints. By using the block heterogeneous mean-field approach, a series of discrete-time dynamical models is formulated and the condition for epidemic outbreaks can be established which is shown to be not only dependent on the network structure but also closely related to the immunization control parameters. Results show that increasing the immunization strength can effectively raise the epidemic threshold, which is different from the predictions obtained through the susceptible-infected-susceptible network framework, where epidemic threshold is independent of the vaccination strength. Furthermore, a significant decrease of vaccine use to control the infectious disease is observed for the local vaccination strategy, which shows the promising applications of the local immunization programs to disease control while calls for accurate local information during the process of disease outbreak.

Safety and immunogenicity of a recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in Sierra Leone: a single-centre, randomised, double-blind, placebo-controlled, phase 2 trial.

PubMed

Zhu, Feng-Cai; Wurie, Alie H; Hou, Li-Hua; Liang, Qi; Li, Yu-Hua; Russell, James B W; Wu, Shi-Po; Li, Jing-Xin; Hu, Yue-Mei; Guo, Qiang; Xu, Wen-Bo; Wurie, Abdul R; Wang, Wen-Juan; Zhang, Zhe; Yin, Wen-Jiao; Ghazzawi, Manal; Zhang, Xu; Duan, Lei; Wang, Jun-Zhi; Chen, Wei

2017-02-11

A recombinant adenovirus type-5 vector-based vaccine expressing the glycoprotein of Ebola Zaire Makona variant showed good safety and immunogenicity in a phase 1 trial of healthy Chinese adults. We aimed to assess the safety and immunogenicity of this vaccine in healthy adults in Sierra Leone and to determine the optimal dose. We did a single-centre, randomised, double-blind, placebo-controlled, phase 2 clinical trial at Sierra Leone-China Friendship Hospital, Freetown, Sierra Leone. We recruited healthy adults aged 18-50 years who were HIV negative, had no history of Ebola virus infection, and had no previous immunisation with other Ebola vaccine candidates. Participants were sequentially enrolled and randomly assigned (2:1:1), by computer-generated block randomisation (block size of eight), to receive the high-dose vaccine (1·6 × 10 11 viral particles), low-dose vaccine (8·0 × 10 10 viral particles), or placebo (containing only vaccine excipients, with no viral particles). Participants, investigators, and study staff (except two study pharmacists) were masked from treatment allocation. The primary safety outcome was occurrence of solicited adverse reactions within 7 days of vaccination, analysed by intention to treat. The primary immunogenicity outcome was glycoprotein-specific antibody responses at days 14, 28, and 168 after vaccination, analysed in all vaccinated participants who had blood samples drawn for antibody tests. The trial is registered with the Pan African Clinical Trials Registry, number PACTR201509001259869, and is completed. During Oct 10-28, 2015, 500 participants were enrolled and randomly assigned to receive the high-dose vaccine (n=250), low-dose vaccine (n=125), or placebo (n=125). 132 (53%) participants in the high-dose group, 60 (48%) in the low-dose group, and 54 (43%) in the placebo group reported at least one solicited adverse reaction within 7 days of vaccination. Most adverse reactions were mild and self-limiting. Solicited injection-site adverse reactions were significantly more frequent in vaccine recipients (65 [26%] in high-dose group and 31 [25%] in low-dose group) than in those receiving placebo (17 [14%]; p=0·0169). Glycoprotein-specific antibody responses were detected from day 14 onwards (geometric mean titre 1251·0 [95% CI 976·6-1602·5] in low-dose group and 1728·4 [1459·4-2047·0] in high-dose group) and peaked at day 28 (1471·8 [1151·0-1881·8] and 2043·1 [1762·4-2368·4]), but declined quickly in the following months (223·3 [148·2-336·4] and 254·2 [185·0-349·5] at day 168). Geometric mean titres in the placebo group remained around 6·0-6·8 throughout the study period. Three serious adverse events (malaria, gastroenteritis, and one fatal asthma episode) were reported in the high-dose vaccine group, but none was deemed related to the vaccine. The recombinant adenovirus type-5 vector-based Ebola vaccine was safe and highly immunogenic in healthy Sierra Leonean adults, and 8·0 × 10 10 viral particles was the optimal dose. Chinese Ministry of Science and Technology and the National Health and Family Planning Commission, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology. Copyright © 2017 Elsevier Ltd. All rights reserved.

Safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine in healthy adults in China: preliminary report of a randomised, double-blind, placebo-controlled, phase 1 trial.

PubMed

Zhu, Feng-Cai; Hou, Li-Hua; Li, Jing-Xin; Wu, Shi-Po; Liu, Pei; Zhang, Gui-Rong; Hu, Yue-Mei; Meng, Fan-Yue; Xu, Jun-Jie; Tang, Rong; Zhang, Jin-Long; Wang, Wen-Juan; Duan, Lei; Chu, Kai; Liang, Qi; Hu, Jia-Lei; Luo, Li; Zhu, Tao; Wang, Jun-Zhi; Chen, Wei

2015-06-06

Up to now, all tested Ebola virus vaccines have been based on the virus strain from the Zaire outbreak in 1976. We aimed to assess the safety and immunogenicity of a novel recombinant adenovirus type-5 vector-based Ebola vaccine expressing the glycoprotein of the 2014 epidemic strain. We did this randomised, double-blind, placebo-controlled, phase 1 clinical trial at one site in Taizhou County, Jiangsu Province, China. Healthy adults (aged 18-60 years) were sequentially enrolled and randomly assigned (2:1), by computer-generated block randomisation (block size of six), to receive placebo, low-dose adenovirus type-5 vector-based Ebola vaccine, or high-dose vaccine. Randomisation was pre-stratified by dose group. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was occurrence of solicited adverse reactions within 7 days of vaccination. The primary immunogenicity endpoints were glycoprotein-specific antibody titres and T-cell responses at day 28 after the vaccination. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT02326194. Between Dec 28, 2014, and Jan 9, 2015, 120 participants were enrolled and randomly assigned to receive placebo (n=40), low-dose vaccine (n=40), or high-dose vaccine. Participants were followed up for 28 days. Overall, 82 (68%) participants reported at least one solicited adverse reaction within 7 days of vaccination (n=19 in the placebo group vs n=27 in the low-dose group vs n=36 in the high-dose group; p=0·0002). The most common reaction was mild pain at the injection site, which was reported in eight (20%) participants in the placebo group, 14 (35%) participants in the low-dose group, and 29 (73%) participants in the high-dose vaccine group (p<0·0001). We recorded no statistical differences in other adverse reactions and laboratory tests across groups. Glycoprotein-specific antibody titres were significantly increased in participants in the low-dose and high-dose vaccine groups at both day 14 (geometric mean titre 421·4 [95% CI 249·7-711·3] and 820·5 [598·9-1124·0], respectively; p<0·0001) and day 28 (682·7 [424·3-1098·5] and 1305·7 [970·1-1757·2], respectively; p<0·0001). T-cell responses peaked at day 14 at a median of 465·0 spot-forming cells (IQR 180·0-1202·5) in participants in the low-dose group and 765·0 cells (400·0-1460·0) in those in the high-dose group. 21 (18%) participants had mild fever (n=9 in the placebo group, n=6 in the low-dose group, and n=6 in the high-dose group). No serious adverse events were recorded. Our findings show that the high-dose vaccine is safe and robustly immunogenic. One shot of the high-dose vaccine could mount glycoprotein-specific humoral and T-cell response against Ebola virus in 14 days. China National Science and Technology, Beijing Institute of Biotechnology, and Tianjin CanSino Biotechnology. Copyright © 2015 Elsevier Ltd. All rights reserved.

MALVAC 2012 scientific forum: accelerating development of second-generation malaria vaccines

PubMed Central

2012-01-01

The World Health Organization (WHO) convened a malaria vaccines committee (MALVAC) scientific forum from 20 to 21 February 2012 in Geneva, Switzerland, to review the global malaria vaccine portfolio, to gain consensus on approaches to accelerate second-generation malaria vaccine development, and to discuss the need to update the vision and strategic goal of the Malaria Vaccine Technology Roadmap. This article summarizes the forum, which included reviews of leading Plasmodium falciparum vaccine candidates for pre-erythrocytic vaccines, blood-stage vaccines, and transmission-blocking vaccines. Other major topics included vaccine candidates against Plasmodium vivax, clinical trial site capacity development in Africa, trial design considerations for a second-generation malaria vaccine, adjuvant selection, and regulatory oversight functions including vaccine licensure. PMID:23140365

Design of therapeutic vaccines as a novel antibody therapy for cardiovascular diseases.

PubMed

Nakagami, Hironori

2017-09-01

Vaccines are primarily used worldwide as a preventive medicine for infectious diseases and have recently been applied to cancer. We and others have developed therapeutic vaccines designed for cardiovascular diseases that are notably different from previous vaccines. In the case of cancer vaccines, a specific protein in cancer cells is a target antigen, and the activation of cytotoxic T cells (CTL) is required to kill and remove the antigen-presenting cancer cells. Our therapeutic vaccines work against hypertension by targeting angiotensin II (Ang II) as the antigen, which is an endogenous hormone. Therapeutic vaccines must avoid CTL activation and induce the blocking antibodies for Ang II. The goal of our therapeutic vaccine for cardiovascular diseases is to induce the specific antibody response toward the target protein without inducing T-cell or antibody-mediated inflammation through the careful selection of the target antigen, carrier protein and adjuvants. The goal of our therapeutic vaccine is similar to that of antibody therapy. Recently, multiple antibody-based drugs have been developed for cancer, immune-related diseases, and dyslipidemia, which are efficient but expensive. If the effect of a therapeutic vaccine is nearly equivalent to antibody therapy as an alternative approach, the lower medical cost and improvement in drug adherence can be advantages of therapeutic vaccines. In this review, we will describe our concept of therapeutic vaccines for cardiovascular diseases and the future directions of therapeutic vaccines as novel antibody therapies. Copyright © 2017. Published by Elsevier Ltd.

Preventing Sin: The Ethics of Vaccines against Smoking

PubMed Central

Lieber, Sarah R.; Millum, Joseph

2016-01-01

Advances in immunotherapy are paving the way toward vaccines that target unhealthy behaviors, such as a vaccine that blocks the action of nicotine, reducing the pleasure caused by smoking. Such a tool could prove to be an effective tool for preventing children from taking up smoking. Would it be permissible? PMID:23650065

Recent advances in synthesis of bacterial rare sugar building blocks and their applications.

PubMed

Emmadi, Madhu; Kulkarni, Suvarn S

2014-07-01

Covering: 1964 to 2013. Bacteria have unusual glycans on their surfaces which distinguish them from the host cells. These unique structures offer avenues for targeting bacteria with specific therapeutics and vaccine. However, these rare sugars are not accessible in acceptable purity and amounts by isolation from natural sources. Thus, procurement of orthogonally protected rare sugar building blocks through efficient chemical synthesis is regarded as a crucial step towards the development of glycoconjugate vaccines. This Highlight focuses on recent advances in the synthesis of the bacterial deoxy amino hexopyranoside building blocks and their application in constructing various biologically important bacterial O-glycans.

HIV-1-Specific IgA Monoclonal Antibodies from an HIV-1 Vaccinee Mediate Galactosylceramide Blocking and Phagocytosis

PubMed Central

2018-01-01

ABSTRACT Vaccine-elicited humoral immune responses comprise an array of antibody forms and specificities, with only a fraction contributing to protective host immunity. Elucidation of antibody effector functions responsible for protective immunity against human immunodeficiency virus type 1 (HIV-1) acquisition is a major goal for the HIV-1 vaccine field. Immunoglobulin A (IgA) is an important part of the host defense against pathogens; however, little is known about the role of vaccine-elicited IgA and its capacity to mediate antiviral functions. To identify the antiviral functions of HIV-1-specific IgA elicited by vaccination, we cloned HIV-1 envelope-specific IgA monoclonal antibodies (MAbs) by memory B cell cultures from peripheral blood mononuclear cells from an RV144 vaccinee and produced two IgA clonal cell lines (HG129 and HG130) producing native, nonrecombinant IgA MAbs. The HG129 and HG130 MAbs mediated phagocytosis by monocytes, and HG129 blocked HIV-1 Env glycoprotein binding to galactosylceramide, an alternative HIV-1 receptor. These findings elucidate potential antiviral functions of vaccine-elicited HIV-1 envelope-specific IgA that may act to block HIV-1 acquisition at the portal of entry by preventing HIV-1 binding to galactosylceramide and mediating antibody Fc receptor-mediated virion phagocytosis. Furthermore, these findings highlight the complex and diverse interactions of vaccine-elicited IgA with pathogens that depend on IgA fine specificity and form (e.g., multimeric or monomeric) in the systemic circulation and mucosal compartments. IMPORTANCE Host-pathogen interactions in vivo involve numerous immune mechanisms that can lead to pathogen clearance. Understanding the nature of antiviral immune mechanisms can inform the design of efficacious HIV-1 vaccine strategies. Evidence suggests that both neutralizing and nonneutralizing antibodies can mediate some protection against HIV in animal models. Although numerous studies have characterized the functional properties of HIV-1-specific IgG, more studies are needed on the functional attributes of HIV-1-specific IgA, specifically for vaccine-elicited IgA. Characterization of the functional properties of HIV-1 Env-specific IgA monoclonal antibodies from human vaccine clinical trials are critical toward understanding the capacity of the host immune response to block HIV-1 acquisition. PMID:29321320

Burrow dusting or oral vaccination prevents plague-associated prairie dog colony collapse

USGS Publications Warehouse

Tripp, Daniel W.; Rocke, Tonie E.; Runge, Jonathan P.; Abbott, Rachel C.; Miller, Michael W.

2017-01-01

Plague impacts prairie dogs (Cynomys spp.), the endangered black-footed ferret (Mustela nigripes) and other sensitive wildlife species. We compared efficacy of prophylactic treatments (burrow dusting with deltamethrin or oral vaccination with recombinant “sylvatic plague vaccine” [RCN-F1/V307]) to placebo treatment in black-tailed prairie dog (C. ludovicianus) colonies. Between 2013 and 2015, we measured prairie dog apparent survival, burrow activity and flea abundance on triplicate plots (“blocks”) receiving dust, vaccine or placebo treatment. Epizootic plague affected all three blocks but emerged asynchronously. Dust plots had fewer fleas per burrow (P < 0.0001), and prairie dogs captured on dust plots had fewer fleas (P < 0.0001) than those on vaccine or placebo plots. Burrow activity and prairie dog density declined sharply in placebo plots when epizootic plague emerged. Patterns in corresponding dust and vaccine plots were less consistent and appeared strongly influenced by timing of treatment applications relative to plague emergence. Deltamethrin or oral vaccination enhanced apparent survival within two blocks. Applying insecticide or vaccine prior to epizootic emergence blunted effects of plague on prairie dog survival and abundance, thereby preventing colony collapse. Successful plague mitigation will likely entail strategic combined uses of burrow dusting and oral vaccination within large colonies or colony complexes.

HIV-1 Tat-based vaccines: from basic science to clinical trials.

PubMed

Fanales-Belasio, Emanuele; Cafaro, Aurelio; Cara, Andrea; Negri, Donatella R M; Fiorelli, Valeria; Butto, Stefano; Moretti, Sonia; Maggiorella, Maria Teresa; Baroncelli, Silvia; Michelini, Zuleika; Tripiciano, Antonella; Sernicola, Leonardo; Scoglio, Arianna; Borsetti, Alessandra; Ridolfi, Barbara; Bona, Roberta; Ten Haaft, Peter; Macchia, Iole; Leone, Pasqualina; Pavone-Cossut, Maria Rosaria; Nappi, Filomena; Vardas, Eftyhia; Magnani, Mauro; Laguardia, Elena; Caputo, Antonella; Titti, Fausto; Ensoli, Barbara

2002-09-01

Vaccination against human immunodeficiency virus (HIV)-1 infection requires candidate antigen(s) (Ag) capable of inducing an effective, broad, and long-lasting immune response against HIV-1 despite mutation events leading to differences in virus clades. The HIV-1 Tat protein is more conserved than envelope proteins, is essential in the virus life cycle and is expressed very early upon virus entry. In addition, both humoral and cellular responses to Tat have been reported to correlate with a delayed progression to disease in both humans and monkeys. This suggested that Tat is an optimal target for vaccine development aimed at controlling virus replication and blocking disease onset. Here are reviewed the results of our studies including the effects of the Tat protein on monocyte-derived dendritic cells (MDDCs) that are key antigen-presenting cells (APCs), and the results from vaccination trials with both the Tat protein or tat DNA in monkeys. We provide evidence that the HIV-1 Tat protein is very efficiently taken up by MDDCs and promotes T helper (Th)-1 type immune responses against itself as well as other Ag. In addition, a Tat-based vaccine elicits an immune response capable of controlling primary infection of monkeys with the pathogenic SHIV89.6P at its early stages allowing the containment of virus spread. Based on these results and on data of Tat conservation and immune cross-recognition in field isolates from different clades, phase I clinical trials are being initiated in Italy for both preventive and therapeutic vaccination.

Mass Measles Vaccination Campaign in Aila Cyclone-Affected Areas of West Bengal, India: An In-depth Analysis and Experiences.

PubMed

Mallik, Sarmila; Mandal, Pankaj Kumar; Ghosh, Pramit; Manna, Nirmalya; Chatterjee, Chitra; Chakrabarty, Debadatta; Bagchi, Saumendra Nath; Dasgupta, Samir

2011-12-01

Disaster-affected populations are highly vulnerable to outbreaks of measles. Therefore, a mass vaccination against measles was conducted in Aila cyclone-affected blocks of West Bengal, India in July 2009. The objectives of the present report were to conduct an in depth analysis of the campaign, and to discuss the major challenges. A block level micro-plan, which included mapping of the villages, health facilities, temporary settlements of disaster-affected population, communications available, formation of vaccination team, information education communication, vaccine storage, waste disposal, surveillance for adverse events following immunization, supervision and monitoring was developed. The rate of six months to five years old children, who were vaccinated by measles vaccine, was 70.7% and that of those who received one dose of vitamin A was 71.3%. Wastage factor for vaccine doses and auto-disable syringes were 1.09 and 1.07, respectively. Only 13 cases of adverse events following immunization were reported. An average of 0.91 puncture-proof containers per vaccination session was used. Despite the major challenges faced due to difficult to reach areas, inadequate infrastructure, manpower and communication, problems of vaccine storage and transport, the campaign achieved a remarkable success regarding measles vaccine coverage, improvements of cold chain infrastructure, formulating an efficient surveillance and reporting system for adverse events following immunization, building self-confidence of the stakeholders, and developing a biomedical waste disposal system.

Mass Measles Vaccination Campaign in Aila Cyclone-Affected Areas of West Bengal, India: An In-depth Analysis and Experiences

PubMed Central

Mallik, Sarmila; Mandal, Pankaj Kumar; Ghosh, Pramit; Manna, Nirmalya; Chatterjee, Chitra; Chakrabarty, Debadatta; Bagchi, Saumendra Nath; Dasgupta, Samir

2011-01-01

Disaster-affected populations are highly vulnerable to outbreaks of measles. Therefore, a mass vaccination against measles was conducted in Aila cyclone-affected blocks of West Bengal, India in July 2009. The objectives of the present report were to conduct an in depth analysis of the campaign, and to discuss the major challenges. A block level micro-plan, which included mapping of the villages, health facilities, temporary settlements of disaster-affected population, communications available, formation of vaccination team, information education communication, vaccine storage, waste disposal, surveillance for adverse events following immunization, supervision and monitoring was developed. The rate of six months to five years old children, who were vaccinated by measles vaccine, was 70.7% and that of those who received one dose of vitamin A was 71.3%. Wastage factor for vaccine doses and auto-disable syringes were 1.09 and 1.07, respectively. Only 13 cases of adverse events following immunization were reported. An average of 0.91 puncture-proof containers per vaccination session was used. Despite the major challenges faced due to difficult to reach areas, inadequate infrastructure, manpower and communication, problems of vaccine storage and transport, the campaign achieved a remarkable success regarding measles vaccine coverage, improvements of cold chain infrastructure, formulating an efficient surveillance and reporting system for adverse events following immunization, building self-confidence of the stakeholders, and developing a biomedical waste disposal system. PMID:23115416

Vaccines for Drug Abuse

PubMed Central

Shen, Xiaoyun; Orson, Frank M.; Kosten, Thomas R.

2012-01-01

Current medications for drug abuse have had only limited success. Anti-addiction vaccines to elicit antibodies that block the pharmacological effects of drugs have great potential for treating drug abuse. We review the status for two vaccines that are undergoing clinical trials (cocaine and nicotine) and two that are still in pre-clinical development (methamphetamine and heroin). We also outline the challenges and ethical concerns for anti-addiction vaccine development and their use as future therapeutics. PMID:22130115

Emerging Targets and Novel Approaches to Ebola Virus Prophylaxis and Treatment

PubMed Central

Choi, Jin Huk; Croyle, Maria A.

2013-01-01

Ebola is a highly virulent pathogen causing severe hemorrhagic fever with a high case fatality rate in humans and non-human primates (NHPs). Although safe and effective vaccines or other medicinal agents to block Ebola infection are currently unavailable, a significant effort has been put forth to identify several promising candidates for the treatment and prevention of Ebola hemorrhagic fever. Among these, recombinant-virus based vectors have been identified as potent vaccine candidates with some affording both pre- and post-exposure protection from the virus. Recently, Investigational New Drug (IND) applications have been approved by the United States (U.S.) Food and Drug Administration (FDA) and Phase I clinical trials initiated for two small molecule therapeutics, 1) anti-sense phosphorodiamidate morphino oligomers (PMOs: AVI-6002, AVI-6003), and 2) lipid-nanoparticle/small interfering RNA (LNP/siRNA: TKM-Ebola). These potential alternatives to vector-based vaccines require multiple doses to achieve therapeutic efficacy which is not ideal with regard to patient compliance and outbreak scenarios. These concerns have fueled a quest for even better vaccination and treatment strategies. Here, we summarize recent advances in vaccines or post-exposure therapeutics for prevention of Ebola hemorrhagic fever. The utility of novel pharmaceutical approaches to refine and overcome barriers associated with the most promising therapeutic platforms will also be discussed. PMID:23813435

Antibodies to the Central Conserved Region of Respiratory Syncytial Virus (RSV) G Protein Block RSV G Protein CX3C-CX3CR1 Binding and Cross-Neutralize RSV A and B Strains0

PubMed Central

Choi, Youngjoo; Mason, Caleb S.; Jones, Les P.; Crabtree, Jackelyn; Jorquera, Patricia A.

2012-01-01

Abstract Respiratory syncytial virus (RSV) is a primary cause of severe lower respiratory tract disease in infants, young children, and the elderly worldwide, and despite decades of effort, there remains no safe and effective vaccine. RSV modifies the host immune response during infection by CX3C chemokine mimicry adversely affecting pulmonary leukocyte chemotaxis and CX3CR1+ RSV-specific T-cell responses. In this study we investigated whether immunization of mice with RSV G protein polypeptides from strain A2 could induce antibodies that block G protein–CX3CR1 interactions of both RSV A and B strains. The results show that mice immunized with RSV A2 G polypeptides generate antibodies that block binding of RSV A2 and B1 native G proteins to CX3CR1, and that these antibodies effectively cross-neutralize both A and B strains of RSV. These findings suggest that vaccines that induce RSV G protein–CX3CR1 blocking antibodies may provide a disease intervention strategy in the efforts to develop safe and efficacious RSV vaccines. PMID:22551066

Bacteria-Targeting Nanoparticles for Managing Infections

NASA Astrophysics Data System (ADS)

Radovic-Moreno, Aleksandar Filip

Bacterial infections continue to be a significant concern particularly in healthcare settings and in the developing world. Current challenges include the increasing spread of drug resistant (DR) organisms, the side effects of antibiotic therapy, the negative consequences of clearing the commensal bacterial flora, and difficulties in developing prophylactic vaccines. This thesis was an investigation of the potential of a class of polymeric nanoparticles (NP) to contribute to the management of bacterial infections. More specifically, steps were taken towards using these NPs (1) to achieve greater spatiotemporal control over drug therapy by more targeted antibiotic delivery to bacteria, and (2) to develop a prophylactic vaccine formulation against the common bacterial sexually transmitted disease (STD) caused by Chlamydia trachomatis. In the first part, we synthesized polymeric NPs containing poly(lactic-co-glycolic acid)-block-poly(L-histidine)-block-poly(ethylene glycol) (PLGA-PLH-PEG). We show that these NPs are able to bind to bacteria under model acidic infection conditions and are able to encapsulate and deliver vancomycin to inhibit the growth of Staphylococcus aureus bacteria in vitro. Further work showed that the PLGA-PLH-PEG-based NPs demonstrated the potential for competition for binding bacteria at a site of infection from soluble protein and model phagocytic and tissue-resident cells in a NP composition dependent manner. The NPs demonstrated low toxicity in vitro, were well tolerated by mice in vivo, and circulated in the blood on timescales comparable to control PLGA-PEG NPs. In the second part, we used PLGA-PLH-PEG-based NPs to design a prophylactic vaccine against the obligate intracellular bacterium Chlamydia trachomatis, the most common cause of bacterial STD in the world. Currently, no vaccines against this pathogen are approved for use in humans. We first formulated NPs encapsulating the TLR7 agonist R848 conjugated to poly(lactic acid) (R848-PLA) in PLGA-PLH-PEG-based NPs, then incubated these R848-NPs with UV-inactivated C. trachomatis bacteria in acidity, forming a construct. Mice immunized with this vaccine via genital or intranasal routes demonstrated protection from genital infection post immunization in a primarily CD4+ T cell-dependent manner. These results may suggest avenues for future work in designing and developing more targeted drug therapies or vaccine formulations for managing bacterial infections using polymeric nanoparticles. (Copies available exclusively from MIT Libraries, libraries.mit.edu/docs - docs mit.edu)

Characterization of a candidate tetravalent vaccine based on 2'-O-methyltransferase mutants

PubMed Central

Züst, Roland; Li, Shi-Hua; Xie, Xuping; Velumani, Sumathy; Chng, Melissa; Toh, Ying-Xiu; Zou, Jing; Dong, Hongping; Shan, Chao; Pang, Jassia; Qin, Cheng-Feng; Newell, Evan W.; Shi, Pei-Yong

2018-01-01

Dengue virus (DENV) is one of the most widespread arboviruses. The four DENV serotypes infect about 400 million people every year, causing 96 million clinical dengue cases, of which approximately 500’000 are severe and potentially life-threatening. The only licensed vaccine has a limited efficacy and is only recommended in regions with high endemicity. We previously reported that 2’-O-methyltransferase mutations in DENV-1 and DENV-2 block their capacity to inhibit type I IFNs and render the viruses attenuated in vivo, making them amenable as vaccine strains; here we apply this strategy to all four DENV serotypes to generate a tetravalent, non-chimeric live-attenuated dengue vaccine. 2’-O-methyltransferase mutants of all four serotypes are highly sensitive to type I IFN inhibition in human cells. The tetravalent formulation is attenuated and immunogenic in mice and cynomolgus macaques and elicits a response that protects from virus challenge. These results show the potential of 2’-O-methyltransferase mutant viruses as a safe, tetravalent, non-chimeric dengue vaccine. PMID:29298302

Prevention of carcinoma of cervix with human papillomavirus vaccine.

PubMed

Gavarasana, S; Kalasapudi, R S; Rao, T D; Thirumala, S

2000-01-01

Carcinoma of cervix is the most common cancer found among the women of India. Though cervical cytology screening was effective in preventing carcinoma of cervix in developed nations, it is considered unsuitable in developing countries. Recent research has established an etiological link between human papillomavirus infection and carcinoma of cervix. In this review, an attempt is made to answer the question, 'whether carcinoma of cervix can be prevented with human papillomavirus vaccine?' Literature search using Pubmed and Medline was carried out and relevant articles were reviewed. There is ample experimental evidence to show that DNA of human papillomavirus integrates with cervical cell genome. Viral genes E6 and E7 of HPV type 16 and 18 inactivate p53 function and Rb gene, thus immortalize the cervical epithelial cells. Recombinant vaccines blocked the function of E6 and E7 genes preventing development of papillomas in animals. Vaccination with HPV-VLPs encoding for genes of E6 and E7 neutralizes HPV integrated genome of malignant cells of uterine cervix. Based on experimental evidence, it is possible to prevent carcinoma of cervix with human papillomavirus vaccine, Further research is necessary to identify a effective and safe HPV vaccine, routes of administration and characteristics of potential beneficiaries.

Efficacy, but not antibody titer or affinity, of a heroin hapten conjugate vaccine correlates with increasing hapten densities on tetanus toxoid, but not on CRM197 carriers.

PubMed

Jalah, Rashmi; Torres, Oscar B; Mayorov, Alexander V; Li, Fuying; Antoline, Joshua F G; Jacobson, Arthur E; Rice, Kenner C; Deschamps, Jeffrey R; Beck, Zoltan; Alving, Carl R; Matyas, Gary R

2015-06-17

Vaccines against drugs of abuse have induced antibodies in animals that blocked the biological effects of the drug by sequestering the drug in the blood and preventing it from crossing the blood-brain barrier. Drugs of abuse are too small to induce antibodies and, therefore, require conjugation of drug hapten analogs to a carrier protein. The efficacy of these conjugate vaccines depends on several factors including hapten design, coupling strategy, hapten density, carrier protein selection, and vaccine adjuvant. Previously, we have shown that 1 (MorHap), a heroin/morphine hapten, conjugated to tetanus toxoid (TT) and mixed with liposomes containing monophosphoryl lipid A [L(MPLA)] as adjuvant, partially blocked the antinociceptive effects of heroin in mice. Herein, we extended those findings, demonstrating greatly improved vaccine induced antinociceptive effects up to 3% mean maximal potential effect (%MPE). This was obtained by evaluating the effects of vaccine efficacy of hapten 1 vaccine conjugates with varying hapten densities using two different commonly used carrier proteins, TT and cross-reactive material 197 (CRM197). Immunization of mice with these conjugates mixed with L(MPLA) induced very high anti-1 IgG peak levels of 400-1500 μg/mL that bound to both heroin and its metabolites, 6-acetylmorphine and morphine. Except for the lowest hapten density for each carrier, the antibody titers and affinity were independent of hapten density. The TT carrier based vaccines induced long-lived inhibition of heroin-induced antinociception that correlated with increasing hapten density. The best formulation contained TT with the highest hapten density of ≥30 haptens/TT molecule and induced %MPE of approximately 3% after heroin challenge. In contrast, the best formulation using CRM197 was with intermediate 1 densities (10-15 haptens/CRM197 molecule), but the %MPE was approximately 13%. In addition, the chemical synthesis of 1, the optimization of the conjugation method, and the methods for the accurate quantification of hapten density are described.

Development and clinical testing of multivalent vaccines based on a diphtheria-tetanus-acellular pertussis vaccine: difficulties encountered and lessons learned.

PubMed

Capiau, Carine; Poolman, Jan; Hoet, Bernard; Bogaerts, Hugues; Andre, Francis

2003-06-02

The widespread use of whole-cell pertussis vaccines in the second half of the 20th century have reduced the incidence of the disease significantly. However, in some countries, concerns about the reactogenicity and potential neurological damage associated with whole-cell vaccines led to a decrease in vaccine acceptance and an increase in morbidity and mortality of pertussis in several countries. This prompted the development of less reactogenic acellular pertussis vaccines combined with diphtheria and tetanus toxoids, initially in Japan and later in other countries. In Europe, the improved diphtheria, tetanus and acellular pertussis (DTPa) vaccine was first introduced in March 1994. The pertussis component of this DTPa vaccine, developed by Glaxo SmithKline, consists of pertussis toxoid, filamentous haemagglutinin and pertactin. The vaccine is well tolerated, with a lower incidence of adverse reactions than after administration of whole-cell vaccines. The long-lasting efficacy and effectiveness of DTPa vaccines have been extensively documented and these are now the cornerstone of a large range of combined vaccines including DTPa-hepatitis B (HBV), DTPa-inactivated polio (IPV) and DTPa-HBV-IPV. A lyophilised Haemophilus influenzae type b (Hib) vaccine can be reconstituted with all of these liquid combinations. The introduction of well-tolerated and efficacious DTPa vaccines and their more polyvalent combinations has improved the acceptance and simplified the implementation of childhood immunisation. This paper is a review of the technical and scientific difficulties encountered and the lessons learned over the 10-year period that it took to develop and introduce six multivalent vaccines using the Glaxo SmithKline DTPa as a building block.

Immunogenicity and malaria transmission reducing potency of Pfs48/45 and Pfs25 encoded by DNA vaccines administered by intramuscular electroporation.

PubMed

Datta, Dibyadyuti; Bansal, Geetha P; Gerloff, Dietlind L; Ellefsen, Barry; Hannaman, Drew; Kumar, Nirbhay

2017-01-05

Pfs48/45 and Pfs25 are leading candidates for the development of Plasmodium falciparum transmission blocking vaccines (TBV). Expression of Pfs48/45 in the erythrocytic sexual stages and presentation to the immune system during infection in the human host also makes it ideal for natural boosting. However, it has been challenging to produce a fully folded, functionally active Pfs48/45, using various protein expression platforms. In this study, we demonstrate that full-length Pfs48/45 encoded by DNA plasmids is able to induce significant transmission reducing immune responses. DNA plasmids encoding Pfs48/45 based on native (WT), codon optimized (SYN), or codon optimized and mutated (MUT1 and MUT2), to prevent any asparagine (N)-linked glycosylation were compared with or without intramuscular electroporation (EP). EP significantly enhanced antibody titers and transmission blocking activity elicited by immunization with SYN Pfs48/45 DNA vaccine. Mosquito membrane feeding assays also revealed improved functional immunogenicity of SYN Pfs48/45 (N-glycosylation sites intact) as compared to MUT1 or MUT2 Pfs48/45 DNA plasmids (all N-glycosylation sites mutated). Boosting with recombinant Pfs48/45 protein after immunization with each of the different DNA vaccines resulted in significant boosting of antibody response and improved transmission reducing capabilities of all four DNA vaccines. Finally, immunization with a combination of DNA plasmids (SYN Pfs48/45 and SYN Pfs25) also provides support for the possibility of combining antigens targeting different life cycle stages in the parasite during transmission through mosquitoes. Copyright © 2016 Elsevier Ltd. All rights reserved.

DEVELOPING A VACCINE AGAINST MULTIPLE PSYCHOACTIVE TARGETS: A CASE STUDY OF HEROIN

PubMed Central

Stowe, G. Neil; Schlosburg, Joel E.; Vendruscolo, Leandro F.; Edwards, Scott; Misra, Kaushik K.; Schulteis, Gery; Zakhari, Joseph S.; Koob, George F.; Janda, Kim D.

2012-01-01

Heroin addiction is a wide-reaching problem with a spectrum of damaging social consequences. Currently approved heroin addiction medications include drugs that bind at the same receptors (e.g. opioid receptors) occupied by heroin and/or its metabolites in the brain, but undesired side effects of these treatments, maintenance dependence and relapse to drug taking remains problematic. A vaccine capable of blocking heroin’s effects could provide an economical, long-lasting and sustainable adjunct to heroin addiction therapy without the side effects associated with available treatment options. Heroin, however, presents a particularly challenging vaccine target as it is metabolized to multiple psychoactive molecules of differing lipophilicity, with differing abilities to cross the blood brain barrier. In this review, we discuss the opiate scaffolding and hapten design considerations to confer immunogenicity as well as the specificity of the immune response towards structurally similar opiates. In addition, we detail different strategies employed in the design of immunoconjugates for a vaccine-based therapy for heroin addiction treatment. PMID:22229311

Gp120/CD4 blocking antibodies are frequently elicited in ART-naïve chronically HIV-1 infected individuals.

PubMed

Carrillo, Jorge; Molinos-Albert, Luis Manuel; Rodríguez de la Concepción, Maria Luisa; Marfil, Silvia; García, Elisabet; Derking, Ronald; Sanders, Rogier W; Clotet, Bonaventura; Blanco, Julià

2015-01-01

Antibodies with the ability to block the interaction of HIV-1 envelope glycoprotein (Env) gp120 with CD4, including those overlapping the CD4 binding site (CD4bs antibodies), can protect from infection by HIV-1, and their elicitation may be an interesting goal for any vaccination strategy. To identify gp120/CD4 blocking antibodies in plasma samples from HIV-1 infected individuals we have developed a competitive flow cytometry-based functional assay. In a cohort of treatment-naïve chronically infected patients, we showed that gp120/CD4 blocking antibodies were frequently elicited (detected in 97% plasma samples) and correlated with binding to trimeric HIV-1 envelope glycoproteins. However, no correlation was observed between functional CD4 binding blockade data and titer of CD4bs antibodies determined by ELISA using resurfaced gp120 proteins. Consistently, plasma samples lacking CD4bs antibodies were able to block the interaction between gp120 and its receptor, indicating that antibodies recognizing other epitopes, such as PGT126 and PG16, can also play the same role. Antibodies blocking CD4 binding increased over time and correlated positively with the capacity of plasma samples to neutralize the laboratory-adapted NL4.3 and BaL virus isolates, suggesting their potential contribution to the neutralizing workforce of plasma in vivo. Determining whether this response can be boosted to achieve broadly neutralizing antibodies may provide valuable information for the design of new strategies aimed to improve the anti-HIV-1 humoral response and to develop a successful HIV-1 vaccine.

Gp120/CD4 Blocking Antibodies Are Frequently Elicited in ART-Naïve Chronically HIV-1 Infected Individuals

PubMed Central

Carrillo, Jorge; Molinos-Albert, Luis Manuel; de la Concepción, Maria Luisa Rodríguez; Marfil, Silvia; García, Elisabet; Derking, Ronald; Sanders, Rogier W.; Clotet, Bonaventura; Blanco, Julià

2015-01-01

Antibodies with the ability to block the interaction of HIV-1 envelope glycoprotein (Env) gp120 with CD4, including those overlapping the CD4 binding site (CD4bs antibodies), can protect from infection by HIV-1, and their elicitation may be an interesting goal for any vaccination strategy. To identify gp120/CD4 blocking antibodies in plasma samples from HIV-1 infected individuals we have developed a competitive flow cytometry-based functional assay. In a cohort of treatment-naïve chronically infected patients, we showed that gp120/CD4 blocking antibodies were frequently elicited (detected in 97% plasma samples) and correlated with binding to trimeric HIV-1 envelope glycoproteins. However, no correlation was observed between functional CD4 binding blockade data and titer of CD4bs antibodies determined by ELISA using resurfaced gp120 proteins. Consistently, plasma samples lacking CD4bs antibodies were able to block the interaction between gp120 and its receptor, indicating that antibodies recognizing other epitopes, such as PGT126 and PG16, can also play the same role. Antibodies blocking CD4 binding increased over time and correlated positively with the capacity of plasma samples to neutralize the laboratory-adapted NL4.3 and BaL virus isolates, suggesting their potential contribution to the neutralizing workforce of plasma in vivo. Determining whether this response can be boosted to achieve broadly neutralizing antibodies may provide valuable information for the design of new strategies aimed to improve the anti-HIV-1 humoral response and to develop a successful HIV-1 vaccine. PMID:25803681

Development of a transmission-blocking malaria vaccine: progress, challenges, and the path forward.

PubMed

Nunes, Julia K; Woods, Colleen; Carter, Terrell; Raphael, Theresa; Morin, Merribeth J; Diallo, Diadier; Leboulleux, Didier; Jain, Sanjay; Loucq, Christian; Kaslow, David C; Birkett, Ashley J

2014-09-29

New interventions are needed to reduce morbidity and mortality associated with malaria, as well as to accelerate elimination and eventual eradication. Interventions that can break the cycle of parasite transmission, and prevent its reintroduction, will be of particular importance in achieving the eradication goal. In this regard, vaccines that interrupt malaria transmission (VIMT) have been highlighted as an important intervention, including transmission-blocking vaccines that prevent human-to-mosquito transmission by targeting the sexual, sporogonic, or mosquito stages of the parasite (SSM-VIMT). While the significant potential of this vaccine approach has been appreciated for decades, the development and licensure pathways for vaccines that target transmission and the incidence of infection, as opposed to prevention of clinical malaria disease, remain ill-defined. This article describes the progress made in critical areas since 2010, highlights key challenges that remain, and outlines important next steps to maximize the potential for SSM-VIMTs to contribute to the broader malaria elimination and eradication objectives. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Development of a bivalent conjugate vaccine candidate against malaria transmission and typhoid fever.

PubMed

An, So Jung; Scaria, Puthupparampil V; Chen, Beth; Barnafo, Emma; Muratova, Olga; Anderson, Charles; Lambert, Lynn; Chae, Myung Hwa; Yang, Jae Seung; Duffy, Patrick E

2018-05-17

Immune responses to poorly immunogenic antigens, such as polysaccharides, can be enhanced by conjugation to carriers. Our previous studies indicate that conjugation to Vi polysaccharide of Salmonella Typhi may also enhance immunogenicity of some protein carriers. We therefore explored the possibility of generating a bivalent vaccine against Plasmodium falciparum malaria and typhoid fever, which are co-endemic in many parts of the world, by conjugating Vi polysaccharide, an approved antigen in typhoid vaccine, to Pfs25, a malaria transmission blocking vaccine antigen in clinical trials. Vi-Pfs25 conjugates induced strong immune responses against both Vi and Pfs25 in mice, whereas the unconjugated antigens are poorly immunogenic. Functional assays of immune sera revealed potent transmission blocking activity mediated by anti-Pfs25 antibody and serum bactericidal activity due to anti-Vi antibody. Pfs25 conjugation to Vi modified the IgG isotype distribution of antisera, inducing a Th2 polarized immune response against Vi antigen. This conjugate may be further developed as a bivalent vaccine to concurrently target malaria and typhoid fever. Copyright © 2018. Published by Elsevier Ltd.

Malaria vaccine R&D in the Decade of Vaccines: breakthroughs, challenges and opportunities.

PubMed

Birkett, Ashley J; Moorthy, Vasee S; Loucq, Christian; Chitnis, Chetan E; Kaslow, David C

2013-04-18

While recent progress has been made in reducing malaria mortality with other interventions, vaccines are still urgently needed to further reduce the incidence of clinical disease, including during pregnancy, and to provide "herd protection" by blocking parasite transmission. The most clinically advanced candidate, RTS,S, is presently undergoing Phase 3 evaluation in young African children across 13 clinical sites in eight African countries. In the 12-month period following vaccination, RTS,S conferred approximately 50% protection from clinical Plasmodium falciparum disease in children aged 5-17 months, and approximately 30% protection in children aged 6-12 weeks when administered in conjunction with Expanded Program for Immunization (EPI) vaccines. The development of more highly efficacious vaccines to prevent clinical disease caused by both P. falciparum and Plasmodium vivax, as well as vaccines to support elimination efforts by inducing immunity that blocks malaria parasite transmission, are priorities. Some key barriers to malaria vaccine development include: a paucity of well-characterized target immunogens and an absence of clear correlates of protection to enable vaccine development targeting all stages of the P. falciparum and P. vivax lifecycles; a limited number of safe and effective delivery systems, including adjuvants, that induce potent, long-lived protective immunity, be it by antibody, CD4+, and/or CD8+ T cell responses; and, for vaccines designed to provide "herd protection" by targeting sexual stage and/or mosquito antigens, the lack of a clear clinical and regulatory pathway to licensure using non-traditional endpoints. Recommendations to overcome these, and other key challenges, are suggested in this document. Copyright © 2013 Elsevier Ltd. All rights reserved.

Depletion of regulatory T cells by anti-ICOS antibody enhances anti-tumor immunity of tumor cell vaccine in prostate cancer.

PubMed

Mo, Lijun; Chen, Qianmei; Zhang, Xinji; Shi, Xiaojun; Wei, Lili; Zheng, Dianpeng; Li, Hongwei; Gao, Jimin; Li, Jinlong; Hu, Zhiming

2017-10-13

ICOS + Treg cells exert important immunosuppressive effects in tumor immunity. We adopt a combination approach of ICOS + Treg cells depletion with tumor cell vaccine to evaluate anti-tumor immunity in mouse prostate cancer model. Streptavidin (SA)-mGM-CSF surface-modified RM-1 cells were prepared as the vaccine and the mouse subcutaneous prostate tumor model was used to evaluate the immunity. Tumor growth, flow cytometry, immunohistochemistry, immunofluorescence and enzyme linked immunosorbent assay (ELISA) were performed to evaluate the therapeutic effects. Our results demonstrated that SA-mGM-CSF vaccine was prepared successfully and tumor growth was inhibited. The tumor size in the combination group was much smaller than that in the vaccine with IgG mAb group. The portions of dendritic cells, CD8 + and CD4 + T cells in the mice blood and tumor tissues were increased after treatment with vaccine. There were more immune-suppressing Tregs infiltrated into tumor after treatment with tumor cell vaccine, and ICOS blocking could deplete the infiltrated Tregs, and T lymphocytes increased more dramatically in the combination therapy group. The concentrations of interferon-γ were increased in all vaccine group, the concentrations of Interleukin-10 and Interleukin-4 were much lower in the combination group. Our study demonstrated that ICOS blocking could deplete the tumor-infiltrated ICOS + Treg cells. Combining GM-CSF surface-modified RM-1 cell vaccine with Anti-ICOS antibody could induce better antitumor immunity than a vaccine alone. Copyright © 2017 Elsevier Ltd. All rights reserved.

Poly(U) and CpG ameliorate the unbalanced T cell immunity and pneumonia of mice with RSV vaccine-enhanced disease.

PubMed

Jia, Ran; Lu, Lu; Liang, Xiaozhen; Sun, Zhiwu; Tan, Lingbing; Xu, Menghua; Su, Liyun; Xu, Jin

2017-09-12

Respiratory Syncycial Virus (RSV) is the most important pathogen responsible for children's severe lower respiratory tract infection. So far no RSV vaccine has yet been authorized for clinical use. The main impediment that blocked development of RSV vaccine is that inactivated RSV vaccine could cause RSV vaccine-enhanced disease (RVED). The mechanism of RVED remains unclear. Recently some researchers found that insufficient activation of innate immunity, including Toll-like receptors (TLRs), might be associated with the onset of RVED. Based on the above findings, this research was conducted to further study the mechanism of RVED. We first vaccinated mice with formalin-inactivated RSV vaccine (FIRSV) and then exposed them to RSV to establish a RVED mouse model. Consequently, we found that mice previously inoculated with FIRSV showed obvious weight loss and extensive pneumonia, as well as T helper 2 cells (Th2)-biased immunity and suppressed CD8 + T cell immunity after viral exposure, suggesting that we have successfully established a RVED mouse model. Then based on this model, we further added Poly(U) (TLR7/8 agonist) and CpG (TLR9 agonist) in FIRSV to see if RVED could be ameliorated. As a result, mice inoculated with FIRSV supplemented with Poly(U) and CpG had a much relieved weight loss and pneumonia, as well as suppressed Th2-biased immunity and strengthened CD8 + T cell function. Thus, the insufficient stimulation of TLR7/8 and (or) TLR9 might play a role in the development of RVED, which could provide evidence for using TLR agonists as vaccine adjuvants to confer a protective immune response against RSV.

Antibody specificities of children living in a malaria endemic area to inhibitory and blocking epitopes on MSP-1 19 of Plasmodium falciparum.

PubMed

Omosun, Y O; Adoro, S; Anumudu, C I; Odaibo, A B; Uthiapibull, C; Holder, A A; Nwagwu, M; Nwuba, R I

2009-03-01

Merozoite surface protein-1(19) (MSP-1(19)) specific antibodies which include processing inhibitory, blocking and neutral antibodies have been identified in individuals exposed to Plasmodium falciparum. Here we intend to look at the effect of single and multiple amino acid substitutions of MSP-1(19) on the recognition by polyclonal antibodies from children living in Igbo-Ora, Nigeria. This would provide us with information on the possibility of eliciting mainly processing inhibitory antibodies with a recombinant MSP-1(19) vaccine. Blood was collected from children in the rainy season and binding of anti-MSP-1(19) antibodies to modified mutants of MSP-1(19) was analysed by ELISA. The MSP-1(19) mutant proteins with single substitutions at positions 22 (Leu-->Arg), 43 (Glu-->Leu) and 53 (Asn-->Arg) and the MSP-1(19) mutant protein with multiple substitutions at positions 27+31+34+43 (Glu-->Tyr, Leu-->Arg, Tyr-->Ser, Glu-->Leu); which had inhibitory epitopes; had the highest recognition. Children recognised both sets of mutants with different age groups having different recognition levels. The percentage of malaria positive individuals (32-80%) with antibodies that bound to the mutants MSP-1(19) containing epitopes that recognise only processing inhibitory and not blocking antibodies, were significantly different from those with antibodies that did not bind to these mutants (21-28%). The amino acid substitutions that abolished the binding of blocking antibodies without affecting the binding of inhibitory antibodies are of particular interest in the design of MSP-1(19) based malaria vaccines. Although these MSP-1(19) mutants have not been found in natural population, their recognition by polyclonal antibodies from humans naturally infected with malaria is very promising for the future use of MSP-1(19) mutants in the design of a malaria vaccine.

Malaria vaccines and human immune responses.

PubMed

Long, Carole A; Zavala, Fidel

2016-08-01

Despite reductions in malaria episodes and deaths over the past decade, there is still significant need for more effective tools to combat this serious global disease. The positive results with the Phase III trial of RTS,S directed to the circumsporozoite protein of Plasmodium falciparum have established that a vaccine against malaria can provide partial protection to children in endemic areas, but its limited efficacy and relatively short window of protection mandate that new generations of more efficacious vaccines must be sought. Evidence shows that anti-parasite immune responses can control infection against other stages as well, but translating these experimental findings into vaccines for blood stages has been disappointing and clinical efforts to test a transmission blocking vaccine are just beginning. Difficulties include the biological complexity of the organism with a large array of stage-specific genes many of which in the erythrocytic stages are antigenically diverse. In addition, it appears necessary to elicit high and long-lasting antibody titers, address the redundant pathways of merozoite invasion, and still seek surrogate markers of protective immunity. Most vaccine studies have focused on a single or a few antigens with an apparent functional role, but this is likely to be too restrictive, and broad, multi-antigen, multi-stage vaccines need further investigation. Finally, novel tools and biological insights involving parasite sexual stages and the mosquito vector will provide new avenues for reducing or blocking malaria transmission. Published by Elsevier Ltd.

Agglutination by anti-capsular polysaccharide antibody is associated with protection against experimental human pneumococcal carriage

PubMed Central

Reiné, J; Zangari, T; Owugha, JT; Pennington, SH; Gritzfeld, JF; Wright, AD; Collins, AM; van Selm, S; de Jonge, MI; Gordon, SB; Weiser, JN; Ferreira, DM

2016-01-01

The ability of pneumococcal conjugate vaccine (PCV) to decrease transmission by blocking the acquisition of colonization has been attributed to herd immunity. We describe the role of mucosal IgG to capsular polysaccharide (CPS) in mediating protection from carriage, translating our findings from a murine model to humans. We used a flow-cytometric assay to quantify antibody-mediated agglutination demonstrating that hyperimmune sera generated against an unencapsulated mutant was poorly agglutinating. Passive immunization with this antiserum was ineffective to block acquisition of colonization compared to agglutinating antisera raised against the encapsulated parent strain. In the human challenge model samples were collected from PCV and control vaccinated adults. In PCV-vaccinated subjects IgG levels to CPS were increased in serum and nasal wash (NW). IgG to the inoculated strain CPS dropped in NW samples after inoculation suggesting its sequestration by colonizing pneumococci. In post-vaccination NW samples pneumococci were heavily agglutinated compared to pre-vaccination samples in subjects protected against carriage. Our results indicate that pneumococcal agglutination mediated by CPS specific antibodies is a key mechanism of protection against acquisition of carriage. Capsule may be the only vaccine target that can elicit strong agglutinating antibody responses, leading to protection against carriage acquisition and generation of herd immunity. PMID:27579859

Enhancing immunogenicity and transmission-blocking activity of malaria vaccines by fusing Pfs25 to IMX313 multimerization technology.

PubMed

Li, Yuanyuan; Leneghan, Darren B; Miura, Kazutoyo; Nikolaeva, Daria; Brian, Iona J; Dicks, Matthew D J; Fyfe, Alex J; Zakutansky, Sarah E; de Cassan, Simone; Long, Carole A; Draper, Simon J; Hill, Adrian V S; Hill, Fergal; Biswas, Sumi

2016-01-08

Transmission-blocking vaccines (TBV) target the sexual-stages of the malaria parasite in the mosquito midgut and are widely considered to be an essential tool for malaria elimination. High-titer functional antibodies are required against target antigens to achieve effective transmission-blocking activity. We have fused Pfs25, the leading malaria TBV candidate antigen to IMX313, a molecular adjuvant and expressed it both in ChAd63 and MVA viral vectors and as a secreted protein-nanoparticle. Pfs25-IMX313 expressed from viral vectors or as a protein-nanoparticle is significantly more immunogenic and gives significantly better transmission-reducing activity than monomeric Pfs25. In addition, we demonstrate that the Pfs25-IMX313 protein-nanoparticle leads to a qualitatively improved antibody response in comparison to soluble Pfs25, as well as to significantly higher germinal centre (GC) responses. These results demonstrate that antigen multimerization using IMX313 is a very promising strategy to enhance antibody responses against Pfs25, and that Pfs25-IMX313 is a highly promising TBV candidate vaccine.

Antibody Responses to a Novel Plasmodium falciparum Merozoite Surface Protein Vaccine Correlate with Protection against Experimental Malaria Infection in Aotus Monkeys

PubMed Central

Cavanagh, David R.; Kocken, Clemens H. M.; White, John H.; Cowan, Graeme J. M.; Samuel, Kay; Dubbeld, Martin A.; der Wel, Annemarie Voorberg-van; Thomas, Alan W.; McBride, Jana S.; Arnot, David E.

2014-01-01

The Block 2 region of the merozoite surface protein-1 (MSP-1) of Plasmodium falciparum has been identified as a target of protective immunity by a combination of seroepidemiology and parasite population genetics. Immunogenicity studies in small animals and Aotus monkeys were used to determine the efficacy of recombinant antigens derived from this region of MSP-1 as a potential vaccine antigen. Aotus lemurinus griseimembra monkeys were immunized three times with a recombinant antigen derived from the Block 2 region of MSP-1 of the monkey-adapted challenge strain, FVO of Plasmodium falciparum, using an adjuvant suitable for use in humans. Immunofluorescent antibody assays (IFA) against erythrocytes infected with P. falciparum using sera from the immunized monkeys showed that the MSP-1 Block 2 antigen induced significant antibody responses to whole malaria parasites. MSP-1 Block 2 antigen-specific enzyme-linked immunosorbent assays (ELISA) showed no significant differences in antibody titers between immunized animals. Immunized animals were challenged with the virulent P. falciparum FVO isolate and monitored for 21 days. Two out of four immunized animals were able to control their parasitaemia during the follow-up period, whereas two out of two controls developed fulminating parasitemia. Parasite-specific serum antibody titers measured by IFA were four-fold higher in protected animals than in unprotected animals. In addition, peptide-based epitope mapping of serum antibodies from immunized Aotus showed distinct differences in epitope specificities between protected and unprotected animals. PMID:24421900

A Large Size Chimeric Highly Immunogenic Peptide Presents Multistage Plasmodium Antigens as a Vaccine Candidate System against Malaria.

PubMed

Lozano, José Manuel; Varela, Yahson; Silva, Yolanda; Ardila, Karen; Forero, Martha; Guasca, Laura; Guerrero, Yuly; Bermudez, Adriana; Alba, Patricia; Vanegas, Magnolia; Patarroyo, Manuel Elkin

2017-11-01

Rational strategies for obtaining malaria vaccine candidates should include not only a proper selection of target antigens for antibody stimulation, but also a versatile molecular design based on ordering the right pieces from the complex pathogen molecular puzzle towards more active and functional immunogens. Classical Plasmodium falciparum antigens regarded as vaccine candidates have been selected as model targets in this study. Among all possibilities we have chosen epitopes of Pf CSP, STARP; MSA1 and Pf 155/RESA from pre- and erythrocyte stages respectively for designing a large 82-residue chimeric immunogen. A number of options aimed at diminishing steric hindrance for synthetic procedures were assessed based on standard Fmoc chemistry such as building block orthogonal ligation; pseudo-proline and microwave-assisted procedures, therefore the large-chimeric target was produced, characterized and immunologically tested. Antigenicity and functional in vivo efficacy tests of the large-chimera formulations administered alone or as antigen mixtures have proven the stimulation of high antibody titers, showing strong correlation with protection and parasite clearance of vaccinated BALB/c mice after being lethally challenged with both P. berghei -ANKA and P. yoelii 17XL malaria strains. Besides, 3D structure features shown by the large-chimera encouraged as to propose using these rational designed large synthetic molecules as reliable vaccine candidate-presenting systems.

Attenuation of the influenza virus by microRNA response element in vivo and protective efficacy against 2009 pandemic H1N1 virus in mice.

PubMed

Feng, Chunlai; Tan, Mingming; Sun, Wenkui; Shi, Yi; Xing, Zheng

2015-09-01

The 2009 influenza pandemics underscored the need for effective vaccines to block the spread of influenza virus infection. Most live attenuated vaccines utilize cold-adapted, temperature-sensitive virus. An alternative to live attenuated virus is presented here, based on microRNA-induced gene silencing. In this study, miR-let-7b target sequences were inserted into the H1N1 genome to engineer a recombinant virus - miRT-H1N1. Female BALB/c mice were vaccinated intranasally with the miRT-H1N1 and challenged with a lethal dose of homologous virus. This miRT-H1N1 virus was attenuated in mice, while it exhibited wild-type characteristics in chicken embryos. Mice vaccinated intranasally with the miRT-H1N1 responded with robust immunity that protected the vaccinated mice from a lethal challenge with the wild-type 2009 pandemic H1N1 virus. These results indicate that the influenza virus containing microRNA response elements (MREs) is attenuated in vivo and can be used to design a live attenuated vaccine. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Genetic diversity of transmission-blocking vaccine candidate Pvs48/45 in Plasmodium vivax populations in China.

PubMed

Feng, Hui; Gupta, Bhavna; Wang, Meilian; Zheng, Wenqi; Zheng, Li; Zhu, Xiaotong; Yang, Yimei; Fang, Qiang; Luo, Enjie; Fan, Qi; Tsuboi, Takafumi; Cao, Yaming; Cui, Liwang

2015-12-01

The male gamete fertilization factor P48/45 in malaria parasites is a prime transmission-blocking vaccine (TBV) candidate. Efforts to develop antimalarial vaccines are often thwarted by genetic diversity of the target antigens. Here we evaluated the genetic diversity of Pvs48/45 gene in global Plasmodium vivax populations. We determined 200 Pvs48/45 sequences collected from temperate and subtropical parasite populations in China. Population genetic and evolutionary analyses were performed to determine the levels of genetic diversity, potential signature of selection, and population differentiation. Analysis of the Pvs48/45 sequences from 200 P. vivax parasites collected in a temperate and a tropical region revealed a low level of genetic diversity (π = 0.0012) with 14 single nucleotide polymorphisms, of which 11 were nonsynonymous. Analysis of 344 Pvs48/45 sequences from nine worldwide P. vivax populations detected a total of 38 haplotypes, of which 13 haplotypes were present only once. Multiple tests for selection confirmed a signature of positive selection on Pvs48/45 with selection skewed to the second cysteine domain. Haplotype network analysis and Wright's fixation index showed large geographical differentiation with the presence of continent-or region-specific mutations in this gene. Pvs48/45 displays low levels of genetic diversity with the presence of region-specific mutations. Some of the mutations may be potential epitope targets based on their positions in the predicted structure, highlighting the need for future evaluation of these mutations in designing Pvs48/45-based TBV.

Bordetella pertussis isolates in Finland: Serotype and fimbrial expression

PubMed Central

Heikkinen, Eriikka; Xing, Dorothy K; Ölander, Rose-Marie; Hytönen, Jukka; Viljanen, Matti K; Mertsola, Jussi; He, Qiushui

2008-01-01

Background Bordetella pertussis causes whooping cough or pertussis in humans. It produces several virulence factors, of which the fimbriae are considered adhesins and elicit immune responses in the host. B. pertussis has three distinct serotypes Fim2, Fim3 or Fim2,3. Generally, B. pertussis Fim2 strains predominate in unvaccinated populations, whereas Fim3 strains are often isolated in vaccinated populations. In Finland, pertussis vaccination was introduced in 1952. The whole-cell vaccine contained two strains, 18530 (Fim3) since 1962 and strain 1772 (Fim2,3) added in 1976. After that the vaccine has remained the same until 2005 when the whole-cell vaccine was replaced by the acellular vaccine containing pertussis toxin and filamentous hemagglutinin. Our aims were to study serotypes of Finnish B. pertussis isolates from 1974 to 2006 in a population with > 90% vaccination coverage and fimbrial expression of the isolates during infection. Serotyping was done by agglutination and serotype-specific antibody responses were determined by blocking ELISA. Results Altogether, 1,109 isolates were serotyped. Before 1976, serotype distributions of Fim2, Fim3 and Fim2,3 were 67%, 19% and 10%, respectively. From 1976 to 1998, 94% of the isolates were Fim2 serotype. Since 1999, the frequency of Fim3 strains started to increase and reached 83% during a nationwide epidemic in 2003. A significant increase in level of serum IgG antibodies against purified fimbriae was observed between paired sera of 37 patients. The patients infected by Fim3 strains had antibodies which blocked the binding of monoclonal antibodies to Fim3 but not to Fim2. Moreover, about one third of the Fim2 strain infected patients developed antibodies capable of blocking of binding of both anti-Fim2 and Fim3 monoclonal antibodies. Conclusion Despite extensive vaccinations in Finland, B. pertussis Fim2 strains were the most common serotype. Emergence of Fim3 strains started in 1999 and coincided with nationwide epidemics. Results of serotype-specific antibody responses suggest that Fim2 strains could express Fim3 during infection, showing a difference in fimbrial expression between in vivo and in vitro. PMID:18816412

Vaccine for BK Polyomavirus-associated Infections in Transplant Recipients | NCI Technology Transfer Center | TTC

Cancer.gov

NCI researches identified a BK polyomavirus (BKV) virulent strain that causes chronic urinary tract infections, and the development of vaccine and therapeutic methods that would block BKV pathogenesis. The NCI Laboratory of Cellular Oncology, seek parties to license or co-develop this technology.

Effect of HBIG combined with hepatitis B vaccine on blocking HBV transmission between mother and infant and its effect on immune cells.

PubMed

Gong, Junling; Liu, Xing

2018-01-01

The effect of hepatitis B immune globulin (HBIG) combined with hepatitis B vaccine on blocking hepatitis B virus (HBV) transmission between mother and infant and its effect on immune cells were studied. Ninety newborn infants confirmed to be HBV surface antigen (HBsAg)-positive were divided equally into three groups. Group A newborns received the hepatitis B vaccine at 0, 1 and 6 months after birth (10 µg/time). Group B newborns received an intramuscular injection of 100 IU HBIG 2 h after birth before the same treatment as group A. Mothers of group C newborns received three gluteus maxinus injections of 200 IU HBIG. The newborns in group C got the same treatment as group B. The blocking effect of HBV transmission between mother and infant was evaluated, and cell immune function was assessed. There were significant differences in comparison of blocking success rates between group A and B, and between group A and C as well (p<0.05). At the end of 12 months follow-up, the CD4 + level and CD4 + /CD8 + ratio in group C were higher thanthose in group A and B (p<0.05). In addition, the level of CD8 + T lymphocyte in group C was lower than those in group A and B (p<0.05). In comparison of levels of CD4 + T lymphocyte at the end of 12 months follow-up and 24 h after birth, the differences were significant (p<0.05) in bothgroup B and C. The differences of IFN-γ levels betweengroups B/C and group A were significant (p<0.05). Forthose newborn infants born to mothers who were positivefor both HBsAg and HBeAg, HBIG intervention formothers during late pregnancy, together with combinedtreatment of HBIG and hepatitis B vaccine for infants, gavebetter blocking result of HBV transmission.

Vaccines Against Malaria

PubMed Central

Ouattara, Amed; Laurens, Matthew B.

2015-01-01

Despite global efforts to control malaria, the illness remains a significant public health threat. Currently, there is no licensed vaccine against malaria, but an efficacious vaccine would represent an important public health tool for successful malaria elimination. Malaria vaccine development continues to be hindered by a poor understanding of antimalarial immunity, a lack of an immune correlate of protection, and the genetic diversity of malaria parasites. Current vaccine development efforts largely target Plasmodium falciparum parasites in the pre-erythrocytic and erythrocytic stages, with some research on transmission-blocking vaccines against asexual stages and vaccines against pregnancy-associated malaria. The leading pre-erythrocytic vaccine candidate is RTS,S, and early results of ongoing Phase 3 testing show overall efficacy of 46% against clinical malaria. The next steps for malaria vaccine development will focus on the design of a product that is efficacious against the highly diverse strains of malaria and the identification of a correlate of protection against disease. PMID:25452593

[Pasteur's rabies vaccination: 130 years ago successfully started in Vienna, however officially rejected].

PubMed

Flamm, Heinz

2015-08-01

The Viennese surgeon Emerich Ullmann who was trained in rabies vaccination by Pasteur personally started his activity in Vienna on 28.6.1886 vaccinating persons of Austria-Hungary been bitten by rabid animals. Whereas Prof. v.Frisch of the other surgical clinic who also had visited Pasteur carried out animal experiments which urged him to disapprove Pasteur's human rabies vaccination. Ullmann vaccinated with great success but soon there appeared obstructions in Viennese medical journals and hateful discussions in the Austrian Parliament against Pasteur and Ullmann. These facts blocked the necessary financial subvention of Ullmann's self financed vaccinations and resulted in their interruption. After a mass infection of rabies in the Bukowina in 1891 the Supreme Sanitary Board formed an Epidemiologic Committee which recommended the establishment of a vaccination unit in an Austrian hospital. In July 1894 the Vaccination Unit was opened in the Viennese hospital Rudolfstiftung, where Emerich Ullmann carried out the rabies vaccinations.

Identification of two novel immunodominant UreB CD4(+) T cell epitopes in Helicobacter pylori infected subjects.

PubMed

Yang, Wu-Chen; Chen, Li; Li, Hai-Bo; Li, Bin; Hu, Jian; Zhang, Jin-Yong; Yang, Shi-Ming; Zou, Quan-Ming; Guo, Hong; Wu, Chao

2013-02-06

An epitope-based vaccine is a promising option for treating Helicobacter pylori (H. pylori) infection. Epitope mapping is the first step in designing an epitope-based vaccine. A pivotal role of CD4(+) T cells in protection against H. pylori has been accepted, but few Th epitopes have been identified. In this study, two novel UreB CD4(+) T cell epitopes were identified using PBMCs obtained from two H. pylori infected subjects. We determined the restriction molecules by antibody blocking and used various Epstein-Barr virus-transformed B lymphocyte cell lines (BLCLs) with different HLA alleles as APCs to present peptides to CD4(+) T cells. These epitopes were DRB1*1404-restricted UreB(373-385) and DRB1*0803-restricted UreB(438-452). The T cells specific to these epitopes not only recognized autologous DCs loaded with recombinant UreB but also those pulsed with H. pylori whole cell lysates, suggesting that these epitope peptides are naturally processed. These epitopes have important value for designing an effective H. pylori vaccine. Copyright © 2012 Elsevier Ltd. All rights reserved.

Induction of Type I Interferons by Therapeutic Nanoparticle-Based Vaccination Is Indispensable to Reinforce Cytotoxic CD8+ T Cell Responses During Chronic Retroviral Infection

PubMed Central

Knuschke, Torben; Rotan, Olga; Bayer, Wibke; Kollenda, Sebastian; Dickow, Julia; Sutter, Kathrin; Hansen, Wiebke; Dittmer, Ulf; Lang, Karl S.; Epple, Matthias; Buer, Jan; Westendorf, Astrid M.

2018-01-01

T cell dysfunction and immunosuppression are characteristic for chronic viral infections and contribute to viral persistence. Overcoming these burdens is the goal of new therapeutic strategies to cure chronic infectious diseases. We recently described that therapeutic vaccination of chronic retrovirus infected mice with a calcium phosphate (CaP) nanoparticle (NP)-based vaccine carrier, functionalized with CpG and viral peptides is able to efficiently reactivate the CD8+ T cell response and improve the eradication of virus infected cells. However, the mechanisms underlying this effect were largely unclear. While type I interferons (IFNs I) are considered to drive T cell exhaustion by persistent immune activation during chronic viral infection, we here describe an indispensable role of IFN I induced by therapeutic vaccination to efficiently reinforce cytotoxic CD8+ T cells (CTL) and improve control of chronic retroviral infection. The induction of IFN I is CpG dependent and leads to significant IFN signaling indicated by upregulation of IFN stimulated genes. By vaccinating chronically retrovirus-infected mice lacking the IFN I receptor (IFNAR−/−) or by blocking IFN I signaling in vivo during therapeutic vaccination, we demonstrate that IFN I signaling is necessary to drive full reactivation of CTLs. Surprisingly, we also identified an impaired suppressive capability of regulatory T cells in the presence of IFNα, which implicates an important role for vaccine-induced IFNα in the regulation of the T cell response during chronic retroviral infection. Our data suggest that inducing IFN I signaling in conjunction with the presentation of viral antigens can reactivate immune functions and reduce viral loads in chronic infections. Therefore, we propose CaP NPs as potential therapeutic tool to treat chronic infections. PMID:29740425

Immunocontraception: Filamentous Bacteriophage as a Platform for Vaccine Development.

PubMed

Samoylova, Tatiana I; Braden, Timothy D; Spencer, Jennifer A; Bartol, Frank F

2017-11-20

Population control of domestic, wild, invasive, and captive animal species is a global issue of importance to public health, animal welfare and the economy. There is pressing need for effective, safe, and inexpensive contraceptive technologies to address this problem. Contraceptive vaccines, designed to stimulate the immune system in order to block critical reproductive events and suppress fertility, may provide a solution. Filamentous bacteriophages can be used as platforms for development of such vaccines. In this review authors highlight structural and immunogenic properties of filamentous phages, and discuss applications of phage-peptide vaccines for advancement of immunocontraception technology in animals. Phages can be engineered to display fusion (non-phage) peptides as coat proteins. Such modifications can be accomplished via genetic manipulation of phage DNA, or by chemical conjugation of synthetic peptides to phage surface proteins. Phage fusions with antigenic determinants induce humoral as well as cell-mediated immune responses in animals, making them attractive as vaccines. Additional advantages of the phage platform include environmental stability, low cost, and safety for immunized animals and those administering the vaccines. Filamentous phages are viable platforms for vaccine development that can be engineered with molecular and organismal specificity. Phage-based vaccines can be produced in abundance at low cost, are environmentally stable, and are immunogenic when administered via multiple routes. These features are essential for a contraceptive vaccine to be operationally practical in animal applications. Adaptability of the phage platform also makes it attractive for design of human immunocontraceptive agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Immunocontraception: Filamentous Bacteriophage as a Platform for Vaccine Development

PubMed Central

Samoylova, Tatiana I.; Braden, Timothy D.; Spencer, Jennifer A.; Bartol, Frank F.

2017-01-01

Background: Population control of domestic, wild, invasive, and captive animal species is a global issue of importance to public health, animal welfare and the economy. There is pressing need for effective, safe, and inexpensive contraceptive technologies to ad-dress this problem. Contraceptive vaccines, designed to stimulate the immune system in order to block critical reproductive events and suppress fertility, may provide a solution. Fil-amentous bacteriophages can be used as platforms for development of such vaccines. Objective: In this review authors highlight structural and immunogenic properties of fila-mentous phages, and discuss applications of phage-peptide vaccines for advancement of immunocontraception technology in animals. Results: Phages can be engineered to display fusion (non-phage) peptides as coat proteins. Such modifications can be accomplished via genetic manipulation of phage DNA, or by chemical conjugation of synthetic peptides to phage surface proteins. Phage fusions with antigenic determinants induce humoral as well as cell-mediated immune responses in ani-mals, making them attractive as vaccines. Additional advantages of the phage platform include environmental stability, low cost, and safety for immunized animals and those ad-ministering the vaccines. Conclusion: Filamentous phages are viable platforms for vaccine development that can be engineered with molecular and organismal specificity. Phage-based vaccines can be pro-duced in abundance at low cost, are environmentally stable, and are immunogenic when administered via multiple routes. These features are essential for a contraceptive vaccine to be operationally practical in animal applications. Adaptability of the phage platform also makes it attractive for design of human immunocontraceptive agents. PMID:28901276

Induction of HIV Neutralizing Antibodies against the MPER of the HIV Envelope Protein by HA/gp41 Chimeric Protein-Based DNA and VLP Vaccines

PubMed Central

Ye, Ling; Wen, Zhiyuan; Dong, Ke; Wang, Xi; Bu, Zhigao; Zhang, Huizhong; Compans, Richard W.; Yang, Chinglai

2011-01-01

Several conserved neutralizing epitopes have been identified in the HIV Env protein and among these, the MPER of gp41 has received great attention and is widely recognized as a promising target. However, little success has been achieved in eliciting MPER-specific HIV neutralizing antibodies by a number of different vaccine strategies. We investigated the ability of HA/gp41 chimeric protein-based vaccines, which were designed to enhance the exposure of the MPER in its native conformation, to induce MPER-specific HIV neutralizing antibodies. In characterization of the HA/gp41 chimeric protein, we found that by mutating an unpaired Cys residue (Cys-14) in its HA1 subunit to a Ser residue, the modified chimeric protein HA-C14S/gp41 showed increased reactivity to a conformation-sensitive monoclonal antibody against HA and formed more stable trimers in VLPs. On the other hand, HA-C14S/gp41 and HA/gp41 chimeric proteins expressed on the cell surfaces exhibited similar reactivity to monoclonal antibodies 2F5 and 4E10. Immunization of guinea pigs using the HA-C14S/gp41 DNA or VLP vaccines induced antibodies against the HIV gp41 as well as to a peptide corresponding to a segment of MPER at higher levels than immunization by standard HIV VLPs. Further, sera from vaccinated guinea pigs were found to exhibit HIV neutralizing activities. Moreover, sera from guinea pigs vaccinated by HA-C14S/gp41 DNA and VLP vaccines but not the standard HIV VLPs, were found to neutralize HIV pseudovirions containing a SIV-4E10 chimeric Env protein. The virus neutralization could be blocked by a MPER-specific peptide, thus demonstrating induction of MPER-specific HIV neutralizing antibodies by this novel vaccine strategy. These results show that induction of MPER-specific HIV neutralizing antibodies can be achieved through a rationally designed vaccine strategy. PMID:21625584

TLR-adjuvanted nanoparticle vaccines differentially influence the quality and longevity of responses to malaria antigen Pfs25.

PubMed

Thompson, Elizabeth A; Ols, Sebastian; Miura, Kazutoyo; Rausch, Kelly; Narum, David L; Spångberg, Mats; Juraska, Michal; Wille-Reece, Ulrike; Weiner, Amy; Howard, Randall F; Long, Carole A; Duffy, Patrick E; Johnston, Lloyd; O'Neil, Conlin P; Loré, Karin

2018-05-17

Transmission-blocking vaccines (TBVs) are considered an integral element of malaria eradication efforts. Despite promising evaluations of Plasmodium falciparum Pfs25-based TBVs in mice, clinical trials have failed to induce robust and long-lived Ab titers, in part due to the poorly immunogenic nature of Pfs25. Using nonhuman primates, we demonstrate that multiple aspects of Pfs25 immunity were enhanced by antigen encapsulation in poly(lactic-co-glycolic acid)-based [(PLGA)-based] synthetic vaccine particles (SVP[Pfs25]) and potent TLR-based adjuvants. SVP[Pfs25] increased Ab titers, Pfs25-specific plasmablasts, circulating memory B cells, and plasma cells in the bone marrow when benchmarked against the clinically tested multimeric form Pfs25-EPA given with GLA-LSQ. SVP[Pfs25] also induced the first reported Pfs25-specific circulating Th1 and Tfh cells to our knowledge. Multivariate correlative analysis indicated several mechanisms for the improved Ab responses. While Pfs25-specific B cells were responsible for increasing Ab titers, T cell responses stimulated increased Ab avidity. The innate immune activation differentially stimulated by the adjuvants revealed a strong correlation between type I IFN polarization, induced by R848 and CpG, and increased Ab half-life and longevity. Collectively, the data identify ways to improve vaccine-induced immunity to poorly immunogenic proteins, both by the choice of antigen and adjuvant formulation, and highlight underlying immunological mechanisms.

Evaluation of formalin-fixed paraffin-embedded tissues from vaccine site-associated sarcomas of cats for papillomavirus DNA and antigen.

PubMed

Kidney, B A; Haines, D M; Ellis, J A; Burnham, M L; Teifke, J P; Czerwinski, G; Jackson, M L

2001-06-01

To determine whether vaccine site-associated sarcomas (VSS) from cats contain papillomavirus antigen or DNA. 50 formalin-fixed paraffin-embedded tissue blocks of VSS from cats. Sections from each tissue block were evaluated for papillomavirus antigen by use of an avidin-biotin-complex immunohistochemical staining method, using rabbit anti-bovine papillomavirus type-1 antibody. The DNA was extracted from sections of each tissue block, and polymerase chain reaction assays were performed, using primers designed to amplify regions of the E5 gene of bovine papillomavirus and consensus primers designed to amplify a region of the L1 gene of animal papillomaviruses. Sections from 20 of the tissue blocks were evaluated by use of nonradioactive in situ hybridization for bovine papillomavirus DNA. Papillomavirus antigen and DNA were not detected in any of the VSS. Results suggest that papillomaviruses likely do not have any direct involvement in the pathogenesis of VSS in cats.

Evaluation of formalin-fixed paraffin-embedded tissues from vaccine site-associated sarcomas of cats for polyomavirus DNA and antigen.

PubMed

Kidney, B A; Haines, D M; Ellis, J A; Burnham, M; Jackson, M L

2001-06-01

To determine whether vaccine site-associated sarcomas (VSS) from cats contain polyomavirus antigen or DNA. 50 formalin-fixed paraffin-embedded tissue blocks of VSS from cats. Sections from each tissue block were evaluated for polyomavirus antigen by use of an avidin-biotin-complex immunohistochemical staining method, using rabbit anti-murine polyomavirus polyclonal antiserum as the primary antibody. The DNA was extracted from sections of each tissue block, and a polymerase chain reaction assay was performed, using primers designed to amplify regions of the bovine polyomavirus genome and consensus polyomavirus primers designed to detect unknown polyomaviruses. Polyomavirus antigen and DNA were not detected in any of the VSS. Results suggest that polyomaviruses likely do not have any direct involvement in the pathogenesis of VSS in cats.

Antibody-Mediated and Cellular Immune Responses Induced in Naive Volunteers by Vaccination with Long Synthetic Peptides Derived from the Plasmodium vivax Circumsporozoite Protein

PubMed Central

Arévalo-Herrera, Myriam; Soto, Liliana; Perlaza, Blanca Liliana; Céspedes, Nora; Vera, Omaira; Lenis, Ana Milena; Bonelo, Anilza; Corradin, Giampietro; Herrera, Sócrates

2011-01-01

Plasmodium vivax circumsporozoite (CS) protein is a leading malaria vaccine candidate. We describe the characterization of specific immune responses induced in 21 malaria-naive volunteers vaccinated with long synthetic peptides derived from the CS protein formulated in Montanide ISA 720. Both antibody- and cell-mediated immune responses were analyzed. Antibodies were predominantly of IgG1 and IgG3 isotypes, recognized parasite proteins on the immunofluorescent antibody test, and partially blocked sporozoite invasion of hepatoma cell lines in vitro. Peripheral blood mononuclear cells from most volunteers (94%) showed IFN-γ production in vitro upon stimulation with both long signal peptide and short peptides containing CD8+ T-cell epitopes. The relatively limited sample size did not allow conclusions about HLA associations with the immune responses observed. In summary, the inherent safety and tolerability together with strong antibody responses, invasion blocking activity, and the IFN-γ production induced by these vaccine candidates warrants further testing in a phase II clinical trial. PMID:21292876

Novel Cocaine Vaccine Linked to a Disrupted Adenovirus Gene Transfer Vector Blocks Cocaine Psychostimulant and Reinforcing Effects

PubMed Central

Wee, Sunmee; Hicks, Martin J; De, Bishnu P; Rosenberg, Jonathan B; Moreno, Amira Y; Kaminsky, Stephen M; Janda, Kim D; Crystal, Ronald G; Koob, George F

2012-01-01

Immunotherapy is a promising treatment for drug addiction. However, insufficient immune responses to vaccines in most subjects pose a challenge. In this study, we tested the efficacy of a new cocaine vaccine (dAd5GNE) in antagonizing cocaine addiction-related behaviors in rats. This vaccine used a disrupted serotype 5 adenovirus (Ad) gene transfer vector coupled to a third-generation cocaine hapten, termed GNE (6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid). Three groups of rats were immunized with dAd5GNE. One group was injected with 3H-cocaine, and radioactivity in the blood and brain was determined. A second group was tested for cocaine-induced locomotor sensitization. A third group was examined for cocaine self-administration, extinction, and reinstatement of responding for cocaine. Antibody titers were determined at various time-points. In each experiment, we added a control group that was immunized with dAd5 without a hapten. The vaccination with dAd5GNE produced long-lasting high titers (>105) of anti-cocaine antibodies in all of the rats. The vaccination inhibited cocaine-induced hyperlocomotor activity and sensitization. Vaccinated rats acquired cocaine self-administration, but they showed less motivation to self-administer cocaine under a progressive-ratio schedule than control rats. When cocaine was not available in a session, control rats exhibited ‘extinction burst' responding, whereas vaccinated rats did not. Moreover, when primed with cocaine, vaccinated rats did not reinstate responding, suggesting a blockade of cocaine-seeking behavior. These data strongly suggest that our dAd5GNE vector-based vaccine may be effective in treating cocaine abuse and addiction. PMID:21918504

Novel cocaine vaccine linked to a disrupted adenovirus gene transfer vector blocks cocaine psychostimulant and reinforcing effects.

PubMed

Wee, Sunmee; Hicks, Martin J; De, Bishnu P; Rosenberg, Jonathan B; Moreno, Amira Y; Kaminsky, Stephen M; Janda, Kim D; Crystal, Ronald G; Koob, George F

2012-04-01

Immunotherapy is a promising treatment for drug addiction. However, insufficient immune responses to vaccines in most subjects pose a challenge. In this study, we tested the efficacy of a new cocaine vaccine (dAd5GNE) in antagonizing cocaine addiction-related behaviors in rats. This vaccine used a disrupted serotype 5 adenovirus (Ad) gene transfer vector coupled to a third-generation cocaine hapten, termed GNE (6-(2R,3S)-3-(benzoyloxy)-8-methyl-8-azabicyclo [3.2.1] octane-2-carboxamido-hexanoic acid). Three groups of rats were immunized with dAd5GNE. One group was injected with (3)H-cocaine, and radioactivity in the blood and brain was determined. A second group was tested for cocaine-induced locomotor sensitization. A third group was examined for cocaine self-administration, extinction, and reinstatement of responding for cocaine. Antibody titers were determined at various time-points. In each experiment, we added a control group that was immunized with dAd5 without a hapten. The vaccination with dAd5GNE produced long-lasting high titers (>10(5)) of anti-cocaine antibodies in all of the rats. The vaccination inhibited cocaine-induced hyperlocomotor activity and sensitization. Vaccinated rats acquired cocaine self-administration, but they showed less motivation to self-administer cocaine under a progressive-ratio schedule than control rats. When cocaine was not available in a session, control rats exhibited 'extinction burst' responding, whereas vaccinated rats did not. Moreover, when primed with cocaine, vaccinated rats did not reinstate responding, suggesting a blockade of cocaine-seeking behavior. These data strongly suggest that our dAd5GNE vector-based vaccine may be effective in treating cocaine abuse and addiction.

Evaluation Studies of the DEN-2/S-1 Vaccine.

DTIC Science & Technology

1981-08-01

1.0 3.0, L o 1 .0 I11 125 11111 1.4 n .6_t _ MICROCOPY RESOLUTION TEST CHART NATIONAL WII ALI 0 MF S’ANDAkLT, ,’I, A ;40- AD EVALUATION STUDIES OF THE...monkeys Vaccination DEN-2/S-l Vaccine /AE TlhACT ( i - ,ewr e e1 If .,ceweu7 amd Iderdtlfy by block number) A dengue-2 live virus vaccine was tested in...viremia was detected in control animals. Serological tests were pi.r- formed on sera taken on post infection days 30,56 and 90. HI tests revealed sero

SagE induces highly effective protective immunity against Streptococcus iniae mainly through an immunogenic domain in the extracellular region.

PubMed

Sun, Yun; Sun, Li; Xing, Ming-qing; Liu, Chun-sheng; Hu, Yong-hua

2013-11-12

Streptococcus iniae is a Gram-positive bacterium and a severe pathogen of a wide range of farmed fish. S. iniae possesses a virulence-associated streptolysin S cluster composed of several components, one of which is SagE. SagE a transmembrane protein with one major extracellular region named ECR. This study aimed to develop a SagE-based DNA candidate vaccine against streptococcosis and examine the immunoprotective mechanism of the vaccine. We constructed a DNA vaccine, pSagE, based on the sagE gene and examined its immunological property in a Japanese flounder (Paralichthys olivaceus) model. The results showed that at 7 days post-vaccination, expression of SagE at transcription and translation levels was detected in the tissues of the vaccinated fish. After challenge with S. iniae at one and two months post-vaccination, pSagE-vaccinated fish exhibited relative percent survival (RPS) of 95% and 88% respectively. Immunological analysis showed that (i) pSagE significantly upregulated the expression of a wide range of immune genes, (ii) pSagE induced the production of specific serum antibodies that bound whole-cell S. iniae, and (iii) treatment of S. iniae with pSagE-induced antibodies blocked bacterial invasion of host cells. To localize the immunoprotective domain of SagE, the ECR-expressing DNA vaccine pSagEECR was constructed. Immunization analysis showed that flounder vaccinated with pSagEECR exhibited a RPS of 68%, and that pSagEECR induced serum antibody production and immune gene expression in a manner similar to, though to lower magnitudes than, those induced by pSagE. We in this study developed a DNA vaccine, pSagE, which induces highly protective immunity against S. iniae. The protective effect of pSagE is probably due to its ability to elicit systemic immune response, in particular that of the humoral branch, which leads to production of specific serum antibodies that impair bacterial infection. These results add insights to the immunoprotective mechanism of fish DNA vaccine.

Ternary particles for effective vaccine delivery to the pulmonary system

NASA Astrophysics Data System (ADS)

Terry, Treniece La'shay

Progress in the fields of molecular biology and genomics has provided great insight into the pathogenesis of disease and the defense mechanisms of the immune system. This knowledge has lead to the classification of an array of abnormal genes, for which, treatment relies on cellular expression of proteins. The utility of DNA-based vaccines hold great promise for the treatment of genetically based and infectious diseases, which ranges from hemophilia, cystic fibrosis, and HIV. Synthetic delivery systems consisting of cationic polymers, such as polyethylenimine (PEI), are capable of condensing DNA into compact structures, maximizing cellular uptake of DNA and yielding high levels of protein expression. To date, short term expression is a major obstacle in the development of gene therapies and has halted their expansion in clinical applications. This study intends to develop a sustained release vaccine delivery system using PLA-PEG block copolymers encapsulating PEI:DNA polyplexes. To enhance the effectiveness of such DNA-based vaccines, resident antigen presenting cells, macrophages and dendritic cells, will be targeted within the alveoli regions of the lungs. Porous microspheres will be engineered with aerodynamic properties capable of achieving deep lung deposition. A fabrication technique using concentric nozzles will be developed to produce porous microspheres. It was observed that modifications in the dispersed to continuous phase ratios have the largest influence on particle size distributions, release rates and encapsulation efficiency which ranged form 80--95% with fourteen days of release. Amphiphilic block copolymers were also used to fabricate porous microspheres. The confirmation of PEG within the biodegradable polymer backbone was found to have a tremendous impact on the microsphere morphology and encapsulation efficiency which varied from 50--90%. Porous microspheres were capable of providing sustained gene expression when tested in vitro using the luciferase reporter gene plasmid DNA. Prolonged expression was obtained for 9 days. PLGA and PLA-PEG microspheres were administered in vivo by intra-tracheal instillation and produced an acute inflammatory response, as observed from the large presence of neutrophils. The response using PLA-PEG microspheres yielded a lower total cell count signifying the incorporation of PEG into the copolymer backbone enhances the biocompatibility of the delivery system.

Potent malaria transmission-blocking antibody responses elicited by Plasmodium falciparum Pfs25 expressed in Escherichia coli after successful protein refolding.

PubMed

Kumar, Rajesh; Angov, Evelina; Kumar, Nirbhay

2014-04-01

Production of Pfs25, a Plasmodium falciparum transmission-blocking vaccine target antigen, in functional conformation with the potential to elicit effective immunogenicity still remains a major challenge. In the current study, codon-harmonized recombinant Pfs25 (CHrPfs25) was expressed in Escherichia coli, and purified protein after simple oxidative refolding steps retained reduction-sensitive conformational epitopes of transmission-blocking monoclonal antibodies. CHrPfs25 formulated in several adjuvants elicited strong immunogenicity in preclinical studies in mice. Antibodies elicited after immunization recognized native Pfs25 on the surface of live gametes of P. falciparum and demonstrated complete malaria transmission-blocking activity. The transmission-blocking efficacy was 100% even after a 1:128 dilution of sera from immunized mice in the complete Freund's adjuvant and Montanide ISA51 groups and after a 1:16 dilution of sera from mice in the alum group. The blocking was mediated by antibodies; purified IgG at concentrations as low as 31.25 μg/ml exhibited 100% transmission blocking in membrane feeding assays employing two different species of mosquitoes, Anopheles gambiae and Anopheles stephensi. This study provides the first evidence for successful expression of biologically functional rPfs25 in E. coli. The extremely potent malaria transmission-blocking activity of antibodies elicited by immunization with purified protein provides strong support for further evaluation of E. coli-derived CHrPfs25 as a malaria transmission-blocking vaccine in human clinical trials.

Whole-Killed Blood-Stage Vaccine-Induced Immunity Suppresses the Development of Malaria Parasites in Mosquitoes.

PubMed

Zhu, Feng; Liu, Taiping; Zhao, Chenhao; Lu, Xiao; Zhang, Jian; Xu, Wenyue

2017-01-01

As a malaria transmission-blocking vaccine alone does not confer a direct benefit to the recipient, it is necessary to develop a vaccine that not only blocks malaria transmission but also protects vaccinated individuals. In this study we observed that a whole-killed blood-stage vaccine (WKV) not only conferred protection against the blood-stage challenge but also markedly inhibited the transmission of different strains of the malaria parasite. Although the parasitemia is much lower in WKV-immunized mice challenged with malaria parasites, the gametocytemia is comparable between control and immunized mice during the early stages of infection. The depletion of CD4 + T cells prior to the adoptive transfer of parasites into WKV-immunized mice has no effect on the development of the malaria parasite in the mosquito, but the adoptive transfer of the serum from the immunized mice into the parasite-inoculated mice remarkably suppresses the development of malaria parasites in mosquitoes. Furthermore, immunized mice challenged with the malaria parasite generate higher levels of parasite-specific Abs and the inflammatory cytokines MCP-1 and IFN-γ. However, the adoptive transfer of parasite-specific IgG or the depletion of MCP-1, but not IFN-γ, to some extent is closely associated with the suppression of malaria parasite development in mosquitoes. These data strongly suggest that WKV-induced immune responses confer protection against the mosquito stage, which is largely dependent on malaria parasite-specific Abs and MCP-1. This finding sheds new light on blocking malaria transmission through the immunization of individuals with the WKV. Copyright © 2016 by The American Association of Immunologists, Inc.

Evidence for a role of regulatory T cells in mediating the atheroprotective effect of apolipoprotein B peptide vaccine.

PubMed

Wigren, M; Kolbus, D; Dunér, P; Ljungcrantz, I; Söderberg, I; Björkbacka, H; Fredrikson, G N; Nilsson, J

2011-05-01

Autoimmune responses against oxidized low-density lipoprotein are considered to play an important pro-inflammatory role in atherosclerosis and to promote disease progression. T-regulatory cells (Tregs) are immunosuppressive cells that have an important part in maintaining self-tolerance and protection against autoimmunity. We investigated whether aBp210, a prototype atherosclerosis vaccine based on a peptide sequence derived from apolipoprotein B, inhibits atherosclerosis through the activation of Tregs. Six-week-old Apoe(-/-) mice were immunized with aBp210 and received booster immunizations 3 and 5 weeks later, as well as 1 week before being killed at 25 weeks of age. At 12 weeks, immunized mice had increased expression of the Treg marker CD25 on circulating CD4 cells, and concanavalin A (Con A)-induced interferon-γ, interleukin (IL)-4, and IL-10 release from splenocytes was markedly depressed. At 25 weeks, there was a fivefold expansion of splenic CD4+ CD25+ Foxp3 Tregs, a 65% decrease in Con A-induced splenic T-cell proliferation and a 37% reduction in the development of atherosclerosis in immunized mice. Administration of blocking antibodies against CD25 neutralized aBp210-induced Treg activation as well as the reduction of atherosclerosis. The present findings demonstrate that immunization of Apoe(-/-) mice with the apolipoprotein B peptide vaccine aBp210 is associated with activation of Tregs. Administration of antibodies against CD25 results in depletion of Tregs and blocking of the atheroprotective effect of the vaccine. Modulation in atherosclerosis-related autoimmunity by antigen-specific activation of Tregs represents a novel approach for treatment of atherosclerosis. © 2010 The Association for the Publication of the Journal of Internal Medicine.

Live Attenuated Vaccine Based on Duck Enteritis Virus against Duck Hepatitis A Virus Types 1 and 3

PubMed Central

Zou, Zhong; Ma, Ji; Huang, Kun; Chen, Huanchun; Liu, Ziduo; Jin, Meilin

2016-01-01

As causative agents of duck viral hepatitis, duck hepatitis A virus type 1 (DHAV-1) and type 3 (DHAV-3) causes significant economic losses in the duck industry. However, a licensed commercial vaccine that simultaneously controls both pathogens is currently unavailable. Here, we generated duck enteritis virus recombinants (rC-KCE-2VP1) containing both VP1 from DHAV-1 (VP1/DHAV-1) and VP1 from DHAV-3 (VP1/DHAV-3) between UL27 and UL26. A self-cleaving 2A-element of FMDV was inserted between the two different types of VP1, allowing production of both proteins from a single open reading frame. Immunofluorescence and Western blot analysis results demonstrated that both VP1 proteins were robustly expressed in rC-KCE-2VP1-infected chicken embryo fibroblasts. Ducks that received a single dose of rC-KCE-2VP1 showed potent humoral and cellular immune responses and were completely protected against challenges of both pathogenic DHAV-1 and DHAV-3 strains. The protection was rapid, achieved as early as 3 days after vaccination. Moreover, viral replication was fully blocked in vaccinated ducks as early as 1 week post-vaccination. These results demonstrated, for the first time, that recombinant rC-KCE-2VP1 is potential fast-acting vaccine against DHAV-1 and DHAV-3. PMID:27777571

Combination of lentivector immunization and low-dose chemotherapy or PD-1/PD-L1 blocking primes self-reactive T cells and induces anti-tumor immunity.

PubMed

Sierro, Sophie R; Donda, Alena; Perret, Rachel; Guillaume, Philippe; Yagita, Hideo; Levy, Frédéric; Romero, Pedro

2011-08-01

In the last two decades, anti-cancer vaccines have yielded disappointing clinical results despite the fact that high numbers of self/tumor-specific T cells can be elicited in immunized patients. Understanding the reasons behind this lack of efficacy is critical in order to design better treatment regimes. Recombinant lentivectors (rLVs) have been successfully used to induce antigen-specific T cells to foreign or mutated tumor antigens. Here, we show that rLV expressing a murine nonmutated self/tumor antigen efficiently primes large numbers of self/tumor-specific CD8(+) T cells. In spite of the large number of tumor-specific T cells, however, no anti-tumor activity could be measured in a therapeutic setting, in mice vaccinated with rLV. Accumulating evidence shows that, in the presence of malignancies, inhibition of T-cell activity may predominate overstimulation. Analysis of tumor-infiltrating lymphocytes revealed that specific anti-tumor CD8(+) T cells fail to produce cytokines and express high levels of inhibitory receptors such as programmed death (PD)-1. Association of active immunization with chemotherapy or antibodies that block inhibitory pathways often leads to better anti-tumor effects. We show here that combining rLV vaccination with either cyclophosphamide or PD-1 and PD-L1 blocking antibodies enhances rLV vaccination efficacy and improves anti-tumor immunity. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Anti-PD-1 inhibits Foxp3+ Treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model.

PubMed

Dyck, Lydia; Wilk, Mieszko M; Raverdeau, Mathilde; Misiak, Alicja; Boon, Louis; Mills, Kingston H G

2016-12-01

The co-inhibitory molecule PD-1 suppresses T cell responses and has been targeted in the treatment of cancer. Here, we examined the role of PD-1 in regulating the balance between regulatory and effector T cells and whether blocking PD-1 could enhance tumour vaccine-induced protective immunity. A significantly higher proportion of tumour-resident T cells expressed PD-1 and Foxp3 compared with T cells in the tumour circulation or draining lymph nodes, and this correlated with a lower frequency of IFN-γ- and TNF-secreting CD8 T cells. Blocking PD-1 with a specific antibody reduced Foxp3 + regulatory T (Treg) cell induction and enhanced proliferation, cytokine production, and tumour killing by CD8 T cells. Treatment of CT26 tumour-bearing mice with anti-PD-1 in combination with a vaccine, comprising heat-shocked irradiated tumour cells and a TLR 7/8 agonist, significantly reduced tumour growth and enhanced survival. Furthermore, surviving mice resisted tumour re-challenge. The rejection of tumours in mice treated with the anti-PD-1 vaccine combination was associated with a reduction in tumour-infiltrating Treg cells and enhancement of IFN-γ-secreting CD8 T cells. Our findings demonstrate that high PD-1 expression correlates with increased tumour-infiltrating Treg cells and reduced effector T cells and that when combined with a potent antigen-adjuvant combination, blocking PD-1 effectively enhances anti-tumour immunity.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Qi, Zhi; Pan, Chungen; Lu, Hong

Research highlights: {yields} One recombinant mimetics of gp41 prehairpin fusion intermediate (PFI) consisting of gp41 N46 sequence, foldon and IgG Fc, designated N46FdFc, was expressed. {yields} N46FdFc-induced antibodies in mice that neutralized HIV-1 infection, inhibited PIE7 binding to PFI, blocked gp41 six-helix bundle formation, and suppressed HIV-1 mediated cell-cell fusion. {yields} These findings provide an important clue for developing recombinant gp41 PFI mimetics-based HIV vaccines. -- Abstract: HIV-1 gp41 prehairpin fusion intermediate (PFI) composed of three N-terminal heptad repeats (NHR) plays a crucial role in viral fusion and entry and represents an attractive target for anti-HIV therapeutics (e.g., enfuvirtide) andmore » vaccines. In present study, we constructed and expressed two recombinant gp41 PFI mimetics, designated N46Fd and N46FdFc. N46Fd consists of N46 (residues 536-581) in gp41 NHR and foldon (Fd), a trimerization motif. N46FdFc is composed of N46Fd fused with human IgG Fc fragment as an immunoenhancer. We immunized mice with N46 peptide, N46Fd and N46FdFc, respectively, and found that only N46FdFc elicited neutralizing antibody response in mice against infection by HIV-1 strains IIIB (clade B, X4), 92US657 (clade B, R5), and 94UG103 (clade A, X4R5). Anti-N46FdFc antibodies inhibited PIE7 binding to PFI, blocked gp41 six-helix bundle formation, and suppressed HIV-1 mediated cell-cell fusion. These findings provide an important clue for developing recombinant gp41 PFI mimetics-based HIV vaccines.« less

Two Case Studies in the Scientific Method: Antisense Experiments and HIV Vaccination Studies.

ERIC Educational Resources Information Center

Guilfoile, Patrick

1999-01-01

Presents two recent cases that can be used in the classroom to illustrate the application of scientific methods in biological research: (1) the use of a complementary RNA or DNA molecule to block the production or translation of an mRNA molecule; and (2) the development of HIV trial vaccines. Contains 20 references. (WRM)

Non-specific sex-differential effect of DTP vaccination may partially explain the excess girl child mortality in Ballabgarh, India.

PubMed

Krishnan, A; Srivastava, R; Dwivedi, P; Ng, N; Byass, P; Pandav, C S

2013-11-01

To test the hypothesis that a gender differential exists in the effect on child mortality of BCG, DTP, measles vaccine as administered under programme conditions in Ballabgarh HDSS area. All live births in 28 villages of Ballabgarh block in North India from 2006 to 2011 were followed until 31 December 2011 or 36 months of age whichever was earlier. The period of analysis was divided into four time periods based on eligibility for vaccines under the national immunisation schedule (BCG for tuberculosis, primary and booster doses of diphtheria-tetanus-pertussis and measles). Cox proportional hazards regression was used to assess the association between sex and risk of mortality by vaccination status using age as the timescale in survival analysis and adjusting for wealth index, access to health care, the presence of a health facility in the village, parental education, type of family, birth order of the child and year of birth. 702 deaths (332 boys and 370 girls) occurred among 12,142 children in the cohort in the 3 years of follow-up giving a cumulative mortality rate of 57.5 per 1000 live births with 35% excess girl child mortality. Age at vaccination for the four vaccines did not differ by sex. There was significant excess mortality among girls after immunisation with DTP, for both primary (HR 1.65; 95% CI:1.17-2.32) and DTPb (2.21; 1.24-3.93) vaccinations. No significant excess morality among girls was noted after exposure to BCG 1.06 (0.67-1.67) or measles 1.34 (0.85-2.12) vaccine. This study supports the contention that DTP vaccination is partially responsible for higher mortality among girls in this study population. © 2013 John Wiley & Sons Ltd.

Fate of Systemically Administered Cocaine in Nonhuman Primates Treated with the dAd5GNE Anticocaine Vaccine

PubMed Central

Hicks, Martin J.; Kaminsky, Stephen M.; De, Bishnu P.; Rosenberg, Jonathan B.; Evans, Suzette M.; Foltin, Richard W.; Andrenyak, David M.; Moody, David E.; Koob, George F.; Janda, Kim D.; Ricart Arbona, Rodolfo J.; Lepherd, Michelle L.

2014-01-01

Abstract Cocaine use disorders are mediated by the cocaine blockade of the dopamine transporter in the central nervous system (CNS). On the basis of the concept that these effects could be obviated if cocaine were prevented from reaching its cognate receptors in the CNS, we have developed an anticocaine vaccine, dAd5GNE, based on a cocaine analog covalently linked to capsid proteins of an E1−E3− serotype 5 adenovirus. While the vaccine effectively blocks systemically administered cocaine from reaching the brain by mediating sequestration of the cocaine in the blood, the fact that cocaine also has significant peripheral effects raises concerns that vaccination-mediated redistribution could lead to adverse effects in the visceral organs. The distribution of systemically administered cocaine at a weight-adjusted typical human dose was evaluated along with cocaine metabolites in both dAd5GNE-vaccinated and control nonhuman primates. dAd5GNE sequestration of cocaine to the blood not only prevented cocaine access to the CNS, but also limited access of both the drug and its metabolites to other cocaine-sensitive organs. The levels of cocaine in the blood of vaccinated animals rapidly decreased, suggesting that while the antibody limits access of the drug and its active metabolites to the brain and sensitive organs of the periphery, it does not prolong drug levels in the blood compartment. Gross and histopathology of major organs found no vaccine-mediated untoward effects. These results build on our earlier measures of efficacy and demonstrate that the dAd5GNE vaccine-mediated redistribution of administered cocaine is not likely to impact the vaccine safety profile. PMID:24649839

Acute Cerebrovascular Radiation Syndrome: Radiation Neurotoxicity , mechanisms of CNS radiation injury, advanced countermeasures for Radiation Protection of Central Nervous System.

NASA Astrophysics Data System (ADS)

Popov, Dmitri; Jones, Jeffrey; Maliev, Slava

Key words: Cerebrovascular Acute Radiation Syndrome (Cv ARS), Radiation Neurotoxins (RNT), Neurotransmitters, Radiation Countermeasures, Antiradiation Vaccine (ArV), Antiradiation Blocking Antibodies, Antiradiation Antidote. Psychoneuroimmunology, Neurotoxicity. ABSTRACT: To review the role of Radiation Neurotoxins in triggering, developing of radiation induced central nervous system injury. Radiation Neurotoxins - rapidly acting blood toxic lethal agent, which activated after irradiation and concentrated, circulated in interstitial fluid, lymph, blood with interactions with cell membranes, receptors and cell compartments. Radiation Neurotoxins - biological molecules with high enzymatic activity and/or specific lipids and activated or modified after irradiation. The Radiation Neurotoxins induce increased permeability of blood vessels, disruption of the blood-brain barrier, blood-cerebrospinal fluid (CSF) barrier and developing severe disorder of blood macro- and micro-circulation. Principles of Radiation Psychoneuro-immunology and Psychoneuro-allergology were applied for determination of pathological processes developed after irradiation or selective administration of Radiation Neurotoxins to radiation naïve mammals. Effects of radiation and exposure to radiation can develop severe irreversible abnormalities of Central Nervous System, brain structures and functions. Antiradiation Vaccine - most effective, advanced methods of protection, prevention, mitigation and treatment and was used for of Acute Radiation Syndromes and elaboration of new technology for immune-prophylaxis and immune-protection against ϒ, Heavy Ion, Neutron irradiation. Results of experiments suggested that blocking, antitoxic, antiradiation antibodies can significantly reduce toxicity of Radiation Toxins. New advanced technology include active immune-prophylaxis with Antiradiation Vaccine and Antiradiation therapy that included specific blocking antibodies to Radiation Neurotoxins. Antiradiation Vaccine and Antiradiation IgG preparations - prospective effective antidote/countermeasure for ϒ-irradiation, heavy ions irradiation, neutron irradiation. Recommendations for treatment and immune-prophylaxis of CNS injury, induced by radiation, were proposed. Specific immune therapy and specific immune prophylaxis reduce symptoms of ACvRS. This manuscript summarizes the results of experiments and considering possibility for blocking toxicological mechanisms of action of Radiation and Radiation Neurotoxins and prevention or diminishing clinical signs of injury of CNS. Experimental data suggest that Antiradiation vaccine and Antiradiation IgG with specific antibodies to Radiation Neurotoxins, Cytotoxins protect CNS against high doses of radiation.

Efficacy and effectiveness of an rVSV-vectored vaccine expressing Ebola surface glycoprotein: interim results from the Guinea ring vaccination cluster-randomised trial.

PubMed

Henao-Restrepo, Ana Maria; Longini, Ira M; Egger, Matthias; Dean, Natalie E; Edmunds, W John; Camacho, Anton; Carroll, Miles W; Doumbia, Moussa; Draguez, Bertrand; Duraffour, Sophie; Enwere, Godwin; Grais, Rebecca; Gunther, Stephan; Hossmann, Stefanie; Kondé, Mandy Kader; Kone, Souleymane; Kuisma, Eeva; Levine, Myron M; Mandal, Sema; Norheim, Gunnstein; Riveros, Ximena; Soumah, Aboubacar; Trelle, Sven; Vicari, Andrea S; Watson, Conall H; Kéïta, Sakoba; Kieny, Marie Paule; Røttingen, John-Arne

2015-08-29

A recombinant, replication-competent vesicular stomatitis virus-based vaccine expressing a surface glycoprotein of Zaire Ebolavirus (rVSV-ZEBOV) is a promising Ebola vaccine candidate. We report the results of an interim analysis of a trial of rVSV-ZEBOV in Guinea, west Africa. For this open-label, cluster-randomised ring vaccination trial, suspected cases of Ebola virus disease in Basse-Guinée (Guinea, west Africa) were independently ascertained by Ebola response teams as part of a national surveillance system. After laboratory confirmation of a new case, clusters of all contacts and contacts of contacts were defined and randomly allocated 1:1 to immediate vaccination or delayed (21 days later) vaccination with rVSV-ZEBOV (one dose of 2 × 10(7) plaque-forming units, administered intramuscularly in the deltoid muscle). Adults (age ≥18 years) who were not pregnant or breastfeeding were eligible for vaccination. Block randomisation was used, with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 vs >20 individuals). The study is open label and masking of participants and field teams to the time of vaccination is not possible, but Ebola response teams and laboratory workers were unaware of allocation to immediate or delayed vaccination. Taking into account the incubation period of the virus of about 10 days, the prespecified primary outcome was laboratory-confirmed Ebola virus disease with onset of symptoms at least 10 days after randomisation. The primary analysis was per protocol and compared the incidence of Ebola virus disease in eligible and vaccinated individuals in immediate vaccination clusters with the incidence in eligible individuals in delayed vaccination clusters. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. Between April 1, 2015, and July 20, 2015, 90 clusters, with a total population of 7651 people were included in the planned interim analysis. 48 of these clusters (4123 people) were randomly assigned to immediate vaccination with rVSV-ZEBOV, and 42 clusters (3528 people) were randomly assigned to delayed vaccination with rVSV-ZEBOV. In the immediate vaccination group, there were no cases of Ebola virus disease with symptom onset at least 10 days after randomisation, whereas in the delayed vaccination group there were 16 cases of Ebola virus disease from seven clusters, showing a vaccine efficacy of 100% (95% CI 74·7-100·0; p=0·0036). No new cases of Ebola virus disease were diagnosed in vaccinees from the immediate or delayed groups from 6 days post-vaccination. At the cluster level, with the inclusion of all eligible adults, vaccine effectiveness was 75·1% (95% CI -7·1 to 94·2; p=0·1791), and 76·3% (95% CI -15·5 to 95·1; p=0·3351) with the inclusion of everyone (eligible or not eligible for vaccination). 43 serious adverse events were reported; one serious adverse event was judged to be causally related to vaccination (a febrile episode in a vaccinated participant, which resolved without sequelae). Assessment of serious adverse events is ongoing. The results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy. WHO, with support from the Wellcome Trust (UK); Médecins Sans Frontières; the Norwegian Ministry of Foreign Affairs through the Research Council of Norway; and the Canadian Government through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre, and Department of Foreign Affairs, Trade and Development. Copyright © 2015 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.

Malaria vaccines and the new malaria agenda.

PubMed

Greenwood, B M; Targett, G A T

2011-11-01

The development of an effective malaria vaccine has taken many decades, but there is now a good chance that the first malaria vaccine will be licensed within the next few years. However, this vaccine (RTS,S) will not be fully effective, and more efficacious, second-generation vaccines will be needed. Good progress is being made in the development of potential vaccines directed at each of the three main stages of the parasite's life cycle, with a variety of different approaches, but many challenges remain, e.g. overcoming the problem of polymorphism in many key parasite antigens. It is likely vaccines that are effective enough to block transmission, and thus contribute to increasing drives towards malaria elimination, will need to contain antigens from different stages of the parasite's life cycle. © 2011 The Authors. Clinical Microbiology and Infection © 2011 European Society of Clinical Microbiology and Infectious Diseases.

pcDNA-IL-12 vaccination blocks eosinophilic inflammation but not airway hyperresponsiveness following murine Toxocara canis infection.

PubMed

Malheiro, Adriana; Aníbal, Fernanda F; Martins-Filho, Olindo Assis; Teixeira-Carvalho, Andréa; Perini, Adenir; Martins, Milton A; Medeiros, Alexandra I; Turato, Walter M; Acencio, Milene P M; Brandão, Izaíra T; Nomizo, Auro; Silva, Célio L; Faccioli, Lúcia H

2008-01-17

We have investigated the effect of pcDNA3-CpG and pcDNA-IL-12, delivered by intradermal gene gun administration, on the blood/lung eosinophilia, airway hyperresponsiveness as well as the immune response in a murine model of toxocariasis. Our results demonstrated that pcDNA-IL-12 but not pcDNA3-CpG vaccination led to a persistent lower blood/bronchoalveolar eosinophilia following Toxocara canis infection, as pcDNA3-CpG led only to an early transient blockage of eosinophil transmigration into bronchoalveolar fluid following T. canis infection. Prominent Type-1 immune response was pointed out as the hallmark of T. canis infection following pcDNA-IL-12 vaccination. Outstanding IFN-gamma/IL-4 ratio besides low levels of IgG1 with subsequent high IgG2a/IgG1 ratio further characterized a Type-1 polarized immunological profile in pcDNA-IL-12-vaccinated animals. Nevertheless, only pcDNA3-CpG was able to prevent airway hyperresponsiveness induced by T. canis infection. The persistent airway hyperresponsiveness observed in pcDNA-IL-12-vaccinated animals demonstrated that the airway constriction involved other immunological mediator than those blocked by pcDNA-IL-12. Together, these data indicated that pcDNA-IL-12 and pcDNA3-CpG vaccines have distinct therapeutic benefits regarding the eosinophilic inflammation/airway hyperresponsiveness triggered by T. canis infection, suggesting their possible use in further combined therapeutic interventions.

Hereditary Hemochromatosis Restores the Virulence of Plague Vaccine Strains

PubMed Central

Quenee, Lauriane E.; Hermanas, Timothy M.; Ciletti, Nancy; Louvel, Helene; Miller, Nathan C.; Elli, Derek; Blaylock, Bill; Mitchell, Anthony; Schroeder, Jay; Krausz, Thomas; Kanabrocki, Joseph; Schneewind, Olaf

2012-01-01

Nonpigmented Yersinia pestis (pgm) strains are defective in scavenging host iron and have been used in live-attenuated vaccines to combat plague epidemics. Recently, a Y. pestis pgm strain was isolated from a researcher with hereditary hemochromatosis who died from laboratory-acquired plague. We used hemojuvelin-knockout (Hjv−/−) mice to examine whether iron-storage disease restores the virulence defects of nonpigmented Y. pestis. Unlike wild-type mice, Hjv−/− mice developed lethal plague when challenged with Y. pestis pgm strains. Immunization of Hjv−/− mice with a subunit vaccine that blocks Y. pestis type III secretion generated protection against plague. Thus, individuals with hereditary hemochromatosis may be protected with subunit vaccines but should not be exposed to live-attenuated plague vaccines. PMID:22896664

Structurally designed attenuated subunit vaccines for S. aureus LukS-PV and LukF-PV confer protection in a mouse bacteremia model.

PubMed

Karauzum, Hatice; Adhikari, Rajan P; Sarwar, Jawad; Devi, V Sathya; Abaandou, Laura; Haudenschild, Christian; Mahmoudieh, Mahta; Boroun, Atefeh R; Vu, Hong; Nguyen, Tam; Warfield, Kelly L; Shulenin, Sergey; Aman, M Javad

2013-01-01

Previous efforts towards S. aureus vaccine development have largely focused on cell surface antigens to induce opsonophagocytic killing aimed at providing sterile immunity, a concept successfully applied to other Gram-positive pathogens such as Streptococcus pneumoniae. However, these approaches have largely failed, possibly in part due to the remarkable diversity of the staphylococcal virulence factors such as secreted immunosuppressive and tissue destructive toxins. S. aureus produces several pore-forming toxins including the single subunit alpha hemolysin as well as bicomponent leukotoxins such as Panton-Valentine leukocidin (PVL), gamma hemolysins (Hlg), and LukED. Here we report the generation of highly attenuated mutants of PVL subunits LukS-PV and LukF-PV that were rationally designed, based on an octameric structural model of the toxin, to be deficient in oligomerization. The attenuated subunit vaccines were highly immunogenic and showed significant protection in a mouse model of S. aureus USA300 sepsis. Protection against sepsis was also demonstrated by passive transfer of rabbit immunoglobulin raised against LukS-PV. Antibodies to LukS-PV inhibited the homologous oligomerization of LukS-PV with LukF-PV as well heterologous oligomerization with HlgB. Importantly, immune sera from mice vaccinated with the LukS mutant not only inhibited the PMN lytic activity produced by the PVL-positive USA300 but also blocked PMN lysis induced by supernatants of PVL-negative strains suggesting a broad protective activity towards other bicomponent toxins. These findings strongly support the novel concept of an anti-virulence, toxin-based vaccine intended for prevention of clinical S. aureus invasive disease, rather than achieving sterile immunity. Such a multivalent vaccine may include attenuated leukotoxins, alpha hemolysin, and superantigens.

Sieve analysis of breakthrough HIV-1 sequences in HVTN 505 identifies vaccine pressure targeting the CD4 binding site of Env-gp120.

PubMed

deCamp, Allan C; Rolland, Morgane; Edlefsen, Paul T; Sanders-Buell, Eric; Hall, Breana; Magaret, Craig A; Fiore-Gartland, Andrew J; Juraska, Michal; Carpp, Lindsay N; Karuna, Shelly T; Bose, Meera; LePore, Steven; Miller, Shana; O'Sullivan, Annemarie; Poltavee, Kultida; Bai, Hongjun; Dommaraju, Kalpana; Zhao, Hong; Wong, Kim; Chen, Lennie; Ahmed, Hasan; Goodman, Derrick; Tay, Matthew Z; Gottardo, Raphael; Koup, Richard A; Bailer, Robert; Mascola, John R; Graham, Barney S; Roederer, Mario; O'Connell, Robert J; Michael, Nelson L; Robb, Merlin L; Adams, Elizabeth; D'Souza, Patricia; Kublin, James; Corey, Lawrence; Geraghty, Daniel E; Frahm, Nicole; Tomaras, Georgia D; McElrath, M Juliana; Frenkel, Lisa; Styrchak, Sheila; Tovanabutra, Sodsai; Sobieszczyk, Magdalena E; Hammer, Scott M; Kim, Jerome H; Mullins, James I; Gilbert, Peter B

2017-01-01

Although the HVTN 505 DNA/recombinant adenovirus type 5 vector HIV-1 vaccine trial showed no overall efficacy, analysis of breakthrough HIV-1 sequences in participants can help determine whether vaccine-induced immune responses impacted viruses that caused infection. We analyzed 480 HIV-1 genomes sampled from 27 vaccine and 20 placebo recipients and found that intra-host HIV-1 diversity was significantly lower in vaccine recipients (P ≤ 0.04, Q-values ≤ 0.09) in Gag, Pol, Vif and envelope glycoprotein gp120 (Env-gp120). Furthermore, Env-gp120 sequences from vaccine recipients were significantly more distant from the subtype B vaccine insert than sequences from placebo recipients (P = 0.01, Q-value = 0.12). These vaccine effects were associated with signatures mapping to CD4 binding site and CD4-induced monoclonal antibody footprints. These results suggest either (i) no vaccine efficacy to block acquisition of any viral genotype but vaccine-accelerated Env evolution post-acquisition; or (ii) vaccine efficacy against HIV-1s with Env sequences closest to the vaccine insert combined with increased acquisition due to other factors, potentially including the vaccine vector.

Sieve analysis of breakthrough HIV-1 sequences in HVTN 505 identifies vaccine pressure targeting the CD4 binding site of Env-gp120

PubMed Central

Edlefsen, Paul T.; Sanders-Buell, Eric; Hall, Breana; Magaret, Craig A.; Fiore-Gartland, Andrew J.; Juraska, Michal; Carpp, Lindsay N.; Karuna, Shelly T.; Bose, Meera; LePore, Steven; Miller, Shana; O'Sullivan, Annemarie; Poltavee, Kultida; Bai, Hongjun; Dommaraju, Kalpana; Zhao, Hong; Wong, Kim; Chen, Lennie; Ahmed, Hasan; Goodman, Derrick; Tay, Matthew Z.; Gottardo, Raphael; Koup, Richard A.; Bailer, Robert; Mascola, John R.; Graham, Barney S.; Roederer, Mario; O’Connell, Robert J.; Michael, Nelson L.; Robb, Merlin L.; Adams, Elizabeth; D’Souza, Patricia; Kublin, James; Corey, Lawrence; Geraghty, Daniel E.; Frahm, Nicole; Tomaras, Georgia D.; McElrath, M. Juliana; Frenkel, Lisa; Styrchak, Sheila; Tovanabutra, Sodsai; Sobieszczyk, Magdalena E.; Hammer, Scott M.; Kim, Jerome H.; Mullins, James I.; Gilbert, Peter B.

2017-01-01

Although the HVTN 505 DNA/recombinant adenovirus type 5 vector HIV-1 vaccine trial showed no overall efficacy, analysis of breakthrough HIV-1 sequences in participants can help determine whether vaccine-induced immune responses impacted viruses that caused infection. We analyzed 480 HIV-1 genomes sampled from 27 vaccine and 20 placebo recipients and found that intra-host HIV-1 diversity was significantly lower in vaccine recipients (P ≤ 0.04, Q-values ≤ 0.09) in Gag, Pol, Vif and envelope glycoprotein gp120 (Env-gp120). Furthermore, Env-gp120 sequences from vaccine recipients were significantly more distant from the subtype B vaccine insert than sequences from placebo recipients (P = 0.01, Q-value = 0.12). These vaccine effects were associated with signatures mapping to CD4 binding site and CD4-induced monoclonal antibody footprints. These results suggest either (i) no vaccine efficacy to block acquisition of any viral genotype but vaccine-accelerated Env evolution post-acquisition; or (ii) vaccine efficacy against HIV-1s with Env sequences closest to the vaccine insert combined with increased acquisition due to other factors, potentially including the vaccine vector. PMID:29149197

Development of a therapeutic vaccine for the treatment of cocaine addiction.

PubMed

Fox, B S

1997-12-15

No pharmacotherapies have yet been approved for the treatment of cocaine addiction. One new approach is to block the effects of cocaine with anti-cocaine antibodies induced by a therapeutic cocaine vaccine. A cocaine vaccine has been developed which induces a cocaine-specific antibody response in rodents. The antibody binds to cocaine in the circulation and can be shown to inhibit the ability of cocaine to enter the brain. Furthermore, anti-cocaine antibody can inhibit cocaine self-administration in rats. These data suggest that a cocaine vaccine may be a powerful therapeutic tool. The intent is to immunized motivated patients with the vaccine as part of a comprehensive treatment program. If the patient uses cocaine after being vaccinated, the antibody will inhibit the reinforcing activity of cocaine and decrease the likelihood of relapse.

Cytomegalovirus vector expressing RAE-1γ induces enhanced anti-tumor capacity of murine CD8+ T cells.

PubMed

Tršan, Tihana; Vuković, Kristina; Filipović, Petra; Brizić, Ana Lesac; Lemmermann, Niels A W; Schober, Kilian; Busch, Dirk H; Britt, William J; Messerle, Martin; Krmpotić, Astrid; Jonjić, Stipan

2017-08-01

Designing CD8 + T-cell vaccines, which would provide protection against tumors is still considered a great challenge in immunotherapy. Here we show the robust potential of cytomegalovirus (CMV) vector expressing the NKG2D ligand RAE-1γ as CD8 + T cell-based vaccine against malignant tumors. Immunization with the CMV vector expressing RAE-1γ, delayed tumor growth or even provided complete protection against tumor challenge in both prophylactic and therapeutic settings. Moreover, a potent tumor control in mice vaccinated with this vector can be further enhanced by blocking the immune checkpoints TIGIT and PD-1. CMV vector expressing RAE-1γ potentiated expansion of KLRG1 + CD8 + T cells with enhanced effector properties. This vaccination was even more efficient in neonatal mice, resulting in the expansion and long-term maintenance of epitope-specific CD8 + T cells conferring robust resistance against tumor challenge. Our data show that immunomodulation of CD8 + T-cell responses promoted by herpesvirus expressing a ligand for NKG2D receptor can provide a powerful platform for the prevention and treatment of CD8 + T-cell sensitive tumors. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Steady progress toward a malaria vaccine.

PubMed

Lyke, Kirsten E

2017-10-01

Great progress has been made in reducing malaria morbidity and mortality, yet the parasite continues to cause a startling 200 million infections and 500 000 deaths annually. Malaria vaccine development is pushing new boundaries by steady advancement toward a licensed product. Despite 50 years of research, the complexity of Plasmoidum falciparum confounds all attempts to eradicate the organism. This very complexity has pushed the boundaries of vaccine development to new heights, yet it remains to be seen if an affordable vaccine can provide durable and high-level protection. Novel vaccines such as RTS,S/AS01E are on the edge of licensure, but old techniques have resurged with the ability to deliver vialed, whole organism vaccines. Novel adjuvants, multistage/multiantigen approaches and transmission blocking vaccines all contribute to a multipronged battle plan to conquer malaria. Vaccines are the most cost-effective tools to control infectious diseases, yet the complexity of malaria has frustrated all attempts to develop an effective product. This review concentrates on recent advances in malaria vaccine development that lend hope that a vaccine can be produced and malaria eradicated.

An HSV-2 Trivalent Vaccine Is Immunogenic in Rhesus Macaques and Highly Efficacious in Guinea Pigs.

PubMed

Awasthi, Sita; Hook, Lauren M; Shaw, Carolyn E; Pahar, Bapi; Stagray, Jacob A; Liu, David; Veazey, Ronald S; Friedman, Harvey M

2017-01-01

A genital herpes vaccine is urgently needed to prevent pain and suffering, reduce the incidence of neonatal herpes, and decrease the risk of HIV acquisition and transmission that accompanies genital infection. We evaluated a trivalent HSV-2 subunit antigen vaccine administered with CpG and alum in rhesus macaques and guinea pigs. The vaccine contains glycoproteins C, D and E (gC2, gD2, gE2) to block virus entry by gD2 and immune evasion by gC2 and gE2. In rhesus macaques, the trivalent vaccine induced plasma and mucosa neutralizing antibodies, antibodies that block gC2 and gE2 immune evasion activities, and stimulated CD4 T cell responses. After intravaginal challenge, a self-limited vaginal infection of brief duration was detected by histopathology and immunohistochemistry in naïve, but not in trivalent immunized macaques. Vaccine efficacy was evaluated in female guinea pigs. Animals were mock immunized, or immunized with gD2, the trivalent vaccine or the trivalent vaccine followed by a booster dose of gD2 (trivalent + gD2). The trivalent and trivalent + gD2 groups were 97% and 99% efficacious, respectively in preventing genital lesions and both outperformed gD2 alone. As a marker of transmission risk, vaginal swabs were evaluated daily for HSV-2 DNA and replication competent virus between five and seven weeks after challenge. HSV-2 DNA shedding was reduced in all groups compared with mock. Shedding of replication competent virus occurred on fewer days in the trivalent than gD2 immunized animals while the trivalent + gD2 group had no shedding of replication competent virus. Overall, the trivalent group had genital lesions on < 1% days and shedding of replication competent virus on 0.2% days. The vaccine has outstanding potential for prevention of genital herpes in humans.

Steps toward a globally available malaria vaccine: harnessing the potential of algae for future low cost vaccines.

PubMed

Jones, Carla S; Mayfield, Stephen P

2013-01-01

Malaria is an infectious disease that threatens half of the world's population. This debilitating disease is caused by infection from parasites of the genus Plasmodium. Insecticides, bed nets and drug therapies have lowered the prevalence and death rate associated with malaria but this disease continues to plague many populations around the world. In recent years, many organizations have suggested developing methods for a complete eradication of malaria. The most straightforward and effective method for this potential eradication will be through the development of a low-cost vaccine. To achieve eradication, it will be necessary to develop new vaccine candidates and novel systems for both the production and delivery of these vaccines. Recently, the green algae Chlamydomonas reinhardtii has been used for the recombinant expression of malaria vaccine candidates including the transmission blocking vaccine candidate Pfs48/45. Here, we discuss the potential of this research on the future development of a low-cost malaria vaccine candidate.

Adenovirus-Based Vaccines against Rhesus Lymphocryptovirus EBNA-1 Induce Expansion of Specific CD8+ and CD4+ T Cells in Persistently Infected Rhesus Macaques

PubMed Central

Leskowitz, R.; Fogg, M. H.; Zhou, X. Y.; Kaur, A.; Silveira, E. L. V.; Villinger, F.; Lieberman, P. M.; Wang, F.

2014-01-01

ABSTRACT The impact of Epstein-Barr virus (EBV) on human health is substantial, but vaccines that prevent primary EBV infections or treat EBV-associated diseases are not yet available. The Epstein-Barr nuclear antigen 1 (EBNA-1) is an important target for vaccination because it is the only protein expressed in all EBV-associated malignancies. We have designed and tested two therapeutic EBV vaccines that target the rhesus (rh) lymphocryptovirus (LCV) EBNA-1 to determine if ongoing T cell responses during persistent rhLCV infection in rhesus macaques can be expanded upon vaccination. Vaccines were based on two serotypes of E1-deleted simian adenovirus and were administered in a prime-boost regimen. To further modulate the response, rhEBNA-1 was fused to herpes simplex virus glycoprotein D (HSV-gD), which acts to block an inhibitory signaling pathway during T cell activation. We found that vaccines expressing rhEBNA-1 with or without functional HSV-gD led to expansion of rhEBNA-1-specific CD8+ and CD4+ T cells in 33% and 83% of the vaccinated animals, respectively. Additional animals developed significant changes within T cell subsets without changes in total numbers. Vaccination did not increase T cell responses to rhBZLF-1, an immediate early lytic phase antigen of rhLCV, thus indicating that increases of rhEBNA-1-specific responses were a direct result of vaccination. Vaccine-induced rhEBNA-1-specific T cells were highly functional and produced various combinations of cytokines as well as the cytolytic molecule granzyme B. These results serve as an important proof of principle that functional EBNA-1-specific T cells can be expanded by vaccination. IMPORTANCE EBV is a common human pathogen that establishes a persistent infection through latency in B cells, where it occasionally reactivates. EBV infection is typically benign and is well controlled by the host adaptive immune system; however, it is considered carcinogenic due to its strong association with lymphoid and epithelial cell malignancies. Latent EBNA-1 is a promising target for a therapeutic vaccine, as it is the only antigen expressed in all EBV-associated malignancies. The goal was to determine if rhEBNA-1-specific T cells could be expanded upon vaccination of infected animals. Results were obtained with vaccines that target EBNA-1 of rhLCV, a virus closely related to EBV. We found that vaccination led to expansion of rhEBNA-1 immune cells that exhibited functions fit for controlling viral infection. This confirms that rhEBNA-1 is a suitable target for therapeutic vaccines. Future work should aim to generate more-robust T cell responses through modified vaccines. PMID:24522914

The design of a capsule polysaccharide conjugate vaccine against Campylobacter jejuni serotype HS15.

PubMed

Bertolo, Lisa; Ewing, Cheryl P; Maue, Alexander; Poly, Frederic; Guerry, Patricia; Monteiro, Mario A

2013-01-25

Campylobacter jejuni infection is now the main cause of diarrhea-related illnesses in humans. An efficacious vaccine for the traveler and developing world market would be welcomed. We are engaged in the discovery and characterization of serotype-specific C. jejuni capsule polysaccharides (CPSs) to study their role in virulence and as protective vaccine antigens. Our prototype conjugate vaccine with serotype HS23 CPS (strain 81-176) has been shown to fully protect non-human primates against diarrhea inflicted by C. jejuni HS23, but ultimately, a useful CPS-based vaccine will have to be multivalent. To this end, we describe here the creation of a CPS-conjugate vaccine against C. jejuni serotype HS15. Structural analysis revealed that a repeating block consisting of L-α-arabinofuranose (Ara) and 6-deoxy-L-α-gulo-heptopyranose (6d-gulo-Hep) comprised the CPS of serotype HS15 type strain ATCC 43442 [→3)-α-L-Araf-(1→3)-6d-L-α-gulo-Hepp(1→](n). Strategically, the non-reducing end of the CPS was activated and used in the attachment of CPS to CRM₁₉₇ to yield a conjugate vaccine. A serological assessment of the CPS(HS15)-CRM₁₉₇ conjugate with an anti-HS15 polyclonal antibody confirmed the conservation of antigenic epitopes, and subsequent inoculation of mice with CPS(HS15)-CRM₁₉₇ revealed that this conjugate was indeed capable of raising anti-CPS(HS15) antibodies. Copyright © 2012 Elsevier Ltd. All rights reserved.

Vaccination of rhesus macaques with the anthrax vaccine adsorbed vaccine produces a serum antibody response that effectively neutralizes receptor-bound protective antigen in vitro.

PubMed

Clement, Kristin H; Rudge, Thomas L; Mayfield, Heather J; Carlton, Lena A; Hester, Arelis; Niemuth, Nancy A; Sabourin, Carol L; Brys, April M; Quinn, Conrad P

2010-11-01

Anthrax toxin (ATx) is composed of the binary exotoxins lethal toxin (LTx) and edema toxin (ETx). They have separate effector proteins (edema factor and lethal factor) but have the same binding protein, protective antigen (PA). PA is the primary immunogen in the current licensed vaccine anthrax vaccine adsorbed (AVA [BioThrax]). AVA confers protective immunity by stimulating production of ATx-neutralizing antibodies, which could block the intoxication process at several steps (binding of PA to the target cell surface, furin cleavage, toxin complex formation, and binding/translocation of ATx into the cell). To evaluate ATx neutralization by anti-AVA antibodies, we developed two low-temperature LTx neutralization activity (TNA) assays that distinguish antibody blocking before and after binding of PA to target cells (noncomplexed [NC] and receptor-bound [RB] TNA assays). These assays were used to investigate anti-PA antibody responses in AVA-vaccinated rhesus macaques (Macaca mulatta) that survived an aerosol challenge with Bacillus anthracis Ames spores. Results showed that macaque anti-AVA sera neutralized LTx in vitro, even when PA was prebound to cells. Neutralization titers in surviving versus nonsurviving animals and between prechallenge and postchallenge activities were highly correlated. These data demonstrate that AVA stimulates a myriad of antibodies that recognize multiple neutralizing epitopes and confirm that change, loss, or occlusion of epitopes after PA is processed from PA83 to PA63 at the cell surface does not significantly affect in vitro neutralizing efficacy. Furthermore, these data support the idea that the full-length PA83 monomer is an appropriate immunogen for inclusion in next-generation anthrax vaccines.

Alga-Produced Cholera Toxin-Pfs25 Fusion Proteins as Oral Vaccines

PubMed Central

Gregory, James A.; Topol, Aaron B.; Doerner, David Z.

2013-01-01

Infectious diseases disproportionately affect indigent regions and are the greatest cause of childhood mortality in developing countries. Practical, low-cost vaccines for use in these countries are paramount to reducing disease burdens and concomitant poverty. Algae are a promising low-cost system for producing vaccines that can be orally delivered, thereby avoiding expensive purification and injectable delivery. We engineered the chloroplast of the eukaryotic alga Chlamydomonas reinhardtii to produce a chimeric protein consisting of the 25-kDa Plasmodium falciparum surface protein (Pfs25) fused to the β subunit of the cholera toxin (CtxB) to investigate an alga-based whole-cell oral vaccine. Pfs25 is a promising malaria transmission-blocking vaccine candidate that has been difficult to produce in traditional recombinant systems due to its structurally complex tandem repeats of epidermal growth factor-like domains. The noncatalytic CtxB domain of the cholera holotoxin assembles into a pentameric structure and acts as a mucosal adjuvant by binding GM1 ganglioside receptors on gut epithelial cells. We demonstrate that CtxB-Pfs25 accumulates as a soluble, properly folded and functional protein within algal chloroplasts, and it is stable in freeze-dried alga cells at ambient temperatures. In mice, oral vaccination using freeze-dried algae that produce CtxB-Pfs25 elicited CtxB-specific serum IgG antibodies and both CtxB- and Pfs25-specific secretory IgA antibodies. These data suggest that algae are a promising system for production and oral delivery of vaccine antigens, but as an orally delivered adjuvant, CtxB is best suited for eliciting secretory IgA antibodies for vaccine antigens against pathogens that invade mucosal surfaces using this strategy. PMID:23603678

Unique IL-13Rα2-based HIV-1 vaccine strategy to enhance mucosal immunity, CD8(+) T-cell avidity and protective immunity.

PubMed

Ranasinghe, C; Trivedi, S; Stambas, J; Jackson, R J

2013-11-01

We have established that mucosal immunization can generate high-avidity human immunodeficiency virus (HIV)-specific CD8(+) T cells compared with systemic immunization, and interleukin (IL)-13 is detrimental to the functional avidity of these T cells. We have now constructed two unique recombinant HIV-1 vaccines that co-express soluble or membrane-bound forms of the IL-13 receptor α2 (IL-13Rα2), which can "transiently" block IL-13 activity at the vaccination site causing wild-type animals to behave similar to an IL-13 KO animal. Following intranasal/intramuscular prime-boost immunization, these IL-13Rα2-adjuvanted vaccines have shown to induce (i) enhanced HIV-specific CD8(+) T cells with higher functional avidity, with broader cytokine/chemokine profiles and greater protective immunity using a surrogate mucosal HIV-1 challenge, and also (ii) excellent multifunctional mucosal CD8(+) T-cell responses, in the lung, genito-rectal nodes (GN), and Peyer's patch (PP). Data revealed that intranasal delivery of these IL-13Rα2-adjuvanted HIV vaccines recruited large numbers of unique antigen-presenting cell subsets to the lung mucosae, ultimately promoting the induction of high-avidity CD8(+) T cells. We believe our novel IL-13R cytokine trap vaccine strategy offers great promise for not only HIV-1, but also as a platform technology against range of chronic infections that require strong sustained high-avidity mucosal/systemic immunity for protection.

Tumor-derived vaccines containing CD200 inhibit immune activation: implications for immunotherapy.

PubMed

Xiong, Zhengming; Ampudia-Mesias, Elisabet; Shaver, Rob; Horbinski, Craig M; Moertel, Christopher L; Olin, Michael R

2016-09-01

There are over 400 ongoing clinical trials using tumor-derived vaccines. This approach is especially attractive for many types of brain tumors, including glioblastoma, yet so far the clinical response is highly variable. One contributor to poor response is CD200, which acts as a checkpoint blockade, inducing immune tolerance. We demonstrate that, in response to vaccination, glioma-derived CD200 suppresses the anti-tumor immune response. In contrast, a CD200 peptide inhibitor that activates antigen-presenting cells overcomes immune tolerance. The addition of the CD200 inhibitor significantly increased leukocyte infiltration into the vaccine site, cytokine and chemokine production, and cytolytic activity. Our data therefore suggest that CD200 suppresses the immune system's response to vaccines, and that blocking CD200 could improve the efficacy of cancer immunotherapy.

A Research Agenda for Malaria Eradication: Vaccines

PubMed Central

2011-01-01

Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of “vaccines that interrupt malaria transmission” (VIMT), which includes not only “classical” transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented. PMID:21311586

A research agenda for malaria eradication: vaccines.

PubMed

2011-01-25

Vaccines could be a crucial component of efforts to eradicate malaria. Current attempts to develop malaria vaccines are primarily focused on Plasmodium falciparum and are directed towards reducing morbidity and mortality. Continued support for these efforts is essential, but if malaria vaccines are to be used as part of a repertoire of tools for elimination or eradication of malaria, they will need to have an impact on malaria transmission. We introduce the concept of "vaccines that interrupt malaria transmission" (VIMT), which includes not only "classical" transmission-blocking vaccines that target the sexual and mosquito stages but also pre-erythrocytic and asexual stage vaccines that have an effect on transmission. VIMT may also include vaccines that target the vector to disrupt parasite development in the mosquito. Importantly, if eradication is to be achieved, malaria vaccine development efforts will need to target other malaria parasite species, especially Plasmodium vivax, where novel therapeutic vaccines against hypnozoites or preventive vaccines with effect against multiple stages could have enormous impact. A target product profile (TPP) for VIMT is proposed and a research agenda to address current knowledge gaps and develop tools necessary for design and development of VIMT is presented.

Vaccines against malaria.

PubMed

Ouattara, Amed; Laurens, Matthew B

2015-03-15

Despite global efforts to control malaria, the illness remains a significant public health threat. Currently, there is no licensed vaccine against malaria, but an efficacious vaccine would represent an important public health tool for successful malaria elimination. Malaria vaccine development continues to be hindered by a poor understanding of antimalarial immunity, a lack of an immune correlate of protection, and the genetic diversity of malaria parasites. Current vaccine development efforts largely target Plasmodium falciparum parasites in the pre-erythrocytic and erythrocytic stages, with some research on transmission-blocking vaccines against asexual stages and vaccines against pregnancy-associated malaria. The leading pre-erythrocytic vaccine candidate is RTS,S, and early results of ongoing Phase 3 testing show overall efficacy of 46% against clinical malaria. The next steps for malaria vaccine development will focus on the design of a product that is efficacious against the highly diverse strains of malaria and the identification of a correlate of protection against disease. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Mimicking acute and chronic stress exposure in naive beef steers alters the acute phase response (APR) associated with vaccination

USDA-ARS?s Scientific Manuscript database

This study was designed to determine the effect of an acute versus chronic stress model on the APR associated with vaccination in naïve beef steers. Steers (n=32; 209 +/- 8 kg) were blocked by body weight and assigned to 1 of 3 treatments: 1) Chronic stress (CHR), 0.5 mg/kg body weight dexamethasone...

A polyvalent hybrid protein elicits antibodies against the diverse allelic types of block 2 in Plasmodium falciparum merozoite surface protein 1.

PubMed

Tetteh, Kevin K A; Conway, David J

2011-10-13

Merozoite surface protein 1 (MSP1) of Plasmodium falciparum has been implicated as an important target of acquired immunity, and candidate components for a vaccine include polymorphic epitopes in the N-terminal polymorphic block 2 region. We designed a polyvalent hybrid recombinant protein incorporating sequences of the three major allelic types of block 2 together with a composite repeat sequence of one of the types and N-terminal flanking T cell epitopes, and compared this with a series of recombinant proteins containing modular sub-components and similarly expressed in Escherichia coli. Immunogenicity of the full polyvalent hybrid protein was tested in both mice and rabbits, and comparative immunogenicity studies of the sub-component modules were performed in mice. The full hybrid protein induced high titre antibodies against each of the major block 2 allelic types expressed as separate recombinant proteins and against a wide range of allelic types naturally expressed by a panel of diverse P. falciparum isolates, while the sub-component modules had partial antigenic coverage as expected. This encourages further development and evaluation of the full MSP1 block 2 polyvalent hybrid protein as a candidate blood-stage component of a malaria vaccine. Copyright © 2011 Elsevier Ltd. All rights reserved.

A DNA vaccine targeting angiomotin inhibits angiogenesis and suppresses tumor growth

NASA Astrophysics Data System (ADS)

Holmgren, Lars; Ambrosino, Elena; Birot, Olivier; Tullus, Carl; Veitonmäki, Niina; Levchenko, Tetyana; Carlson, Lena-Maria; Musiani, Piero; Iezzi, Manuela; Curcio, Claudia; Forni, Guido; Cavallo, Federica; Kiessling, Rolf

2006-06-01

Endogenous angiogenesis inhibitors have shown promise in preclinical trials, but clinical use has been hindered by low half-life in circulation and high production costs. Here, we describe a strategy that targets the angiostatin receptor angiomotin (Amot) by DNA vaccination. The vaccination procedure generated antibodies that detected Amot on the endothelial cell surface. Purified Ig bound to the endothelial cell membrane and inhibited endothelial cell migration. In vivo, DNA vaccination blocked angiogenesis in the matrigel plug assay and prevented growth of transplanted tumors for up to 150 days. We further demonstrate that a combination of DNA vaccines encoding Amot and the extracellular and transmembrane domains of the human EGF receptor 2 (Her-2)/neu oncogene inhibited breast cancer progression and impaired tumor vascularization in Her-2/neu transgenic mice. No toxicity or impairment of normal blood vessels could be detected. This work shows that DNA vaccination targeting Amot may be used to mimic the effect of angiostatin. cancer vaccines | neoplasia | neovascularization | breast cancer | angiostatin

Ethical issues in using a cocaine vaccine to treat and prevent cocaine abuse and dependence.

PubMed

Hall, W; Carter, L

2004-08-01

A "cocaine vaccine" is a promising immunotherapeutic approach to treating cocaine dependence which induces the immune system to form antibodies that prevent cocaine from crossing the blood brain barrier to act on receptor sites in the brain. Studies in rats show that cocaine antibodies block cocaine from reaching the brain and prevent the reinstatement of cocaine self administration. A successful phase 1 trial of a human cocaine vaccine has been reported. The most promising application of a cocaine vaccine is to prevent relapse to dependence in abstinent users who voluntarily enter treatment. Any use of a vaccine to treat cocaine addicts under legal coercion raises major ethical issues. If this is done at all, it should be carefully trialled first, and only after considerable clinical experience has been obtained in using the vaccine to treat voluntary patients. There will need to be an informed community debate about what role, if any, a cocaine vaccine may have as a way of preventing cocaine addiction in children and adolescents.

Economic and practical challenges to the formulation of vaccines against endemic infectious diseases such as malaria.

PubMed

Plebanski, Magdalena; Lopez, Ester; Proudfoot, Owen; Cooke, Brian M; Itzstein, Mark von; Coppel, Ross L

2006-09-01

Herein, we analyze in general the current vaccine market and identify potential factors driving and modulating supply and demand for vaccines. An emphasis is placed on changes in regulation in the last 20 years which have led to increased indirect costs of production, and which can create a barrier against the timely use of technological advances to reduce direct costs. Other defining industry characteristics, such as firm numbers and sizes, cost and pricing strategies, nature extent and impact of Government involvement and international regulation are noted. These considerations, far from being removed from basic vaccine research, influence its ability to achieve aims that can be then progressed into effective vaccine products. We discuss specifically the development of particulate vaccines against malaria, a major lethal disease and health problem prevalent in Africa, including some key economic and methodological challenges and opportunities. We note some practical issues blocking the development of effective particulate vaccines for the Third World, mainly driven by the regulatory spiral noted above.

Factors affecting vaccine handling and storage practices among immunization service providers in Ibadan, Oyo State, Nigeria.

PubMed

Dairo, David M; Osizimete, Oyarebu E

2016-06-01

Improper handling has been identified as one of the major reasons for the decline in vaccine potency at the time of administration. Loss of potency becomes evident when immunised individuals contract the diseases the vaccines were meant to prevent. Assessing the factors associated with vaccine handling and storage practices. This was a cross-sectional study. Three-stage sampling was used to recruit 380 vaccine handlers from 273 health facilities from 11 Local Government areas in Ibadan. Data was analysed using SPSS version 16. Seventy-three percent were aware of vaccine handling and storage guidelines with 68.4% having ever read such guidelines. Only 15.3% read a guideline less than 1 month prior to the study. About 65.0% had received training on vaccine management. Incorrect handling practices reported included storing injections with vaccines (13.7%) and maintaining vaccine temperature using ice blocks (7.6%). About 43.0% had good knowledge of vaccine management, while 66.1% had good vaccine management practices. Respondents who had good knowledge of vaccine handling and storage [OR=10.0, 95%CI (5.28 - 18.94), p < 0.001] and had received formal training on vaccine management [OR=5.3, 95%CI (2.50 - 11.14), p< 0.001] were more likely to have good vaccine handling and storage practices. Regular training is recommended to enhance vaccine handling and storage practices.

Anti-Cocaine Vaccine Based on Coupling a Cocaine Analog to a Disrupted Adenovirus

PubMed Central

Koob, George; Hicks, Martin J.; Wee, Sunmee; Rosenberg, Jonathan B.; De, Bishnu P.; Kaminksy, Stephen M.; Moreno, Amira; Janda, Kim D.; Crystal, Ronald G.

2012-01-01

The challenge in developing an anti-cocaine vaccine is that cocaine is a small molecule, invisible to the immune system. Leveraging the knowledge that adenovirus (Ad) capsid proteins are highly immunogenic in humans, we hypothesized that linking a cocaine hapten to Ad capsid proteins would elicit high-affinity, high-titer antibodies against cocaine, sufficient to sequester systemically administered cocaine and prevent access to the brain, thus suppressing cocaine-induced behaviors. Based on these concepts, we developed dAd5GNE, a disrupted E1−E3− serotype 5 Ad with GNE, a stable cocaine analog, covalently linked to the Ad capsid proteins. In pre-clinical studies, dAd5GNE evoked persistent, high titer, high affinity IgG anti-cocaine antibodies, and was highly effective in blocking cocaine-induced hyperactivity and cocaine self-administration behavior in rats. Future studies will be designed to expand the efficacy studies, carry out relevant toxicology studies, and test dAd5GNE in human cocaine addicts. PMID:22229312

Efficient mucosal delivery of the HIV-1 Tat protein using the synthetic lipopeptide MALP-2 as adjuvant.

PubMed

Borsutzky, Stefan; Fiorelli, Valeria; Ebensen, Thomas; Tripiciano, Antonella; Rharbaoui, Faiza; Scoglio, Arianna; Link, Claudia; Nappi, Filomena; Morr, Michael; Buttó, Stefano; Cafaro, Aurelio; Mühlradt, Peter F; Ensoli, Barbara; Guzmán, Carlos A

2003-06-01

A major requirement for HIV/AIDS research is the development of a mucosal vaccine that stimulates humoral and cell-mediated immune responses at systemic and mucosal levels, thereby blocking virus replication at the entry port. Thus, a vaccine prototype based on biologically active HIV-1 Tat protein as antigen and the synthetic lipopeptide, macrophage-activating lipopeptide-2 (MALP-2), asa mucosal adjuvant was developed. Intranasal administration to mice stimulated systemic and mucosal anti-Tat antibody responses, and Tat-specific T cell responses, that were more efficient than those observed after i.p. immunization with Tat plus incomplete Freund's adjuvant. Major linear B cell epitopes mapped within aa 1-20 and 46-60, whereas T cell epitopes were identified within aa 36-50 and 56-70. These epitopes have also been described in vaccinated primates and in HIV-1-infected individuals with better prognosis. Analysis of the anti-Tat IgG isotypes in serum, and the cytokine profile of spleen cells indicated that a dominant Th1 helper response was stimulated by Tat plus MALP-2, as opposed to the Th2 response observed with Tat plus incomplete Freund's adjuvant. Tat-specific IFN-gamma-producing cells were significantly increased only in response to Tat plus MALP-2. These data suggest that Malp-2 may represent an optimal mucosal adjuvant for candidate HIV vaccines based on Tat alone or in combination with other HIV antigens.

Development of an epitope-blocking-enzyme-linked immunosorbent assay to differentiate between animals infected with and vaccinated against foot-and-mouth disease virus.

PubMed

Oem, Jae Ku; Chang, Byung Sik; Joo, Hoo Don; Yang, Mi Young; Kim, Gwang Jae; Park, Jee Yong; Ko, Young Joon; Kim, Yong Ju; Park, Jong Hyeon; Joo, Yi Seok

2007-06-01

An epitope-blocking ELISA (EB-ELISA) was developed to distinguish animals infected with foot-and-mouth-disease (FMDV) from those immunized with commercial vaccines. The assay used monoclonal antibodies to target the 3B core repeat motif (QKPLK) and purified recombinant 3AB proteins from the major B cell line epitopes of FMDV. Sera from uninfected and regularly vaccinated cattle, pigs, goats, and sheep (raised in FMDV free areas) were screened to evaluate the specificity of the EB-ELISA. The specificity scores of the assays were 99.8-100% and 100%, respectively. Reference sera from cattle, pigs, goats, and sheep experimentally infected with FMDV tested positive, with only a single exception. Antibodies formed in response to FMDV 3B appeared 1 week after infection and persisted at high levels for more than 8 weeks within the sera collected from serial bleeding of animals infected with FMDV O/SKR/2000. The EB-ELISA was used to differentiate between farms vaccinated against and those infected with FMDV (FMDV Asia serotype) during the 2005 epidemic in Mongolia by detecting antibodies against the FMDV Asia serotype in outbreak farms. This EB-ELISA method shows promise as an effective tool for FMDV control and eradication.

Performance and carcass characteristics of commercial feedlot cattle from a study of vaccine and direct-fed microbial effects on Escherichia col O157:H7 fecal shedding.

PubMed

Cull, C A; Renter, D G; Bello, N M; Ives, S E; Babcock, A H

2015-06-01

The objective of this study was to quantify cattle performance and carcass characteristics associated with administration of a siderophore receptor and porin proteins-based vaccine (VAC) and a direct-fed microbial (DFM), which were originally evaluated for their impact on O157:H7 fecal shedding in a commercial feedlot population. Cattle (P = 17,148) were randomly allocated into 40 pens grouped by allocation dates into 10 complete blocks; pens within block were randomly allocated to control, VAC, DFM, or VAC + DFM treatment groups in a 2 × 2 factorial design. The DFM (Bovamine) was fed daily at the labeled dose of 10 cfu/animal of Lactobacillus acidophilus for the duration of the intervention period (mean = 86.6 d). The VAC cattle were vaccinated on Days 0 and 21 whereas unvaccinated cattle were not given a placebo or rehandled on Day 21. Data were analyzed using general and generalized linear mixed models that accounted for the study design. Main effects of DFM and VAC are reported as there were no significant treatment interactions for any of the outcomes evaluated. Vaccinated cattle had lower total weight gain (P < 0.01), ADG (P = 0.03), and cumulative DMI during the intervention period (P < 0.01) compared with unvaccinated cattle, whereas the DFM increased total weight gain (P = 0.03) and G:F (P = 0.05) during the intervention period. Daily DMI was decreased (P < 0.01) in vaccinated pens compared with unvaccinated pens during a 5-d period immediately following revaccination. After the intervention period was completed, cattle were sorted following the standard operating procedure for the feedlot and all cattle were fed the DFM from that point until harvest. Each steer was individually identified through harvest. At harvest, vaccinated cattle had more total days on feed (P < 0.01) with a larger HCW (P = 0.01) than nonvaccinated cattle, whereas cattle not fed the DFM during the intervention period had a significantly larger HCW (P < 0.01) than those fed the DFM during the intervention period. We conclude that the use of these DFM and vaccine products have differential and independent effects on cattle performance and carcass characteristics in a commercial feedlot setting. Although the magnitude of these effects may vary among production systems, a more comprehensive understanding of the potential production costs of preharvest food safety pathogen control programs is essential if such programs are to be fully adopted in the industry.

Antibody Recognition of a Highly Conserved Influenza Virus Epitope

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ekiert, Damian C.; Bhabha, Gira; Elsliger, Marc-André

2009-05-21

Influenza virus presents an important and persistent threat to public health worldwide, and current vaccines provide immunity to viral isolates similar to the vaccine strain. High-affinity antibodies against a conserved epitope could provide immunity to the diverse influenza subtypes and protection against future pandemic viruses. Cocrystal structures were determined at 2.2 and 2.7 angstrom resolutions for broadly neutralizing human antibody CR6261 Fab in complexes with the major surface antigen (hemagglutinin, HA) from viruses responsible for the 1918 H1N1 influenza pandemic and a recent lethal case of H5N1 avian influenza. In contrast to other structurally characterized influenza antibodies, CR6261 recognizes amore » highly conserved helical region in the membrane-proximal stem of HA1 and HA2. The antibody neutralizes the virus by blocking conformational rearrangements associated with membrane fusion. The CR6261 epitope identified here should accelerate the design and implementation of improved vaccines that can elicit CR6261-like antibodies, as well as antibody-based therapies for the treatment of influenza.« less

Comparative Assessment of Transmission-Blocking Vaccine Candidates against Plasmodium falciparum

PubMed Central

Kapulu, M. C.; Da, D. F.; Miura, K.; Li, Y; Blagborough, A. M.; Churcher, T. S.; Nikolaeva, D.; Williams, A. R.; Goodman, A. L.; Sangare, I.; Turner, A. V.; Cottingham, M. G.; Nicosia, A.; Straschil, U.; Tsuboi, T.; Gilbert, S. C.; Long, Carole A.; Sinden, R. E.; Draper, S. J.; Hill, A. V. S.; Cohuet, A.; Biswas, S.

2015-01-01

Malaria transmission-blocking vaccines (TBVs) target the development of Plasmodium parasites within the mosquito, with the aim of preventing malaria transmission from one infected individual to another. Different vaccine platforms, mainly protein-in-adjuvant formulations delivering the leading candidate antigens, have been developed independently and have reported varied transmission-blocking activities (TBA). Here, recombinant chimpanzee adenovirus 63, ChAd63, and modified vaccinia virus Ankara, MVA, expressing AgAPN1, Pfs230-C, Pfs25, and Pfs48/45 were generated. Antibody responses primed individually against all antigens by ChAd63 immunization in BALB/c mice were boosted by the administration of MVA expressing the same antigen. These antibodies exhibited a hierarchy of inhibitory activity against the NF54 laboratory strain of P. falciparum in Anopheles stephensi mosquitoes using the standard membrane feeding assay (SMFA), with anti-Pfs230-C and anti-Pfs25 antibodies giving complete blockade. The observed rank order of inhibition was replicated against P. falciparum African field isolates in A. gambiae in direct membrane feeding assays (DMFA). TBA achieved was IgG concentration dependent. This study provides the first head-to-head comparative analysis of leading antigens using two different parasite sources in two different vector species, and can be used to guide selection of TBVs for future clinical development using the viral-vectored delivery platform. PMID:26063320

Malaria transmission blocking immunity and sexual stage vaccines for interrupting malaria transmission in Latin America

PubMed Central

Arévalo-Herrera, Myriam; Solarte, Yezid; Marin, Catherin; Santos, Mariana; Castellanos, Jenniffer; Beier, John C; Valencia, Sócrates Herrera

2016-01-01

Malaria is a vector-borne disease that is considered to be one of the most serious public health problems due to its high global mortality and morbidity rates. Although multiple strategies for controlling malaria have been used, many have had limited impact due to the appearance and rapid dissemination of mosquito resistance to insecticides, parasite resistance to multiple antimalarial drug, and the lack of sustainability. Individuals in endemic areas that have been permanently exposed to the parasite develop specific immune responses capable of diminishing parasite burden and the clinical manifestations of the disease, including blocking of parasite transmission to the mosquito vector. This is referred to as transmission blocking (TB) immunity (TBI) and is mediated by specific antibodies and other factors ingested during the blood meal that inhibit parasite development in the mosquito. These antibodies recognize proteins expressed on either gametocytes or parasite stages that develop in the mosquito midgut and are considered to be potential malaria vaccine candidates. Although these candidates, collectively called TB vaccines (TBV), would not directly stop malaria from infecting individuals, but would stop transmission from infected person to non-infected person. Here, we review the progress that has been achieved in TBI studies and the development of TBV and we highlight their potential usefulness in areas of low endemicity such as Latin America. PMID:21881775

Tyrosine 110 in the measles virus phosphoprotein is required to block STAT1 phosphorylation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Devaux, Patricia; Messling, Veronika von; Songsungthong, Warangkhana

2007-03-30

The measles virus (MV) P gene encodes three proteins: P, an essential polymerase cofactor, and C and V, which have multiple functions including immune evasion. We show here that the MV P protein also contributes to immune evasion, and that tyrosine 110 is required to block nuclear translocation of the signal transducer and activator of transcription factors (STAT) after interferon type I treatment. In particular, MV P inhibits STAT1 phosphorylation. This is shown not only by transient expression but also by reverse genetic analyses based on a new functional infectious cDNA derived from a MV vaccine vial (Moraten strain). Ourmore » study also identifies a conserved sequence around P protein tyrosine 110 as a candidate interaction site with a cellular protein.« less

Rationalization of a nanoparticle-based nicotine nanovaccine as an effective next-generation nicotine vaccine: A focus on hapten localization.

PubMed

Zhao, Zongmin; Hu, Yun; Harmon, Theresa; Pentel, Paul; Ehrich, Marion; Zhang, Chenming

2017-09-01

A lipid-polymeric hybrid nanoparticle-based next-generation nicotine nanovaccine was rationalized in this study to combat nicotine addiction. A series of nanovaccines, which had nicotine-haptens localized on carrier protein (LPKN), nanoparticle surface (LPNK), or both (LPNKN), were designed to study the impact of hapten localization on their immunological efficacy. All three nanovaccines were efficiently taken up and processed by dendritic cells. LPNKN induced a significantly higher immunogenicity against nicotine and a significantly lower anti-carrier protein antibody level compared to LPKN and LPNK. Meanwhile, it was found that the anti-nicotine antibodies elicited by LPKN and LPNKN bind nicotine stronger than those elicited by LPKN, and LPNK and LPNKN resulted in a more balanced Th1-Th2 immunity than LPKN. Moreover, LPNKN exhibited the best ability to block nicotine from entering the brain of mice. Collectively, the results demonstrated that the immunological efficacy of the hybrid nanoparticle-based nicotine vaccine could be enhanced by modulating hapten localization, providing a promising strategy to combatting nicotine addiction. Copyright © 2017 Elsevier Ltd. All rights reserved.

The grafting of universal T-helper epitopes enhances immunogenicity of HIV-1 Tat concurrently improving its safety profile.

PubMed

Kashi, Venkatesh P; Jacob, Rajesh A; Shamanna, Raghavendra A; Menon, Malini; Balasiddaiah, Anangi; Varghese, Rebu K; Bachu, Mahesh; Ranga, Udaykumar

2014-01-01

Extracellular Tat (eTat) plays an important role in HIV-1 pathogenesis. The presence of anti-Tat antibodies is negatively correlated with disease progression, hence making Tat a potential vaccine candidate. The cytotoxicity and moderate immunogenicity of Tat however remain impediments for developing Tat-based vaccines. Here, we report a novel strategy to concurrently enhance the immunogenicity and safety profile of Tat. The grafting of universal helper T-lymphocyte (HTL) epitopes, Pan DR Epitope (PADRE) and Pol711 into the cysteine rich domain (CRD) and the basic domain (BD) abolished the transactivation potential of the Tat protein. The HTL-Tat proteins elicited a significantly higher titer of antibodies as compared to the wild-type Tat in BALB/c mice. While the N-terminal epitope remained immunodominant in HTL-Tat immunizations, an additional epitope in exon-2 was recognized with comparable magnitude suggesting a broader immune recognition. Additionally, the HTL-Tat proteins induced cross-reactive antibodies of high avidity that efficiently neutralized exogenous Tat, thus blocking the activation of a Tat-defective provirus. With advantages such as presentation of multiple B-cell epitopes, enhanced antibody response and importantly, transactivation-deficient Tat protein, this approach has potential application for the generation of Tat-based HIV/AIDS vaccines.

Outcomes of polio eradication activities in Uttar Pradesh, India: the Social Mobilization Network (SM Net) and Core Group Polio Project (CGPP)

PubMed Central

2011-01-01

Background The primary strategy to interrupt transmission of wild poliovirus in India is to improve supplemental immunization activities and routine immunization coverage in priority districts with a focus on 107 high-risk blocks of western Uttar Pradesh and central Bihar. Villages or urban areas with a history of wild poliovirus transmission, or hard-to-reach or resistant populations are categorized as high-risk areas within blocks. The Social Mobilization Network (SM Net) was formed in Uttar Pradesh in 2003 to support polio eradication efforts through improved planning, implementation and monitoring of social mobilization activities in those high-risk areas. In this paper, we examine the vaccination outcomes in districts of SM Net where the CORE Group works. Methods We carried out a secondary data analysis of routine monitoring information collected by the SM Net and the Government of India. These data include information about vaccination outcomes in SM Net areas and non-SM Net areas within the districts where the CORE Group operates. Statistical analysis was used to compare, between SM Net and non-SM Net areas, vaccination outcomes considered sensitive to social mobilization efforts of the SM Net. We employed Generalized Estimating Equations (GEE) statistical method to account for Intra-cluster Correlation (ICC), and used 'Quasi-likelihood under the independence model criterion (QIC)' as the model selection method. Results Vaccination outcomes in SM Net areas were as high as or higher than in non-SM Net areas. There was considerable variation in vaccination outcomes between districts. Conclusions While not conclusive, the results suggest that the social mobilization efforts of the SM Net and the CORE Group are helping to increase vaccination levels in high-risk areas of Uttar Pradesh. Vaccination outcomes in CORE Group areas were equal or higher than in non-CORE, non-SM Net areas. This occurred even though SM Net areas are those with more community resistance to polio vaccination and/or are have harder-to-reach populations than non-SM Net areas. Other likely explanations for the relatively good vaccination performance in SM Net areas are not apparent. PMID:21569256

Ethical and policy issues in using vaccines to treat and prevent cocaine and nicotine dependence.

PubMed

Hall, Wayne; Gartner, Coral

2011-05-01

To describe the rationale of vaccines against cocaine and nicotine, to review progress in developing and trialing vaccines to treat dependence on these drugs and to discuss some of the ethical issues that may arise from their use in legally coerced addiction treatment or for prevention of addiction in adolescents. Several randomized controlled trials of cocaine and nicotine vaccines for relapse prevention have produced mixed results. The studies demonstrate that it is possible to raise antibodies to cocaine and nicotine in humans. In abstinent patients who show high levels of drug antibodies, the rewarding effects of these drugs are attenuated. Phase 2 trials have not found nicotine vaccines to be superior to placebo because only a third of those vaccinated develop sufficient levels of antibody to block the effects of nicotine. Vaccines are a novel approach to relapse prevention that need to more reliably induce immunity in a larger proportion of vaccinated patients if they are to protect against relapse after achieving abstinence. Vaccines are unlikely to prevent addiction in adolescents. Their use under legal coercion should only be considered after considerable experience with their use in voluntary patients.

Synergy in anti-malarial pre-erythrocytic and transmission-blocking antibodies is achieved by reducing parasite density

PubMed Central

Betancourt, Michael; Upton, Leanna M; Angrisano, Fiona; Morin, Merribeth J

2018-01-01

Anti-malarial pre-erythrocytic vaccines (PEV) target transmission by inhibiting human infection but are currently partially protective. It has been posited, but never demonstrated, that co-administering transmission-blocking vaccines (TBV) would enhance malaria control. We hypothesized a mechanism that TBV could reduce parasite density in the mosquito salivary glands, thereby enhancing PEV efficacy. This was tested using a multigenerational population assay, passaging Plasmodium berghei to Anopheles stephensi mosquitoes. A combined efficacy of 90.8% (86.7–94.2%) was observed in the PEV +TBV antibody group, higher than the estimated efficacy of 83.3% (95% CrI 79.1–87.0%) if the two antibodies acted independently. Higher PEV efficacy at lower mosquito parasite loads was observed, comprising the first direct evidence that co-administering anti-sporozoite and anti-transmission interventions act synergistically, enhancing PEV efficacy across a range of TBV doses and transmission intensities. Combining partially effective vaccines of differing anti-parasitic classes is a pragmatic, powerful way to accelerate malaria elimination efforts. PMID:29914622

Quantitative analyses reveal distinct sensitivities of the capture of HIV-1 primary viruses and pseudoviruses to broadly neutralizing antibodies.

PubMed

Kim, Jiae; Jobe, Ousman; Peachman, Kristina K; Michael, Nelson L; Robb, Merlin L; Rao, Mangala; Rao, Venigalla B

2017-08-01

Development of vaccines capable of eliciting broadly neutralizing antibodies (bNAbs) is a key goal to controlling the global AIDS epidemic. To be effective, bNAbs must block the capture of HIV-1 to prevent viral acquisition and establishment of reservoirs. However, the role of bNAbs, particularly during initial exposure of primary viruses to host cells, has not been fully examined. Using a sensitive, quantitative, and high-throughput qRT-PCR assay, we found that primary viruses were captured by host cells and converted into a trypsin-resistant form in less than five minutes. We discovered, unexpectedly, that bNAbs did not block primary virus capture, although they inhibited the capture of pseudoviruses/IMCs and production of progeny viruses at 48h. Further, viruses escaped bNAb inhibition unless the bNAbs were present in the initial minutes of exposure of virus to host cells. These findings will have important implications for HIV-1 vaccine design and determination of vaccine efficacy. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Evaluation of formalin-fixed paraffin-embedded tissues obtained from vaccine site-associated sarcomas of cats for DNA of feline immunodeficiency virus.

PubMed

Kidney, B A; Ellis, J A; Haines, D M; Jackson, M L

2000-09-01

To evaluate the use of a polymerase chain reaction (PCR) method for detection of feline immunodeficiency virus (FIV) DNA, using formalin-fixed paraffin-embedded (FFPE) tissues, and to use this method to evaluate tissues obtained from vaccine site-associated sarcomas (VSS) of cats for FIV DNA. 50 FFPE tissue blocks from VSS of cats and 50 FFPE tissue blocks from cutaneous non-vaccine site-associated fibrosarcomas (non-VSS) of cats. DNA was extracted from FFPE sections of each tumor and regions of the gag gene of FIV were amplified by a PCR, using 3 sets of primers. Sensitivity of the method was compared between frozen and FFPE tissues, using splenic tissue obtained from a cat that had been experimentally infected with FIV. We did not detect FIV DNA in VSS or non-VSS tissues. Sensitivity of the PCR method was identical for frozen or FFPE tissues. It is possible to detect FIV DNA in FFPE tissues by use of a PCR. We did not find evidence to support direct FIV involvement in the pathogenesis of VSS in cats.

Active vaccination with vaccinia virus A33 protects mice against lethal vaccinia and ectromelia viruses but not against cowpoxvirus; elucidation of the specific adaptive immune response.

PubMed

Paran, Nir; Lustig, Shlomo; Zvi, Anat; Erez, Noam; Israely, Tomer; Melamed, Sharon; Politi, Boaz; Ben-Nathan, David; Schneider, Paula; Lachmi, Batel; Israeli, Ofir; Stein, Dana; Levin, Reuven; Olshevsky, Udy

2013-07-10

Vaccinia virus protein A33 (A33VACV) plays an important role in protection against orthopoxviruses, and hence is included in experimental multi-subunit smallpox vaccines. In this study we show that single-dose vaccination with recombinant Sindbis virus expressing A33VACV, is sufficient to protect mice against lethal challenge with vaccinia virus WR (VACV-WR) and ectromelia virus (ECTV) but not against cowpox virus (CPXV), a closely related orthopoxvirus. Moreover, a subunit vaccine based on the cowpox virus A33 ortholog (A33CPXV) failed to protect against cowpox and only partially protected mice against VACV-WR challenge. We mapped regions of sequence variation between A33VACV and A33CPXVand analyzed the role of such variations in protection. We identified a single protective region located between residues 104-120 that harbors a putative H-2Kd T cell epitope as well as a B cell epitope - a target for the neutralizing antibody MAb-1G10 that blocks spreading of extracellular virions. Both epitopes in A33CPXV are mutated and predicted to be non-functional. Whereas vaccination with A33VACV did not induce in-vivo CTL activity to the predicted epitope, inhibition of virus spread in-vitro, and protection from lethal VACV challenge pointed to the B cell epitope highlighting the critical role of residue L118 and of adjacent compensatory residues in protection. This epitope's critical role in protection, as well as its modifications within the orthopoxvirus genus should be taken in context with the failure of A33 to protect against CPXV as demonstrated here. These findings should be considered when developing new subunit vaccines and monoclonal antibody based therapeutics against orthopoxviruses, especially variola virus, the etiologic agent of smallpox.

Active vaccination with vaccinia virus A33 protects mice against lethal vaccinia and ectromelia viruses but not against cowpoxvirus; elucidation of the specific adaptive immune response

PubMed Central

2013-01-01

Vaccinia virus protein A33 (A33VACV) plays an important role in protection against orthopoxviruses, and hence is included in experimental multi-subunit smallpox vaccines. In this study we show that single-dose vaccination with recombinant Sindbis virus expressing A33VACV, is sufficient to protect mice against lethal challenge with vaccinia virus WR (VACV-WR) and ectromelia virus (ECTV) but not against cowpox virus (CPXV), a closely related orthopoxvirus. Moreover, a subunit vaccine based on the cowpox virus A33 ortholog (A33CPXV) failed to protect against cowpox and only partially protected mice against VACV-WR challenge. We mapped regions of sequence variation between A33VACV and A33CPXVand analyzed the role of such variations in protection. We identified a single protective region located between residues 104–120 that harbors a putative H-2Kd T cell epitope as well as a B cell epitope - a target for the neutralizing antibody MAb-1G10 that blocks spreading of extracellular virions. Both epitopes in A33CPXV are mutated and predicted to be non-functional. Whereas vaccination with A33VACV did not induce in-vivo CTL activity to the predicted epitope, inhibition of virus spread in-vitro, and protection from lethal VACV challenge pointed to the B cell epitope highlighting the critical role of residue L118 and of adjacent compensatory residues in protection. This epitope’s critical role in protection, as well as its modifications within the orthopoxvirus genus should be taken in context with the failure of A33 to protect against CPXV as demonstrated here. These findings should be considered when developing new subunit vaccines and monoclonal antibody based therapeutics against orthopoxviruses, especially variola virus, the etiologic agent of smallpox. PMID:23842430

Juvenile-specific cathepsin proteases in Fasciola spp.: their characteristics and vaccine efficacies.

PubMed

Meemon, Krai; Sobhon, Prasert

2015-08-01

Fasciolosis, caused by Fasciola hepatica and Fasciola gigantica, is one of the most neglected tropical zoonotic diseases. One sustainable control strategy against these infections is the employment of vaccines that target proteins essential for parasites' invasion and nutrition acquiring processes. Cathepsin proteases are the most abundantly expressed proteins in Fasciola spp. that have been tested successfully as vaccines against fasciolosis in experimental as well as large animals because of their important roles in digestion of nutrients, invasion, and migration. Specifically, juvenile-specific cathepsin proteases are the more effective vaccines because they could block the invasion and migration of juvenile parasites whose immune evasion mechanism has not yet been fully developed. Moreover, because of high sequence similarity and identity of cathepsins from juveniles with those of adults, the vaccines can attack both the juvenile and adult stages. In this article, the characteristics and vaccine potentials of juvenile-specific cathepsins, i.e., cathepsins L and B, of Fasciola spp. were reviewed.

Blocking of opioid receptors in experimental formaline-inactivated respiratory syncytial virus (FI-RSV) immunopathogenesis: from beneficial to harmful impacts.

PubMed

Salimi, Vahid; Mirzaei, Habib; Ramezani, Ali; Tahamtan, Alireza; Jamali, Abbas; Shahabi, Shahram; Golaram, Maryam; Minaei, Bagher; Gharagozlou, Mohammad Javad; Mahmoodi, Mahmood; Bont, Louis; Shokri, Fazel; Mokhtari-Azad, Talat

2018-04-01

Opioid system plays a significant role in pathophysiological processes, such as immune response and impacts on disease severity. Here, we investigated the effect of opioid system on the immunopathogenesis of respiratory syncytial virus (RSV) vaccine (FI-RSV)-mediated illness in a widely used mouse model. Female Balb/c mice were immunized at days 0 and 21 with FI-RSV (2 × 10 6  pfu, i.m.) and challenged with RSV-A2 (3 × 10 6  pfu, i.n.) at day 42. Nalmefene as a universal opioid receptors blocker administered at a dose of 1 mg/kg in combination with FI-RSV (FI-RSV + NL), and daily after live virus challenge (RSV + NL). Mice were sacrificed at day 5 after challenge and bronchoalveolar lavage (BAL) fluid and lungs were harvested to measure airway immune cells influx, T lymphocyte subtypes, cytokines/chemokines secretion, lung histopathology, and viral load. Administration of nalmefene in combination with FI-RSV (FI-RSV + NL-RSV) resulted in the reduction of the immune cells infiltration to the BAL fluid, the ratio of CD4/CD8 T lymphocyte, the level of IL-5, IL-10, MIP-1α, lung pathology, and restored weight loss after RSV infection. Blocking of opioid receptors during RSV infection in vaccinated mice (FI-RSV-RSV + NL) had no significant effects on RSV immunopathogenesis. Moreover, administration of nalmefene in combination with FI-RSV and blocking opioid receptors during RSV infection (FI-RSV + NL-RSV + NL) resulted in an increased influx of the immune cells to the BAL fluid, increases the level of IFN-γ, lung pathology, and weight loss in compared to control condition. Although nalmefene administration within FI-RSV vaccine decreases vaccine-enhanced infection during subsequent exposure to the virus, opioid receptor blocking during RSV infection aggravates the host inflammatory response to RSV infection. Thus, caution is required due to beneficial/harmful functions of opioid systems while targeting as potentially therapies.

Global genetic diversity of the Plasmodium vivax transmission-blocking vaccine candidate Pvs48/45.

PubMed

Vallejo, Andres F; Martinez, Nora L; Tobon, Alejandra; Alger, Jackeline; Lacerda, Marcus V; Kajava, Andrey V; Arévalo-Herrera, Myriam; Herrera, Sócrates

2016-04-12

Plasmodium vivax 48/45 protein is expressed on the surface of gametocytes/gametes and plays a key role in gamete fusion during fertilization. This protein was recently expressed in Escherichia coli host as a recombinant product that was highly immunogenic in mice and monkeys and induced antibodies with high transmission-blocking activity, suggesting its potential as a P. vivax transmission-blocking vaccine candidate. To determine sequence polymorphism of natural parasite isolates and its potential influence on the protein structure, all pvs48/45 sequences reported in databases from around the world as well as those from low-transmission settings of Latin America were compared. Plasmodium vivax parasite isolates from malaria-endemic regions of Colombia, Brazil and Honduras (n = 60) were used to sequence the Pvs48/45 gene, and compared to those previously reported to GenBank and PlasmoDB (n = 222). Pvs48/45 gene haplotypes were analysed to determine the functional significance of genetic variation in protein structure and vaccine potential. Nine non-synonymous substitutions (E35K, Y196H, H211N, K250N, D335Y, E353Q, A376T, K390T, K418R) and three synonymous substitutions (I73, T149, C156) that define seven different haplotypes were found among the 282 isolates from nine countries when compared with the Sal I reference sequence. Nucleotide diversity (π) was 0.00173 for worldwide samples (range 0.00033-0.00216), resulting in relatively high diversity in Myanmar and Colombia, and low diversity in Mexico, Peru and South Korea. The two most frequent substitutions (E353Q: 41.9 %, K250N: 39.5 %) were predicted to be located in antigenic regions without affecting putative B cell epitopes or the tertiary protein structure. There is limited sequence polymorphism in pvs48/45 with noted geographical clustering among Asian and American isolates. The low genetic diversity of the protein does not influence the predicted antigenicity or protein structure and, therefore, supports its further development as transmission-blocking vaccine candidate.

Pharmacokinetic Correlates of the Effects of a Heroin Vaccine on Heroin Self-Administration in Rats

PubMed Central

Raleigh, Michael D.; Pentel, Paul R.; LeSage, Mark G.

2014-01-01

The purpose of this study was to evaluate the effects of a morphine-conjugate vaccine (M-KLH) on the acquisition, maintenance, and reinstatement of heroin self-administration (HSA) in rats, and on heroin and metabolite distribution during heroin administration that approximated the self-administered dosing rate. Vaccination with M-KLH blocked heroin-primed reinstatement of heroin responding. Vaccination also decreased HSA at low heroin unit doses but produced a compensatory increase in heroin self-administration at high unit doses. Vaccination shifted the heroin dose-response curve to the right, indicating reduced heroin potency, and behavioral economic demand curve analysis further confirmed this effect. In a separate experiment heroin was administered at rates simulating heroin exposure during HSA. Heroin and its active metabolites, 6-acetylmorphine (6-AM) and morphine, were retained in plasma and metabolite concentrations were reduced in brain in vaccinated rats compared to controls. Reductions in 6-AM concentrations in brain after vaccination were consistent with the changes in HSA rates accompanying vaccination. These data provide evidence that 6-AM is the principal mediator of heroin reinforcement, and the principal target of the M-KLH vaccine, in this model. While heroin vaccines may have potential as therapies for heroin addiction, high antibody to drug ratios appear to be important for obtaining maximal efficacy. PMID:25536404

Expression of Plasmodium falciparum Circumsporozoite Proteins in Escherichia coli for Potential Use in a Human Malaria Vaccine

NASA Astrophysics Data System (ADS)

Young, James F.; Hockmeyer, Wayne T.; Gross, Mitchell; Ripley Ballou, W.; Wirtz, Robert A.; Trosper, James H.; Beaudoin, Richard L.; Hollingdale, Michael R.; Miller, Louis H.; Diggs, Carter L.; Rosenberg, Martin

1985-05-01

The circumsporozoite (CS) protein of the human malaria parasite Plasmodium falciparum may be the most promising target for the development of a malaria vaccine. In this study, proteins composed of 16, 32, or 48 tandem copies of a tetrapeptide repeating sequence found in the CS protein were efficiently expressed in the bacterium Escherichia coli. When injected into mice, these recombinant products resulted in the production of high titers of antibodies that reacted with the authentic CS protein on live sporozoites and blocked sporozoite invasion of human hepatoma cells in vitro. These CS protein derivatives are therefore candidates for a human malaria vaccine.

Comparison of homologous and heterologous prime-boost vaccine approaches using Modified Vaccinia Ankara and soluble protein to induce neutralizing antibodies by the human cytomegalovirus pentamer complex in mice.

PubMed

Chiuppesi, Flavia; Wussow, Felix; Scharf, Louise; Contreras, Heidi; Gao, Han; Meng, Zhuo; Nguyen, Jenny; Barry, Peter A; Bjorkman, Pamela J; Diamond, Don J

2017-01-01

Since neutralizing antibodies (NAb) targeting the human cytomegalovirus (HCMV) pentamer complex (PC) potently block HCMV host cell entry, anti-PC NAb induction is thought to be important for a vaccine formulation to prevent HCMV infection. By developing a vaccine strategy based on soluble PC protein and using a previously generated Modified Vaccinia Ankara vector co-expressing all five PC subunits (MVA-PC), we compared HCMV NAb induction by homologous immunization using prime-boost vaccine regimen employing only PC protein or MVA-PC and heterologous immunization using prime-boost combinations of PC protein and MVA-PC. Utilizing a recently isolated anti-PC NAb, we produced highly pure soluble PC protein that displayed conformational and linear neutralizing epitopes, interfered with HCMV entry, and was recognized by antibodies induced by HCMV during natural infection. Mice vaccinated by different immunization routes with the purified PC protein in combination with a clinically approved adjuvant formulation elicited high-titer and durable HCMV NAb. While MVA-PC and soluble PC protein either alone or in combination elicited robust HCMV NAb, significantly different potencies of these vaccine approaches were observed in dependence on immunization schedule. Using only two immunizations, vaccination with MVA-PC alone or prime-boost combinations of MVA-PC and PC protein was significantly more effective in stimulating HCMV NAb than immunization with PC protein alone. In contrast, with three immunizations, NAb induced by soluble PC protein either alone or combined with two boosts of MVA-PC increased to levels that exceeded NAb titer stimulated by MVA-PC alone. These results provide insights into the potency of soluble protein and MVA to elicit NAb by the HCMV PC via homologous and heterologous prime-boost immunization, which may contribute to develop clinically deployable vaccine strategies to prevent HCMV infection.

Immunogenicity and safety of an investigational multicomponent, recombinant, meningococcal serogroup B vaccine (4CMenB) administered concomitantly with routine infant and child vaccinations: results of two randomised trials.

PubMed

Vesikari, Timo; Esposito, Susanna; Prymula, Roman; Ypma, Ellen; Kohl, Igor; Toneatto, Daniela; Dull, Peter; Kimura, Alan

2013-03-09

Meningococcal serogroup B disease disproportionately affects infants. We assessed lot-to-lot consistency, safety and immunogenicity, and the effect of concomitant vaccination on responses to routine vaccines of an investigational multicomponent vaccine (4CMenB) in this population. We did primary and booster phase 3 studies between March 31, 2008, and Aug 16, 2010, in 70 sites in Europe. We used two series of sponsor-supplied, computer-generated randomisation envelopes to allocate healthy 2 month-old infants to receive routine vaccinations (diphtheria-tetanus-acellular pertussis, inactivated poliovirus, hepatitis B plus Haemophilus influenzae type b, and seven-valent pneumococcal vaccine) at 2, 4, and 6 months of age alone, or concomitantly with 4CMenB or serogroup C conjugate vaccine (MenC) in: 1) an open-label, lot-to-lot immunogenicity and safety substudy of three 4CMenB lots compared with routine vaccines alone (1:1:1:1, block size eight); or 2) an observer-blind, lot-to-lot safety substudy of three 4CMenB lots compared with MenC (1:1:1:3, block size six). At 12 months, 4CMenB-primed children from either substudy were randomised (1:1, block size two) to receive 4CMenB booster, with or without measles-mumps-rubella-varicella (MMRV) vaccine. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroup B test strains, and on randomly selected subsets of serum samples for routine vaccines; laboratory personnel were masked to assignment. The first coprimary outcome was lot-to-lot consistency (hSBA geometric mean ratio of all lots between 0·5 and 2·0), and the second was an immune response (hSBA titre ≥5) for each of the three strains. The primary outcome for the booster study was immune response to booster dose. Immunogenicity data for 4CMenB were for the modified intention-to-treat population, including all infants from the open-label substudy who provided serum samples. The safety population included all participants who contributed safety data after at least one dose of study vaccine. These trials are registered with ClinicalTrials.gov, numbers NCT00657709 and NCT00847145. We enrolled 2627 infants in the open-label phase, 1003 in the observer-blind phase, and 1555 in the booster study. Lot-to-lot consistency was shown for the three 4CMenB lots, with the lowest 95% lower confidence limit being 0·74 and the highest upper limit being 1·33. Of 1181–1184 infants tested 1 month after three 4CMenB doses (all lots pooled), 100% (95% CI 99–100) had hSBA titres of 5 or more against strains selective for factor H binding protein and neisserial adhesin A, and 84% (82–86) for New Zealand outer-membrane vesicle. In a subset (n=100), 84% (75–91) of infants had hSBA titres of 5 or more against neisseria heparin binding antigen. At 12 months of age, waning titres were boosted by a fourth dose, such that 95–100% of children had hSBA titres of 5 or more for all antigens, with or without concomitant MMRV. Immune responses to routine vaccines were much the same with or without concomitant 4CMenB, but concomitant vaccination was associated with increased reactogenicity. 77% (1912 of 2478) of infants had fever of 38·5°C or higher after any 4CMenB dose, compared with 45% (295 of 659) after routine vaccines alone and 47% (228 of 490) with MenC, but only two febrile seizures were deemed probably related to 4CMenB. 4CMenB is immunogenic in infants and children aged 12 months with no clinically relevant interference with routine vaccines, but increases reactogenicity when administered concomitantly with routine vaccines. This breakthrough vaccine offers an innovative solution to the major remaining cause of bacterial meningitis in infant and toddlers. Novartis Vaccines and Diagnostics.

Characterization of a new chimeric marker vaccine candidate with a mutated antigenic E2-epitope.

PubMed

Reimann, Ilona; Depner, Klaus; Utke, Katrin; Leifer, Immanuel; Lange, Elke; Beer, Martin

2010-04-21

A new chimeric pestivirus "CP7_E1E2alf_TLA", based on the infectious cDNA of bovine viral diarrhea virus (BVDV) strain CP7, was constructed. The substitution of BVDV E1 and E2 with the respective proteins of classical swine fever (CSF) strain Alfort 187 allows an optimal heterodimerization of E1 and E2 in the chimeric virus, which is beneficial for efficient and authentic virus assembly and growth. In addition, for implementation of E2-based marker diagnostics, the previously described antigenic CSFV-specific TAVSPTTLR epitope was exchanged with the corresponding E2-epitope of BVDV strain CP7. Recombinant virus CP7_E1E2alf_TLA displayed a growth defect, and was not reacting with monoclonal antibodies used in commercial E2 antibody blocking ELISAs. Therefore, efficacy as well as marker properties of CP7_E1E2alf_TLA were investigated in an animal experiment with both a high dose and a low dose vaccine preparation. All CP7_E1E2alf_TLA-vaccinated animals seroconverted until day 28 post-vaccination with neutralizing antibodies. Furthermore, at the day of challenge infection CP7_E1E2alf_TLA-immunized animals showed distinct lower ELISA values in a commercial CSFV E2 antibody test in comparison to the C-strain vaccinated controls. However, E2-ELISA reactivity as well as neutralizing titers were directly connected to the dosage used for vaccination, and only the low dose group had E2-ELISA values below threshold until challenge infection. Following challenge infection with highly virulent CSFV strain Koslov, all vaccinees were protected, however, short-term fever episodes and very limited CSFV genome detection with very low copy numbers could be observed. In conclusion, manipulation of the TAVSPTTLR-epitope within the tested chimeric virus resulted in an slightly reduced efficacy, but the E2 marker properties unexpectedly did not allow a clear differentiation of infected from vaccinated animals in some cases. Copyright 2009 Elsevier B.V. All rights reserved.

Prostate Tumor Antigen Discovery: Development of a Novel Genetic Approach

DTIC Science & Technology

2001-12-01

HIV infection and AIDS), 20 MUC-1 (associated with breast cancer), EBNA-1 (associated with Epstein Barr Virus infection), CA19.9 (associated with... developed with DCs transfected with RNA from LNCaP cell lines. These studies established the feasibility of using PSA as a vaccine for prostate cancer...effective as an adjunct therapy for this malignancy. There are several road blocks to developing a successful cancer vaccine . Products of tumor cells that are

Layer-By-Layer Nanoparticle Vaccines Carrying the G Protein CX3C Motif Protect against RSV Infection and Disease.

PubMed

Jorquera, Patricia A; Oakley, Katie E; Powell, Thomas J; Palath, Naveen; Boyd, James G; Tripp, Ralph A

2015-10-12

Respiratory syncytial virus (RSV) is the single most important cause of serious lower respiratory tract infections in young children; however no effective treatment or vaccine is currently available. Previous studies have shown that therapeutic treatment with a monoclonal antibody (clone 131-2G) specific to the RSV G glycoprotein CX3C motif, mediates virus clearance and decreases leukocyte trafficking to the lungs of RSV-infected mice. In this study, we show that vaccination with layer-by-layer nanoparticles (LbL-NP) carrying the G protein CX3C motif induces blocking antibodies that prevent the interaction of the RSV G protein with the fractalkine receptor (CX3CR1) and protect mice against RSV replication and disease pathogenesis. Peptides with mutations in the CX3C motif induced antibodies with diminished capacity to block G protein-CX3CR1 binding. Passive transfer of these anti-G protein antibodies to mice infected with RSV improved virus clearance and decreased immune cell trafficking to the lungs. These data suggest that vaccination with LbL-NP loaded with the CX3C motif of the RSV G protein can prevent manifestations of RSV disease by preventing the interaction between the G protein and CX3CR1 and recruitment of immune cells to the airways.

Bordetella Pertussis virulence factors in the continuing evolution of whooping cough vaccines for improved performance.

PubMed

Dorji, Dorji; Mooi, Frits; Yantorno, Osvaldo; Deora, Rajendar; Graham, Ross M; Mukkur, Trilochan K

2018-02-01

Despite high vaccine coverage, whooping cough caused by Bordetella pertussis remains one of the most common vaccine-preventable diseases worldwide. Introduction of whole-cell pertussis (wP) vaccines in the 1940s and acellular pertussis (aP) vaccines in 1990s reduced the mortality due to pertussis. Despite induction of both antibody and cell-mediated immune (CMI) responses by aP and wP vaccines, there has been resurgence of pertussis in many countries in recent years. Possible reasons hypothesised for resurgence have ranged from incompliance with the recommended vaccination programmes with the currently used aP vaccine to infection with a resurged clinical isolates characterised by mutations in the virulence factors, resulting in antigenic divergence with vaccine strain, and increased production of pertussis toxin, resulting in dampening of immune responses. While use of these vaccines provide varying degrees of protection against whooping cough, protection against infection and transmission appears to be less effective, warranting continuation of efforts in the development of an improved pertussis vaccine formulations capable of achieving this objective. Major approaches currently under evaluation for the development of an improved pertussis vaccine include identification of novel biofilm-associated antigens for incorporation in current aP vaccine formulations, development of live attenuated vaccines and discovery of novel non-toxic adjuvants capable of inducing both antibody and CMI. In this review, the potential roles of different accredited virulence factors, including novel biofilm-associated antigens, of B. pertussis in the evolution, formulation and delivery of improved pertussis vaccines, with potential to block the transmission of whooping cough in the community, are discussed.

Why functional pre-erythrocytic and bloodstage malaria vaccines fail: a meta-analysis of fully protective immunizations and novel immunological model.

PubMed

Guilbride, D Lys; Gawlinski, Pawel; Guilbride, Patrick D L

2010-05-19

Clinically protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants. We identify and evaluate 1916 immunization studies between 1965-February 2010, and exclude partially or nonprotective results to find 177 completely protective immunization experiments. Detailed reexamination reveals an unexpectedly mundane basis for selective vaccine failure: live malaria parasites in the skin inhibit vaccine function. We next show published molecular and cellular data support a testable, novel model where parasite-host interactions in the skin induce malaria-specific regulatory T cells, and subvert early antigen-specific immunity to parasite-specific immunotolerance. This ensures infection and tolerance to reinfection. Exposure to Plasmodium-infected mosquito bites therefore systematically triggers immunosuppression of endemic vaccine-elicited responses. The extensive vaccine trial data solidly substantiate this model experimentally. We conclude skinstage-initiated immunosuppression, unassociated with bloodstage parasites, systematically blocks vaccine function in the field. Our model exposes novel molecular and procedural strategies to significantly and quickly increase protective efficacy in both pipeline and currently ineffective malaria vaccines, and forces fundamental reassessment of central precepts determining vaccine development. This has major implications for accelerated local eliminations of malaria, and significantly increases potential for eradication.

Genetic appraisal of serological response post vaccination against enterotoxaemia (ET) in Malpura and Avikalin sheep.

PubMed

Gowane, G R; Akram, Najif; Prince, L L L; Prakash, Ved; Kumar, Arun

2017-04-01

Enterotoxaemia (ET) is a fatal enteric disease of small ruminants attributable to a toxigenic type of Clostridium perfringens. The key strategy for prevention of ET is the management and vaccination. Present study aimed at identifying the sources of variation for ET vaccine response especially against epsilon toxin in 173 sheep that included 83 Avikalin and 90 Malpura lambs raised at the institute flock in the semi-arid region of India. The mean age at vaccination was 90 days. Sera were tested by blocking ELISA. Study showed significant variability for response to ET vaccine. 5.2% animals had + positivity, 20.8% animals had ++ positivity, 51.4% animals had +++ positivity and 22.5% animals had ++++ positivity. Amongst environmental determinants, breed, season, sex and age at vaccination proved to be non-significant sources of variation (P > 0.05). MHC genotypes with DRB1 gene and DQA2 genes also revealed non-significant association with ET vaccine response; however, a trend of decreasing PI values with increasing ranks was observed. Study revealed strong response of epsilon toxin along with complexity of the ET vaccine response as phenotype to be explained by genetic and non-genetic factors. The importance of better management practices and vaccination is suggested for preventive measures.

Antigen-specific immature dendritic cell vaccine ameliorates anti-dsDNA antibody-induced renal damage in a mouse model.

PubMed

Xia, Yumin; Jiang, Shan; Weng, Shenhong; Lv, Xiaochun; Cheng, Hong; Fang, Chunhong

2011-12-01

Dendritic cells (DCs) can inhibit immune response by clonal anergy when immature. Recent studies have shown that immature DCs (iDCs) may serve as a live cell vaccine after specific antigen pulse based on its potential of blocking antibody production. In this study, we aimed to investigate the effects of nuclear antigen-pulsed iDCs in the treatment of lupus-like renal damages induced by anti-dsDNA antibodies. iDCs were generated from haemopoietic stem cells in bone marrow and then pulsed in vitro with nuclear antigen. The iDC vaccine and corresponding controls were injected into mice with lupus-like renal damages. The evaluation of disease was monitored by biochemical parameters and histological scores. Anti-dsDNA antibody isotypes and T-lymphocyte-produced cytokines were analysed for elucidating therapeutic mechanisms. RESULTS; The mice treated with antigen-pulsed iDCs had a sustained remission of renal damage compared with those injected with non-pulsed iDCs or other controls, including decreased anti-dsDNA antibody level, less proteinuria, lower blood urea nitrogen and serum creatinine values, and improved histological evaluation. Analysis on isotypes of anti-dsDNA antibody showed that iDC vaccine preferentially inhibited the production of IgG3, IgG2b and IgG2a. Furthermore, administration of antigen-treated iDCs to mice resulted in significantly reduced IL-2, IL-4 and IL-12 and IFN-γ produced by T-memory cells. Conversely, the vaccination of antigen-pulsed mature DCs led to increased anti-dsDNA antibody production and an aggravation of lupus-like disease in the model. CONCLUSIONS; These results suggested the high potency of iDC vaccine in preventing lupus-like renal injuries induced by pathogenic autoantibodies.

Block the Buzzing, Bites, and Bumps: Preventing Mosquito-Borne Illnesses

MedlinePlus

... Ten Mosquito Facts West Nile Virus Dengue Fever Malaria Zika Virus Infection Zika Virus Information and Resources References The live attenuated dengue vaccine TV003 elicits complete protection against dengue in a ...

Immunology of scorpion toxins and perspectives for generation of anti-venom vaccines.

PubMed

Gazarian, Karlen G; Gazarian, Tatiana; Hernández, Ricardo; Possani, Lourival D

2005-05-16

Scorpions and other venomous animals contain concentrates of biologically active substances developed to block vital physiological and biochemical functions of the victims. These have contrasting human health concerns, provide important pharmacological raw material and pose a serious threat to human life and health in tropical and subtropical regions. Because only occasional and minor quantities of venom are introduced into the human organism with a scorpion sting and their mortal effect is an acute phenomenon these substances are unknown to the immune defense system and thus no immunity has appeared against them during evolution. Antidotes prepared from animal anti-sera are effective against some species of scorpions but depend on the manufacturer and the availability of product to the medical community. Although significant progress has been made in immunological studies of certain groups of toxins, few centers are dedicated to this research. Information is still insufficient to generate a comprehensive picture of the subject and to propose vaccines against venoms. A novel approach based on mimotopes selected from phage-displayed random peptide libraries show potential to impel further progress of toxin immunological studies and to provide putative vaccine resources. In this report we revise the "state of the art" in the field.

Characterization and Implementation of a Diverse Simian Immunodeficiency Virus SIVsm Envelope Panel in the Assessment of Neutralizing Antibody Breadth Elicited in Rhesus Macaques by Multimodal Vaccines Expressing the SIVmac239 Envelope

PubMed Central

Kilgore, Katie M.; Murphy, Megan K.; Burton, Samantha L.; Wetzel, Katherine S.; Smith, S. Abigail; Xiao, Peng; Reddy, Sharmila; Francella, Nicholas; Sodora, Donald L.; Silvestri, Guido; Cole, Kelly S.; Villinger, Francois; Robinson, James E.; Pulendran, Bali; Hunter, Eric; Collman, Ronald G.; Amara, Rama R.

2015-01-01

ABSTRACT Antibodies that can neutralize diverse viral strains are likely to be an important component of a protective human immunodeficiency virus type 1 (HIV-1) vaccine. To this end, preclinical simian immunodeficiency virus (SIV)-based nonhuman primate immunization regimens have been designed to evaluate and enhance antibody-mediated protection. However, these trials often rely on a limited selection of SIV strains with extreme neutralization phenotypes to assess vaccine-elicited antibody activity. To mirror the viral panels used to assess HIV-1 antibody breadth, we created and characterized a novel panel of 14 genetically and phenotypically diverse SIVsm envelope (Env) glycoproteins. To assess the utility of this panel, we characterized the neutralizing activity elicited by four SIVmac239 envelope-expressing DNA/modified vaccinia virus Ankara vector- and protein-based vaccination regimens that included the immunomodulatory adjuvants granulocyte-macrophage colony-stimulating factor, Toll-like receptor (TLR) ligands, and CD40 ligand. The SIVsm Env panel exhibited a spectrum of neutralization sensitivity to SIV-infected plasma pools and monoclonal antibodies, allowing categorization into three tiers. Pooled sera from 91 rhesus macaques immunized in the four trials consistently neutralized only the highly sensitive tier 1a SIVsm Envs, regardless of the immunization regimen. The inability of vaccine-mediated antibodies to neutralize the moderately resistant tier 1b and tier 2 SIVsm Envs defined here suggests that those antibodies were directed toward epitopes that are not accessible on most SIVsm Envs. To achieve a broader and more effective neutralization profile in preclinical vaccine studies that is relevant to known features of HIV-1 neutralization, more emphasis should be placed on optimizing the Env immunogen, as the neutralization profile achieved by the addition of adjuvants does not appear to supersede the neutralizing antibody profile determined by the immunogen. IMPORTANCE Many in the HIV/AIDS vaccine field believe that the ability to elicit broadly neutralizing antibodies capable of blocking genetically diverse HIV-1 variants is a critical component of a protective vaccine. Various SIV-based nonhuman primate vaccine studies have investigated ways to improve antibody-mediated protection against a heterologous SIV challenge, including administering adjuvants that might stimulate a greater neutralization breadth. Using a novel SIV neutralization panel and samples from four rhesus macaque vaccine trials designed for cross comparison, we show that different regimens expressing the same SIV envelope immunogen consistently elicit antibodies that neutralize only the very sensitive tier 1a SIV variants. The results argue that the neutralizing antibody profile elicited by a vaccine is primarily determined by the envelope immunogen and is not substantially broadened by including adjuvants, resulting in the conclusion that the envelope immunogen itself should be the primary consideration in efforts to elicit antibodies with greater neutralization breadth. PMID:26018167

Studies on the Pathogenesis of Hepatitis A and Feasibility Studies on a Hepatitis A Vaccine.

DTIC Science & Technology

1986-03-14

virus ; Vaccine; Recombinant DNA; 06 01 Pathogenesis; Immunity 06 02 19. ABSTRACT (Continue on reverse if necessary and identify by block numberf te...objectives of this work are to fur- ther our knowledge of the pathogenesis of hepatitis A virus (HAy) infection in man, and to develop recombinant...expression vectors for hepatitis A virus antigens that can be used to stimulate mucosal immunity. Two viral cDNA sequences encoding different forms of capsid

Measuring the Effects of an Ever-Changing Environment on Malaria Control

DTIC Science & Technology

2004-04-01

immunity on improved protection has been described in relationship to vaccine trials against Lyme disease (5). Herd immunity has been shown to play a...rural northern Ghana. Am. J. Trop. Med. Hyg. 59:80–85. 5. de Silva, A. M., S. R. Telford III, L. R. Brunet, S. W. Barthold, and E. Fikrig. 1996. Borrelia ...burgdorferi OspA is an arthropod-specific transmission-block- ing Lyme disease vaccine. Exp. Med. 183:271–275. 6. Diallo, D. A., A. Habluetzel, N

Blocking Blood Supply to Breast Carcinoma With a DNA Vaccine Encoding VEGF Receptor-2

DTIC Science & Technology

2006-03-01

recognize antigens in the form of 8 to 10 amino acid long peptides, presented to T- cell receptors (TCRs) on the cell surface as complexes with major... receptor , and providing tumor- associated antigens , our DNA vaccine can efficiently activate DCs, NK cells , and CTLs, presumably in Peyer’s patches. The... immunoreceptor in immune cell activation and natural killing. Immunity. 2002;17:19-29. (5) Snyder MR, Weyand CM, Goronzy JJ. The double life of NK receptors

Prediction of common epitopes on hemagglutinin of the influenza A virus (H1 subtype).

PubMed

Guo, Chunyan; Xie, Xin; Li, Huijin; Zhao, Penghua; Zhao, Xiangrong; Sun, Jingying; Wang, Haifang; Liu, Yang; Li, Yan; Hu, Qiaoxia; Hu, Jun; Li, Yuan

2015-02-01

Influenza A virus infection is a persistent threat to public health worldwide due to hemagglutinin (HA) variation. Current vaccines against influenza A virus provide immunity to viral isolates similar to vaccine strains. Antibodies against common epitopes provide immunity to diverse influenza virus strains and protect against future pandemic influenza. Therefore, it is vital to analyze common HA antigenic epitopes of influenza virus. In this study, 14 strains of monoclonal antibodies with high sensitivity to common epitopes of influenza virus antigens identified in our previous study were selected as the tool to predict common HA epitopes. The common HA antigenic epitopes were divided into four categories by ELISA blocking experiments, and separately, into three categories according to the preliminary results of computer simulation. Comparison between the results of computer simulations and ELISA blocking experiments indicated that at least two classes of common epitopes are present in influenza virus HA. This study provides experimental data for improving the prediction of HA epitopes of influenza virus (H1 subtype) and the development of a potential universal vaccine as well as a novel approach for the prediction of epitopes on other pathogenic microorganisms. Copyright © 2014 Elsevier Inc. All rights reserved.

Crotoxin: Structural Studies, Mechanism of Action and Cloning of Its Gene

DTIC Science & Technology

1989-12-01

n the acidic subunit was reported In the above reference. The N-terminus was blocked by pyroglutamate , although the residue was refractory to the...immunogens. as 1potential vaccines against crotoxin and its homologs. Acidic and basic suburdts of crotoxin were sequenced and their higher- ordered...and acidic subunits ot crotoxin. The acidic subunit peptides were difficult, since two of the three peptides were blocked at the amino-terminus by

Development and evaluation of a competitive ELISA using a monoclonal antibody for antibody detection after goose parvovirus virus-like particles (VLPs) and vaccine immunization in goose sera.

PubMed

Wang, Qian; Ju, Huanyu; Li, Yanwei; Jing, Zhiqiang; Guo, Lu; Zhao, Yu; Ma, Bo; Gao, Mingchun; Zhang, Wenlong; Wang, Junwei

2014-12-01

An assay protocol based on a monoclonal antibody-based competitive enzyme-linked immunosorbent assay (MAb-based C-ELISA) for detecting antibodies against goose parvovirus (GPV) and its virus-like particles (VLPs) is described. The assay was developed using baculovirus-expressed recombinant VP2 virus-like particles (rVP2-VLPs) as antigens and a monoclonal antibody against GPV as the competitive antibody. Of the four anti-GPV MAbs that were screened, MAb 1G3 was selected as it was blocked by the GPV positive serum. Based on the distribution of percent inhibition (PI) of the known negative sera (n=225), a cut-off value was set at 36% inhibition. Using this cut-off value, the sensitivity of the assay was 93.3% and the specificity was 95.8%, as compared with the gold standard (virus neutralization assay). The rVP2-VLPs did not react with anti-sera to other goose pathogens, indicating that it is specific for the recognization of goose parvovirus antibodies. The assay was then validated with serum samples from goslings vaccinated with several VLPs (rVP1-VLPs, rVP2-VLPs, rVP3-VLPs, and rCGV-VLPs) and other vaccines (inactivated and attenuated). The C-ELISA described in this study is a sensitive and specific diagnostic test and should have wide applications for the sero-diagnosis and immunologic surveillance of GPV. Copyright © 2014 Elsevier B.V. All rights reserved.

Serologic response of captive coyotes (Canis latrans Say) to canine parvovirus and accompanying profiles of canine coronavirus titers.

PubMed

Green, J S; Bruss, M L; Evermann, J F; Bergstrom, P K

1984-01-01

Fifty-five of 66 (83%) coyote pups from bitches vaccinated against canine parvovirus (CPV) were seropositive for CPV antibodies at birth. The CPV antibody titer in the pups declined with a half-life of 6.7 days until by the 8th week, only two of 41 (5%) pups were seropositive for CPV antibodies. At 8 wk, 41 of the pups were vaccinated against CPV (killed feline origin vaccine), but only one of 37 (3%) was positive for CPV antibodies at 11 wk. The 8-wk-old pups were either too young to respond to the CPV vaccine; they had sufficient undetectable, maternally-derived CPV antibodies to block active immunization; 3 wk was not a sufficient time for an immunological response from the pups; or the vaccine was poorly antigenic. Twenty of the 66 pups (30%) were seropositive for canine coronavirus (CCV) antibodies at birth, and all but three of the 20 were whelped from bitches that were also seropositive for CCV antibodies. Vaccination of females prior to whelping appeared to provide protection to their pups from CPV-induced mortality.

The future potential for cocaine vaccines.

PubMed

Orson, Frank M; Wang, Rongfu; Brimijoin, Stephen; Kinsey, Berma M; Singh, Rana Ak; Ramakrishnan, Muthu; Wang, Helen Y; Kosten, Thomas R

2014-09-01

Addiction to cocaine is a major problem around the world, but especially in developed countries where the combination of wealth and user demand has created terrible social problems. Although only some users become truly addicted, those who are often succumb to a downward spiral in their lives from which it is very difficult to escape. From the medical perspective, the lack of effective and safe, non-addictive therapeutics has instigated efforts to develop alternative approaches for treatment, including anticocaine vaccines designed to block cocaine's pharmacodynamic effects. This paper discusses the implications of cocaine pharmacokinetics for robust vaccine antibody responses, the results of human vaccine clinical trials, new developments in animal models for vaccine evaluation, alternative vaccine formulations and complementary therapy to enhance anticocaine effectiveness. Robust anti-cocaine antibody responses are required for benefit to cocaine abusers, but since any reasonably achievable antibody level can be overcome with higher drug doses, sufficient motivation to discontinue use is also essential so that the relative barrier to cocaine effects will be appropriate for each individual. Combining a vaccine with achievable levels of an enzyme to hydrolyze cocaine to inactive metabolites, however, may substantially increase the blockade and improve treatment outcomes.

The future potential for cocaine vaccines

PubMed Central

Orson, Frank M; Wang, Rongfu; Brimijoin, Stephen; Kinsey, Berma M; Singh, Rana AK; Ramakrishnan, Muthu; Wang, Helen Y; Kosten, Thomas R

2014-01-01

Introduction Addiction to cocaine is a major problem around the world, but especially in developed countries where the combination of wealth and user demand has created terrible social problems. Although only some users become truly addicted, those who are often succumb to a downward spiral in their lives from which it is very difficult to escape. From the medical perspective, the lack of effective and safe, non-addictive therapeutics has instigated efforts to develop alternative approaches for treatment, including anticocaine vaccines designed to block cocaine’s pharmacodynamic effects. Areas covered This paper discusses the implications of cocaine pharmacokinetics for robust vaccine antibody responses, the results of human vaccine clinical trials, new developments in animal models for vaccine evaluation, alternative vaccine formulations and complementary therapy to enhance anticocaine effectiveness. Expert opinion Robust anti-cocaine antibody responses are required for benefit to cocaine abusers, but since any reasonably achievable antibody level can be overcome with higher drug doses, sufficient motivation to discontinue use is also essential so that the relative barrier to cocaine effects will be appropriate for each individual. Combining a vaccine with achievable levels of an enzyme to hydrolyze cocaine to inactive metabolites, however, may substantially increase the blockade and improve treatment outcomes. PMID:24835496

Flea-borne transmission model to evaluate vaccine efficacy against naturally acquired bubonic plague.

PubMed

Jarrett, Clayton O; Sebbane, Florent; Adamovicz, Jeffrey J; Andrews, Gerard P; Hinnebusch, B Joseph

2004-04-01

A flea-to-mouse transmission model was developed for use in testing new candidate vaccines for the ability to protect against flea-borne plague. The model was used to evaluate a recombinant fusion protein vaccine consisting of the Yersinia pestis F1 and V antigens. After one to three challenges with Y. pestis-infected fleas, 14 of 15 unvaccinated control mice developed plague, with an average septicemia level of 9.2 x 10(8) Y. pestis CFU/ml. None of 15 vaccinated mice developed the disease after similar challenges, and serological testing indicated that transmitted bacteria were eliminated by the immune system before extensive replication and systemic infection could occur. The transmission and development of disease in control mice correlated with the number of bites by blocked fleas but not with the total number of fleabites. The model provides a means to directly assess the efficacy of new vaccines to prevent naturally acquired bubonic plague and to study events at the vector-host interface that lead to dissemination and disease.

Determining the activity of mucosal adjuvants.

PubMed

Baudner, Barbara C; Giudice, Giuseppe Del

2010-01-01

Mucosal vaccination offers the advantage of blocking pathogens at the portal of entry, improving patient's compliance, facilitating vaccine delivery, and decreasing the risk of unwanted spread of infectious agents via contaminated syringes.Recent advances in vaccinology have created an array of vaccine constructs that can be delivered to mucosal surfaces of the respiratory, gastrointestinal, and genitourinary tracts using intranasal, oral, and vaginal routes. Due to the different characteristics of mucosal immune response, as compared with systemic response, mucosal immunization requires particular methods of antigen presentation. Well-tolerated adjuvants that enhance the efficacy of such vaccines will play an important role in mucosal immunization. Among promising mucosal adjuvants, mutants of cholera toxin and the closely related heat-labile enterotoxin (LT) of enterotoxigenic Escherichia coli present powerful tools, augmenting the local and systemic serum antibody response to co-administered antigens.In this chapter, we describe the formulation and application of vaccines using the genetically modified LTK63 mutant as a prototype of the family of these mucosal adjuvants and the tools to determine its activity in the mouse model.

Efficacy of combined hepatitis B immunoglobulin and hepatitis B vaccine in blocking father-infant transmission of hepatitis B viral infection.

PubMed

Cao, L-H; Liu, Z-M; Zhao, P-L; Sun, S-C; Xu, D-B; Shao, M-H; Zhang, J-D

2015-05-04

The aim of this study was to examine the efficacy of combined immunization of hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine (HBVac) in blocking father-infant transmission of hepatitis B virus (HBV). Newborns positive at birth for blood HBV sur-face antigen (HBsAg) and/or HBV DNA were selected and immunized with HBIG combination HBVac. At 7 months, HBV markers and HBV DNA of each neonate were measured using electrochemiluminescence with the Cobas-e-411 Automatic Electrochemiluminescence Immuno-assay Analyzer and fluorescence quantitative polymerase chain reaction. Among all 7-month-old subjects, the negative conversion rates of HBV DNA and HBsAg were 48/61 (78.7%) and 19/41 (46.3%), respectively. Therefore, this study demonstrated that prompt combination injection of HBIG and HBVac can protect some of the HBV DNA- and/ or HBsAg-positive newborns from HBV.

Protein Energy Malnutrition during Vaccination Has Limited Influence on Vaccine Efficacy but Abolishes Immunity if Administered during Mycobacterium tuberculosis Infection

PubMed Central

Hoang, Truc; Agger, Else Marie; Cassidy, Joseph P.; Christensen, Jan P.

2015-01-01

Protein energy malnutrition (PEM) increases susceptibility to infectious diseases, including tuberculosis (TB), but it is not clear how PEM influences vaccine-promoted immunity to TB. We demonstrate that PEM during low-level steady-state TB infection in a mouse model results in rapid relapse of Mycobacterium tuberculosis, as well as increased pathology, in both Mycobacterium bovis BCG-vaccinated and unvaccinated animals. PEM did not change the overall numbers of CD4 T cells in BCG-vaccinated animals but resulted in an almost complete loss of antigen-specific cytokine production. Furthermore, there was a change in cytokine expression characterized by a gradual loss of multifunctional antigen-specific CD4 T cells and an increased proportion of effector cells expressing gamma interferon and tumor necrosis factor alpha (IFN-γ+ TNF-α+ and IFN-γ+ cells). PEM during M. tuberculosis infection completely blocked the protection afforded by the H56-CAF01 subunit vaccine, and this was associated with a very substantial loss of the interleukin-2-positive memory CD4 T cells promoted by this vaccine. Similarly, PEM during the vaccination phase markedly reduced the H56-CAF01 vaccine response, influencing all cytokine-producing CD4 T cell subsets, with the exception of CD4 T cells positive for TNF-α only. Importantly, this impairment was reversible and resupplementation of protein during infection rescued both the vaccine-promoted T cell response and the protective effect of the vaccine against M. tuberculosis infection. PMID:25754202

Eculizumab treatment and impaired opsonophagocytic killing of meningococci by whole blood from immunized adults.

PubMed

Konar, Monica; Granoff, Dan M

2017-08-17

Eculizumab, a humanized anti-complement C5 monoclonal antibody (mAb) for treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome, blocks the terminal complement pathway required for serum bactericidal activity (SBA). Because treated patients are at >1000-fold increased risk of meningococcal disease, vaccination is recommended; whether vaccination can protect by opsonophagocytic activity in the absence of SBA is not known. Meningococci were added to anticoagulated blood from 12 healthy adults vaccinated with meningococcal serogroup B and serogroup A, C, W, Y vaccines. Bacterial survival was measured after 3-hour incubation in the presence of eculizumab or control complement factor D inhibitor ACH-4471, which blocks the complement alternative pathway (AP) and is in phase 2 development for treatment of PNH. In the absence of inhibitors, colony formation units (CFUs) per milliliter in blood from all 12 immunized subjects decreased from ∼4000 at time 0 to sterile cultures at 3 hours. In the presence of eculizumab, there was a >22-fold increase in geometric mean CFUs per milliliter (90 596 and 114 683 CFU/mL for serogroup B and C strains, respectively; P < .0001 compared with time 0). In the presence of ACH-4471, there was a >12-fold decrease (23 and 331 CFU/mL, respectively; P < .0001). The lack of meningococci killing by blood containing eculizumab resulted from inhibition of release of C5a, a C5 split product needed for upregulation of phagocytosis. The results provide an explanation for the large number of cases of meningococcal disease in immunized patients being treated with eculizumab and suggest that vaccination may provide better protection against meningococcal disease in patients treated with an AP-specific inhibitor. © 2017 by The American Society of Hematology.

A malaria vaccine for travelers and military personnel: Requirements and top candidates.

PubMed

Teneza-Mora, Nimfa; Lumsden, Joanne; Villasante, Eileen

2015-12-22

Malaria remains an important health threat to non-immune travelers with the explosive growth of global travel. Populations at high risk of acquiring malaria infections include once semi-immune travelers who visit friends and relatives, military forces, business travelers and international tourists with destinations to sub-Saharan Africa, where malaria transmission intensity is high. Most malaria cases have been associated with poor compliance with existing preventive measures, including chemoprophylaxis. High risk groups would benefit immensely from an efficacious vaccine to protect them against malaria infection and together make up a sizable market for such a vaccine. The attributes of an ideal malaria vaccine for non-immune travelers and military personnel include a protective efficacy of 80% or greater, durability for at least 6 months, an acceptable safety profile and compatibility with existing preventive measures. It is very likely that a malaria vaccine designed to effectively prevent infection and clinical disease in the non-immune traveler and military personnel will also protect semi-immune residents of malaria-endemic areas and contribute to malaria elimination by reducing or blocking malaria transmission. The RTS,S vaccine (GlaxoSmithKline) and the PfSPZ Vaccine (Sanaria Inc) are the leading products that would make excellent vaccine candidates for these vulnerable populations. Published by Elsevier Ltd.

Contribution of antibody production against neuraminidase to the protection afforded by influenza vaccines

PubMed Central

Marcelin, Glendie; Sandbulte, Matthew R.; Webby, Richard J.

2012-01-01

SUMMARY Vaccines are instrumental in controlling the burden of influenza virus infection in humans and animals. Antibodies raised against both major viral surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), can contribute to protective immunity. Vaccine-induced HA antibodies have been characterized extensively, and they generally confer protection by blocking the attachment and fusion of a homologous virus onto host cells. Though not as well characterized, some functions of NA antibodies in influenza vaccine-mediated immunity have been recognized for many years. In this review we summarize the case for NA antibodies in influenza vaccine-mediated immunity. In the absence of well-matched HA antibodies, NA antibodies can provide varying degrees of protection against disease. NA proteins of seasonal influenza vaccines have been shown in some instances to elicit serum antibodies with cross-reactivity to avian- and swine-origin influenza strains, in addition to HA drift variants. NA-mediated immunity has been linked to [i] conserved NA epitopes amongst otherwise antigenically distinct strains, partly attributable to the segmented influenza viral genome; [ii] inhibition of NA enzymatic activity; and [iii] the NA content in vaccine formulations. There is potential to enhance the effectiveness of existing and future influenza vaccines by focusing greater attention on the antigenic characteristics and potency of the NA protein. PMID:22438243

Recombinant vaccines against T. gondii: comparison between homologous and heterologous vaccination protocols using two viral vectors expressing SAG1.

PubMed

Mendes, Érica Araújo; Fonseca, Flavio G; Casério, Bárbara M; Colina, Janaína P; Gazzinelli, Ricardo Tostes; Caetano, Braulia C

2013-01-01

The use of recombinant viral vectors expressing T. gondii antigens is a safe and efficient approach to induce immune response against the parasite and a valuable tool for vaccine development. We have previously protected mice from toxoplasmosis by immunizing the animals with an adenovirus expressing the protein SAG1 (AdSAG1) of T. gondii. We are now looking for ways to improve the vaccination strategy and enhance protection. One limitation of homologous vaccinations (sequential doses of the same vector) is induction of anti-vector immune response that blocks cell transduction, restricts transgene expression and, consequently, compromises the overall outcome of vaccination. One way to avert the effects of anti-vector response is to use different viruses in prime and boost (heterologous vaccination). Bearing this in mind, we generated a modified Vaccinia Virus Ankara encoding SAG1 (MVASAG1), to be tested as boost agent after prime with AdSAG1. Although minor differences were observed in the magnitude of the anti-SAG1 immune response induced by each vaccination protocol, the heterologous immunization with AdSAG1 followed by MVASAG1 resulted in improved capacity to control brain cyst formation in a model of chronic toxoplasmosis in C57BL/6 mice.

A practical approach to vaccination of patients with autoimmune inflammatory rheumatic diseases in Australia.

PubMed

Wong, Peter K K; Bagga, Hanish; Barrett, Claire; Hanrahan, Paddy; Johnson, Doug; Katrib, Amel; Leder, Karin; Marabani, Mona; Pentony, Peta; Riordan, John; White, Ray; Young, Laurel

2017-05-01

Autoimmune inflammatory rheumatic diseases (AIIRD), such as rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis are often complicated by infection, which results in significant morbidity and mortality. The increased risk of infection is probably due to a combination of immunosuppressive effects of the AIIRD, comorbidities and the use of immunosuppressive conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) and more recently, targeted synthetic DMARDs and biologic DMARDs that block specific pro-inflammatory enzymes, cytokines or cell types. The use of these various DMARDs has revolutionised the treatment of AIIRD. This has led to a marked improvement in quality of life for AIIRD patients, who often now travel for prolonged periods. Many infections are preventable with vaccination. However, as protective immune responses induced by vaccination may be impaired by immunosuppression, where possible, vaccination may need to be performed prior to initiation of immunosuppression. Vaccination status should also be reviewed when planning overseas travel. Limited data regarding vaccine efficacy in patients with AIIRD make prescriptive guidelines difficult. However, a vaccination history should be part of the initial work-up in all AIIRD patients. Those caring for AIIRD patients should regularly consider vaccination to prevent infection within the practicalities of routine clinical practice. © 2017 Royal Australasian College of Physicians.

Development and validation of an epitope-blocking ELISA using an anti-haemagglutinin monoclonal antibody for specific detection of antibodies in sheep and goat sera directed against peste des petits ruminants virus.

PubMed

Bodjo, Sanne Charles; Baziki, Jean-de-Dieu; Nwankpa, Nick; Chitsungo, Ethel; Koffi, Yao Mathurin; Couacy-Hymann, Emmanuel; Diop, Mariame; Gizaw, Daniel; Tajelser, Idris Badri Adam; Lelenta, Mamadou; Diallo, Adama; Tounkara, Karim

2018-07-01

Peste des petits ruminants (PPR) is a contagious and economically important disease affecting production of small ruminants (i.e., sheep and goats). Taking into consideration the lessons learnt from the Global Rinderpest Eradication Programme (GREP), PPR is now targeted by the international veterinary community as the next animal disease to be eradicated. To support the African continental programme for the control of PPR, the Pan African Veterinary Vaccine Centre of the African Union (AU-PANVAC) is developing diagnostics tools. Here, we describe the development of a blocking enzyme-linked immunosorbent assay (bELISA) that allows testing of a large number of samples for specific detection of antibodies directed against PPR virus in sheep and goat sera. The PPR bELISA uses an anti-haemagglutinin (H) monoclonal antibody (MAb) as a competitor antibody, and tests results are interpreted using the percentage of inhibition (PI) of MAb binding generated by the serum sample. PI values below or equal to 18% (PI ≤ 18%) are negative, PI values greater than or equal to 25% (PI ≥ 25%) are positive, and PI values greater than 18% and below 25% are doubtful. The diagnostic specificity (DSp) and diagnostic sensitivity (DSe) were found to be 100% and 93.74%, respectively. The H-based PPR-bELISA showed good correlation with the virus neutralization test (VNT), the gold standard test, with a kappa value of 0.947. The H-based PPR-bELISA is more specific than the commercial kit ID Screen® PPR Competition (N-based PPR-cELISA) from IDvet (France), but the commercial kit is slightly more sensitive than the H-based PPR-bELISA. The validation process also indicated good repeatability and reproducibility of the H-based PPR-bELISA, making this new test a suitable tool for the surveillance and sero-monitoring of the vaccination campaign.

Oral immunization of BALB/c mice with Giardia duodenalis recombinant cyst wall protein inhibits shedding of cysts.

PubMed

Larocque, R; Nakagaki, K; Lee, P; Abdul-Wahid, A; Faubert, G M

2003-10-01

The process of encystation is a key step in the Giardia duodenalis life cycle that allows this intestinal protozoan to survive between hosts during person-to-person, animal-to-person, waterborne, or food-borne transmission. The release of cysts from infected persons and animals is the main contributing factor to contamination of the environment. Genes coding for cyst wall proteins (CWPs), which could be used for developing a transmission-blocking vaccine, have been cloned. Since the immunogenicity of recombinant Giardia CWP is unknown, we have investigated the immunogenicity of recombinant CWP2 (rCWP2) and its efficacy in interfering with the phenomenon of encystation taking place in the small bowels of BALB/c mice vaccinated with the recombinant protein. Here we report that the immunization of BALB/c mice with rCWP2 stimulated the immune system in a manner comparable to that for a live infection with Giardia muris cysts. Fecal and serum anti-rCWP2 immunoglobulin A (IgA) antibodies were detected in the immunized mice. In addition, anti-rCWP2 IgG1 and IgG2a antibodies were detected in the serum. mRNAs coding for Th1 and Th2 types of cytokines were detected in spleen and Peyer's patch cells from immunized mice. When the vaccinated mice were challenged with live cysts, the animals shed fewer cysts. We conclude that rCWP2 is a possible candidate antigen for the development of a transmission-blocking vaccine.

An international collaborative study to determine the prevalence of contagious caprine pleuropneumonia by monoclonal antibody-based cELISA.

PubMed

Peyraud, Armelle; Poumarat, François; Tardy, Florence; Manso-Silván, Lucía; Hamroev, Karomatullo; Tilloev, Tillo; Amirbekov, Mullojon; Tounkara, Karim; Bodjo, Charles; Wesonga, Hezron; Nkando, Isabel Gacheri; Jenberie, Shiferaw; Yami, Martha; Cardinale, Eric; Meenowa, Deodass; Jaumally, Mahmad Reshad; Yaqub, Tahir; Shabbir, Muhammad Zubair; Mukhtar, Nadia; Halimi, Mohibullah; Ziay, Ghulam Mohammad; Schauwers, Willy; Noori, Hafizullah; Rajabi, Ali Madad; Ostrowski, Stéphane; Thiaucourt, François

2014-02-24

Few serological tests are available for detecting antibodies against Mycoplasma capricolum subsp. capripneumoniae, the causal agent of contagious caprine pleuropneumonia (CCPP). The complement fixation test, the test prescribed for international trade purposes, uses a crude antigen that cross-reacts with all the other mycoplasma species of the "mycoides cluster" frequently infecting goat herds. The lack of a more specific test has been a real obstacle to the evaluation of the prevalence and economic impact of CCPP worldwide. A new competitive ELISA kit for CCPP, based on a previous blocking ELISA, was formatted at CIRAD and used to evaluate the prevalence of CCPP in some regions of Kenya, Ethiopia, Mauritius, Tajikistan and Pakistan in an international collaborative study. The strict specificity of the test was confirmed in CCPP-free goat herds exposed to other mycoplasma species of the "mycoides cluster". Prevalence studies were performed across the enzootic range of the disease in Africa and Asia. Seroprevalence was estimated at 14.6% in the Afar region of Ethiopia, whereas all the herds presented for CCPP vaccination in Kenya tested positive (individual seroprevalence varied from 6 to 90% within each herd). In Mauritius, where CCPP emerged in 2009, nine of 62 herds tested positive. In Central Asia, where the disease was confirmed only recently, no positive animals were detected in the Wakhan District of Afghanistan or across the border in neighboring areas of Tajikistan, whereas seroprevalence varied between 2.7% and 44.2% in the other districts investigated and in northern Pakistan. The test was also used to monitor seroconversion in vaccinated animals. This newly formatted CCPP cELISA kit has retained the high specificity of the original kit. It can therefore be used to evaluate the prevalence of CCPP in countries or regions without vaccination programs. It could also be used to monitor the efficacy of vaccination campaigns as high-quality vaccines induce high rates of seroconversion.

An international collaborative study to determine the prevalence of contagious caprine pleuropneumonia by monoclonal antibody-based cELISA

PubMed Central

2014-01-01

Background Few serological tests are available for detecting antibodies against Mycoplasma capricolum subsp. capripneumoniae, the causal agent of contagious caprine pleuropneumonia (CCPP). The complement fixation test, the test prescribed for international trade purposes, uses a crude antigen that cross-reacts with all the other mycoplasma species of the “mycoides cluster” frequently infecting goat herds. The lack of a more specific test has been a real obstacle to the evaluation of the prevalence and economic impact of CCPP worldwide. A new competitive ELISA kit for CCPP, based on a previous blocking ELISA, was formatted at CIRAD and used to evaluate the prevalence of CCPP in some regions of Kenya, Ethiopia, Mauritius, Tajikistan and Pakistan in an international collaborative study. Results The strict specificity of the test was confirmed in CCPP-free goat herds exposed to other mycoplasma species of the “mycoides cluster”. Prevalence studies were performed across the enzootic range of the disease in Africa and Asia. Seroprevalence was estimated at 14.6% in the Afar region of Ethiopia, whereas all the herds presented for CCPP vaccination in Kenya tested positive (individual seroprevalence varied from 6 to 90% within each herd). In Mauritius, where CCPP emerged in 2009, nine of 62 herds tested positive. In Central Asia, where the disease was confirmed only recently, no positive animals were detected in the Wakhan District of Afghanistan or across the border in neighboring areas of Tajikistan, whereas seroprevalence varied between 2.7% and 44.2% in the other districts investigated and in northern Pakistan. The test was also used to monitor seroconversion in vaccinated animals. Conclusions This newly formatted CCPP cELISA kit has retained the high specificity of the original kit. It can therefore be used to evaluate the prevalence of CCPP in countries or regions without vaccination programs. It could also be used to monitor the efficacy of vaccination campaigns as high-quality vaccines induce high rates of seroconversion. PMID:24565080

Engineering synthetic vaccines using cues from natural immunity

PubMed Central

Irvine, Darrell J.; Swartz, Melody A.; Szeto, Gregory L.

2014-01-01

Vaccines aim to protect against or treat diseases through manipulation of the immune response, promoting either immunity or tolerance. The former generate antibodies and T-cells poised to protect against future pathogen encounter or attack diseased cells such as tumors; the latter, which are far less developed, block pathogenic autoreactive T-cells and autoantibodies that target self tissue. Enormous challenges remain, however, as a consequence of our incomplete understanding of human immunity. A rapidly growing field of research is the design of synthetic materials in vaccines to 1) target organs, tissues, cells, or intracellular compartments; 2) co-deliver immunomodulatory signals that control the quality of the immune response; or 3) directly act as immune regulators, and there exists great potential for well-defined materials to further our understanding of immunity. Here we describe recent advances in the design of synthetic materials to direct immune responses, highlighting successes and challenges in prophylactic, therapeutic, and tolerance-inducing vaccines. PMID:24150416

Vaccination against Lyme disease: past, present, and future.

PubMed

Embers, Monica E; Narasimhan, Sukanya

2013-01-01

Lyme borreliosis is a zoonotic disease caused by Borrelia burgdorferi sensu lato bacteria transmitted to humans and domestic animals by the bite of an Ixodes spp. tick (deer tick). Despite improvements in diagnostic tests and public awareness of Lyme disease, the reported cases have increased over the past decade to approximately 30,000 per year. Limitations and failed public acceptance of a human vaccine, comprised of the outer surface A (OspA) lipoprotein of B. burgdorferi, led to its demise, yet current research has opened doors to new strategies for protection against Lyme disease. In this review we discuss the enzootic cycle of B. burgdorferi, and the unique opportunities it poses to block infection or transmission at different levels. We present the correlates of protection for this infectious disease, the pros and cons of past vaccination strategies, and new paradigms for future vaccine design that would include elements of both the vector and the pathogen.

Vaccines for cocaine abuse.

PubMed

Orson, Frank M; Kinsey, Berma M; Singh, Rana A K; Wu, Yan; Kosten, Thomas R

2009-04-01

Treatments for cocaine abuse have been disappointingly ineffective, especially in comparison with those for some other abused substances. A new approach, using vaccination to elicit specific antibodies to block the access of cocaine to the brain, has shown considerable promise in animal models, and more recently in human trials. The mechanism of action for the antibody effect on cocaine is very likely to be the straightforward and intuitive result of the binding of the drug in circulation by antibodies, thereby reducing its entry into the central nervous system and thus its pharmacological effects. The effectiveness of such antibodies on drug pharmacodynamics is a function of both the quantitative and the qualitative properties of the antibodies, and this combination will determine the success of the clinical applications of anti-cocaine vaccines in helping addicts discontinue cocaine abuse. This review will discuss these issues and present the current developmental status of cocaine conjugate vaccines.

Vaccination against Lyme disease: past, present, and future

PubMed Central

Embers, Monica E.; Narasimhan, Sukanya

2013-01-01

Lyme borreliosis is a zoonotic disease caused by Borrelia burgdorferi sensu lato bacteria transmitted to humans and domestic animals by the bite of an Ixodes spp. tick (deer tick). Despite improvements in diagnostic tests and public awareness of Lyme disease, the reported cases have increased over the past decade to approximately 30,000 per year. Limitations and failed public acceptance of a human vaccine, comprised of the outer surface A (OspA) lipoprotein of B. burgdorferi, led to its demise, yet current research has opened doors to new strategies for protection against Lyme disease. In this review we discuss the enzootic cycle of B. burgdorferi, and the unique opportunities it poses to block infection or transmission at different levels. We present the correlates of protection for this infectious disease, the pros and cons of past vaccination strategies, and new paradigms for future vaccine design that would include elements of both the vector and the pathogen. PMID:23407755

Does BCG vaccine prevent tuberculous meningitis?

PubMed Central

Thilothammal, N; Krishnamurthy, P V; Runyan, D K; Banu, K

1996-01-01

The reported efficacy of BCG vaccine in preventing pulmonary tuberculosis varies from 0-80%; however, its efficacy in preventing tuberculous meningitis ranges from 52%-84%. A case-control study was conducted to assess the efficacy of BCG in preventing tuberculous meningitis in children. New cases of tuberculous meningitis, confirmed bacteriologically, were registered as cases. Controls were children suffering from febrile convulsions attending the same hospital. A total of 107 cases and 321 controls, block matched for age, were registered. Vaccination status was determined from the history reported by the mother and by BCG scar reading. Data regarding socioeconomic status, crowding, and nutritional status were collected. Using multiple logistic regression analysis the odds ratio obtained for the presence of BCG scar was 0.23 (95% confidence interval (CI) 0.14 to 0.37) and the protective efficacy of BCG vaccine in preventing tuberculous meningitis in children was found to be 77% (95% CI 71 to 83%). PMID:8660078

pH-Responsive Nanoparticle Vaccines for Dual-Delivery of Antigens and Immunostimulatory Oligonucleotides

PubMed Central

Wilson, John T.; Keller, Salka; Manganiello, Matthew J.; Cheng, Connie; Lee, Chen-Chang; Opara, Chinonso; Convertine, Anthony; Stayton, Patrick S.

2013-01-01

Protein subunit vaccines offer important potential advantages over live vaccine vectors, but generally elicit weaker and shorter-lived cellular immune responses. Here we investigate the use of pH-responsive, endosomolytic polymer nanoparticles that were originally developed for RNA delivery as vaccine delivery vehicles for enhancing cellular and humoral immune responses. Micellar nanoparticles were assembled from amphiphilic diblock copolymers composed of an ampholytic core-forming block and a re-designed polycationic corona block doped with thiol-reactive pyridyl disulfide groups to enable dual-delivery of antigens and immunostimulatory CpG oligodeoxynucleotide (CpG ODN) adjuvants. Polymers assembled into 23 nm particles with simultaneous packaging of CpG ODN and a thiolated protein antigen, ovalbumin (ova). Conjugation of ova to nanoparticles significantly enhanced antigen cross-presentation in vitro relative to free ova or an unconjugated, physical mixture of the parent compounds. Subcutaneous vaccination of mice with ova-nanoparticle conjugates elicited a significantly higher CD8+ T cell response (0.5% IFN-ɣ+ of CD8+) compared to mice vaccinated with free ova or a physical mixture of the two components. Significantly, immunization with ova-nanoparticle conjugates electrostatically complexed with CpG ODN (dual-delivery) enhanced CD8+ T cell responses (3.4% IFN-ɣ+ of CD8+) 7-, 18-, and 8-fold relative to immunization with conjugates, ova administered with free CpG, or a formulation containing free ova and CpG complexed to micelles, respectively. Similarly, dual-delivery carriers significantly increased CD4+IFN-ɣ+ (Th1) responses, and elicited a balanced IgG1/IgG2c antibody response. Intradermal administration further augmented cellular immune responses, with dual-delivery carriers inducing ~7% antigen-specific CD8+ T cells. This work demonstrates the ability of pH-responsive, endosomolytic nanoparticles to actively promote antigen cross-presentation and augment cellular and humoral immune responses via dual-delivery of protein antigens and CpG ODN. Hence, pH-responsive polymeric nanoparticles offer promise as a delivery platform for protein subunit vaccines. PMID:23590591

PD-1 or PD-L1 Blockade Restores Antitumor Efficacy Following SSX2 Epitope-Modified DNA Vaccine Immunization.

PubMed

Rekoske, Brian T; Smith, Heath A; Olson, Brian M; Maricque, Brett B; McNeel, Douglas G

2015-08-01

DNA vaccines have demonstrated antitumor efficacy in multiple preclinical models, but low immunogenicity has been observed in several human clinical trials. This has led to many approaches seeking to improve the immunogenicity of DNA vaccines. We previously reported that a DNA vaccine encoding the cancer-testis antigen SSX2, modified to encode altered epitopes with increased MHC class I affinity, elicited a greater frequency of cytolytic, multifunctional CD8(+) T cells in non-tumor-bearing mice. We sought to test whether this optimized vaccine resulted in increased antitumor activity in mice bearing an HLA-A2-expressing tumor engineered to express SSX2. We found that immunization of tumor-bearing mice with the optimized vaccine elicited a surprisingly inferior antitumor effect relative to the native vaccine. Both native and optimized vaccines led to increased expression of PD-L1 on tumor cells, but antigen-specific CD8(+) T cells from mice immunized with the optimized construct expressed higher PD-1. Splenocytes from immunized animals induced PD-L1 expression on tumor cells in vitro. Antitumor activity of the optimized vaccine could be increased when combined with antibodies blocking PD-1 or PD-L1, or by targeting a tumor line not expressing PD-L1. These findings suggest that vaccines aimed at eliciting effector CD8(+) T cells, and DNA vaccines in particular, might best be combined with PD-1 pathway inhibitors in clinical trials. This strategy may be particularly advantageous for vaccines targeting prostate cancer, a disease for which antitumor vaccines have demonstrated clinical benefit and yet PD-1 pathway inhibitors alone have shown little efficacy to date. ©2015 American Association for Cancer Research.

Safety and efficacy of an oxycodone vaccine: Addressing some of the unique considerations posed by opioid abuse

PubMed Central

Peterson, S. J.; Laudenbach, M.; Baruffaldi, F.; Carroll, F. I.; Comer, S. D.; Navarro, H. A.; Langston, T. L.; Runyon, S. P.; Winston, S.; Pravetoni, M.; Pentel, P. R.

2017-01-01

Among vaccines aimed at treating substance use disorders, those targeting opioids present several unique medication development challenges. 1) Opioid overdose is a common complication of abuse, so it is desirable for an opioid vaccine to block the toxic as well as the addictive effects of opioids. 2) It is important that an opioid vaccine not interfere with the action of opioid antagonists used to reverse opioid overdose or treat addiction. 3) Some opioids are immunosuppressive and chronic ongoing opioid use could interfere with vaccine immunogenicity. 4) Although antibody-bound oxycodone is unable to enter the brain because of its size, it might still be able to activate peripheral opioid receptors. To assess vaccine impact on opioid toxicity, rats vaccinated with oxycodone conjugated to keyhole limpet hemocyanin subunit dimer (OXY-dKLH) adsorbed to alum or controls vaccinated with dKLH were compared with regard to oxycodone-induced hotplate analgesia and oxycodone-induced respiratory depression and bradycardia. Vaccination shifted the dose-response curves to the right, representing protection, for each of these endpoints. Naloxone was equally effective in both OXY-dKLH and control groups, providing complete and rapid reversal of respiratory depression. The administration of a long-acting naltrexone formulation during vaccination did not impair vaccine immunogenicity in mice. Similarly, serum anti-oxycodone antibody titers were not altered by continuous morphine infusion during vaccination compared to opioid-naïve controls. Competitive ELISA assay showed negligible or low affinity of immune antiserum for endogenous opioids or opioid antagonists. In vitro receptor binding assays showed that antibody-bound oxycodone does not activate mu opioid receptors. These data support further study of OXY-dKLH as a potential treatment for oxycodone abuse and suggest that vaccination might also reduce the severity of oxycodone overdose. PMID:29194445

[Immunisation schedule of the Spanish Association of Paediatrics: 2015 recommendations].

PubMed

Moreno-Pérez, D; Álvarez García, F J; Arístegui Fernández, J; Cilleruelo Ortega, M J; Corretger Rauet, J M; García Sánchez, N; Hernández Merino, A; Hernández-Sampelayo Matos, T; Merino Moína, M; Ortigosa Del Castillo, L; Ruiz-Contreras, J

2015-01-01

The Advisory Committee on Vaccines of the Spanish Association of Paediatrics updates the immunisation schedule every year, taking into account epidemiological data as well as evidence on the safety, effectiveness and efficiency of current vaccines, including levels of recommendation. In our opinion, this is the optimal vaccination calendar for all children resident in Spain. Regarding the vaccines included in the official unified immunization schedule, the Committee emphasizes the administration of the first dose of hepatitis B either at birth or at 2 months of life; the recommendation of the first dose of MMR and varicella vaccine at the age of 12 months, with the second dose at the age of 2-3 years; DTaP or Tdap vaccine at the age of 6 years, followed by another Tdap booster dose at 11-12 years old; Tdap strategies for pregnant women and household contacts of the newborn, and immunization against human papillomavirus in girls aged 11-12 years old with a 2 dose scheme (0, 6 months). The Committee reasserts its recommendation to include vaccination against pneumococcal disease in the routine immunisation schedule, the same as it is being conducted in Western European countries. The recently authorised meningococcal B vaccine, currently blocked in Spain, exhibits the profile of a universal vaccine. The Committe insists on the need of having the vaccine available in communitary pharmacies. It has also proposed the free availability of varicella vaccines. Their efectiveness and safety have been confirmed when they are administred from the second year of life. Vaccination against rotavirus is recommended in all infants. The Committee stresses the need to vaccinate population groups considered at risk against influenza and hepatitis A. Copyright © 2014. Published by Elsevier Espana.

Towards the Rational Design of a Candidate Vaccine against Pregnancy Associated Malaria: Conserved Sequences of the DBL6ε Domain of VAR2CSA

PubMed Central

Badaut, Cyril; Bertin, Gwladys; Rustico, Tatiana; Fievet, Nadine; Massougbodji, Achille; Gaye, Alioune; Deloron, Philippe

2010-01-01

Background Placental malaria is a disease linked to the sequestration of Plasmodium falciparum infected red blood cells (IRBC) in the placenta, leading to reduced materno-fetal exchanges and to local inflammation. One of the virulence factors of P. falciparum involved in cytoadherence to chondroitin sulfate A, its placental receptor, is the adhesive protein VAR2CSA. Its localisation on the surface of IRBC makes it accessible to the immune system. VAR2CSA contains six DBL domains. The DBL6ε domain is the most variable. High variability constitutes a means for the parasite to evade the host immune response. The DBL6ε domain could constitute a very attractive basis for a vaccine candidate but its reported variability necessitates, for antigenic characterisations, identifying and classifying commonalities across isolates. Methodology/Principal Findings Local alignment analysis of the DBL6ε domain had revealed that it is not as variable as previously described. Variability is concentrated in seven regions present on the surface of the DBL6ε domain. The main goal of our work is to classify and group variable sequences that will simplify further research to determine dominant epitopes. Firstly, variable sequences were grouped following their average percent pairwise identity (APPI). Groups comprising many variable sequences sharing low variability were found. Secondly, ELISA experiments following the IgG recognition of a recombinant DBL6ε domain, and of peptides mimicking its seven variable blocks, allowed to determine an APPI cut-off and to isolate groups represented by a single consensus sequence. Conclusions/Significance A new sequence approach is used to compare variable regions in sequences that have extensive segmental gene relationship. Using this approach, the VAR2CSA DBL6 domain is composed of 7 variable blocks with limited polymorphism. Each variable block is composed of a limited number of consensus types. Based on peptide based ELISA, variable blocks with 85% or greater sequence identity are expected to be recognized equally well by antibody and can be considered the same consensus type. Therefore, the analysis of the antibody response against the classified small number of sequences should be helpful to determine epitopes. PMID:20585655

The antigenic evolution of influenza: drift or thrift?

PubMed Central

Wikramaratna, Paul S.; Sandeman, Michi; Recker, Mario; Gupta, Sunetra

2013-01-01

It is commonly assumed that antibody responses against the influenza virus are polarized in the following manner: strong antibody responses are directed at highly variable antigenic epitopes, which consequently undergo ‘antigenic drift’, while weak antibody responses develop against conserved epitopes. As the highly variable epitopes are in a constant state of flux, current antibody-based vaccine strategies are focused on the conserved epitopes in the expectation that they will provide some level of clinical protection after appropriate boosting. Here, we use a theoretical model to suggest the existence of epitopes of low variability, which elicit a high degree of both clinical and transmission-blocking immunity. We show that several epidemiological features of influenza and its serological and molecular profiles are consistent with this model of ‘antigenic thrift’, and that identifying the protective epitopes of low variability predicted by this model could offer a more viable alternative to regularly update the influenza vaccine than exploiting responses to weakly immunogenic conserved regions. PMID:23382423

Adjuvanticity of a CTLA-4 3' UTR complementary oligonucleotide for emulsion formulated recombinant subunit and inactivated vaccines.

PubMed

Li, Xin; Yang, Lei; Zhao, Peiyan; Yao, Yun; Lu, Fangjie; Tu, Liqun; Liu, Jiwei; Li, Zhiqin; Yu, Yongli; Wang, Liying

2017-04-25

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is recognized as a critical inhibitory regulator of T-cell proliferation and activation, opposing the action of CD28-mediated co-stimulation. Interfering or blocking CTLA-4 can result in continuous T-cell activation required for the full immune response to pathogenic microbes and vaccines. To test if nucleic acid-based CTLA-4 inhibitors could be developed into a novel adjuvant, we designed two oligonucleotides, CMD-1 and CMD-2, with the sequences complementary to the conserve regions identical between human and mouse CTLA-4 mRNA 3' untranslated region (3' UTR), and tested their in vitro effects on CTLA-4 production and their adjuvanticity for vaccines in mice. We found that CMD-1 inhibited the antigen-induced CTLA-4 up-regulation on the CD4 + T cells by interfering its mRNA expression, maintained higher levels of CD80 and CD86 on the CD11c + cells and promoted the recalled proliferation of the CD4 + T cells and CD19 + B cells, and that the CMD-1 enhanced the antibody response against recombinant PCV2b capsid protein or inactivated foot-and-mouth disease virus in both ICR and BALB/c mice. These data suggest that the CMD-1 could be used as a novel vaccine adjuvant capable of inhibiting inhibitory signals rather than inducing stimulatory signals of immune cells. Copyright © 2017 Elsevier Ltd. All rights reserved.

The control of rabies in Malaya through compulsory mass vaccination of dogs.

PubMed

WELLS, C W

1954-01-01

A fulminating extension of rabies-which has been enzootic in northern Malaya since 1924-occurred in Kuala Lumpur in April 1952. The outbreak was suppressed by the compulsory mass vaccination of dogs, stringent legislation, and intensive stray-dog destruction. Similar measures are being employed in the current campaign, the aim of which is the complete eradication of the disease.From an average annual incidence of 112 confirmed canine cases prior to 1952-when a total of 198 cases was reported-the incidence fell to 15 cases (all in unvaccinated dogs) for the period January-November 1953, during the last 5(1/2) months of which no case in either animals or man was reported. It is considered that the extensive publicity campaign and strict enforcement of the control measures have contributed measurably to the present improved position.Statistics relating to confirmed cases in dogs previously vaccinated with (a) phenolized 20% brain-tissue suspension vaccine (buffalo origin) and (b) chicken-embryo vaccine (Flury strain) are quoted and their probable significance in favour of the latter under Malayan conditions is discussed. The hypothesis that the development of rabies may, in many instances, have been blocked by the vaccine is advanced.The plan for a pan-Federation compulsory vaccination campaign in 1954, to consolidate the 1952-3 improvements, is outlined.

Chimeric Vaccine Stimulation of Human Dendritic Cell Indoleamine 2, 3-Dioxygenase Occurs via the Non-Canonical NF-κB Pathway

PubMed Central

Kim, Nan-Sun; Mbongue, Jacques C.; Nicholas, Dequina A.; Esebanmen, Grace E.; Unternaehrer, Juli J.; Firek, Anthony F.; Langridge, William H. R.

2016-01-01

A chimeric protein vaccine composed of the cholera toxin B subunit fused to proinsulin (CTB-INS) was shown to suppress type 1 diabetes onset in NOD mice and upregulate biosynthesis of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1) in human dendritic cells (DCs). Here we demonstrate siRNA inhibition of the NF-κB-inducing kinase (NIK) suppresses vaccine-induced IDO1 biosynthesis as well as IKKα phosphorylation. Chromatin immunoprecipitation (ChIP) analysis of CTB-INS inoculated DCs showed that RelB bound to NF-κB consensus sequences in the IDO1 promoter, suggesting vaccine stimulation of the non-canonical NF-κB pathway activates IDO1 expression in vivo. The addition of Tumor Necrosis Factor Associated Factors (TRAF) TRAF 2, 3 and TRAF6 blocking peptides to vaccine inoculated DCs was shown to inhibit IDO1 biosynthesis. This experimental outcome suggests vaccine activation of the TNFR super-family receptor pathway leads to upregulation of IDO1 biosynthesis in CTB-INS inoculated dendritic cells. Together, our experimental data suggest the CTB-INS vaccine uses a TNFR-dependent signaling pathway of the non-canonical NF-κB signaling pathway resulting in suppression of dendritic cell mediated type 1 diabetes autoimmunity. PMID:26881431

Immunization With Fc-Based Recombinant Epstein–Barr Virus gp350 Elicits Potent Neutralizing Humoral Immune Response in a BALB/c Mice Model

PubMed Central

Zhao, Bingchun; Zhang, Xiao; Krummenacher, Claude; Song, Shuo; Gao, Ling; Zhang, Haojiong; Xu, Miao; Feng, Lin; Feng, Qisheng; Zeng, Musheng; Xu, Yuting; Zeng, Yixin

2018-01-01

Epstein–Barr virus (EBV) was the first human virus proved to be closely associated with tumor development, such as lymphoma, nasopharyngeal carcinoma, and EBV-associated gastric carcinoma. Despite many efforts to develop prophylactic vaccines against EBV infection and diseases, no candidates have succeeded in effectively blocking EBV infection in clinical trials. Previous investigations showed that EBV gp350 plays a pivotal role in the infection of B-lymphocytes. Nevertheless, using monomeric gp350 proteins as antigens has not been effective in preventing infection. Multimeric forms of the antigen are more potently immunogenic than monomers; however, the multimerization elements used in previous constructs are not approved for human clinical trials. To prepare a much-needed EBV prophylactic vaccine that is potent, safe, and applicable, we constructed an Fc-based form of gp350 to serve as a dimeric antigen. Here, we show that the Fc-based gp350 antigen exhibits dramatically enhanced immunogenicity compared with wild-type gp350 protein. The complete or partial gp350 ectodomain was fused with the mouse IgG2a Fc domain. Fusion with the Fc domain did not impair gp350 folding, binding to a conformation-dependent neutralizing antibody (nAb) and binding to its receptor by enzyme-linked immunosorbent assay and surface plasmon resonance. Specific antibody titers against gp350 were notably enhanced by immunization with gp350-Fc dimers compared with gp350 monomers. Furthermore, immunization with gp350-Fc fusion proteins elicited potent nAbs against EBV. Our data strongly suggest that an EBV gp350 vaccine based on Fc fusion proteins may be an efficient candidate to prevent EBV infection in clinical applications. PMID:29765376

Synergistic and antagonistic interactions between bednets and vaccines in the control of malaria.

PubMed

Artzy-Randrup, Yael; Dobson, Andrew P; Pascual, Mercedes

2015-03-10

It is extremely likely that the malaria vaccines currently in development will be used in conjunction with treated bednets and other forms of malaria control. The interaction of different intervention methods is at present poorly understood in a disease such as malaria where immunity is more complex than for other pathogens that have been successfully controlled by vaccination. Here we develop a general mathematical model of malaria transmission to examine the interaction between vaccination and bednets. Counterintuitively, we find that the frailty of malaria immunity will potentially cause both synergistic and antagonistic interactions between vaccination and the use of bednets. We explore the conditions that create these tensions, and outline strategies that minimize their detrimental impact. Our analysis specifically considers the three leading vaccine classes currently in development: preerythrocytic (PEV), blood stage (BSV), and transmission blocking (TBV). We find that the combination of BSV with treated bednets can lead to increased morbidity with no added value in terms of elimination; the interaction is clearly antagonistic. In contrast, there is strong synergy between PEV and treated bednets that may facilitate elimination, although transient stages are likely to increase morbidity. The combination of TBV with treated bednets is synergistic, lowering both morbidity and elimination thresholds. Our results suggest that vaccines will not provide a straightforward solution to malaria control, and that future programs need to consider the synergistic and antagonistic interactions between vaccines and treated bednets.

Formulation and coating of microneedles with inactivated influenza virus to improve vaccine stability and immunogenicity

PubMed Central

Kim, Yeu-Chun; Quan, Fu-Shi; Compans, Richard W.; Kang, Sang-Moo; Prausnitz, Mark R.

2009-01-01

Microneedle patches coated with solid-state influenza vaccine have been developed to improve vaccine efficacy and patient coverage. However, dip coating microneedles with influenza vaccine can reduce antigen activity. In this study, we sought to determine the experimental factors and mechanistic pathways by which inactivated influenza vaccine can lose activity, as well as develop and assess improved microneedle coating formulations that protect the antigen from activity loss. After coating microneedles using a standard vaccine formulation, antigenicity was reduced to just 2%, as measured by hemagglutination activity. The presence of carboxymethylcellulose, which was added to increase viscosity of the coating formulation, was shown to contribute to vaccine activity loss. After screening a panel of candidate stabilizers, the addition of trehalose to the coating formulation was shown to protect the antigen and retain 48–82% antigen activity for all three major strains of seasonal influenza: H1N1, H3N2 and B. Influenza vaccine coated in this way also exhibited thermal stability, such that activity loss was independent of temperature over the range of 4 – 37°C for 24 h. Dynamic light scattering measurements showed that antigen activity loss was associated with virus particle aggregation, and that stabilization using trehalose largely blocked this aggregation. Finally, microneedles using an optimized vaccine coating formulation were applied to the skin to vaccinate mice. Microneedle vaccination induced robust systemic and functional antibodies and provided complete protection against lethal challenge infection similar to conventional intramuscular injection. Overall, these results show that antigen activity loss during microneedle coating can be largely prevented through optimized formulation and that stabilized microneedle patches can be used for effective vaccination. PMID:19840825

Molecular Evolution of a Type 1 Wild-Vaccine Poliovirus Recombinant during Widespread Circulation in China

PubMed Central

Liu, Hong-Mei; Zheng, Du-Ping; Zhang, Li-Bi; Oberste, M. Steven; Pallansch, Mark A.; Kew, Olen M.

2000-01-01

Type 1 wild-vaccine recombinant polioviruses were isolated from poliomyelitis patients in China from 1991 to 1993. We compared the sequences of 34 recombinant isolates over the 1,353-nucleotide (nt) genomic interval (nt 2480 to 3832) encoding the major capsid protein, VP1, and the protease, 2A. All recombinants had a 367-nt block of sequence (nt 3271 to 3637) derived from the Sabin 1 oral poliovirus vaccine strain spanning the 3′-terminal sequences of VP1 (115 nt) and the 5′ half of 2A (252 nt). The remaining VP1 sequences were closely (up to 99.5%) related to those of a major genotype of wild type 1 poliovirus endemic to China up to 1994. In contrast, the non-vaccine-derived sequences at the 3′ half of 2A were more distantly related (<90% nucleotide sequence match) to those of other contemporary wild polioviruses from China. The vaccine-derived sequences of the earliest (April 1991) isolates completely matched those of Sabin 1. Later isolates diverged from the early isolates primarily by accumulation of synonymous base substitutions (at a rate of ∼3.7 × 10−2 substitutions per synonymous site per year) over the entire VP1-2A interval. Distinct evolutionary lineages were found in different Chinese provinces. From the combined epidemiologic and evolutionary analyses, we propose that the recombinant virus arose during mixed infection of a single individual in northern China in early 1991 and that its progeny spread by multiple independent chains of transmission into some of the most populous areas of China within a year of the initiating infection. PMID:11070012

Selective Effects of a Morphine Conjugate Vaccine on Heroin and Metabolite Distribution and Heroin-Induced Behaviors in Rats

PubMed Central

Pravetoni, M.; Harris, A.C.; Birnbaum, A.K.; Pentel, P.R.

2013-01-01

Morphine conjugate vaccines have effectively reduced behavioral effects of heroin in rodents and primates. To better understand how these effects are mediated, heroin and metabolite distribution studies were performed in rats in the presence and absence of vaccination. In non-vaccinated rats 6-monoacetylmorphine (6-MAM) was the predominant opioid in plasma and brain as early as 1 minute after i.v. administration of heroin and for up to 14 minutes. Vaccination with morphine conjugated to keyhole limpet hemocyanin (M-KLH) elicited high titers and concentrations of antibodies with high affinity for heroin, 6-MAM, and morphine. Four minutes after heroin administration vaccinated rats showed substantial retention of all three opioids in plasma compared to controls and reduced 6-MAM and morphine, but not heroin, distribution to brain. Administration of 6-MAM rather than heroin in M-KLH vaccinated rats showed a similar drug distribution pattern. Vaccination reduced heroin-induced analgesia and blocked heroin-induced locomotor activity throughout 2 weeks of repeated testing. Higher serum opioid-specific antibody concentrations were associated with higher plasma opioid concentrations, lower brain 6-MAM and morphine concentrations, and lower heroin-induced locomotor activity. Serum antibody concentrations over 0.2 mg/ml were associated with substantial effects on these measures. These data support a critical role for 6-MAM in mediating the early effects of i.v. heroin and suggest that reducing 6-MAM concentration in brain is essential to the efficacy of morphine conjugate vaccines. PMID:23220743

Naturally acquired antibody responses to recombinant Pfs230 and Pfs48/45 transmission blocking vaccine candidates.

PubMed

Jones, Sophie; Grignard, Lynn; Nebie, Issa; Chilongola, Jaffu; Dodoo, Daniel; Sauerwein, Robert; Theisen, Michael; Roeffen, Will; Singh, Shrawan Kumar; Singh, Rajesh Kumar; Singh, Sanjay; Kyei-Baafour, Eric; Tetteh, Kevin; Drakeley, Chris; Bousema, Teun

2015-07-01

Pfs48/45 and Pfs230 are Plasmodium falciparum sexual stage proteins and promising malaria transmission-blocking vaccine candidates. Antibody responses against these proteins may be naturally acquired and target antigens may be under selective pressure. This has consequences for the future evaluation of vaccine immunogenicity and efficacy in populations naturally exposed to malaria. We determined naturally acquired antibody responses to the recombinant proteins Pfs48/45-10C and Pfs230-230CMB in children from three malaria endemic settings in Ghana, Tanzania and Burkina Faso. We also examined genetic polymorphisms in the P. falciparum gene pfs48/45. Antibody prevalence was 1.1-18.2% for 10C and 6.7-18.9% for 230CMB. In Burkina Faso we observed evidence of an age-dependent acquisition pattern for both 10C (p < 0.001) and 230CMB (p = 0.031). Membrane feeding assays on a separate dataset demonstrated an association between functional transmission reducing activity and antibody prevalence for both 10C (p = 0.017) and 230CMB (p = 0.049). 17 single nucleotide polymorphisms were found in pfs48/45 (from 126 samples), with 5 non-synonymous SNPs in the Pfs48/45 10C region. We conclude there are naturally acquired antibody responses to both vaccine candidates which have functional relevance by reducing the transmissibility of infected individuals. We identified genetic polymorphisms, in pfs48/45 which exhibited geographical specificity. Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Abasic Phosphorothioate Oligomers Inhibit HIV-1 Reverse Transcription and Block Virus Transmission across Polarized Ectocervical Organ Cultures

PubMed Central

Fraietta, Joseph A.; Mueller, Yvonne M.; Lozenski, Karissa L.; Ratner, Deena; Boesteanu, Alina C.; Hancock, Aidan S.; Lackman-Smith, Carol; Zentner, Isaac J.; Chaiken, Irwin M.; Chung, Suhman; LeGrice, Stuart F. J.; Snyder, Beth A.; Mankowski, Marie K.; Jones, Natalie M.; Hope, Jennifer L.; Gupta, Phalguni; Anderson, Sharon H.; Wigdahl, Brian

2014-01-01

In the absence of universally available antiretroviral (ARV) drugs or a vaccine against HIV-1, microbicides may offer the most immediate hope for controlling the AIDS pandemic. The most advanced and clinically effective microbicides are based on ARV agents that interfere with the earliest stages of HIV-1 replication. Our objective was to identify and characterize novel ARV-like inhibitors, as well as demonstrate their efficacy at blocking HIV-1 transmission. Abasic phosphorothioate 2′ deoxyribose backbone (PDB) oligomers were evaluated in a variety of mechanistic assays and for their ability to inhibit HIV-1 infection and virus transmission through primary human cervical mucosa. Cellular and biochemical assays were used to elucidate the antiviral mechanisms of action of PDB oligomers against both lab-adapted and primary CCR5- and CXCR4-utilizing HIV-1 strains, including a multidrug-resistant isolate. A polarized cervical organ culture was used to test the ability of PDB compounds to block HIV-1 transmission to primary immune cell populations across ectocervical tissue. The antiviral activity and mechanisms of action of PDB-based compounds were dependent on oligomer size, with smaller molecules preventing reverse transcription and larger oligomers blocking viral entry. Importantly, irrespective of molecular size, PDBs potently inhibited virus infection and transmission within genital tissue samples. Furthermore, the PDB inhibitors exhibited excellent toxicity and stability profiles and were found to be safe for vaginal application in vivo. These results, coupled with the previously reported intrinsic anti-inflammatory properties of PDBs, support further investigations in the development of PDB-based topical microbicides for preventing the global spread of HIV-1. PMID:25224013

A trivalent subunit antigen glycoprotein vaccine as immunotherapy for genital herpes in the guinea pig genital infection model.

PubMed

Awasthi, Sita; Hook, Lauren M; Shaw, Carolyn E; Friedman, Harvey M

2017-12-02

An estimated 417 million people worldwide ages 15 to 49 are infected with herpes simplex virus type 2 (HSV-2), the most common cause of genital ulcer disease. Some individuals experience frequent recurrences of genital lesions, while others only have subclinical infection, yet all risk transmitting infection to their intimate partners. A vaccine was developed that prevents shingles, which is a recurrent infection caused by varicella-zoster virus (VZV), a closely related member of the Herpesviridae family. The success of the VZV vaccine has stimulated renewed interest in a therapeutic vaccine for genital herpes. We have been evaluating a trivalent subunit antigen vaccine for prevention of genital herpes. Here, we assess the trivalent vaccine as immunotherapy in guinea pigs that were previously infected intravaginally with HSV-2. The trivalent vaccine contains HSV-2 glycoproteins C, D, and E (gC2, gD2, gE2) subunit antigens administered with CpG and alum as adjuvants. We previously demonstrated that antibodies to gD2 neutralize the virus while antibodies to gC2 and gE2 block their immune evasion activities, including evading complement attack and inhibiting activities mediated by the IgG Fc domain, respectively. Here, we demonstrate that the trivalent vaccine significantly boosts ELISA titers and neutralizing antibody titers. The trivalent vaccine reduces the frequency of recurrent genital lesions and vaginal shedding of HSV-2 DNA by approximately 50% and almost totally eliminates vaginal shedding of replication-competent virus, suggesting that the trivalent vaccine is a worthy candidate for immunotherapy of genital herpes.

Efficacy and effectiveness of an rVSV-vectored vaccine in preventing Ebola virus disease: final results from the Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!).

PubMed

Henao-Restrepo, Ana Maria; Camacho, Anton; Longini, Ira M; Watson, Conall H; Edmunds, W John; Egger, Matthias; Carroll, Miles W; Dean, Natalie E; Diatta, Ibrahima; Doumbia, Moussa; Draguez, Bertrand; Duraffour, Sophie; Enwere, Godwin; Grais, Rebecca; Gunther, Stephan; Gsell, Pierre-Stéphane; Hossmann, Stefanie; Watle, Sara Viksmoen; Kondé, Mandy Kader; Kéïta, Sakoba; Kone, Souleymane; Kuisma, Eewa; Levine, Myron M; Mandal, Sema; Mauget, Thomas; Norheim, Gunnstein; Riveros, Ximena; Soumah, Aboubacar; Trelle, Sven; Vicari, Andrea S; Røttingen, John-Arne; Kieny, Marie-Paule

2017-02-04

rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa. We did an open-label, cluster-randomised ring vaccination trial (Ebola ça Suffit!) in the communities of Conakry and eight surrounding prefectures in the Basse-Guinée region of Guinea, and in Tomkolili and Bombali in Sierra Leone. We assessed the efficacy of a single intramuscular dose of rVSV-ZEBOV (2×10 7 plaque-forming units administered in the deltoid muscle) in the prevention of laboratory confirmed Ebola virus disease. After confirmation of a case of Ebola virus disease, we definitively enumerated on a list a ring (cluster) of all their contacts and contacts of contacts including named contacts and contacts of contacts who were absent at the time of the trial team visit. The list was archived, then we randomly assigned clusters (1:1) to either immediate vaccination or delayed vaccination (21 days later) of all eligible individuals (eg, those aged ≥18 years and not pregnant, breastfeeding, or severely ill). An independent statistician generated the assignment sequence using block randomisation with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 individuals vs >20 individuals). Ebola response teams and laboratory workers were unaware of assignments. After a recommendation by an independent data and safety monitoring board, randomisation was stopped and immediate vaccination was also offered to children aged 6-17 years and all identified rings. The prespecified primary outcome was a laboratory confirmed case of Ebola virus disease with onset 10 days or more from randomisation. The primary analysis compared the incidence of Ebola virus disease in eligible and vaccinated individuals assigned to immediate vaccination versus eligible contacts and contacts of contacts assigned to delayed vaccination. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193. In the randomised part of the trial we identified 4539 contacts and contacts of contacts in 51 clusters randomly assigned to immediate vaccination (of whom 3232 were eligible, 2151 consented, and 2119 were immediately vaccinated) and 4557 contacts and contacts of contacts in 47 clusters randomly assigned to delayed vaccination (of whom 3096 were eligible, 2539 consented, and 2041 were vaccinated 21 days after randomisation). No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9-100·0, p=0·0045), and the calculated intraclass correlation coefficient was 0·035. Additionally, we defined 19 non-randomised clusters in which we enumerated 2745 contacts and contacts of contacts, 2006 of whom were eligible and 1677 were immediately vaccinated, including 194 children. The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomisation among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters. The estimated vaccine efficacy here was 100% (95% CI 79·3-100·0, p=0·0033). 52% of contacts and contacts of contacts assigned to immediate vaccination and in non-randomised clusters received the vaccine immediately; vaccination protected both vaccinated and unvaccinated people in those clusters. 5837 individuals in total received the vaccine (5643 adults and 194 children), and all vaccinees were followed up for 84 days. 3149 (53·9%) of 5837 individuals reported at least one adverse event in the 14 days after vaccination; these were typically mild (87·5% of all 7211 adverse events). Headache (1832 [25·4%]), fatigue (1361 [18·9%]), and muscle pain (942 [13·1%]) were the most commonly reported adverse events in this period across all age groups. 80 serious adverse events were identified, of which two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness); all three recovered without sequelae. The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters. WHO, UK Wellcome Trust, the UK Government through the Department of International Development, Médecins Sans Frontières, Norwegian Ministry of Foreign Affairs (through the Research Council of Norway's GLOBVAC programme), and the Canadian Government (through the Public Health Agency of Canada, Canadian Institutes of Health Research, International Development Research Centre and Department of Foreign Affairs, Trade and Development). Copyright © 2017 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.

A nonallergenic birch pollen allergy vaccine consisting of hepatitis PreS-fused Bet v 1 peptides focuses blocking IgG toward IgE epitopes and shifts immune responses to a tolerogenic and Th1 phenotype.

PubMed

Marth, Katharina; Breyer, Isabella; Focke-Tejkl, Margarete; Blatt, Katharina; Shamji, Mohamed H; Layhadi, Janice; Gieras, Anna; Swoboda, Ines; Zafred, Domen; Keller, Walter; Valent, Peter; Durham, Stephen R; Valenta, Rudolf

2013-04-01

Allergen-specific immunotherapy is the only allergen-specific and disease-modifying treatment for allergy. The construction and characterization of a vaccine for birch pollen allergy is reported. Two nonallergenic peptides, PA and PB, derived from the IgE-reactive areas of the major birch pollen allergen Bet v 1 were fused to the hepatitis B surface protein, PreS, in four recombinant fusion proteins containing different numbers and combinations of the peptides. Fusion proteins expressed in Escherichia coli and purified to homogeneity showed a lack of IgE reactivity and allergenic activity when tested with sera and basophils from patients allergic to birch pollen. Compared to Bet v 1 allergen, peptides PA and PB showed reduced T cell activation in PBMCs from allergic patients, whereas PreS fusion proteins induced less IL-5 and more IL-10 and IFN-γ. Immunization of rabbits with the fusion proteins, in particular with a PreS fusion protein 2PAPB-PreS, containing two copies of each peptide, induced high levels of IgG Abs against the major IgE-reactive site on Bet v 1 and related allergens. These IgG Abs inhibited allergic patients' IgE binding to Bet v 1 better than did IgG induced by immunization with complete Bet v 1. Furthermore, 2PAPB-PreS-induced IgG inhibited Bet v 1-induced basophil activation in allergic patients and CD23-facilitated allergen presentation. Our study exemplifies novel beneficial features for a PreS carrier-based peptide vaccine for birch pollen, which, in addition to the established reduction in allergenic activity, include the enhanced focusing of blocking Ab responses toward IgE epitopes, immunomodulatory activity, and reduction of CD23-facilitated allergen presentation.

A Nonallergenic Birch Pollen Allergy Vaccine Consisting of Hepatitis PreS–Fused Bet v 1 Peptides Focuses Blocking IgG toward IgE Epitopes and Shifts Immune Responses to a Tolerogenic and Th1 Phenotype

PubMed Central

Marth, Katharina; Breyer, Isabella; Focke-Tejkl, Margarete; Blatt, Katharina; Shamji, Mohamed H.; Layhadi, Janice; Gieras, Anna; Swoboda, Ines; Zafred, Domen; Keller, Walter; Valent, Peter; Durham, Stephen R.; Valenta, Rudolf

2014-01-01

Allergen-specific immunotherapy is the only allergen-specific and disease-modifying treatment for allergy. The construction and characterization of a vaccine for birch pollen allergy is reported. Two nonallergenic peptides, PA and PB, derived from the IgE-reactive areas of the major birch pollen allergen Bet v 1 were fused to the hepatitis B surface protein, PreS, in four recombinant fusion proteins containing different numbers and combinations of the peptides. Fusion proteins expressed in Escherichia coli and purified to homogeneity showed a lack of IgE reactivity and allergenic activity when tested with sera and basophils from patients allergic to birch pollen. Compared to Bet v 1 allergen, peptides PA and PB showed reduced T cell activation in PBMCs from allergic patients, whereas PreS fusion proteins induced less IL-5 and more IL-10 and IFN-γ. Immunization of rabbits with the fusion proteins, in particular with a PreS fusion protein 2PAPB-PreS, containing two copies of each peptide, induced high levels of IgG Abs against the major IgE-reactive site on Bet v 1 and related allergens. These IgG Abs inhibited allergic patients’ IgE binding to Bet v 1 better than did IgG induced by immunization with complete Bet v 1. Furthermore, 2PAPB-PreS–induced IgG inhibited Bet v 1–induced basophil activation in allergic patients and CD23-facilitated allergen presentation. Our study exemplifies novel beneficial features for a PreS carrier–based peptide vaccine for birch pollen, which, in addition to the established reduction in allergenic activity, include the enhanced focusing of blocking Ab responses toward IgE epitopes, immunomodulatory activity, and reduction of CD23-facilitated allergen presentation. PMID:23440415

Development of bioluminescence imaging of respiratory syncytial virus (RSV) in virus-infected live mice and its use for evaluation of therapeutics and vaccines.

PubMed

Fuentes, Sandra; Arenas, Diego; Moore, Martin M; Golding, Hana; Khurana, Surender

2017-01-23

Respiratory Syncytial virus (RSV) is one of the leading causes of pneumonia among infants with no human vaccine or efficient curative treatments. Efforts are underway to develop new RSV vaccines and therapeutics. There is a dire need for animal models for preclinical evaluation and selection of products against RSV. Herein, we developed a whole body bioluminescence imaging to follow replication of RSV A2 virus strain expressing firefly luciferase (RSVA2-line19-FFL) in live BALB/c mice that can be used as an extremely sensitive readout for studying effects of antiviral and vaccines in living mice. Strong bioluminescence signal was detected in the nasal cavity and in the lungs following intranasal infection of mice with RSVA2-line19-FFL. The kinetics of viral replication in lungs quantified by daily live imaging strongly correlated with viral titers measured by ex-vivo plaque assay and by assessing viral RNA by qRT-PCR. Vaccination of mice with a pre-fusion F protein elicited high neutralizing antibody titers conferring strong protective immunity against virus replication in the nasal cavity and lungs. In contrast, post-challenge treatment of mice with the monoclonal antibody Palivizumab two days after infection reduced viral replication in the nasal cavity at day 4, but only modestly reduced virus loads in the lungs by day 5. In contrast to RSV bioluminescence, plaque assay did not detect viral titers in lungs on day 5 in Palivizumab-treated animals. This difference between viral loads measured by the two assays was found to be due to coating of virions with the Palivizumab that blocked infection of target cells in vitro and shows importance of live imaging in evaluation of RSV therapeutics. This recombinant RSV based live imaging animal model is convenient and valuable tool that can be used to study host dissemination of RSV and evaluation of antiviral compounds and vaccines against RSV. Published by Elsevier Ltd.

Effects of a Saccharomyces cerevisiae fermentation product in receiving diets of newly weaned beef steers II: Digestibility and response to a vaccination challenge.

PubMed

Deters, E L; Stokes, R S; Genther-Schroeder, O N; Hansen, S L

2018-06-15

Thirty-six newly weaned, crossbred beef steers (323 ± 12 kg; SD) from a single-source were used in a 56-d study to examine the effects of a Saccharomyces cerevisiae fermentation product (SCFP; Original XPC, Diamond V, Cedar Rapids, IA) on total tract nutrient digestibility and response to a vaccination challenge. Twelve d after arrival, steers were blocked by body weight (BW) and randomly assigned to treatments: SCFP at 0 (CON), 14 (SCFP14), or 28 (SCFP28) g·steer-1·d-1. Steers were fed via bunks that measured individual intake and received ear tags (CowManager, Select Sires, Plain City, OH) that recorded rumination and activity. Body weights were collected on d -1, 0, 14, 28, 42, 55, and 56. Titanium dioxide was fed as an indigestible marker to all steers from d 12 to 27, followed by consecutive d fecal samples, for determination of total tract nutrient digestibility. On d 34, steers received a Mannheimia haemolytica vaccination (One Shot, Zoetis, Kalamazoo, MI) to induce an acute phase protein (APP) response. Blood was collected from all steers on d 34 (prior to vaccination) and 3, 6, 9, 11, and 14 d post-vaccination. Data were analyzed using Proc Mixed of SAS (experimental unit = steer; n = 12/treatment); the model included the fixed effect of treatment and block and the random effect of steer. Blood measures, ear tag, and dry matter intake (DMI) data for the 15-d vaccination period were analyzed as repeated measures. Contrast statements (CON vs. SCFP14; SCFP14 vs. SCFP28) were used to compare treatment means. Digestibility of dry matter and organic matter was greater for SCFP14 vs. SCFP28 (P ≤ 0.03). Steers fed SCFP14 exhibited greater crude protein digestibility compared to CON (P < 0.01). Steers fed SCFP14 exhibited greater DMI for 15 d post-vaccination (P = 0.02) and greater ADG from d 28 to 56 (P = 0.05) vs. SCFP28-fed steers. Post-vaccination, steers fed SCFP14 spent less time ruminating per kg of dry matter, neutral detergent fiber (NDF), and physically effective NDF consumed than CON or SCFP28 (P ≤ 0.07). Serum IL-8 and haptoglobin concentrations tended to be lesser for steers fed SCFP14 vs. SCFP28 (P ≤ 0.08). Ceruloplasmin concentrations were lesser on d 14 post-vaccination for steers fed SCFP14 vs. CON or SCFP28 (treatment × d; P = 0.004); there were no differences on other sampling days due to treatment. Although no overall performance benefit was noted, steers fed SCFP14 responded better to a vaccination challenge vs. SCFP28-fed steers.

Immunization with apical membrane antigen 1 confers sterile infection-blocking immunity against Plasmodium sporozoite challenge in a rodent model.

PubMed

Schussek, Sophie; Trieu, Angela; Apte, Simon H; Sidney, John; Sette, Alessandro; Doolan, Denise L

2013-10-01

Apical membrane antigen 1 (AMA-1) is a leading blood-stage malaria vaccine candidate. Consistent with a key role in erythrocytic invasion, AMA-1-specific antibodies have been implicated in AMA-1-induced protective immunity. AMA-1 is also expressed in sporozoites and in mature liver schizonts where it may be a target of protective cell-mediated immunity. Here, we demonstrate for the first time that immunization with AMA-1 can induce sterile infection-blocking immunity against Plasmodium sporozoite challenge in 80% of immunized mice. Significantly higher levels of gamma interferon (IFN-γ)/interleukin-2 (IL-2)/tumor necrosis factor (TNF) multifunctional T cells were noted in immunized mice than in control mice. We also report the first identification of minimal CD8(+) and CD4(+) T cell epitopes on Plasmodium yoelii AMA-1. These data establish AMA-1 as a target of both preerythrocytic- and erythrocytic-stage protective immune responses and validate vaccine approaches designed to induce both cellular and humoral immunity.

Characterization of biomolecular nanoconjugates by high-throughput delivery and spectroscopic difference

PubMed Central

DeLong, Robert K; Risor, Azure; Kanomata, Masaaki; Laymon, Amanda; Jones, Brooke; Zimmerman, Scott D; Williams, Joseph; Witkowski, Colette; Warner, Mathew; Ruff, Michael; Garrad, Richard; Fallon, John K; Hickey, Anthony J; Sedaghat-Herati, Reza

2013-01-01

Aims Nanoparticle conjugates have the potential for delivering siRNA, splice-shifting oligomers or nucleic acid vaccines, and can be applicable to anticancer therapeutics. This article compares tripartite conjugates with gold nanoparticles or synthetic methoxypoly(ethylene glycol)-block-polyamidoamine dendrimers. Materials & methods Interactions with model liposomes of a 1:1 molar ratio of tripalmitin:cholesterol or phospholipid:cholesterol were investigated by high-throughput absorbance, as well as fluorescence difference and cellular luminescence assays. Results Spectral differences and dynamic light-scattering spectroscopy shifts demonstrated the interaction of conjugates with liposomes. Biological activity was demonstrated by upregulation of gene expression via splice-shifting oligomers, delivery of anti-B-Raf siRNA in cultured human cancer cells or tuberculosis antigen 85B plasmid expression vector in a coculture model of antigen presentation. Conclusion The data suggests that gold nanoparticles and methoxypoly(ethylene glycol)-block-polyamidoamine dendrimer nanoconjugates may have potential for binding, stabilization and delivery of splice-shifting oligomers, siRNA and nucleic acid vaccines for preclinical trials. PMID:22943129

Adolescent Attitudes toward Influenza Vaccination and Vaccine Uptake in a School-Based Influenza Vaccination Intervention: A Mediation Analysis

ERIC Educational Resources Information Center

Painter, Julia E.; Sales, Jessica M.; Pazol, Karen; Wingood, Gina M.; Windle, Michael; Orenstein, Walter A.; DiClemente, Ralph J.

2011-01-01

Background: School-based vaccination programs may provide an effective strategy to immunize adolescents against influenza. This study examined whether adolescent attitudes toward influenza vaccination mediated the relationship between receipt of a school-based influenza vaccination intervention and vaccine uptake. Methods: Participants were…

[What should be known for the introduction of an HPV vaccine?].

PubMed

Muñoz, Nubia; Jacquard, Anne-Carole

2008-10-01

Genital human papillomavirus (HPV) infection is one of the most common sexually transmitted infections worldwide. Two HPV vaccines are now available in many countries: (i) the first vaccine is quadrivalent and indicated in the prevention of CIN 2/3, cervical cancers, VIN 2/3, VaIN 2/3 and genital warts associated with the HPV types 6, 11, 16 and 18, (ii) the second vaccine is bivalent and indicated in the prevention of CIN 2+ and cervical cancers associated with the HPV types 16 and 18. To critically review all epidemiological aspects of the HPV infection and its relation with preneoplasic lesions of the cervix and cervical cancer to assist the relevant public health authorities to make plans for the introduction of HPV vaccines that have been recently commercialized. Only articles published in English in peer reviewed journals have been selected in Date base PubMed (National Library of Medicine - National Institutes of Health) with Keywords HPV, risk factor, cervical cancer, CIN2/3, incidence, prevalence, transmission, prevention, genital cancer, HPV vaccines, screening. A critical review of most papers published during the last 10 years was made. The topics covered included: diseases caused by HPV, prevalence, incidence and transmission of HPV, risk factors for the acquisition of HPV, natural history of HPV infection, risk factors determining the progression from HPV to cancer, protective factors blocking the progression from infection to cancer (screening) and primary prevention of HPV by vaccines and other methods. The information was interpreted and summarized. It was concluded that HPV infection is one of the most common sexually transmitted infections, that it is the necessary cause of cervical cancer and the cause of other genital cancers and cancers of the upper aerodigestive tract. Fortunately most infections regress, but those infections that persist are the ones leading to cancer. Primary prevention by the introduction of prophylactic vaccines is the ideal means of preventing cervical cancer and other cancers associated to HPV. This review is to my knowledge, the most comprehensive and up-to date review to be published in French on HPV epidemiology and related diseases. It will be of great value to educate medical and paramedical personnel on HPV infection and associated diseases and it will be of great help to public health authorities and decision makers when they have to evaluate the convenience of introducing HPV vaccination in a given population.

Immunization with a Vaccine Combining Herpes Simplex Virus 2 (HSV-2) Glycoprotein C (gC) and gD Subunits Improves the Protection of Dorsal Root Ganglia in Mice and Reduces the Frequency of Recurrent Vaginal Shedding of HSV-2 DNA in Guinea Pigs Compared to Immunization with gD Alone ▿

PubMed Central

Awasthi, Sita; Lubinski, John M.; Shaw, Carolyn E.; Barrett, Shana M.; Cai, Michael; Wang, Fushan; Betts, Michael; Kingsley, Susan; DiStefano, Daniel J.; Balliet, John W.; Flynn, Jessica A.; Casimiro, Danilo R.; Bryan, Janine T.; Friedman, Harvey M.

2011-01-01

Attempts to develop a vaccine to prevent genital herpes simplex virus 2 (HSV-2) disease have been only marginally successful, suggesting that novel strategies are needed. Immunization with HSV-2 glycoprotein C (gC-2) and gD-2 was evaluated in mice and guinea pigs to determine whether adding gC-2 to a gD-2 subunit vaccine would improve protection by producing antibodies that block gC-2 immune evasion from complement. Antibodies produced by gC-2 immunization blocked the interaction between gC-2 and complement C3b, and passive transfer of gC-2 antibody protected complement-intact mice but not C3 knockout mice against HSV-2 challenge, indicating that gC-2 antibody is effective, at least in part, because it prevents HSV-2 evasion from complement. Immunization with gC-2 also produced neutralizing antibodies that were active in the absence of complement; however, the neutralizing titers were higher when complement was present, with the highest titers in animals immunized with both antigens. Animals immunized with the gC-2-plus-gD-2 combination had robust CD4+ T-cell responses to each immunogen. Multiple disease parameters were evaluated in mice and guinea pigs immunized with gC-2 alone, gD-2 alone, or both antigens. In general, gD-2 outperformed gC-2; however, the gC-2-plus-gD-2 combination outperformed gD-2 alone, particularly in protecting dorsal root ganglia in mice and reducing recurrent vaginal shedding of HSV-2 DNA in guinea pigs. Therefore, the gC-2 subunit antigen enhances a gD-2 subunit vaccine by stimulating a CD4+ T-cell response, by producing neutralizing antibodies that are effective in the absence and presence of complement, and by blocking immune evasion domains that inhibit complement activation. PMID:21813597

Costs of delivering human papillomavirus vaccination to schoolgirls in Mwanza Region, Tanzania

PubMed Central

2012-01-01

Background Cervical cancer is the leading cause of female cancer-related deaths in Tanzania. Vaccination against human papillomavirus (HPV) offers a new opportunity to control this disease. This study aimed to estimate the costs of a school-based HPV vaccination project in three districts in Mwanza Region (NCT ID: NCT01173900), Tanzania and to model incremental scaled-up costs of a regional vaccination program. Methods We first conducted a top-down cost analysis of the vaccination project, comparing observed costs of age-based (girls born in 1998) and class-based (class 6) vaccine delivery in a total of 134 primary schools. Based on the observed project costs, we then modeled incremental costs of a scaled-up vaccination program for Mwanza Region from the perspective of the Tanzanian government, assuming that HPV vaccines would be delivered through the Expanded Programme on Immunization (EPI). Results Total economic project costs for delivering 3 doses of HPV vaccine to 4,211 girls were estimated at about US$349,400 (including a vaccine price of US$5 per dose). Costs per fully-immunized girl were lower for class-based delivery than for age-based delivery. Incremental economic scaled-up costs for class-based vaccination of 50,290 girls in Mwanza Region were estimated at US$1.3 million. Economic scaled-up costs per fully-immunized girl were US$26.41, including HPV vaccine at US$5 per dose. Excluding vaccine costs, vaccine could be delivered at an incremental economic cost of US$3.09 per dose and US$9.76 per fully-immunized girl. Financial scaled-up costs, excluding costs of the vaccine and salaries of existing staff were estimated at US$1.73 per dose. Conclusions Project costs of class-based vaccination were found to be below those of age-based vaccination because of more eligible girls being identified and higher vaccine uptake. We estimate that vaccine can be delivered at costs that would make HPV vaccination a very cost-effective intervention. Potentially, integrating HPV vaccine delivery with cost-effective school-based health interventions and a reduction of vaccine price below US$5 per dose would further reduce the costs per fully HPV-immunized girl. PMID:23148516

Costs of delivering human papillomavirus vaccination to schoolgirls in Mwanza Region, Tanzania.

PubMed

Quentin, Wilm; Terris-Prestholt, Fern; Changalucha, John; Soteli, Selephina; Edmunds, W John; Hutubessy, Raymond; Ross, David A; Kapiga, Saidi; Hayes, Richard; Watson-Jones, Deborah

2012-11-13

Cervical cancer is the leading cause of female cancer-related deaths in Tanzania. Vaccination against human papillomavirus (HPV) offers a new opportunity to control this disease. This study aimed to estimate the costs of a school-based HPV vaccination project in three districts in Mwanza Region (NCT ID: NCT01173900), Tanzania and to model incremental scaled-up costs of a regional vaccination program. We first conducted a top-down cost analysis of the vaccination project, comparing observed costs of age-based (girls born in 1998) and class-based (class 6) vaccine delivery in a total of 134 primary schools. Based on the observed project costs, we then modeled incremental costs of a scaled-up vaccination program for Mwanza Region from the perspective of the Tanzanian government, assuming that HPV vaccines would be delivered through the Expanded Programme on Immunization (EPI). Total economic project costs for delivering 3 doses of HPV vaccine to 4,211 girls were estimated at about US$349,400 (including a vaccine price of US$5 per dose). Costs per fully-immunized girl were lower for class-based delivery than for age-based delivery. Incremental economic scaled-up costs for class-based vaccination of 50,290 girls in Mwanza Region were estimated at US$1.3 million. Economic scaled-up costs per fully-immunized girl were US$26.41, including HPV vaccine at US$5 per dose. Excluding vaccine costs, vaccine could be delivered at an incremental economic cost of US$3.09 per dose and US$9.76 per fully-immunized girl. Financial scaled-up costs, excluding costs of the vaccine and salaries of existing staff were estimated at US$1.73 per dose. Project costs of class-based vaccination were found to be below those of age-based vaccination because of more eligible girls being identified and higher vaccine uptake. We estimate that vaccine can be delivered at costs that would make HPV vaccination a very cost-effective intervention. Potentially, integrating HPV vaccine delivery with cost-effective school-based health interventions and a reduction of vaccine price below US$5 per dose would further reduce the costs per fully HPV-immunized girl.

Ebolavirus Vaccines: Progress in the Fight Against Ebola Virus Disease.

PubMed

Wu, Xiao-Xin; Yao, Hang-Ping; Wu, Nan-Ping; Gao, Hai-Nv; Wu, Hai-Bo; Jin, Chang-Zhong; Lu, Xiang-Yun; Xie, Tian-Shen; Li, Lan-Juan

2015-01-01

Ebolaviruses are highly infectious pathogens that cause lethal Ebola virus disease (EVD) in humans and non-human primates (NHPs). Due to their high pathogenicity and transmissibility, as well as the potential to be misused as a bioterrorism agent, ebolaviruses would threaten the health of global populations if not controlled. In this review, we describe the origin and structure of ebolaviruses and the development of vaccines from the beginning of the 1980s, including conventional ebolavirus vaccines, DNA vaccines, Ebola virus-like particles (VLPs), vaccinia virus-based vaccines, Venezuelan equine encephalitis virus (VEEV)-like replicon particles, Kunjin virus-based vaccine, recombinant Zaire Ebolavirusx2206;VP30, recombinant cytomegalovirus (CMV)-based vaccines, recombinant rabies virus (RABV)-based vaccines, recombinant paramyxovirus-based vaccines, adenovirus-based vaccines and vesicular stomatitis virus (VSV)-based vaccines. No licensed vaccine or specific treatment is currently available to counteract ebolavirus infection, although DNA plasmids and several viral vector approaches have been evaluated as promising vaccine platforms. These vaccine candidates have been confirmed to be successful in protecting NHPs against lethal infection. Moreover, these vaccine candidates were successfully advanced to clinical trials. The present review provides an update of the current research on Ebola vaccines, with the aim of providing an overview on current prospects in the fight against EVD. © 2015 The Author(s) Published by S. Karger AG, Basel.

Design of a Phase III cluster randomized trial to assess the efficacy and safety of a malaria transmission blocking vaccine.

PubMed

Delrieu, Isabelle; Leboulleux, Didier; Ivinson, Karen; Gessner, Bradford D

2015-03-24

Vaccines interrupting Plasmodium falciparum malaria transmission targeting sexual, sporogonic, or mosquito-stage antigens (SSM-VIMT) are currently under development to reduce malaria transmission. An international group of malaria experts was established to evaluate the feasibility and optimal design of a Phase III cluster randomized trial (CRT) that could support regulatory review and approval of an SSM-VIMT. The consensus design is a CRT with a sentinel population randomly selected from defined inner and buffer zones in each cluster, a cluster size sufficient to assess true vaccine efficacy in the inner zone, and inclusion of ongoing assessment of vaccine impact stratified by distance of residence from the cluster edge. Trials should be conducted first in areas of moderate transmission, where SSM-VIMT impact should be greatest. Sample size estimates suggest that such a trial is feasible, and within the range of previously supported trials of malaria interventions, although substantial issues to implementation exist. Copyright © 2015 Elsevier Ltd. All rights reserved.

Impact of inactivated poliovirus vaccine on mucosal immunity: implications for the polio eradication endgame

PubMed Central

Parker, Edward PK; Molodecky, Natalie A; Pons-Salort, Margarita; O’Reilly, Kathleen M; Grassly, Nicholas C

2015-01-01

The polio eradication endgame aims to bring transmission of all polioviruses to a halt. To achieve this aim, it is essential to block viral replication in individuals via induction of a robust mucosal immune response. Although it has long been recognized that inactivated poliovirus vaccine (IPV) is incapable of inducing a strong mucosal response on its own, it has recently become clear that IPV may boost immunity in the intestinal mucosa among individuals previously immunized with oral poliovirus vaccine. Indeed, mucosal protection appears to be stronger following a booster dose of IPV than oral poliovirus vaccine, especially in older children. Here, we review the available evidence regarding the impact of IPV on mucosal immunity, and consider the implications of this evidence for the polio eradication endgame. We conclude that the implementation of IPV in both routine and supplementary immunization activities has the potential to play a key role in halting poliovirus transmission, and thereby hasten the eradication of polio. PMID:26159938

Broad blockade antibody responses in human volunteers after immunization with a multivalent norovirus VLP candidate vaccine: immunological analyses from a phase I clinical trial.

PubMed

Lindesmith, Lisa C; Ferris, Martin T; Mullan, Clancy W; Ferreira, Jennifer; Debbink, Kari; Swanstrom, Jesica; Richardson, Charles; Goodwin, Robert R; Baehner, Frank; Mendelman, Paul M; Bargatze, Robert F; Baric, Ralph S

2015-03-01

Human noroviruses (NoVs) are the primary cause of acute gastroenteritis and are characterized by antigenic variation between genogroups and genotypes and antigenic drift of strains within the predominant GII.4 genotype. In the context of this diversity, an effective NoV vaccine must elicit broadly protective immunity. We used an antibody (Ab) binding blockade assay to measure the potential cross-strain protection provided by a multivalent NoV virus-like particle (VLP) candidate vaccine in human volunteers. Sera from ten human volunteers immunized with a multivalent NoV VLP vaccine (genotypes GI.1/GII.4) were analyzed for IgG and Ab blockade of VLP interaction with carbohydrate ligand, a potential correlate of protective immunity to NoV infection and illness. Immunization resulted in rapid rises in IgG and blockade Ab titers against both vaccine components and additional VLPs representing diverse strains and genotypes not represented in the vaccine. Importantly, vaccination induced blockade Ab to two novel GII.4 strains not in circulation at the time of vaccination or sample collection. GII.4 cross-reactive blockade Ab titers were more potent than responses against non-GII.4 VLPs, suggesting that previous exposure history to this dominant circulating genotype may impact the vaccine Ab response. Further, antigenic cartography indicated that vaccination preferentially activated preexisting Ab responses to epitopes associated with GII.4.1997. Study interpretations may be limited by the relevance of the surrogate neutralization assay and the number of immunized participants evaluated. Vaccination with a multivalent NoV VLP vaccine induces a broadly blocking Ab response to multiple epitopes within vaccine and non-vaccine NoV strains and to novel antigenic variants not yet circulating at the time of vaccination. These data reveal new information about complex NoV immune responses to both natural exposure and to vaccination, and support the potential feasibility of an efficacious multivalent NoV VLP vaccine for future use in human populations. ClinicalTrials.gov NCT01168401.

Broad Blockade Antibody Responses in Human Volunteers after Immunization with a Multivalent Norovirus VLP Candidate Vaccine: Immunological Analyses from a Phase I Clinical Trial

PubMed Central

Lindesmith, Lisa C.; Ferris, Martin T.; Mullan, Clancy W.; Ferreira, Jennifer; Debbink, Kari; Swanstrom, Jesica; Richardson, Charles; Goodwin, Robert R.; Baehner, Frank; Mendelman, Paul M.; Bargatze, Robert F.; Baric, Ralph S.

2015-01-01

Background Human noroviruses (NoVs) are the primary cause of acute gastroenteritis and are characterized by antigenic variation between genogroups and genotypes and antigenic drift of strains within the predominant GII.4 genotype. In the context of this diversity, an effective NoV vaccine must elicit broadly protective immunity. We used an antibody (Ab) binding blockade assay to measure the potential cross-strain protection provided by a multivalent NoV virus-like particle (VLP) candidate vaccine in human volunteers. Methods and Findings Sera from ten human volunteers immunized with a multivalent NoV VLP vaccine (genotypes GI.1/GII.4) were analyzed for IgG and Ab blockade of VLP interaction with carbohydrate ligand, a potential correlate of protective immunity to NoV infection and illness. Immunization resulted in rapid rises in IgG and blockade Ab titers against both vaccine components and additional VLPs representing diverse strains and genotypes not represented in the vaccine. Importantly, vaccination induced blockade Ab to two novel GII.4 strains not in circulation at the time of vaccination or sample collection. GII.4 cross-reactive blockade Ab titers were more potent than responses against non-GII.4 VLPs, suggesting that previous exposure history to this dominant circulating genotype may impact the vaccine Ab response. Further, antigenic cartography indicated that vaccination preferentially activated preexisting Ab responses to epitopes associated with GII.4.1997. Study interpretations may be limited by the relevance of the surrogate neutralization assay and the number of immunized participants evaluated. Conclusions Vaccination with a multivalent NoV VLP vaccine induces a broadly blocking Ab response to multiple epitopes within vaccine and non-vaccine NoV strains and to novel antigenic variants not yet circulating at the time of vaccination. These data reveal new information about complex NoV immune responses to both natural exposure and to vaccination, and support the potential feasibility of an efficacious multivalent NoV VLP vaccine for future use in human populations. Trial Registration ClinicalTrials.gov NCT01168401 PMID:25803642

Vaccine-Mediated Activation of Human TLR4 Is Affected by Modulation of Culture Conditions during Whole-Cell Pertussis Vaccine Preparation

PubMed Central

Hoonakker, Marieke E.; Verhagen, Lisa M.; Pupo, Elder; de Haan, Alex; Metz, Bernard; Hendriksen, Coenraad F. M.; Han, Wanda G. H.; Sloots, Arjen

2016-01-01

The potency of whole-cell pertussis (wP) vaccines is still determined by an intracerebral mouse protection test. To allow development of suitable in vitro alternatives to this test, insight into relevant parameters to monitor the consistency of vaccine quality is essential. To this end, a panel of experimental wP vaccines of varying quality was prepared by sulfate-mediated suppression of the BvgASR master virulence regulatory system of Bordetella pertussis during cultivation. This system regulates the transcription of a range of virulence proteins, many of which are considered important for the induction of effective host immunity. The protein compositions and in vivo potencies of the vaccines were BvgASR dependent, with the vaccine containing the highest amount of virulence proteins having the highest in vivo potency. Here, the capacities of these vaccines to stimulate human Toll-like receptors (hTLR) 2 and 4 and the role these receptors play in wP vaccine-mediated activation of antigen-presenting cells in vitro were studied. Prolonged BvgASR suppression was associated with a decreased capacity of vaccines to activate hTLR4. In contrast, no significant differences in hTLR2 activation were observed. Similarly, vaccine-induced activation of MonoMac-6 and monocyte-derived dendritic cells was strongest with the highest potency vaccine. Blocking of TLR2 and TLR4 showed that differences in antigen-presenting cell activation could be largely attributed to vaccine-dependent variation in hTLR4 signalling. Interestingly, this BvgASR-dependent decrease in hTLR4 activation coincided with a reduction in GlcN-modified lipopolysaccharides in these vaccines. Accordingly, expression of the lgmA-C genes, required for this glucosamine modification, was significantly reduced in bacteria exposed to sulfate. Together, these findings demonstrate that the BvgASR status of bacteria during wP vaccine preparation is critical for their hTLR4 activation capacity and suggest that including such parameters to assess consistency of newly produced vaccines could bring in vitro testing of vaccine quality a step closer. PMID:27548265

Bacterial phospholipases C as vaccine candidate antigens against cystic fibrosis respiratory pathogens: the Mycobacterium abscessus model.

PubMed

Le Moigne, Vincent; Rottman, Martin; Goulard, Céline; Barteau, Benoît; Poncin, Isabelle; Soismier, Nathalie; Canaan, Stéphane; Pitard, Bruno; Gaillard, Jean-Louis; Herrmann, Jean-Louis

2015-04-27

Vaccine strategies represent one of the fighting answers against multiresistant bacteria in a number of clinical settings like cystic fibrosis (CF). Mycobacterium abscessus, an emerging CF pathogen, raises difficult therapeutic problems due to its intrinsic antibiotic multiresistance. By reverse vaccinology, we identified M. abscessus phospholipase C (MA-PLC) as a potential vaccine target. We deciphered here the protective response generated by vaccination with plasmid DNA encoding the MA-PLC formulated with a tetra functional block copolymer 704, in CF (ΔF508) mice. Protection was tested against aerosolized smooth and rough (hypervirulent) variants of M. abscessus. MA-PLC DNA vaccination (days 0, 21, 42) elicited a strong antibody response. A significant protective effect was obtained against aerosolized M. abscessus (S variant) in ΔF508 mice, but not in wild-type FVB littermates; similar results were observed when: (i) challenging mice with the "hypervirulent" R variant, and; (ii) immunizing mice with purified MA-PLC protein. High IgG titers against MA-PLC protein were measured in CF patients with M. abscessus infection; interestingly, significant titers were also detected in CF patients positive for Pseudomonas aeruginosa versus P. aeruginosa-negative controls. MA-PLC DNA- and PLC protein-vaccinated mice cleared more rapidly M. abscessus than β-galactosidase DNA- or PBS- vaccinated mice in the context of CF. PLCs could constitute interesting vaccine targets against common PLC-producing CF pathogens like P. aeruginosa. Copyright © 2015 Elsevier Ltd. All rights reserved.

Successful comeback of the single-dose live oral cholera vaccine CVD 103-HgR.

PubMed

Herzog, Christian

2016-01-01

Effective and easy to administer cholera vaccines are in need more than ever, for at risk populations and travellers alike. In many parts of the world cholera is still endemic, causing outbreaks and constituting repeatedly serious public health problems. The oral live cholera vaccine CVD 103-HgR (Orochol, Mutachol), the first genetically modified organism (GMO) used as vaccine, was in its time (launched 1993, Switzerland) the ideal cholera vaccine: single-dose, protective efficacy of 80-100% against moderate to severe cholera, acting within 8 days and exhibiting excellent safety, indiscernible from placebo. However, there were strong headwinds: In the 1990s the indication for cholera vaccines was generally downplayed by experts and in 1997 the European Commission called for a moratorium of GMOs which blocked the registration in the European Union. Thus, demand for this vaccine remained low and in 2003 it was taken off the market for economic reasons. After a decade in obscurity it (Vaxchora) has resurfaced again, now produced in the U.S. and equipped with a U.S. FDA license (June 10, 2016). What had happened? This commentary gives a critical account of an almost unbelievable string of misadventures, emerging adverse circumstances and man-made failures which nearly killed this single-dose live oral cholera vaccine. The good news is that patience and persistence lead to success in the end, allowing good science to prevail for the benefit of those in need. Copyright © 2016 Elsevier Ltd. All rights reserved.

The relationship between mucosal immunity, nasopharyngeal carriage, asymptomatic transmission and the resurgence of Bordetella pertussis

PubMed Central

Gill, Christopher; Rohani, Pejman; Thea, Donald M

2017-01-01

The incidence of whooping cough in the US has been rising slowly since the 1970s, but the pace of this has accelerated sharply since acellular pertussis vaccines replaced the earlier whole cell vaccines in the late 1990s. A similar trend occurred in many other countries, including the UK, Canada, Australia, Ireland, and Spain, following the switch to acellular vaccines. The key question is why. Two leading theories (short duration of protective immunologic persistence and evolutionary shifts in the pathogen to evade the vaccine) explain some but not all of these shifts, suggesting that other factors may also be important. In this synthesis, we argue that sterilizing mucosal immunity that blocks or abbreviates the duration of nasopharyngeal carriage of Bordetella pertussis and impedes person-to-person transmission (including between asymptomatically infected individuals) is a critical factor in this dynamic. Moreover, we argue that the ability to induce such mucosal immunity is fundamentally what distinguishes whole cell and acellular pertussis vaccines and may be pivotal to understanding much of the resurgence of this disease in many countries that adopted acellular vaccines. Additionally, we offer the hypothesis that observed herd effects generated by acellular vaccines may reflect a modification of disease presentation leading to reduced potential for transmission by those already infected, as opposed to inducing resistance to infection among those who have been exposed. PMID:28928960

Well-defined block copolymers for gene delivery to dendritic cells: probing the effect of polycation chain-length.

PubMed

Tang, Rupei; Palumbo, R Noelle; Nagarajan, Lakshmi; Krogstad, Emily; Wang, Chun

2010-03-03

The development of safe and efficient polymer carriers for DNA vaccine delivery requires mechanistic understanding of structure-function relationship of the polymer carriers and their interaction with antigen-presenting cells. Here we have synthesized a series of diblock copolymers with well-defined chain-length using atom transfer radical polymerization and characterized the influence of polycation chain-length on the physico-chemical properties of the polymer/DNA complexes as well as the interaction with dendritic cells. The copolymers consist of a hydrophilic poly(ethylene glycol) block and a cationic poly(aminoethyl methacrylate) (PAEM) block. The average degree of polymerization (DP) of the PAEM block was varied among 19, 39, and 75, with nearly uniform distribution. With increasing PAEM chain-length, polyplexes formed by the diblock copolymers and plasmid DNA had smaller average particle size and showed higher stability against electrostatic destabilization by salt and heparin. The polymers were not toxic to mouse dendritic cells (DCs) and only displayed chain-length-dependent toxicity at a high concentration (1mg/mL). In vitro gene transfection efficiency and polyplex uptake in DCs were also found to correlate with chain-length of the PAEM block with the longer polymer chain favoring transfection and cellular uptake. The polyplexes induced a modest up-regulation of surface markers for DC maturation that was not significantly dependent on PAEM chain-length. Finally, the polyplex prepared from the longest PAEM block (DP of 75) achieved an average of 20% enhancement over non-condensed anionic dextran in terms of uptake by DCs in the draining lymph nodes 24h after subcutaneous injection into mice. Insights gained from studying such structurally well-defined polymer carriers and their interaction with dendritic cells may contribute to improved design of practically useful DNA vaccine delivery systems. Copyright 2009 Elsevier B.V. All rights reserved.

Purified coronavirus Spike protein nanoparticles induce coronavirus neutralizing antibodies in mice

PubMed Central

Mu, Haiyan; Taylor, Justin K; Massare, Michael; Flyer, David C

2014-01-01

Development of vaccination strategies for emerging pathogens are particularly challenging because of the sudden nature of the emergence of these viruses and the long process needed for traditional vaccine development. Therefore, there is a need for development of a rapid method of vaccine development that can respond to emerging pathogens in a short time frame. The emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East respiratory syndrome (MERS-CoV) in late 2012 demonstrate the importance of coronaviruses as emerging pathogens. The spike glycoproteins of coronaviruses reside on the surface of the virion and are responsible for virus entry. The spike glycoprotein is the major immunodominant antigen of coronaviruses and has proven to be an excellent target for vaccine designs that seek to block coronavirus entry and promote antibody targeting of infected cells. Vaccination strategies for coronaviruses have involved live attenuated virus, recombinant viruses, non-replicative virus-like particles expressing coronavirus proteins or DNA plasmids expressing coronavirus genes. None of these strategies has progressed to an approved human coronavirus vaccine in the ten years since SARS-CoV emerged. Here we describe a novel method for generating MERS-CoV and SARS-CoV full-length spike nanoparticles, which in combination with adjuvants are able to produce high titer antibodies in mice. PMID:24736006

A trivalent subunit antigen glycoprotein vaccine as immunotherapy for genital herpes in the guinea pig genital infection model

PubMed Central

Awasthi, Sita; Hook, Lauren M.; Shaw, Carolyn E.; Friedman, Harvey M.

2017-01-01

ABSTRACT An estimated 417 million people worldwide ages 15 to 49 are infected with herpes simplex virus type 2 (HSV-2), the most common cause of genital ulcer disease. Some individuals experience frequent recurrences of genital lesions, while others only have subclinical infection, yet all risk transmitting infection to their intimate partners. A vaccine was developed that prevents shingles, which is a recurrent infection caused by varicella-zoster virus (VZV), a closely related member of the Herpesviridae family. The success of the VZV vaccine has stimulated renewed interest in a therapeutic vaccine for genital herpes. We have been evaluating a trivalent subunit antigen vaccine for prevention of genital herpes. Here, we assess the trivalent vaccine as immunotherapy in guinea pigs that were previously infected intravaginally with HSV-2. The trivalent vaccine contains HSV-2 glycoproteins C, D, and E (gC2, gD2, gE2) subunit antigens administered with CpG and alum as adjuvants. We previously demonstrated that antibodies to gD2 neutralize the virus while antibodies to gC2 and gE2 block their immune evasion activities, including evading complement attack and inhibiting activities mediated by the IgG Fc domain, respectively. Here, we demonstrate that the trivalent vaccine significantly boosts ELISA titers and neutralizing antibody titers. The trivalent vaccine reduces the frequency of recurrent genital lesions and vaginal shedding of HSV-2 DNA by approximately 50% and almost totally eliminates vaginal shedding of replication-competent virus, suggesting that the trivalent vaccine is a worthy candidate for immunotherapy of genital herpes. PMID:28481687

A multiantigen vaccine targeting neu, IGFBP-2, and IGF-IR prevents tumor progression in mice with preinvasive breast disease.

PubMed

Disis, Mary L; Gad, Ekram; Herendeen, Daniel R; Lai, Vy Phan-; Park, Kyong Hwa; Cecil, Denise L; O'Meara, Megan M; Treuting, Piper M; Lubet, Ronald A

2013-12-01

A multiantigen multipeptide vaccine, targeting proteins expressed in preinvasive breast lesions, can stimulate type I CD4(+) T cells which have been shown to be deficient in both patients with breast cancer and mice that develop mammary tumors. Transgenic mice (TgMMTV-neu) were immunized with a multiantigen peptide vaccine specific for neu, insulin-like growth factor-binding protein 2 and insulin-like growth factor receptor-I at a time when some of the animals already had preinvasive lesions (18 weeks of age). Although immunization with each individual antigen was partially effective in inhibiting tumor growth, immunization with the multiantigen vaccine was highly effective, blocking development of palpable lesions in 65% of mice and slowing tumor growth in the infrequent palpable tumors, which did arise. Protection was mediated by CD4(+) T cells, and the few slow-growing tumors that did develop demonstrated a significant increase in intratumoral CD8(+) T cells as compared with controls (P = 0.0007). We also combined the vaccine with agents that were, by themselves, partially effective inhibitors of tumor progression in this model; lapatinib and the RXR agonist bexarotene. Although the combination of lapatinib and vaccination performed similarly to vaccination alone (P = 0.735), bexarotene and vaccination significantly enhanced disease-free survival (P < 0.0001), and approximately 90% of the mice showed no pathologic evidence of carcinomas at one year. The vaccine also demonstrated significant clinical efficacy in an additional transgenic model of breast cancer (TgC3(I)-Tag). Chemoimmunoprevention combinations may be an effective approach to breast cancer prevention even when the vaccine is administered in the presence of subclinical disease.

Effects of pre-existing orthopoxvirus-specific immunity on the performance of Modified Vaccinia virus Ankara-based influenza vaccines.

PubMed

Altenburg, Arwen F; van Trierum, Stella E; de Bruin, Erwin; de Meulder, Dennis; van de Sandt, Carolien E; van der Klis, Fiona R M; Fouchier, Ron A M; Koopmans, Marion P G; Rimmelzwaan, Guus F; de Vries, Rory D

2018-04-24

The replication-deficient orthopoxvirus modified vaccinia virus Ankara (MVA) is a promising vaccine vector against various pathogens and has an excellent safety record. However, pre-existing vector-specific immunity is frequently suggested to be a drawback of MVA-based vaccines. To address this issue, mice were vaccinated with MVA-based influenza vaccines in the presence or absence of orthopoxvirus-specific immunity. Importantly, protective efficacy of an MVA-based influenza vaccine against a homologous challenge was not impaired in the presence of orthopoxvirus-specific pre-existing immunity. Nonetheless, orthopoxvirus-specific pre-existing immunity reduced the induction of antigen-specific antibodies under specific conditions and completely prevented induction of antigen-specific T cell responses by rMVA-based vaccination. Notably, antibodies induced by vaccinia virus vaccination, both in mice and humans, were not capable of neutralizing MVA. Thus, when using rMVA-based vaccines it is important to consider the main correlate of protection induced by the vaccine, the vaccine dose and the orthopoxvirus immune status of vaccine recipients.

Development of an opsonophagocytic killing assay for group a streptococcus.

PubMed

Jones, Scott; Moreland, Nicole J; Zancolli, Marta; Raynes, Jeremy; Loh, Jacelyn M S; Smeesters, Pierre R; Sriskandan, Shiranee; Carapetis, Jonathan R; Fraser, John D; Goldblatt, David

2018-05-15

Group A Streptococcus (GAS) or Streptococcus pyogenes is responsible for an estimated 500,000 deaths worldwide each year. Protection against GAS infection is thought to be mediated by phagocytosis, enhanced by bacteria-specific antibody. There are no licenced GAS vaccines, despite many promising candidates in preclinical and early stage clinical development, the most advanced of which are based on the GAS M-protein. Vaccine progress has been hindered, in part, by the lack of a standardised functional assay suitable for vaccine evaluation. Current assays, developed over 50 years ago, rely on non-immune human whole blood as a source of neutrophils and complement. Variations in complement and neutrophil activity between donors result in variable data that is difficult to interpret. We have developed an opsonophagocytic killing assay (OPKA) for GAS that utilises dimethylformamide (DMF)-differentiated human promyelocytic leukemia cells (HL-60) as a source of neutrophils and baby rabbit complement, thus removing the major sources of variation in current assays. We have standardised the OPKA for several clinically relevant GAS strain types (emm1, emm6 and emm12) and have shown antibody-specific killing for each emm-type using M-protein specific rabbit antisera. Specificity was demonstrated by pre-incubation of the antisera with homologous M-protein antigens that blocked antibody-specific killing. Additional qualifications of the GAS OPKA, including the assessment of the accuracy, precision, linearity and the lower limit of quantification, were also performed. This GAS OPKA assay has the potential to provide a robust and reproducible platform to accelerate GAS vaccine development. Copyright © 2018 Elsevier Ltd. All rights reserved.

Brucellosis: Improved Diagnostics and Vaccine Insights from Synthetic Glycans.

PubMed

Bundle, David R; McGiven, John

2017-12-19

Brucellosis is a serious zoonotic bacterial disease that is ranked by the World Health Organization among the top seven "neglected zoonoses" that threaten human health and cause poverty. It is a costly, highly contagious disease that affects ruminants, cattle, sheep, goats, and other productive animals such as pigs. Symptoms include abortions, infertility, decreased milk production, weight loss, and lameness. Brucellosis is also the most common bacterial disease that is transmitted from animals to humans, with approximately 500 000 new human cases each year. Detection and slaughter of infected animals is required to eradicate the disease, as vaccination alone is currently insufficient. However, as the most protective vaccines compromise serodiagnosis, this creates policy dilemmas, and these often result in the failure of eradication and control programs. Detection of antibodies to the Brucella bacterial cell wall O-polysaccharide (OPS) component of smooth lipopolysaccharide is used in diagnosis of this disease, and the same molecule contributes important protective efficacy to currently deployed veterinary whole-cell vaccines. This has set up a long-standing paradox that while Brucella OPS confers protective efficacy to vaccines, its presence results in similar antibody profiles in infected and vaccinated animals. Consequently, differentiation of infected from vaccinated animals (DIVA) is not possible, and this limits efforts to combat the disease. Recent clarification of the chemical structure of Brucella OPS as a block copolymer of two oligosaccharide sequences has provided an opportunity to utilize unique oligosaccharides only available via chemical synthesis in serodiagnostic tests for the disease. These oligosaccharides show excellent sensitivity and specificity compared with the native polymer used in current commercial tests and have the added advantage of assisting discrimination between brucellosis and infections caused by several bacteria with OPS that share some structural features with those of Brucella. During synthesis and immunochemical evaluation of these synthetic antigens, it became apparent that an opportunity existed to create a polysaccharide-protein conjugate vaccine that would not create antibodies that give false positive results in diagnostic tests for infection. This objective was reduced to practice, and immunization of mice showed that antibodies to the Brucella A antigen could be developed without reacting in a diagnostic test based on the M antigen. A conjugate vaccine of this type could readily be developed for use in humans and animals. However, as chemical methods advance and modern methods of bacterial engineering mature, it is expected that the principles elucidated by these studies could be applied to the development of an inexpensive and cost-effective vaccine to combat endemic brucellosis in animals.

Mutations in the Fusion Protein of Measles Virus That Confer Resistance to the Membrane Fusion Inhibitors Carbobenzoxy-d-Phe-l-Phe-Gly and 4-Nitro-2-Phenylacetyl Amino-Benzamide

PubMed Central

Ha, Michael N.; Delpeut, Sébastien; Noyce, Ryan S.; Sisson, Gary; Black, Karen M.; Lin, Liang-Tzung; Bilimoria, Darius; Plemper, Richard K.; Privé, Gilbert G.

2017-01-01

ABSTRACT The inhibitors carbobenzoxy (Z)-d-Phe-l-Phe-Gly (fusion inhibitor peptide [FIP]) and 4-nitro-2-phenylacetyl amino-benzamide (AS-48) have similar efficacies in blocking membrane fusion and syncytium formation mediated by measles virus (MeV). Other homologues, such as Z-d-Phe, are less effective but may act through the same mechanism. In an attempt to map the site of action of these inhibitors, we generated mutant viruses that were resistant to the inhibitory effects of Z-d-Phe-l-Phe-Gly. These 10 mutations were localized to the heptad repeat B (HRB) region of the fusion protein, and no changes were observed in the viral hemagglutinin, which is the receptor attachment protein. Mutations were validated in a luciferase-based membrane fusion assay, using transfected fusion and hemagglutinin expression plasmids or with syncytium-based assays in Vero, Vero-SLAM, and Vero-Nectin 4 cell lines. The changes I452T, D458N, D458G/V459A, N462K, N462H, G464E, and I483R conferred resistance to both FIP and AS-48 without compromising membrane fusion. The inhibitors did not block hemagglutinin protein-mediated binding to the target cell. Edmonston vaccine/laboratory and IC323 wild-type strains were equally affected by the inhibitors. Escape mutations were mapped upon a three-dimensional (3D) structure modeled from the published crystal structure of parainfluenzavirus 5 fusion protein. The most effective mutations were situated in a region located near the base of the globular head and its junction with the alpha-helical stalk of the prefusion protein. We hypothesize that the fusion inhibitors could interfere with the structural changes that occur between the prefusion and postfusion conformations of the fusion protein. IMPORTANCE Due to lapses in vaccination worldwide that have caused localized outbreaks, measles virus (MeV) has regained importance as a pathogen. Antiviral agents against measles virus are not commercially available but could be useful in conjunction with MeV eradication vaccine programs and as a safeguard in oncolytic viral therapy. Three decades ago, the small hydrophobic peptide Z-d-Phe-l-Phe-Gly (FIP) was shown to block MeV infections and syncytium formation in monkey kidney cell lines. The exact mechanism of its action has yet to be determined, but it does appear to have properties similar to those of another chemical inhibitor, AS-48, which appears to interfere with the conformational change in the viral F protein that is required to elicit membrane fusion. Escape mutations were used to map the site of action for FIP. Knowledge gained from these studies could help in the design of new inhibitors against morbilliviruses and provide additional knowledge concerning the mechanism of virus-mediated membrane fusion. PMID:28904193

Preparation of a Burkholderia Mallei Vaccine

DTIC Science & Technology

1999-01-01

infections in animals as some of the human ones, there are 10 specific animal diseases including: calf septicaemia, bovine mastitis , porcine oedema disease...middle logarithmic phase and placed on a Formvar-coated nickel grid (400 mesh) for 2 min. The grid was blocked for 30 min with 0.5% bovine serum albumin

Mutation-induced changes of transmembrane pore size revealed by combined ion-channel conductance and single vesicle permeabilization analyses

USDA-ARS?s Scientific Manuscript database

Permeabilization of the endomembrane system by viroporins is instrumental in the progression of host-cell infection by many viral pathogens. Thus, blocking/attenuation of viroporin activity provides a generic methodology for antiviral and vaccine development. We have described that permeabilization ...

Booster vaccinations: can immunologic memory outpace disease pathogenesis?

PubMed

Pichichero, Michael E

2009-12-01

Almost all current vaccines work by the induction of antibodies in serum or on the mucosa to block adherence of pathogens to epithelial cells or interfere with microbial invasion of the bloodstream. However, antibody levels usually decline after vaccination to undetectable amounts if further vaccination does not occur. Persistence of vaccine-induced antibodies usually goes well beyond the time when they should have decayed to undetectable levels because of ongoing "natural" boosting or other immunologic mechanisms. The production of memory B and T cells is of clear importance, but the likelihood that a memory response will be fast enough in the absence of a protective circulating antibody level likely depends on the pace of pathogenesis of a specific organism. This concept is discussed with regard to Haemophilus influenzae type b, Streptococcus pneumoniae, and Neisseria meningitidis; hepatitis A and B; diphtheria, tetanus, and pertussis; polio, measles, mumps, rubella, and varicella; rotavirus; and human papilloma virus. With infectious diseases for which the pace of pathogenesis is less rapid, some individuals will contract infection before the memory response is fully activated and implemented. With infectious diseases for which the pace of pathogenesis is slow, immune memory should be sufficient to prevent disease.

Applications of nanomaterials as vaccine adjuvants

PubMed Central

Zhu, Motao; Wang, Rongfu; Nie, Guangjun

2014-01-01

Vaccine adjuvants are applied to amplify the recipient's specific immune responses against pathogen infection or malignancy. A new generation of adjuvants is being developed to meet the demands for more potent antigen-specific responses, specific types of immune responses, and a high margin of safety. Nanotechnology provides a multifunctional stage for the integration of desired adjuvant activities performed by the building blocks of tailor-designed nanoparticles. Using nanomaterials for antigen delivery can provide high bioavailability, sustained and controlled release profiles, and targeting and imaging properties resulting from manipulation of the nanomaterials’ physicochemical properties. Moreover, the inherent immune-regulating activity of particular nanomaterials can further promote and shape the cellular and humoral immune responses toward desired types. The combination of both the delivery function and immunomodulatory effect of nanomaterials as adjuvants is thought to largely benefit the immune outcomes of vaccination. In this review, we will address the current achievements of nanotechnology in the development of novel adjuvants. The potential mechanisms by which nanomaterials impact the immune responses to a vaccine and how physicochemical properties, including size, surface charge and surface modification, impact their resulting immunological outcomes will be discussed. This review aims to provide concentrated information to promote new insights for the development of novel vaccine adjuvants. PMID:25483497

Immunization of Mice with Anthrax Protective Antigen Limits Cardiotoxicity but Not Hepatotoxicity Following Lethal Toxin Challenge.

PubMed

Devera, T Scott; Prusator, Dawn K; Joshi, Sunil K; Ballard, Jimmy D; Lang, Mark L

2015-06-25

Protective immunity against anthrax is inferred from measurement of vaccine antigen-specific neutralizing antibody titers in serum samples. In animal models, in vivo challenges with toxin and/or spores can also be performed. However, neither of these approaches considers toxin-induced damage to specific organ systems. It is therefore important to determine to what extent anthrax vaccines and existing or candidate adjuvants can provide organ-specific protection against intoxication. We therefore compared the ability of Alum, CpG DNA and the CD1d ligand α-galactosylceramide (αGC) to enhance protective antigen-specific antibody titers, to protect mice against challenge with lethal toxin, and to block cardiotoxicity and hepatotoxicity. By measurement of serum cardiac Troponin I (cTnI), and hepatic alanine aminotransferase (ALT), and aspartate aminotransferase (AST), it was apparent that neither vaccine modality prevented hepatic intoxication, despite high Ab titers and ultimate survival of the subject. In contrast, cardiotoxicity was greatly diminished by prior immunization. This shows that a vaccine that confers survival following toxin exposure may still have an associated morbidity. We propose that organ-specific intoxication should be monitored routinely during research into new vaccine modalities.

Repertoire of epitopes recognized by serum IgG from humans vaccinated with herpes simplex virus 2 glycoprotein D.

PubMed

Whitbeck, J Charles; Huang, Zhen-Yu; Cairns, Tina M; Gallagher, John R; Lou, Huan; Ponce-de-Leon, Manuel; Belshe, Robert B; Eisenberg, Roselyn J; Cohen, Gary H

2014-07-01

The results of a clinical trial of a subunit vaccine against genital herpes were recently reported (R. B. Belshe, P. A. Leone, D. I. Bernstein, A. Wald, M. J. Levin, J. T. Stapleton, I. Gorfinkel, R. L. Morrow, M. G. Ewell, A. Stokes-Riner, G. Dubin, T. C. Heineman, J. M. Schulte, C. D. Deal, N. Engl. J. Med. 366: 34-43, 2012, doi:10.1056/NEJMoa1103151). The vaccine consisted of a soluble form of herpes simplex virus 2 (HSV-2) glycoprotein D (gD2) with adjuvant. The goal of the current study was to examine the composition of the humoral response to gD2 within a selected subset of vaccinated individuals. Serum samples from 30 vaccine recipients were selected based upon relative enzyme-linked immunosorbent assay (ELISA) titers against gD2; 10 samples had high titers, 10 had medium titers, and the remaining 10 had low ELISA titers. We employed a novel, biosensor-based monoclonal antibody (MAb)-blocking assay to determine whether gD2 vaccination elicited IgG responses against epitopes overlapping those of well-characterized MAbs. Importantly, IgGs from the majority of gD2-immunized subjects competed for gD binding with four antigenically distinct virus-neutralizing MAbs (MC2, MC5, MC23, and DL11). Screening of patient IgGs against overlapping peptides spanning the gD2 ectodomain revealed that about half of the samples contained antibodies against linear epitopes within the N and C termini of gD2. We found that the virus-neutralizing abilities of the 10 most potent samples correlated with overall gD-binding activity and to an even greater extent with the combined content of IgGs against the epitopes of MAbs MC2, MC5, MC23, and DL11. This suggests that optimal virus-neutralizing activity is achieved by strong and balanced responses to the four major discontinuous neutralizing epitopes of gD2. Importance: Several herpes simplex virus 2 (HSV-2) subunit vaccine studies have been conducted in human subjects using a recombinant form of HSV-2 glycoprotein D (gD2). Although several distinct, well-characterized virus-neutralizing epitopes on gD2 are targeted by murine monoclonal antibodies, it is not known whether the same epitopes are targeted by the humoral response to gD2 in humans. We have developed a novel, biosensor-based competition assay to directly address this important question. Using this approach, we identified epitopes that elicit strong humoral responses in humans, as well as other epitopes that elicit much weaker responses. These data provide new insight into the human response to known neutralizing gD2 epitopes and reveal characteristics of this response that may guide future vaccine development. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Repertoire of Epitopes Recognized by Serum IgG from Humans Vaccinated with Herpes Simplex Virus 2 Glycoprotein D

PubMed Central

Huang, Zhen-Yu; Cairns, Tina M.; Gallagher, John R.; Lou, Huan; Ponce-de-Leon, Manuel; Belshe, Robert B.; Eisenberg, Roselyn J.; Cohen, Gary H.

2014-01-01

ABSTRACT The results of a clinical trial of a subunit vaccine against genital herpes were recently reported (R. B. Belshe, P. A. Leone, D. I. Bernstein, A. Wald, M. J. Levin, J. T. Stapleton, I. Gorfinkel, R. L. Morrow, M. G. Ewell, A. Stokes-Riner, G. Dubin, T. C. Heineman, J. M. Schulte, C. D. Deal, N. Engl. J. Med. 366:34–43, 2012, doi:10.1056/NEJMoa1103151). The vaccine consisted of a soluble form of herpes simplex virus 2 (HSV-2) glycoprotein D (gD2) with adjuvant. The goal of the current study was to examine the composition of the humoral response to gD2 within a selected subset of vaccinated individuals. Serum samples from 30 vaccine recipients were selected based upon relative enzyme-linked immunosorbent assay (ELISA) titers against gD2; 10 samples had high titers, 10 had medium titers, and the remaining 10 had low ELISA titers. We employed a novel, biosensor-based monoclonal antibody (MAb)-blocking assay to determine whether gD2 vaccination elicited IgG responses against epitopes overlapping those of well-characterized MAbs. Importantly, IgGs from the majority of gD2-immunized subjects competed for gD binding with four antigenically distinct virus-neutralizing MAbs (MC2, MC5, MC23, and DL11). Screening of patient IgGs against overlapping peptides spanning the gD2 ectodomain revealed that about half of the samples contained antibodies against linear epitopes within the N and C termini of gD2. We found that the virus-neutralizing abilities of the 10 most potent samples correlated with overall gD-binding activity and to an even greater extent with the combined content of IgGs against the epitopes of MAbs MC2, MC5, MC23, and DL11. This suggests that optimal virus-neutralizing activity is achieved by strong and balanced responses to the four major discontinuous neutralizing epitopes of gD2. IMPORTANCE Several herpes simplex virus 2 (HSV-2) subunit vaccine studies have been conducted in human subjects using a recombinant form of HSV-2 glycoprotein D (gD2). Although several distinct, well-characterized virus-neutralizing epitopes on gD2 are targeted by murine monoclonal antibodies, it is not known whether the same epitopes are targeted by the humoral response to gD2 in humans. We have developed a novel, biosensor-based competition assay to directly address this important question. Using this approach, we identified epitopes that elicit strong humoral responses in humans, as well as other epitopes that elicit much weaker responses. These data provide new insight into the human response to known neutralizing gD2 epitopes and reveal characteristics of this response that may guide future vaccine development. PMID:24789783

Vector-based genetically modified vaccines: Exploiting Jenner's legacy.

PubMed

Ramezanpour, Bahar; Haan, Ingrid; Osterhaus, Ab; Claassen, Eric

2016-12-07

The global vaccine market is diverse while facing a plethora of novel developments. Genetic modification (GM) techniques facilitate the design of 'smarter' vaccines. For many of the major infectious diseases of humans, like AIDS and malaria, but also for most human neoplastic disorders, still no vaccines are available. It may be speculated that novel GM technologies will significantly contribute to their development. While a promising number of studies is conducted on GM vaccines and GM vaccine technologies, the contribution of GM technology to newly introduced vaccines on the market is disappointingly limited. In this study, the field of vector-based GM vaccines is explored. Data on currently available, actually applied, and newly developed vectors is retrieved from various sources, synthesised and analysed, in order to provide an overview on the use of vector-based technology in the field of GM vaccine development. While still there are only two vector-based vaccines on the human vaccine market, there is ample activity in the fields of patenting, preclinical research, and different stages of clinical research. Results of this study revealed that vector-based vaccines comprise a significant part of all GM vaccines in the pipeline. This study further highlights that poxviruses and adenoviruses are among the most prominent vectors in GM vaccine development. After the approval of the first vectored human vaccine, based on a flavivirus vector, vaccine vector technology, especially based on poxviruses and adenoviruses, holds great promise for future vaccine development. It may lead to cheaper methods for the production of safe vaccines against diseases for which no or less perfect vaccines exist today, thus catering for an unmet medical need. After the introduction of Jenner's vaccinia virus as the first vaccine more than two centuries ago, which eventually led to the recent eradication of smallpox, this and other viruses may now be the basis for constructing vectors that may help us control other major scourges of mankind. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Modeling the Economic and Epidemiologic Impact of Hookworm Vaccine and Mass Drug Administration (MDA) in Brazil, a High Transmission Setting

PubMed Central

Bartsch, Sarah M.; Hotez, Peter J.; Hertenstein, Daniel L.; Diemert, David J.; Zapf, Kristina M.; Bottazzi, Maria Elena; Bethony, Jeffrey M.; Brown, Shawn T.; Lee, Bruce Y.

2017-01-01

Background Although mass drug administration (MDA) has helped reduce morbidity attributed to soil-transmitted helminth infections in children, its limitations for hookworm infection have motivated the development of a human hookworm vaccine to both improve morbidity control and ultimately help block hookworm transmission leading to elimination. However, the potential economic and epidemiologic impact of a preventive vaccine has not been fully evaluated. Methods We developed a dynamic compartment model coupled to a clinical and economics outcomes model representing both the human and hookworm populations in a high transmission region of Brazil. Experiments simulated different implementation scenarios of MDA and vaccination under varying circumstances. Results Considering only intervention costs, both annual MDA and vaccination were highly cost-effective (ICERs ≤$790/DALY averted) compared to no intervention, with vaccination resulting in lower incremental cost-effectiveness ratios (ICERs ≤$444/DALY averted). From the societal perspective, vaccination was economically dominant (i.e., less costly and more effective) than annual MDA in all tested scenarios, except when vaccination was less efficacious (20% efficacy, 5 year duration) and MDA coverage was 75%. Increasing the vaccine's duration of protection and efficacy, and including a booster injection in adulthood all increased the benefits of vaccination (i.e., resulted in lower hookworm prevalence, averted more disability-adjusted life years, and saved more costs). Assuming its target product profile, a pediatric hookworm vaccine drastically decreased hookworm prevalence in children to 14.6% after 20 years, compared to 57.2% with no intervention and 54.1% with MDA. The addition of a booster in adulthood further reduced the overall prevalence from 68.0% to 36.0%, nearly eliminated hookworm infection in children. Conclusion Using a human hookworm vaccine would be cost-effective and in many cases economically dominant, providing both health benefits and cost-savings. It could become a key technology in effecting control and elimination efforts for hookworm globally. PMID:27002501

Modeling the economic and epidemiologic impact of hookworm vaccine and mass drug administration (MDA) in Brazil, a high transmission setting.

PubMed

Bartsch, Sarah M; Hotez, Peter J; Hertenstein, Daniel L; Diemert, David J; Zapf, Kristina M; Bottazzi, Maria Elena; Bethony, Jeffrey M; Brown, Shawn T; Lee, Bruce Y

2016-04-27

Although mass drug administration (MDA) has helped reduce morbidity attributed to soil-transmitted helminth infections in children, its limitations for hookworm infection have motivated the development of a human hookworm vaccine to both improve morbidity control and ultimately help block hookworm transmission leading to elimination. However, the potential economic and epidemiologic impact of a preventive vaccine has not been fully evaluated. We developed a dynamic compartment model coupled to a clinical and economics outcomes model representing both the human and hookworm populations in a high transmission region of Brazil. Experiments simulated different implementation scenarios of MDA and vaccination under varying circumstances. Considering only intervention costs, both annual MDA and vaccination were highly cost-effective (ICERs ≤ $790/DALY averted) compared to no intervention, with vaccination resulting in lower incremental cost-effectiveness ratios (ICERs ≤ $444/DALY averted). From the societal perspective, vaccination was economically dominant (i.e., less costly and more effective) versus annual MDA in all tested scenarios, except when vaccination was less efficacious (20% efficacy, 5 year duration) and MDA coverage was 75%. Increasing the vaccine's duration of protection and efficacy, and including a booster injection in adulthood all increased the benefits of vaccination (i.e., resulted in lower hookworm prevalence, averted more disability-adjusted life years, and saved more costs). Assuming its target product profile, a pediatric hookworm vaccine drastically decreased hookworm prevalence in children to 14.6% after 20 years, compared to 57.2% with no intervention and 54.1% with MDA. The addition of a booster in adulthood further reduced the overall prevalence from 68.0% to 36.0% and nearly eliminated hookworm infection in children. Using a human hookworm vaccine would be cost-effective and in many cases economically dominant, providing both health benefits and cost-savings. It could become a key technology in effecting control and elimination efforts for hookworm globally. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sugar epitopes as potential universal disease transmission blocking targets.

PubMed

Dinglasan, Rhoel R; Valenzuela, Jesús G; Azad, Abdu F

2005-01-01

One promising method to prevent vector-borne diseases is through the use of transmission blocking vaccines (TBVs). However, developing several anti-pathogen TBVs may be impractical. In this study, we have identified a conserved candidate carbohydrate target in the midguts of several Arthropod vectors. A screen of the novel GlycoChip glycan array found that the anti-carbohydrate malaria transmission blocking monoclonal antibody (MG96) preferentially recognized D-mannose (alpha) and the type II lactosamine disaccharide. The specificity for D-mannose was confirmed by competition ELISA using alpha-methyl mannoside as inhibitor. Con A, which identifies terminal mannose residues, did not inhibit MG96 reactivity with mosquito midgut lysates, suggesting that Con A has differential recognition of this monosaccharide. However, the jack bean lectin, Jacalin, which recognizes D-mannose (alpha), d-galactose (alpha/beta) and the T antigen, not only displays a similar banding profile to that recognized by MG96 on immunoblot but was also shown to effectively inhibit MG96. Wheat-germ agglutinin, which recognizes N-acetyllactosamine units, only partially inhibited MG96 reactivity. This highlights the contribution of both glycan moieties to the MG96 epitope or glycotope. Enzyme deglycosylation results suggest that MG96 recognizes a mannose alpha1-6 substitution on an O-linked oligosaccharide. Taken together, the data suggest that MG96 recognizes a discontinuous glycotope composed of Manalpha1-6 proximal to Galbeta1-4GlcNAc-alpha-O-R glycans on arthropod vector midguts. As such, these glycotopes may represent potential transmission blocking vaccine targets for a wide range of vector-borne pathogens.

Immunogenicity of a DNA-launched replicon-based canine parvovirus DNA vaccine expressing VP2 antigen in dogs.

PubMed

Dahiya, Shyam S; Saini, Mohini; Kumar, Pankaj; Gupta, Praveen K

2012-10-01

A replicon-based DNA vaccine encoding VP2 gene of canine parvovirus (CPV) was developed by cloning CPV-VP2 gene into a replicon-based DNA vaccine vector (pAlpha). The characteristics of a replicon-based DNA vaccine like, self-amplification of transcripts and induction of apoptosis were analyzed in transfected mammalian cells. When the pAlpha-CPV-VP2 was injected intradermal as DNA-launched replicon-based DNA vaccine in dogs, it induced CPV-specific humoral and cell mediated immune responses. The virus neutralization antibody and lymphocyte proliferative responses were higher than conventional CPV DNA vaccine and commercial CPV vaccine. These results indicated that DNA-launched replicon-based CPV DNA vaccine was effective in inducing both CPV-specific humoral and cellular immune responses and can be considered as effective alternative to conventional CPV DNA vaccine and commercial CPV vaccine. Crown Copyright © 2012. Published by Elsevier India Pvt Ltd. All rights reserved.

Ceftiofur hydrochloride affects the humoral and cellular immune response in pigs after vaccination against swine influenza and pseudorabies.

PubMed

Pomorska-Mól, Małgorzata; Czyżewska-Dors, Ewelina; Kwit, Krzysztof; Wierzchosławski, Karol; Pejsak, Zygmunt

2015-10-22

Cephalosporins are a class of antibiotics that are active against many Gram-positive and some Gram-negative bacteria. Beyond their antibacterial activity, they are reported to have various immunomodulatory properties. It has been shown that they reduce the secretion of cytokines as well as influence the humoral and cellular immune response. In the field conditions antibiotics are frequently administered at the same time as vaccines in pigs and, in the view of their potential immunomodulatory properties, it is important to examine their effect on the development and persistence of the post-vaccinal immune response. Ceftiofur is a very popular veterinary medicine third-generation cephalosporin with a broad spectrum of activity. It has been shown that it can inhibit cytokines secretion and in this way can potentially affect host immune response. The influence of ceftiofur on the immune response has not yet been investigated in pigs. In the present study we evaluated the influence of therapeutic doses of ceftiofur hydrochloride on the post-vaccinal immune response after vaccination with two model vaccines (live and inactivated). Seventy pigs were divided into five groups: control, unvaccinated (C), control vaccinated against swine influenza (SI-V), control vaccinated against pseudorabies (PR-V), vaccinated against SI during ceftiofur administration (SI-CEF) and vaccinated against PR during ceftiofur administration (PR-CEF). Pigs from SICEF and PR-CEF groups received therapeutic dose of ceftiofur for five days. Pigs from SI-CEF, PR-CEF, SIV and PR-V groups were vaccinated against SI and PR. Antibodies to PRV were determined with the use of blocking ELISA tests (IDEXX Laboratories, USA). Humoral responses to SIV were assessed based on haemagglutination inhibition assay. T-cell response was analyzed with the use of proliferation test. The concentrations of IFN- γ and IL-4 in culture supernatant were determined with the use of ELISA kits Invitrogen Corporation, USA). The significant delay in the development of humoral response against pseudorabies virus (PRV) as well as a significant suppression of production of antibodies against swine influenza virus (SIV) was found in pigs receiving ceftiofur hydrochloride at the time of vaccination. The cellular immune response against PRV was also significantly affected by ceftiofur. In contrast, there were no significant differences between vaccinated groups with regard to the T-cell response against SIV. From day 28 of study to day 70, the concentration of INF-γ in culture supernatants were significantly lower in group treated with ceftiofur after restimulation with PRV. While, no significant differences were observed after restimulation of PBMC with H3N2 SIV. The effect of an antibiotic therapy with ceftiofur hydrochloride on the humoral and cellular post-vaccinal immune responses in pigs was investigated. Ceftiofur hydrochloride was given in therapeutic doses. The results of the present study indicate that both, humoral and cell-mediated post-vaccinal immune responses can be modulated by treatment with ceftiofur hydrochloride. The results of our study point out that caution should be taken when administered this antibiotic during vaccination of pigs.

Novel transgenic rice-based vaccines.

PubMed

Azegami, Tatsuhiko; Itoh, Hiroshi; Kiyono, Hiroshi; Yuki, Yoshikazu

2015-04-01

Oral vaccination can induce both systemic and mucosal antigen-specific immune responses. To control rampant mucosal infectious diseases, the development of new effective oral vaccines is needed. Plant-based vaccines are new candidates for oral vaccines, and have some advantages over the traditional vaccines in cost, safety, and scalability. Rice seeds are attractive for vaccine production because of their stability and resistance to digestion in the stomach. The efficacy of some rice-based vaccines for infectious, autoimmune, and other diseases has been already demonstrated in animal models. We reported the efficacy in mice, safety, and stability of a rice-based cholera toxin B subunit vaccine called MucoRice-CTB. To advance MucoRice-CTB for use in humans, we also examined its efficacy and safety in primates. The potential of transgenic rice production as a new mucosal vaccine delivery system is reviewed from the perspective of future development of effective oral vaccines.

Trivalent MDCK cell culture-derived influenza vaccine Optaflu (Novartis Vaccines).

PubMed

Doroshenko, Alexander; Halperin, Scott A

2009-06-01

Annual influenza epidemics continue to have a considerable impact in both developed and developing countries. Vaccination remains the principal measure to prevent seasonal influenza and reduce associated morbidity and mortality. The WHO recommends using established mammalian cell culture lines as an alternative to egg-based substrates in the manufacture of influenza vaccine. In June 2007, the EMEA approved Optaflu, a Madin Darby canine kidney cell culture-derived influenza vaccine manufactured by Novartis Vaccines. This review examines the advantages and disadvantages of cell culture-based technology for influenza vaccine production, compares immunogenicity and safety data for Optaflu with that of currently marketed conventional egg-based influenza vaccines, and considers the prospects for wider use of cell culture-based influenza vaccines.

Development and characterization of a recombinant, hypoallergenic, peptide-based vaccine for grass pollen allergy.

PubMed

Focke-Tejkl, Margarete; Weber, Milena; Niespodziana, Katarzyna; Neubauer, Angela; Huber, Hans; Henning, Rainer; Stegfellner, Gottfried; Maderegger, Bernhard; Hauer, Martina; Stolz, Frank; Niederberger, Verena; Marth, Katharina; Eckl-Dorna, Julia; Weiss, Richard; Thalhamer, Josef; Blatt, Katharina; Valent, Peter; Valenta, Rudolf

2015-05-01

Grass pollen is one of the most important sources of respiratory allergies worldwide. This study describes the development of a grass pollen allergy vaccine based on recombinant hypoallergenic derivatives of the major timothy grass pollen allergens Phl p 1, Phl p 2, Phl p 5, and Phl p 6 by using a peptide-carrier approach. Fusion proteins consisting of nonallergenic peptides from the 4 major timothy grass pollen allergens and the PreS protein from hepatitis B virus as a carrier were expressed in Escherichia coli and purified by means of chromatography. Recombinant PreS fusion proteins were tested for allergenic activity and T-cell activation by means of IgE serology, basophil activation testing, T-cell proliferation assays, and xMAP Luminex technology in patients with grass pollen allergy. Rabbits were immunized with PreS fusion proteins to characterize their immunogenicity. Ten hypoallergenic PreS fusion proteins were constructed, expressed, and purified. According to immunogenicity and induction of allergen-specific blocking IgG antibodies, 4 hypoallergenic fusion proteins (BM321, BM322, BM325, and BM326) representing Phl p 1, Phl p 2, Phl p 5, and Phl p 6 were included as components in the vaccine termed BM32. BM321, BM322, BM325, and BM326 showed almost completely abolished allergenic activity and induced significantly reduced T-cell proliferation and release of proinflammatory cytokines in patients' PBMCs compared with grass pollen allergens. On immunization, they induced allergen-specific IgG antibodies, which inhibited patients' IgE binding to all 4 major allergens of grass pollen, as well as allergen-induced basophil activation. A recombinant hypoallergenic grass pollen allergy vaccine (BM32) consisting of 4 recombinant PreS-fused grass pollen allergen peptides was developed for safe immunotherapy of grass pollen allergy. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Detoxified pneumolysin derivative Plym2 directly protects against pneumococcal infection via induction of inflammatory cytokines.

PubMed

Lu, Jingcai; Sun, Tianxu; Hou, Hongjia; Xu, Man; Gu, Tiejun; Dong, Yunliang; Wang, Dandan; Chen, Pinxu; Wu, Chunlai; Liang, Chunshu; Sun, Shiyang; Jiang, Chunlai; Kong, Wei; Wu, Yongge

2014-01-01

Streptococcus pneumoniae is a major cause of infectious disease and complications worldwide, such as pneumonia, otitis media, bacteremia and meningitis. New generation protein-based pneumococcal vaccines are recognized as alternative vaccine candidates. Pneumolysin (Ply) is a cholesterol-dependent cytolysin produced by all clinical isolates of S. pneumoniae. Our research group previously developed a highly detoxified Ply mutant designated Plym2 by replacement of two animo acids (C428G and W433F). Exhibiting undetectable levels of cytotoxicity, Plym2 could still elicit high titer neutralizing antibodies against the native toxin. However, evaluation of the active immunoprotective effects of Plym2 by subcutaneous immunization and lethal challenge with S. pneumoniae in mice did not yield favorable results. In the present work, we confirmed the previous observations by using passive immunization and systemic challenge. Results of the passive immunization were consistent with those of active immunization. Further experiments were conducted to explain the inability of high titer neutralizing antibodies against Ply to protect mice from S. pneumoniae challenge. Pneumococcal Ply is known to be the major factor responsible for the induction of inflammation that benefits the host. Proinflammatory cytokines facilitate the clearance of invaders by the recruitment and activation of leukocytes at the early infection stage. We demonstrated that Plym2 could induce proinflammatory cytokines similarly to wild-type Ply. A systemic infection model was used to clarify that Plym2 lacking cytolytic activity could protect mice from intraperitoneal challenge directly, while antibodies to the mutant had no effect. Therefore, the protective function of Plym2 may be due to its induction of proinflammatory cytokines. When used in the systemic infection model, Plym2 antibodies may block the induction of proinflammatory cytokines by Ply. These findings demonstrate that a Ply-based vaccine would not be an effective primary vaccine component, but it may be beneficial as an adjuvant to stimulate cytokine production.

Induction of immunity following vaccination with a chemically attenuated malaria vaccine correlates with persistent antigenic stimulation.

PubMed

Reiman, Jennifer M; Kumar, Sanjai; Rodriguez, Ingrid B; Gnidehou, Sedami; Ito, Koichi; Stanisic, Danielle I; Lee, Moses; McPhun, Virginia; Majam, Victoria; Willemsen, Nicole M; Batzloff, Michael R; Raja, Amber I; Dooley, Brad; Hoffman, Stephen L; Yanow, Stephanie K; Good, Michael F

2018-01-01

Blood stage malaria parasites attenuated with seco-cyclopropyl pyrrolo indole (CPI) analogues induce robust immunity in mice to homologous and heterologous malaria parasites and are being considered for the development of a human vaccine. However, it is not understood how attenuated parasites induce immunity. We showed that following vaccination, parasite DNA persisted in blood for several months, raising the possibility that ongoing immune stimulation may be critical. However, parasites were not seen microscopically beyond 24 h postvaccination. We aimed to provide a mechanistic understanding of immune induction. Mice were vaccinated with chemically attenuated Plasmodium chabaudi parasites. PCR and adoptive transfer studies were used to determine the presence of parasites and antigen in vivo . In other experiments, Plasmodium falciparum parasitised red blood cells were attenuated in vitro and RNA and antigen expression studied. We show that blood transferred from vaccinated mice into naïve mice activates T cells and induces complete protective immunity in the recipient mice strongly suggesting that there is persistence of parasite antigen postvaccination. This is supported by the presence of parasite RNA in vaccinated mice and both RNA and antigen expression in P. falciparum cultures treated with CPI drugs in vitro . In addition, drugs that block parasite growth also prevent the induction of immunity in vaccinated mice, indicating that some growth of attenuated parasites is required for immune induction. Attenuated parasites persist at submicroscopic levels in the blood of mice postvaccination with the ability to activate T cells and induce ongoing protective immune responses.

Molecular basis of immunogenicity to botulinum neurotoxins and uses of the defined antigenic regions.

PubMed

Atassi, M Z

2015-12-01

Intensive research in this laboratory over the last 19 years has aimed at understanding the molecular bases for immune recognition of botulinum neurotoxin, types A and B and the role of anti-toxin immune responses in defense against the toxin. Using 92 synthetic 19-residue peptides that overlapped by 5 residues and comprised an entire toxin (A or B) we determined the peptides' ability to bind anti-toxin Abs of human, mouse, horse and chicken. We also localized the epitopes recognized by Abs of cervical dystonia patients who developed immunoresistance to correlate toxin during treatment with BoNT/A or BoNT/B. For BoNT/A, patients' blocking Abs bound to 13 regions (5 on L and 8 on H subunit) on the surface and the response to each region was under separate MHC control. The responses were defined by the structure of the antigen and by the MHC of the host. The antigenic regions coincided or overlapped with synaptosomes (SNPS) binding regions. Antibody binding blocked the toxin's ability to bind to neuronal cells. In fact selected synthetic peptides were able to inhibit the toxin's action in vivo. A combination of three synthetic strong antigenic peptides detected blocking Abs in 88% of immunoresistant patients' sera. Administration of selected epitopes, pre-linked at their N(α) group to monomethoxyployethylene glycol, into mice with ongoing blocking anti-toxin Abs, reduced blocking Ab levels in the recipients. This may be suitable for clinical applications. Defined epitopes should also be valuable in synthetic vaccines design. Copyright © 2015 Elsevier Ltd. All rights reserved.

Prophylactic and therapeutic vaccination with carrier-bound Bet v 1 peptides lacking allergen-specific T cell epitopes reduces Bet v 1-specific T cell responses via blocking antibodies in a murine model for birch pollen allergy.

PubMed

Linhart, B; Narayanan, M; Focke-Tejkl, M; Wrba, F; Vrtala, S; Valenta, R

2014-02-01

Vaccines consisting of allergen-derived peptides lacking IgE reactivity and allergen-specific T cell epitopes bound to allergen-unrelated carrier molecules have been suggested as candidates for allergen-specific immunotherapy. To study whether prophylactic and therapeutic vaccination with carrier-bound peptides from the major birch pollen allergen Bet v 1 lacking allergen-specific T cell epitopes has influence on Bet v 1-specific T cell responses. Three Bet v 1-derived peptides, devoid of Bet v 1-specific T cell epitopes, were coupled to KLH and adsorbed to aluminium hydroxide to obtain a Bet v 1-specific allergy vaccine. Groups of BALB/c mice were immunized with the peptide vaccine before or after sensitization to Bet v 1. Bet v 1- and peptide-specific antibody responses were analysed by ELISA. T cell and cytokine responses to Bet v 1, KLH, and the peptides were studied in proliferation assays. The effects of peptide-specific and allergen-specific antibodies on T cell responses and allergic lung inflammation were studied using specific antibodies. Prophylactic and therapeutic vaccination with carrier-bound Bet v 1 peptides induced a Bet v 1-specific IgG antibody response without priming/boosting of Bet v 1-specific T cells. Prophylactic and therapeutic vaccination of mice with the peptide vaccine induced Bet v 1-specific antibodies which suppressed Bet v 1-specific T cell responses and allergic lung inflammation. Vaccination with carrier-bound allergen-derived peptides lacking allergen-specific T cell epitopes induces allergen-specific IgG antibodies which suppress allergen-specific T cell responses and allergic lung inflammation. © 2013 John Wiley & Sons Ltd.

Smallpox eradication in West and Central Africa.

PubMed

Foege, W H; Millar, J D; Henderson, D A

1975-01-01

The history of smallpox eradication in the 20 countries of West and Central Africa from Mauritania to Zaire is recounted, including background, evolution of strategy, assessment, maintenance, costs, and significance of the campaign. Smallpox was endemic in these countries, peaking each year at the end of the spring dry season, usually occurring in isolated villages only periodically. The average case fatality was 14.5%, but twice as high in infants and older adults. Clinical exams showed that those with actual vaccination scars rarely got smallpox. The campaign was made feasible because of lyophilized heat-stable vaccine and bifurcated needles or jet injectors. The initial strategy called for mass vaccination and assessment of achieved vaccination. Between 1967 and 1969 100 million persons were vaccinated at collecting points; by 1972, 28 million more children had been protected. In 1966 an outbreak of 34 cases in Nigeria was blocked within 3 weeks of initiation of surveillance and containment. This effort also demonstrated that actual smallpox transmission was slow and relatively ineffective, and further that vaccination of contacts even after exposure was effective. The strategy was replaced by surveillance-containment begun in the seasonal low. The results were that smallpox disappeared within 5 months in an area of 12 million, and within 1 year in 19 of the 20 countries. Maintenance vaccination to prevent importation of the virus is continuing. The cost of the program was $15 million to the U.S. sponsors, or 1/10 the yearly price of smallpox control in the U.S.

Vaccine-induced anti-HA2 antibodies promote virus fusion and enhance influenza virus respiratory disease.

PubMed

Khurana, Surender; Loving, Crystal L; Manischewitz, Jody; King, Lisa R; Gauger, Phillip C; Henningson, Jamie; Vincent, Amy L; Golding, Hana

2013-08-28

Vaccine-induced disease enhancement has been described in connection with several viral vaccines in animal models and in humans. We investigated a swine model to evaluate mismatched influenza vaccine-associated enhanced respiratory disease (VAERD) after pH1N1 infection. Vaccinating pigs with whole inactivated H1N2 (human-like) virus vaccine (WIV-H1N2) resulted in enhanced pneumonia and disease after pH1N1 infection. WIV-H1N2 immune sera contained high titers of cross-reactive anti-pH1N1 hemagglutinin (HA) antibodies that bound exclusively to the HA2 domain but not to the HA1 globular head. No hemagglutination inhibition titers against pH1N1 (challenge virus) were measured. Epitope mapping using phage display library identified the immunodominant epitope recognized by WIV-H1N2 immune sera as amino acids 32 to 77 of pH1N1-HA2 domain, close to the fusion peptide. These cross-reactive anti-HA2 antibodies enhanced pH1N1 infection of Madin-Darby canine kidney cells by promoting virus membrane fusion activity. The enhanced fusion activity correlated with lung pathology in pigs. This study suggests a role for fusion-enhancing anti-HA2 antibodies in VAERD, in the absence of receptor-blocking virus-neutralizing antibodies. These findings should be considered during the evaluation of universal influenza vaccines designed to elicit HA2 stem-targeting antibodies.

Vaxjo: a web-based vaccine adjuvant database and its application for analysis of vaccine adjuvants and their uses in vaccine development.

PubMed

Sayers, Samantha; Ulysse, Guerlain; Xiang, Zuoshuang; He, Yongqun

2012-01-01

Vaccine adjuvants are compounds that enhance host immune responses to co-administered antigens in vaccines. Vaxjo is a web-based central database and analysis system that curates, stores, and analyzes vaccine adjuvants and their usages in vaccine development. Basic information of a vaccine adjuvant stored in Vaxjo includes adjuvant name, components, structure, appearance, storage, preparation, function, safety, and vaccines that use this adjuvant. Reliable references are curated and cited. Bioinformatics scripts are developed and used to link vaccine adjuvants to different adjuvanted vaccines stored in the general VIOLIN vaccine database. Presently, 103 vaccine adjuvants have been curated in Vaxjo. Among these adjuvants, 98 have been used in 384 vaccines stored in VIOLIN against over 81 pathogens, cancers, or allergies. All these vaccine adjuvants are categorized and analyzed based on adjuvant types, pathogens used, and vaccine types. As a use case study of vaccine adjuvants in infectious disease vaccines, the adjuvants used in Brucella vaccines are specifically analyzed. A user-friendly web query and visualization interface is developed for interactive vaccine adjuvant search. To support data exchange, the information of vaccine adjuvants is stored in the Vaccine Ontology (VO) in the Web Ontology Language (OWL) format.

Vaxjo: A Web-Based Vaccine Adjuvant Database and Its Application for Analysis of Vaccine Adjuvants and Their Uses in Vaccine Development

PubMed Central

Sayers, Samantha; Ulysse, Guerlain; Xiang, Zuoshuang; He, Yongqun

2012-01-01

Vaccine adjuvants are compounds that enhance host immune responses to co-administered antigens in vaccines. Vaxjo is a web-based central database and analysis system that curates, stores, and analyzes vaccine adjuvants and their usages in vaccine development. Basic information of a vaccine adjuvant stored in Vaxjo includes adjuvant name, components, structure, appearance, storage, preparation, function, safety, and vaccines that use this adjuvant. Reliable references are curated and cited. Bioinformatics scripts are developed and used to link vaccine adjuvants to different adjuvanted vaccines stored in the general VIOLIN vaccine database. Presently, 103 vaccine adjuvants have been curated in Vaxjo. Among these adjuvants, 98 have been used in 384 vaccines stored in VIOLIN against over 81 pathogens, cancers, or allergies. All these vaccine adjuvants are categorized and analyzed based on adjuvant types, pathogens used, and vaccine types. As a use case study of vaccine adjuvants in infectious disease vaccines, the adjuvants used in Brucella vaccines are specifically analyzed. A user-friendly web query and visualization interface is developed for interactive vaccine adjuvant search. To support data exchange, the information of vaccine adjuvants is stored in the Vaccine Ontology (VO) in the Web Ontology Language (OWL) format. PMID:22505817

An Overview on the Field of Micro- and Nanotechnologies for Synthetic Peptide-Based Vaccines

PubMed Central

Salvador, Aiala; Igartua, Manoli; Hernández, Rosa Maria; Pedraz, José Luis

2011-01-01

The development of synthetic peptide-based vaccines has many advantages in comparison with vaccines based on live attenuated organisms, inactivated or killed organism, or toxins. Peptide-based vaccines cannot revert to a virulent form, allow a better conservation, and are produced more easily and safely. However, they generate a weaker immune response than other vaccines, and the inclusion of adjuvants and/or the use of vaccine delivery systems is almost always needed. Among vaccine delivery systems, micro- and nanoparticulated ones are attractive, because their particulate nature can increase cross-presentation of the peptide. In addition, they can be passively or actively targeted to antigen presenting cells. Furthermore, particulate adjuvants are able to directly activate innate immune system in vivo. Here, we summarize micro- and nanoparticulated vaccine delivery systems used in the field of synthetic peptide-based vaccines as well as strategies to increase their immunogenicity. PMID:21773041

The current state of therapeutic and T cell-based vaccines against human papillomaviruses

PubMed Central

Yang, Andrew; Farmer, Emily; Lin, John; Wu, T-C.; Hung, Chien-Fu

2016-01-01

Human papillomavirus (HPV) is known to be a necessary factor for many gynecologic malignancies and is also associated with a subset of head and neck malignancies. This knowledge has created the opportunity to control these HPV-associated cancers through vaccination. However, despite the availability of prophylactic HPV vaccines, HPV infections remain extremely common worldwide. In addition, while prophylactic HPV vaccines have been effective in preventing infection, they are ineffective at clearing pre-existing HPV infections. Thus, there is an urgent need for therapeutic and T cell-based vaccines to treat existing HPV infections and HPV-associated lesions and cancers. Unlike prophylactic vaccines, which generate neutralizing antibodies, therapeutic, and T cell-based vaccines enhance cell-mediated immunity against HPV antigens. Our review will cover various therapeutic and T cell-based vaccines in development for the treatment of HPV-associated diseases. Furthermore, we review the strategies to enhance the efficacy of therapeutic vaccines and the latest clinical trials on therapeutic and T cell-based HPV vaccines. PMID:27932207

Supplemental dietary L-arginine attenuates intestinal mucosal disruption during a coccidial vaccine challenge in broiler chickens

USDA-ARS?s Scientific Manuscript database

The present study investigated the effects of dietary arginine (Arg) supplementation on intestinal barrier integrity in broiler chickens undergoing coccidial challenge. The design of this study was a randomized complete block employing a 3 x 2 factorial arrangement (n = 8) with 3 level of Arg (1.11,...

Design of a shear-thinning recoverable peptide hydrogel from native sequences and application for influenza H1N1 vaccine adjuvant

USDA-ARS?s Scientific Manuscript database

Peptide hydrogels are considered injectable materials for drug delivery and tissue engineering applications. Most published hydrogel-forming sequences contain either alternating-charged and noncharged residues or amphiphilic blocks. Here, we report a self-assembling peptide, h9e (FLIVIGSIIGPGGDGPGGD...

Vaccination and the TAP-independent antigen processing pathways.

PubMed

López, Daniel; Lorente, Elena; Barriga, Alejandro; Johnstone, Carolina; Mir, Carmen

2013-09-01

The cytotoxic CD8(+) T lymphocyte-mediated cellular response is important for the elimination of virus-infected cells and requires the prior recognition of short viral peptide antigens previously translocated to the endoplasmic reticulum by the transporter associated with antigen processing (TAP). However, individuals with nonfunctional TAP complexes or infected cells with TAP molecules blocked by specific viral proteins, such as the cowpoxvirus, a component of the first source of early empirical vaccination against smallpox, are still able to present several HLA class I ligands generated by the TAP-independent antigen processing pathways to specific cytotoxic CD8(+) T lymphocytes. Currently, bioterrorism and emerging infectious diseases have renewed interest in poxviruses. Recent works that have identified HLA class I ligands and epitopes in virus-infected TAP-deficient cells have implications for the study of both the effectiveness of early empirical vaccination and the analysis of HLA class I antigen processing in TAP-deficient subjects.

The Case for Adolescent HIV Vaccination in South Africa

PubMed Central

Moodley, Nishila; Gray, Glenda; Bertram, Melanie

2016-01-01

Abstract Despite comprising 0.7% of the world population, South Africa is home to 18% of the global human immunodeficiency virus (HIV) prevalence. Unyielding HIV subepidemics among adolescents threaten national attempts to curtail the disease burden. Should an HIV vaccine become available, establishing its point of entry into the health system becomes a priority. This study assesses the impact of school-based HIV vaccination and explores how variations in vaccine characteristics affect cost-effectiveness. The cost per quality adjusted life year (QALY) gained associated with school-based adolescent HIV vaccination services was assessed using Markov modeling that simulated annual cycles based on national costing data. The estimation was based on a life expectancy of 70 years and employs the health care provider perspective. The simultaneous implementation of HIV vaccination services with current HIV management programs would be cost-effective, even at relatively higher vaccine cost. At base vaccine cost of US$ 12, the incremental cost effectiveness ratio (ICER) was US$ 43 per QALY gained, with improved ICER values yielded at lower vaccine costs. The ICER was sensitive to duration of vaccine mediated protection and variations in vaccine efficacy. Data from this work demonstrate that vaccines offering longer duration of protection and at lower cost would result in improved ICER values. School-based HIV vaccine services of adolescents, in addition to current HIV prevention and treatment health services delivered, would be cost-effective. PMID:26825890

The Case for Adolescent HIV Vaccination in South Africa: A Cost-Effectiveness Analysis.

PubMed

Moodley, Nishila; Gray, Glenda; Bertram, Melanie

2016-01-01

Despite comprising 0.7% of the world population, South Africa is home to 18% of the global human immunodeficiency virus (HIV) prevalence. Unyielding HIV subepidemics among adolescents threaten national attempts to curtail the disease burden. Should an HIV vaccine become available, establishing its point of entry into the health system becomes a priority. This study assesses the impact of school-based HIV vaccination and explores how variations in vaccine characteristics affect cost-effectiveness. The cost per quality adjusted life year (QALY) gained associated with school-based adolescent HIV vaccination services was assessed using Markov modeling that simulated annual cycles based on national costing data. The estimation was based on a life expectancy of 70 years and employs the health care provider perspective. The simultaneous implementation of HIV vaccination services with current HIV management programs would be cost-effective, even at relatively higher vaccine cost. At base vaccine cost of US$ 12, the incremental cost effectiveness ratio (ICER) was US$ 43 per QALY gained, with improved ICER values yielded at lower vaccine costs. The ICER was sensitive to duration of vaccine mediated protection and variations in vaccine efficacy. Data from this work demonstrate that vaccines offering longer duration of protection and at lower cost would result in improved ICER values. School-based HIV vaccine services of adolescents, in addition to current HIV prevention and treatment health services delivered, would be cost-effective.

A Phase III Clinical Trial of the Epidermal Growth Factor Vaccine CIMAvax-EGF as Switch Maintenance Therapy in Advanced Non-Small Cell Lung Cancer Patients.

PubMed

Rodriguez, Pedro C; Popa, Xitllaly; Martínez, Odeth; Mendoza, Silvia; Santiesteban, Eduardo; Crespo, Tatiana; Amador, Rosa M; Fleytas, Ricardo; Acosta, Soraida C; Otero, Yanine; Romero, Gala N; de la Torre, Ana; Cala, Mireysi; Arzuaga, Lina; Vello, Loisel; Reyes, Delmairis; Futiel, Niurka; Sabates, Teresa; Catala, Mauricio; Flores, Yoanna I; Garcia, Beatriz; Viada, Carmen; Lorenzo-Luaces, Patricia; Marrero, Maria A; Alonso, Liuba; Parra, Jenelin; Aguilera, Nadia; Pomares, Yaisel; Sierra, Patricia; Rodríguez, Gryssell; Mazorra, Zaima; Lage, Agustin; Crombet, Tania; Neninger, Elia

2016-08-01

EGFR is a well-validated target for patients with non-small cell lung cancer (NSCLC). CIMAvax-EGF is a therapeutic cancer vaccine composed of human recombinant EGF conjugated to a carrier protein and Montanide ISA51 as adjuvant. The vaccine is intended to induce antibodies against self EGFs that block EGF-EGFR interaction. To evaluate overall survival, safety, immunogenicity, and EGF concentration in serum after CIMAvax-EGF, a randomized phase III trial was done in patients with advanced NSCLC. Four to 6 weeks after first-line chemotherapy, 405 patients with stage IIIB/IV NSCLC were randomly assigned to a vaccine group, which received CIMAvax-EGF or a control group, treated with best supportive care. Long-term vaccination was very safe. Most frequent adverse reactions were grade 1 or 2 injection-site pain, fever, vomiting, and headache. Vaccination induced anti-EGF antibodies and decreased serum EGF concentration. In the safety population, median survival time (MST) was 10.83 months in the vaccine arm versus 8.86 months in the control arm. These differences were not significant according the standard log rank (HR, 0.82; P = 0.100), but according a weighted log rank (P = 0.04) that was applied once the nonproportionality of the HR was verified. Survival benefit was significant (HR, 0.77; P = 0.036) in the per-protocol setting (patients receiving at least four vaccine doses): MST was 12.43 months for the vaccine arm versus 9.43 months for the control arm. MST was higher (14.66 months) for vaccinated patients with high EGF concentration at baseline. Switch maintenance with CIMAvax-EGF was well tolerated and significantly increased MST of patients that completed induction vaccination. Baseline EGF concentration predicted survival benefit. Clin Cancer Res; 22(15); 3782-90. ©2016 AACR. ©2016 American Association for Cancer Research.

Peptides designed to spatially depict the Epstein-Barr virus major virion glycoprotein gp350 neutralization epitope elicit antibodies that block virus-neutralizing antibody 72A1 interaction with the native gp350 molecule.

PubMed

Tanner, Jerome E; Coinçon, Mathieu; Leblond, Valérie; Hu, Jing; Fang, Janey M; Sygusch, Jurgen; Alfieri, Caroline

2015-05-01

Epstein-Barr virus (EBV) is the etiologic agent of infectious mononucleosis and the root cause of B-cell lymphoproliferative disease in individuals with a weakened immune system, as well as a principal cofactor in nasopharyngeal carcinoma, various lymphomas, and other cancers. The EBV major virion surface glycoprotein gp350 is viewed as the best vaccine candidate to prevent infectious mononucleosis in healthy EBV-naive persons and EBV-related cancers in at-risk individuals. Previous epitope mapping of gp350 revealed only one dominant neutralizing epitope, which has been shown to be the target of the monoclonal antibody 72A1. Computer modeling of the 72A1 antibody interaction with the gp350 amino terminus was used to identify gp350 amino acids that could form strong ionic, electrostatic, or hydrogen bonds with the 72A1 antibody. Peptide DDRTTLQLAQNPVYIPETYPYIKWDN (designated peptide 2) and peptide GSAKPGNGSYFASVKTEMLGNEID (designated peptide 3) were designed to spatially represent the gp350 amino acids predicted to interact with the 72A1 antibody paratope. Peptide 2 bound to the 72A1 antibody and blocked 72A1 antibody recognition of the native gp350 molecule. Peptide 2 and peptide 3 were recognized by human IgG and shown to elicit murine antibodies that could target gp350 and block its recognition by the 72A1 antibody. This work provides a structural mapping of the interaction between the EBV-neutralizing antibody 72A1 and the major virion surface protein gp350. gp350 mimetic peptides that spatially depict the EBV-neutralizing epitope would be useful as a vaccine to focus the immune system exclusively to this important virus epitope. The production of virus-neutralizing antibodies targeting the Epstein-Barr virus (EBV) major surface glycoprotein gp350 is important for the prevention of infectious mononucleosis and EBV-related cancers. The data presented here provide the first in silico map of the gp350 interaction with a virus-blocking monoclonal antibody. Immunization with gp350 peptides identified by in silico mapping generated antibodies that cross-react with the EBV gp350 molecule and block recognition of the gp350 molecule by a virus-neutralizing antibody. Through its ability to focus the immune system exclusively on the gp350 sequence important for viral entry, these peptides may form the basis of an EBV vaccine candidate. This strategy would sidestep the production of other irrelevant gp350 antibodies that divert the immune system from generating a protective antiviral response or that impede access to the virus-blocking epitope by protective antibodies. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Story and science

PubMed Central

Shelby, Ashley; Ernst, Karen

2013-01-01

With little or no evidence-based information to back up claims of vaccine danger, anti-vaccine activists have relied on the power of storytelling to infect an entire generation of parents with fear of and doubt about vaccines. These parent accounts of perceived vaccine injury, coupled with Andrew Wakefield’s fraudulent research study linking the MMR vaccine to autism, created a substantial amount of vaccine hesitancy in new parents, which manifests in both vaccine refusal and the adoption of delayed vaccine schedules. The tools used by the medical and public health communities to counteract the anti-vaccine movement include statistics, research, and other evidence-based information, often delivered verbally or in the form of the CDC’s Vaccine Information Statements. This approach may not be effective enough on its own to convince vaccine-hesitant parents that vaccines are safe, effective, and crucial to their children’s health. Utilizing some of the storytelling strategies used by the anti-vaccine movement, in addition to evidence-based vaccine information, could potentially offer providers, public health officials, and pro-vaccine parents an opportunity to mount a much stronger defense against anti-vaccine messaging. PMID:23811786

Salmonella-based plague vaccines for bioterrorism.

PubMed

Calhoun, Leona Nicole; Kwon, Young-Min

2006-04-01

Yersinia pestis, the causative agent of plague, is an emerging threat as a means of bioterrorism. Accordingly, the Working Group on Civilian Biodefense, as well as the Centers for Disease Control and Prevention, has specified Y. pestis as a prime candidate for use in bioterrorism. As the threat of bioterrorism increases, so does the need for an effective vaccine against this potential agent. Experts agree that a stable, non-invasive vaccine would be necessary for the rapid large-scale immunization of a population following a bioterrorism attack. Thus far, live Salmonella-based oral vaccines show the most potential for this purpose. When delivered via a mucosal route, Salmonella-based plague vaccines show the ability to protect against the deadly pneumonic form of plague. Also, mass production, distribution, and administration are easier and less costly for attenuated Salmonella-based plague vaccines than for plague vaccines consisting of purified proteins. Most attenuated Salmonella-based plague vaccines have utilized a plasmid-based expression system to deliver plague antigen(s) to the mucosa. However, these systems are frequently associated with plasmid instability, an increased metabolic burden upon the vaccine strain, and highly undesirable antibiotic resistance genes. The future of Salmonella-based plague vaccines seems to lie in the use of chromosomally encoded plague antigens and the use of in vivo inducible promoters to drive their expression. This method of vaccine development has been proven to greatly increase the retention of foreign genes, and also eliminates the need for antibiotic resistance genes within Salmonella-based vaccines.

A Stable Heroin Analogue That Can Serve as a Vaccine Hapten to Induce Antibodies That Block the Effects of Heroin and Its Metabolites in Rodents and That Cross-React Immunologically with Related Drugs of Abuse

PubMed Central

2017-01-01

An improved synthesis of a haptenic heroin surrogate 1 (6-AmHap) is reported. The intermediate needed for the preparation of 1 was described in the route in the synthesis of 2 (DiAmHap). A scalable procedure was developed to install the C-3 amido group. Using the Boc protectng group in 18 allowed preparation of 1 in an overall yield of 53% from 4 and eliminated the necessity of preparing the diamide 13. Hapten 1 was conjugated to tetanus toxoid and mixed with liposomes containing monophosphoryl lipid A as an adjuvant. The 1 vaccine induced high anti-1 IgG levels that reduced heroin-induced antinociception and locomotive behavioral changes following repeated subcutaneous and intravenous heroin challenges in mice and rats. Vaccinated mice had reduced heroin-induced hyperlocomotion following a 50 mg/kg heroin challenge. The 1 vaccine-induced antibodies bound to heroin and other abused opioids, including hydrocodone, oxycodone, hydromorphone, oxymorphone, and codeine. PMID:29236495

Vaccines against Botulism.

PubMed

Sundeen, Grace; Barbieri, Joseph T

2017-09-02

Botulinum neurotoxins (BoNT) cause the flaccid paralysis of botulism by inhibiting the release of acetylcholine from motor neurons. There are seven serotypes of BoNT (A-G), with limited therapies, and no FDA approved vaccine for botulism. An investigational formalin-inactivated penta-serotype-BoNT/A-E toxoid vaccine was used to vaccinate people who are at high risk of contracting botulism. However, this formalin-inactivated penta-serotype-BoNT/A-E toxoid vaccine was losing potency and was discontinued. This article reviews the different vaccines being developed to replace the discontinued toxoid vaccine. These vaccines include DNA-based, viral vector-based, and recombinant protein-based vaccines. DNA-based vaccines include plasmids or viral vectors containing the gene encoding one of the BoNT heavy chain receptor binding domains (HC). Viral vectors reviewed are adenovirus, influenza virus, rabies virus, Semliki Forest virus, and Venezuelan Equine Encephalitis virus. Among the potential recombinant protein vaccines reviewed are HC, light chain-heavy chain translocation domain, and chemically or genetically inactivated holotoxin.

Vaccines against Botulism

PubMed Central

Sundeen, Grace; Barbieri, Joseph T.

2017-01-01

Botulinum neurotoxins (BoNT) cause the flaccid paralysis of botulism by inhibiting the release of acetylcholine from motor neurons. There are seven serotypes of BoNT (A-G), with limited therapies, and no FDA approved vaccine for botulism. An investigational formalin-inactivated penta-serotype-BoNT/A-E toxoid vaccine was used to vaccinate people who are at high risk of contracting botulism. However, this formalin-inactivated penta-serotype-BoNT/A-E toxoid vaccine was losing potency and was discontinued. This article reviews the different vaccines being developed to replace the discontinued toxoid vaccine. These vaccines include DNA-based, viral vector-based, and recombinant protein-based vaccines. DNA-based vaccines include plasmids or viral vectors containing the gene encoding one of the BoNT heavy chain receptor binding domains (HC). Viral vectors reviewed are adenovirus, influenza virus, rabies virus, Semliki Forest virus, and Venezuelan Equine Encephalitis virus. Among the potential recombinant protein vaccines reviewed are HC, light chain-heavy chain translocation domain, and chemically or genetically inactivated holotoxin. PMID:28869493

The Babesia bovis hap2 gene is not required for blood stage replication, but expressed upon in vitro sexual stage induction

PubMed Central

Hussein, Hala E.; Bastos, Reginaldo G.; Schneider, David A.; Johnson, Wendell C.; Adham, Fatma K.; Davis, William C.; Laughery, Jacob M.; Herndon, David R.; Alzan, Heba F.

2017-01-01

Babesia bovis, is a tick borne apicomplexan parasite responsible for important cattle losses globally. Babesia parasites have a complex life cycle including asexual replication in the mammalian host and sexual reproduction in the tick vector. Novel control strategies aimed at limiting transmission of the parasite are needed, but transmission blocking vaccine candidates remain undefined. Expression of HAP2 has been recognized as critical for the fertilization of parasites in the Babesia-related Plasmodium, and is a leading candidate for a transmission blocking vaccine against malaria. Hereby we identified the B. bovis hap2 gene and demonstrated that it is widely conserved and differentially transcribed during development within the tick midgut, but not by blood stage parasites. The hap2 gene was disrupted by transfecting B. bovis with a plasmid containing the flanking regions of the hap2 gene and the GPF-BSD gene under the control of the ef-1α-B promoter. Comparison of in vitro growth between a hap2-KO B. bovis clonal line and its parental wild type strain showed that HAP2 is not required for the development of B. bovis in erythrocytes. However, xanthurenic acid-in vitro induction experiments of sexual stages of parasites recovered after tick transmission resulted in surface expression of HAP2 exclusively in sexual stage induced parasites. In addition, hap2-KO parasites were not able to develop such sexual stages as defined both by morphology and by expression of the B. bovis sexual marker genes 6-Cys A and B. Together, the data strongly suggests that tick midgut stage differential expression of hap2 is associated with the development of B. bovis sexual forms. Overall these studies are consistent with a role of HAP2 in tick stages of the parasite and suggest that HAP2 is a potential candidate for a transmission blocking vaccine against bovine babesiosis. PMID:28985216

A Population-Based Evaluation of a Publicly Funded, School-Based HPV Vaccine Program in British Columbia, Canada: Parental Factors Associated with HPV Vaccine Receipt

PubMed Central

Ogilvie, Gina; Anderson, Maureen; Marra, Fawziah; McNeil, Shelly; Pielak, Karen; Dawar, Meena; McIvor, Marilyn; Ehlen, Thomas; Dobson, Simon; Money, Deborah; Patrick, David M.; Naus, Monika

2010-01-01

Background Information on factors that influence parental decisions for actual human papillomavirus (HPV) vaccine receipt in publicly funded, school-based HPV vaccine programs for girls is limited. We report on the level of uptake of the first dose of the HPV vaccine, and determine parental factors associated with receipt of the HPV vaccine, in a publicly funded school-based HPV vaccine program in British Columbia, Canada. Methods and Findings All parents of girls enrolled in grade 6 during the academic year of September 2008–June 2009 in the province of British Columbia were eligible to participate. Eligible households identified through the provincial public health information system were randomly selected and those who consented completed a validated survey exploring factors associated with HPV vaccine uptake. Bivariate and multivariate analyses were conducted to calculate adjusted odds ratios to identify the factors that were associated with parents' decision to vaccinate their daughter(s) against HPV. 2,025 parents agreed to complete the survey, and 65.1% (95% confidence interval [CI] 63.1–67.1) of parents in the survey reported that their daughters received the first dose of the HPV vaccine. In the same school-based vaccine program, 88.4% (95% CI 87.1–89.7) consented to the hepatitis B vaccine, and 86.5% (95% CI 85.1–87.9) consented to the meningococcal C vaccine. The main reasons for having a daughter receive the HPV vaccine were the effectiveness of the vaccine (47.9%), advice from a physician (8.7%), and concerns about daughter's health (8.4%). The main reasons for not having a daughter receive the HPV vaccine were concerns about HPV vaccine safety (29.2%), preference to wait until the daughter is older (15.6%), and not enough information to make an informed decision (12.6%). In multivariate analysis, overall attitudes to vaccines, the impact of the HPV vaccine on sexual practices, and childhood vaccine history were predictive of parents having a daughter receive the HPV vaccine in a publicly funded school-based HPV vaccine program. By contrast, having a family with two parents, having three or more children, and having more education was associated with a decreased likelihood of having a daughter receive the HPV vaccine. Conclusions This study is, to our knowledge, one of the first population-based assessments of factors associated with HPV vaccine uptake in a publicly funded school-based program worldwide. Policy makers need to consider that even with the removal of financial and health care barriers, parents, who are key decision makers in the uptake of this vaccine, are still hesitant to have their daughters receive the HPV vaccine, and strategies to ensure optimal HPV vaccine uptake need to be employed. Please see later in the article for the Editors' Summary PMID:20454567

Story and science: how providers and parents can utilize storytelling to combat anti-vaccine misinformation.

PubMed

Shelby, Ashley; Ernst, Karen

2013-08-01

With little or no evidence-based information to back up claims of vaccine danger, anti-vaccine activists have relied on the power of storytelling to infect an entire generation of parents with fear of and doubt about vaccines. These parent accounts of perceived vaccine injury, coupled with Andrew Wakefield's fraudulent research study linking the MMR vaccine to autism, created a substantial amount of vaccine hesitancy in new parents, which manifests in both vaccine refusal and the adoption of delayed vaccine schedules. The tools used by the medical and public health communities to counteract the anti-vaccine movement include statistics, research, and other evidence-based information, often delivered verbally or in the form of the CDC's Vaccine Information Statements. This approach may not be effective enough on its own to convince vaccine-hesitant parents that vaccines are safe, effective, and crucial to their children's health. Utilizing some of the storytelling strategies used by the anti-vaccine movement, in addition to evidence-based vaccine information, could potentially offer providers, public health officials, and pro-vaccine parents an opportunity to mount a much stronger defense against anti-vaccine messaging.

From non school-based, co-payment to school-based, free Human Papillomavirus vaccination in Flanders (Belgium): a retrospective cohort study describing vaccination coverage, age-specific coverage and socio-economic inequalities.

PubMed

Lefevere, Eva; Theeten, Heidi; Hens, Niel; De Smet, Frank; Top, Geert; Van Damme, Pierre

2015-09-22

School-based, free HPV vaccination for girls in the first year of secondary school was introduced in Flanders (Belgium) in 2010. Before that, non school-based, co-payment vaccination for girls aged 12-18 was in place. We compared vaccination coverage, age-specific coverage and socio-economic inequalities in coverage - 3 important parameters contributing to the effectiveness of the vaccination programs - under both vaccination systems. We used retrospective administrative data from different sources. Our sample consisted of all female members of the National Alliance of Christian Mutualities born in 1995, 1996, 1998 or 1999 (N=66,664). For each vaccination system we described the cumulative proportion HPV vaccination initiation and completion over time. We used life table analysis to calculate age-specific rates of HPV vaccination initiation and completion. Analyses were done separately for higher income and low income groups. Under non school-based, co-payment vaccination the proportions HPV vaccination initiation and completion slowly rose over time. By age 17, the proportion HPV vaccination initiation/completion was 0.75 (95% CI 0.74-076)/0.66 (95% CI 0.65-0.67). The median age at vaccination initiation/completion was 14.4 years (95% CI 14.4-14.5)/15.4 years (95% CI 15.3-15.4). Socio-economic inequalities in coverage widened over time and with age. Under school-based, free vaccination rates of HPV vaccination initiation were substantially higher. By age 14,the proportion HPV vaccination initiation/completion was 0.90 (95% CI 0.90-0.90)/0.87 (95% CI 0.87-0.88). The median age at vaccination initiation/completion was 12.7 years (95% CI 12.7-12.7)/13.3 years (95% CI 13.3-13.3). Socio-economic inequalities in coverage and in age-specific coverage were substantially smaller. Copyright © 2015. Published by Elsevier Ltd.

Ricin-Holotoxin-Based Vaccines: Induction of Potent Ricin-Neutralizing Antibodies.

PubMed

Sabo, Tamar; Kronman, Chanoch; Mazor, Ohad

2016-01-01

Ricin is one of the most potent and lethal toxins known to which there is no available antidote. Currently, the most promising therapy is based on neutralizing antibodies elicited by active vaccination or given passively. Here, detailed protocols are provided for the production of two ricin holotoxin-based vaccines: monomerized subunit-based vaccine, and a formaldehyde-based ricin toxoid vaccine. Both vaccines were found to be stable with no toxic activity reversion even after long-term storage while eliciting high anti-ricin antibody titers possessing a potent neutralizing activity. The use of these vaccines is highly suitable for both the production of sera that can be used in passive protection experiments and immunization aimed to isolate potent anti-ricin monoclonal antibodies.

PEG-PLA-PEG block copolymeric nanoparticles for oral immunization against hepatitis B.

PubMed

Jain, Arvind K; Goyal, Amit K; Mishra, Neeraj; Vaidya, Bhuvaneshwar; Mangal, Sharad; Vyas, Suresh P

2010-03-15

PLA/PLGA nanoparticles are well known as efficient vaccine delivery systems, but they have got limitation in oral vaccine delivery because of their sensitivity to harsh gastric environment. The aim of present study was to improve the stability of PLA nanoparticles in such environment by copolymerizing PLA with PEG. Nanoparticles were formulated using different block copolymers AB, ABA and BAB (where 'A' is PLA and 'B' is PEG) encapsulating hepatitis B surface antigen (HBsAg) to evaluate their efficacy as oral vaccine delivery system. The results of in vitro studies engrave the efficiency of copolymeric nanoparticles to retain encapsulated antigen and average particle size even after 2 h incubation in simulated gastric fluid and simulated intestinal fluid. Fluorescence microscopic studies indicated efficient uptake of copolymeric nanoparticles by gut mucosa of immunized mice model as compared to control. Finally copolymeric and PLA nanoparticles, encapsulating HBsAg, were evaluated for their adjuvancity in generating immune response after oral administration. PLA nanoparticles could not generate an effective immune response due to stability issues. On the other hand, oral administration of copolymeric nanoparticles exhibited effective levels of humoral immunity along with the mucosal (sIgA) and cellular immune response (T(H)1). The results of in vitro and in vivo studies demonstrate that BAB nanoparticles depict enhanced mucosal uptake leading to effective immune response as compared to other copolymeric nanoparticles. Present study indicates the efficacy of BAB nanoparticles as a promising carrier for oral immunization. 2009 Elsevier B.V. All rights reserved.

Dual Plug-and-Display Synthetic Assembly Using Orthogonal Reactive Proteins for Twin Antigen Immunization.

PubMed

Brune, Karl D; Buldun, Can M; Li, Yuanyuan; Taylor, Iona J; Brod, Florian; Biswas, Sumi; Howarth, Mark

2017-05-17

Engineering modular platforms to control biomolecular architecture can advance both the understanding and the manipulation of biological systems. Icosahedral particles uniformly displaying single antigens stimulate potent immune activation and have been successful in various licensed vaccines. However, it remains challenging to display multiple antigens on a single particle and to induce broader immunity protective across strains or even against distinct diseases. Here, we design a dually addressable synthetic nanoparticle by engineering the multimerizing coiled-coil IMX313 and two orthogonally reactive split proteins. SpyCatcher protein forms an isopeptide bond with SpyTag peptide through spontaneous amidation. SnoopCatcher forms an isopeptide bond with SnoopTag peptide through transamidation. SpyCatcher-IMX-SnoopCatcher provides a modular platform, whereby SpyTag-antigen and SnoopTag-antigen can be multimerized on opposite faces of the particle simply upon mixing. We demonstrate efficient derivatization of the platform with model proteins and complex pathogen-derived antigens. SpyCatcher-IMX-SnoopCatcher was expressed in Escherichia coli and was resilient to lyophilization or extreme temperatures. For the next generation of malaria vaccines, blocking the transmission of the parasite from human to mosquito is an important goal. SpyCatcher-IMX-SnoopCatcher multimerization of the leading transmission-blocking antigens Pfs25 and Pfs28 greatly enhanced the antibody response to both antigens in comparison to the monomeric proteins. This dual plug-and-display architecture should help to accelerate vaccine development for malaria and other diseases.

No evidence for positive selection at two potential targets for malaria transmission-blocking vaccines in Anopheles gambiae s.s.

PubMed

Crawford, Jacob E; Rottschaefer, Susan M; Coulibaly, Boubacar; Sacko, Madjou; Niaré, Oumou; Riehle, Michelle M; Traore, Sékou F; Vernick, Kenneth D; Lazzaro, Brian P

2013-06-01

Human malaria causes nearly a million deaths in sub-Saharan Africa each year. The evolution of drug-resistance in the parasite and insecticide resistance in the mosquito vector has complicated control measures and made the need for new control strategies more urgent. Anopheles gambiae s.s. is one of the primary vectors of human malaria in Africa, and parasite-transmission-blocking vaccines targeting Anopheles proteins have been proposed as a possible strategy to control the spread of the disease. However, the success of these hypothetical technologies would depend on the successful ability to broadly target mosquito populations that may be genetically heterogeneous. Understanding the evolutionary pressures shaping genetic variation among candidate target molecules offers a first step towards evaluating the prospects of successfully deploying such technologies. We studied the population genetics of genes encoding two candidate target proteins, the salivary gland protein saglin and the basal lamina structural protein laminin, in wild populations of the M and S molecular forms of A. gambiae in Mali. Through analysis of intraspecific genetic variation and interspecific comparisons, we found no evidence of positive natural selection at the genes encoding these proteins. On the contrary, we found evidence for particularly strong purifying selection at the laminin gene. These results provide insight into the patterns of genetic diversity of saglin and laminin, and we discuss these findings in relation to the potential development of these molecules as vaccine targets. Copyright © 2013 Elsevier B.V. All rights reserved.

Production of adenovirus vectors and their use as a delivery system for influenza vaccines

PubMed Central

Vemula, Sai V.; Mittal, Suresh K.

2010-01-01

IMPORTANCE OF THE FIELD With the emergence of highly pathogenic avian influenza H5N1 viruses that have crossed species barriers and are responsible for lethal infections in humans in many countries, there is an urgent need for the development of effective vaccines which can be produced in large quantities at a short notice and confer broad protection against these H5N1 variants. In order to meet the potential global vaccine demand in a pandemic scenario, new vaccine-production strategies must be explored in addition to the currently used egg-based technology for seasonal influenza. AREAS COVERED IN THIS REVIEW Adenovirus (Ad) based influenza vaccines represent an attractive alternative/supplement to the currently licensed egg-based influenza vaccines. Ad-based vaccines are relatively inexpensive to manufacture, and their production process does not require either chicken eggs or labor intensive and time-consuming processes necessitating enhanced biosafety facilities. Most importantly, in a pandemic situation, this vaccine strategy could offer a stockpiling option to reduce the response time before a strain-matched vaccine could be developed. WHAT THE READER WILL GAIN This review discusses Ad-vector technology and the current progress in the development of Ad-based influenza vaccines. TAKE HOME MESSAGE Ad vector-based influenza vaccines for pandemic preparedness are under development to meet the global vaccine demand. PMID:20822477

Dendritic cell based vaccines: progress in immunotherapy studies for prostate cancer.

PubMed

Ragde, Haakon; Cavanagh, William A; Tjoa, Benjamin A

2004-12-01

No effective treatment is currently available for metastatic prostate cancer. Dendritic cell (DC) based cancer vaccine research has emerged from the laboratories to human clinical trials. We describe progress in the development of DC based prostate cancer vaccine. The literature was reviewed for major contributions to a growing number of studies that demonstrate the potential of DC based immunotherapeutics for prostate cancer. Background topics relating to DC based immunotherapy theory and practice are also addressed. DCs have been recognized as the most efficient antigen presenting cells that have the capacity to initiate naive T cell response in vitro and in vivo. During their differentiation and maturation pathways, dendritic cells can efficiently capture, process and present antigens for T cell activation. These characteristics make DC an attractive choice as the cellular adjuvant for cancer vaccines. Advances in DC generation, loading, and maturation methodologies have made it possible to generate clinical grade vaccines for various human trials. More than 100 DC vaccine trials, including 7 studies of patients with advanced prostate cancer have been reported to date. These vaccines were generally well tolerated with no significant adverse toxicity reported. Clinical responders have been identified in these studies. The new prospects opened by DC based vaccines for prostate cancer are fascinating. When compared to conventional treatments, DC vaccinations have few side effects. Improvements in patient selection, vaccine delivery strategies, immune monitoring and vaccine manufacturing will be crucial in moving DC based prostate cancer vaccines closer to the clinics.

Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir

PubMed Central

Marshall, Jason D.; Dorwart, Michael R.; Heeke, Darren S.; Rao, Eileen; Tummala, Padmaja; Yu, Li; Cohen, Gary H.; Eisenberg, Roselyn J.

2017-01-01

ABSTRACT Several prophylactic vaccines targeting herpes simplex virus 2 (HSV-2) have failed in the clinic to demonstrate sustained depression of viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing antibodies (NAbs), their induction of robust CD8 T cells has largely been unreported, even though evidence for the importance of HSV-2 antigen-specific CD8 T cells is mounting in animal models and in translational studies involving subjects with active HSV-2-specific immune responses. We developed a subunit vaccine composed of the NAb targets gD and gB and the novel T cell antigen and tegument protein UL40, and we compared this vaccine to a whole-inactivated-virus vaccine (formaldehyde-inactivated HSV-2 [FI-HSV-2]). We evaluated different formulations in combination with several Th1-inducing Toll-like receptor (TLR) agonists in vivo. In mice, the TLR9 agonist cytosine-phosphate-guanine (CpG) oligodeoxynucleotide formulated in a squalene-based oil-in-water emulsion promoted most robust, functional HSV-2 antigen-specific CD8 T cell responses and high titers of neutralizing antibodies, demonstrating its superiority to vaccines adjuvanted by monophosphoryl lipid A (MPL)-alum. We further established that FI-HSV-2 alone or in combination with adjuvants as well as adjuvanted subunit vaccines were successful in the induction of NAbs and T cell responses in guinea pigs. These immunological responses were coincident with a suppression of vaginal HSV-2 shedding, low lesion scores, and a reduction in latent HSV-2 DNA in dorsal root ganglia to undetectable levels. These data support the further preclinical and clinical development of prophylactic HSV-2 vaccines that contain appropriate antigen and adjuvant components responsible for programming elevated CD8 T cell responses. IMPORTANCE Millions of people worldwide are infected with herpes simplex virus 2 (HSV-2), and to date, an efficacious prophylactic vaccine has not met the rigors of clinical trials. Attempts to develop a vaccine have focused primarily on glycoproteins necessary for HSV-2 entry as target antigens and to which the dominant neutralizing antibody response is directed during natural infection. Individuals with asymptomatic infection have exhibited T cell responses against specific HSV-2 antigens not observed in symptomatic individuals. We describe for the first time the immunogenicity profile in animal models of UL40, a novel HSV-2 T cell antigen that has been correlated with asymptomatic HSV-2 disease. Additionally, vaccine candidates adjuvanted by a robust formulation of the CpG oligonucleotide delivered in emulsion were superior to unadjuvanted or MPL-alum-adjuvanted formulations at eliciting a robust cell-mediated immune response and blocking the establishment of a latent viral reservoir in the guinea pig challenge model of HSV-2 infection. PMID:28228587

Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir.

PubMed

Hensel, Michael T; Marshall, Jason D; Dorwart, Michael R; Heeke, Darren S; Rao, Eileen; Tummala, Padmaja; Yu, Li; Cohen, Gary H; Eisenberg, Roselyn J; Sloan, Derek D

2017-05-01

Several prophylactic vaccines targeting herpes simplex virus 2 (HSV-2) have failed in the clinic to demonstrate sustained depression of viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing antibodies (NAbs), their induction of robust CD8 T cells has largely been unreported, even though evidence for the importance of HSV-2 antigen-specific CD8 T cells is mounting in animal models and in translational studies involving subjects with active HSV-2-specific immune responses. We developed a subunit vaccine composed of the NAb targets gD and gB and the novel T cell antigen and tegument protein UL40, and we compared this vaccine to a whole-inactivated-virus vaccine (formaldehyde-inactivated HSV-2 [FI-HSV-2]). We evaluated different formulations in combination with several Th1-inducing Toll-like receptor (TLR) agonists in vivo In mice, the TLR9 agonist cytosine-phosphate-guanine (CpG) oligodeoxynucleotide formulated in a squalene-based oil-in-water emulsion promoted most robust, functional HSV-2 antigen-specific CD8 T cell responses and high titers of neutralizing antibodies, demonstrating its superiority to vaccines adjuvanted by monophosphoryl lipid A (MPL)-alum. We further established that FI-HSV-2 alone or in combination with adjuvants as well as adjuvanted subunit vaccines were successful in the induction of NAbs and T cell responses in guinea pigs. These immunological responses were coincident with a suppression of vaginal HSV-2 shedding, low lesion scores, and a reduction in latent HSV-2 DNA in dorsal root ganglia to undetectable levels. These data support the further preclinical and clinical development of prophylactic HSV-2 vaccines that contain appropriate antigen and adjuvant components responsible for programming elevated CD8 T cell responses. IMPORTANCE Millions of people worldwide are infected with herpes simplex virus 2 (HSV-2), and to date, an efficacious prophylactic vaccine has not met the rigors of clinical trials. Attempts to develop a vaccine have focused primarily on glycoproteins necessary for HSV-2 entry as target antigens and to which the dominant neutralizing antibody response is directed during natural infection. Individuals with asymptomatic infection have exhibited T cell responses against specific HSV-2 antigens not observed in symptomatic individuals. We describe for the first time the immunogenicity profile in animal models of UL40, a novel HSV-2 T cell antigen that has been correlated with asymptomatic HSV-2 disease. Additionally, vaccine candidates adjuvanted by a robust formulation of the CpG oligonucleotide delivered in emulsion were superior to unadjuvanted or MPL-alum-adjuvanted formulations at eliciting a robust cell-mediated immune response and blocking the establishment of a latent viral reservoir in the guinea pig challenge model of HSV-2 infection. Copyright © 2017 American Society for Microbiology.

The current state of therapeutic and T cell-based vaccines against human papillomaviruses.

PubMed

Yang, Andrew; Farmer, Emily; Lin, John; Wu, T-C; Hung, Chien-Fu

2017-03-02

Human papillomavirus (HPV) is known to be a necessary factor for many gynecologic malignancies and is also associated with a subset of head and neck malignancies. This knowledge has created the opportunity to control these HPV-associated cancers through vaccination. However, despite the availability of prophylactic HPV vaccines, HPV infections remain extremely common worldwide. In addition, while prophylactic HPV vaccines have been effective in preventing infection, they are ineffective at clearing pre-existing HPV infections. Thus, there is an urgent need for therapeutic and T cell-based vaccines to treat existing HPV infections and HPV-associated lesions and cancers. Unlike prophylactic vaccines, which generate neutralizing antibodies, therapeutic, and T cell-based vaccines enhance cell-mediated immunity against HPV antigens. Our review will cover various therapeutic and T cell-based vaccines in development for the treatment of HPV-associated diseases. Furthermore, we review the strategies to enhance the efficacy of therapeutic vaccines and the latest clinical trials on therapeutic and T cell-based HPV vaccines. Copyright © 2016 Elsevier B.V. All rights reserved.

Role of T-cell epitope-based vaccine in prophylactic and therapeutic applications

PubMed Central

Testa, James S; Philip, Ramila

2013-01-01

Prophylactic and therapeutic vaccines against viral infections have advanced in recent years from attenuated live vaccines to subunit-based vaccines. An ideal prophylactic vaccine should mimic the natural immunity induced by an infection, in that it should generate long-lasting adaptive immunity. To complement subunit vaccines, which primarily target an antibody response, different methodologies are being investigated to develop vaccines capable of driving cellular immunity. T-cell epitope discovery is central to this concept. In this review, the significance of T-cell epitope-based vaccines for prophylactic and therapeutic applications is discussed. Additionally, methodologies for the discovery of T-cell epitopes, as well as recent developments in the clinical testing of these vaccines for various viral infections, are explained. PMID:23630544

Advances in therapeutic vaccines for pancreatic cancer.

PubMed

Plate, Janet M D

2012-08-01

Pancreatic cancer is one of the most difficult-to-treat cancers. Despite surgical resection, radiation and/or chemotherapy, greater than 94% of people with pancreatic cancer do not survive beyond 5 years. In fact, median survival after diagnosis of metastatic pancreatic cancer is 4.5 months. The majority of patients are diagnosed with nonresectable, metastatic disease, and chemotherapy only extends their median survival by less than 2 months with only 18% of those treated surviving beyond 1 year. Despite the severity of their disease, most patients exhibit tumor specific cellular immunity to their pancreatic cancer antigens. Obviously their immunity is ineffective in preventing tumor growth. Recent studies have demonstrated that the tumor microenvironment may hold the key to determining the nature of the tumors' ability to escape from immune attack. Preliminary clinical trials have suggested that blocking these escape mechanisms may result in survival benefit to the patients, and phase I and II clinical trials with tumor vaccines have led to some survival benefits. Perhaps combining therapies directed against immune escape mechanisms with tumor vaccines will result in even greater survival benefit for patients with pancreatic cancer. While therapeutic vaccines for pancreatic cancers have been reviewed previously (Plate, 2011), updates on recent preliminary reports of two clinical vaccine trials are worthy of our attention.

Vaccination of carp against SVCV with an oral DNA vaccine or an insect cells-based subunit vaccine.

PubMed

Embregts, C W E; Rigaudeau, D; Tacchi, L; Pijlman, G P; Kampers, L; Veselý, T; Pokorová, D; Boudinot, P; Wiegertjes, G F; Forlenza, M

2018-03-19

We recently reported on a successful vaccine for carp against SVCV based on the intramuscular injection of a DNA plasmid encoding the SVCV glycoprotein (SVCV-G). This shows that the intramuscular (i.m.) route of vaccination is suitable to trigger protective responses against SVCV, and that the SVCV G-protein is a suitable vaccine antigen. Yet, despite the general success of DNA vaccines, especially against fish rhabdoviruses, their practical implementation still faces legislative as well as consumer's acceptance concerns. Furthermore, the i.m. route of plasmid administration is not easily combined with most of the current vaccination regimes largely based on intraperitoneal or immersion vaccination. For this reason, in the current study we evaluated possible alternatives to a DNA-based i.m. injectable vaccine using the SVCV-G protein as the vaccine antigen. To this end, we tested two parallel approaches: the first based on the optimization of an alginate encapsulation method for oral delivery of DNA and protein antigens; the second based on the baculovirus recombinant expression of transmembrane SVCV-G protein in insect cells, administered as whole-cell subunit vaccine through the oral and injection route. In addition, in the case of the oral DNA vaccine, we also investigated the potential benefits of the mucosal adjuvants Escherichia coli lymphotoxin subunit B (LTB). Despite the use of various vaccine types, doses, regimes, and administration routes, no protection was observed, contrary to the full protection obtained with our reference i.m. DNA vaccine. The limited protection observed under the various conditions used in this study, the nature of the host, of the pathogen, the type of vaccine and encapsulation method, will therefore be discussed in details to provide an outlook for future vaccination strategies against SVCV. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Advances in hepatitis C virus vaccines, part two: advances in hepatitis C virus vaccine formulations and modalities.

PubMed

Roohvand, Farzin; Kossari, Niloufar

2012-04-01

Developing a vaccine against HCV is an important medical and global priority. Unavailability and potential dangers associated with using attenuated HCV viral particles for vaccine preparation have resulted in the use of HCV genes and proteins formulated in novel vaccine modalities. In part one of this review, advances in basic knowledge for HCV vaccine design were provided. Herein, a detailed and correlated patents (searched by Espacenet) and literatures (searched by Pubmed) review on HCV vaccine formulations and modalities is provided, including: subunit, DNA, epitopic-peptide/polytopic, live vector- and whole yeast-based vaccines. Less-touched areas in vaccine studies such as mucosal, plant-based, and chimeric HBV/HCV vaccines are also discussed. Furthermore, results of preclinical/clinical studies on selected HCV vaccines as well as pros and cons of different strategies are reviewed. Finally, potential strategies for creation and/or improvement of HCV vaccine formulations are discussed. Promising outcomes of a few HCV vaccine modalities in phase I/II clinical trials predict the accessibility of at least partially effective vaccines to inhibit or treat the chronic state of HCV infection (specially in combination with standard antiviral therapy). ChronVac-C (plasmid DNA), TG4040 (MVA-based), and GI-5005 (whole yeast-based) might be the most obvious HCV vaccine candidates to be approved in the near future.

Transcytosis-blocking abs elicited by an oligomeric immunogen based on the membrane proximal region of HIV-1 gp41 target non-neutralizing epitopes.

PubMed

Matoba, Nobuyuki; Griffin, Tagan A; Mittman, Michele; Doran, Jeffrey D; Alfsen, Annette; Montefiori, David C; Hanson, Carl V; Bomsel, Morgane; Mor, Tsafrir S

2008-05-01

CTB-MPR(649-684), a translational fusion protein consisting of cholera toxin B subunit (CTB) and residues 649 684 of gp41 membrane proximal region (MPR), is a candidate vaccine aimed at blocking early steps of HIV-1 mucosal transmission. Bacterially produced CTB MPR(649-684) was purified to homogeneity by two affinity chromatography steps. Similar to gp41 and derivatives thereof, the MPR domain can specifically and reversibly self-associate. The affinities of the broadly-neutralizing monoclonal Abs 4E10 and 2F5 to CTB MPR(649-684) were equivalent to their nanomolar affinities toward an MPR peptide. The fusion protein's affinity to GM1 ganglioside was comparable to that of native CTB. Rabbits immunized with CTB-MPR(649-684) raised only a modest level of anti-MPR(649-684) Abs. However, a prime-boost immunization with CTB-MPR(649-684) and a second MPR(649-684)-based immunogen elicited a more productive anti-MPR(649-684) antibody response. These Abs strongly blocked the epithelial transcytosis of a primary subtype B HIV-1 isolate in a human tight epithelial model, expanding our previously reported results using a clade D virus. The Abs recognized epitopes at the N-terminal portion of the MPR peptide, away from the 2F5 and 4E10 epitopes and were not effective in neutralizing infection of CD4+ cells. These results indicate distinct vulnerabilities of two separate interactions of HIV-1 with human cells - Abs against the C-terminal portion of the MPR can neutralize CD4+-dependent infection, while Abs targeting the MPR's N-terminal portion can effectively block galactosyl ceramide dependent transcytosis. We propose that Abs induced by MPR(649-684)-based immunogens may provide broad protective value independent of infection neutralization.

Development of a vaccine to mitigate greenhouse gas emissions in agriculture: vaccination of sheep with methanogen fractions induces antibodies that block methane production in vitro.

PubMed

Wedlock, D N; Pedersen, G; Denis, M; Dey, D; Janssen, P H; Buddle, B M

2010-02-01

To develop an understanding of the immune responses of ruminants to methanogens, and to provide proof of a concept that harnessing the immune system of ruminants is a potentially viable approach to mitigate greenhouse gas emissions from agriculture. Four subcellular fractions, namely cytoplasmic, two cell-wall preparations, and cell wall-derived proteins were prepared from Methanobrevibacter ruminantium M1. Twenty sheep (10 months of age) were vaccinated with these fractions or with whole cells (n=4 per group). Sheep were re-vaccinated once after 3 weeks, and antibody responses to M. ruminantium M1 antigens in sera and saliva measured using ELISA at 2 weeks after the second vaccination. Antigens recognised by the antisera were visualised using Western blotting. The antisera were tested in vitro for their impact on M. ruminantium M1, measuring the effect on cell growth, methane production, and ability to induce agglutination. Basal levels (pre-vaccination) of antibodies against M. ruminantium M1 antigens were low. Vaccination with the antigenic fractions induced strong antibody responses in serum. Both IgG and IgA responses to methanogen antigens were detected in saliva following vaccination. Western blot analysis of the antisera indicated reactivity of antibodies, and a wide range of proteins was present in the different methanogen fractions. Antisera against the various fractions agglutinated methanogens in an in-vitro assay. In addition, these antisera decreased the growth of a pure culture of a methanogen and production of methane in vitro. Antigens from methanogens are immunogenic in ruminants, and antisera from sheep vaccinated with fractions of methanogens have a significant impact on these organisms, inducing cell agglutination, and decreasing growth of methanogens and production of methane. Only antisera to selected methanogen fractions were able to achieve these effects. The results demonstrate the feasibility of a vaccination strategy to mitigate emission of methane.

Vaccination against CD99 inhibits atherogenesis in low-density lipoprotein receptor-deficient mice.

PubMed

van Wanrooij, Eva J A; de Vos, Paula; Bixel, M Gabriele; Vestweber, Dietmar; van Berkel, Theo J C; Kuiper, Johan

2008-06-01

Murine CD99 was recently found to be expressed on leukocytes and endothelial cells, where it is concentrated at inter-endothelial contacts. Blockade of CD99 by specific antibodies inhibits leukocyte extravasation to inflamed sites in vivo. The aim of the present study is to show the role of CD99 in atherosclerosis using a CD99 vaccination protocol to block the function of CD99 during atherosclerosis. We constructed a DNA vaccine against CD99 by cloning the extracellular domain of murine CD99 into pcDNA3. Vaccination was performed by oral administration of attenuated Salmonella typhimurium transformed with pcDNA3-CD99. This vaccination results in a CD99-specific, CD8-mediated cytotoxic response and subsequent reduction of CD99-expressing cells. We showed that CD99 is expressed on vascular endothelium overlying atherosclerotic plaques and found that CD99 expression is upregulated during western-type diet feeding. CD99 vaccination induced the formation of CD8-positive T cells that were cytotoxic against cells transfected with pcDNA3-CD99. Activation of CD8(+) T cells was demonstrated by a 30% increase in CD8(+)CD69(+) double-positive T cells in spleen and mediastinal lymph nodes. Furthermore, lymphocytes isolated from CD99-vaccinated mice specifically lysed CD99-expressing cells. More importantly, vaccination against CD99 attenuated atherosclerotic lesion formation in the aortic valve leaflets by 38% and in the carotid artery by 69% compared with mice that were vaccinated with a control vector. Furthermore, a lower number of cells were found in atherosclerotic lesions, implying that fewer leukocytes were recruited to these sites. These observations were accompanied by a decrease in CD99 expression on leukocytes. We conclude that vaccination against CD99 decreases atherogenesis by the selective removal of CD99-expressing cells, which could reduce leukocyte recruitment into atherosclerotic lesions and attenuate atherogenesis.

Comparison of self-reported and recorded vaccinations and health effects in Australian Gulf War veterans.

PubMed

Kelsall, Helen; McKenzie, Dean; Sim, Malcolm; Leder, Karin; Ross, James; Forbes, Andrew; Ikin, Jillian

2008-08-05

Vaccinations, and multiple vaccinations in particular, have been associated with adverse health effects in veterans of the 1990/1991 Gulf War. However, exposure assessment has usually been based on self-report and recall bias may have influenced the results. We investigated agreement between self-reported and recorded vaccinations and the relationship with health status in Australian Gulf War veterans. Agreement between self-reported and recorded vaccinations was highest for plague (kappa=0.80), and kappa coefficients were greater than 0.60 for polio and 'other unlisted' vaccines, between 0.41 and 0.60 for hepatitis B, hepatitis A, typhoid and pertussis, and less than 0.40 for the other listed vaccines. The associations of increasing number of self-reported vaccinations in dose response relationships with total number of symptoms, functional impairment, and poorer physical health were not observed when based on recorded vaccination data, although the actual difference in estimates was small and statistically significant only for total number of symptoms. Vaccinations were not associated with adverse health effects when exposure assessment was based on recorded vaccinations. It would be prudent that future research studies should be based on recorded vaccination data.

Mass Vaccination with a New, Less Expensive Oral Cholera Vaccine Using Public Health Infrastructure in India: The Odisha Model

PubMed Central

Kar, Shantanu K.; Sah, Binod; Patnaik, Bikash; Kim, Yang Hee; Kerketta, Anna S.; Shin, Sunheang; Rath, Shyam Bandhu; Ali, Mohammad; Mogasale, Vittal; Khuntia, Hemant K.; Bhattachan, Anuj; You, Young Ae; Puri, Mahesh K.; Lopez, Anna Lena; Maskery, Brian; Nair, Gopinath B.; Clemens, John D.; Wierzba, Thomas F.

2014-01-01

Introduction The substantial morbidity and mortality associated with recent cholera outbreaks in Haiti and Zimbabwe, as well as with cholera endemicity in countries throughout Asia and Africa, make a compelling case for supplementary cholera control measures in addition to existing interventions. Clinical trials conducted in Kolkata, India, have led to World Health Organization (WHO)-prequalification of Shanchol, an oral cholera vaccine (OCV) with a demonstrated 65% efficacy at 5 years post-vaccination. However, before this vaccine is widely used in endemic areas or in areas at risk of outbreaks, as recommended by the WHO, policymakers will require empirical evidence on its implementation and delivery costs in public health programs. The objective of the present report is to describe the organization, vaccine coverage, and delivery costs of mass vaccination with a new, less expensive OCV (Shanchol) using existing public health infrastructure in Odisha, India, as a model. Methods All healthy, non-pregnant residents aged 1 year and above residing in selected villages of the Satyabadi block (Puri district, Odisha, India) were invited to participate in a mass vaccination campaign using two doses of OCV. Prior to the campaign, a de jure census, micro-planning for vaccination and social mobilization activities were implemented. Vaccine coverage for each dose was ascertained as a percentage of the censused population. The direct vaccine delivery costs were estimated by reviewing project expenditure records and by interviewing key personnel. Results The mass vaccination was conducted during May and June, 2011, in two phases. In each phase, two vaccine doses were given 14 days apart. Sixty-two vaccination booths, staffed by 395 health workers/volunteers, were established in the community. For the censused population, 31,552 persons (61% of the target population) received the first dose and 23,751 (46%) of these completed their second dose, with a drop-out rate of 25% between the two doses. Higher coverage was observed among females and among 6–17 year-olds. Vaccine cost at market price (about US$1.85/dose) was the costliest item. The vaccine delivery cost was $0.49 per dose or $1.13 per fully vaccinated person. Discussion This is the first undertaken project to collect empirical evidence on the use of Shanchol within a mass vaccination campaign using existing public health program resources. Our findings suggest that mass vaccination is feasible but requires detailed micro-planning. The vaccine and delivery cost is affordable for resource poor countries. Given that the vaccine is now WHO pre-qualified, evidence from this study should encourage oral cholera vaccine use in countries where cholera remains a public health problem. PMID:24516675

Mass vaccination with a new, less expensive oral cholera vaccine using public health infrastructure in India: the Odisha model.

PubMed

Kar, Shantanu K; Sah, Binod; Patnaik, Bikash; Kim, Yang Hee; Kerketta, Anna S; Shin, Sunheang; Rath, Shyam Bandhu; Ali, Mohammad; Mogasale, Vittal; Khuntia, Hemant K; Bhattachan, Anuj; You, Young Ae; Puri, Mahesh K; Lopez, Anna Lena; Maskery, Brian; Nair, Gopinath B; Clemens, John D; Wierzba, Thomas F

2014-02-01

The substantial morbidity and mortality associated with recent cholera outbreaks in Haiti and Zimbabwe, as well as with cholera endemicity in countries throughout Asia and Africa, make a compelling case for supplementary cholera control measures in addition to existing interventions. Clinical trials conducted in Kolkata, India, have led to World Health Organization (WHO)-prequalification of Shanchol, an oral cholera vaccine (OCV) with a demonstrated 65% efficacy at 5 years post-vaccination. However, before this vaccine is widely used in endemic areas or in areas at risk of outbreaks, as recommended by the WHO, policymakers will require empirical evidence on its implementation and delivery costs in public health programs. The objective of the present report is to describe the organization, vaccine coverage, and delivery costs of mass vaccination with a new, less expensive OCV (Shanchol) using existing public health infrastructure in Odisha, India, as a model. All healthy, non-pregnant residents aged 1 year and above residing in selected villages of the Satyabadi block (Puri district, Odisha, India) were invited to participate in a mass vaccination campaign using two doses of OCV. Prior to the campaign, a de jure census, micro-planning for vaccination and social mobilization activities were implemented. Vaccine coverage for each dose was ascertained as a percentage of the censused population. The direct vaccine delivery costs were estimated by reviewing project expenditure records and by interviewing key personnel. The mass vaccination was conducted during May and June, 2011, in two phases. In each phase, two vaccine doses were given 14 days apart. Sixty-two vaccination booths, staffed by 395 health workers/volunteers, were established in the community. For the censused population, 31,552 persons (61% of the target population) received the first dose and 23,751 (46%) of these completed their second dose, with a drop-out rate of 25% between the two doses. Higher coverage was observed among females and among 6-17 year-olds. Vaccine cost at market price (about US$1.85/dose) was the costliest item. The vaccine delivery cost was $0.49 per dose or $1.13 per fully vaccinated person. This is the first undertaken project to collect empirical evidence on the use of Shanchol within a mass vaccination campaign using existing public health program resources. Our findings suggest that mass vaccination is feasible but requires detailed micro-planning. The vaccine and delivery cost is affordable for resource poor countries. Given that the vaccine is now WHO pre-qualified, evidence from this study should encourage oral cholera vaccine use in countries where cholera remains a public health problem.

Plant-based vaccines for animals and humans: recent advances in technology and clinical trials

PubMed Central

Takeyama, Natsumi; Kiyono, Hiroshi; Yuki, Yoshikazu

2015-01-01

It has been about 30 years since the first plant engineering technology was established. Although the concept of plant-based pharmaceuticals or vaccines motivates us to develop practicable commercial products using plant engineering, there are some difficulties in reaching the final goal: to manufacture an approved product. At present, the only plant-made vaccine approved by the United States Department of Agriculture is a Newcastle disease vaccine for poultry that is produced in suspension-cultured tobacco cells. The progress toward commercialization of plant-based vaccines takes much effort and time, but several candidate vaccines for use in humans and animals are in clinical trials. This review discusses plant engineering technologies and regulations relevant to the development of plant-based vaccines and provides an overview of human and animal vaccines currently under clinical trials. PMID:26668752

Dynamic vaccine blocks relapse to compulsive intake of heroin

PubMed Central

Schlosburg, Joel E.; Vendruscolo, Leandro F.; Bremer, Paul T.; Lockner, Jonathan W.; Wade, Carrie L.; Nunes, Ashlee A. K.; Stowe, G. Neil; Edwards, Scott; Janda, Kim D.; Koob, George F.

2013-01-01

Heroin addiction, a chronic relapsing disorder characterized by excessive drug taking and seeking, requires constant psychotherapeutic and pharmacotherapeutic interventions to minimize the potential for further abuse. Vaccine strategies against many drugs of abuse are being developed that generate antibodies that bind drug in the bloodstream, preventing entry into the brain and nullifying psychoactivity. However, this strategy is complicated by heroin’s rapid metabolism to 6-acetylmorphine and morphine. We recently developed a “dynamic” vaccine that creates antibodies against heroin and its psychoactive metabolites by presenting multihaptenic structures to the immune system that match heroin’s metabolism. The current study presents evidence of effective and continuous sequestration of brain-permeable constituents of heroin in the bloodstream following vaccination. The result is efficient blockade of heroin activity in treated rats, preventing various features of drugs of abuse: heroin reward, drug-induced reinstatement of drug seeking, and reescalation of compulsive heroin self-administration following abstinence in dependent rats. The dynamic vaccine shows the capability to significantly devalue the reinforcing and motivating properties of heroin, even in subjects with a history of dependence. In addition, targeting a less brain-permeable downstream metabolite, morphine, is insufficient to prevent heroin-induced activity in these models, suggesting that heroin and 6-acetylmorphine are critical players in heroin’s psychoactivity. Because the heroin vaccine does not target opioid receptors or common opioid pharmacotherapeutics, it can be used in conjunction with available treatment options. Thus, our vaccine represents a promising adjunct therapy for heroin addiction, providing continuous heroin antagonism, requiring minimal medical monitoring and patient compliance. PMID:23650354

Parental Vaccine Acceptance: A Logistic Regression Model Using Previsit Decisions.

PubMed

Lee, Sara; Riley-Behringer, Maureen; Rose, Jeanmarie C; Meropol, Sharon B; Lazebnik, Rina

2017-07-01

This study explores how parents' intentions regarding vaccination prior to their children's visit were associated with actual vaccine acceptance. A convenience sample of parents accompanying 6-week-old to 17-year-old children completed a written survey at 2 pediatric practices. Using hierarchical logistic regression, for hospital-based participants (n = 216), vaccine refusal history ( P < .01) and vaccine decision made before the visit ( P < .05) explained 87% of vaccine refusals. In community-based participants (n = 100), vaccine refusal history ( P < .01) explained 81% of refusals. Over 1 in 5 parents changed their minds about vaccination during the visit. Thirty parents who were previous vaccine refusers accepted current vaccines, and 37 who had intended not to vaccinate choose vaccination. Twenty-nine parents without a refusal history declined vaccines, and 32 who did not intend to refuse before the visit declined vaccination. Future research should identify key factors to nudge parent decision making in favor of vaccination.

Swine influenza virus vaccine serologic cross-reactivity to contemporary US swine H3N2 and efficacy in pigs infected with an H3N2 similar to 2011-2012 H3N2v.

PubMed

Kitikoon, Pravina; Gauger, Phillip C; Anderson, Tavis K; Culhane, Marie R; Swenson, Sabrina; Loving, Crystal L; Perez, Daniel R; Vincent, Amy L

2013-12-01

Swine influenza A virus (IAV) reassortment with 2009 H1N1 pandemic (H1N1pdm09) virus has been documented, and new genotypes and subclusters of H3N2 have since expanded in the US swine population. An H3N2 variant (H3N2v) virus with the H1N1pdm09 matrix gene and the remaining genes of swine triple reassortant H3N2 caused outbreaks at agricultural fairs in 2011-2012. To assess commercial swine IAV vaccines' efficacy against H3N2 viruses, including those similar to H3N2v, antisera to three vaccines were tested by hemagglutinin inhibition (HI) assay against contemporary H3N2. Vaccine 1, with high HI cross-reactivity, was further investigated for efficacy against H3N2 virus infection in pigs with or without maternally derived antibodies (MDA). In addition, efficacy of a vaccine derived from whole inactivated virus (WIV) was compared with live attenuated influenza virus (LAIV) against H3N2. Hemagglutinin inhibition cross-reactivity demonstrated that contemporary swine H3N2 viruses have drifted from viruses in current swine IAV vaccines. The vaccine with the highest level of HI cross-reactivity significantly protected pigs without MDA. However, the presence of MDA at vaccination blocked vaccine efficacy. The performance of WIV and LAIV was comparable in the absence of MDA. Swine IAV in the United States is complex and dynamic. Vaccination to minimize virus shedding can help limit transmission of virus among pigs and people. However, vaccines must be updated. A critical review of the use of WIV in sows is required in the context of the current IAV ecology and vaccine application in pigs with MDA. Published 2013. This article is a U.S. Government work and is in the public domain in the USA.

The European Regulatory Environment of RNA-Based Vaccines.

PubMed

Hinz, Thomas; Kallen, Kajo; Britten, Cedrik M; Flamion, Bruno; Granzer, Ulrich; Hoos, Axel; Huber, Christoph; Khleif, Samir; Kreiter, Sebastian; Rammensee, Hans-Georg; Sahin, Ugur; Singh-Jasuja, Harpreet; Türeci, Özlem; Kalinke, Ulrich

2017-01-01

A variety of different mRNA-based drugs are currently in development. This became possible, since major breakthroughs in RNA research during the last decades allowed impressive improvements of translation, stability and delivery of mRNA. This article focuses on antigen-encoding RNA-based vaccines that are either directed against tumors or pathogens. mRNA-encoded vaccines are developed both for preventive or therapeutic purposes. Most mRNA-based vaccines are directly administered to patients. Alternatively, primary autologous cells from cancer patients are modified ex vivo by the use of mRNA and then are adoptively transferred to patients. In the EU no regulatory guidelines presently exist that specifically address mRNA-based vaccines. The existing regulatory framework, however, clearly defines that mRNA-based vaccines in most cases have to be centrally approved. Interestingly, depending on whether RNA-based vaccines are directed against tumors or infectious disease, they are formally considered gene therapy products or not, respectively. Besides an overview on the current clinical use of mRNA vaccines in various therapeutic areas a detailed discussion of the current regulatory situation is provided and regulatory perspectives are discussed.

A profile of anti-vaccination lobbying on the South African internet, 2011-2013.

PubMed

Burnett, Rosemary Joyce; von Gogh, Lauren Jennifer; Moloi, Molelekeng H; François, Guido

2015-11-01

The South African Vaccination and Immunisation Centre receives many requests to explain the validity of internet-based anti-vaccination claims. Previous global studies on internet-based anti-vaccination lobbying had not identified anti-vaccination web pages originating in South Africa (SA). To characterise SA internet-based anti-vaccination lobbying. In 2011, searches for anti-vaccination content were performed using Google, Yahoo and MSN-Bing, limited to English-language SA web pages. Content analysis was performed on web pages expressing anti-vaccination sentiment about infant vaccination. This was repeated in 2012 and 2013 using Google, with the first 700 web pages per search being analysed. Blogs/forums, articles and e-shops constituted 40.3%, 55.2% and 4.5% of web pages, respectively. Authors were lay people (63.5%), complementary/alternative medicine (CAM) practitioners (23.1%), medical professionals practising CAM (7.7%) and medical professionals practising only allopathic medicine (5.8%). Advertisements appeared on 55.2% of web pages. Of these, 67.6% were sponsored by or linked to organisations with financial interests in discrediting vaccines, with 80.0% and 24.0% of web pages sponsored by these organisations claiming respectively that vaccines are ineffective and that vaccination is profit driven. The vast majority of web pages (92.5%) claimed that vaccines are not safe, and 77.6% of anti-vaccination claims originated from the USA. South Africans are creating web pages or blogs for local anti-vaccination lobbying. Research is needed to understand what influence internet-based anti-vaccination lobbying has on the uptake of infant vaccination in SA.

Comparison of Current Regulatory Status for Gene-Based Vaccines in the U.S., Europe and Japan

PubMed Central

Nakayama, Yoshikazu; Aruga, Atsushi

2015-01-01

Gene-based vaccines as typified by plasmid DNA vaccines and recombinant viral-vectored vaccines are expected as promising solutions against infectious diseases for which no effective prophylactic vaccines exist such as HIV, dengue virus, Ebola virus and malaria, and for which more improved vaccines are needed such as tuberculosis and influenza virus. Although many preclinical and clinical trials have been conducted to date, no DNA vaccines or recombinant viral-vectored vaccines expressing heterologous antigens for human use have yet been licensed in the U.S., Europe or Japan. In this research, we describe the current regulatory context for gene-based prophylactic vaccines against infectious disease in the U.S., Europe, and Japan. We identify the important considerations, in particular, on the preclinical assessments that would allow these vaccines to proceed to clinical trials, and the differences on the regulatory pathway for the marketing authorization in each region. PMID:26344953

A potential disruptive technology in vaccine development: gene-based vaccines and their application to infectious diseases.

PubMed

Kaslow, David C

2004-10-01

Vaccine development requires an amalgamation of disparate disciplines and has unique economic and regulatory drivers. Non-viral gene-based delivery systems, such as formulated plasmid DNA, are new and potentially disruptive technologies capable of providing 'cheaper, simpler, and more convenient-to-use' vaccines. Typically and somewhat ironically, disruptive technologies have poorer product performance, at least in the near-term, compared with the existing conventional technologies. Because successful product development requires that the product's performance must meet or exceed the efficacy threshold for a desired application, the appropriate selection of the initial product applications for a disruptive technology is critical for its successful evolution. In this regard, the near-term successes of gene-based vaccines will likely be for protection against bacterial toxins and acute viral and bacterial infections. Recent breakthroughs, however, herald increasing rather than languishing performance improvements in the efficacy of gene-based vaccines. Whether gene-based vaccines ultimately succeed in eliciting protective immunity in humans to persistent intracellular pathogens, such as HIV, malaria and tuberculosis, for which the conventional vaccine technologies have failed, remains to be determined. A success against any one of the persistent intracellular pathogens would be sufficient proof that gene-based vaccines represent a disruptive technology against which future vaccine technologies will be measured.

Vaxvec: The first web-based recombinant vaccine vector database and its data analysis

PubMed Central

Deng, Shunzhou; Martin, Carly; Patil, Rasika; Zhu, Felix; Zhao, Bin; Xiang, Zuoshuang; He, Yongqun

2015-01-01

A recombinant vector vaccine uses an attenuated virus, bacterium, or parasite as the carrier to express a heterologous antigen(s). Many recombinant vaccine vectors and related vaccines have been developed and extensively investigated. To compare and better understand recombinant vectors and vaccines, we have generated Vaxvec (http://www.violinet.org/vaxvec), the first web-based database that stores various recombinant vaccine vectors and those experimentally verified vaccines that use these vectors. Vaxvec has now included 59 vaccine vectors that have been used in 196 recombinant vector vaccines against 66 pathogens and cancers. These vectors are classified to 41 viral vectors, 15 bacterial vectors, 1 parasitic vector, and 1 fungal vector. The most commonly used viral vaccine vectors are double-stranded DNA viruses, including herpesviruses, adenoviruses, and poxviruses. For example, Vaxvec includes 63 poxvirus-based recombinant vaccines for over 20 pathogens and cancers. Vaxvec collects 30 recombinant vector influenza vaccines that use 17 recombinant vectors and were experimentally tested in 7 animal models. In addition, over 60 protective antigens used in recombinant vector vaccines are annotated and analyzed. User-friendly web-interfaces are available for querying various data in Vaxvec. To support data exchange, the information of vaccine vectors, vaccines, and related information is stored in the Vaccine Ontology (VO). Vaxvec is a timely and vital source of vaccine vector database and facilitates efficient vaccine vector research and development. PMID:26403370

Oral Modeling of an Adenovirus-Based Quadrivalent Influenza Vaccine in Ferrets and Mice.

PubMed

Scallan, Ciaran D; Lindbloom, Jonathan D; Tucker, Sean N

2016-06-01

Oral vaccines delivered as tablets offer a number of advantages over traditional parenteral-based vaccines including the ease of delivery, lack of needles, no need for trained medical personnel, and the ability to formulate into temperature-stable tablets. We have been evaluating an oral vaccine platform based on recombinant adenoviral vectors for the purpose of creating a prophylactic vaccine to prevent influenza, and have demonstrated vaccine efficacy in animal models and substantial immunogenicity in humans. These studies have evaluated monovalent vaccines to date. To protect against the major circulating A and B influenza strains, a multivalent influenza vaccine will be required. In this study, the immunogenicity of orally delivered monovalent, bivalent, trivalent, and quadrivalent vaccines was tested in ferrets and mice. The various vaccine combinations were tested by blending monovalent recombinant adenovirus vaccines, each expressing hemagglutinin from a single strain. Human tablet delivery was modeled in animals by oral gavage in mice and by endoscopic delivery in ferrets. We demonstrated minimal interference between the various vaccine vectors when used in combination and that the oral quadrivalent vaccine compared favorably to an approved trivalent inactivated vaccine. The quadrivalent vaccine presented here produced immune responses that we predict should be capable of providing protection against multiple influenza strains, and the platform should have applications to other multivalent vaccines. Vaxart, Inc.

Screening and identification of linear B-cell epitopes and entry-blocking peptide of severe acute respiratory syndrome (SARS)-associated coronavirus using synthetic overlapping peptide library.

PubMed

Hu, Hongbo; Li, Li; Kao, Richard Y; Kou, Binbin; Wang, Zhanguo; Zhang, Liang; Zhang, Huiyuan; Hao, Zhiyong; Tsui, Wayne H; Ni, Anping; Cui, Lianxian; Fan, Baoxing; Guo, Feng; Rao, Shuan; Jiang, Chengyu; Li, Qian; Sun, Manji; He, Wei; Liu, Gang

2005-01-01

A 10-mer overlapping peptide library has been synthesized for screening and identification of linear B-cell epitopes of severe acute respiratory syndrome associated coronavirus (SARS-CoV), which spanned the major structural proteins of SARS-CoV. One hundred and eleven candidate peptides were positive according to the result of PEPscan, which were assembled into 22 longer peptides. Five of these peptides showed high cross-immunoreactivities (approximately 66.7 to 90.5%) to SARS convalescent patients' sera from the severest epidemic regions of the China mainland. Most interestingly, S(471-503), a peptide located at the receptor binding domain (RBD) of SARS-CoV, could specifically block the binding between the RBD and angiotensin-converting enzyme 2, resulting in the inhibition of SARS-CoV entrance into host cells in vitro. The study demonstrated that S(471-503) peptide was a potential immunoantigen for the development of peptide-based vaccine or a candidate for further drug evaluation against the SARS-CoV virus-cell fusion.

Home-based child vaccination records--a reflection on form.

PubMed

Brown, David W; Gacic-Dobo, Marta; Young, Stacy L

2014-04-01

Home-based child vaccination records play an important role in documenting immunization services received by children. We report some of the results of a review of home-based vaccination records from 55 countries. In doing so, we categorize records into three groups (vaccination only cards, vaccination plus cards, child health books) and describe differences in characteristics related to the quality of data recorded on immunization. Moreover, we highlight areas of potential concern and areas in need of further research and investigation to improve our understanding of the home-based vaccination record form related to improved data quality from immunization service delivery. Copyright © 2014. Published by Elsevier Ltd.

Advances in inducing adaptive immunity using cell-based cancer vaccines: Clinical applications in pancreatic cancer.

PubMed

Kajihara, Mikio; Takakura, Kazuki; Kanai, Tomoya; Ito, Zensho; Matsumoto, Yoshihiro; Shimodaira, Shigetaka; Okamoto, Masato; Ohkusa, Toshifumi; Koido, Shigeo

2016-05-14

The incidence of pancreatic ductal adenocarcinoma (PDA) is on the rise, and the prognosis is extremely poor because PDA is highly aggressive and notoriously difficult to treat. Although gemcitabine- or 5-fluorouracil-based chemotherapy is typically offered as a standard of care, most patients do not survive longer than 1 year. Therefore, the development of alternative therapeutic approaches for patients with PDA is imperative. As PDA cells express numerous tumor-associated antigens that are suitable vaccine targets, one promising treatment approach is cancer vaccines. During the last few decades, cell-based cancer vaccines have offered encouraging results in preclinical studies. Cell-based cancer vaccines are mainly generated by presenting whole tumor cells or dendritic cells to cells of the immune system. In particular, several clinical trials have explored cell-based cancer vaccines as a promising therapeutic approach for patients with PDA. Moreover, chemotherapy and cancer vaccines can synergize to result in increased efficacies in patients with PDA. In this review, we will discuss both the effect of cell-based cancer vaccines and advances in terms of future strategies of cancer vaccines for the treatment of PDA patients.

A systematic review and meta-analysis of the effects of educating parents on the benefits and schedules of childhood vaccinations in low and middle-income countries.

PubMed

Lukusa, Lungeni Auguy; Ndze, Valantine Ngum; Mbeye, Nyanyiwe Masingi; Wiysonge, Charles Shey

2018-03-26

Public health benefits of childhood vaccinations risk being derailed by low vaccination coverage in low and middle-income countries. One reason for the low coverage is poor parental knowledge of the importance of completing vaccination schedules. We therefore assessed the effects on childhood vaccination coverage, of educating parents and other persons assuming the parental role. We prospectively registered the systematic review, published the protocol, and used standard Cochrane methods to collect and synthesise the evidence. We found six eligible randomised trials with 4248 participants. Three trials assessed health-facility based education of mothers on the importance of completing vaccination schedules; immediately after birth and three months later (one study) or during the first vaccination visit (two studies). The other trials assessed community-based education, including information campaigns on the importance of vaccines using audiotaped presentations and leaflet distributions (one study); structured group discussions on benefits and costs of childhood vaccination and local action plans for improving vaccine uptake (one study); and home-based information sessions using graphic cards showing benefits and costs of childhood vaccinations and location of vaccination centres (one study). Combining the data shows that these interventions lead to substantial improvements in childhood vaccination coverage (relative increase 36%, 95% confidence interval 14% to 62%). There was no difference between the effects of community-based and facility-based education. Therefore, education in communities and health facilities on the importance of childhood vaccinations should be integrated into all vaccination programmes in low and middle-income countries; accompanied by robust monitoring of impacts and use of data for action.

Proteogenomic analysis of the total and surface-exposed proteomes of Plasmodium vivax salivary gland sporozoites

PubMed Central

Swearingen, Kristian E.; Lindner, Scott E.; Flannery, Erika L.; Vaughan, Ashley M.; Morrison, Robert D.; Patrapuvich, Rapatbhorn; Koepfli, Cristian; Muller, Ivo; Jex, Aaron; Moritz, Robert L.; Kappe, Stefan H. I.; Sattabongkot, Jetsumon

2017-01-01

Plasmodium falciparum and Plasmodium vivax cause the majority of human malaria cases. Research efforts predominantly focus on P. falciparum because of the clinical severity of infection and associated mortality rates. However, P. vivax malaria affects more people in a wider global range. Furthermore, unlike P. falciparum, P. vivax can persist in the liver as dormant hypnozoites that can be activated weeks to years after primary infection, causing relapse of symptomatic blood stages. This feature makes P. vivax unique and difficult to eliminate with the standard tools of vector control and treatment of symptomatic blood stage infection with antimalarial drugs. Infection by Plasmodium is initiated by the mosquito-transmitted sporozoite stage, a highly motile invasive cell that targets hepatocytes in the liver. The most advanced malaria vaccine for P. falciparum (RTS,S, a subunit vaccine containing of a portion of the major sporozoite surface protein) conferred limited protection in Phase III trials, falling short of WHO-established vaccine efficacy goals. However, blocking the sporozoite stage of infection in P. vivax, before the establishment of the chronic liver infection, might be an effective malaria vaccine strategy to reduce the occurrence of relapsing blood stages. It is also thought that a multivalent vaccine comprising multiple sporozoite surface antigens will provide better protection, but a comprehensive analysis of proteins in P. vivax sporozoites is not available. To inform sporozoite-based vaccine development, we employed mass spectrometry-based proteomics to identify nearly 2,000 proteins present in P. vivax salivary gland sporozoites. Analysis of protein post-translational modifications revealed extensive phosphorylation of glideosome proteins as well as regulators of transcription and translation. Additionally, the sporozoite surface proteins CSP and TRAP, which were recently discovered to be glycosylated in P. falciparum salivary gland sporozoites, were also observed to be similarly modified in P. vivax sporozoites. Quantitative comparison of the P. vivax and P. falciparum salivary gland sporozoite proteomes revealed a high degree of similarity in protein expression levels, including among invasion-related proteins. Nevertheless, orthologs with significantly different expression levels between the two species could be identified, as well as highly abundant, species-specific proteins with no known orthologs. Finally, we employed chemical labeling of live sporozoites to isolate and identify 36 proteins that are putatively surface-exposed on P. vivax salivary gland sporozoites. In addition to identifying conserved sporozoite surface proteins identified by similar analyses of other Plasmodium species, our analysis identified several as-yet uncharacterized proteins, including a putative 6-Cys protein with no known ortholog in P. falciparum. PMID:28759593

Fine Specificity of Plasmodium vivax Duffy Binding Protein Binding Engagement of the Duffy Antigen on Human Erythrocytes

PubMed Central

Siddiqui, Asim A.; Xainli, Jia; Schloegel, Jesse; Carias, Lenore; Ntumngia, Francis; Shoham, Menachem; Casey, Joanne L.; Foley, Michael; Adams, John H.

2012-01-01

Plasmodium vivax invasion of human erythrocytes requires interaction of the P. vivax Duffy binding protein (PvDBP) with its host receptor, the Duffy antigen (Fy) on the erythrocyte surface. Consequently, PvDBP is a leading vaccine candidate. The binding domain of PvDBP lies in a cysteine-rich portion of the molecule called region II (PvDBPII). PvDBPII contains three distinct subdomains based upon intramolecular disulfide bonding patterns. Subdomain 2 (SD2) is highly polymorphic and is thought to contain many key residues for binding to Fy, while SD1 and SD3 are comparatively conserved and their role in Fy binding is not well understood. To examine the relative contributions of the different subdomains to binding to Fy and their abilities to elicit strain-transcending binding-inhibitory antibodies, we evaluated recombinant proteins from SD1+2, SD2, SD3, and SD3+, which includes 24 residues of SD2. All of the recombinant subdomains, except for SD2, bound variably to human erythrocytes, with constructs containing SD3 showing the best binding. Antisera raised in laboratory animals against SD3, SD3+, and SD2+3 inhibited the binding of full-length PvDBPII, which is strain transcending, whereas antisera generated to SD1+2 and SD2 failed to generate blocking antibodies. All of the murine monoclonal antibodies generated to full-length PvDBPII that had significant binding-inhibitory activity recognized only SD3. Thus, SD3 binds Fy and elicits blocking antibodies, indicating that it contains residues critical to Fy binding that could be the basis of a strain-transcending candidate vaccine against P. vivax. PMID:22615246

Fine specificity of Plasmodium vivax Duffy binding protein binding engagement of the Duffy antigen on human erythrocytes.

PubMed

Siddiqui, Asim A; Xainli, Jia; Schloegel, Jesse; Carias, Lenore; Ntumngia, Francis; Shoham, Menachem; Casey, Joanne L; Foley, Michael; Adams, John H; King, Christopher L

2012-08-01

Plasmodium vivax invasion of human erythrocytes requires interaction of the P. vivax Duffy binding protein (PvDBP) with its host receptor, the Duffy antigen (Fy) on the erythrocyte surface. Consequently, PvDBP is a leading vaccine candidate. The binding domain of PvDBP lies in a cysteine-rich portion of the molecule called region II (PvDBPII). PvDBPII contains three distinct subdomains based upon intramolecular disulfide bonding patterns. Subdomain 2 (SD2) is highly polymorphic and is thought to contain many key residues for binding to Fy, while SD1 and SD3 are comparatively conserved and their role in Fy binding is not well understood. To examine the relative contributions of the different subdomains to binding to Fy and their abilities to elicit strain-transcending binding-inhibitory antibodies, we evaluated recombinant proteins from SD1+2, SD2, SD3, and SD3+, which includes 24 residues of SD2. All of the recombinant subdomains, except for SD2, bound variably to human erythrocytes, with constructs containing SD3 showing the best binding. Antisera raised in laboratory animals against SD3, SD3+, and SD2+3 inhibited the binding of full-length PvDBPII, which is strain transcending, whereas antisera generated to SD1+2 and SD2 failed to generate blocking antibodies. All of the murine monoclonal antibodies generated to full-length PvDBPII that had significant binding-inhibitory activity recognized only SD3. Thus, SD3 binds Fy and elicits blocking antibodies, indicating that it contains residues critical to Fy binding that could be the basis of a strain-transcending candidate vaccine against P. vivax.

Tackling Bet v 1 and associated food allergies with a single hybrid protein.

PubMed

Hofer, Heidi; Asam, Claudia; Hauser, Michael; Nagl, Birgit; Laimer, Josef; Himly, Martin; Briza, Peter; Ebner, Christof; Lang, Roland; Hawranek, Thomas; Bohle, Barbara; Lackner, Peter; Ferreira, Fátima; Wallner, Michael

2017-08-01

Allergy vaccines should be easily applicable, safe, and efficacious. For Bet v 1-mediated birch pollen and associated food allergies, a single wild-type allergen does not provide a complete solution. We aimed to combine immunologically relevant epitopes of Bet v 1 and the 2 clinically most important related food allergens from apple and hazelnut to a single hybrid protein, termed MBC4. After identification of T cell epitope-containing parts on each of the 3 parental allergens, the hybrid molecule was designed to cover relevant epitopes and evaluated in silico. Thereby a mutation was introduced into the hybrid sequence, which should alter the secondary structure without compromising the immunogenic properties of the molecule. MBC4 and the parental allergens were purified to homogeneity. Analyses of secondary structure elements revealed substantial changes rendering the hybrid de facto nonreactive with patients' serum IgE. Nevertheless, the protein was monomeric in solution. MBC4 was able to activate T-cell lines from donors with birch pollen allergy and from mice immunized with the parental allergens. Moreover, on immunization of mice and rabbits, MBC4 induced cross-reactive IgG antibodies, which were able to block the binding of human serum IgE. Directed epitope rearrangements combined with a knowledge-based structural modification resulted in a protein unable to bind IgE from allergic patients. Still, properties to activate specific T cells or induce blocking antibodies were conserved. This suggests that MBC4 is a suitable vaccine candidate for the simultaneous treatment of Bet v 1 and associated food allergies. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Mechanisms of Cross-protection by Influenza Virus M2-based Vaccines.

PubMed

Lee, Yu-Na; Kim, Min-Chul; Lee, Young-Tae; Kim, Yu-Jin; Kang, Sang-Moo

2015-10-01

Current influenza virus vaccines are based on strain-specific surface glycoprotein hemagglutinin (HA) antigens and effective only when the predicted vaccine strains and circulating viruses are well-matched. The current strategy of influenza vaccination does not prevent the pandemic outbreaks and protection efficacy is reduced or ineffective if mutant strains emerge. It is of high priority to develop effective vaccines and vaccination strategies conferring a broad range of cross protection. The extracellular domain of M2 (M2e) is highly conserved among human influenza A viruses and has been utilized to develop new vaccines inducing cross protection against different subtypes of influenza A virus. However, immune mechanisms of cross protection by M2e-based vaccines still remain to be fully elucidated. Here, we review immune correlates and mechanisms conferring cross protection by M2e-based vaccines. Molecular and cellular immune components that are known to be involved in M2 immune-mediated protection include antibodies, B cells, T cells, alveolar macrophages, Fc receptors, complements, and natural killer cells. Better understanding of protective mechanisms by immune responses induced by M2e vaccination will help facilitate development of broadly cross protective vaccines against influenza A virus.

Glycosaminoglycans mediate retention of the poxvirus type I interferon binding protein at the cell surface to locally block interferon antiviral responses

PubMed Central

Montanuy, Imma; Alejo, Ali; Alcami, Antonio

2011-01-01

Eradication of smallpox was accomplished 30 yr ago, but poxviral infections still represent a public health concern due to the potential release of variola virus or the emergence of zoonotic poxviruses, such as monkeypox virus. A critical determinant of poxvirus virulence is the inhibition of interferons (IFNs) by the virus-encoded type I IFN-binding protein (IFNα/βBP). This immunomodulatory protein is secreted and has the unique property of interacting with the cell surface in order to prevent IFN-mediated antiviral responses. However, the mechanism of its attachment to the cell surface remains unknown. Using surface plasmon resonance and cell-binding assays, we report that the IFNα/βBP from vaccinia virus, the smallpox vaccine, interacts with cell surface glycosaminoglycans (GAGs). Analysis of the contribution of different regions of the protein to cell surface binding demonstrated that clusters of basic residues in the first immunoglobulin domain mediate GAG interactions. Furthermore, mutation of the GAG-interaction motifs does not affect its IFN-binding and -blocking capacity. Functional conservation of GAG-binding sites is demonstrated for the IFNα/βBP from variola and monkeypox viruses, extending our understanding of immune modulation by the most virulent human poxviruses. These results are relevant for the design of improved vaccines and intervention strategies.—Montanuy, I., Alejo, A., Alcami, A. Glycosaminoglycans mediate retention of the poxvirus type I interferon binding protein at the cell surface to locally block interferon antiviral responses. PMID:21372110

Human Papillomavirus Vaccine Uptake in Adolescent Boys: An Evidence Review.

PubMed

Voss, Danielle S; Wofford, Linda G

2016-10-01

Despite evidence-based guidelines recommending routine vaccination against human papillomavirus (HPV) for adolescent boys, ages 11-12 years, vaccine uptake among this population remains low. To examine reasons for low HPV quadrivalent vaccine uptake and methods available to increase vaccine uptake among adolescent males, ages 11-12 years. Of 341 identified studies, 30 were included from three databases. The 30 studies were grouped into six categories: population-specific, problem-specific, educational interventions, theory-specific, political implications, and foundational guidelines and Websites. Among eight studies, low vaccine uptake was attributed to lack of parental, adolescent, and physician knowledge of HPV4 vaccine availability and recommendations. HPV4 vaccine educational interventions for parents and adolescents were the most effective for promoting vaccine uptake. Theory applications and gain-framed messages were shown to be effective for assessing HPV vaccine attitudes and perceptions. Political implication studies reveal the need for political and financial measures to encourage HPV vaccine acceptability among the population. To promote HPV vaccine uptake among adolescent males, providers must remain current with HPV vaccine recommendations and offer parental and adolescent HPV education focusing on benefits of vaccine acceptance and risks of vaccine refusal. The results of this review inform our understanding of effective educational strategies to positively impact HPV vaccine uptake in adolescent males. Based on this review, clinicians can employ several evidence-based educational strategies to facilitate HPV vaccine uptake. © 2016 Sigma Theta Tau International.

Factors affecting HPV vaccine acceptance in west Austria: Do we need to revise the current immunization scheme?

PubMed

Borena, Wegene; Luckner-Hornischer, Anita; Katzgraber, Franz; Holm-von Laer, Dorothee

2016-12-01

Austria introduced a school-based gender-neutral human papillomavirus (HPV) immunization program in February 2014. In order to assure high coverage, factors influencing acceptance of the vaccine need to be identified. In this study we aim to assess parents' attitude and related socio-demographic factors in relation to the newly implemented gender-neutral, school-based HPV Immunization program. Parents of 4th grade school children in 20 randomly selected primary schools were asked to fill out questionnaires on socio-demographic factors and on the level of information and attitude towards HPV infection and HPV vaccine. A total of 439 parents with 449 vaccine eligible children participated in the study. Fifty nine percent of vaccine eligible girls and 51.8% of eligible boys received the first dose of the vaccine. Fear of side effects and child being too young for the vaccine were the most commonly cited reasons by parents electing not to let child receive the vaccine. Children who had received other school-based vaccines have more than fifteen times higher probability of receiving HPV vaccine. To have received HPV-related information from physicians positively influenced vaccine acceptance (OR (95% CI)=1.60 (1.06-2.43)). Higher paternal (fathers') educational status significantly increased the chances of a male child to be HPV vaccinated (OR (95% CI)=2.45 (1.29-4.78)). Despite the efforts to provide HPV vaccine free-of-costs and as a school-based program, the study found that a significant proportion of vaccine eligible children failed to receive the vaccine. Involvement front line physicians and men with higher educational status may be utilised by public health policy makers in the effort to increase awareness. For a better acceptability of the vaccine, there is a need to consider lifting the age of "eligibility" for the school-based vaccination program. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

[Economic evaluation of an infant immunization program in Mexico, based on 13-valent pneumococcal conjugated vaccines].

PubMed

Muciño-Ortega, Emilio; Mould-Quevedo, Joaquín Federico; Farkouh, Raymond; Strutton, David

2011-01-01

Vaccination is an effective intervention for reduce child morbidity and mortality associated to pneumococcus. The availability of new anti-pneumococcal vaccines makes it necessary to evaluate its potential impact on public health and costs related to their implementation. The aim of this study was to estimate the cost-effectiveness and cost-utility of immunization strategies based on pneumococcal conjugated vaccines (PCV's) currently available in Mexico from a third payer perspective. A decision tree model was developed to assess both, economic and health impact, of anti-pneumococcal vaccination in children <2 years (lifetime time horizon, discount rate: 5% annual). Comparators were: no-vaccination (reference) and strategies based on 7, 10 and 13-valent PCV's. Effectiveness measures were: child deaths avoided, life-years gained (LYG) and quality adjusted life years (QALY's) gained. Effectiveness, utility, local epidemiology and cost of treating pneumococcal diseases were extracted from published sources. Univariate sensitivity analysis were performed. Immunization dominates no-vaccination: strategy based on 13-valent vaccine prevented 16.205 deaths, gained 331.230 LY's and 332.006 QALY's and saved US$1.307/child vaccinated. Strategies based on 7 and 10-valent PCV's prevented 13.806 and 5.589 deaths, gained 282.193 and 114.251 LY's, 282.969 and 114.972 QALY's and saved US$1.084 and US$731/child vaccinated, respectively. These results were robust to variations in herd immunity and lower immunogenicity of 10-valent vaccine. In Mexico, immunization strategies based on 7, 10 and 13-valent PCV's would be cost-saving interventions, however, health outcomes and savings of the strategy based on 13-valent vaccine are greater than those estimated for 7 and 10-valent PCV's. Copyright © 2011 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

[Real-time monitoring of anti-influenza vaccination in the 65 and over population in France based on vaccine sales].

PubMed

Pivette, M; Auvigne, V; Guérin, P; Mueller, J E

2017-04-01

The aim of this study was to describe a tool based on vaccine sales to estimate vaccination coverage against seasonal influenza in near real-time in the French population aged 65 and over. Vaccine sales data available on sale-day +1 came from a stratified sample of 3004 pharmacies in metropolitan France. Vaccination coverage rates were estimated between 2009 and 2014 and compared with those obtained based on vaccination refund data from the general health insurance scheme. The seasonal vaccination coverage estimates were highly correlated with those obtained from refund data. They were also slightly higher, which can be explained by the inclusion of non-reimbursed vaccines and the consideration of all individuals aged 65 and over. We have developed an online tool that provides estimates of daily vaccination coverage during each vaccination campaign. The developed tool provides a reliable and near real-time estimation of vaccination coverage among people aged 65 and over. It can be used to evaluate and adjust public health messages. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Acceptability of School-Based Health Centers for Human Papillomavirus Vaccination Visits: A Mixed-Methods Study

ERIC Educational Resources Information Center

Hansen, Caitlin E.; Okoloko, Edirin; Ogunbajo, Adedotun; North, Anna; Niccolai, Linda M.

2017-01-01

Background: Countries with high human papillomavirus (HPV) vaccination rates have achieved this success largely through school-based vaccination. Using school-based health centers (SBHCs) in the United States, where HPV vaccine remains underutilized, could improve uptake. In this mixed-methods study, we examined acceptability, facilitators, and…

An M2e-based synthetic peptide vaccine for influenza A virus confers heterosubtypic protection from lethal virus challenge.

PubMed

Ma, Ji-Hong; Yang, Fu-Ru; Yu, Hai; Zhou, Yan-Jun; Li, Guo-Xin; Huang, Meng; Wen, Feng; Tong, Guangzhi

2013-07-09

Vaccination is considered as the most effective preventive method to control influenza. The hallmark of influenza virus is the remarkable variability of its major surface glycoproteins, HA and NA, which allows the virus to evade existing anti-influenza immunity in the target population. So it is necessary to develop a novel vaccine to control animal influenza virus. Also we know that the ectodomain of influenza matrix protein 2 (M2e) is highly conserved in animal influenza A viruses, so a vaccine based on the M2e could avoid several drawbacks of the traditional vaccines. In this study we designed a novel tetra-branched multiple antigenic peptide (MAP) based vaccine, which was constructed by fusing four copies of M2e to one copy of foreign T helper (Th) cell epitope, and then investigated its immune responses. Our results show that the M2e-MAP induced strong M2e-specific IgG antibody,which responses following 2 doses immunization in the presence of Freunds' adjuvant. M2e-MAP vaccination limited viral replication substantially. Also it could attenuate histopathological damage in the lungs of challenged mice and counteracted weight loss. M2e-MAP-based vaccine protected immunized mice against the lethal challenge with PR8 virus. Based on these findings, M2e-MAP-based vaccine seemed to provide useful information for the research of M2e-based influenza vaccine. Also it show huge potential to study vaccines for other similarly viruses.

Novel vaccines targeting dendritic cells by coupling allergoids to nonoxidized mannan enhance allergen uptake and induce functional regulatory T cells through programmed death ligand 1.

PubMed

Sirvent, Sofía; Soria, Irene; Cirauqui, Cristina; Cases, Bárbara; Manzano, Ana I; Diez-Rivero, Carmen M; Reche, Pedro A; López-Relaño, Juan; Martínez-Naves, Eduardo; Cañada, F Javier; Jiménez-Barbero, Jesús; Subiza, Javier; Casanovas, Miguel; Fernández-Caldas, Enrique; Subiza, José Luis; Palomares, Oscar

2016-08-01

Allergen immunotherapy (AIT) is the only curative treatment for allergy. AIT faces pitfalls related to efficacy, security, duration, and patient compliance. Novel vaccines overcoming such inconveniences are in demand. We sought to study the immunologic mechanisms of action for novel vaccines targeting dendritic cells (DCs) generated by coupling glutaraldehyde-polymerized grass pollen allergoids to nonoxidized mannan (PM) compared with glutaraldehyde-polymerized allergoids (P) or native grass pollen extracts (N). Skin prick tests and basophil activation tests with N, P, or PM were performed in patients with grass pollen allergy. IgE-blocking experiments, flow cytometry, confocal microscopy, cocultures, suppression assays, real-time quantitative PCR, ELISAs, and ELISpot assays were performed to assess allergen capture by human DCs and T-cell responses. BALB/c mice were immunized with PM, N, or P. Antibody levels, cytokine production by splenocytes, and splenic forkhead box P3 (FOXP3)(+) regulatory T (Treg) cells were quantified. Experiments with oxidized PM were also performed. PM displays in vivo hypoallergenicity, induces potent blocking antibodies, and is captured by human DCs much more efficiently than N or P by mechanisms depending on mannose receptor- and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin-mediated internalization. PM endorses human DCs to generate functional FOXP3(+) Treg cells through programmed death ligand 1. Immunization of mice with PM induces a shift to nonallergic responses and increases the frequency of splenic FOXP3(+) Treg cells. Mild oxidation impairs these effects in human subjects and mice, demonstrating the essential role of preserving the carbohydrate structure of mannan. Allergoids conjugated to nonoxidized mannan represent suitable vaccines for AIT. Our findings might also be of the utmost relevance to development of therapeutic interventions in other immune tolerance-related diseases. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Serosurvey of rubella in five blocks of Tamil Nadu.

PubMed

Ramamurty, Nalini; Murugan, S; Raja, D; Elango, Varalaksmi; Mohana; Dhanagaran, D

2006-01-01

Rubella, normally a mild, self-limiting disease characterized by rash, fever and lymphadenopathy, is a vaccine preventable disease. It carries little morbidity and apparently only minor complications in children. Infection during early pregnancy may lead to congenital rubella infection. Presence of rubella specific IgG in an unvaccinated population is a long term marker of previous rubella infection, which helps to assess the immune status of that population. Though many seroprevalence studies on rebella have been reported earlier from India, no study has been conducted in recent years. We undertook this study in 2003 in five blocks identified by the Integrated Child Development Scheme (ICDS), in the five districts of Tamil Nadu to assess the immune status to rubella in two age groups (1-5 yr boys and girls and 10-16 yr adolescent girls) before vaccination and draw strategies for future vaccination programme. A total of 300 blood samples were collected by vein puncture from girls and boys of 1-5 yr age and adolescent girls of 10-16 yr age. Samples were tested for the presence of rubella specific IgG antibody by ELISA. Of the 300 samples tested, 145 (48.3%) were negative for rubella IgG antibodies. The seronegativity was 82.2 per cent in 1-5 yr and 13.5 per cent in the 10-16 yr age groups, the difference was statistically significant (P<0.001). Large percentage of children, 82.2 per cent in the 1-5 yr age group and 13.5 per cent in 10-16 yr population were susceptible to rubella infection highlighting the fact that there was a risk of congenital rubella syndrome. There is a need to implement routine measles, mumps, rubella (MMR) immunization programme for under five children and mass scale one time immunization with monovalent rubella vaccine for adolescent girls.

Effect of hepatitis B vaccination in hepatitis B surface antibody-negative pregnant mothers on the vertical transmission of hepatitis B virus from father to infant.

PubMed

Cao, Li-Hua; Li, Yun-Ru; Wang, Shou-Yun; Liu, Zhi-Min; Sun, Shao-Chun; Xu, Dong-Bo; Zhang, Ji-Dong

2015-07-01

The aim of the present study was to investigate the effects of vaccination with the hepatitis B vaccine (HBVac) in HB surface antibody (HBsAb)-negative pregnant mothers on the vertical transmission of HB virus (HBV) from father to infant. All the fathers tested positive for the serum HBV DNA and HB surface antigen (HBsAg) markers. The pregnant females were divided into an observation group or a control group depending on whether their serum was HBsAb-negative or positive. A total of 93 healthy individuals without HBV infection were included in a blank group, while 96 females who were serum HBV marker-negative or HB core antibody (HBcAb)-positive/(HBsAb)-negative were included in the observation group. The control group comprised 89 females who all tested positive for serum HBsAb, HB envelope antibodies and HBcAb. In the observation group, the positive rate of HBV DNA in the newborns was 7.29% (7/96), the positive rate of HBsAg was 3.13% (3/96) and the positive rate of HBsAb was 81.3% (78/96). In the control group, the positive rates of HBV DNA, HBsAg and HBsAb in the newborns were 4.49% (4/89), 2.25% (2/89) and 89.9% (80/89), respectively. No statistically significant differences were observed between the two groups. Therefore, the results of the present study indicate that HBVac treatment for HBsAb-negative pregnant females may have a positive role in blocking the vertical transmission of HBV from father to infant, as long as the vaccination is able to induce the production of a sufficient quantity of HBsAb. The HBVac exhibited no difference compared with pre-pregnancy HBsAb in blocking the vertical transmission of HBV from father to infant.

Anti-Epidermal Growth Factor Vaccine Antibodies Enhance the Efficacy of Tyrosine Kinase Inhibitors and Delay the Emergence of Resistance in EGFR Mutant Lung Cancer Cells.

PubMed

Codony-Servat, Jordi; García-Roman, Silvia; Molina-Vila, Miguel Ángel; Bertran-Alamillo, Jordi; Giménez-Capitán, Ana; Viteri, Santiago; Cardona, Andrés F; d'Hondt, Erik; Karachaliou, Niki; Rosell, Rafael

2018-05-08

Mutations in EGFR correlate with impaired response to immune checkpoint inhibitors and the development of novel immunotherapeutic approaches for EGFR mutant non-small cell lung cancer (NSCLC) is of particular interest. Immunization against EGF has demonstrated efficacy in a phase III trial including unselected NSCLC patients, but little was known about the mechanisms involved in the effects of the anti-EGF antibodies generated by vaccination (anti-EGF VacAbs) or their activity in tumor cells with EGFR mutations. The EGFR-mutant, NSCLC cell lines H1975 and PC9, together with several gefitinib and osimertinib-resistant cells derived from PC9, were treated with anti-EGF VacAbs and/or EGFR tyrosine kinase inhibitors (TKIs). Cell viability was analyzed by proliferation assays, cell cycle by fluorescence-activated cell sorting analysis and levels of RNA and proteins by quantitative retro-transcription PCR and Western blotting. Anti-EGF VacAbs generated in rabbits suppressed EGF-induced cell proliferation and cycle progression and inhibited downstream EGFR signaling in EGFR-mutant cells. Sera from patients immunized with an EGF vaccine were also able to block activation of EGFR effectors. In combination, the anti-EGF VacAbs significantly enhanced the antitumor activity of all TKIs tested, suppressed Erk1/2 phosphorylation, blocked the activation of signal transducer and activator of transcription 3 (STAT3) and downregulated the expression of AXL. Finally, anti-EGF VacAbs significantly delayed the emergence in vitro of EGFR TKI resistant clones. EGFR-mutant patients can derive benefit from immunization against EGF, particularly if combined with EGFR TKIs. A Phase I trial of an EGF vaccine in combination with afatinib has been initiated. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

A genetically inactivated two-component acellular pertussis vaccine, alone or combined with tetanus and reduced-dose diphtheria vaccines, in adolescents: a phase 2/3, randomised controlled non-inferiority trial.

PubMed

Sricharoenchai, Sirintip; Sirivichayakul, Chukiat; Chokephaibulkit, Kulkanya; Pitisuttithum, Punnee; Dhitavat, Jittima; Pitisuthitham, Arom; Phongsamart, Wanatpreeya; Boonnak, Kobporn; Lapphra, Keswadee; Sabmee, Yupa; Wittawatmongkol, Orasri; Chinwangso, Pailinrut; Poredi, Indrajeet Kumar; Petre, Jean; Thai, Pham Hong; Viviani, Simonetta

2018-01-01

Increasing evidence shows that protection induced by acellular pertussis vaccines is short-lived, requiring repeated booster vaccination to control pertussis disease. We aimed to assess the safety and immunogenicity of a recombinant acellular pertussis vaccine containing genetically inactivated pertussis toxin and filamentous haemagglutinin, as either a monovalent vaccine (aP [PTgen/FHA] ) or in combination with tetanus and reduced-dose diphtheria vaccines (TdaP [PTgen/FHA] ), versus a licensed tetanus and reduced-dose diphtheria and acellular pertussis combination vaccine (Tdap). We did this phase 2/3, randomised controlled non-inferiority trial at two sites in Bangkok, Thailand. Healthy adolescents (aged 12-17 years) were randomly assigned (1:1:1), via a computer-generated randomisation list with block sizes of three, to receive one dose (0·5 mL) of aP (PTgen/FHA) , TdaP (PTgen/FHA) , or Tdap (comparator). Clinical research staff responsible for participant randomisation, vaccine preparation and administration, and accountability were aware of group allocation. However, allocation was concealed from all other site study staff, data management personnel, statisticians, laboratory staff, and study participants. The primary outcome was non-inferior immunogenicity of TdaP (PTgen/FHA) to Tdap based on seroconversion rates (a four-fold increase or more) for pertussis toxin and filamentous haemagglutinin IgG antibodies 28 days after vaccination, with a predefined 10% margin of equivalence. We did analysis by per protocol. This study is registered with the Thai Clinical Trial Registry, number TCTR20150703002. Between July 6 and Aug 20, 2015, we allocated 450 participants to receive one dose of TdaP (PTgen/FHA) (n=150), aP (PTgen/FHA) (n=150), or comparator Tdap (n=150). 28 days after vaccination, seroconversion rates for anti-pertussis toxin IgG were 96·6% (95% CI 93·8-99·5; n=144) in the TdaP (PTgen/FHA) group and 55·0% (47·1-63·0; n=82) in the comparator Tdap group (difference 41·6%, 95% CI 33·1-50·1; p<0·0001). Seroconversion rates for anti-filamentous haemagglutinin were 82·6% (95% CI 76·5-88·6; n=123) in the TdaP (PTgen/FHA) group and 54·4% (46·4-62·4; n=81) in the comparator group (difference 28·2%, 95% CI 18·1-38·2 p<0·0001). 28 days after vaccination, seroconversion rates in the aP (PTgen/FHA) group were 96·0% (95% CI 92·8-99·1; n=142) for anti-pertussis toxin IgG and 93·2% (89·2-97·3; n=138) for anti-filamentous haemagglutinin IgG. These findings support the non-inferior immunogenicity of TdaP (PTgen/FHA) over comparator Tdap. Reactogenicity and incidence of adverse events were similar between groups. The new TdaP (PTgen/FHA) vaccine is safe and induces higher pertussis responses 28 days after vaccination than does the available licensed Tdap booster vaccine. Results of our trial led to the licensure of new acellular pertussis vaccines containing genetically inactivated pertussis toxin in Thailand. The availability of recombinant monovalent pertussis vaccines that induce high antibody responses provides the medical community and consumers with the opportunity to vaccinate against pertussis when immunisation against diphtheria and tetanus is not required or not desired. Studies are underway to pave the way for licensure studies of this acellular pertussis vaccine in other countries. BioNet-Asia. Copyright © 2018 Elsevier Ltd. All rights reserved.

Vaxvec: The first web-based recombinant vaccine vector database and its data analysis.

PubMed

Deng, Shunzhou; Martin, Carly; Patil, Rasika; Zhu, Felix; Zhao, Bin; Xiang, Zuoshuang; He, Yongqun

2015-11-27

A recombinant vector vaccine uses an attenuated virus, bacterium, or parasite as the carrier to express a heterologous antigen(s). Many recombinant vaccine vectors and related vaccines have been developed and extensively investigated. To compare and better understand recombinant vectors and vaccines, we have generated Vaxvec (http://www.violinet.org/vaxvec), the first web-based database that stores various recombinant vaccine vectors and those experimentally verified vaccines that use these vectors. Vaxvec has now included 59 vaccine vectors that have been used in 196 recombinant vector vaccines against 66 pathogens and cancers. These vectors are classified to 41 viral vectors, 15 bacterial vectors, 1 parasitic vector, and 1 fungal vector. The most commonly used viral vaccine vectors are double-stranded DNA viruses, including herpesviruses, adenoviruses, and poxviruses. For example, Vaxvec includes 63 poxvirus-based recombinant vaccines for over 20 pathogens and cancers. Vaxvec collects 30 recombinant vector influenza vaccines that use 17 recombinant vectors and were experimentally tested in 7 animal models. In addition, over 60 protective antigens used in recombinant vector vaccines are annotated and analyzed. User-friendly web-interfaces are available for querying various data in Vaxvec. To support data exchange, the information of vaccine vectors, vaccines, and related information is stored in the Vaccine Ontology (VO). Vaxvec is a timely and vital source of vaccine vector database and facilitates efficient vaccine vector research and development. Copyright © 2015 Elsevier Ltd. All rights reserved.

Multi-faceted Approach to Vaccine Development Against Escherichia coli O157:H7

DTIC Science & Technology

2006-03-15

36 Intimin as a vaccine candidate .................................................................................. 39 Transgenic Plant -based...41 Transgenic Plant -based Vaccines Unique advantages of plant vaccines Transgenic plants have been engineered to produce recombinant...strategies. Foremost, the vaccine can be delivered by ingestion of the edible part of the transgenic plant . The plant cell wall acts as a capsule that

Recent developments in leishmaniasis vaccine delivery systems.

PubMed

Bhowmick, Sudipta; Ali, Nahid

2008-07-01

The observation that recovery from infection with Leishmania confers immunity to reinfection suggests that control of leishmaniasis by vaccination may be possible. New generation vaccines, particularly those based on recombinant proteins and DNA, are found to be less immunogenic. There is an urgent need for the development of new and improved vaccine adjuvants. Based on their principal mechanisms of action, adjuvants can be broadly separated into two classes: immunostimulatory adjuvants and vaccine delivery systems. Vaccine delivery systems can carry both antigen and adjuvant for effective delivery to the antigen-presenting cells (APCs). In this article, we review the adjuvants, the delivery systems and their combinations used in the search of an effective vaccine against leishmaniasis. Based on current knowledge, cationic liposomes appear to have better prospects as effective delivery systems for developing a vaccine for leishmaniasis.

Viral vector vaccines protect cockatiels from inflammatory lesions after heterologous parrot bornavirus 2 challenge infection.

PubMed

Runge, Solveig; Olbert, Marita; Herden, Christiane; Malberg, Sara; Römer-Oberdörfer, Angela; Staeheli, Peter; Rubbenstroth, Dennis

2017-01-23

Avian bornaviruses are causative agents of proventricular dilatation disease (PDD), a chronic neurologic and often fatal disorder of psittacines including endangered species. To date no causative therapy or immunoprophylaxis is available. Our previous work has shown that viral vector vaccines can delay the course of homologous bornavirus challenge infections but failed to protect against PDD when persistent infection was not prevented. The goal of this study was to refine our avian bornavirus vaccination and infection model to better represent natural bornavirus infections in order to achieve full protection against a heterologous challenge infection. We observed that parrot bornavirus 2 (PaBV-2) readily infected cockatiels (Nymphicus hollandicus) by combined intramuscular and subcutaneous injection with as little as 10 2.7 foci-forming units (ffu) per bird, whereas a 500-fold higher dose of the same virus administered via peroral and oculonasal route did not result in persistent infection. These results indicated that experimental bornavirus challenge infections with this virus should be performed via the parenteral route. Prime-boost vaccination of cockatiels with Newcastle disease virus (NDV) and modified vaccinia virus Ankara (MVA) vectors expressing the nucleoprotein and phosphoprotein genes of PaBV-4 substantially blocked bornavirus replication following parenteral challenge infection with 10 3.5 ffu of heterologous PaBV-2. Only two out of six vaccinated birds had very low viral levels detectable in a few organs. As a consequence, only one vaccinated bird developed mild PDD-associated microscopic lesions, while mock-vaccinated controls were not protected against PaBV-2 infection and inflammation. Our results demonstrate that NDV and MVA vector vaccines can protect against invasive heterologous bornavirus challenge infections and subsequent PDD. These vector vaccines represent a promising tool to combat avian bornaviruses in psittacine populations. Copyright © 2016 Elsevier Ltd. All rights reserved.

Cost-effectiveness of new-generation oral cholera vaccines: a multisite analysis.

PubMed

Jeuland, Marc; Cook, Joseph; Poulos, Christine; Clemens, John; Whittington, Dale

2009-09-01

We evaluated the cost-effectiveness of a low-cost cholera vaccine licensed and used in Vietnam, using recently collected data from four developing countries where cholera is endemic. Our analysis incorporated new findings on vaccine herd protective effects. Using data from Matlab, Bangladesh, Kolkata, India, North Jakarta, Indonesia, and Beira, Mozambique, we calculated the net public cost per disability-adjusted life year avoided for three immunization strategies: 1) school-based vaccination of children 5 to 14 years of age; 2) school-based vaccination of school children plus use of the schools to vaccinate children aged 1 to 4 years; and 3) community-based vaccination of persons aged 1 year and older. We determined cost-effectiveness when vaccine herd protection was or was not considered, and compared this with commonly accepted cutoffs of gross domestic product (GDP) per person to classify interventions as cost-effective or very-cost effective. Without including herd protective effects, deployment of this vaccine would be cost-effective only in school-based programs in Kolkata and Beira. In contrast, after considering vaccine herd protection, all three programs were judged very cost-effective in Kolkata and Beira. Because these cost-effectiveness calculations include herd protection, the results are dependent on assumed vaccination coverage rates. Ignoring the indirect effects of cholera vaccination has led to underestimation of the cost-effectiveness of vaccination programs with oral cholera vaccines. Once these effects are included, use of the oral killed whole cell vaccine in programs to control endemic cholera meets the per capita GDP criterion in several developing country settings.

Safety of herpes zoster vaccine in the shingles prevention study: a randomized trial.

PubMed

Simberkoff, Michael S; Arbeit, Robert D; Johnson, Gary R; Oxman, Michael N; Boardman, Kathy D; Williams, Heather M; Levin, Myron J; Schmader, Kenneth E; Gelb, Lawrence D; Keay, Susan; Neuzil, Kathleen; Greenberg, Richard N; Griffin, Marie R; Davis, Larry E; Morrison, Vicki A; Annunziato, Paula W

2010-05-04

The herpes zoster vaccine is effective in preventing herpes zoster and postherpetic neuralgia in immunocompetent older adults. However, its safety has not been described in depth. To describe local adverse effects and short- and long-term safety profiles of herpes zoster vaccine in immunocompetent older adults. Randomized, placebo-controlled trial with enrollment from November 1998 to September 2001 and follow-up through April 2004 (mean, 3.4 years). A Veterans Affairs Coordinating Center generated the permutated block randomization scheme, which was stratified by site and age. Participants and follow-up study personnel were blinded to treatment assignments. (ClinicalTrials.gov registration number: NCT00007501) 22 U.S. academic centers. 38 546 immunocompetent adults 60 years or older, including 6616 who participated in an adverse events substudy. Single dose of herpes zoster vaccine or placebo. Serious adverse events and rashes in all participants and inoculation-site events in substudy participants during the first 42 days after inoculation. Thereafter, vaccination-related serious adverse events and deaths were monitored in all participants, and hospitalizations were monitored in substudy participants. After inoculation, 255 (1.4%) vaccine recipients and 254 (1.4%) placebo recipients reported serious adverse events. Local inoculation-site side effects were reported by 1604 (48%) vaccine recipients and 539 (16%) placebo recipients in the substudy. A total of 977 (56.6%) of the vaccine recipients reporting local side effects were aged 60 to 69 years, and 627 (39.2%) were older than 70 years. After inoculation, herpes zoster occurred in 7 vaccine recipients versus 24 placebo recipients. Long-term follow-up (mean, 3.39 years) showed that rates of hospitalization or death did not differ between vaccine and placebo recipients. Participants in the substudy were not randomly selected. Confirmation of reported serious adverse events with medical record data was not always obtained. Herpes zoster vaccine is well tolerated in older, immunocompetent adults. Cooperative Studies Program, Department of Veterans Affairs, Office of Research and Development; grants from Merck to the Veterans Affairs Cooperative Studies Program; and the James R. and Jesse V. Scott Fund for Shingles Research.

IL-4 and IL-13 mediated down-regulation of CD8 expression levels can dampen anti-viral CD8⁺ T cell avidity following HIV-1 recombinant pox viral vaccination.

PubMed

Wijesundara, Danushka K; Jackson, Ronald J; Tscharke, David C; Ranasinghe, Charani

2013-09-23

We have shown that mucosal HIV-1 recombinant pox viral vaccination can induce high, avidity HIV-specific CD8(+) T cells with reduced interleukin (IL)-4 and IL-13 expression compared to, systemic vaccine delivery. In the current study how these cytokines act to regulate anti-viral CD8(+) T, cell avidity following HIV-1 recombinant pox viral prime-boost vaccination was investigated. Out of a panel of T cell avidity markers tested, only CD8 expression levels were found to be enhanced on, KdGag197-205 (HIV)-specific CD8(+) T cells obtained from IL-13(-/-), IL-4(-/-) and signal transducer and, activator of transcription of 6 (STAT6)(-/-) mice compared to wild-type (WT) controls following, vaccination. Elevated CD8 expression levels in this instance also correlated with polyfunctionality, (interferon (IFN)-γ, tumour necorsis factor (TNF)-α and IL-2 production) and the avidity of HIVspecific CD8(+) T cells. Furthermore, mucosal vaccination and vaccination with the novel adjuvanted IL-13 inhibitor (i.e. IL-13Rα2) vaccines significantly enhanced CD8 expression levels on HIV-specific CD8(+), T cells, which correlated with avidity. Using anti-CD8 antibodies that blocked CD8 availability on CD8(+), T cells, it was established that CD8 played an important role in increasing HIV-specific CD8(+) T cell avidity and polyfunctionality in IL-4(-/-), IL-13(-/-) and STAT6(-/-) mice compared to WT controls, following vaccination. Collectively, our data demonstrate that IL-4 and IL-13 dampen CD8 expression levels on anti-viral CD8(+) T cells, which can down-regulate anti-viral CD8(+) T cell avidity and, polyfunctionality following HIV-1 recombinant pox viral vaccination. These findings can be exploited to, design more efficacious vaccines not only against HIV-1, but many chronic infections where high, avidity CD8(+) T cells help protection. Copyright © 2013 Elsevier Ltd. All rights reserved.

Anti-CD25 monoclonal antibody enhances the protective efficacy of Schistosoma japonicum GST vaccine via inhibition of CD4+CD25+Foxp3+ regulatory T cells.

PubMed

Tang, Chun-Lian; Yang, Jin; Cheng, Liang-Yu; Cheng, Lan-Fang; Liu, Zhi-Ming

2017-10-01

The effect of anti-CD25 monoclonal antibody (anti-CD25 mAb) on the protection efficacy of Schistosoma japonicum 26 kDa GST (glutathione-S-transferase) vaccine was evaluated. Mice were immunized with GST before infection with S. japonicum cercariae and then injected with anti-CD25 mAb. The worm reduction rate was promoted from 24.18% in mice with GST immunization to 47.09% in mice with GST plus anti-CD25 mAb. Compared with the control group, the percentages of splenic CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) were significantly lower after administration of anti-CD25 mAb; meanwhile, elevated levels of IFN-γ and IL-2 were secreted by splenocytes. These results indicate that the poor protective efficacy of the GST vaccine against S. japonicum results from the presence of CD4 + CD25 + Foxp3 + Tregs, while anti-CD25 mAb can partially block CD4 + CD25 + Foxp3 + Tregs and thus enhance the protective efficacy of the GST vaccine.

Protective Efficacy of the Conserved NP, PB1, and M1 Proteins as Immunogens in DNA- and Vaccinia Virus-Based Universal Influenza A Virus Vaccines in Mice

PubMed Central

Wang, Wenling; Li, Renqing; Deng, Yao; Lu, Ning; Chen, Hong; Meng, Xin; Wang, Wen; Wang, Xiuping; Yan, Kexia; Qi, Xiangrong; Zhang, Xiangmin; Xin, Wei; Lu, Zhenhua; Li, Xueren; Bian, Tao; Gao, Yingying; Tan, Wenjie

2015-01-01

The conventional hemagglutinin (HA)- and neuraminidase (NA)-based influenza vaccines need to be updated most years and are ineffective if the glycoprotein HA of the vaccine strains is a mismatch with that of the epidemic strain. Universal vaccines targeting conserved viral components might provide cross-protection and thus complement and improve conventional vaccines. In this study, we generated DNA plasmids and recombinant vaccinia viruses expressing the conserved proteins nucleoprotein (NP), polymerase basic 1 (PB1), and matrix 1 (M1) from influenza virus strain A/Beijing/30/95 (H3N2). BALB/c mice were immunized intramuscularly with a single vaccine based on NP, PB1, or M1 alone or a combination vaccine based on all three antigens and were then challenged with lethal doses of the heterologous influenza virus strain A/PR/8/34 (H1N1). Vaccines based on NP, PB1, and M1 provided complete or partial protection against challenge with 1.7 50% lethal dose (LD50) of PR8 in mice. Of the three antigens, NP-based vaccines induced protection against 5 LD50 and 10 LD50 and thus exhibited the greatest protective effect. Universal influenza vaccines based on the combination of NP, PB1, and M1 induced a strong immune response and thus might be an alternative approach to addressing future influenza virus pandemics. PMID:25834017

Protective Efficacy of the Conserved NP, PB1, and M1 Proteins as Immunogens in DNA- and Vaccinia Virus-Based Universal Influenza A Virus Vaccines in Mice.

PubMed

Wang, Wenling; Li, Renqing; Deng, Yao; Lu, Ning; Chen, Hong; Meng, Xin; Wang, Wen; Wang, Xiuping; Yan, Kexia; Qi, Xiangrong; Zhang, Xiangmin; Xin, Wei; Lu, Zhenhua; Li, Xueren; Bian, Tao; Gao, Yingying; Tan, Wenjie; Ruan, Li

2015-06-01

The conventional hemagglutinin (HA)- and neuraminidase (NA)-based influenza vaccines need to be updated most years and are ineffective if the glycoprotein HA of the vaccine strains is a mismatch with that of the epidemic strain. Universal vaccines targeting conserved viral components might provide cross-protection and thus complement and improve conventional vaccines. In this study, we generated DNA plasmids and recombinant vaccinia viruses expressing the conserved proteins nucleoprotein (NP), polymerase basic 1 (PB1), and matrix 1 (M1) from influenza virus strain A/Beijing/30/95 (H3N2). BALB/c mice were immunized intramuscularly with a single vaccine based on NP, PB1, or M1 alone or a combination vaccine based on all three antigens and were then challenged with lethal doses of the heterologous influenza virus strain A/PR/8/34 (H1N1). Vaccines based on NP, PB1, and M1 provided complete or partial protection against challenge with 1.7 50% lethal dose (LD50) of PR8 in mice. Of the three antigens, NP-based vaccines induced protection against 5 LD50 and 10 LD50 and thus exhibited the greatest protective effect. Universal influenza vaccines based on the combination of NP, PB1, and M1 induced a strong immune response and thus might be an alternative approach to addressing future influenza virus pandemics. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Characterization of monoclonal antibodies directed against the bovine herpesvirus-1 glycoprotein E and use for the differentiation between vaccinated and infected animals.

PubMed

Letellier, C; Delangre, A; De Smet, A; Kerkhofs, P

2001-12-04

A panel of seven monoclonal antibodies (MAbs) directed against the bovine herpesvirus-1 (BHV-1) glycoprotein E (gE) was obtained. For that purpose, mice were either tolerized to BHV-1 gE-negative virus and then immunized with wild type BHV-1 or immunized with plasmid DNA expressing the gE and gI glycoproteins. The MAbs were characterized by their reactivity with the gE protein or the gE/gI complex and by competition experiments. Results showed that the MAbs were directed against three antigenic domains, two located on the gE glycoprotein and one on the gE/gI complex. Blocking experiments were performed with sera from experimentally vaccinated and infected cattle. A competition was observed between gE-positive bovine sera and six of the seven MAbs. The bovine sera thus recognized two of the three antigenic sites. Field sera were then tested in blocking enzyme-linked immunosorbent assay using one horseradish peroxidase-conjugated MAb. A specificity of 98.2% and a sensitivity of 98.2% compared to the commercially available test were observed.

Ontology-supported research on vaccine efficacy, safety and integrative biological networks.

PubMed

He, Yongqun

2014-07-01

While vaccine efficacy and safety research has dramatically progressed with the methods of in silico prediction and data mining, many challenges still exist. A formal ontology is a human- and computer-interpretable set of terms and relations that represent entities in a specific domain and how these terms relate to each other. Several community-based ontologies (including Vaccine Ontology, Ontology of Adverse Events and Ontology of Vaccine Adverse Events) have been developed to support vaccine and adverse event representation, classification, data integration, literature mining of host-vaccine interaction networks, and analysis of vaccine adverse events. The author further proposes minimal vaccine information standards and their ontology representations, ontology-based linked open vaccine data and meta-analysis, an integrative One Network ('OneNet') Theory of Life, and ontology-based approaches to study and apply the OneNet theory. In the Big Data era, these proposed strategies provide a novel framework for advanced data integration and analysis of fundamental biological networks including vaccine immune mechanisms.

Ontology-supported Research on Vaccine Efficacy, Safety, and Integrative Biological Networks

PubMed Central

He, Yongqun

2016-01-01

Summary While vaccine efficacy and safety research has dramatically progressed with the methods of in silico prediction and data mining, many challenges still exist. A formal ontology is a human- and computer-interpretable set of terms and relations that represent entities in a specific domain and how these terms relate to each other. Several community-based ontologies (including the Vaccine Ontology, Ontology of Adverse Events, and Ontology of Vaccine Adverse Events) have been developed to support vaccine and adverse event representation, classification, data integration, literature mining of host-vaccine interaction networks, and analysis of vaccine adverse events. The author further proposes minimal vaccine information standards and their ontology representations, ontology-based linked open vaccine data and meta-analysis, an integrative One Network (“OneNet”) Theory of Life, and ontology-based approaches to study and apply the OneNet theory. In the Big Data era, these proposed strategies provide a novel framework for advanced data integration and analysis of fundamental biological networks including vaccine immune mechanisms. PMID:24909153

A CRISPR/Cas9 and Cre/Lox system-based express vaccine development strategy against re-emerging Pseudorabies virus.

PubMed

Liang, Xun; Sun, Leqiang; Yu, Teng; Pan, Yongfei; Wang, Dongdong; Hu, Xueying; Fu, Zhenfang; He, Qigai; Cao, Gang

2016-01-18

Virus evolves rapidly to escape vaccine-induced immunity, posing a desperate demand for efficient vaccine development biotechnologies. Here we present an express vaccine development strategy based on CRISPR/Cas9 and Cre/Lox system against re-emerging Pseudorabies virus, which caused the recent devastating swine pseudorabies outbreak in China. By CRISPR/Cas9 system, the virulent genes of the newly isolated strain were simultaneously substituted by marker genes, which were subsequently excised using Cre/Lox system for vaccine safety concern. Notably, single cell FACS technology was applied to further promote virus purification efficiency. The combination of these state-of-art technologies greatly accelerated vaccine development. Finally, vaccination and challenge experiments proved this vaccine candidate's protective efficacy in pigs and the promise to control current pseudorabies outbreak. This is, to our knowledge, the first successful vaccine development based on gene edit technologies, demonstrating these technologies leap from laboratory to industry. It may pave the way for future express antiviral vaccine development.

A CRISPR/Cas9 and Cre/Lox system-based express vaccine development strategy against re-emerging Pseudorabies virus

PubMed Central

Liang, Xun; Sun, Leqiang; Yu, Teng; Pan, Yongfei; Wang, Dongdong; Hu, Xueying; Fu, Zhenfang; He, Qigai; Cao, Gang

2016-01-01

Virus evolves rapidly to escape vaccine-induced immunity, posing a desperate demand for efficient vaccine development biotechnologies. Here we present an express vaccine development strategy based on CRISPR/Cas9 and Cre/Lox system against re-emerging Pseudorabies virus, which caused the recent devastating swine pseudorabies outbreak in China. By CRISPR/Cas9 system, the virulent genes of the newly isolated strain were simultaneously substituted by marker genes, which were subsequently excised using Cre/Lox system for vaccine safety concern. Notably, single cell FACS technology was applied to further promote virus purification efficiency. The combination of these state-of-art technologies greatly accelerated vaccine development. Finally, vaccination and challenge experiments proved this vaccine candidate’s protective efficacy in pigs and the promise to control current pseudorabies outbreak. This is, to our knowledge, the first successful vaccine development based on gene edit technologies, demonstrating these technologies leap from laboratory to industry. It may pave the way for future express antiviral vaccine development. PMID:26777545

Vaccines of the future.

PubMed

Nossal, G J V

2011-12-30

Vaccines of the future can be divided into three broad groups, namely those of the near future (<10 years); the medium-term future (10-19 years); and the long-term future (20-50 years). For the near future, there is some "low hanging fruit" which is clearly on the horizon, such as a Vi-conjugate vaccine for typhoid or a protein-based vaccine for Neisseria meningitidis serogroup B. Just slightly more distant will be vaccines for shigellosis and a common protein vaccine for Streptococcus pneumoniae. Also in this group, but not as far advanced, will be a vaccine for Group A streptococcus. I place vaccines for the "big three", malaria, tuberculosis and HIV/AIDS in the medium term basket. The sporozoite malaria vaccine RTS-S is closest, but surely a definitive malaria vaccine will also require antigens from other stages of the life cycle. A tuberculosis vaccine will be either a re-engineered BCG; or a molecular vaccine with several protein antigens; or one based on prime-boost strategies. What will delay this is the high cost of clinical trials. For HIV/AIDS, the partial success of the Sanofi-Pasteur prime-boost vaccine has given some hope. I still place much faith in antibody-based vaccines and especially on mimotopes of the env transitional state assumed after initial CD4 binding. Monoclonal antibodies are also leading us in interesting directions. Longer term, the vaccine approach will be successful for autoimmune diseases, e.g. juvenile diabetes and coeliac disease. Cancer vaccines are also briefly surveyed. Adjunct issues needing to be addressed include more extensive combinations; alternate delivery systems; and more intelligently designed adjuvants based on knowledge of the innate immune system. Copyright © 2011. Published by Elsevier Ltd.

The impact of vaccination and patient characteristics on influenza vaccination uptake of elderly people: A discrete choice experiment.

PubMed

de Bekker-Grob, Esther W; Veldwijk, Jorien; Jonker, Marcel; Donkers, Bas; Huisman, Jan; Buis, Sylvia; Swait, Joffre; Lancsar, Emily; Witteman, Cilia L M; Bonsel, Gouke; Bindels, Patrick

2018-03-07

To improve information for patients and to facilitate a vaccination coverage that is in line with the EU and World Health Organization goals, we aimed to quantify how vaccination and patient characteristics impact on influenza vaccination uptake of elderly people. An online discrete choice experiment (DCE) was conducted among 1261 representatives of the Dutch general population aged 60 years or older. In the DCE, we used influenza vaccination scenarios based on five vaccination characteristics: effectiveness, risk of severe side effects, risk of mild side effects, protection duration, and absorption time. A heteroscedastic multinomial logit model was used, taking scale and preference heterogeneity (based on 19 patient characteristics) into account. Vaccination and patient characteristics both contributed to explain influenza vaccination uptake. Assuming a base case respondent and a realistic vaccination scenario, the predicted uptake was 58%. One-way changes in vaccination characteristics and patient characteristics changed this uptake from 46% up to 61% and from 37% up to 95%, respectively. The strongest impact on vaccination uptake was whether the patient had been vaccinated last year, whether s/he had experienced vaccination side effects, and the patient's general attitude towards vaccination. Although vaccination characteristics proved to influence influenza vaccination uptake, certain patient characteristics had an even higher impact on influenza vaccination uptake. Policy makers and general practitioners can use these insights to improve their communication plans and information regarding influenza vaccination for individuals aged 60 years or older. For instance, physicians should focus more on patients who had experienced side effects due to vaccination in the past, and policy makers should tailor the standard information folder to patients who had been vaccinated last year and to patient who had not. Copyright © 2018 Elsevier Ltd. All rights reserved.

GNP-GAPDH1-22 nanovaccines prevent neonatal listeriosis by blocking microglial apoptosis and bacterial dissemination

PubMed Central

Marimon, José María; Freire, Javier; Salcines-Cuevas, David; Carmen Fariñas, M.; onzalez-Rico, Claudia; Marradi, Marco; Garcia, Isabel; Alkorta-Gurrutxaga, Mirian; San Nicolas-Gomez, Aida; Castañeda-Sampedro, Ana; Yañez-Diaz, Sonsoles; Penades, Soledad; Punzon, Carmen; Gomez-Roman, Javier; Rivera, Fernando; Fresno, Manuel; Alvarez-Dominguez, Carmen

2017-01-01

Clinical cases of neonatal listeriosis are associated with brain disease and fetal loss due to complications in early or late pregnancy, which suggests that microglial function is altered. This is believed to be the first study to link microglial apoptosis with neonatal listeriosis and listeriosis-associated brain disease, and to propose a new nanovaccine formulation that reverses all effects of listeriosis and confers Listeria monocytogenes (LM)-specific immunity. We examined clinical cases of neonatal listeriosis in 2013–2015 and defined two useful prognostic immune biomarkers to design listeriosis vaccines: high anti-GAPDH1-22 titres and tumor necrosis factor (TNF)/interleukin (IL)-6 ratios. Therefore, we developed a nanovaccine with gold glyco-nanoparticles conjugated to LM peptide 1-22 of GAPDH (Lmo2459), GNP-GAPDH1-22 nanovaccinesformulated with a pro-inflammatory Toll-like receptor 2/4-targeted adjuvant. Neonates born to non-vaccinated pregnant mice with listeriosis, showed brain and vascular diseases and significant microglial dysfunction by induction of TNF-α-mediated apoptosis. This programmed TNF-mediated suicide explains LM dissemination in brains and livers and blocks production of early pro-inflammatory cytokines such as IL-1β and interferon-α/β. In contrast, neonates born to GNP-GAPDH1–22-vaccinated mothers before LM infection, did not develop listeriosis or brain diseases and had functional microglia. In nanovaccinated mothers, immune responses shifted towards Th1/IL-12 pro-inflammatory cytokine profiles and high production of anti-GAPDH1–22 antibodies, suggesting good induction of LM-specific memory. PMID:28903312

GNP-GAPDH1-22 nanovaccines prevent neonatal listeriosis by blocking microglial apoptosis and bacterial dissemination.

PubMed

Calderon-Gonzalez, Ricardo; Frande-Cabanes, Elisabet; Teran-Navarro, Hector; Marimon, José María; Freire, Javier; Salcines-Cuevas, David; Carmen Fariñas, M; Onzalez-Rico, Claudia; Marradi, Marco; Garcia, Isabel; Alkorta-Gurrutxaga, Mirian; San Nicolas-Gomez, Aida; Castañeda-Sampedro, Ana; Yañez-Diaz, Sonsoles; Penades, Soledad; Punzon, Carmen; Gomez-Roman, Javier; Rivera, Fernando; Fresno, Manuel; Alvarez-Dominguez, Carmen

2017-08-15

Clinical cases of neonatal listeriosis are associated with brain disease and fetal loss due to complications in early or late pregnancy, which suggests that microglial function is altered. This is believed to be the first study to link microglial apoptosis with neonatal listeriosis and listeriosis-associated brain disease, and to propose a new nanovaccine formulation that reverses all effects of listeriosis and confers Listeria monocytogenes (LM)-specific immunity. We examined clinical cases of neonatal listeriosis in 2013-2015 and defined two useful prognostic immune biomarkers to design listeriosis vaccines: high anti-GAPDH 1-22 titres and tumor necrosis factor (TNF)/interleukin (IL)-6 ratios. Therefore, we developed a nanovaccine with gold glyco-nanoparticles conjugated to LM peptide 1-22 of GAPDH (Lmo2459), GNP-GAPDH 1-22 nanovaccinesformulated with a pro-inflammatory Toll-like receptor 2/4-targeted adjuvant. Neonates born to non-vaccinated pregnant mice with listeriosis, showed brain and vascular diseases and significant microglial dysfunction by induction of TNF-α-mediated apoptosis. This programmed TNF-mediated suicide explains LM dissemination in brains and livers and blocks production of early pro-inflammatory cytokines such as IL-1β and interferon-α/β. In contrast, neonates born to GNP-GAPDH 1-22 -vaccinated mothers before LM infection, did not develop listeriosis or brain diseases and had functional microglia. In nanovaccinated mothers, immune responses shifted towards Th1/IL-12 pro-inflammatory cytokine profiles and high production of anti-GAPDH 1-22 antibodies, suggesting good induction of LM-specific memory.

In vitro evolution of allergy vaccine candidates, with maintained structure, but reduced B cell and T cell activation capacity.

PubMed

Nilsson, Ola B; Adedoyin, Justus; Rhyner, Claudio; Neimert-Andersson, Theresa; Grundström, Jeanette; Berndt, Kurt D; Crameri, Reto; Grönlund, Hans

2011-01-01

Allergy and asthma to cat (Felis domesticus) affects about 10% of the population in affluent countries. Immediate allergic symptoms are primarily mediated via IgE antibodies binding to B cell epitopes, whereas late phase inflammatory reactions are mediated via activated T cell recognition of allergen-specific T cell epitopes. Allergen-specific immunotherapy relieves symptoms and is the only treatment inducing a long-lasting protection by induction of protective immune responses. The aim of this study was to produce an allergy vaccine designed with the combined features of attenuated T cell activation, reduced anaphylactic properties, retained molecular integrity and induction of efficient IgE blocking IgG antibodies for safer and efficacious treatment of patients with allergy and asthma to cat. The template gene coding for rFel d 1 was used to introduce random mutations, which was subsequently expressed in large phage libraries. Despite accumulated mutations by up to 7 rounds of iterative error-prone PCR and biopanning, surface topology and structure was essentially maintained using IgE-antibodies from cat allergic patients for phage enrichment. Four candidates were isolated, displaying similar or lower IgE binding, reduced anaphylactic activity as measured by their capacity to induce basophil degranulation and, importantly, a significantly lower T cell reactivity in lymphoproliferative assays compared to the original rFel d 1. In addition, all mutants showed ability to induce blocking antibodies in immunized mice.The approach presented here provides a straightforward procedure to generate a novel type of allergy vaccines for safer and efficacious treatment of allergic patients.

Efficacy and immunogenicity of a Vi-tetanus toxoid conjugate vaccine in the prevention of typhoid fever using a controlled human infection model of Salmonella Typhi: a randomised controlled, phase 2b trial.

PubMed

Jin, Celina; Gibani, Malick M; Moore, Maria; Juel, Helene B; Jones, Elizabeth; Meiring, James; Harris, Victoria; Gardner, Jonathan; Nebykova, Anna; Kerridge, Simon A; Hill, Jennifer; Thomaides-Brears, Helena; Blohmke, Christoph J; Yu, Ly-Mee; Angus, Brian; Pollard, Andrew J

2017-12-02

Salmonella enterica serovar Typhi (S Typhi) is responsible for an estimated 20 million infections and 200 000 deaths each year in resource poor regions of the world. Capsular Vi-polysaccharide-protein conjugate vaccines (Vi-conjugate vaccines) are immunogenic and can be used from infancy but there are no efficacy data for the leading candidate vaccine being considered for widespread use. To address this knowledge gap, we assessed the efficacy of a Vi-tetanus toxoid conjugate vaccine using an established human infection model of S Typhi. In this single-centre, randomised controlled, phase 2b study, using an established outpatient-based human typhoid infection model, we recruited healthy adult volunteers aged between 18 and 60 years, with no previous history of typhoid vaccination, infection, or prolonged residency in a typhoid-endemic region. Participants were randomly assigned (1:1:1) to receive a single dose of Vi-conjugate (Vi-TT), Vi-polysaccharide (Vi-PS), or control meningococcal vaccine with a computer-generated randomisation schedule (block size 6). Investigators and participants were masked to treatment allocation, and an unmasked team of nurses administered the vaccines. Following oral ingestion of S Typhi, participants were assessed with daily blood culture over a 2-week period and diagnosed with typhoid infection when meeting pre-defined criteria. The primary endpoint was the proportion of participants diagnosed with typhoid infection (ie, attack rate), defined as persistent fever of 38°C or higher for 12 h or longer or S Typhi bacteraemia, following oral challenge administered 1 month after Vi-vaccination (Vi-TT or Vi-PS) compared with control vaccination. Analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT02324751, and is ongoing. Between Aug 18, 2015, and Nov 4, 2016, 112 participants were enrolled and randomly assigned; 34 to the control group, 37 to the Vi-PS group, and 41 to the Vi-TT group. 103 participants completed challenge (31 in the control group, 35 in the Vi-PS group, and 37 in the Vi-TT group) and were included in the per-protocol population. The composite criteria for typhoid diagnosis was met in 24 (77%) of 31 participants in the control group, 13 (35%) of 37 participants in the Vi-TT group, and 13 (35%) of 35 participants in the Vi-PS group to give vaccine efficacies of 54·6% (95% CI 26·8-71·8) for Vi-TT and 52·0% (23·2-70·0) for Vi-PS. Seroconversion was 100% in Vi-TT and 88·6% in Vi-PS participants, with significantly higher geometric mean titres detected 1-month post-vaccination in Vi-TT vaccinees. Four serious adverse events were reported during the conduct of the study, none of which were related to vaccination (one in the Vi-TT group and three in the Vi-PS group). Vi-TT is a highly immunogenic vaccine that significantly reduces typhoid fever cases when assessed using a stringent controlled model of typhoid infection. Vi-TT use has the potential to reduce both the burden of typhoid fever and associated health inequality. The Bill & Melinda Gates Foundation and the European Commission FP7 grant, Advanced Immunization Technologies (ADITEC). Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Immunization-elicited Broadly Protective Antibody Reveals Ebolavirus Fusion Loop as a Site of Vulnerability

PubMed Central

Zhao, Xuelian; Howell, Katie A.; He, Shihua; Brannan, Jennifer M.; Wec, Anna Z.; Davidson, Edgar; Turner, Hannah L.; Chiang, Chi-I; Lei, Lin; Fels, J. Maximilian; Vu, Hong; Shulenin, Sergey; Turonis, Ashley N.; Kuehne, Ana I.; Liu, Guodong; Ta, Mi; Wang, Yimeng; Sundling, Christopher; Xiao, Yongli; Spence, Jennifer S.; Doranz, Benjamin J.; Holtsberg, Frederick W.; Ward, Andrew B.; Chandran, Kartik; Dye, John M.; Qiu, Xiangguo; Li, Yuxing; Aman, M. Javad

2018-01-01

Summary While neutralizing antibodies are highly effective against ebolavirus infections, current experimental ebolavirus vaccines primarily elicit species-specific antibody responses. Here we describe an immunization-elicited macaque antibody (CA45) that clamps the internal fusion loop with the N-terminus of the ebolavirus glycoproteins (GP) and potently neutralizes Ebola, Sudan, Bundibugyo, and Reston viruses. CA45, alone or in combination with an antibody that blocks receptor binding, provided full protection against all pathogenic ebolaviruses in mice, guinea pigs, and ferrets. Analysis of memory B cells from the immunized macaque suggests that elicitation of broadly neutralizing antibodies (bNAbs) for ebolaviruses is possible but difficult, potentially due to the rarity of bNAb clones and their precursors. Unexpectedly, germline-reverted CA45, while exhibiting negligible binding to full-length GP, bound a proteolytically remodeled GP with picomolar affinity, suggesting that engineered ebolavirus vaccines could trigger rare bNAb precursors more robustly. These findings have important implications for developing pan-ebolavirus vaccine and immunotherapeutic cocktails. PMID:28525756

Ontology-based Brucella vaccine literature indexing and systematic analysis of gene-vaccine association network.

PubMed

Hur, Junguk; Xiang, Zuoshuang; Feldman, Eva L; He, Yongqun

2011-08-26

Vaccine literature indexing is poorly performed in PubMed due to limited hierarchy of Medical Subject Headings (MeSH) annotation in the vaccine field. Vaccine Ontology (VO) is a community-based biomedical ontology that represents various vaccines and their relations. SciMiner is an in-house literature mining system that supports literature indexing and gene name tagging. We hypothesize that application of VO in SciMiner will aid vaccine literature indexing and mining of vaccine-gene interaction networks. As a test case, we have examined vaccines for Brucella, the causative agent of brucellosis in humans and animals. The VO-based SciMiner (VO-SciMiner) was developed to incorporate a total of 67 Brucella vaccine terms. A set of rules for term expansion of VO terms were learned from training data, consisting of 90 biomedical articles related to Brucella vaccine terms. VO-SciMiner demonstrated high recall (91%) and precision (99%) from testing a separate set of 100 manually selected biomedical articles. VO-SciMiner indexing exhibited superior performance in retrieving Brucella vaccine-related papers over that obtained with MeSH-based PubMed literature search. For example, a VO-SciMiner search of "live attenuated Brucella vaccine" returned 922 hits as of April 20, 2011, while a PubMed search of the same query resulted in only 74 hits. Using the abstracts of 14,947 Brucella-related papers, VO-SciMiner identified 140 Brucella genes associated with Brucella vaccines. These genes included known protective antigens, virulence factors, and genes closely related to Brucella vaccines. These VO-interacting Brucella genes were significantly over-represented in biological functional categories, including metabolite transport and metabolism, replication and repair, cell wall biogenesis, intracellular trafficking and secretion, posttranslational modification, and chaperones. Furthermore, a comprehensive interaction network of Brucella vaccines and genes were identified. The asserted and inferred VO hierarchies provide semantic support for inferring novel knowledge of association of vaccines and genes from the retrieved data. New hypotheses were generated based on this analysis approach. VO-SciMiner can be used to improve the efficiency for PubMed searching in the vaccine domain.

Ontology-based Brucella vaccine literature indexing and systematic analysis of gene-vaccine association network

PubMed Central

2011-01-01

Background Vaccine literature indexing is poorly performed in PubMed due to limited hierarchy of Medical Subject Headings (MeSH) annotation in the vaccine field. Vaccine Ontology (VO) is a community-based biomedical ontology that represents various vaccines and their relations. SciMiner is an in-house literature mining system that supports literature indexing and gene name tagging. We hypothesize that application of VO in SciMiner will aid vaccine literature indexing and mining of vaccine-gene interaction networks. As a test case, we have examined vaccines for Brucella, the causative agent of brucellosis in humans and animals. Results The VO-based SciMiner (VO-SciMiner) was developed to incorporate a total of 67 Brucella vaccine terms. A set of rules for term expansion of VO terms were learned from training data, consisting of 90 biomedical articles related to Brucella vaccine terms. VO-SciMiner demonstrated high recall (91%) and precision (99%) from testing a separate set of 100 manually selected biomedical articles. VO-SciMiner indexing exhibited superior performance in retrieving Brucella vaccine-related papers over that obtained with MeSH-based PubMed literature search. For example, a VO-SciMiner search of "live attenuated Brucella vaccine" returned 922 hits as of April 20, 2011, while a PubMed search of the same query resulted in only 74 hits. Using the abstracts of 14,947 Brucella-related papers, VO-SciMiner identified 140 Brucella genes associated with Brucella vaccines. These genes included known protective antigens, virulence factors, and genes closely related to Brucella vaccines. These VO-interacting Brucella genes were significantly over-represented in biological functional categories, including metabolite transport and metabolism, replication and repair, cell wall biogenesis, intracellular trafficking and secretion, posttranslational modification, and chaperones. Furthermore, a comprehensive interaction network of Brucella vaccines and genes were identified. The asserted and inferred VO hierarchies provide semantic support for inferring novel knowledge of association of vaccines and genes from the retrieved data. New hypotheses were generated based on this analysis approach. Conclusion VO-SciMiner can be used to improve the efficiency for PubMed searching in the vaccine domain. PMID:21871085

New vaccines against influenza virus

PubMed Central

Lee, Young-Tae; Kim, Ki-Hye; Ko, Eun-Ju; Lee, Yu-Na; Kim, Min-Chul; Kwon, Young-Man; Tang, Yinghua; Cho, Min-Kyoung; Lee, Youn-Jeong

2014-01-01

Vaccination is one of the most effective and cost-benefit interventions that prevent the mortality and reduce morbidity from infectious pathogens. However, the licensed influenza vaccine induces strain-specific immunity and must be updated annually based on predicted strains that will circulate in the upcoming season. Influenza virus still causes significant health problems worldwide due to the low vaccine efficacy from unexpected outbreaks of next epidemic strains or the emergence of pandemic viruses. Current influenza vaccines are based on immunity to the hemagglutinin antigen that is highly variable among different influenza viruses circulating in humans and animals. Several scientific advances have been endeavored to develop universal vaccines that will induce broad protection. Universal vaccines have been focused on regions of viral proteins that are highly conserved across different virus subtypes. The strategies of universal vaccines include the matrix 2 protein, the hemagglutinin HA2 stalk domain, and T cell-based multivalent antigens. Supplemented and/or adjuvanted vaccination in combination with universal target antigenic vaccines would have much promise. This review summarizes encouraging scientific advances in the field with a focus on novel vaccine designs. PMID:24427759

A PfRH5-Based Vaccine Is Efficacious against Heterologous Strain Blood-Stage Plasmodium falciparum Infection in Aotus Monkeys

PubMed Central

Douglas, Alexander D.; Baldeviano, G. Christian; Lucas, Carmen M.; Lugo-Roman, Luis A.; Crosnier, Cécile; Bartholdson, S. Josefin; Diouf, Ababacar; Miura, Kazutoyo; Lambert, Lynn E.; Ventocilla, Julio A.; Leiva, Karina P.; Milne, Kathryn H.; Illingworth, Joseph J.; Spencer, Alexandra J.; Hjerrild, Kathryn A.; Alanine, Daniel G.W.; Turner, Alison V.; Moorhead, Jeromy T.; Edgel, Kimberly A.; Wu, Yimin; Long, Carole A.; Wright, Gavin J.; Lescano, Andrés G.; Draper, Simon J.

2015-01-01

Summary Antigenic diversity has posed a critical barrier to vaccine development against the pathogenic blood-stage infection of the human malaria parasite Plasmodium falciparum. To date, only strain-specific protection has been reported by trials of such vaccines in nonhuman primates. We recently showed that P. falciparum reticulocyte binding protein homolog 5 (PfRH5), a merozoite adhesin required for erythrocyte invasion, is highly susceptible to vaccine-inducible strain-transcending parasite-neutralizing antibody. In vivo efficacy of PfRH5-based vaccines has not previously been evaluated. Here, we demonstrate that PfRH5-based vaccines can protect Aotus monkeys against a virulent vaccine-heterologous P. falciparum challenge and show that such protection can be achieved by a human-compatible vaccine formulation. Protection was associated with anti-PfRH5 antibody concentration and in vitro parasite-neutralizing activity, supporting the use of this in vitro assay to predict the in vivo efficacy of future vaccine candidates. These data suggest that PfRH5-based vaccines have potential to achieve strain-transcending efficacy in humans. PMID:25590760

Construction and Nonclinical Testing of a Puumala Virus Synthetic M Gene-Based DNA Vaccine

DTIC Science & Technology

2012-12-12

immunogenic hantavirus M gene-based DNA vaccines against the HFRS hantaviruses , we ini- tiated preclinical testing of these vaccines, delivered using a...Testing of a Puumala Virus Synthetic M Gene-Based DNA Vaccine 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR (S) 5d. PROJECT...Vaccination with pWRG/ PUU-M(s2) protected hamsters against infection with PUUV but not against infection by related HFRS-associated hantaviruses

Combining Adoptive Cell Therapy with Cytomegalovirus-Based Vaccine Is Protective against Solid Skin Tumors.

PubMed

Grenier, Jeremy M; Yeung, Stephen T; Qiu, Zhijuan; Jellison, Evan R; Khanna, Kamal M

2017-01-01

Despite many years of research, cancer vaccines have largely been ineffective in the treatment of established cancers. Many barriers to immune-mediated destruction of malignant cells exist, and these likely limit the efficacy of cancer vaccines. In this study, we sought to enhance the efficacy of a cytomegalovirus (CMV)-based vaccine targeting melanoma by combining vaccination with other forms of immunotherapy. Adoptive cell therapy in humans and in animal models has been shown to be effective for tumor regression. Thus, in this study, we assessed whether CMV-based vaccines in combination with adoptively transferred antitumor T cells could provide greater antitumor protection than either therapy alone. Our results show that adoptive cell therapy greatly enhanced the antitumor effects of CMV-based vaccines targeting the foreign model antigen, OVA, or the melanoma differentiation antigen, gp100. Combination adoptive cell therapy and vaccination induced the upregulation of the inhibitory ligands, PD-L1, and Qa-1 b , on B16 tumor cells. This expression paralleled the infiltration of tumors by vaccine-stimulated T cells which also expressed high levels of the receptors PD-1 and NKG2A/C/E, suggesting a potential mechanism of tumor immune evasion. Surprisingly, therapeutic blockade of the PD-1/PD-L1 and NKG2A/Qa-1 b axes did not delay tumor growth following vaccination, suggesting that the presence of inhibitory ligands within malignant tissue may not be an effective biomarker for successful combination therapy with CMV-based vaccines. Overall, our studies show that therapeutic CMV-based vaccines in combination with adoptive T cell transfer alone are effective for tumor rejection.

Combining Adoptive Cell Therapy with Cytomegalovirus-Based Vaccine Is Protective against Solid Skin Tumors

PubMed Central

Grenier, Jeremy M.; Yeung, Stephen T.; Qiu, Zhijuan; Jellison, Evan R.; Khanna, Kamal M.

2018-01-01

Despite many years of research, cancer vaccines have largely been ineffective in the treatment of established cancers. Many barriers to immune-mediated destruction of malignant cells exist, and these likely limit the efficacy of cancer vaccines. In this study, we sought to enhance the efficacy of a cytomegalovirus (CMV)-based vaccine targeting melanoma by combining vaccination with other forms of immunotherapy. Adoptive cell therapy in humans and in animal models has been shown to be effective for tumor regression. Thus, in this study, we assessed whether CMV-based vaccines in combination with adoptively transferred antitumor T cells could provide greater antitumor protection than either therapy alone. Our results show that adoptive cell therapy greatly enhanced the antitumor effects of CMV-based vaccines targeting the foreign model antigen, OVA, or the melanoma differentiation antigen, gp100. Combination adoptive cell therapy and vaccination induced the upregulation of the inhibitory ligands, PD-L1, and Qa-1b, on B16 tumor cells. This expression paralleled the infiltration of tumors by vaccine-stimulated T cells which also expressed high levels of the receptors PD-1 and NKG2A/C/E, suggesting a potential mechanism of tumor immune evasion. Surprisingly, therapeutic blockade of the PD-1/PD-L1 and NKG2A/Qa-1b axes did not delay tumor growth following vaccination, suggesting that the presence of inhibitory ligands within malignant tissue may not be an effective biomarker for successful combination therapy with CMV-based vaccines. Overall, our studies show that therapeutic CMV-based vaccines in combination with adoptive T cell transfer alone are effective for tumor rejection. PMID:29387061

Human papillomavirus vaccine policy and delivery in Latin America and the Caribbean.

PubMed

Andrus, Jon Kim; Lewis, Merle J; Goldie, Sue J; García, Patricia J; Winkler, Jennifer L; Ruiz-Matus, Cuauhtémoc; de Quadros, Ciro A

2008-08-19

Cervical cancer caused by human papillomavirus (HPV) is a major preventable public health problem. Two vaccines are now available for primary prevention of HPV infection and their introduction offers new opportunities to enhance comprehensive cervical cancer prevention and control. Currently, HPV vaccine price is a significant barrier to rapid vaccine introduction and access. Therefore, making evidence-based decisions about whether and how to introduce HPV vaccine into the immunization schedule in the countries of Latin America and the Caribbean (LAC) requires a rigorous analysis of several factors. These include: estimates of disease burden, cost-effectiveness, operational feasibility of reaching a population of adolescent females and other key analyses that have been used in recent years to support the introduction of other vaccines, such as rotavirus and pneumococcal conjugate vaccines. Given the large number of public health priorities that are competing for limited public resources, developing and using a sound evidence base is of particular importance for vaccines, like HPV, which are currently available only at prices higher than other vaccines now in use. HPV vaccination provides the opportunity to dramatically improve women's health and partnerships must also be broad-based and effectively coordinated. This can be achieved by developing programs based on the lessons learned from vaccination strategies used to eliminate rubella and neonatal tetanus and for scaling up influenza vaccination in countries of LAC.

The Twenty-Year Story of a Plant-Based Vaccine Against Hepatitis B: Stagnation or Promising Prospects?

PubMed Central

Pniewski, Tomasz

2013-01-01

Hepatitis B persists as a common human disease despite effective vaccines having been employed for almost 30 years. Plants were considered as alternative sources of vaccines, to be mainly orally administered. Despite 20-year attempts, no real anti-HBV plant-based vaccine has been developed. Immunization trials, based on ingestion of raw plant tissue and conjugated with injection or exclusively oral administration of lyophilized tissue, were either impractical or insufficient due to oral tolerance acquisition. Plant-produced purified HBV antigens were highly immunogenic when injected, but their yields were initially insufficient for practical purposes. However, knowledge and technology have progressed, hence new plant-derived anti-HBV vaccines can be proposed today. All HBV antigens can be efficiently produced in stable or transient expression systems. Processing of injection vaccines has been developed and needs only to be successfully completed. Purified antigens can be used for injection in an equivalent manner to the present commercial vaccines. Although oral vaccines require improvement, plant tissue, lyophilized or extracted and converted into tablets, etc., may serve as a boosting vaccine. Preliminary data indicate also that both vaccines can be combined in an effective parenteral-oral immunization procedure. A partial substitution of injection vaccines with oral formulations still offers good prospects for economically viable and efficacious anti-HBV plant-based vaccines. PMID:23337199

Peptide Vaccines for Leishmaniasis.

PubMed

De Brito, Rory C F; Cardoso, Jamille M De O; Reis, Levi E S; Vieira, Joao F; Mathias, Fernando A S; Roatt, Bruno M; Aguiar-Soares, Rodrigo Dian D O; Ruiz, Jeronimo C; Resende, Daniela de M; Reis, Alexandre B

2018-01-01

Due to an increase in the incidence of leishmaniases worldwide, the development of new strategies such as prophylactic vaccines to prevent infection and decrease the disease have become a high priority. Classic vaccines against leishmaniases were based on live or attenuated parasites or their subunits. Nevertheless, the use of whole parasite or their subunits for vaccine production has numerous disadvantages. Therefore, the use of Leishmania peptides to design more specific vaccines against leishmaniases seems promising. Moreover, peptides have several benefits in comparison with other kinds of antigens, for instance, good stability, absence of potentially damaging materials, antigen low complexity, and low-cost to scale up. By contrast, peptides are poor immunogenic alone, and they need to be delivered correctly. In this context, several approaches described in this review are useful to solve these drawbacks. Approaches, such as, peptides in combination with potent adjuvants, cellular vaccinations, adenovirus, polyepitopes, or DNA vaccines have been used to develop peptide-based vaccines. Recent advancements in peptide vaccine design, chimeric, or polypeptide vaccines and nanovaccines based on particles attached or formulated with antigenic components or peptides have been increasingly employed to drive a specific immune response. In this review, we briefly summarize the old, current, and future stands on peptide-based vaccines, describing the disadvantages and benefits associated with them. We also propose possible approaches to overcome the related weaknesses of synthetic vaccines and suggest future guidelines for their development.

77 FR 30015 - Advisory Committee on Immunization Practices (ACIP)

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-21

..., influenza, pneumococcal vaccines, measles-mumps-rubella vaccine, pertussis, development of evidence- based recommendations, Institute of Medicine vaccine committee report, and anthrax vaccine adsorbed and vaccine supply...

Respiratory nanoparticle-based vaccines and challenges associated with animal models and translation.

PubMed

Renukaradhya, Gourapura J; Narasimhan, Balaji; Mallapragada, Surya K

2015-12-10

Vaccine development has had a huge impact on human health. However, there is a significant need to develop efficacious vaccines for several existing as well as emerging respiratory infectious diseases. Several challenges need to be overcome to develop efficacious vaccines with translational potential. This review focuses on two aspects to overcome some barriers - 1) the development of nanoparticle-based vaccines, and 2) the choice of suitable animal models for respiratory infectious diseases that will allow for translation. Nanoparticle-based vaccines, including subunit vaccines involving synthetic and/or natural polymeric adjuvants and carriers, as well as those based on virus-like particles offer several key advantages to help overcome the barriers to effective vaccine development. These include the ability to deliver combinations of antigens, target the vaccine formulation to specific immune cells, enable cross-protection against divergent strains, act as adjuvants or immunomodulators, allow for sustained release of antigen, enable single dose delivery, and potentially obviate the cold chain. While mouse models have provided several important insights into the mechanisms of infectious diseases, they are often a limiting step in translation of new vaccines to the clinic. An overview of different animal models involved in vaccine research for respiratory infections, with advantages and disadvantages of each model, is discussed. Taken together, advances in nanotechnology, combined with the right animal models for evaluating vaccine efficacy, has the potential to revolutionize vaccine development for respiratory infections. Copyright © 2015 Elsevier B.V. All rights reserved.

Advanced medical countermeasures for radiological accidents and nuclear disasters: prevention, prophylaxis, treatment and pre- and post-exposure management.

NASA Astrophysics Data System (ADS)

Popov, Dmitri; Maliev, Slava; Jones, Jeffrey

Countermeasures against nuclear terrorism to prevent or limit the number of irradiated human population or radiation intoxications include early identification of the nuclear terrorism event and all persons which exposed by radiation, decontamination program and procedures, radiation control, and medical countermeasures which include medical diagnosis,differential diagnosis of Acute Radiation Syndromes by Immune Enzyme Assay , pre-exposure vaccination with Human Antiradiation Vaccine, post-exposure specific treatment - de-intoxication with Radiation Antidote IgG (blocking Antiradiation Antibodies). Our Advanced Medical Technology elaborated as a part of effective countermeasure include Plan of Action.Countermeasures against nuclear terrorism to prevent or limit the number of high level of lethality and severe forms of radiation illness or intoxications include A.early identification of the nuclear terrorism event and persons exposed,b. appropriate decontamination, c. radiation control, and d.medical countermeasures and medical management of ARS. Medical countermeasures, which include medical interventions such as active immuneprophylaxis with Human Antiradiation Vaccine , passive immune-prophylaxis with Antiradiation Antitoxins immune-globulins IgG , and chemoprophylaxis - post-exposure antioxidants prophylaxis and antibioticprophylaxis. Medical countermeasures with Antiradiation Vaccine should be initiated before an exposure (if individuals are identified as being at high risk for exposure)but after a confirmed exposure event Antiradiation Vaccine not effective and Antiradiation Antidot IgG must be applyed for treatment of Acute Radiation Syndromes.

Targeting the Intratumoral Dendritic Cells by the Oncolytic Adenoviral Vaccine Expressing RANTES Elicits Potent Antitumor Immunity

PubMed Central

Lapteva, Natalia; Aldrich, Melissa; Weksberg, David; Rollins, Lisa; Goltsova, Tatiana; Chen, Si-Yi; Huang, Xue F.

2014-01-01

Summary Dendritic cells (DCs) are professional antigen (Ag)-presenting cells capable of inducing immune responses to tumor Ags and, therefore, play a central role in the induction of antitumor immunity. There is a large amount of evidence, however, about paucity of tumor-associated DCs and that DCs’ immunogenic functions are suppressed in a tumor environment. Here we describe a potent in situ vaccine targeting tumoral DCs in vivo. This vaccine comprised of an oncolytic adenovirus expressing RANTES (regulated upon activation, normally T expressed, and presumably secreted) (Ad-RANTES-E1A), enhanced tumor infiltration, and maturation of Ag-presenting cells in vivo. In this study, we show that intratumoral vaccinations with Ad-RANTES-E1A induced significant primary tumor growth regression and blocked metastasis formation in JC and E.G-7 murine tumor models. This vaccine recruited DCs, macrophages, natural killer cells, and CD8+ T cells to the tumor site, and thus enhanced Ag-specific cytotoxic T lymphocyte responses and natural killer cell responses. DCs purified from the Ad-RANTES-E1A–treated E.G-7 tumors secreted significantly higher levels of interferon-γ and interleukin-12, as compared with control groups and more efficiently enhanced CD8+ T-cell response. This in situ immunization strategy could be a potent antitumor immunotherapy approach for aggressive established tumors. PMID:19238013

Typhoid fever vaccination strategies.

PubMed

Date, Kashmira A; Bentsi-Enchill, Adwoa; Marks, Florian; Fox, Kimberley

2015-06-19

Typhoid vaccination is an important component of typhoid fever prevention and control, and is recommended for public health programmatic use in both endemic and outbreak settings. We reviewed experiences with various vaccination strategies using the currently available typhoid vaccines (injectable Vi polysaccharide vaccine [ViPS], oral Ty21a vaccine, and injectable typhoid conjugate vaccine [TCV]). We assessed the rationale, acceptability, effectiveness, impact and implementation lessons of these strategies to inform effective typhoid vaccination strategies for the future. Vaccination strategies were categorized by vaccine disease control strategy (preemptive use for endemic disease or to prevent an outbreak, and reactive use for outbreak control) and vaccine delivery strategy (community-based routine, community-based campaign and school-based). Almost all public health typhoid vaccination programs used ViPS vaccine and have been in countries of Asia, with one example in the Pacific and one experience using the Ty21a vaccine in South America. All vaccination strategies were found to be acceptable, feasible and effective in the settings evaluated; evidence of impact, where available, was strongest in endemic settings and in the short- to medium-term. Vaccination was cost-effective in high-incidence but not low-incidence settings. Experience in disaster and outbreak settings remains limited. TCVs have recently become available and none are WHO-prequalified yet; no program experience with TCVs was found in published literature. Despite the demonstrated success of several typhoid vaccination strategies, typhoid vaccines remain underused. Implementation lessons should be applied to design optimal vaccination strategies using TCVs which have several anticipated advantages, such as potential for use in infant immunization programs and longer duration of protection, over the ViPS and Ty21a vaccines for typhoid prevention and control. Copyright © 2015. Published by Elsevier Ltd.

Cost-Effectiveness Evaluation of Quadrivalent Human Papilloma Virus Vaccine for HPV-Related Disease in Iran

PubMed Central

Khatibi, Mohsen; Rasekh, Hamid Reza; Shahverdi, Zohreh; jamshidi, Hamid Reza

2014-01-01

Human Papilloma Virus (HPV) vaccine has been added recently to the Iran Drug List. So, decision makers need information beyond that available from RCTs to recommend funding for this vaccination program to add it to the National Immunization program in Iran. Modeling and economic studies have addressed some of those information needs in foreign countries. In order to determine the long term benefit of this vaccine and impact of vaccine program on the future rate of cervical cancer in Iran, we described a model, based on the available economic and health effects of human papilloma virus (HPV), to estimate the cost-effectiveness of HPV vaccination of 15-year-old girls in Iran. Our objective is to estimate the cost-effectiveness of HPV vaccination in Iran against cervical cancer based on available data; incremental cost-effectiveness ratio (ICER) calculations were based on a model comparing a cohort of 15-year-old girls with and without vaccination. We developed a static model based on available data in Iran on the epidemiology of HPV related health outcome. The model compared the cohort of all 15-year old girls alive in the year 2013 with and without vaccination. The cost per QALY, which was found based on our assumption for the vaccination of 15-years old girl to current situation was 439,000,000 Iranian Rial rate (IRR). By considering the key parameters in our sensitivity analysis, value varied from 251,000,000 IRR to 842,000,000 IRR. In conclusion, quadrivalent HPV vaccine (Gardasil) is not cost-effective in Iran based on the base-case parameters value. PMID:24711850

Strengthening vaccination policies in Latin America: an evidence-based approach.

PubMed

Tapia-Conyer, Roberto; Betancourt-Cravioto, Miguel; Saucedo-Martínez, Rodrigo; Motta-Murguía, Lourdes; Gallardo-Rincón, Héctor

2013-08-20

Despite many successes in the region, Latin American vaccination policies have significant shortcomings, and further work is needed to maintain progress and prepare for the introduction of newly available vaccines. In order to address the challenges facing Latin America, the Commission for the Future of Vaccines in Latin America (COFVAL) has made recommendations for strengthening evidence-based policy-making and reducing regional inequalities in immunisation. We have conducted a comprehensive literature review to assess the feasibility of these recommendations. Standardisation of performance indicators for disease burden, vaccine coverage, epidemiological surveillance and national health resourcing can ensure comparability of the data used to assess vaccination programmes, allowing deeper analysis of how best to provide services. Regional vaccination reference schemes, as used in Europe, can be used to develop best practice models for vaccine introduction and scheduling. Successful models exist for the continuous training of vaccination providers and decision-makers, with a new Latin American diploma aiming to contribute to the successful implementation of vaccination programmes. Permanent, independent vaccine advisory committees, based on the US Advisory Committee on Immunization Practices (ACIP), could facilitate the uptake of new vaccines and support evidence-based decision-making in the administration of national immunisation programmes. Innovative financing mechanisms for the purchase of new vaccines, such as advance market commitments and cost front-loading, have shown potential for improving vaccine coverage. A common regulatory framework for vaccine approval is needed to accelerate delivery and pool human, technological and scientific resources in the region. Finally, public-private partnerships between industry, government, academia and non-profit sectors could provide new investment to stimulate vaccine development in the region, reducing prices in the long term. These reforms are now crucial, particularly as vaccines for previously neglected, developing-world diseases become available. In summary, a regionally-coordinated health policy will reduce vaccination inequality in Latin America. Copyright © 2013 Elsevier Ltd. All rights reserved.

Efficacy, Safety, and Interactions of a Live Infectious Bursal Disease Virus Vaccine for Chickens Based on Strain IBD V877.

PubMed

Geerligs, Harm J; Ons, Ellen; Boelm, Gert Jan; Vancraeynest, Dieter

2015-03-01

Infectious bursal disease (IBD) is a highly contagious disease in young chickens which can result in high morbidity and mortality and also in great economic losses. The main target for the virus is the lymphoid tissue with a special predilection for the bursa of Fabricius. Several vaccines are available to control the disease. Intermediate plus vaccines are used in chickens with high maternal antibody titers which face high infection pressure. An example of an intermediate plus vaccine is a live vaccine based on IBD strain V877. The results of an efficacy study in commercial broilers with different levels of maternally derived antibodies (MDA) showed that the V877-based IBD vaccine can break through maternal antibody titers of higher than 1100 as determined by an IBD ELISA. The safety of the vaccine was demonstrated in a study in which specific-pathogen-free (SPF) chickens were vaccinated with a tenfold dose of the vaccine strain and a tenfold dose of the vaccine strain after five back passages in SPF chickens. The vaccine virus caused lesions, as could be expected for an intermediate plus vaccine, but the scores were not much higher than the maximal scores allowed for mild IBD vaccines in the European Pharmacopoeia, and reversion to virulence was absent. In studies in SPF chickens, there were no negative impacts by the IBD V877 vaccine on the efficacy of a live QX-like IB vaccine and a live Newcastle disease La Sota vaccine in vaccination challenge studies, although the IBD vaccine had a negative effect on the antibody response generated by the QX-like IB vaccine. It is concluded that the IBD V877 vaccine has the capacity to break through high levels of MDA, has a satisfactory safety profile, and interactions with other live vaccines are limited. In order to limit bursal lesions after vaccination it is recommended to confirm the presence of MDA before vaccinating with the V877 vaccine.

Farming of Plant-Based Veterinary Vaccines and Their Applications for Disease Prevention in Animals

PubMed Central

Liew, Pit Sze; Hair-Bejo, Mohd

2015-01-01

Plants have been studied for the production of pharmaceutical compounds for more than two decades now. Ever since the plant-made poultry vaccine against Newcastle disease virus made a breakthrough and went all the way to obtain regulatory approval, research to use plants for expression and delivery of vaccine proteins for animals was intensified. Indeed, in view of the high production costs of veterinary vaccines, plants represent attractive biofactories and offer many promising advantages in the production of recombinant vaccine proteins. Furthermore, the possibility of conducting immunogenicity and challenge studies in target animals has greatly exaggerated the progress. Although there are no edible plant-produced animal vaccines in the market, plant-based vaccine technology has great potentials. In this review, development, uses, and advantages of plant-based recombinant protein production in various expression platforms are discussed. In addition, examples of plant-based veterinary vaccines showing strong indication in terms of efficacy in animal disease prevention are also described. PMID:26351454

Immunogenicity and safety of three aluminium hydroxide adjuvanted vaccines with reduced doses of inactivated polio vaccine (IPV-Al) compared with standard IPV in young infants in the Dominican Republic: a phase 2, non-inferiority, observer-blinded, randomised, and controlled dose investigation trial.

PubMed

Rivera, Luis; Pedersen, Rasmus S; Peña, Lourdes; Olsen, Klaus J; Andreasen, Lars V; Kromann, Ingrid; Nielsen, Pernille I; Sørensen, Charlotte; Dietrich, Jes; Bandyopadhyay, Ananda S; Thierry-Carstensen, Birgit

2017-07-01

Cost and supply constraints are key challenges in the use of inactivated polio vaccine (IPV). Dose reduction through adsorption to aluminium hydroxide (Al) is a promising option, and establishing its effectiveness in the target population is a crucial milestone in developing IPV-Al. The aim of this clinical trial was to show the non-inferiority of three IPV-Al vaccines to standard IPV. In this phase 2, non-inferiority, observer-blinded, randomised, controlled, single-centre trial in the Dominican Republic, healthy infants aged 6 weeks, not previously polio vaccinated, were allocated after computer-generated randomisation by block-size of four, to receive one of four IPV formulations (three-times reduced dose [1/3 IPV-Al], five-times reduced dose [1/5 IPV-Al], ten-times reduced dose [1/10 IPV-Al], or IPV) intramuscularly in the thigh at 6, 10, and 14 weeks of age. The primary outcome was seroconversion for poliovirus types 1, 2, and 3 with titres more than or equal to four-fold higher than the estimated maternal antibody titre and more than or equal to 8 after three vaccinations. Non-inferiority was concluded if the lower two-sided 90% CI of the seroconversion rate difference between IPV-Al and IPV was greater than -10%. The safety analyses were based on the safety analysis set (randomly assigned participants who received at least one trial vaccination) and the immunogenicity analyses were based on the per-protocol population. This study is registered with ClinicalTrials.gov registration, number NCT02347423. Between Feb 2, 2015, and Sept 26, 2015, we recruited 824 infants. The per-protocol population included 820 infants; 205 were randomly assigned to receive 1/3 IPV-Al, 205 to receive 1/5 IPV-Al, 204 to receive 1/10 IPV-Al, and 206 to receive IPV. The proportion of individuals meeting the primary endpoint of seroconversion for poliovirus types 1, 2, and 3 was already high for the three IPV-Al vaccines after two vaccinations, but was higher after three vaccinations (ie, after completion of the expanded programme of immunisation schedule): 1/3 IPV-Al 98·5% (n=202, type 1), 97·6% (n=200; type 2), and 99·5% (n=204, type 3); 1/5 IPV-Al: 99·5% (n=204, type 1), 96·1% (n=197, type 2), and 98·5% (n=202, type 3); and 1/10 IPV-Al: 98·5% (n=201, type 1), 94·6% (n=193, type 2), and 99·5% (n=203, type 3). All three IPV-Al were non-inferior to IPV, with absolute differences in percentage seroconversion for each poliovirus type being greater than -10% (1/3 IPV-Al type 1, -1·46 [-3·60 to 0·10], type 2, -0·98 [-3·62 to 1·49], and type 3, -0·49 [-2·16 to 0·86]; 1/5 IPV-Al type 1, -0·49 [-2·16 to 0·86], type 2, -2·45 [-5·47 to 0·27], and type 3, -1·46 [-3·60 to 0·10]; and 1/10 IPV-Al type 1, -1·47 [-3·62 to 0·10], type 2, -3·94 [-7·28 to -0·97], and type 3, -0·49 [-2·17 to 0·86]). Three serious adverse events occurred that were unrelated to the vaccine. The lowest dose (1/10 IPV-Al) of the vaccine performed well both after two and three doses. Based on these results, this new vaccine is under investigation in phase 3 trials. Bill & Melinda Gates Foundation. Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Cost-benefit comparisons of investments in improved water supply and cholera vaccination programs.

PubMed

Jeuland, Marc; Whittington, Dale

2009-05-18

This paper presents the first cost-benefit comparison of improved water supply investments and cholera vaccination programs. Specifically, we compare two water supply interventions -- deep wells with public hand pumps and biosand filters (an in-house, point-of-use water treatment technology) -- with two types of cholera immunization programs with new-generation vaccines -- general community-based and targeted and school-based programs. In addition to these four stand-alone investments, we also analyze five combinations of water and vaccine interventions: (1) borehole+hand pump and community-based cholera vaccination, (2) borehole+hand pump and school-based cholera vaccination, (3) biosand filter and community-based cholera vaccination, (4) biosand filter and school-based cholera vaccination, and (5) biosand filter and borehole+hand pump. Using recent data applicable to developing country locations for parameters such as disease incidence, the effectiveness of vaccine and water supply interventions against diarrheal diseases, and the value of a statistical life, we construct cost-benefit models for evaluating these interventions. We then employ probabilistic sensitivity analysis to estimate a frequency distribution of benefit-cost ratios for all four interventions, given a wide variety of possible parameter combinations. Our results demonstrate that there are many plausible conditions in developing countries under which these interventions will be attractive, but that the two improved water supply interventions and the targeted cholera vaccination program are much more likely to yield attractive cost-benefit outcomes than a community-based vaccination program. We show that implementing community-based cholera vaccination programs after borehole+hand pump or biosand filters have already been installed will rarely be justified. This is especially true when the biosand filters are already in place, because these achieve substantial cholera risk reductions on their own. On the other hand, implementing school-based cholera vaccination programs after the installation of boreholes with hand pump is more likely to be economically attractive. Also, if policymakers were to first invest in cholera vaccinations, then subsequently investing in water interventions is still likely to yield positive economic outcomes. This is because point-of-use water treatment delivers health benefits other than reduced cholera, and deep boreholes+hand pumps often yield non-health benefits such as time savings. However, cholera vaccination programs are much cheaper than the water supply interventions on a household basis. Donors and governments with limited budgets may thus determine that cholera vaccination programs are more equitable than water supply interventions because more people can receive benefits with a given budget. Practical considerations may also favor cholera vaccination programs in the densely crowded slums of South Asian and African cities where there may be insufficient space in housing units for some point-of-use technologies, and where non-networked water supply options are limited.

Matrix-M™ adjuvant enhances immunogenicity of both protein- and modified vaccinia virus Ankara-based influenza vaccines in mice.

PubMed

Magnusson, Sofia E; Altenburg, Arwen F; Bengtsson, Karin Lövgren; Bosman, Fons; de Vries, Rory D; Rimmelzwaan, Guus F; Stertman, Linda

2018-04-01

Influenza viruses continuously circulate in the human population and escape recognition by virus neutralizing antibodies induced by prior infection or vaccination through accumulation of mutations in the surface proteins hemagglutinin (HA) and neuraminidase (NA). Various strategies to develop a vaccine that provides broad protection against different influenza A viruses are under investigation, including use of recombinant (r) viral vectors and adjuvants. The replication-deficient modified vaccinia virus Ankara (MVA) is a promising vaccine vector that efficiently induces B and T cell responses specific for the antigen of interest. It is assumed that live vaccine vectors do not require an adjuvant to be immunogenic as the vector already mediates recruitment and activation of immune cells. To address this topic, BALB/c mice were vaccinated with either protein- or rMVA-based HA influenza vaccines, formulated with or without the saponin-based Matrix-M™ adjuvant. Co-formulation with Matrix-M significantly increased HA vaccine immunogenicity, resulting in antigen-specific humoral and cellular immune responses comparable to those induced by unadjuvanted rMVA-HA. Of special interest, rMVA-HA immunogenicity was also enhanced by addition of Matrix-M, demonstrated by enhanced HA inhibition antibody titres and cellular immune responses. Matrix-M added to either protein- or rMVA-based HA vaccines mediated recruitment and activation of antigen-presenting cells and lymphocytes to the draining lymph node 24 and 48 h post-vaccination. Taken together, these results suggest that adjuvants can be used not only with protein-based vaccines but also in combination with rMVA to increase vaccine immunogenicity, which may be a step forward to generate new and more effective influenza vaccines.

Expedient Route To Access Rare Deoxy Amino l-Sugar Building Blocks for the Assembly of Bacterial Glycoconjugates.

PubMed

Sanapala, Someswara Rao; Kulkarni, Suvarn S

2016-04-13

Bacterial glycoproteins and oligosaccharides contain several rare deoxy amino l-sugars which are virtually absent in the human cells. This structural difference between the bacterial and host cell surface glycans can be exploited for the development of carbohydrate based vaccines and target specific drugs. However, the unusual deoxy amino l-sugars present in the bacterial glycoconjugates are not available from natural sources. Thus, procurement of orthogonally protected rare l-sugar building blocks through efficient chemical synthesis is a crucial step toward the synthesis of structurally well-defined and homogeneous complex glycans. Herein, we report a general and expedient methodology to access a variety of unusual deoxy amino l-sugars starting from readily available l-rhamnose and l-fucose via highly regioselective, one-pot double serial and double parallel displacements of the corresponding 2,4-bistriflates using azide and nitrite anions as nucleophiles. Alternatively, regioselective monotriflation at O2, O3, and O4 of l-rhamnose/l-fucose allowed selective inversions at respective positions leading to diverse rare sugars. The orthogonally protected deoxy amino l-sugar building blocks could be stereoselectively assembled to obtain biologically relevant bacterial O-glycans, as exemplified by the first total synthesis of the amino linker-attached, conjugation-ready tetrasaccharide of O-PS of Yersinia enterocolitica O:50 strain 3229 and the trisaccharide of Pseudomonas chlororaphis subsp. aureofaciens strain M71.

A highly pathogenic porcine reproductive and respiratory syndrome virus candidate vaccine based on Japanese encephalitis virus replicon system

PubMed Central

Huang, Lihong; Liu, Shukai; Zang, Fuyu; Xing, Jinchao; Zhang, Youyue; Liang, Jiaqi; Zhang, Guihong

2017-01-01

In the swine industry, porcine reproductive and respiratory syndrome (PRRS) is a highly contagious disease which causes heavy economic losses worldwide. Effective prevention and disease control is an important issue. In this study, we described the construction of a Japanese encephalitis virus (JEV) DNA-based replicon with a cytomegalovirus (CMV) promoter based on the genome of Japanese encephalitis live vaccine virus SA14-14-2, which is capable of offering a potentially novel way to develop and produce vaccines against a major pathogen of global health. This JEV DNA-based replicon contains a large deletion in the structural genes (C-prM-E). A PRRSV GP5/M was inserted into the deletion position of JEV DNA-based replicons to develop a chimeric replicon vaccine candidate for PRRSV. The results showed that BALB/c mice models with the replicon vaccines pJEV-REP-G-2A-M-IRES and pJEV-REP-G-2A-M stimulated antibody responses and induced a cellular immune response. Analysis of ELSA data showed that vaccination with the replicon vaccine expressing GP5/M induced a better antibodies response than traditional DNA vaccines. Therefore, the results suggested that this ectopic expression system based on JEV DNA-based replicons may represent a useful molecular platform for various biological applications, and the JEV DNA-based replicons expressing GP5/M can be further developed into a novel, safe vaccine candidate for PRRS. PMID:28740748

Barriers to and facilitators of child influenza vaccine - perspectives from parents, teens, marketing and healthcare professionals.

PubMed

Bhat-Schelbert, Kavitha; Lin, Chyongchiou Jeng; Matambanadzo, Annamore; Hannibal, Kristin; Nowalk, Mary Patricia; Zimmerman, Richard K

2012-03-23

The CDC recommends annual influenza vaccination for all children age 6 months and older, yet vaccination rates remain modest. Effective strategies to improve influenza vaccination for children are needed. Eight focus groups with 91 parents, teens, pediatric healthcare staff and providers, and immunization and marketing experts were conducted, audiotaped, transcribed verbatim, and coded based on grounded theory. Three themes emerged: barriers, facilitators, and strategies. Barriers included fear, misinformation, and mistrust, with exacerbation of these barriers attributed to media messages. Many considered influenza vaccination unnecessary and inconvenient, but would accept vaccination if recipients or other family members were considered high risk, if recommended by their doctor or another trusted person, or if offered or mandated by the school. Access to better information regarding influenza disease burden and vaccine safety and efficacy were notable facilitators, as were prevention of the inconvenience of missing work or important events, and if the child requests to receive the vaccine. Marketing strategies included incentives, jingles, videos, wearable items, strategically-located information sheets or posters, and promotion by informed counselors. Practice-based strategies included staff buy-in, standing orders protocols, vaccination clinics, and educational videos. Teen-specific strategies included message delivery through schools, texting, internet, and social networking sites. To improve influenza vaccination rates for children using practice-based interventions, participants suggested campaigns that provide better information regarding the vaccine, the disease and its implications, and convenient access to vaccination. Strategies targeting adolescents should use web-based social marketing technologies and campaigns based in schools. Copyright © 2012 Elsevier Ltd. All rights reserved.

Rational design of gene-based vaccines.

PubMed

Barouch, Dan H

2006-01-01

Vaccine development has traditionally been an empirical discipline. Classical vaccine strategies include the development of attenuated organisms, whole killed organisms, and protein subunits, followed by empirical optimization and iterative improvements. While these strategies have been remarkably successful for a wide variety of viruses and bacteria, these approaches have proven more limited for pathogens that require cellular immune responses for their control. In this review, current strategies to develop and optimize gene-based vaccines are described, with an emphasis on novel approaches to improve plasmid DNA vaccines and recombinant adenovirus vector-based vaccines. Copyright 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Recombinant vesicular stomatitis virus-based vaccines against Ebola and Marburg virus infections.

PubMed

Geisbert, Thomas W; Feldmann, Heinz

2011-11-01

The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with a high mortality rate in humans and nonhuman primates. Among the most-promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Importantly, a single injection of blended rVSV-based filovirus vaccines was shown to completely protect nonhuman primates against Marburg virus and 3 different species of Ebola virus. These rVSV-based vaccines have also shown utility when administered as a postexposure treatment against filovirus infections, and a rVSV-based Ebola virus vaccine was recently used to treat a potential laboratory exposure. Here, we review the history of rVSV-based vaccines and pivotal animal studies showing their utility in combating Ebola and Marburg virus infections.

Recombinant Vesicular Stomatitis Virus–Based Vaccines Against Ebola and Marburg Virus Infections

PubMed Central

Feldmann, Heinz

2011-01-01

The filoviruses, Marburg virus and Ebola virus, cause severe hemorrhagic fever with a high mortality rate in humans and nonhuman primates. Among the most-promising filovirus vaccines under development is a system based on recombinant vesicular stomatitis virus (rVSV) that expresses a single filovirus glycoprotein (GP) in place of the VSV glycoprotein (G). Importantly, a single injection of blended rVSV-based filovirus vaccines was shown to completely protect nonhuman primates against Marburg virus and 3 different species of Ebola virus. These rVSV-based vaccines have also shown utility when administered as a postexposure treatment against filovirus infections, and a rVSV-based Ebola virus vaccine was recently used to treat a potential laboratory exposure. Here, we review the history of rVSV-based vaccines and pivotal animal studies showing their utility in combating Ebola and Marburg virus infections. PMID:21987744

A PCV2 vaccine based on genotype 2b is more effective than a 2a-based vaccine to protect against PCV2b or combined PCV2a/2b viremia in pigs with concurrent PCV2, PRRSV and PPV infection.

PubMed

Opriessnig, Tanja; O'Neill, Kevin; Gerber, Priscilla F; de Castro, Alessandra M M G; Gimenéz-Lirola, Luis G; Beach, Nathan M; Zhou, Lei; Meng, Xiang-Jin; Wang, Chong; Halbur, Patrick G

2013-01-07

The predominant genotype of porcine circovirus (PCV) in the pig population today is PCV2b yet PCV2a-based commercial vaccines are considered effective in protecting against porcine circovirus associated disease. The objective of this study was to compare the ability of PCV2a- and PCV2b-based vaccines to control PCV2b viremia in a challenge model that mimics the U.S. field situation. Sixty-three pigs were randomly assigned to one of eight groups. Sixteen pigs were vaccinated with an experimental live-attenuated chimeric PCV1-2a vaccine based on genotype 2a and another 16 pigs with a chimeric PCV1-2b vaccine based on genotype 2b. Challenge was done 28 days post vaccination (dpv) using PCV2b (or a combination of PCV2a and PCV2b), porcine reproductive and respiratory syndrome virus (PRRSV), and porcine parvovirus (PPV) to mimic what commonly occurs in the field. The experiment was terminated 21 days post challenge (dpc) or 49dpv. Pigs vaccinated with the chimeric PCV1-2b vaccine had significantly higher levels of PCV1-2b viremia and shedding of the PCV1-2b vaccine virus in feces and nasal secretions but also a more robust humoral immune response as evidenced by significantly higher ELISA S/P ratios compared to the PCV1-2a vaccination. Regardless of challenge, the PCV1-2b vaccination significantly reduced the prevalence and amount of PCV2 viremia compared to the PCV1-2a vaccination. Interestingly, in the non-vaccinated pigs concurrent PCV2a infection resulted in clinical disease and increased macroscopic lung lesions compared to pigs challenged with PCV2b alone, further supporting the idea that concurrent PCV2a/PCV2b infection is necessary for optimal PCV2 replication. Copyright © 2012 Elsevier Ltd. All rights reserved.

A history of adolescent school based vaccination in Australia.

PubMed

Ward, Kirsten; Quinn, Helen; Menzies, Robert; McIntyre, Peter

2013-06-30

As adolescents have become an increasingly prominent target group for vaccination, school-based vaccination has emerged as an efficient and effective method of delivering nationally recommended vaccines to this often hard to reach group. School-based delivery of vaccines has occurred in Australia for over 80 years and has demonstrated advantages over primary care delivery for this part of the population. In the last decade school-based vaccination programs have become routine practice across all Australian states and territories. Using existing records and the recollection of experts we have compiled a history of school-based vaccination in Australia, primarily focusing on adolescents. This work is copyright. Apart from any use as permitted under the Copyright Act 1968, no part may be reproduced by any process without prior written permission from the Commonwealth. Requests and inquiries concerning reproduction and rights should be addressed to the Commonwealth Copyright Administration, Attorney General's Department, Robert Garran Offices, National Circuit, Barton ACT 2600 or posted at http://www.ag.gov.au/cca.

Evidence based vaccinology.

PubMed

Nalin, David R

2002-02-22

Evidence based vaccinology (EBV) is the identification and use of the best evidence in making and implementing decisions during all of the stages of the life of a vaccine, including pre-licensure vaccine development and post-licensure manufacture and research, and utilization of the vaccine for disease control. Vaccines, unlike most pharmaceuticals, are in a continuous process of development both before and after licensure. Changes in biologics manufacturing technology and changes that vaccines induce in population and disease biology lead to periodic review of regimens (and sometimes dosage) based on changing immunologic data or public perceptions relevant to vaccine safety and effectiveness. EBV includes the use of evidence based medicine (EBM) both in clinical trials and in national disease containment programs. The rationale for EBV is that the highest evidentiary standards are required to maintain a rigorous scientific basis of vaccine quality control in manufacture and to ensure valid determination of vaccine efficacy, field effectiveness and safety profiles (including post-licensure safety monitoring), cost-benefit analyses, and risk:benefit ratios. EBV is increasingly based on statistically validated, clearly defined laboratory, manufacturing, clinical and epidemiological research methods and procedures, codified as good laboratory practices (GLP), good manufacturing practices (GMP), good clinical research practices (GCRP) and in clinical and public health practice (good vaccination practices, GVP). Implementation demands many data-driven decisions made by a spectrum of specialists pre- and post-licensure, and is essential to maintaining public confidence in vaccines.

The Web-Based DNA Vaccine Database DNAVaxDB and Its Usage for Rational DNA Vaccine Design.

PubMed

Racz, Rebecca; He, Yongqun

2016-01-01

A DNA vaccine is a vaccine that uses a mammalian expression vector to express one or more protein antigens and is administered in vivo to induce an adaptive immune response. Since the 1990s, a significant amount of research has been performed on DNA vaccines and the mechanisms behind them. To meet the needs of the DNA vaccine research community, we created DNAVaxDB ( http://www.violinet.org/dnavaxdb ), the first Web-based database and analysis resource of experimentally verified DNA vaccines. All the data in DNAVaxDB, which includes plasmids, antigens, vaccines, and sources, is manually curated and experimentally verified. This chapter goes over the detail of DNAVaxDB system and shows how the DNA vaccine database, combined with the Vaxign vaccine design tool, can be used for rational design of a DNA vaccine against a pathogen, such as Mycobacterium bovis.

A clinical trial examining the effect of increased total CRM(197) carrier protein dose on the antibody response to Haemophilus influenzae type b CRM(197) conjugate vaccine.

PubMed

Usonis, Vytautas; Bakasenas, Vytautas; Lockhart, Stephen; Baker, Sherryl; Gruber, William; Laudat, France

2008-08-18

CRM(197) is a carrier protein in certain conjugate vaccines. When multiple conjugate vaccines with the same carrier protein are administered simultaneously, reduced response to vaccines and/or antigens related to the carrier protein may occur. This study examined responses of infants who, in addition to diphtheria toxoid/tetanus toxoid/acellular pertussis vaccine (DTaP) received either diphtheria CRM(197)-based Haemophilus influenzae type b conjugate vaccine (HbOC) or HbOC and a diphtheria CRM(197)-based combination 9-valent pneumococcal conjugate vaccine/meningococcal group C conjugate vaccine. Administration of conjugate vaccines with CRM(197) carrier protein load >50 microg did not reduce response to CRM(197) conjugate vaccines or immunogenicity to immunologically cross-reactive diphtheria toxoid.

DNA vaccines: roles against diseases

PubMed Central

Khan, Kishwar Hayat

2013-01-01

Vaccination is the most successful application of immunological principles to human health. Vaccine efficacy needs to be reviewed from time to time and its safety is an overriding consideration. DNA vaccines offer simple yet effective means of inducing broad-based immunity. These vaccines work by allowing the expression of the microbial antigen inside host cells that take up the plasmid. These vaccines function by generating the desired antigen inside the cells, with the advantage that this may facilitate presentation through the major histocompatibility complex. This review article is based on a literature survey and it describes the working and designing strategies of DNA vaccines. Advantages and disadvantages for this type of vaccines have also been explained, together with applications of DNA vaccines. DNA vaccines against cancer, tuberculosis, Edwardsiella tarda, HIV, anthrax, influenza, malaria, dengue, typhoid and other diseases were explored. PMID:24432284

5 year efficacy of a bivalent killed whole-cell oral cholera vaccine in Kolkata, India: a cluster-randomised, double-blind, placebo-controlled trial.

PubMed

Bhattacharya, Sujit K; Sur, Dipika; Ali, Mohammad; Kanungo, Suman; You, Young Ae; Manna, Byomkesh; Sah, Binod; Niyogi, Swapan K; Park, Jin Kyung; Sarkar, Banwarilal; Puri, Mahesh K; Kim, Deok Ryun; Deen, Jacqueline L; Holmgren, Jan; Carbis, Rodney; Dhingra, Mandeep Singh; Donner, Allan; Nair, G Balakrish; Lopez, Anna Lena; Wierzba, Thomas F; Clemens, John D

2013-12-01

Efficacy and safety of a two-dose regimen of bivalent killed whole-cell oral cholera vaccine (Shantha Biotechnics, Hyderabad, India) to 3 years is established, but long-term efficacy is not. We aimed to assess protective efficacy up to 5 years in a slum area of Kolkata, India. In our double-blind, cluster-randomised, placebo-controlled trial, we assessed incidence of cholera in non-pregnant individuals older than 1 year residing in 3933 dwellings (clusters) in Kolkata, India. We randomly allocated participants, by dwelling, to receive two oral doses of modified killed bivalent whole-cell cholera vaccine or heat-killed Escherichia coli K12 placebo, 14 days apart. Randomisation was done by use of a computer-generated sequence in blocks of four. The primary endpoint was prevention of episodes of culture-confirmed Vibrio cholerae O1 diarrhoea severe enough for patients to seek treatment in a health-care facility. We identified culture-confirmed cholera cases among participants seeking treatment for diarrhoea at a study clinic or government hospital between 14 days and 1825 days after receipt of the second dose. We assessed vaccine protection in a per-protocol population of participants who had completely ingested two doses of assigned study treatment. 69 of 31 932 recipients of vaccine and 219 of 34 968 recipients of placebo developed cholera during 5 year follow-up (incidence 2·2 per 1000 in the vaccine group and 6·3 per 1000 in the placebo group). Cumulative protective efficacy of the vaccine at 5 years was 65% (95% CI 52-74; p<0·0001), and point estimates by year of follow-up suggested no evidence of decline in protective efficacy. Sustained protection for 5 years at the level we reported has not been noted previously with other oral cholera vaccines. Established long-term efficacy of this vaccine could assist policy makers formulate rational vaccination strategies to reduce overall cholera burden in endemic settings. Bill & Melinda Gates Foundation and the governments of South Korea and Sweden. Copyright © 2013 Elsevier Ltd. All rights reserved.

Clarification of vaccines: An overview of filter based technology trends and best practices.

PubMed

Besnard, Lise; Fabre, Virginie; Fettig, Michael; Gousseinov, Elina; Kawakami, Yasuhiro; Laroudie, Nicolas; Scanlan, Claire; Pattnaik, Priyabrata

2016-01-01

Vaccines are derived from a variety of sources including tissue extracts, bacterial cells, virus particles, recombinant mammalian, yeast and insect cell produced proteins and nucleic acids. The most common method of vaccine production is based on an initial fermentation process followed by purification. Production of vaccines is a complex process involving many different steps and processes. Selection of the appropriate purification method is critical to achieving desired purity of the final product. Clarification of vaccines is a critical step that strongly impacts product recovery and subsequent downstream purification. There are several technologies that can be applied for vaccine clarification. Selection of a harvesting method and equipment depends on the type of cells, product being harvested, and properties of the process fluids. These techniques include membrane filtration (microfiltration, tangential-flow filtration), centrifugation, and depth filtration (normal flow filtration). Historically vaccine harvest clarification was usually achieved by centrifugation followed by depth filtration. Recently membrane based technologies have gained prominence in vaccine clarification. The increasing use of single-use technologies in upstream processes necessitated a shift in harvest strategies. This review offers a comprehensive view on different membrane based technologies and their application in vaccine clarification, outlines the challenges involved and presents the current state of best practices in the clarification of vaccines. Copyright © 2015 Elsevier Inc. All rights reserved.

A new intranasal influenza vaccine based on a novel polycationic lipid-ceramide carbamoyl-spermine (CCS). II. Studies in mice and ferrets and mechanism of adjuvanticity.

PubMed

Even-Or, Orli; Joseph, Aviva; Itskovitz-Cooper, Noga; Samira, Sarit; Rochlin, Eli; Eliyahu, Hagit; Goldwaser, Itzik; Balasingam, Shobana; Mann, Alex J; Lambkin-Williams, Rob; Kedar, Eli; Barenholz, Yechezkel

2011-03-16

We recently showed that lipid assemblies comprised of a novel polycationic sphingolipid (ceramide carbamoyl-spermine, CCS) are an effective adjuvant/carrier when complexed with cholesterol (CCS/C) for influenza and other vaccines administered parenterally and intranasally (i.n.) in mice. Here we expand these studies to ferrets, an established model of influenza infection. We also address the question of why the CCS/C-based liposomal vaccine (also known as VaxiSome™) in mice is superior to vaccines based on liposomes of other lipid compositions (neutral, anionic or cationic). Ferrets immunized i.n. with CCS/C-influenza vaccine produced significantly higher hemagglutination inhibition (HI) antibody titers compared to ferrets immunized intramuscularly with the unadjuvanted influenza vaccine, indicating that the CCS/C-based vaccine is very immunogenic. Furthermore, the i.n. adjuvanted vaccine was shown to significantly reduce the severity of influenza virus infection in ferrets following homologous viral challenge as determined by weight loss, temperature rise and viral titer. No adverse reactions were observed. Pharmacokinetic and biodistribution studies following i.n. administration in mice of CCS/C-based vaccine showed that both the lipids and antigens are retained in the nose and lung for at least 24h, and it appears that this retention correlates with the superior immunogenicity elicited by the adjuvanted vaccine formulation. The CCS lipid also increases production of cytokines (mainly IFN gamma, IL-2 and IL-12) and co-stimulatory molecules' expression, which might further explain the robust adjuvantation of this liposome-based vaccine. Copyright © 2011 Elsevier Ltd. All rights reserved.

Impact of a website based educational program for increasing vaccination coverage among adolescents.

PubMed

Esposito, Susanna; Bianchini, Sonia; Tagliabue, Claudia; Umbrello, Giulia; Madini, Barbara; Di Pietro, Giada; Principi, Nicola

2018-04-03

Data regarding the use of technology to improve adolescent knowledge on vaccines are scarce. The main aim of this study was to evaluate whether different web-based educational programmes for adolescents might increase their vaccination coverage. Overall, 917 unvaccinated adolescents (389 males, 42.4%; mean age ± standard deviation, 14.0 ± 2.2 years) were randomized 1:1:1 into the following groups: no intervention (n = 334), website educational program only (n = 281), or website plus face to face lesson (n = 302) groups. The use of the website plus the lesson significantly increased the overall knowledge of various aspects of vaccine-preventable disease and reduced the fear of vaccines (p < 0.001). A significant increase in vaccination coverage was observed for tetanus, diphtheria, acellular pertussis and conjugated meningococcal ACYW vaccines in the 2 groups using the website (p < 0.001), and better results were observed in the group that had also received the lesson; in this last group, significant results were observed in the increase in vaccination coverage for meningococcal B vaccine (p < 0.001). Overall, the majority of the participants liked the experience of the website, although they considered it important to further discuss vaccines with parents, experts and teachers. This study is the first to evaluate website based education of adolescents while considering all of the vaccines recommended for this age group. Our results demonstrate the possibility of increasing vaccination coverage by using a website based educational program with tailored information. However, to be most effective, this program should be supplemented with face-to-face discussions of vaccines at school and at home. Thus, specific education should also include teachers and parents so that they will be prepared to discuss with adolescents what is true and false in the vaccination field.

Hexavalent IPV-based combination vaccines for public-sector markets of low-resource countries

PubMed Central

Mahmood, Kutub; Pelkowski, Sonia; Atherly, Deborah; Sitrin, Robert; Donnelly, John J

2013-01-01

In anticipation of the successful eradication of wild polio virus, alternative vaccination strategies for public-sector markets of low-resource countries are extremely important, but are still under development. Following polio eradication, inactivated polio vaccine (IPV) would be the only polio vaccine available, and would be needed for early childhood immunization for several years, as maintenance of herd immunity will be important for sustaining polio eradication. Low-cost combination vaccines containing IPV could provide reliable and continuous immunization in the post-polio eradication period. Combination vaccines can potentially simplify complex pediatric routine immunization schedules, improve compliance, and reduce costs. Hexavalent vaccines containing Diphtheria (D), Tetanus (T), whole cell pertussis (wP), Hepatitis B (HBV), Haemophilus b (Hib) and the three IPV serotype antigens have been considered as the ultimate combination vaccine for routine immunization. This product review evaluates potential hexavalent vaccine candidates by composition, probable time to market, expected cost of goods, presentation, and technical feasibility and offers suggestions for development of low-cost hexavalent combination vaccines. Because there are significant technical challenges facing wP-based hexavalent vaccine development, this review also discusses other alternative approaches to hexavalent that could also ensure a timely and reliable supply of low-cost IPV based combination vaccines. PMID:23787559

Can dendritic cells improve whole cancer cell vaccines based on immunogenically killed cancer cells?

PubMed Central

Cicchelero, Laetitia; Denies, Sofie; Devriendt, Bert; de Rooster, Hilde; Sanders, Niek N

2015-01-01

Immunogenic cell death (ICD) offers interesting opportunities in cancer cell (CC) vaccine manufacture, as it increases the immunogenicity of the dead CC. Furthermore, fusion of CCs with dendritic cells (DCs) is considered a superior method for generating whole CC vaccines. Therefore, in this work, we determined in naive mice whether immunogenically killed CCs per se (CC vaccine) elicit an antitumoral immune response different from the response observed when immunogenically killed CCs are associated with DCs through fusion (fusion vaccine) or through co-incubation (co-incubation vaccine). After tumor inoculation, the type of immune response in the prophylactically vaccinated mice differed between the groups. In more detail, fusion vaccines elicited a humoral anticancer response, whereas the co-incubation and CC vaccine mainly induced a cellular response. Despite these differences, all three approaches offered a prophylactic protection against tumor development in the murine mammary carcinoma model. In summary, it can be concluded that whole CC vaccines based on immunogenically killed CCs may not necessarily require association with DCs to elicit a protective anticancer immune response. If this finding can be endorsed in other cancer models, the manufacture of CC vaccines would greatly benefit from this new insight, as production of DC-based vaccines is laborious, time-consuming and expensive. PMID:26587315

Plant-made vaccines against West Nile virus are potent, safe, and economically feasible

PubMed Central

Chen, Qiang

2015-01-01

The threat of West Nile virus (WNV) epidemics with increasingly severe neuroinvasive infections demands the development and licensing of effective vaccines. To date, vaccine candidates based on inactivated, live-attenuated, or chimeric virus, and viral DNA and WNV protein subunits have been developed. Some have been approved for veterinary use or are under clinical investigation, yet no vaccine has been licensed for human use. Reaching the milestone of a commercialized human vaccine, however, may largely depend on the economics of vaccine production. Analysis suggests that currently only novel low-cost production technologies would allow vaccination to outcompete the cost of surveillance and clinical treatment. Here, we review progress using plants to address the economic challenges of WNV vaccine production. The advantages of plants as hosts for vaccine production in cost, speed and scalability, especially those of viral vector-based transient expression systems, are discussed. The progress in developing WNV subunit vaccines in plants is reviewed within the context of their expression, characterization, downstream processing, and immunogenicity in animal models. The development of vaccines based on enveloped and non-enveloped virus-like particles is also discussed. These advancements suggest that plants may provide a production platform that offers potent, safe and affordable human vaccines against WNV. PMID:25676782

Hexavalent IPV-based combination vaccines for public-sector markets of low-resource countries.

PubMed

Mahmood, Kutub; Pelkowski, Sonia; Atherly, Deborah; Sitrin, Robert D; Donnelly, John J

2013-09-01

In anticipation of the successful eradication of wild polio virus, alternative vaccination strategies for public-sector markets of low-resource countries are extremely important, but are still under development. Following polio eradication, inactivated polio vaccine (IPV) would be the only polio vaccine available, and would be needed for early childhood immunization for several years, as maintenance of herd immunity will be important for sustaining polio eradication. Low-cost combination vaccines containing IPV could provide reliable and continuous immunization in the post-polio eradication period. Combination vaccines can potentially simplify complex pediatric routine immunization schedules, improve compliance, and reduce costs. Hexavalent vaccines containing Diphtheria (D), Tetanus (T), whole cell pertussis (wP), Hepatitis B (HBV), Haemophilus b (Hib) and the three IPV serotype antigens have been considered as the ultimate combination vaccine for routine immunization. This product review evaluates potential hexavalent vaccine candidates by composition, probable time to market, expected cost of goods, presentation, and technical feasibility and offers suggestions for development of low-cost hexavalent combination vaccines. Because there are significant technical challenges facing wP-based hexavalent vaccine development, this review also discusses other alternative approaches to hexavalent that could also ensure a timely and reliable supply of low-cost IPV based combination vaccines.

Plant-made vaccines against West Nile virus are potent, safe, and economically feasible.

PubMed

Chen, Qiang

2015-05-01

The threat of West Nile virus (WNV) epidemics with increasingly severe neuroinvasive infections demands the development and licensing of effective vaccines. To date, vaccine candidates based on inactivated, live-attenuated, or chimeric virus, and viral DNA and WNV protein subunits have been developed. Some have been approved for veterinary use or are under clinical investigation, yet no vaccine has been licensed for human use. Reaching the milestone of a commercialized human vaccine, however, may largely depend on the economics of vaccine production. Analysis suggests that currently only novel low-cost production technologies would allow vaccination to outcompete the cost of surveillance and clinical treatment. Here, we review progress using plants to address the economic challenges of WNV vaccine production. The advantages of plants as hosts for vaccine production in cost, speed and scalability, especially those of viral vector-based transient expression systems, are discussed. The progress in developing WNV subunit vaccines in plants is reviewed within the context of their expression, characterization, downstream processing, and immunogenicity in animal models. The development of vaccines based on enveloped and non-enveloped virus-like particles is also discussed. These advancements suggest that plants may provide a production platform that offers potent, safe and affordable human vaccines against WNV. Copyright © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Control of poultry coccidiosis: changing trends.

PubMed

Tewari, A K; Maharana, B R

2011-06-01

Coccidiosis is the most important protozoan disease affecting the poultry industry worldwide. Control of poultry coccidiosis is presently based on managerial skills and the use of prophylactic coccidiostatic drugs. With the emergence of drug resistant Eimeria strains, emphasis has been laid on development and use of safer vaccines; some of them have been commercialized successfully. The present review deals with the various factors responsible for the development of clinical coccidiosis in poultry as well as an overview of the currently available inducers and boosters of immunity against coccidiosis. There are three groups of vaccines currently available against coccidiosis which can be distinguished on the basis of characteristics of the Eimeria species included in the respective products, viz. vaccines based on live virulent strains, vaccines based on live attenuated strains, and vaccines based on live strains that are relatively tolerant to the ionophore compounds. The latter vaccine combines the early chemotherapeutic effect of ionophores with the late prophylactic effect of vaccination. Although in the near future more varieties of oocyst based live vaccines are expected, identification of selective coccidian-specific immunoprotective molecules is likely to get more attention to facilitate the sustainable control of poultry coccidiosis.

Vesicular stomatitis virus-based vaccines protect nonhuman primates against Bundibugyo ebolavirus.

PubMed

Mire, Chad E; Geisbert, Joan B; Marzi, Andrea; Agans, Krystle N; Feldmann, Heinz; Geisbert, Thomas W

2013-01-01

Ebola virus (EBOV) causes severe and often fatal hemorrhagic fever in humans and nonhuman primates (NHPs). Currently, there are no licensed vaccines or therapeutics for human use. Recombinant vesicular stomatitis virus (rVSV)-based vaccine vectors, which encode an EBOV glycoprotein in place of the VSV glycoprotein, have shown 100% efficacy against homologous Sudan ebolavirus (SEBOV) or Zaire ebolavirus (ZEBOV) challenge in NHPs. In addition, a single injection of a blend of three rVSV vectors completely protected NHPs against challenge with SEBOV, ZEBOV, the former Côte d'Ivoire ebolavirus, and Marburg virus. However, recent studies suggest that complete protection against the newly discovered Bundibugyo ebolavirus (BEBOV) using several different heterologous filovirus vaccines is more difficult and presents a new challenge. As BEBOV caused nearly 50% mortality in a recent outbreak any filovirus vaccine advanced for human use must be able to protect against this new species. Here, we evaluated several different strategies against BEBOV using rVSV-based vaccines. Groups of cynomolgus macaques were vaccinated with a single injection of a homologous BEBOV vaccine, a single injection of a blended heterologous vaccine (SEBOV/ZEBOV), or a prime-boost using heterologous SEBOV and ZEBOV vectors. Animals were challenged with BEBOV 29-36 days after initial vaccination. Macaques vaccinated with the homologous BEBOV vaccine or the prime-boost showed no overt signs of illness and survived challenge. In contrast, animals vaccinated with the heterologous blended vaccine and unvaccinated control animals developed severe clinical symptoms consistent with BEBOV infection with 2 of 3 animals in each group succumbing. These data show that complete protection against BEBOV will likely require incorporation of BEBOV glycoprotein into the vaccine or employment of a prime-boost regimen. Fortunately, our results demonstrate that heterologous rVSV-based filovirus vaccine vectors employed in the prime-boost approach can provide protection against BEBOV using an abbreviated regimen, which may have utility in outbreak settings.

Optimal H1N1 vaccination strategies based on self-interest versus group interest.

PubMed

Shim, Eunha; Meyers, Lauren Ancel; Galvani, Alison P

2011-02-25

Influenza vaccination is vital for reducing H1N1 infection-mediated morbidity and mortality. To reduce transmission and achieve herd immunity during the initial 2009-2010 pandemic season, the US Centers for Disease Control and Prevention (CDC) recommended that initial priority for H1N1 vaccines be given to individuals under age 25, as these individuals are more likely to spread influenza than older adults. However, due to significant delay in vaccine delivery for the H1N1 influenza pandemic, a large fraction of population was exposed to the H1N1 virus and thereby obtained immunity prior to the wide availability of vaccines. This exposure affects the spread of the disease and needs to be considered when prioritizing vaccine distribution. To determine optimal H1N1 vaccine distributions based on individual self-interest versus population interest, we constructed a game theoretical age-structured model of influenza transmission and considered the impact of delayed vaccination. Our results indicate that if individuals decide to vaccinate according to self-interest, the resulting optimal vaccination strategy would prioritize adults of age 25 to 49 followed by either preschool-age children before the pandemic peak or older adults (age 50-64) at the pandemic peak. In contrast, the vaccine allocation strategy that is optimal for the population as a whole would prioritize individuals of ages 5 to 64 to curb a growing pandemic regardless of the timing of the vaccination program. Our results indicate that for a delayed vaccine distribution, the priorities that are optimal at a population level do not align with those that are optimal according to individual self-interest. Moreover, the discordance between the optimal vaccine distributions based on individual self-interest and those based on population interest is even more pronounced when vaccine availability is delayed. To determine optimal vaccine allocation for pandemic influenza, public health agencies need to consider both the changes in infection risks among age groups and expected patterns of adherence.

'It's a logistical nightmare!' Recommendations for optimising human papillomavirus school-based vaccination experience.

PubMed

Robbins, Spring Chenoa Cooper; Bernard, Diana; McCaffery, Kirsten; Skinner, S Rachel

2010-09-01

To date, no published studies examine procedural factors of the school-based human papillomavirus (HPV) vaccination program from the perspective of those involved. This study examines the factors that were perceived to impact optimal vaccination experience. Schools across Sydney were selected to reflect a range of vaccination coverage at the school level and different school types to ensure a range of experiences. Semi-structured focus groups were conducted with girls; and one-on-one interviews were undertaken with parents, teachers and nurses until saturation of data in all emergent themes was reached. Focus groups and interviews explored participants' experiences in school-based HPV vaccination. Transcripts were analysed, letting themes emerge. Themes related to participants' experience of the organisational, logistical and procedural aspects of the vaccination program and their perceptions of an optimal process were organised into two categories: (1) preparation for the vaccination program and (2) vaccination day strategies. In (1), themes emerged regarding commitment to the process from those involved, planning time and space for vaccinations, communication within and between agencies, and flexibility. In (2), themes included vaccinating the most anxious girls first, facilitating peer support, use of distraction techniques, minimising waiting time girls, and support staff. A range of views exists on what constitutes an optimal school-based program. Several findings were identified that should be considered in the development of guidelines for implementing school-based programs. Future research should evaluate how different approaches to acquiring parental consent, and the use of anxiety and fear reduction strategies impact experience and uptake in the school-based setting.

Challenges for Serology-Based Characterization of Foot-and-Mouth Disease Outbreaks in Endemic Areas; Identification of Two Separate Lineages of Serotype O FMDV in Uganda in 2011.

PubMed

Namatovu, A; Belsham, G J; Ayebazibwe, C; Dhikusooka, M T; Wekesa, S N; Siegismund, H R; Muwanika, V B; Tjørnehøj, K

2015-10-01

Control of foot-and-mouth disease (FMD) in Uganda by ring vaccination largely depends on costly trivalent vaccines, and use of monovalent vaccines could improve the cost effectiveness. This, however, requires application of highly specific diagnostic tests. This study investigated outbreaks of FMD in seven Ugandan districts, during 2011, using the PrioCHECK® FMDV NS ELISA, solid-phase blocking ELISAs (SPBEs) and virus neutralization tests (VNTs), together with virological analyses for characterization of the responsible viruses. Two hundred and eighteen (218) cattle and 23 goat sera as well as 82 oropharyngeal fluid/epithelial tissue samples were collected. Some 50% of the cattle and 17% of the goat sera were positive by the PrioCHECK® FMDV NS ELISA, while SPBEs identified titres ≥80 for antibodies against serotype O FMD virus (FMDV) in 51% of the anti-NSP positive cattle sera. However, 35% of the anti-NSP positive cattle sera had SPBE titres ≥80 against multiple serotypes, primarily against serotypes O, SAT 1 and SAT 3. Comparison of SPBEs and VNTs for the detection of antibodies against serotypes O, SAT 1 and SAT 3 in 72 NSP positive cattle sera showed comparable results against serotype O (P = 0.181), while VNTs detected significantly fewer samples positive for antibodies against SAT 1 and SAT 3 than the SPBEs (P < 0.001). Detection of antibodies against serotype O was consistent with the isolation of serotype O FMDVs from 13 samples. Four of these viruses were sequenced and belonged to two distinct lineages within the East Africa-2 (EA-2) topotype, each differing from the currently used vaccine strain (EA-1 topotype). The relationships of these lineages to other serotype O viruses in the Eastern Africa region are discussed. To enhance the control of FMD in Uganda, there is need to improve the specificity of the SAT-SPBEs, perform vaccine matching and implement improved regional FMD control. © 2013 Blackwell Verlag GmbH.

Emerging Bordetella pertussis Strains Induce Enhanced Signaling of Human Pattern Recognition Receptors TLR2, NOD2 and Secretion of IL-10 by Dendritic Cells

PubMed Central

Hovingh, Elise S.; van Gent, Marjolein; Hamstra, Hendrik-Jan; Demkes, Marc; Mooi, Frits R.; Pinelli, Elena

2017-01-01

Vaccines against pertussis have been available for more than 60 years. Nonetheless, this highly contagious disease is reemerging even in countries with high vaccination coverage. Genetic changes of Bordetella pertussis over time have been suggested to contribute to the resurgence of pertussis, as these changes may favor escape from vaccine-induced immunity. Nonetheless, studies on the effects of these bacterial changes on the immune response are limited. Here, we characterize innate immune recognition and activation by a collection of genetically diverse B. pertussis strains isolated from Dutch pertussis patients before and after the introduction of the pertussis vaccines. For this purpose, we used HEK-Blue cells transfected with human pattern recognition receptors TLR2, TLR4, NOD2 and NOD1 as a high throughput system for screening innate immune recognition of more than 90 bacterial strains. Physiologically relevant human monocyte derived dendritic cells (moDC), purified from peripheral blood of healthy donors were also used. Findings indicate that, in addition to inducing TLR2 and TLR4 signaling, all B. pertussis strains activate the NOD-like receptor NOD2 but not NOD1. Furthermore, we observed a significant increase in TLR2 and NOD2, but not TLR4, activation by strains circulating after the introduction of pertussis vaccines. When using moDC, we observed that the recently circulating strains induced increased activation of these cells with a dominant IL-10 production. In addition, we observed an increased expression of surface markers including the regulatory molecule PD-L1. Expression of PD-L1 was decreased upon blocking TLR2. These in vitro findings suggest that emerging B. pertussis strains have evolved to dampen the vaccine-induced inflammatory response, which would benefit survival and transmission of this pathogen. Understanding how this disease has resurged in a highly vaccinated population is crucial for the design of improved vaccines against pertussis. PMID:28076445

Immunization with recombinant SFTSV/NSs protein does not promote virus clearance in SFTSV-infected C57BL/6J mice.

PubMed

Liu, Rong; Huang, Dou-Dou; Bai, Jie-Ying; Zhuang, Lu; Lu, Qing-Bin; Zhang, Xiao-Ai; Liu, Wei; Wang, Jing-Yu; Cao, Wu-Chun

2015-03-01

The severe fever with thrombocytopenia syndrome (SFTS), caused by a novel Phlebovirus in the Bunyaviridae family named SFTS virus (SFTSV), is an emerging hemorrhagic fever with a wide distribution and high case-fatality rate. Neither effective treatment nor vaccines are available to treat and prevent this disease to date. It was recently reported that SFTSV nonstructural protein in S segment (SFTSV/NSs) functioned as the interferon (IFN) antagonist targeting for suppressing host's innate immunity. This study was designed to investigate the potential of recombinant SFTSV (rSFTSV)/NSs protein for inducing anti-NSs antibodies by pre-exposure vaccination to block SFTSV/NSs in the SFTSV-infected C57BL/6J mice. All mice in the rSFTSV/NSs-vaccinated group, negative control group, and blank control group survived with no visible clinical abnormities throughout the experiment, except for their sacrifice for sampling at each observation point. However, unexpectedly, a negative effect on the bodyweight of rSFTSV/NSs-vaccinated mice was observed after 21 days postinoculation. Pre-exposure vaccination with rSFTSV/NSs did not accelerate virus removal in mice though high titer of anti-NSs antibodies and elevated IFN-γ were detected in sera. Before virus challenge, the rSFTSV/NSs-vaccinated mice and negative control mice had a larger amount of platelets (PLT) than the blank control mice, which indicated that Freund's adjuvants could stimulate PLT production. In the aspect of cytokines, the rSFTSV/NSs-vaccinated mice had a 5- to 10-fold increase in interleukin (IL)-2, IL-5, IL-6, IFN-γ, and tumor necrosis factor-α, which probably just had a negative effect on the bodyweight of mice. In general, therefore, previous vaccination with rSFTSV/NSs did not accelerate virus clearance in the SFTSV-infected mice.

A single-dose cytomegalovirus-based vaccine encoding tetanus toxin fragment C induces sustained levels of protective tetanus toxin antibodies in mice.

PubMed

Tierney, Rob; Nakai, Toru; Parkins, Christopher J; Caposio, Patrizia; Fairweather, Neil F; Sesardic, Dorothea; Jarvis, Michael A

2012-04-26

The current commercially available vaccine used to prevent tetanus disease following infection with the anaerobic bacterium Clostridium tetani is safe and effective. However, tetanus remains a major source of mortality in developing countries. In 2008, neonatal tetanus was estimated to have caused >59,000 deaths, accounting for 1% of worldwide infant mortality, primarily in poorer nations. The cost of multiple vaccine doses administered by injection necessary to achieve protective levels of anti-tetanus toxoid antibodies is the primary reason for low vaccine coverage. Herein, we show that a novel vaccine strategy using a cytomegalovirus (CMV)-based vaccine platform induces protective levels of anti-tetanus antibodies that are durable (lasting >13 months) in mice following only a single dose. This study demonstrates the ability of a 'single-dose' CMV-based vaccine strategy to induce durable protection, and supports the potential for a tetanus vaccine based on CMV to impact the incidence of tetanus in developing countries. Copyright © 2012 Elsevier Ltd. All rights reserved.

The Ontology of Vaccine Adverse Events (OVAE) and its usage in representing and analyzing adverse events associated with US-licensed human vaccines.

PubMed

Marcos, Erica; Zhao, Bin; He, Yongqun

2013-11-26

Licensed human vaccines can induce various adverse events (AE) in vaccinated patients. Due to the involvement of the whole immune system and complex immunological reactions after vaccination, it is difficult to identify the relations among vaccines, adverse events, and human populations in different age groups. Many known vaccine adverse events (VAEs) have been recorded in the package inserts of US-licensed commercial vaccine products. To better represent and analyze VAEs, we developed the Ontology of Vaccine Adverse Events (OVAE) as an extension of the Ontology of Adverse Events (OAE) and the Vaccine Ontology (VO). Like OAE and VO, OVAE is aligned with the Basic Formal Ontology (BFO). The commercial vaccines and adverse events in OVAE are imported from VO and OAE, respectively. A new population term 'human vaccinee population' is generated and used to define VAE occurrence. An OVAE design pattern is developed to link vaccine, adverse event, vaccinee population, age range, and VAE occurrence. OVAE has been used to represent and classify the adverse events recorded in package insert documents of commercial vaccines licensed by the USA Food and Drug Administration (FDA). OVAE currently includes over 1,300 terms, including 87 distinct types of VAEs associated with 63 human vaccines licensed in the USA. For each vaccine, occurrence rates for every VAE in different age groups have been logically represented in OVAE. SPARQL scripts were developed to query and analyze the OVAE knowledge base data. To demonstrate the usage of OVAE, the top 10 vaccines accompanying with the highest numbers of VAEs and the top 10 VAEs most frequently observed among vaccines were identified and analyzed. Asserted and inferred ontology hierarchies classify VAEs in different levels of AE groups. Different VAE occurrences in different age groups were also analyzed. The ontology-based data representation and integration using the FDA-approved information from the vaccine package insert documents enables the identification of adverse events from vaccination in relation to predefined parts of the population (age groups) and certain groups of vaccines. The resulting ontology-based VAE knowledge base classifies vaccine-specific VAEs and supports better VAE understanding and future rational AE prevention and treatment.

Side-by-side comparison of gene-based smallpox vaccine with MVA in nonhuman primates.

PubMed

Golden, Joseph W; Josleyn, Matthew; Mucker, Eric M; Hung, Chien-Fu; Loudon, Peter T; Wu, T C; Hooper, Jay W

2012-01-01

Orthopoxviruses remain a threat as biological weapons and zoonoses. The licensed live-virus vaccine is associated with serious health risks, making its general usage unacceptable. Attenuated vaccines are being developed as alternatives, the most advanced of which is modified-vaccinia virus Ankara (MVA). We previously developed a gene-based vaccine, termed 4pox, which targets four orthopoxvirus antigens, A33, B5, A27 and L1. This vaccine protects mice and non-human primates from lethal orthopoxvirus disease. Here, we investigated the capacity of the molecular adjuvants GM-CSF and Escherichia coli heat-labile enterotoxin (LT) to enhance the efficacy of the 4pox gene-based vaccine. Both adjuvants significantly increased protective antibody responses in mice. We directly compared the 4pox plus LT vaccine against MVA in a monkeypox virus (MPXV) nonhuman primate (NHP) challenge model. NHPs were vaccinated twice with MVA by intramuscular injection or the 4pox/LT vaccine delivered using a disposable gene gun device. As a positive control, one NHP was vaccinated with ACAM2000. NHPs vaccinated with each vaccine developed anti-orthopoxvirus antibody responses, including those against the 4pox antigens. After MPXV intravenous challenge, all control NHPs developed severe disease, while the ACAM2000 vaccinated animal was well protected. All NHPs vaccinated with MVA were protected from lethality, but three of five developed severe disease and all animals shed virus. All five NHPs vaccinated with 4pox/LT survived and only one developed severe disease. None of the 4pox/LT-vaccinated animals shed virus. Our findings show, for the first time, that a subunit orthopoxvirus vaccine delivered by the same schedule can provide a degree of protection at least as high as that of MVA.

Side-by-Side Comparison of Gene-Based Smallpox Vaccine with MVA in Nonhuman Primates

PubMed Central

Golden, Joseph W.; Josleyn, Matthew; Mucker, Eric M.; Hung, Chien-Fu; Loudon, Peter T.; Wu, T. C.; Hooper, Jay W.

2012-01-01

Orthopoxviruses remain a threat as biological weapons and zoonoses. The licensed live-virus vaccine is associated with serious health risks, making its general usage unacceptable. Attenuated vaccines are being developed as alternatives, the most advanced of which is modified-vaccinia virus Ankara (MVA). We previously developed a gene-based vaccine, termed 4pox, which targets four orthopoxvirus antigens, A33, B5, A27 and L1. This vaccine protects mice and non-human primates from lethal orthopoxvirus disease. Here, we investigated the capacity of the molecular adjuvants GM-CSF and Escherichia coli heat-labile enterotoxin (LT) to enhance the efficacy of the 4pox gene-based vaccine. Both adjuvants significantly increased protective antibody responses in mice. We directly compared the 4pox plus LT vaccine against MVA in a monkeypox virus (MPXV) nonhuman primate (NHP) challenge model. NHPs were vaccinated twice with MVA by intramuscular injection or the 4pox/LT vaccine delivered using a disposable gene gun device. As a positive control, one NHP was vaccinated with ACAM2000. NHPs vaccinated with each vaccine developed anti-orthopoxvirus antibody responses, including those against the 4pox antigens. After MPXV intravenous challenge, all control NHPs developed severe disease, while the ACAM2000 vaccinated animal was well protected. All NHPs vaccinated with MVA were protected from lethality, but three of five developed severe disease and all animals shed virus. All five NHPs vaccinated with 4pox/LT survived and only one developed severe disease. None of the 4pox/LT-vaccinated animals shed virus. Our findings show, for the first time, that a subunit orthopoxvirus vaccine delivered by the same schedule can provide a degree of protection at least as high as that of MVA. PMID:22860117

Single-cycle adenovirus vectors in the current vaccine landscape.

PubMed

Barry, Michael

2018-02-01

Traditional inactivated and protein vaccines generate strong antibodies, but struggle to generate T cell responses. Attenuated pathogen vaccines generate both, but risk causing the disease they aim to prevent. Newer gene-based vaccines drive both responses and avoid the risk of infection. While these replication-defective (RD) vaccines work well in small animals, they can be weak in humans because they do not replicate antigen genes like more potent replication-competent (RC) vaccines. RC vaccines generate substantially stronger immune responses, but also risk causing their own infections. To circumvent these problems, we developed single-cycle adenovirus (SC-Ad) vectors that amplify vaccine genes, but that avoid the risk of infection. This review will discuss these vectors and their prospects for use as vaccines. Areas covered: This review provides a background of different types of vaccines. The benefits of gene-based vaccines and their ability to replicate antigen genes are described. Adenovirus vectors are discussed and compared to other vaccine types. Replication-defective, single-cycle, and replication-competent Ad vaccines are compared. Expert commentary: The potential utility of these vaccines are discussed when used against infectious diseases and as cancer vaccines. We propose a move away from replication-defective vaccines towards more robust replication-competent or single-cycle vaccines.

Recombinant and epitope-based vaccines on the road to the market and implications for vaccine design and production.

PubMed

Oyarzún, Patricio; Kobe, Bostjan

2016-03-03

Novel vaccination approaches based on rational design of B- and T-cell epitopes - epitope-based vaccines - are making progress in the clinical trial pipeline. The epitope-focused recombinant protein-based malaria vaccine (termed RTS,S) is a next-generation approach that successfully reached phase-III trials, and will potentially become the first commercial vaccine against a human parasitic disease. Progress made on methods such as recombinant DNA technology, advanced cell-culture techniques, immunoinformatics and rational design of immunogens are driving the development of these novel concepts. Synthetic recombinant proteins comprising both B- and T-cell epitopes can be efficiently produced through modern biotechnology and bioprocessing methods, and can enable the induction of large repertoires of immune specificities. In particular, the inclusion of appropriate CD4+ T-cell epitopes is increasingly considered a key vaccine component to elicit robust immune responses, as suggested by results coming from HIV-1 clinical trials. In silico strategies for vaccine design are under active development to address genetic variation in pathogens and several broadly protective "universal" influenza and HIV-1 vaccines are currently at different stages of clinical trials. Other methods focus on improving population coverage in target populations by rationally considering specificity and prevalence of the HLA proteins, though a proof-of-concept in humans has not been demonstrated yet. Overall, we expect immunoinformatics and bioprocessing methods to become a central part of the next-generation epitope-based vaccine development and production process.

Sources of information for assessing human papillomavirus vaccination history among young women.

PubMed

Niccolai, Linda M; McBride, Vanessa; Julian, Pamela R

2014-05-23

Assessing history of human papillomavirus (HPV) vaccination is important for monitoring vaccine uptake, impact, and effectiveness. Based on data collected from 1720 women with high-grade cervical lesions reported to a statewide surveillance system in Connecticut, we found that available medical records did not contain HPV vaccination information for 34% of women, and 43% of women could not be reached for interview. When both were used for data collection, concordance of vaccination history (83%) and sensitivity of self-report (96%) were both high. Reviewing medical records based on self-reported information about vaccine providers increased confirmation of vaccination histories in this sample by 18%. The vaccine registry in Connecticut is not currently utilized for HPV vaccinations, but efforts to increase use for adolescent vaccines could be useful in the future to overcome limitations of other sources. Copyright © 2014 Elsevier Ltd. All rights reserved.

Comparative analysis of the immune responses induced by native versus recombinant versions of the ASP-based vaccine against the bovine intestinal parasite Cooperia oncophora.

PubMed

González-Hernández, Ana; Borloo, Jimmy; Peelaers, Iris; Casaert, Stijn; Leclercq, Georges; Claerebout, Edwin; Geldhof, Peter

2018-01-01

The protective capacities of a native double-domain activation-associated secreted protein (ndd-ASP)-based vaccine against the cattle intestinal nematode Cooperia oncophora has previously been demonstrated. However, protection analysis upon vaccination with a recombinantly produced antigen has never been performed. Therefore, the aim of the current study was to test the protective potential of a Pichia-produced double-domain ASP (pdd-ASP)-based vaccine against C. oncophora. Additionally, we aimed to compare the cellular and humoral mechanisms underlying the vaccine-induced responses by the native (ndd-ASP) and recombinant vaccines. Immunisation of cattle with the native C. oncophora vaccine conferred significant levels of protection after an experimental challenge infection, whereas the recombinant vaccine did not. Moreover, vaccination with ndd-ASP resulted in a higher proliferation of CD4-T cells both systemically and in the small intestinal mucosa when compared with animals vaccinated with the recombinant antigen. In terms of humoral response, although both native and recombinant vaccines induced similar levels of antibodies, animals vaccinated with the native vaccine were able to raise antibodies with greater specificity towards ndd-ASP in comparison with antibodies raised by vaccination with the recombinant vaccine, suggesting a differential immune recognition towards the ndd-ASP and pdd-ASP. Finally, the observation that animals displaying antibodies with higher percentages of recognition towards ndd-ASP also exhibited the lowest egg counts suggests a potential relationship between antibody specificity and protection. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Understanding vaccination rates and attitudes among patients with rheumatoid arthritis.

PubMed

Sandler, Diana S; Ruderman, Eric M; Brown, Tiffany; Lee, Ji Young; Mixon, Amanda; Liss, David T; Baker, David W

2016-03-01

Appropriate vaccinations are important for patients with rheumatoid arthritis (RA), who are often treated with highly immunosuppressive therapies that increase their risk of infection. However, rates of vaccination among patients with RA are below optimal levels. We conducted a patient survey to assess self-reported vaccination status and to compare that status with electronic health record (EHR) data. We recruited randomly selected patients with RA in an academic practice in 2013. Eligible participants had a diagnosis of RA, at least 1 visit to a rheumatology clinic in each of the previous 2 years, were 18 years or older, and had English listed as their preferred language. The survey included the following domains: a) patient self-reported receipt of influenza, pneumococcal (PNVX), and herpes zoster (HZVX) vaccinations; b) attitudes about these vaccines, including reasons for unvaccinated status, if applicable; and c) provider recommendations about these vaccines. Based on participants' self-report, we found a high vaccination rate for influenza during the previous season (79.4%), a moderate rate of any previous vaccination for pneumococcus (53.9%), and a very low rate of any previous vaccination for herpes zoster (7.8%). If we assume that all self-reports are accurate and we include vaccinations recorded in the EHR that were not reported by patients, the vaccination rates were approximately 8% to 9% higher for PNVX and HZVX. Vaccination rates are low among patients with RA based on self-report data. Further research is needed to investigate system-level barriers to vaccination and the impact of evidence-based, provider-level interventions on vaccination rates.

Immunogenicity and protection efficacy of subunit-based smallpox vaccines using variola major antigens.

PubMed

Sakhatskyy, Pavlo; Wang, Shixia; Zhang, Chuanyou; Chou, Te-Hui; Kishko, Michael; Lu, Shan

2008-02-05

The viral strain responsible for smallpox infection is variola major (VARV). As a result of the successful eradication of smallpox with the vaccinia virus (VACV), the general population is no longer required to receive a smallpox vaccine, and will have no protection against smallpox. This lack of immunity is a concern due to the potential for use of smallpox as a biological weapon. Considerable progress has been made in the development of subunit-based smallpox vaccines resulting from the identification of VACV protective antigens. It also offers the possibility of using antigens from VARV to formulate the next generation subunit-based smallpox vaccines. Here, we show that codon-optimized DNA vaccines expressing three VARV antigens (A30, B7 and F8) and their recombinant protein counterparts elicited high-titer, cross-reactive, VACV neutralizing antibody responses in mice. Vaccinated mice were protected from intraperitoneal and intranasal challenges with VACV. These results suggest the feasibility of a subunit smallpox vaccine based on VARV antigen sequences to induce immunity against poxvirus infection.

Using Dynamic Transmission Modeling to Determine Vaccination Coverage Rate Based on 5-Year Economic Burden of Infectious Disease: An Example of Pneumococcal Vaccine.

PubMed

Wen, Yu-Wen; Wu, Hsin; Chang, Chee-Jen

2015-05-01

Vaccination can reduce the incidence and mortality of an infectious disease and thus increase the years of life and productivity for the entire society. But when determining the vaccination coverage rate, its economic burden is usually not taken into account. This article aimed to use a dynamic transmission modeling (DTM), which is based on a susceptible-infectious-recovered model and is a system of differential equations, to find the optimal vaccination coverage rate based on the economic burden of an infectious disease. Vaccination for pneumococcal diseases was used as an example to demonstrate the main purpose. 23-Valent pneumococcal polysaccharide vaccines (PPV23) and 13-valent pneumococcal conjugate vaccines (PCV13) have shown their cost-effectiveness in elderly and children, respectively. Scenarios analysis of PPV23 to elderly aged 65+ years and of PCV13 to children aged 0 to 4 years was applied to assess the optimal vaccination coverage rate based on the 5-year economic burden. Model parameters were derived from Taiwan's National Health Insurance Research Database, government data, and published literature. Various vaccination coverage rates, the vaccine efficacy, and all epidemiologic parameters were substituted into DTM, and all differential equations were solved in R Statistical Software. If the coverage rate of PPV23 for the elderly and of PCV13 for the children both reach 50%, the economic burden due to pneumococcal disease will be acceptable. This article provided an alternative perspective from the economic burden of diseases to obtain a vaccination coverage rate using the DTM. This will provide valuable information for vaccination policy decision makers. Copyright © 2015 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Impact of educational interventions on adolescent attitudes and knowledge regarding vaccination: A pilot study

PubMed Central

Carolan, Kate; Verran, Joanna; Crossley, Matthew; Redfern, James; Whitton, Nicola

2018-01-01

Background Current immunisation levels in England currently fall slightly below the threshold recommended by the World Health Organization, and the three-year trend for vaccination uptake is downwards. Attitudes towards vaccination can affect future decisions on whether or not to vaccinate, and this can have significant public health implications. Interventions can impact future vaccination decisions, and these interventions can take several forms. Relatively little work has been reported on the use of vaccination interventions in young people, who form the next generation of individuals likely to make vaccination decisions. Method We investigated the impact of two different types of educational intervention on attitudes towards vaccination in young people in England. A cohort of young people (n = 63) was recruited via a local school. This group was divided into three sub-groups; one (n = 21) received a presentation-based intervention, one (n = 26) received an interactive simulation-based intervention, and the third (n = 16) received no intervention. Participants supplied information on (1) their attitudes towards vaccination, and (2) their information needs and views on personal choice concerning vaccination, at three time points: immediately before and after the intervention, and after six months. Results Neither intervention had a significant effect on participants’ attitudes towards vaccination. However, the group receiving the presentation-based intervention saw a sustained uplift in confidence about information needs, which was not observed in the simulation-based intervention group. Discussion Our findings with young people are consistent with previous work on vaccination interventions aimed at adults, which have shown limited effectiveness, and which can actually reduce intention to vaccinate. Our findings on the most effective mode of delivery for the intervention should inform future discussion in the growing “games for health” domain, which proposes the use of interactive digital resources in healthcare education. PMID:29351325

Trends in Childhood Influenza Vaccination Coverage—U.S., 2004–2012

PubMed Central

Lu, Peng-Jun; O'Halloran, Alissa; Meghani, Ankita; Grabowsky, Mark; Singleton, James A.

2014-01-01

Objective We compared estimates of childhood influenza vaccination coverage by health status, age, and racial/ethnic group across eight consecutive influenza seasons (2004 through 2012) based on two survey systems to assess trends in childhood influenza vaccination coverage in the U.S. Methods We used National Health Interview Survey (NHIS) and National Immunization Survey-Flu (NIS-Flu) data to estimate receipt of at least one dose of influenza vaccination among children aged 6 months to 17 years based on parental report. We computed estimates using Kaplan-Meier survival analysis methods. Results Based on the NHIS, overall influenza vaccination coverage with at least one dose of influenza vaccine among children increased from 16.2% during the 2004–2005 influenza season to 47.1% during the 2011–2012 influenza season. Children with health conditions that put them at high risk for complications from influenza had higher influenza vaccination coverage than children without these health conditions for all the seasons studied. In seven of the eight seasons studied, there were no significant differences in influenza vaccination coverage between non-Hispanic black and non-Hispanic white children. Influenza vaccination coverage estimates for children were slightly higher based on NIS-Flu data compared with NHIS data for the 2010–2011 and 2011–2012 influenza seasons (4.1 and 4.4 percentage points higher, respectively); both NIS-Flu and NHIS estimates had similar patterns of decreasing vaccination coverage with increasing age. Conclusions Although influenza vaccination coverage among children continued to increase, by the 2011–2012 influenza season, only slightly less than half of U.S. children were vaccinated against influenza. Much improvement is needed to ensure all children aged ≥6 months are vaccinated annually against influenza. PMID:25177053

Impact of educational interventions on adolescent attitudes and knowledge regarding vaccination: A pilot study.

PubMed

Carolan, Kate; Verran, Joanna; Crossley, Matthew; Redfern, James; Whitton, Nicola; Amos, Martyn

2018-01-01

Current immunisation levels in England currently fall slightly below the threshold recommended by the World Health Organization, and the three-year trend for vaccination uptake is downwards. Attitudes towards vaccination can affect future decisions on whether or not to vaccinate, and this can have significant public health implications. Interventions can impact future vaccination decisions, and these interventions can take several forms. Relatively little work has been reported on the use of vaccination interventions in young people, who form the next generation of individuals likely to make vaccination decisions. We investigated the impact of two different types of educational intervention on attitudes towards vaccination in young people in England. A cohort of young people (n = 63) was recruited via a local school. This group was divided into three sub-groups; one (n = 21) received a presentation-based intervention, one (n = 26) received an interactive simulation-based intervention, and the third (n = 16) received no intervention. Participants supplied information on (1) their attitudes towards vaccination, and (2) their information needs and views on personal choice concerning vaccination, at three time points: immediately before and after the intervention, and after six months. Neither intervention had a significant effect on participants' attitudes towards vaccination. However, the group receiving the presentation-based intervention saw a sustained uplift in confidence about information needs, which was not observed in the simulation-based intervention group. Our findings with young people are consistent with previous work on vaccination interventions aimed at adults, which have shown limited effectiveness, and which can actually reduce intention to vaccinate. Our findings on the most effective mode of delivery for the intervention should inform future discussion in the growing "games for health" domain, which proposes the use of interactive digital resources in healthcare education.

Prime-boost bacillus Calmette-Guérin vaccination with lentivirus-vectored and DNA-based vaccines expressing antigens Ag85B and Rv3425 improves protective efficacy against Mycobacterium tuberculosis in mice.

PubMed

Xu, Ying; Yang, Enzhuo; Wang, Jianguang; Li, Rui; Li, Guanghua; Liu, Guoyuan; Song, Na; Huang, Qi; Kong, Cong; Wang, Honghai

2014-10-01

To prevent the global spread of tuberculosis (TB), more effective vaccines and vaccination strategies are urgently needed. As a result of the success of bacillus Calmette-Guérin (BCG) in protecting children against miliary and meningeal TB, the majority of individuals will have been vaccinated with BCG; hence, boosting BCG-primed immunity will probably be a key component of future vaccine strategies. In this study, we compared the ability of DNA-, protein- and lentiviral vector-based vaccines that express the antigens Ag85B and Rv3425 to boost the effects of BCG in the context of immunity and protection against Mycobacterium tuberculosis in C57BL/6 mice. Our results demonstrated that prime-boost BCG vaccination with a lentiviral vector expressing the antigens Ag85B and Rv3425 significantly enhanced immune responses, including T helper type 1 and CD8(+) cytotoxic T lymphocyte responses, compared with DNA- and protein-based vaccines. However, lentivirus-vectored and DNA-based vaccines greatly improved the protective efficacy of BCG against M. tuberculosis, as indicated by a lack of weight loss and significantly reduced bacterial loads and histological damage in the lung. Our study suggests that the use of lentiviral or DNA vaccines containing the antigens Ag85B and Rv3425 to boost BCG is a good choice for the rational design of an efficient vaccination strategy against TB. © 2014 John Wiley & Sons Ltd.

Immunogenicity against Far Eastern and Siberian subtypes of tick-borne encephalitis (TBE) virus elicited by the currently available vaccines based on the European subtype: systematic review and meta-analysis.

PubMed

Domnich, Alexander; Panatto, Donatella; Arbuzova, Eva Klementievna; Signori, Alessio; Avio, Ulderico; Gasparini, Roberto; Amicizia, Daniela

2014-01-01

Tick-borne encephalitis (TBE) virus, which is usually divided into European, Far Eastern and Siberian subtypes, is a serious public health problem in several European and Asian countries. Vaccination is the most effective measure to prevent TBE; cross-subtype protection elicited by the TBE vaccines is biologically plausible since all TBE virus subtypes are closely related. This manuscript systematically explores available data on the cross-subtype immunogenicity elicited by the currently available Western vaccines based on the European subtype. Completed immunization course of 3 doses of both Western vaccines determined very high seroconversion/seropositivity rates against both Far Eastern and Siberian subtypes among previously flavivirus-naïve subjects. All but one study found no statistically significant difference in titers of neutralizing antibodies against strains belonging to homologous and heterologous subtypes. Pooled analysis of randomized controlled trials on head-to-head comparison of immunogenicity of Western and Russian TBE vaccines did not reveal differences in seroconversion rates against Far Eastern isolates in either hemagglutination inhibition (risk ratio = 0.98, p = 0.83) or enzyme-linked immunosorbent (risk ratio = 0.95, p = 0.44) assays after 2 vaccine doses. This suggests that, in regions where a heterogeneous TBE virus population circulates, vaccines based on the European subtype may be used alongside vaccines based on the Far Eastern subtype. Studies on the field effectiveness of TBE vaccines and investigation of vaccination failures, especially in countries where different subtypes co-circulate, will further elucidate TBE vaccination-induced cross-subtype protection.

Immunogenicity against Far Eastern and Siberian subtypes of tick-borne encephalitis (TBE) virus elicited by the currently available vaccines based on the European subtype: Systematic review and meta-analysis

PubMed Central

Domnich, Alexander; Panatto, Donatella; Arbuzova, Eva Klementievna; Signori, Alessio; Avio, Ulderico; Gasparini, Roberto; Amicizia, Daniela

2014-01-01

Tick-borne encephalitis (TBE) virus, which is usually divided into European, Far Eastern and Siberian subtypes, is a serious public health problem in several European and Asian countries. Vaccination is the most effective measure to prevent TBE; cross-subtype protection elicited by the TBE vaccines is biologically plausible since all TBE virus subtypes are closely related. This manuscript systematically explores available data on the cross-subtype immunogenicity elicited by the currently available Western vaccines based on the European subtype. Completed immunization course of 3 doses of both Western vaccines determined very high seroconversion/seropositivity rates against both Far Eastern and Siberian subtypes among previously flavivirus-naïve subjects. All but one study found no statistically significant difference in titers of neutralizing antibodies against strains belonging to homologous and heterologous subtypes. Pooled analysis of randomized controlled trials on head-to-head comparison of immunogenicity of Western and Russian TBE vaccines did not reveal differences in seroconversion rates against Far Eastern isolates in either hemagglutination inhibition (risk ratio = 0.98, p = 0.83) or enzyme-linked immunosorbent (risk ratio = 0.95, p = 0.44) assays after 2 vaccine doses. This suggests that, in regions where a heterogeneous TBE virus population circulates, vaccines based on the European subtype may be used alongside vaccines based on the Far Eastern subtype. Studies on the field effectiveness of TBE vaccines and investigation of vaccination failures, especially in countries where different subtypes co-circulate, will further elucidate TBE vaccination-induced cross-subtype protection. PMID:25483679

Development of an epitope-based HIV-1 vaccine strategy from HIV-1 lipopeptide to dendritic-based vaccines.

PubMed

Surenaud, Mathieu; Lacabaratz, Christine; Zurawski, Gérard; Lévy, Yves; Lelièvre, Jean-Daniel

2017-10-01

Development of a safe, effective and globally affordable Human Immunodeficiency Virus strain 1 (HIV-1) vaccine offers the best hope for future control of the HIV-1 pandemic. However, with the exception of the recent RV144 trial, which elicited a modest level of protection against infection, no vaccine candidate has shown efficacy in preventing HIV-1 infection or in controlling virus replication in humans. There is also a great need for a successful immunotherapeutic vaccine since combination antiretroviral therapy (cART) does not eliminate the reservoir of HIV-infected cells. But to date, no vaccine candidate has proven to significantly alter the natural history of an individual with HIV-1 infection. Areas covered: For over 25 years, the ANRS (France Recherche Nord&Sud Sida-HIV hépatites) has been committed to an original program combining basic science and clinical research developing an epitope-based vaccine strategy to induce a multiepitopic cellular response against HIV-1. This review describes the evolution of concepts, based on strategies using HIV-1 lipopeptides towards the use of dendritic cell (DC) manipulation. Expert commentary: Understanding the crucial role of DCs in immune responses allowed moving from the non-specific administration of HIV-1 sequences with lipopeptides to DC-based vaccines. These DC-targeting strategies should improve HIV-1 vaccine efficacy.

A home-school-doctor model to break the barriers for uptake of human papillomavirus vaccine.

PubMed

Lee, Albert; Wong, Martin C S; Chan, Tracy T; Chan, Paul K S

2015-09-21

A high coverage of human papillomavirus (HPV) vaccination is required to achieve a clinically significant reduction in disease burden. Countries implementing free-of-charge national vaccination program for adolescent girls are still challenged by the sub-optimal uptake rate. Voluntary on-site school-based mass vaccination programs have demonstrated high coverage. Here, we tested whether this could be an option for countries without a government-supported vaccination program as in Hong Kong. A Home-School-Doctor model was evolved based on extensive literature review of various health promotion models together with studies on HPV vaccination among adolescent girls. The outcome measure was uptake of vaccination. Factors associated with the outcome were measured by validated surveys in which 4,631 students from 24 school territory wide participated. Chi-square test was used to analyze association between the categorical variables and the outcome. Multivariate analysis was performed to identify independent variables associated with the outcome with vaccine group as case and non-vaccine group as control. In multivariate analysis, parental perception of usefulness of the Home-School-Doctor model had a very high odds ratio for uptake of HPV vaccination (OR 26.6, 95% CI 16.4, 41.9). Paying a reasonable price was another independent factor associated with increased uptake (OR 1.71, 95% CI 1.39, 2.1 for those with parents willing to pay US$125-250 for vaccination). For parents and adolescents who were not sure where to get vaccination, this model was significantly associated with improved uptake rate (OR 1.66, 95% CI 1.23, 2.23). Concerns with side effects of vaccine (OR 0.70, 95% CI 0.55, 0.88), allowing daughters to make their own decisions (OR 0.49, 95% CI 0.38, 0.64) and not caring much about daughters' social life (95% CI 0.45, 0.92) were factors associated with a lower uptake. The findings of this study have added knowledge on how a school-based vaccination program would improve vaccine uptake rate even when the users need to pay. Our findings are consistent with other study that the most acceptable way to achieve high uptake of HPV vaccine is to offer voluntary school-based vaccination. A model of care incorporating the efforts and expertise of academics and health professionals working closely with school can be applied to improve the uptake of vaccine among adolescent girls. Subsidized voluntary school-based vaccination scheme can be an option.

A novel alphavirus replicon-vectored vaccine delivered by adenovirus induces sterile immunity against classical swine fever.

PubMed

Sun, Yuan; Li, Hong-Yu; Tian, Da-Yong; Han, Qiu-Ying; Zhang, Xin; Li, Na; Qiu, Hua-Ji

2011-10-26

Low efficacy of gene-based vaccines due to inefficient gene delivery and expression has been major bottleneck of their applications. Efforts have been made to improve the efficacy, such as gene gun and electroporation, but the strategies are difficult to put into practical use. In this study, we developed and evaluated an adenovirus-delivered, alphavirus replicon-vectored vaccine (chimeric vector-based vaccine) expressing the E2 gene of classical swine fever virus (CSFV) (rAdV-SFV-E2). Rabbits immunized with rAdV-SFV-E2 developed CSFV-specific antibodies as early as 9 days and as long as 189 days and completely protected from challenge with C-strain. Pigs immunized with rAdV-SFV-E2 (n=5) developed robust humoral and cell-mediated responses to CSFV and were completely protected from subsequent lethal CSFV infection clinically and virologically. The level of immunity and protection induced by rAdV-SFV-E2 was comparable to that provided by the currently used live attenuated vaccine, C-strain. In contrast, both the conventional alphavirus replicon-vectored vaccine pSFV1CS-E2 and conventional adenovirus-vectored vaccine rAdV-E2 provided incomplete protection. The chimeric vector-based vaccine represents the first gene-based vaccine that is able to confer sterile immunity and complete protection against CSFV. The new-concept vaccination strategy may also be valuable in vaccine development against other pathogens. Copyright © 2011 Elsevier Ltd. All rights reserved.

A national examination of pharmacy-based immunization statutes and their association with influenza vaccinations and preventive health.

PubMed

McConeghy, Kevin W; Wing, Coady

2016-06-24

A series of state-level statute changes have allowed pharmacists to provide influenza vaccinations in community pharmacies. The study aim was to estimate the effects of pharmacy-based immunization statutes changes on per capita influenza vaccine prescriptions, adult vaccination rates, and the utilization of other preventive health services. A quasi-experimental study that compares vaccination outcomes over time before and after states allowed pharmacy-based immunization. Measures of per capita pharmacy prescriptions for influenza vaccines in each state came from a proprietary pharmacy prescription database. Data on adult vaccination rates and preventive health utilization were studied using multiple waves of the Behavioral Risk Factor Surveillance System (BRFSS). The primary outcomes were changes in per capita influenza vaccine pharmacy prescriptions, adult vaccination rates, and preventive health interventions following changes. Between 2007 and 2013, the number of influenza vaccinations dispensed in community pharmacies increased from 3.2 to 20.9 million. After one year, adopting pharmacist immunization statutes increased per capita influenza vaccine prescriptions by an absolute difference (AD) of 2.6% (95% CI: 1.1-4.2). Adopting statutes did not lead to a significant absolute increase in adult vaccination rates (AD 0.9%, 95% CI: -0.3, 2.2). There also was no observed difference in adult vaccination rates among adults at high-risk of influenza complications (AD 0.8%, 95% CI: -0.2, 1.8) or among standard demographic subgroups. There also was no observed difference in the receipt of preventive health services, including routine physician office visits (AD -1.9%, 95% CI: -4.9, 1.1). Pharmacists are providing millions of influenza vaccines as a consequence of immunization statutes, but we do not observe significant differences in adult influenza vaccination rates. The main gains from pharmacy-based immunization may be in providing a more convenient way to obtain an important health service. Published by Elsevier Ltd.

Rural parents' vaccination-related attitudes and intention to vaccinate middle and high school children against influenza following educational influenza vaccination intervention

PubMed Central

Painter, Julia E.; Pazol, Karen; Gargano, Lisa M.; Orenstein, Walter; Hughes, James M.; DiClemente, Ralph J.

2011-01-01

Objective: This study examined changes in parental influenza vaccination attitudes and intentions after participating in school-based educational influenza vaccination intervention. Methods: Participants were drawn from three counties participating in a school-based influenza vaccination intervention in rural Georgia (baseline N=324; follow-up N=327). Data were collected pre- and post-intervention from phone surveys with parents’ with children attending middle- and high-school. Attitudes, beliefs, vaccination history, and intention to vaccinate were assessed.  Results:  Parents who participated in the intervention conditions reported significantly higher influenza vaccination rates in their adolescents, relative to a control group, as well as increased vaccination rates post-intervention participation relative to their baseline rates. Intervention participants reported greater intention to have their adolescent vaccinated in the coming year compared to control parents.  Significant differences were observed post intervention in perceived barriers and benefits of vaccination. Conclusions: These findings suggest that a school-delivered educational influenza vaccination intervention targeting parents and teens may influence influenza vaccination in rural communities. Future influenza vaccination efforts geared toward the parents of rural middle- and high-school students may benefit from addressing barriers and benefits of influenza vaccination. PMID:22048112

Serology and longevity of immunity against Echinococcus granulosus in sheep and llama induced by an oil-based EG95 vaccine.

PubMed

Poggio, T V; Jensen, O; Mossello, M; Iriarte, J; Avila, H G; Gertiser, M L; Serafino, J J; Romero, S; Echenique, M A; Dominguez, D E; Barrios, J R; Heath, D

2016-08-01

An oil-based formulation of the EG95 vaccine to protect grazing animals against infection with Echinococcus granulosus was formulated in Argentina. The efficacy of the vaccine was monitored by serology in sheep and llama (Lama glama) and was compared to the serology in sheep previously published using a QuilA-adjuvanted vaccine. Long-term efficacy was also tested in sheep by challenging with E. granulosus eggs of the G1 strain 4 years after the beginning of the trial. The serological results for both sheep and llama were similar to those described previously, except that there was a more rapid response after the first vaccination. A third vaccination given after 1 year resulted in a transient boost in serology that lasted for about 12 months, which was similar to results previously described. Sheep challenged after 4 years with three vaccinations presented 84·2% reduction of live cysts counts compared with control group, and after a fourth vaccination prior to challenge, this reduction was 94·7%. The oil-based vaccine appeared to be bio-equivalent to the QuilA vaccine. © 2016 John Wiley & Sons Ltd.

Vaccine development for allergen-specific immunotherapy based on recombinant allergens and synthetic allergen peptides: Lessons from the past and novel mechanisms of action for the future

PubMed Central

Valenta, Rudolf; Campana, Raffaela; Focke-Tejkl, Margit; Niederberger, Verena

2016-01-01

In the past, the development of more effective, safe, convenient, broadly applicable, and easy to manufacture vaccines for allergen-specific immunotherapy (AIT) has been limited by the poor quality of natural allergen extracts. Progress made in the field of molecular allergen characterization has now made it possible to produce defined vaccines for AIT and eventually for preventive allergy vaccination based on recombinant DNA technology and synthetic peptide chemistry. Here we review the characteristics of recombinant and synthetic allergy vaccines that have reached clinical evaluation and discuss how molecular vaccine approaches can make AIT more safe and effective and thus more convenient. Furthermore, we discuss how new technologies can facilitate the reproducible manufacturing of vaccines of pharmaceutical grade for inhalant, food, and venom allergens. Allergy vaccines in clinical trials based on recombinant allergens, recombinant allergen derivatives, and synthetic peptides allow us to target selectively different immune mechanisms, and certain of those show features that might make them applicable not only for therapeutic but also for prophylactic vaccination. PMID:26853127

Chikungunya Virus Vaccines: Viral Vector-Based Approaches.

PubMed

Ramsauer, Katrin; Tangy, Frédéric

2016-12-15

In 2013, a major chikungunya virus (CHIKV) epidemic reached the Americas. In the past 2 years, >1.7 million people have been infected. In light of the current epidemic, with millions of people in North and South America at risk, efforts to rapidly develop effective vaccines have increased. Here, we focus on CHIKV vaccines that use viral-vector technologies. This group of vaccine candidates shares an ability to potently induce humoral and cellular immune responses by use of highly attenuated and safe vaccine backbones. So far, well-described vectors such as modified vaccinia virus Ankara, complex adenovirus, vesicular stomatitis virus, alphavirus-based chimeras, and measles vaccine Schwarz strain (MV/Schw) have been described as potential vaccines. We summarize here the recent data on these experimental vaccines, with a focus on the preclinical and clinical activities on the MV/Schw-based candidate, which is the first CHIKV-vectored vaccine that has completed a clinical trial. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Novel Adjuvants and Immunomodulators for Veterinary Vaccines.

PubMed

Heegaard, Peter M H; Fang, Yongxiang; Jungersen, Gregers

2016-01-01

Adjuvants are crucial for efficacy of vaccines, especially subunit and recombinant vaccines. Rational vaccine design, including knowledge-based and molecularly defined adjuvants tailored for directing and potentiating specific types of host immune responses towards the antigens included in the vaccine is becoming a reality with our increased understanding of innate and adaptive immune activation. This will allow future vaccines to induce immune reactivity having adequate specificity as well as protective and recallable immune effector mechanisms in appropriate body compartments, including mucosal surfaces. Here we describe these new developments and, when possible, relate new immunological knowledge to the many years of experience with traditional, empirical adjuvants. Finally, some protocols are given for production of emulsion (oil-based) and liposome-based adjuvant/antigen formulations.

Complement-mediated bactericidal activity of anti-factor H binding protein monoclonal antibodies against the meningococcus relies upon blocking factor H binding.

PubMed

Giuntini, Serena; Reason, Donald C; Granoff, Dan M

2011-09-01

Binding of the complement-downregulating protein factor H (fH) to the surface of the meningococcus is important for survival of the organism in human serum. The meningococcal vaccine candidate factor H binding protein (fHbp) is an important ligand for human fH. While some fHbp-specific monoclonal antibodies (MAbs) block binding of fH to fHbp, the stoichiometry of blocking in the presence of high serum concentrations of fH and its effect on complement-mediated bactericidal activity are unknown. To investigate this question, we constructed chimeric antibodies in which the human IgG1 constant region was paired with three murine fHbp-specific binding domains designated JAR 3, JAR 5, and MAb502. By surface plasmon resonance, the association rates for binding of all three MAbs to immobilized fHbp were >50-fold higher than that for binding of fH to fHbp, and the MAb dissociation rates were >500-fold lower than that for fH. While all three MAbs elicited similar C1q-dependent C4b deposition on live bacteria (classical complement pathway), only those antibodies that inhibited binding of fH to fHbp (JAR 3 and JAR 5) had bactericidal activity with human complement. MAb502, which did not inhibit fH binding, had complement-mediated bactericidal activity only when tested with fH-depleted human complement. When an IgG1 anti-fHbp MAb binds to sparsely exposed fHbp on the bacterial surface, there appears to be insufficient complement activation for bacteriolysis unless fH binding also is inhibited. The ability of fHbp vaccines to elicit protective antibodies, therefore, is likely to be enhanced if the antibody repertoire is of high avidity and includes fH-blocking activity.

Impact of Targeted Tuberculosis Vaccination Among a Mining Population in South Africa: A Model-Based Study.

PubMed

Shrestha, Sourya; Chihota, Violet; White, Richard G; Grant, Alison D; Churchyard, Gavin J; Dowdy, David W

2017-12-15

Optimizing the use of new tools, such as vaccines, may play a crucial role in reaching global targets for tuberculosis (TB) control. Some of the most promising candidate vaccines target adults, although high-coverage mass vaccinations may be logistically more challenging among this population than among children. Vaccine-delivery strategies that target high-risk groups or settings might yield proportionally greater impact than do those that target the general population. We developed an individual-based TB transmission model representing a hypothetical population consisting of people who worked in South African gold mines or lived in associated labor-sending communities. We simulated the implementation of a postinfection adult vaccine with 60% efficacy and a mean effect duration of 10 years. We then compared the impact of a mine-targeted vaccination strategy, in which miners were vaccinated while in the mines, with that of a community-targeted strategy, in which random individuals within the labor-sending communities were vaccinated. Mine-targeted vaccination averted an estimated 0.37 TB cases per vaccine dose compared with 0.25 for community-targeted vaccination, for a relative efficacy of 1.46 (95% range, 1.13-1.91). The added benefit of mine-targeted vaccination primarily reflected the disproportionate demographic burden of TB among the population of adult males as a whole. As novel vaccines for TB are developed, venue-based vaccine delivery that targets high-risk demographic groups may improve both vaccine feasibility and the impact on transmission. © The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Successful introduction of an underutilized elderly pneumococcal vaccine in a national immunization program by integrating the pre-existing public health infrastructure.

PubMed

Yang, Tae Un; Kim, Eunsung; Park, Young-Joon; Kim, Dongwook; Kwon, Yoon Hyung; Shin, Jae Kyong; Park, Ok

2016-03-18

Although pneumococcal vaccines had been recommended for the elderly population in South Korea for a considerable period of time, the coverage has been well below the optimal level. To increase the vaccination rate with integrating the pre-existing public health infrastructure and governmental funding, the Korean government introduced an elderly pneumococcal vaccination into the national immunization program with a 23-valent pneumococcal polysaccharide vaccine in May 2013. The aim of this study was to assess the performance of the program in increasing the vaccine coverage rate and maintaining stable vaccine supply and safe vaccination during the 20 months of the program. We qualitatively and quantitatively analyzed the process of introducing and the outcomes of the program in terms of the systematic organization, efficiency, and stability at the national level. A staggered introduction during the first year utilizing the public sector, with a target coverage of 60%, was implemented based on the public demand for an elderly pneumococcal vaccination, vaccine supply capacity, vaccine delivery capacity, safety, and sustainability. During the 20-month program period, the pneumococcal vaccine coverage rate among the population aged ≥65 years increased from 5.0% to 57.3% without a noticeable vaccine shortage or safety issues. A web-based integrated immunization information system, which includes the immunization registry, vaccine supply chain management, and surveillance of adverse events following immunization, reduced programmatic errors and harmonized the overall performance of the program. Introduction of an elderly pneumococcal vaccination in the national immunization program based on strong government commitment, meticulous preparation, financial support, and the pre-existing public health infrastructure resulted in an efficient, stable, and sustainable increase in vaccination coverage. Copyright © 2016. Published by Elsevier Ltd.

Pre-clinical efficacy and safety of experimental vaccines based on non-replicating vaccinia vectors against yellow fever.

PubMed

Schäfer, Birgit; Holzer, Georg W; Joachimsthaler, Alexandra; Coulibaly, Sogue; Schwendinger, Michael; Crowe, Brian A; Kreil, Thomas R; Barrett, P Noel; Falkner, Falko G

2011-01-01

Currently existing yellow fever (YF) vaccines are based on the live attenuated yellow fever virus 17D strain (YFV-17D). Although, a good safety profile was historically attributed to the 17D vaccine, serious adverse events have been reported, making the development of a safer, more modern vaccine desirable. A gene encoding the precursor of the membrane and envelope (prME) protein of the YFV-17D strain was inserted into the non-replicating modified vaccinia virus Ankara and into the D4R-defective vaccinia virus. Candidate vaccines based on the recombinant vaccinia viruses were assessed for immunogenicity and protection in a mouse model and compared to the commercial YFV-17D vaccine. The recombinant live vaccines induced γ-interferon-secreting CD4- and functionally active CD8-T cells, and conferred full protection against lethal challenge already after a single low immunization dose of 10(5) TCID(50). Surprisingly, pre-existing immunity against wild-type vaccinia virus did not negatively influence protection. Unlike the classical 17D vaccine, the vaccinia virus-based vaccines did not cause mortality following intracerebral administration in mice, demonstrating better safety profiles. The non-replicating recombinant YF candidate live vaccines induced a broad immune response after single dose administration, were effective even in the presence of a pre-existing immunity against vaccinia virus and demonstrated an excellent safety profile in mice.

A public health initiative to increase annual influenza immunization among hospital health care personnel: the San Diego Hospital Influenza Immunization Partnership.

PubMed

Sawyer, Mark H; Peddecord, K Michael; Wang, Wendy; Deguire, Michelle; Miskewitch-Dzulynsky, Michelle; Vuong, David D

2012-09-01

A public health department-supported intervention to increase influenza immunization among hospital-based health care practitioners (HCPs) in San Diego County took place between 2005 and 2008. The study included all major hospitals in the county, with a population of approximately 3.5 million. Information on hospital activities was collected from before, during and after initiative activities. Vaccination status and demographics were collected directly from HCP using hospital-based and random-dialed telephone surveys. Between 2006 and 2008, hospitals increased promotion activities and reported increases in vaccination rates. Based on the random-dialed surveys, HCP influenza vaccination coverage rates did not increase significantly. Vaccination rates were significantly higher in HCPs who reported that employers provided free vaccination and those who believed that their employers mandated influenza vaccination. This local public health initiative and concurrent state legislation were effective in increasing employer efforts to promote influenza vaccination; however, population-based surveys of HCPs did not show significant increases in influenza vaccination. Overall, this study suggests that public health leadership, intensive employer promotion activities, and state-required declinations alone were not sufficient to significantly increase HCP influenza vaccination. Policymakers and employers should consider mandates to achieve optimal influenza vaccination among HCPs. Copyright © 2012 Association for Professionals in Infection Control and Epidemiology, Inc. Published by Mosby, Inc. All rights reserved.

A respiratory syncytial virus (RSV) vaccine based on parainfluenza virus 5 (PIV5)

PubMed Central

Phan, Shannon I.; Chen, Zhenhai; Xu, Pei; Li, Zhuo; Gao, Xiudan; Foster, Stephanie L.; Teng, Michael N.; Tripp, Ralph A.; Sakamoto, Kaori; He, Biao

2014-01-01

Human respiratory syncytial virus (RSV) is a leading cause of severe respiratory disease and hospitalizations in infants and young children. It also causes significant morbidity and mortality in elderly and immune compromised individuals. No licensed vaccine currently exists. Parainfluenza virus 5 (PIV5) is a paramyxovirus that causes no known human illness and has been used as a platform for vector-based vaccine development. To evaluate the efficacy of PIV5 as a RSV vaccine vector, we generated two recombinant PIV5 viruses - one expressing the fusion (F) protein and the other expressing the attachment glycoprotein (G) of RSV strain A2 (RSV A2). The vaccine strains were used separately for single-dose vaccinations in BALB/c mice. The results showed that both vaccines induced RSV antigen-specific antibody responses, with IgG2a/IgG1 ratios similar to those seen in wild-type RSV A2 infection. After challenging the vaccinated mice with RSV A2, histopathology of lung sections showed that the vaccines did not exacerbate lung lesions relative to RSV A2-immunized mice. Importantly, both F and G vaccines induced protective immunity. Therefore, PIV5 presents an attractive platform for vector-based vaccines against RSV infection. PMID:24717150

VIOLIN: vaccine investigation and online information network.

PubMed

Xiang, Zuoshuang; Todd, Thomas; Ku, Kim P; Kovacic, Bethany L; Larson, Charles B; Chen, Fang; Hodges, Andrew P; Tian, Yuying; Olenzek, Elizabeth A; Zhao, Boyang; Colby, Lesley A; Rush, Howard G; Gilsdorf, Janet R; Jourdian, George W; He, Yongqun

2008-01-01

Vaccines are among the most efficacious and cost-effective tools for reducing morbidity and mortality caused by infectious diseases. The vaccine investigation and online information network (VIOLIN) is a web-based central resource, allowing easy curation, comparison and analysis of vaccine-related research data across various human pathogens (e.g. Haemophilus influenzae, human immunodeficiency virus (HIV) and Plasmodium falciparum) of medical importance and across humans, other natural hosts and laboratory animals. Vaccine-related peer-reviewed literature data have been downloaded into the database from PubMed and are searchable through various literature search programs. Vaccine data are also annotated, edited and submitted to the database through a web-based interactive system that integrates efficient computational literature mining and accurate manual curation. Curated information includes general microbial pathogenesis and host protective immunity, vaccine preparation and characteristics, stimulated host responses after vaccination and protection efficacy after challenge. Vaccine-related pathogen and host genes are also annotated and available for searching through customized BLAST programs. All VIOLIN data are available for download in an eXtensible Markup Language (XML)-based data exchange format. VIOLIN is expected to become a centralized source of vaccine information and to provide investigators in basic and clinical sciences with curated data and bioinformatics tools for vaccine research and development. VIOLIN is publicly available at http://www.violinet.org.

Efficacy of commercial vaccines against newly emerging avian influenza H5N8 virus in Egypt.

PubMed

Kandeil, Ahmed; Sabir, Jamal S M; Abdelaal, Ahmed; Mattar, Ehab H; El-Taweel, Ahmed N; Sabir, Mumdooh J; Khalil, Ahmed Aly; Webby, Richard; Kayali, Ghazi; Ali, Mohamed A

2018-06-26

The newly emerging, highly pathogenic avian influenza (HPAI) H5N8 virus of clade 2.3.4.4 was recently detected in wild birds and domestic poultry in Egypt in the 2016/2017 winter season. Vaccination based on commercial H5 vaccines is used as an essential control strategy in Egyptian poultry. Here, we studied the efficacy of the eight most common commercial H5 poultry vaccines in the Egyptian market and compared them with an experimental vaccine based on the Egyptian LPAI H5N8 virus that was prepared by using reverse genetics. The experimental vaccine and Re-5 commercial vaccine were able to completely protect chickens and significantly reduce virus shedding. Our results indicate that most of the commercial poultry H5 vaccines used in the present study were ineffective because the seed viruses in these vaccines are genetically distinct from the H5N8 viruses currently circulating in Egypt. Although some of the commercial vaccines protected chickens from mortality, they failed to prevent chickens from shedding the virus. Accordingly, we recommend updating and reinforcing the H5N8 prevention and control strategies in Egypt. The vaccination strategy should be reconsidered based on currently circulating viruses.

Vaxar: A Web-Based Database of Laboratory Animal Responses to Vaccinations and Its Application in the Meta-Analysis of Different Animal Responses to Tuberculosis Vaccinations

PubMed Central

Todd, Thomas; Dunn, Natalie; Xiang, Zuoshuang; He, Yongqun

2016-01-01

Animal models are indispensable for vaccine research and development. However, choosing which species to use and designing a vaccine study that is optimized for that species is often challenging. Vaxar (http://www.violinet.org/vaxar/) is a web-based database and analysis system that stores manually curated data regarding vaccine-induced responses in animals. To date, Vaxar encompasses models from 35 animal species including rodents, rabbits, ferrets, primates, and birds. These 35 species have been used to study more than 1300 experimentally tested vaccines for 164 pathogens and diseases significant to humans and domestic animals. The responses to vaccines by animals in more than 1500 experimental studies are recorded in Vaxar; these data can be used for systematic meta-analysis of various animal responses to a particular vaccine. For example, several variables, including animal strain, animal age, and the dose or route of either vaccination or challenge, might affect host response outcomes. Vaxar can also be used to identify variables that affect responses to different vaccines in a specific animal model. All data stored in Vaxar are publically available for web-based queries and analyses. Overall Vaxar provides a unique systematic approach for understanding vaccine-induced host immunity. PMID:27053566

Vaccination with OVA-bound nanoparticles encapsulating IL-7 inhibits the growth of OVA-expressing E.G7 tumor cells in vivo.

PubMed

Toyota, Hiroko; Yanase, Noriko; Yoshimoto, Takayuki; Harada, Mitsunori; Kato, Yasuki; Mizuguchi, Junichiro

2015-01-01

Immunotherapy has gained special attention due to its specific effects on tumor cells and systemic action to block metastasis. We recently demonstrated that ovalbumin (OVA) conjugated to the surface of nanoparticles (NPs) (OVA‑NPs) can manipulate humoral immune responses. In the present study, we aimed to ascertain whether vaccination with OVA-NPs entrapping IL-7 (OVA-NPs-IL-7) are able to induce antitumor immune responses in vivo. Pretreatment with a subcutaneous inoculation of OVA-NPs delayed the growth of thymic lymphoma cells expressing a model tumor antigen OVA (E.G7-OVA), and OVA-NPs-IL-7 substantially blocked the growth of E.G7-OVA tumor cells, although NPs-IL-7 alone had a meager effect, as assessed by the mean tumor size and the percentage of tumor-free mice. However, pretreatment with OVA-NPs-IL-7 failed to reduce the growth of parental thymic tumor cells, suggesting that the antitumor effect was antigen-specific. A tetramer assay revealed that vaccination with OVA-NPs-IL-7 tended to enhance the proportion of cytotoxic T cells (CTLs) specific for OVA. When the tumor-free mice inoculated with OVA-NPs-IL-7 plus EG.7 cells were rechallenged with E.G7-OVA cells, they demonstrated reduced growth compared with that in the control mice. Thus, a single subcutaneous injection of OVA-NPs-IL-7 into mice induced tumor-specific and also memory-like immune responses, resulting in regression of tumor cells. Antigens on NPs entrapping IL-7 would be a promising carrier to develop and enhance immune responses, including humoral and cellular immunity as well as a method of drug delivery to a specific target of interest.

Evolution of the Transmission-Blocking Vaccine Candidates Pvs28 and Pvs25 in Plasmodium vivax: Geographic Differentiation and Evidence of Positive Selection

PubMed Central

Cornejo, Omar E.; Durrego, Ester; Stanley, Craig E.; Castillo, Andreína I.; Herrera, Sócrates; Escalante, Ananias A.

2016-01-01

Transmission-blocking (TB) vaccines are considered an important tool for malaria control and elimination. Among all the antigens characterized as TB vaccines against Plasmodium vivax, the ookinete surface proteins Pvs28 and Pvs25 are leading candidates. These proteins likely originated by a gene duplication event that took place before the radiation of the known Plasmodium species to primates. We report an evolutionary genetic analysis of a worldwide sample of pvs28 and pvs25 alleles. Our results show that both genes display low levels of genetic polymorphism when compared to the merozoite surface antigens AMA-1 and MSP-1; however, both ookinete antigens can be as polymorphic as other merozoite antigens such as MSP-8 and MSP-10. We found that parasite populations in Asia and the Americas are geographically differentiated with comparable levels of genetic diversity and specific amino acid replacements found only in the Americas. Furthermore, the observed variation was mainly accumulated in the EGF2- and EGF3-like domains for P. vivax in both proteins. This pattern was shared by other closely related non-human primate parasites such as Plasmodium cynomolgi, suggesting that it could be functionally important. In addition, examination with a suite of evolutionary genetic analyses indicated that the observed patterns are consistent with positive natural selection acting on Pvs28 and Pvs25 polymorphisms. The geographic pattern of genetic differentiation and the evidence for positive selection strongly suggest that the functional consequences of the observed polymorphism should be evaluated during development of TBVs that include Pvs25 and Pvs28. PMID:27347876

Cost-effectiveness analysis of influenza and pneumococcal vaccination for Hong Kong elderly in long-term care facilities.

PubMed

You, J H S; Wong, W C W; Ip, M; Lee, N L S; Ho, S C

2009-11-01

To compare cost and quality-adjusted life-years (QALYs) gained by influenza vaccination with or without pneumococcal vaccination in the elderly living in long-term care facilities (LTCFs). Cost-effectiveness analysis based on Markov modelling over 5 years, from a Hong Kong public health provider's perspective, on a hypothetical cohort of LTCF residents aged > or = 65 years. Benefit-cost ratio (BCR) and net present value (NPV) of two vaccination strategies versus no vaccination were estimated. The cost and QALYs gained by two vaccination strategies were compared by Student's t-test in probabilistic sensitivity analysis (10,000 Monte Carlo simulations). Both vaccination strategies had high BCRs and NPVs (6.39 and US$334 for influenza vaccination; 5.10 and US$332 for influenza plus pneumococcal vaccination). In base case analysis, the two vaccination strategies were expected to cost less and gain higher QALYs than no vaccination. In probabilistic sensitivity analysis, the cost of combined vaccination and influenza vaccination was significantly lower (p<0.001) than the cost of no vaccination. Both vaccination strategies gained significantly higher (p<0.001) QALYs than no vaccination. The QALYs gained by combined vaccination were significantly higher (p = 0.030) than those gained by influenza vaccination alone. The total cost of combined vaccination was significantly lower (p = 0.011) than that of influenza vaccination. Influenza vaccination with or without pneumococcal vaccination appears to be less costly with higher QALYs gained than no vaccination, over a 5-year period, for elderly people living in LTCFs from the perspective of a Hong Kong public health organisation. Combined vaccination was more likely to gain higher QALYs with lower total cost than influenza vaccination alone.

Effectiveness of Varicella Vaccination Program in Preventing Laboratory-Confirmed Cases in Children in Seoul, Korea.

PubMed

Lee, Young Hwa; Choe, Young June; Cho, Sung Il; Kang, Cho Ryok; Bang, Ji Hwan; Oh, Myoung Don; Lee, Jong Koo

2016-12-01

A universal one-dose varicella vaccination program was introduced in 2005 in Republic of Korea. However, the incidence of varicella in Korea has tripled over the last decade. We conducted a community based 1:1 matched case-control study to assess the effectiveness of one MAV strain-based vaccine and three Oka strain-based vaccines licensed for use in Korea. All cases were children in Seoul, Korea with varicella who were reported to the National Notifiable Disease Surveillance System in Seoul during 2013. The controls were age-matched children with mumps or scarlet fever but no history of varicella. We included 537 cases and 537 controls. The overall effectiveness of one dose of varicella vaccination was 13% (95% confidence interval [CI], -17.3-35.6). Of the four licensed varicella vaccines, only one was highly effective (88.9%; 95% CI, 52.1-97.4). The vaccine effectiveness for the other vaccines were 71.4% (95% CI, -37.5-94.1), -5% (95% CI, -61.9-31.9), and -100% (95% CI, -700-50.0). The overall effectiveness of vaccination was 75.8% (95% CI, 22.8-92.4) in the first year after vaccination and decreased thereafter; the effectiveness became -7.2% (95% CI, -130.9-59.2) in the fourth year after vaccination. Further studies are warranted to investigate reduced effectiveness of varicella vaccines in Korea.

Ontology-Based Combinatorial Comparative Analysis of Adverse Events Associated with Killed and Live Influenza Vaccines

PubMed Central

Sarntivijai, Sirarat; Xiang, Zuoshuang; Shedden, Kerby A.; Markel, Howard; Omenn, Gilbert S.; Athey, Brian D.; He, Yongqun

2012-01-01

Vaccine adverse events (VAEs) are adverse bodily changes occurring after vaccination. Understanding the adverse event (AE) profiles is a crucial step to identify serious AEs. Two different types of seasonal influenza vaccines have been used on the market: trivalent (killed) inactivated influenza vaccine (TIV) and trivalent live attenuated influenza vaccine (LAIV). Different adverse event profiles induced by these two groups of seasonal influenza vaccines were studied based on the data drawn from the CDC Vaccine Adverse Event Report System (VAERS). Extracted from VAERS were 37,621 AE reports for four TIVs (Afluria, Fluarix, Fluvirin, and Fluzone) and 3,707 AE reports for the only LAIV (FluMist). The AE report data were analyzed by a novel combinatorial, ontology-based detection of AE method (CODAE). CODAE detects AEs using Proportional Reporting Ratio (PRR), Chi-square significance test, and base level filtration, and groups identified AEs by ontology-based hierarchical classification. In total, 48 TIV-enriched and 68 LAIV-enriched AEs were identified (PRR>2, Chi-square score >4, and the number of cases >0.2% of total reports). These AE terms were classified using the Ontology of Adverse Events (OAE), MedDRA, and SNOMED-CT. The OAE method provided better classification results than the two other methods. Thirteen out of 48 TIV-enriched AEs were related to neurological and muscular processing such as paralysis, movement disorders, and muscular weakness. In contrast, 15 out of 68 LAIV-enriched AEs were associated with inflammatory response and respiratory system disorders. There were evidences of two severe adverse events (Guillain-Barre Syndrome and paralysis) present in TIV. Although these severe adverse events were at low incidence rate, they were found to be more significantly enriched in TIV-vaccinated patients than LAIV-vaccinated patients. Therefore, our novel combinatorial bioinformatics analysis discovered that LAIV had lower chance of inducing these two severe adverse events than TIV. In addition, our meta-analysis found that all previously reported positive correlation between GBS and influenza vaccine immunization were based on trivalent influenza vaccines instead of monovalent influenza vaccines. PMID:23209624

Liposomes containing monophosphoryl lipid A and QS-21 serve as an effective adjuvant for soluble circumsporozoite protein malaria vaccine FMP013.

PubMed

Genito, Christopher J; Beck, Zoltan; Phares, Timothy W; Kalle, Fanta; Limbach, Keith J; Stefaniak, Maureen E; Patterson, Noelle B; Bergmann-Leitner, Elke S; Waters, Norman C; Matyas, Gary R; Alving, Carl R; Dutta, Sheetij

2017-07-05

Malaria caused by Plasmodium falciparum continues to threaten millions of people living in the tropical parts of the world. A vaccine that confers sterile and life-long protection remains elusive despite more than 30years of effort and resources invested in solving this problem. Antibodies to a malaria vaccine candidate circumsporozoite protein (CSP) can block invasion and can protect humans against malaria. We have manufactured the Falciparum Malaria Protein-013 (FMP013) vaccine based on the nearly full-length P. falciparum CSP 3D7 strain sequence. We report here immunogenicity and challenge data on FMP013 antigen in C57BL/6 mice formulated with two novel adjuvants of the Army Liposome Formulation (ALF) series and a commercially available adjuvant Montanide ISA 720 (Montanide) as a control. ALF is a liposomal adjuvant containing a synthetic monophosphoryl lipid A (3D-PHAD®). In our study, FMP013 was adjuvanted with ALF alone, ALF containing aluminum hydroxide (ALFA) or ALF containing QS-21 (ALFQ). Adjuvants ALF and ALFA induced similar antibody titers and protection against transgenic parasite challenge that were comparable to Montanide. ALFQ was superior to the other three adjuvants as it induced higher antibody titers with improved boosting after the third immunization, higher serum IgG2c titers, and enhanced protection. FMP013+ALFQ also augmented the numbers of splenic germinal center-derived activated B-cells and antibody secreting cells compared to Montanide. Further, FMP013+ALFQ induced antigen-specific IFN-γ ELISPOT activity, CD4 + T-cells and a T H 1-biased cytokine profile. These results demonstrate that soluble CSP can induce a potent and sterile protective immune response when formulated with the QS-21 containing adjuvant ALFQ. Comparative mouse immunogenicity data presented here were used as the progression criteria for an ongoing non-human primate study and a regulatory toxicology study in preparation for a controlled human malaria infection (CHMI) trial. Published by Elsevier Ltd.

HPV prevalence and type-distribution in cervical cancer and premalignant lesions of the cervix: A population-based study from Northern Ireland.

PubMed

Anderson, Lesley A; O'Rorke, Michael A; Wilson, Robbie; Jamison, Jackie; Gavin, Anna T

2016-07-01

Assessment of Human papillomavirus (HPV) prevalence and genotype distribution is important for monitoring the impact of prophylactic HPV vaccination. This study aimed to demonstrate the HPV genotypes predominating in pre-malignant and cervical cancers in Northern Ireland (NI) before the vaccination campaign has effect. Formalin fixed paraffin embedded tissue blocks from 2,303 women aged 16-93 years throughout NI were collated between April 2011 and February 2013. HPV DNA was amplified by PCR and HPV genotyping undertaken using the Roche(®) linear array detection kit. In total, 1,241 out of 1,830 eligible samples (68.0%) tested positive for HPV, with the majority of these [1,181/1,830 (64.5%)] having high-risk (HR) HPV infection; 37.4% were positive for HPV-16 (n = 684) and 5.1% for HPV-18 (n = 93). HPV type-specific prevalence was 48.1%, 65.9%, 81.3%, 92.2%, and 64.3% among cervical intraepithelial neoplasias (CIN) Grades I-III, squamous cell carcinomas (SCC) and adenocarcinoma (AC) cases, respectively. Most SCC cases (81.3%) had only one HPV genotype detected and almost a third (32.0%) of all cervical pathologies were HPV negative including 51.9% of CIN I (n = 283), 34.1% CIN II (n = 145), 18.7% of CIN III (n = 146), 7.8% of SCC (n = 5), and 35.7% of AC (n = 5) cases. This study provides important baseline data for monitoring the effect of HPV vaccination in NI and for comparison with other UK regions. The coverage of other HR-HPV genotypes apart from 16 and 18, including HPV-45, 31, 39, and 52, and the potential for cross protection, should be considered when considering future polyvalent vaccines. © 2015 Wiley Periodicals, Inc.

Oral Immunization with a Multivalent Epitope-Based Vaccine, Based on NAP, Urease, HSP60, and HpaA, Provides Therapeutic Effect on H. pylori Infection in Mongolian gerbils.

PubMed

Guo, Le; Yang, Hua; Tang, Feng; Yin, Runting; Liu, Hongpeng; Gong, Xiaojuan; Wei, Jun; Zhang, Ying; Xu, Guangxian; Liu, Kunmei

2017-01-01

Epitope-based vaccine is a promising strategy for therapeutic vaccination against Helicobacter pylori ( H. pylori ) infection. A multivalent subunit vaccine containing various antigens from H. pylori is superior to a univalent subunit vaccine. However, whether a multivalent epitope-based vaccine is superior to a univalent epitope-based vaccine in therapeutic vaccination against H. pylori , remains unclear. In this study, a multivalent epitope-based vaccine named CWAE against H. pylori urease, neutrophil-activating protein (NAP), heat shock protein 60 (HSP60) and H. pylori adhesin A (HpaA) was constructed based on mucosal adjuvant cholera toxin B subunit (CTB), Th1-type adjuvant NAP, multiple copies of selected B and Th cell epitopes (UreA 27-53 , UreA 183-203 , HpaA 132-141 , and HSP60 189-203 ), and also the epitope-rich regions of urease B subunit (UreB 158-251 and UreB 321-385 ) predicted by bioinformatics. Immunological properties of CWAE vaccine were characterized in BALB/c mice model. Its therapeutic effect was evaluated in H. pylori -infected Mongolian gerbil model by comparing with a univalent epitope-based vaccine CTB-UE against H. pylori urease that was constructed in our previous studies. Both CWAE and CTB-UE could induce similar levels of specific antibodies against H. pylori urease, and had similar inhibition effect of H. pylori urease activity. However, only CWAE could induce high levels of specific antibodies to NAP, HSP60, HpaA, and also the synthetic peptides epitopes (UreB 158-172 , UreB 181-195 , UreB 211-225 , UreB 349-363 , HpaA 132-141 , and HSP60 189-203 ). In addition, oral therapeutic immunization with CWAE significantly reduced the number of H. pylori colonies in the stomach of Mongolian gerbils, compared with oral immunization using CTB-UE or H. pylori urease. The protection of CWAE was associated with higher levels of mixed CD4 + T cell (Th cell) response, IgG, and secretory IgA (sIgA) antibodies to H. pylori . These results indic ate that a multivalent epitope-based vaccine including Th and B cell epitopes from various H. pylori antigens could be a promising candidate against H. pylori infection.

Oral Immunization with a Multivalent Epitope-Based Vaccine, Based on NAP, Urease, HSP60, and HpaA, Provides Therapeutic Effect on H. pylori Infection in Mongolian gerbils

PubMed Central

Guo, Le; Yang, Hua; Tang, Feng; Yin, Runting; Liu, Hongpeng; Gong, Xiaojuan; Wei, Jun; Zhang, Ying; Xu, Guangxian; Liu, Kunmei

2017-01-01

Epitope-based vaccine is a promising strategy for therapeutic vaccination against Helicobacter pylori (H. pylori) infection. A multivalent subunit vaccine containing various antigens from H. pylori is superior to a univalent subunit vaccine. However, whether a multivalent epitope-based vaccine is superior to a univalent epitope-based vaccine in therapeutic vaccination against H. pylori, remains unclear. In this study, a multivalent epitope-based vaccine named CWAE against H. pylori urease, neutrophil-activating protein (NAP), heat shock protein 60 (HSP60) and H. pylori adhesin A (HpaA) was constructed based on mucosal adjuvant cholera toxin B subunit (CTB), Th1-type adjuvant NAP, multiple copies of selected B and Th cell epitopes (UreA27–53, UreA183–203, HpaA132–141, and HSP60189–203), and also the epitope-rich regions of urease B subunit (UreB158–251 and UreB321–385) predicted by bioinformatics. Immunological properties of CWAE vaccine were characterized in BALB/c mice model. Its therapeutic effect was evaluated in H. pylori-infected Mongolian gerbil model by comparing with a univalent epitope-based vaccine CTB-UE against H. pylori urease that was constructed in our previous studies. Both CWAE and CTB-UE could induce similar levels of specific antibodies against H. pylori urease, and had similar inhibition effect of H. pylori urease activity. However, only CWAE could induce high levels of specific antibodies to NAP, HSP60, HpaA, and also the synthetic peptides epitopes (UreB158–172, UreB181–195, UreB211–225, UreB349–363, HpaA132–141, and HSP60189–203). In addition, oral therapeutic immunization with CWAE significantly reduced the number of H. pylori colonies in the stomach of Mongolian gerbils, compared with oral immunization using CTB-UE or H. pylori urease. The protection of CWAE was associated with higher levels of mixed CD4+ T cell (Th cell) response, IgG, and secretory IgA (sIgA) antibodies to H. pylori. These results indic ate that a multivalent epitope-based vaccine including Th and B cell epitopes from various H. pylori antigens could be a promising candidate against H. pylori infection. PMID:28824883

Vesicular Stomatitis Virus Pseudotyped with Ebola Virus Glycoprotein Serves as a Protective, Noninfectious Vaccine against Ebola Virus Challenge in Mice

PubMed Central

Lennemann, Nicholas J.; Herbert, Andrew S.; Brouillette, Rachel; Rhein, Bethany; Bakken, Russell A.; Perschbacher, Katherine J.; Cooney, Ashley L.; Miller-Hunt, Catherine L.; Ten Eyck, Patrick; Biggins, Julia; Olinger, Gene; Dye, John M.

2017-01-01

ABSTRACT The recent Ebola virus (EBOV) epidemic in West Africa demonstrates the potential for a significant public health burden caused by filoviral infections. No vaccine or antiviral is currently FDA approved. To expand the vaccine options potentially available, we assessed protection conferred by an EBOV vaccine composed of vesicular stomatitis virus pseudovirions that lack native G glycoprotein (VSVΔG) and bear EBOV glycoprotein (GP). These pseudovirions mediate a single round of infection. Both single-dose and prime/boost vaccination regimens protected mice against lethal challenge with mouse-adapted Ebola virus (ma-EBOV) in a dose-dependent manner. The prime/boost regimen provided significantly better protection than a single dose. As N-linked glycans are thought to shield conserved regions of the EBOV GP receptor-binding domain (RBD), thereby blocking epitopes within the RBD, we also tested whether VSVΔG bearing EBOV GPs that lack GP1 N-linked glycans provided effective immunity against challenge with ma-EBOV or a more distantly related virus, Sudan virus. Using a prime/boost strategy, high doses of GP/VSVΔG partially or fully denuded of N-linked glycans on GP1 protected mice against ma-EBOV challenge, but these mutants were no more effective than wild-type (WT) GP/VSVΔG and did not provide cross protection against Sudan virus. As reported for other EBOV vaccine platforms, the protection conferred correlated with the quantity of EBOV GP-specific Ig produced but not with the production of neutralizing antibodies. Our results show that EBOV GP/VSVΔG pseudovirions serve as a successful vaccination platform in a rodent model of Ebola virus disease and that GP1 N-glycan loss does not influence immunogenicity or vaccination success. IMPORTANCE The West African Ebola virus epidemic was the largest to date, with more than 28,000 people infected. No FDA-approved vaccines are yet available, but in a trial vaccination strategy in West Africa, recombinant, infectious VSV encoding the Ebola virus glycoprotein effectively prevented virus-associated disease. VSVΔG pseudovirion vaccines may prove as efficacious and have better safety, but they have not been tested to date. Thus, we tested the efficacy of VSVΔG pseudovirions bearing Ebola virus glycoprotein as a vaccine platform. We found that wild-type Ebola virus glycoprotein, in the context of this platform, provides robust protection of EBOV-challenged mice. Further, we found that removal of the heavy glycan shield surrounding conserved regions of the glycoprotein does not enhance vaccine efficacy. PMID:28615211

Nanoparticulate STING agonists are potent lymph node–targeted vaccine adjuvants

PubMed Central

Hanson, Melissa C.; Crespo, Monica P.; Abraham, Wuhbet; Moynihan, Kelly D.; Szeto, Gregory L.; Chen, Stephanie H.; Melo, Mariane B.; Mueller, Stefanie; Irvine, Darrell J.

2015-01-01

Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8+ T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4+ T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. Further, NP-cdGMP promoted durable antibody titers that were substantially higher than those promoted by the well-studied TLR agonist monophosphoryl lipid A and comparable to a much larger dose of unformulated cdGMP, without the systemic toxicity of the latter. These results demonstrate that nanoparticulate delivery safely targets CDNs to the dLNs and enhances the efficacy of this adjuvant. Moreover, this approach can be broadly applied to other small-molecule immunomodulators of interest for vaccines and immunotherapy. PMID:25938786

Nanoparticulate STING agonists are potent lymph node-targeted vaccine adjuvants.

PubMed

Hanson, Melissa C; Crespo, Monica P; Abraham, Wuhbet; Moynihan, Kelly D; Szeto, Gregory L; Chen, Stephanie H; Melo, Mariane B; Mueller, Stefanie; Irvine, Darrell J

2015-06-01

Cyclic dinucleotides (CDNs) are agonists of stimulator of IFN genes (STING) and have potential as vaccine adjuvants. However, cyclic di-GMP (cdGMP) injected s.c. shows minimal uptake into lymphatics/draining lymph nodes (dLNs) and instead is rapidly distributed to the bloodstream, leading to systemic inflammation. Here, we encapsulated cdGMP within PEGylated lipid nanoparticles (NP-cdGMP) to redirect this adjuvant to dLNs. Compared with unformulated CDNs, encapsulation blocked systemic dissemination and markedly enhanced dLN accumulation in murine models. Delivery of NP-cdGMP increased CD8+ T cell responses primed by peptide vaccines and enhanced therapeutic antitumor immunity. A combination of a poorly immunogenic liposomal HIV gp41 peptide antigen and NP-cdGMP robustly induced type I IFN in dLNs, induced a greater expansion of vaccine-specific CD4+ T cells, and greatly increased germinal center B cell differentiation in dLNs compared with a combination of liposomal HIV gp41 and soluble CDN. Further, NP-cdGMP promoted durable antibody titers that were substantially higher than those promoted by the well-studied TLR agonist monophosphoryl lipid A and comparable to a much larger dose of unformulated cdGMP, without the systemic toxicity of the latter. These results demonstrate that nanoparticulate delivery safely targets CDNs to the dLNs and enhances the efficacy of this adjuvant. Moreover, this approach can be broadly applied to other small-molecule immunomodulators of interest for vaccines and immunotherapy.

A heterologous prime-boost Ebola virus vaccine regimen induces durable neutralizing antibody response and prevents Ebola virus-like particle entry in mice.

PubMed

Chen, Tan; Li, Dapeng; Song, Yufeng; Yang, Xi; Liu, Qingwei; Jin, Xia; Zhou, Dongming; Huang, Zhong

2017-09-01

Ebola virus (EBOV) is one of the most virulent pathogens known to humans. Neutralizing antibodies play a major role in the protection against EBOV infections. Thus, an EBOV vaccine capable of inducing a long-lasting neutralizing antibody response is highly desirable. We report here that a heterologous prime-boost vaccine regimen can elicit durable EBOV-neutralizing antibody response in mice. A chimpanzee serotype 7 adenovirus expressing EBOV GP (denoted AdC7-GP) was generated and used for priming. A truncated version of EBOV GP1 protein (denoted GP1t) was produced at high levels in Drosophila S2 cells and used for boosting. Mouse immunization studies showed that the AdC7-GP prime/GP1t boost vaccine regimen was more potent in eliciting neutralizing antibodies than either the AdC7-GP or GP1t alone. Neutralizing antibodies induced by the heterologous prime-boost regimen sustained at high titers for at least 18 weeks after immunization. Significantly, in vivo challenge studies revealed that the entry of reporter EBOV-like particles was efficiently blocked in mice receiving the heterologous prime-boost regimen even at 18 weeks after the final dose of immunization. These results suggest that this novel AdC7-GP prime/GP1t boost regimen represents an EBOV vaccine approach capable of establishing long-term protection, and therefore warrants further development. Copyright © 2017 Elsevier B.V. All rights reserved.

Recent advances in microparticle and nanoparticle delivery vehicles for mucosal vaccination.

PubMed

McNeela, E A; Lavelle, E C

2012-01-01

The great potential of mucosal vaccination is widely accepted but progress in the clinical development of subunit mucosal vaccines has been disappointing. Of the available approaches, the use of polymer-based microparticles is attractive because these delivery vehicles can be specifically tailored for vaccines and they offer the potential for integration of adjuvant. Here we address recent developments in the use of particulates as mucosal vaccines and the potential of novel targeting strategies, formulation approaches and adjuvant combinations to enhance the efficacy of particle-based mucosal vaccines. This review discusses the current status of mucosal vaccines based on particles and highlights several of the strategies that are currently under investigation for improving their immunogenicity. These include enhancing the stability of formulations in the luminal environment, increasing uptake by specifically targeting particles to mucosal inductive sites, and augmenting immunogenicity through co-formulation with immunostimulatory agents.

Communication technologies to improve HPV vaccination initiation and completion: A systematic review.

PubMed

Francis, Diane B; Cates, Joan R; Wagner, Kyla P Garrett; Zola, Tracey; Fitter, Jenny E; Coyne-Beasley, Tamera

2017-07-01

This systematic review examines the effectiveness of communication technology interventions on HPV vaccination initiation and completion. A comprehensive search strategy was used to identify existing randomized controlled trials testing the impact of computer-, mobile- or internet-based interventions on receipt of any dose of the HPV vaccine. Twelve relevant studies were identified with a total of 38,945 participants. The interventions were delivered using several different methods, including electronic health record (i.e. recall/reminder) prompts, text messaging, automated phone calls, interactive computer videos, and email. Vaccine initiation and completion was greater for technology-based studies relative to their control conditions. There is evidence that interventions utilizing communication technologies as their sole or primary mode for HPV vaccination intervention delivery may increase vaccination coverage. Communication technologies hold much promise for the future of HPV vaccination efforts, especially initiatives in practice-based settings. Copyright © 2017 Elsevier B.V. All rights reserved.

Protein and modified vaccinia virus Ankara-based influenza virus nucleoprotein vaccines are differentially immunogenic in BALB/c mice.

PubMed

Altenburg, A F; Magnusson, S E; Bosman, F; Stertman, L; de Vries, R D; Rimmelzwaan, G F

2017-10-01

Because of the high variability of seasonal influenza viruses and the eminent threat of influenza viruses with pandemic potential, there is great interest in the development of vaccines that induce broadly protective immunity. Most probably, broadly protective influenza vaccines are based on conserved proteins, such as nucleoprotein (NP). NP is a vaccine target of interest as it has been shown to induce cross-reactive antibody and T cell responses. Here we tested and compared various NP-based vaccine preparations for their capacity to induce humoral and cellular immune responses to influenza virus NP. The immunogenicity of protein-based vaccine preparations with Matrix-M™ adjuvant as well as recombinant viral vaccine vector modified Vaccinia virus Ankara (MVA) expressing the influenza virus NP gene, with or without modifications that aim at optimization of CD8 + T cell responses, was addressed in BALB/c mice. Addition of Matrix-M™ adjuvant to NP wild-type protein-based vaccines significantly improved T cell responses. Furthermore, recombinant MVA expressing the influenza virus NP induced strong antibody and CD8 + T cell responses, which could not be improved further by modifications of NP to increase antigen processing and presentation. © 2017 British Society for Immunology.

What Vaccines Do You Need?

MedlinePlus

... Recommendations Why Immunize? Vaccines: The Basics The Adult Vaccine Quiz Language: English Español (Spanish) Recommend on Facebook Tweet Share Compartir Vaccines are recommended for adults based on age, health ...

Barriers and Facilitators of HPV Vaccination in the VFC Program.

PubMed

Fleming, Wayne S; Sznajder, Kristin K; Nepps, Margaret; Boktor, Sameh W

2018-06-01

This study determined facilitators and barriers to human papillomavirus (HPV) vaccination perceived by providers of healthcare in the federally funded Pennsylvania Vaccines for Children (PA VFC) program. The cross-sectional study gathered descriptive data through a survey research design. Providers of healthcare were recruited through an email containing a link to an 18-question online survey. The survey was divided into four main sections which assessed the perceived facilitators and barriers to HPV vaccination of PA VFC program-eligibles. Survey respondents represented 65 of 66 Pennsylvania counties covered by the PA VFC Program. The study recruited 772 PA VFC participating healthcare facilities for a response rate of 52%. Ninety eight percent of the responding facilities reported that they offered the HPV vaccine. The most common barriers to vaccine administration were the parental belief that HPV vaccination is associated with sexual activity and parent/patient refusal of the HPV vaccination which together accounted for (44%) of responses. The majority of respondents (75.6%) indicated counseling parents and adolescents on the benefits of HPV vaccination was a very important factor in HPV vaccination uptake. Healthcare provider facility based training (32%) and web-based training for healthcare providers (22%) were the most recommended avenues for HPV training. The most common barrier to HPV vaccination was identified as the parental misconception that HPV vaccination is associated with sexual activity. Providers believed that the best way to increase HPV vaccination is through counseling parents and adolescents on the benefits of HPV vaccination and to correct misconceptions and change attitudes. Providers are desirous of receiving HPV web-based or workplace training.

Acceptance of Vaccinations in Pandemic Outbreaks: A Discrete Choice Experiment

PubMed Central

Determann, Domino; Korfage, Ida J.; Lambooij, Mattijs S.; Bliemer, Michiel; Richardus, Jan Hendrik; Steyerberg, Ewout W.; de Bekker-Grob, Esther W.

2014-01-01

Background Preventive measures are essential to limit the spread of new viruses; their uptake is key to their success. However, the vaccination uptake in pandemic outbreaks is often low. We aim to elicit how disease and vaccination characteristics determine preferences of the general public for new pandemic vaccinations. Methods In an internet-based discrete choice experiment (DCE) a representative sample of 536 participants (49% participation rate) from the Dutch population was asked for their preference for vaccination programs in hypothetical communicable disease outbreaks. We used scenarios based on two disease characteristics (susceptibility to and severity of the disease) and five vaccination program characteristics (effectiveness, safety, advice regarding vaccination, media attention, and out-of-pocket costs). The DCE design was based on a literature review, expert interviews and focus group discussions. A panel latent class logit model was used to estimate which trade-offs individuals were willing to make. Results All above mentioned characteristics proved to influence respondents’ preferences for vaccination. Preference heterogeneity was substantial. Females who stated that they were never in favor of vaccination made different trade-offs than males who stated that they were (possibly) willing to get vaccinated. As expected, respondents preferred and were willing to pay more for more effective vaccines, especially if the outbreak was more serious (€6–€39 for a 10% more effective vaccine). Changes in effectiveness, out-of-pocket costs and in the body that advises the vaccine all substantially influenced the predicted uptake. Conclusions We conclude that various disease and vaccination program characteristics influence respondents’ preferences for pandemic vaccination programs. Agencies responsible for preventive measures during pandemics can use the knowledge that out-of-pocket costs and the way advice is given affect vaccination uptake to improve their plans for future pandemic outbreaks. The preference heterogeneity shows that information regarding vaccination needs to be targeted differently depending on gender and willingness to get vaccinated. PMID:25057914

Acceptance of vaccinations in pandemic outbreaks: a discrete choice experiment.

PubMed

Determann, Domino; Korfage, Ida J; Lambooij, Mattijs S; Bliemer, Michiel; Richardus, Jan Hendrik; Steyerberg, Ewout W; de Bekker-Grob, Esther W

2014-01-01

Preventive measures are essential to limit the spread of new viruses; their uptake is key to their success. However, the vaccination uptake in pandemic outbreaks is often low. We aim to elicit how disease and vaccination characteristics determine preferences of the general public for new pandemic vaccinations. In an internet-based discrete choice experiment (DCE) a representative sample of 536 participants (49% participation rate) from the Dutch population was asked for their preference for vaccination programs in hypothetical communicable disease outbreaks. We used scenarios based on two disease characteristics (susceptibility to and severity of the disease) and five vaccination program characteristics (effectiveness, safety, advice regarding vaccination, media attention, and out-of-pocket costs). The DCE design was based on a literature review, expert interviews and focus group discussions. A panel latent class logit model was used to estimate which trade-offs individuals were willing to make. All above mentioned characteristics proved to influence respondents' preferences for vaccination. Preference heterogeneity was substantial. Females who stated that they were never in favor of vaccination made different trade-offs than males who stated that they were (possibly) willing to get vaccinated. As expected, respondents preferred and were willing to pay more for more effective vaccines, especially if the outbreak was more serious (€6-€39 for a 10% more effective vaccine). Changes in effectiveness, out-of-pocket costs and in the body that advises the vaccine all substantially influenced the predicted uptake. We conclude that various disease and vaccination program characteristics influence respondents' preferences for pandemic vaccination programs. Agencies responsible for preventive measures during pandemics can use the knowledge that out-of-pocket costs and the way advice is given affect vaccination uptake to improve their plans for future pandemic outbreaks. The preference heterogeneity shows that information regarding vaccination needs to be targeted differently depending on gender and willingness to get vaccinated.

Potential Vaccine for Anthrax

DTIC Science & Technology

1989-09-30

were then subjected to dehydration , embedding (in Epon 812) and cutting of the blocks. The sections were then stained with uranyl acetate and lead...the alcohol dehydrant . Epon 812 on the other hand requires a rigorous alcohol series dehydration followed by curing at 60°C for 48 hr or more. LR...be identified and utilized in structural characterization of the HF-extracted polysaccharide. Acid hydrolysis was done according to the Pazur and

Functional characterization and comparison of Plasmodium falciparum proteins as targets of transmission-blocking antibodies.

PubMed

Nikolaeva, Daria; Illingworth, Joseph J; Miura, Kazutoyo; Alanine, Daniel Gw; Brian, Iona J; Li, Yuanyuan; Fyfe, Alex J; Da, Dari F; Cohuet, Anna; Long, Carole A; Draper, Simon J; Biswas, Sumi

2017-10-31

Plasmodium falciparum malaria continues to evade control efforts, utilizing highly specialized sexual-stages to transmit infection between the human host and mosquito vector. In a vaccination model, antibodies directed to sexual-stage antigens, when ingested in the mosquito blood meal, can inhibit parasite growth in the midgut and consequently arrest transmission. Despite multiple datasets for the Plasmodium sexual-stage transcriptome and proteome, there have been no rational screens to identify candidate antigens for transmission-blocking vaccine (TBV) development. This study characterizes 12 proteins from across the P. falciparum sexual-stages as possible TBV targets. Recombinant proteins are heterologously expressed as full-length ectodomains in a mammalian HEK293 cell system. The proteins recapitulate native parasite epitopes as assessed by indirect fluorescence assay and a proportion exhibits immunoreactivity when tested against sera from individuals living in malaria-endemic Burkina Faso and Mali. Purified IgG generated to the mosquito-stage parasite antigen enolase demonstrates moderate inhibition of parasite development in the mosquito midgut by the ex vivo standard membrane feeding assay. The findings support the use of rational screens and comparative functional assessments in identifying proteins of the P. falciparum transmission pathway and establishing a robust pre-clinical TBV pipeline. Copyright © 2017, The American Society for Biochemistry and Molecular Biology.

A rabies serosurvey of domestic dogs in rural Tanzania: results of a rapid fluorescent focus inhibition test (RFFIT) and a liquid-phase blocking ELISA used in parallel.

PubMed Central

Cleaveland, S.; Barrat, J.; Barrat, M. J.; Selve, M.; Kaare, M.; Esterhuysen, J.

1999-01-01

During a serosurvey of domestic dogs in Tanzania, a rapid fluorescent focus inhibition test (RFFIT) and a liquid-phase blocking ELISA (LPBE) were used to measure rabies antibodies in vaccinated and unvaccinated dogs. Post-vaccination titres measured by LPBE correlated closely with those found by RFFIT. Of 567 unvaccinated dogs tested using the LPBE, 42 (7.4%) were seropositive, with titres exceeding 32. Of this group, 233 dogs were tested using the RFFIT and 115 (49.4%) were seropositive, with titres exceeding 0.5 IU/ml. Two lines of evidence pointed to the greater specificity of the LPBE when measuring rabies antibodies induced by natural infections: (a) no seropositive dogs were detected among the 162 unvaccinated dogs from the rabies-free island of Pemba, Tanzania, when using LPBE, whereas 15/145 (10.3%) dogs of the same group were seropositive using RFFIT; (b) among Tanzanian dogs there was a close association between the location of rabies cases and location of seropositive dogs when using LPBE, but not when using RFFIT. These results suggest that LPBE may be of value in rabies seroepidemiological studies and could be developed as a reference technique for the detection of rabies antibody in domestic dogs. PMID:10487652

Adenovirus-based genetic vaccines for biodefense.

PubMed

Boyer, Julie L; Kobinger, Gary; Wilson, James M; Crystal, Ronald G

2005-02-01

The robust host responses elicited against transgenes encoded by (E1-)(E3-) adenovirus (Ad) gene transfer vectors can be used to develop Ad-based vectors as platform technologies for vaccines against potential bioterror pathogens. This review focuses on pathogens of major concern as bioterror agents and why Ad vectors are ideal as anti-bioterror vaccine platforms, providing examples from our laboratories of using Ad vectors as vaccines against potential bioterror pathogens and how Ad vectors can be developed to enhance vaccine efficacy in the bioterror war.

Is Colombia reaching the goals on infant immunization coverage? A quantitative survey from 80 municipalities.

PubMed

Narváez, Javier; Osorio, May Bibiana; Castañeda-Orjuela, Carlos; Alvis Zakzuk, Nelson; Cediel, Natalia; Chocontá-Piraquive, Luz Ángela; de La Hoz-Restrepo, Fernando

2017-03-13

This study aimed to evaluate the coverage of the Colombian Expanded Program on Immunization among children less than 6years old, to evaluate the timeliness of immunization, to assess the coverage of newly introduced vaccines, and to identify factors associated with lack of immunization. We conducted a cross-sectional survey in 80 municipalities of Colombia, using a two-stage cluster random sampling. We attempted to contact all children less than 6years old living in the sampled blocks, and asked their caregivers to provide immunization record cards. We also collected basic sociodemographic information. We reached 81% of the attempted household contacts, identifying 18,232 children; of them, 14,805 (83%) had an immunization record card. Coverage for traditional vaccines was above 90%: BCG (tuberculosis) 95.7% (95%CI: 95.1-96.4), pentavalent vaccine 93.3% (92.4-94.3), MMR (measles, mumps, rubella) initial dose 94.5% (93.5-95.6); but it was lower for recently introduced vaccines: rotavirus 80% (77.8-82.1), influenza 48.4% (45.9-50.8). Results for timely vaccination were not equally successful: pentavalent vaccine 44.2% (41.4-47.1), MMR initial dose 71.2% (68.9-73.4). Mother's education was significantly associated with higher immunization odds. Older age, a greater number of siblings, low socioeconomic status, and not having health insurance were significantly associated with lower immunization odds. There was significant heterogeneity in immunization rates by municipality across the country. Although absolute immunization coverage for traditional vaccines met the goal of 90% for the 80 municipalities combined, disparities in coverage across municipalities, delayed immunization, and decline of coverage with age, are common problems in Colombia that may result in reduced protection. Newly introduced vaccines require additional efforts to reach the goal. These results highlight the association of health inequities with low immunization coverage and delayed immunization. Identification of vulnerable populations and their missed opportunities for vaccination may help to improve the reach of immunization programs. Copyright © 2017 Elsevier Ltd. All rights reserved.

Head-to-head immunogenicity comparison of Edmonston-Zagreb vs. AIK-C measles vaccine strains in infants aged 8-12 months: A randomized clinical trial.

PubMed

Izadi, Shahrokh; Zahraei, Seyed Mohsen; Salehi, Masoud; Mohammadi, Mahdi; Tabatabaei, Seyed Mehdi; Mokhtari-Azad, Talat

2018-01-29

A non-inferiority multi-centre parallel randomized double-blind trial was implemented in Zahedan district, Sistan-va-Baluchestan province, Iran, to compare the performance of the two measles vaccines which are in use in the National Immunization Programme of Iran and are of two different measles virus vaccine strains: Edmonston-Zagreb (EZ) strain vs. AIK-C strain. The main outcome measure was appearance of anti-measles antibody in sera. 200 infants, 8-12 months old, whose parents consented for their children to be included in the study, were randomized in permutation blocks of size 4-8 in four Urban Health Clinics. Having given a pre-vaccination blood sample, they received measles-rubella vaccine containing one of the vaccine strains mentioned before. After 60 days, the second blood sample was taken. The sera of the pre- and post-vaccination blood samples were tested for anti-measles antibodies in the National Reference Measles Laboratory. Parents, laboratory technicians and statistician were blind to groupings. Of the 200 children equally randomized in the two arms, 185 who were seronegative before vaccination (88 in the EZ arm and 97 in the AIK-C arm) were entered in the final analysis. The seroconversion rate in the EZ arm was 76.1% (95% CI: 60.2-85.2%), and that in the AIK-C arm was 58.7%; (95% CI: 48.8-68.7%). The absolute rate difference was 17. 4% (4.1-30.9%; P-value: .012), and the relative seroconversion rate of EZ to AIK-C was 1.3 (95% CI: 1.1-1.6; P-value: .012). No adverse events were reported during the study period. A considerable difference in the seropositivity of different measles containing vaccines could be demonstrated in the first year of life. Iranian Registry of Clinical Trials Registration Number: IRCT2016032827144N1; May 10, 2016 (www.who.int/ictrp/network/irct/en/). Copyright © 2017 Elsevier Ltd. All rights reserved.

Bacteriophage T4 as a Nanoparticle Platform to Display and Deliver Pathogen Antigens: Construction of an Effective Anthrax Vaccine.

PubMed

Tao, Pan; Li, Qin; Shivachandra, Sathish B; Rao, Venigalla B

2017-01-01

Protein-based subunit vaccines represent a safer alternative to the whole pathogen in vaccine development. However, limitations of physiological instability and low immunogenicity of such vaccines demand an efficient delivery system to stimulate robust immune responses. The bacteriophage T4 capsid-based antigen delivery system can robustly elicit both humoral and cellular immune responses without any adjuvant. Therefore, it offers a strong promise as a novel antigen delivery system. Currently Bacillus anthracis, the causative agent of anthrax, is a serious biothreat agent and no FDA-approved anthrax vaccine is available for mass vaccination. Here, we describe a potential anthrax vaccine using a T4 capsid platform to display and deliver the 83 kDa protective antigen, PA, a key component of the anthrax toxin. This T4 vaccine platform might serve as a universal antigen delivery system that can be adapted to develop vaccines against any infectious disease.

Biodegradable polymeric microsphere-based vaccines and their applications in infectious diseases.

PubMed

Lin, Chi-Ying; Lin, Shih-Jie; Yang, Yi-Chen; Wang, Der-Yuan; Cheng, Hwei-Fang; Yeh, Ming-Kung

2015-01-01

Vaccination, which provides effective, safe infectious disease protection, is among the most important recent public health and immunological achievements. However, infectious disease remains the leading cause of death in developing countries because several vaccines require repeated administrations and children are often incompletely immunized. Microsphere-based systems, providing controlled release delivery, can obviate the need for repeat immunizations. Here, we review the function of sustained and pulsatile release of biodegradable polymeric microspheres in parenteral and mucosal single-dose vaccine administration. We also review the active-targeting function of polymeric particles. With their shield and co-delivery functions, polymeric particles are applied to develop single-dose and mucosally administered vaccines as well as to improve subunit vaccines. Because polymeric particles are easily surface-modified, they have been recently used in vaccine development for cancers and many infectious diseases without effective vaccines (e.g., human immunodeficiency virus infection). These polymeric particle functions yield important vaccine carriers and multiple benefits.

Identifying gnostic predictors of the vaccine response.

PubMed

Haining, W Nicholas; Pulendran, Bali

2012-06-01

Molecular predictors of the response to vaccination could transform vaccine development. They would allow larger numbers of vaccine candidates to be rapidly screened, shortening the development time for new vaccines. Gene-expression based predictors of vaccine response have shown early promise. However, a limitation of gene-expression based predictors is that they often fail to reveal the mechanistic basis of their ability to classify response. Linking predictive signatures to the function of their component genes would advance basic understanding of vaccine immunity and also improve the robustness of vaccine prediction. New analytic tools now allow more biological meaning to be extracted from predictive signatures. Functional genomic approaches to perturb gene expression in mammalian cells permit the function of predictive genes to be surveyed in highly parallel experiments. The challenge for vaccinologists is therefore to use these tools to embed mechanistic insights into predictors of vaccine response. Copyright © 2012 Elsevier Ltd. All rights reserved.

Quality of Web-Based Educational Interventions for Clinicians on Human Papillomavirus Vaccine: Content and Usability Assessment

PubMed Central

Bishop, James M; McDonald, Skye L; Kahn, Jessica A; Kreps, Gary L

2018-01-01

Background Human papillomavirus (HPV) vaccination rates fall far short of Healthy People 2020 objectives. A leading reason is that clinicians do not recommend the vaccine consistently and strongly to girls and boys in the age group recommended for vaccination. Although Web-based HPV vaccine educational interventions for clinicians have been created to promote vaccination recommendations, rigorous evaluations of these interventions have not been conducted. Such evaluations are important to maximize the efficacy of educational interventions in promoting clinician recommendations for HPV vaccination. Objective The objectives of our study were (1) to expand previous research by systematically identifying HPV vaccine Web-based educational interventions developed for clinicians and (2) to evaluate the quality of these Web-based educational interventions as defined by access, content, design, user evaluation, interactivity, and use of theory or models to create the interventions. Methods Current HPV vaccine Web-based educational interventions were identified from general search engines (ie, Google), continuing medical education search engines, health department websites, and professional organization websites. Web-based educational interventions were included if they were created for clinicians (defined as individuals qualified to deliver health care services, such as physicians, clinical nurses, and school nurses, to patients aged 9 to 26 years), delivered information about the HPV vaccine and how to increase vaccination rates, and provided continuing education credits. The interventions’ content and usability were analyzed using 6 key indicators: access, content, design, evaluation, interactivity, and use of theory or models. Results A total of 21 interventions were identified, out of which 7 (33%) were webinars, 7 (33%) were videos or lectures, and 7 (33%) were other (eg, text articles, website modules). Of the 21 interventions, 17 (81%) identified the purpose of the intervention, 12 (57%) provided the date that the information had been updated (7 of these were updated within the last 6 months), 14 (67%) provided the participants with the opportunity to provide feedback on the intervention, and 5 (24%) provided an interactive component. None of the educational interventions explicitly stated that a theory or model was used to develop the intervention. Conclusions This analysis demonstrates that a substantial proportion of Web-based HPV vaccine educational interventions has not been developed using established health education and design principles. Interventions designed using these principles may increase strong and consistent HPV vaccination recommendations by clinicians. PMID:29453187

Facilitators and barriers to the use of standing orders for vaccination in obstetrics and gynecology settings.

PubMed

Barnard, Juliana G; Dempsey, Amanda F; Brewer, Sarah E; Pyrzanowski, Jennifer; Mazzoni, Sara E; O'Leary, Sean T

2017-01-01

Many young and middle-aged women receive their primary health care from their obstetrician-gynecologists. A recent change to vaccination recommendations during pregnancy has forced the integration of new clinical processes at obstetrician-gynecology practices. Evidence-based best practices for vaccination delivery include the establishment of vaccination standing orders. As part of an intervention to increase adoption of evidence-based vaccination strategies for women in safety-net and private obstetrician-gynecology settings, we conducted a qualitative study to identify the facilitators and barriers experienced by obstetrician-gynecology sites when establishing vaccination standing orders. At 6 safety-net and private obstetrician-gynecology practices, 51 semistructured interviews were completed by trained qualitative researchers over 2 years with clinical staff and vaccination program personnel. Standardized qualitative research methods were used during data collection and team-based data analysis to identify major themes and subthemes within the interview data. All study practices achieved partial to full implementation of vaccine standing orders for human papillomavirus, tetanus diphtheria pertussis, and influenza vaccines. Facilitating factors for vaccine standing order adoption included process standardization, acceptance of a continual modification process, and staff training. Barriers to vaccine standing order adoption included practice- and staff-level competing demands, pregnant women's preference for medical providers to discuss vaccine information with them, and staff hesitation in determining HPV vaccine eligibility. With guidance and commitment to integration of new processes, obstetrician-gynecology practices are able to establish vaccine standing orders for pregnant and nonpregnant women. Attention to certain process barriers can aid the adoption of processes to support the delivery of vaccinations in obstetrician-gynecology practice setting, and provide access to preventive health care for many women. Copyright © 2016 Elsevier Inc. All rights reserved.

The effect of exercise on vaccine-related pain, anxiety and fear during HPV vaccinations in adolescents.

PubMed

Lee, V Y; Booy, R; Skinner, R; Edwards, K M

2018-05-31

With increased school-based vaccinations for improved coverage rates and practicality, the World Health Organization (WHO) recently endorsed research to identify possible interventions to reduce vaccine-related pain in mass clinical and school-based settings. In particular, the lack of research in adolescents indicate a particular need in this population. Acute exercise has analgesic effects and has been used as a behavioural adjuvant to vaccination. Here, we examine the effect of exercise on vaccine-related pain, anxiety and fear in adolescents, during a school-based program for HPV vaccinations. 116 students (Female: 61, Male: 55) aged 11-13 years were randomly allocated to either an Exercise (n = 60) or Control (n = 56) group. All participants completed demographic and Trait-anxiety questionnaires prior to receiving the vaccine according to usual care. The Exercise group also performed upper body exercise for 15 min prior to receiving the vaccine. Immediately after the vaccine administration, all participants reported on pain, anxiety and fear at the time of receiving the vaccine. Female adolescents in the Exercise group reported significantly less pain (3.64; 95% CI, 2.98-4.30) than Controls (4.58; 95% CI, 3.96-5.19; p = 0.04). Further, females reported greater pain and anxiety than males in the Control group but not the Exercise group. This study supports the use of exercise prior to vaccine administration, especially in female adolescents who are particularly vulnerable to negative experiences during vaccination procedures. Furthermore, the ease of application, as well as the benefit of exercise, provides support for the use of simple exercise prior to vaccination in mass vaccination settings. Clinical trial registry: ANZCTR, ACTRN12614001185651. Copyright © 2018 Elsevier Ltd. All rights reserved.

The impact of non-financial and financial encouragements on participation in non school-based human papillomavirus vaccination: a retrospective cohort study.

PubMed

Lefevere, Eva; Hens, Niel; De Smet, Frank; Beutels, Philippe

2016-04-01

Adolescent vaccination coverage under a system of non school-based vaccination is likely to be suboptimal, but might be increased by targeted encouragement campaigns. We analysed the effect on human papillomavirus (HPV) vaccination initiation by girls aged 12-18 of two campaigns set up in Flanders (Belgium) in 2007 and 2009: a personal information campaign and a combined personal information and financial incentive campaign. We analysed (objective) data on HPV vaccination behaviour from the National Alliance of Christian Mutualities (NACM), Flanders' largest sickness fund. We used z-scores to compare the monthly proportion of girls initiating HPV vaccination over time between carefully selected intervention and control groups. Separate analyses were done for older and younger girls. Total sample sizes of the intervention (control) groups were 221 (243) for the personal information campaign and 629 (5,322) for the combined personal information and financial incentive campaign. The personal information campaign significantly increased vaccination initiation, with older girls reacting faster. One year after the campaign the percentages of vaccination initiation for the oldest girls were 64.6 and 42.8 % in the intervention and control group, respectively (z = 3.35, p = 0.0008); for the youngest girls the percentages were 78.4 and 68.1 % (z = 1.71, p = 0.09). The combined personal information and financial incentive campaign increased vaccination initiation among certain age groups. One year after the campaign the difference in percentage points for HPV vaccination initiation between intervention and control groups varied between 18.5 % (z = 3.65, p = 0.0002) and 5.1 % (z = 1.12, p = 0.26). Under a non school-based vaccination system, personal information and removing out-of-pocket costs had a significant positive effect on HPV vaccination initiation, although the effect substantially varied in magnitude. Overall, the obtained vaccination rates remained far below those realised under school-based HPV vaccination.

A population based study comparing changes in rotavirus burden on the Island of Ireland between a highly vaccinated population and an unvaccinated population.

PubMed

Armstrong, Gillian; Gallagher, Naomh; Cabrey, Paul; Graham, Adele M; McKeown, Paul J; Jackson, Sarah; Dallat, Mary; Smithson, Richard D

2016-09-07

Rotavirus infection is a leading cause of gastroenteritis in infants and children globally. Reductions in rotavirus activity have been observed following introduction of rotavirus vaccination programmes, however a reductions have also been reported in some unvaccinated countries. The Island of Ireland incorporates the two jurisdictions Northern Ireland (NI) and the Republic of Ireland (IE). Both have similarities in climate, demography, morbidity and mortality but distinct health administrations and vaccination policies. Rotarix was added to the childhood immunisation programme in NI on the 1 July 2013. IE have not introduced routine rotavirus vaccination to date. The aim of this population based ecological study was to evaluate the impact of the rotavirus vaccine on burden of rotavirus disease in NI, and to compare with IE as an unvaccinated control population. This will help determine if the changes seen were due to the rotavirus vaccine, or due to confounding factors. A number of population based measures of disease burden were compared in both jurisdictions pre-vaccine (six years; 2007/08-2012/13) and post-vaccine (two years; 2013/14-2014/15). The data sources included national rotavirus surveillance data based on laboratory reports/notifications; hospital admission data; and notifications of gastroenteritis in under 2year olds. In the post-vaccination period, rotavirus incidence in NI dropped by 54% while in IE it increased by 19% compared to the pre-vaccine period. Notifications of gastroenteritis in under 2s in NI declined by 53% and hospital admissions in under 5year olds in NI declined by 40% in the post vaccine period. This natural experiment demonstrated a significant reduction in rotavirus disease activity post-vaccine introduction in NI with associated reductions in healthcare utilisation, with a concurrent increase in rotavirus disease activity in the non-vaccinated population in IE. These findings support rotavirus vaccination as an effective measure to reduce childhood morbidity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effectiveness of Rubella vaccine in a rubella outbreak in Guangzhou city, China, 2014.

PubMed

Chang, Caiyun; Mo, Xianghuan; Hu, Pei; Liang, Wenjia; Ma, Huilai; An, Zhijie; Liu, Jun; Zheng, Huizhen

2015-06-22

WHO recommends the use of rubella-containing vaccine (RCVs) to prevent rubella and congenital rubella syndrome (CRS). Most licensed rubella vaccines in use globally are based on RA27/3 strains and have estimated vaccine effectiveness (VE) rates of 95-100%. In contrast, China uses a BRD-II strain-based rubella vaccine. Few field studies have been conducted that estimate VE of China's RCV. On March 17, 2014, a rubella outbreak was reported in a middle school in Guangzhou city, China. We conducted an investigation to understand reasons for the outbreak, and we used that investigation to estimate vaccine effectiveness of China's rubella vaccine. To identify cases, investigators reviewed records kept by the school doctor and absentee records kept by teachers. Self-administered questionnaires were sent to parents of all students to collect information about the students' symptoms, the results of any physician consultation, and disease history. We obtained demographic information and illness information for all students in the school; vaccination status was determined by inspection of official, parent-held vaccination records. A retrospective cohort study was conducted in 13 classes that had secondary cases of rubella. Using the secondary attack rates, we evaluated VE by the number of RCV doses received and age at vaccination. During the period February 17-May 23, 2014, 162 students (50 suspected cases, 88 probable cases, 24 confirmed cases) were diagnosed with rubella, yielding an overall attack rate of 10% (162/1621). Cases occurred in 27 classes (73%) of 37 classrooms. Secondary cases occurred in 13 classes (35%) of 37 classrooms. A total of 1130 students (69.7%) have vaccination certificates; 419 (37%) students were record-confirmed to have received RCV. For those vaccinated using BRD-II strain vaccine, vaccine effectiveness (VE) was 94% (95%CI: 75-98). VE for measles, mumps, and rubella (MMR) vaccine which is based on either BRD-II or RA27/3 strain was 89% (95%CI: 56-97). VE of a single dose of domestic monovalent rubella vaccine that used BRD-II strain vaccine was 93% (95%CI: 73-98). VE for those who received the vaccine between 1 and 2 years of age was 95% (95% CI: 67-99) while the VE was 100% for those vaccinated after 2 years of age. VE among those who received RCV <12 years ago was 100% while VE among those who received RCV ≥12 years ago was 92% (95%CI: 70-98). The rubella vaccines used in China that are based on the BRD-II rubella vaccine strain have VE of 94%, which is similar to the more commonly used RA27/3-based RCVs. Low vaccination coverage contributed to this outbreak; early reporting of an outbreak is necessary for effective outbreak response immunization. Copyright © 2015 Elsevier Ltd. All rights reserved.

[The historical development of immunization in Germany. From compulsory smallpox vaccination to a National Action Plan on Immunization].

PubMed

Klein, S; Schöneberg, I; Krause, G

2012-11-01

In the German Reich, smallpox vaccinations were organized by the state. A mandatory vaccination throughout the empire was introduced in 1874, which was continued in the Federal Republic of Germany (FRG) and the German Democratic Republic (GDR) until 1982/1983. From 1935, health departments were responsible for vaccinations. In the GDR, immunization was tightly organized: The state made great efforts to achieve high vaccination rates. Responsibilities were clearly defined at all levels and for all ages. While vaccination was initially mandatory only at the regional level, the legally mandated immunization schedule later contained compulsory vaccinations, e.g., against measles. In the beginning there were mandatory vaccinations in the FRG at the Länder level. Since 1961, the Federal Epidemics Act has impeded obligatory vaccinations. Instead, voluntary vaccinations based on recommendations were stressed. Since the 1980s, vaccinations have been shifted from the public health service sector to office-based physicians. Today, public health authorities offer mainly supplementary vaccinations. In 2007, protective immunizations were introduced as compulsory benefits of the statutory health insurance (SHI). Recently, the German federal states developed a National Vaccination Plan to support immunization strategies.

Ethical and legal challenges of vaccines and vaccination: Reflections.

PubMed

Jesani, Amar; Johari, Veena

2017-01-01

Vaccines and vaccination have emerged as key medical scientific tools for prevention of certain diseases. Documentation of the history of vaccination shows that the initial popular resistance to universal vaccination was based on false assumptions and eventually gave way to acceptance of vaccines and trust in their ability to save lives. The successes of the global eradication of smallpox, and now of polio, have only strengthened the premier position occupied by vaccines in disease prevention. However, the success of vaccines and public trust in their ability to eradicate disease are now under challenge, as increasing numbers of people refuse vaccination, questioning the effectiveness of vaccines and the need to vaccinate.

Nucleic acid-based vaccines targeting respiratory syncytial virus: Delivering the goods.

PubMed

Smith, Trevor R F; Schultheis, Katherine; Broderick, Kate E

2017-11-02

Respiratory syncytial virus (RSV) is a massive medical burden on a global scale. Infants, children and the elderly represent the vulnerable populations. Currently there is no approved vaccine to protect against the disease. Vaccine development has been hindered by several factors including vaccine enhanced disease (VED) associated with formalin-inactivated RSV vaccines, inability of target populations to raise protective immune responses after vaccination or natural viral infection, and a lack of consensus concerning the most appropriate virus-associated target antigen. However, with recent advances in the molecular understanding of the virus, and design of highly characterized vaccines with enhanced immunogenicity there is new belief a RSV vaccine is possible. One promising approach is nucleic acid-based vaccinology. Both DNA and mRNA RSV vaccines are showing promising results in clinically relevant animal models, supporting their transition into humans. Here we will discuss this strategy to target RSV, and the ongoing studies to advance the nucleic acid vaccine platform as a viable option to protect vulnerable populations from this important disease.