Sample records for vaccine candidates based

  1. Recombinant BCG vaccine candidates.

    PubMed

    Hernàndez-Pando, Rogelio; Castañòn, Mauricio; Espitia, Clara; Lopez-Vidal, Yolanda

    2007-06-01

    Given the variable protective efficacy provided by Mycobacterium bovis BCG (Bacillus Calmette-Guérin), there is a concerted effort worldwide to develop better vaccines that could be used to reduce the burden of tuberculosis. Recombinant BCG (rBCG) are vaccine candidates that offer some potential in this area. In this paper, we will discuss the molecular methods used to generate rBCG, and the results obtained with some of these new vaccines as compared with the conventional BCG vaccine in diverse animal models. Tuberculosis vaccine candidates based on rBCG are promising candidates, and some of them are now being tested in clinical trials.

  2. Study of rubella candidate vaccine based on a structurally modified plant virus.

    PubMed

    Trifonova, Ekaterina A; Zenin, Vladimir A; Nikitin, Nikolai A; Yurkova, Maria S; Ryabchevskaya, Ekaterina M; Putlyaev, Egor V; Donchenko, Ekaterina K; Kondakova, Olga A; Fedorov, Alexey N; Atabekov, Joseph G; Karpova, Olga V

    2017-08-01

    A novel rubella candidate vaccine based on a structurally modified plant virus - spherical particles (SPs) - was developed. SPs generated by the thermal remodelling of the tobacco mosaic virus are promising platforms for the development of vaccines. SPs combine unique properties: biosafety, stability, high immunogenicity and the effective adsorption of antigens. We assembled in vitro and characterised complexes (candidate vaccine) based on SPs and the rubella virus recombinant antigen. The candidate vaccine induced a strong humoral immune response against rubella. The IgG isotypes ratio indicated the predominance of IgG1 which plays a key role in immunity to natural rubella infection. The immune response was generally directed against the rubella antigen within the complexes. We suggest that SPs can act as a platform (depot) for the rubella antigen, enhancing specific immune response. Our results demonstrate that SPs-antigen complexes can be an effective and safe candidate vaccine against rubella. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Ebola vaccines in clinical trial: The promising candidates

    PubMed Central

    Wang, Yuxiao; Li, Jingxin; Hu, Yuemei; Liang, Qi; Wei, Mingwei; Zhu, Fengcai

    2017-01-01

    ABSTRACT Ebola virus disease (EVD) has become a great threat to humans across the world in recent years. The 2014 Ebola epidemic in West Africa caused numerous deaths and attracted worldwide attentions. Since no specific drugs and treatments against EVD was available, vaccination was considered as the most promising and effective method of controlling this epidemic. So far, 7 vaccine candidates had been developed and evaluated through clinical trials. Among them, the recombinant vesicular stomatitis virus-based vaccine (rVSV-EBOV) is the most promising candidate, which demonstrated a significant protection against EVD in phase III clinical trial. However, several concerns were still associated with the Ebola vaccine candidates, including the safety profile in some particular populations, the immunization schedule for emergency vaccination, and the persistence of the protection. We retrospectively reviewed the current development of Ebola vaccines and discussed issues and challenges remaining to be investigated in the future. PMID:27764560

  4. Anti-Lyme Subunit Vaccines: Design and Development of Peptide-Based Vaccine Candidates.

    PubMed

    Small, Christina M; Mwangi, Waithaka; Esteve-Gassent, Maria D

    2016-01-01

    Vaccinology today has been presented with several avenues to improve protection against infectious disease. The recent employment of the reverse vaccinology technique has changed the face of vaccine development against many pathogens, including Borrelia burgdorferi, the causative agent of Lyme disease. Using this technique, genomics and in silico analyses come together to identify potentially antigenic epitopes in a high-throughput fashion. The forward methodology of vaccine development was used previously to generate the only licensed human vaccine for Lyme disease, which is no longer on the market. Using reverse vaccinology to identify new antigens and isolate specific epitopes to protect against B. burgdorferi, subunit vaccines will be generated that lack reactogenic and nonspecific epitopes, yielding more effective vaccine candidates. Additionally, novel epitopes are being utilized and are presently in the commercialization pipeline both for B. burgdorferi and other spirochaetal pathogens. The versatility and methodology of the subunit protein vaccine are described as it pertains to Lyme disease from conception to performance evaluation.

  5. Marker vaccine strategies and candidate CSFV marker vaccines.

    PubMed

    Dong, Xiao-Nan; Chen, Ying-Hua

    2007-01-04

    Classical swine fever (CSF) is an economically important highly contagious disease of swine worldwide. Classical swine fever virus (CSFV) is its etiological agent, and the only natural hosts are domestic pigs and wild boars. Although field CSFV strains vary in the virulence, they all result in serious losses in pig industry. Highly virulent field strains generally cause acute disease and high mortality; moderately virulent field strains raise subacute or chronic infections; postnatal infection by low virulent field strains produces subclinical infection and mortality in the new-born piglets. CSFV can cross the placental barrier, and this transplacental transmission usually results in mortality of fetuses and birth of congenitally infected pigs with a late-onset disease and death. Two main strategies to control CSF epidemic are systematic prophylactic vaccination with live attenuated vaccines (such as C-strain) and non-vaccination stamping-out policy. But neither of them is satisfying enough. Marker vaccine and companion serological diagnostic test is thought to be a promising strategy for future control and eradication of CSF. During the past 15 years, various candidate marker vaccines were constructed and evaluated in the animal experiments, including recombinant chimeric vaccines, recombinant deletion vaccines, DNA vaccines, subunit vaccines and peptide vaccines. Among them, two subunit vaccines entered the large scale marker vaccine trial of EU in 1999. Although they failed to fulfil all the demands of the Scientific Veterinary Committee, they successfully induced solid immunity against CSFV in the vaccinated pigs. It can be expected that new potent marker vaccines might be commercially available and used in systematic prophylactic vaccination campaign or emergency vaccination in the next 15 years. Here, we summarized current strategies and candidate CSFV marker vaccines. These strategies and methods are also helpful for the development of new

  6. Vaccine candidates for malaria: what's new?

    PubMed

    Takashima, Eizo; Morita, Masayuki; Tsuboi, Takafumi

    2016-01-01

    Although it is more than a decade since the parasite genome information was obtained, standardized novel genome-wide selection/prioritization strategies for candidacy of malaria vaccine antigens are still sought. In the quest to systematically identify candidates, it is impossible to overemphasize the usefulness of wheat germ cell-free technology in expressing quality proteins for the post-genome vaccine candidate discovery.

  7. Combat pneumococcal infections: adhesins as candidates for protein-based vaccine development.

    PubMed

    Gamez, Gustavo; Hammerschmidt, Sven

    2012-03-01

    Streptococcus pneumoniae (pneumococcus) is an asymptomatic colonizer of the upper respiratory tract in humans. However, these apparently harmless bacteria have also a high virulence potential and are known as the etiologic agent of respiratory and life-threatening invasive diseases. Dissemination of pneumococci from the nasopharynx into the lungs or bloodstream leads to community-acquired pneumonia, septicaemia and meningitis. Traditionally, pneumococcal diseases are treated with antibiotics and prevented with polysaccharide-based vaccines. However, due to the dramatic increase in antibiotic resistance and limitations of the current available vaccines, the burden of diseases remains high. Thus, combating pneumococcal transmission and infections has emphasized the need for a new generation of protein-based vaccines. Interactions of pneumococci with soluble host proteins or cellular receptors are crucial for adherence, colonization, transmigration of host barriers and immune evasion. Therefore, surface-exposed proteins involved in these pathogenic processes and virtually expressed by all pneumococcal strains and serotypes are the prime potential targets for an immunogenic and highly protective pneumococcal-derived carrier protein of a vaccine. In this review, we will address the state of the art in deciphering, i). the conservation, distribution and pathogenic role of recently discovered pneumococcal adhesins in colonization and invasive diseases, ii). the interactions of these virulence factors with host-proteins and receptors, iii). the subversion of the host immune and cellular responses, and iv). the potential of pneumococcal adhesins as vaccine candidates.

  8. 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

  9. Production of EV71 vaccine candidates

    PubMed Central

    Chong, Pele; Hsieh, Shih-Yang; Liu, Chia-Chyi; Chou, Ai-Hsiang; Chang, Jui-Yuan; Wu, Suh-Chin; Liu, Shih-Jen; Chow, Yen-Hung; Su, Ih-Jen; Klein, Michel

    2012-01-01

    Enterovirus 71 (EV71) is now recognized as an emerging neurotropic virus in Asia and with Coxsackie virus (CV) it is the other major causative agent of hand-foot-mouth diseases (HFMD). Effective medications and/or prophylactic vaccines against HFMD are urgently needed. From a scientific (the feasibility of bioprocess, immunological responses and potency in animal challenge model) and business development (cost of goods) points of view, we in this review address and discuss the pros and cons of different EV71 vaccine candidates that have been produced and evaluated in animal models. Epitope-based synthetic peptide vaccine candidates containing residues 211–225 of VP1 formulated with Freund’s adjuvant (CFA/IFA) elicited low EV71 virus neutralizing antibody responses, but were protective in the suckling mouse challenge model. Among recombinant EV71 subunits (rVP1, rVP2 and rVP3) expressed in E. coli, purified and formulated with CFA/IFA, only VP1 elicited mouse antibody responses with measurable EV71-specific virus neutralization titers. Immunization of mice with either a DNA plasmid containing VP1 gene or VP1 expressed in Salmonella typhimurium also generated neutralizing antibody responses and protected animals against a live EV71 challenge. Recombinant EV71 virus-like particles (rVLP) produced from baculovirus formulated either with CFA/IFA or alum elicited good virus neutralization titers in both mice and non-human primates, and were found to be protective in the suckling mouse EV71 challenge model. Synthetic peptides or recombinant EV71 subunit vaccines (rVP1 and rVLP) formulated in alum were found to be poorly immunogenic in rabbits. Only formalin-inactivated (FI) EV71 virions formulated in alum elicited cross-neutralizing antibodies against different EV71 genotypes in mice, rabbits and non-human primates but induced weak neutralizing responses against CAV16. From a regulatory, economic and market acceptability standpoint, FI-EV71 virion vaccines are the

  10. Production of EV71 vaccine candidates.

    PubMed

    Chong, Pele; Hsieh, Shih-Yang; Liu, Chia-Chyi; Chou, Ai-Hsiang; Chang, Jui-Yuan; Wu, Suh-Chin; Liu, Shih-Jen; Chow, Yen-Hung; Su, Ih-Jen; Klein, Michel

    2012-12-01

    Enterovirus 71 (EV71) is now recognized as an emerging neurotropic virus in Asia and with Coxsackie virus (CV) it is the other major causative agent of hand-foot-mouth diseases (HFMD). Effective medications and/or prophylactic vaccines against HFMD are urgently needed. From a scientific (the feasibility of bioprocess, immunological responses and potency in animal challenge model) and business development (cost of goods) points of view, we in this review address and discuss the pros and cons of different EV71 vaccine candidates that have been produced and evaluated in animal models. Epitope-based synthetic peptide vaccine candidates containing residues 211-225 of VP1 formulated with Freund's adjuvant (CFA/IFA) elicited low EV71 virus neutralizing antibody responses, but were protective in the suckling mouse challenge model. Among recombinant EV71 subunits (rVP1, rVP2 and rVP3) expressed in E. coli, purified and formulated with CFA/IFA, only VP1 elicited mouse antibody responses with measurable EV71-specific virus neutralization titers. Immunization of mice with either a DNA plasmid containing VP1 gene or VP1 expressed in Salmonella typhimurium also generated neutralizing antibody responses and protected animals against a live EV71 challenge. Recombinant EV71 virus-like particles (rVLP) produced from baculovirus formulated either with CFA/IFA or alum elicited good virus neutralization titers in both mice and non-human primates, and were found to be protective in the suckling mouse EV71 challenge model. Synthetic peptides or recombinant EV71 subunit vaccines (rVP1 and rVLP) formulated in alum were found to be poorly immunogenic in rabbits. Only formalin-inactivated (FI) EV71 virions formulated in alum elicited cross-neutralizing antibodies against different EV71 genotypes in mice, rabbits and non-human primates but induced weak neutralizing responses against CAV16. From a regulatory, economic and market acceptability standpoint, FI-EV71 virion vaccines are the most

  11. Leishmaniasis: vaccine candidates and perspectives.

    PubMed

    Singh, Bhawana; Sundar, Shyam

    2012-06-06

    Leishmania is a protozoan parasite and a causative agent of the various clinical forms of leishmaniasis. High cost, resistance and toxic side effects of traditional drugs entail identification and development of therapeutic alternatives. The sound understanding of parasite biology is key for identifying novel drug targets, that can induce the cell mediated immunity (mainly CD4+ and CD8+ IFN-gamma mediated responses) polarized towards a Th1 response. These aspects are important in designing a new vaccine along with the consideration of the candidates with respect to their ability to raise memory response in order to improve the vaccine performance. This review is an effort to identify molecules according to their homology with the host and their ability to be used as potent vaccine candidates. Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.

  12. The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates.

    PubMed

    Mazur, Natalie I; Higgins, Deborah; Nunes, Marta C; Melero, José A; Langedijk, Annefleur C; Horsley, Nicole; Buchholz, Ursula J; Openshaw, Peter J; McLellan, Jason S; Englund, Janet A; Mejias, Asuncion; Karron, Ruth A; Simões, Eric Af; Knezevic, Ivana; Ramilo, Octavio; Piedra, Pedro A; Chu, Helen Y; Falsey, Ann R; Nair, Harish; Kragten-Tabatabaie, Leyla; Greenough, Anne; Baraldi, Eugenio; Papadopoulos, Nikolaos G; Vekemans, Johan; Polack, Fernando P; Powell, Mair; Satav, Ashish; Walsh, Edward E; Stein, Renato T; Graham, Barney S; Bont, Louis J

    2018-06-15

    The global burden of disease caused by respiratory syncytial virus (RSV) is increasingly recognised, not only in infants, but also in older adults (aged ≥65 years). Advances in knowledge of the structural biology of the RSV surface fusion glycoprotein have revolutionised RSV vaccine development by providing a new target for preventive interventions. The RSV vaccine landscape has rapidly expanded to include 19 vaccine candidates and monoclonal antibodies (mAbs) in clinical trials, reflecting the urgency of reducing this global health problem and hence the prioritisation of RSV vaccine development. The candidates include mAbs and vaccines using four approaches: (1) particle-based, (2) live-attenuated or chimeric, (3) subunit, (4) vector-based. Late-phase RSV vaccine trial failures highlight gaps in knowledge regarding immunological protection and provide lessons for future development. In this Review, we highlight promising new approaches for RSV vaccine design and provide a comprehensive overview of RSV vaccine candidates and mAbs in clinical development to prevent one of the most common and severe infectious diseases in young children and older adults worldwide. Copyright © 2018 World Health Organization. Published by Elsevier Ltd/Inc/BV. All rights reserved. Published by Elsevier Ltd.. All rights reserved.

  13. Blood-stage malaria vaccines: post-genome strategies for the identification of novel vaccine candidates.

    PubMed

    Ntege, Edward H; Takashima, Eizo; Morita, Masayuki; Nagaoka, Hikaru; Ishino, Tomoko; Tsuboi, Takafumi

    2017-08-01

    An efficacious malaria vaccine is necessary to advance the current control measures towards malaria elimination. To-date, only RTS,S/AS01, a leading pre-erythrocytic stage vaccine completed phase 3 trials, but with an efficacy of 28-36% in children, and 18-26% in infants, that waned over time. Blood-stage malaria vaccines protect against disease, and are considered effective targets for the logical design of next generation vaccines to improve the RTS,S field efficacy. Therefore, novel blood-stage vaccine candidate discovery efforts are critical, albeit with several challenges including, high polymorphisms in vaccine antigens, poor understanding of targets of naturally protective immunity, and difficulties in the expression of high AT-rich plasmodial proteins. Areas covered: PubMed ( www.ncbi.nlm.nih.gov/pubmed ) was searched to review the progress and future prospects of malaria vaccine research and development. We focused on post-genome vaccine candidate discovery, malaria vaccine development, sequence diversity, pre-clinical and clinical trials. Expert commentary: Post-genome high-throughput technologies using wheat germ cell-free protein synthesis technology and immuno-profiling with sera from malaria patients with clearly defined outcomes are highlighted to overcome current challenges of malaria vaccine candidate discovery.

  14. Vaccine candidate discovery for the next generation of malaria vaccines.

    PubMed

    Tuju, James; Kamuyu, Gathoni; Murungi, Linda M; Osier, Faith H A

    2017-10-01

    Although epidemiological observations, IgG passive transfer studies and experimental infections in humans all support the feasibility of developing highly effective malaria vaccines, the precise antigens that induce protective immunity remain uncertain. Here, we review the methodologies applied to vaccine candidate discovery for Plasmodium falciparum malaria from the pre- to post-genomic era. Probing of genomic and cDNA libraries with antibodies of defined specificities or functional activity predominated the former, whereas reverse vaccinology encompassing high throughput in silico analyses of genomic, transcriptomic or proteomic parasite data sets is the mainstay of the latter. Antibody-guided vaccine design spanned both eras but currently benefits from technological advances facilitating high-throughput screening and downstream applications. We make the case that although we have exponentially increased our ability to identify numerous potential vaccine candidates in a relatively short space of time, a significant bottleneck remains in their validation and prioritization for evaluation in clinical trials. Longitudinal cohort studies provide supportive evidence but results are often conflicting between studies. Demonstration of antigen-specific antibody function is valuable but the relative importance of one mechanism over another with regards to protection remains undetermined. Animal models offer useful insights but may not accurately reflect human disease. Challenge studies in humans are preferable but prohibitively expensive. In the absence of reliable correlates of protection, suitable animal models or a better understanding of the mechanisms underlying protective immunity in humans, vaccine candidate discovery per se may not be sufficient to provide the paradigm shift necessary to develop the next generation of highly effective subunit malaria vaccines. © 2017 The Authors. Immunology Published by John Wiley & Sons Ltd.

  15. Vaccines for leishmaniasis: from proteome to vaccine candidates.

    PubMed

    Schroeder, Juliane; Aebischer, Toni

    2011-01-01

    Leishmania spp. cause a wide spectrum of tropical diseases which are threatening an estimated 350 million people around the globe. While in most cases non-fatal, the disease is associated with high morbidity, social stigmata and poverty. However, the most severe form visceral leishmaniasis can be fatal if left untreated. Chemotherapeutics are available but show high toxicity, costs and are prone to resistance development due to prolonged treatment periods. Healing is associated with a life-long resistance to re-infection and this argues for the feasibility of vaccination. However, despite much effort, no such vaccine has become available yet. Here, the status of vaccine development in this field is briefly summarized before the focus is set on the promise of reverse vaccinology for anti-Leishmania vaccine development in the post-genomic era. We report on our own experience with this approach using an instructive example of successful candidate vaccine antigen identification.

  16. Advanced Vaccine Candidates for Lassa Fever

    PubMed Central

    Lukashevich, Igor S.

    2012-01-01

    Lassa virus (LASV) is the most prominent human pathogen of the Arenaviridae. The virus is transmitted to humans by a rodent reservoir, Mastomys natalensis, and is capable of causing lethal Lassa Fever (LF). LASV has the highest human impact of any of the viral hemorrhagic fevers (with the exception of Dengue Fever) with an estimated several hundred thousand infections annually, resulting in thousands of deaths in Western Africa. The sizeable disease burden, numerous imported cases of LF in non-endemic countries, and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. Presently there is no licensed vaccine against LF or approved treatment. Recently, several promising vaccine candidates have been developed which can potentially target different groups at risk. The purpose of this manuscript is to review the LASV pathogenesis and immune mechanisms involved in protection. The current status of pre-clinical development of the advanced vaccine candidates that have been tested in non-human primates will be discussed. Major scientific, manufacturing, and regulatory challenges will also be considered. PMID:23202493

  17. Advanced vaccine candidates for Lassa fever.

    PubMed

    Lukashevich, Igor S

    2012-10-29

    Lassa virus (LASV) is the most prominent human pathogen of the Arenaviridae. The virus is transmitted to humans by a rodent reservoir, Mastomys natalensis, and is capable of causing lethal Lassa Fever (LF). LASV has the highest human impact of any of the viral hemorrhagic fevers (with the exception of Dengue Fever) with an estimated several hundred thousand infections annually, resulting in thousands of deaths in Western Africa. The sizeable disease burden, numerous imported cases of LF in non-endemic countries, and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. Presently there is no licensed vaccine against LF or approved treatment. Recently, several promising vaccine candidates have been developed which can potentially target different groups at risk. The purpose of this manuscript is to review the LASV pathogenesis and immune mechanisms involved in protection. The current status of pre-clinical development of the advanced vaccine candidates that have been tested in non-human primates will be discussed. Major scientific, manufacturing, and regulatory challenges will also be considered.

  18. Novel Sequence-Based Mapping of Recently Emerging H5NX Influenza Viruses Reveals Pandemic Vaccine Candidates

    PubMed Central

    Anderson, Christopher S.; DeDiego, Marta L.; Thakar, Juilee; Topham, David J.

    2016-01-01

    Recently, an avian influenza virus, H5NX subclade 2.3.4.4, emerged and spread to North America. This subclade has frequently reassorted, leading to multiple novel viruses capable of human infection. Four cases of human infections, three leading to death, have already occurred. Existing vaccine strains do not protect against these new viruses, raising a need to identify new vaccine candidate strains. We have developed a novel sequence-based mapping (SBM) tool capable of visualizing complex protein sequence data sets using a single intuitive map. We applied SBM on the complete set of avian H5 viruses in order to better understand hemagglutinin protein variance amongst H5 viruses and identify any patterns associated with this variation. The analysis successfully identified the original reassortments that lead to the emergence of this new subclade of H5 viruses, as well as their known unusual ability to re-assort among neuraminidase subtypes. In addition, our analysis revealed distinct clusters of 2.3.4.4 variants that would not be covered by existing strains in the H5 vaccine stockpile. The results suggest that our method may be useful for pandemic candidate vaccine virus selection. PMID:27494186

  19. Pilot scale production of highly efficacious and stable enterovirus 71 vaccine candidates.

    PubMed

    Chou, Ai-Hsiang; Liu, Chia-Chyi; Chang, Cheng-Peng; Guo, Meng-Shin; Hsieh, Shih-Yang; Yang, Wen-Hsueh; Chao, Hsin-Ju; Wu, Chien-Long; Huang, Ju-Lan; Lee, Min-Shi; Hu, Alan Yung-Chi; Lin, Sue-Chen; Huang, Yu-Yun; Hu, Mei-Hua; Chow, Yen-Hung; Chiang, Jen-Ron; Chang, Jui-Yuan; Chong, Pele

    2012-01-01

    Enterovirus 71 (EV71) has caused several epidemics of hand, foot and mouth diseases (HFMD) in Asia and now is being recognized as an important neurotropic virus. Effective medications and prophylactic vaccine against EV71 infection are urgently needed. Based on the success of inactivated poliovirus vaccine, a prototype chemically inactivated EV71 vaccine candidate has been developed and currently in human phase 1 clinical trial. In this report, we present the development of a serum-free cell-based EV71 vaccine. The optimization at each step of the manufacturing process was investigated, characterized and quantified. In the up-stream process development, different commercially available cell culture media either containing serum or serum-free was screened for cell growth and virus yield using the roller-bottle technology. VP-SFM serum-free medium was selected based on the Vero cell growth profile and EV71 virus production. After the up-stream processes (virus harvest, diafiltration and concentration), a combination of gel-filtration liquid chromatography and/or sucrose-gradient ultracentrifugation down-stream purification processes were investigated at a pilot scale of 40 liters each. Although the combination of chromatography and sucrose-gradient ultracentrifugation produced extremely pure EV71 infectious virus particles, the overall yield of vaccine was 7-10% as determined by a VP2-based quantitative ELISA. Using chromatography as the downstream purification, the virus yield was 30-43%. To retain the integrity of virus neutralization epitopes and the stability of the vaccine product, the best virus inactivation was found to be 0.025% formalin-treatment at 37 °C for 3 to 6 days. Furthermore, the formalin-inactivated virion vaccine candidate was found to be stable for >18 months at 4 °C and a microgram of viral proteins formulated with alum adjuvant could induce strong virus-neutralizing antibody responses in mice, rats, rabbits, and non-human primates. These

  20. Parallel conduction of the phase I preventive and therapeutic trials based on the Tat vaccine candidate.

    PubMed

    Bellino, S; Francavilla, V; Longo, O; Tripiciano, A; Paniccia, G; Arancio, A; Fiorelli, V; Scoglio, A; Collacchi, B; Campagna, M; Lazzarin, A; Tambussi, G; Din, C Tassan; Visintini, R; Narciso, P; Antinori, A; D'Offizi, G; Giulianelli, M; Carta, M; Di Carlo, A; Palamara, G; Giuliani, M; Laguardia, M E; Monini, P; Magnani, M; Ensoli, F; Ensoli, B

    2009-09-01

    The native HIV-1 Tat protein was chosen as vaccine candidate for phase I clinical trials in both uninfected (ClinicalTrials.gov identifier: NCT00529698) and infected volunteers (ClinicalTrials.gov identifier: NCT00505401). The rationale was based on the role of Tat in the natural infection and AIDS pathogenesis, on the association of Tat-specific immune responses with the asymptomatic stage and slow-progression rate as well as on its sequence conservation among HIV clades (http://www.hiv1tat-vaccines.info/). The parallel conduction in the same clinical centers of randomized, double blind, placebo-controlled phase I studies both in healthy, immunologically competent adults and in HIV-infected, clinically asymptomatic, individuals represents a unique occasion to compare the vaccine-induced immune response in both the preventive and therapeutic setting. In both studies, the same lot of the native Tat protein was administered 5 times, every four weeks, subcute (SC) with alum adjuvant or intradermic (ID), in the absence of adjuvant, at 7.5 microg, 15 microg or 30 microg doses, respectively. The primary and secondary endpoints of these studies were the safety and immunogenicity of the vaccine candidate, respectively. The study lasted 52 weeks and monitoring was conducted for on additional 3 years. The results of both studies indicated that the Tat vaccine is safe and well tolerated both locally and systemically and it is highly immunogenic at all the dosages and by both routes of administration. Vaccination with Tat induced a balanced immune response in uninfected and infected individuals. In particular, therapeutic immunization induced functional antibodies and partially reverted the marked Th1 polarization of anti-Tat immunity seen in natural infection, and elicited a more balanced Th1/Th2 immune response. Further, the number of CD4 T cells correlated positively with anti-Tat antibody titers. Based on these results, a phase II study is ongoing in infected drug

  1. A Candidate H1N1 Pandemic Influenza Vaccine Elicits Protective Immunity in Mice

    PubMed Central

    Steitz, Julia; Barlow, Peter G.; Hossain, Jaber; Kim, Eun; Okada, Kaori; Kenniston, Tom; Rea, Sheri; Donis, Ruben O.; Gambotto, Andrea

    2010-01-01

    Background In 2009 a new pandemic disease appeared and spread globally. The recent emergence of the pandemic influenza virus H1N1 first isolated in Mexico and USA raised concerns about vaccine availability. We here report our development of an adenovirus-based influenza H1N1 vaccine tested for immunogenicity and efficacy to confer protection in animal model. Methods We generated two adenovirus(Ad5)-based influenza vaccine candidates encoding the wildtype or a codon-optimized hemagglutinin antigen (HA) from the recently emerged swine influenza isolate A/California/04/2009 (H1N1)pdm. After verification of antigen expression, immunogenicity of the vaccine candidates were tested in a mouse model using dose escalations for subcutaneous immunization. Sera of immunized animals were tested in microneutalization and hemagglutination inhibition assays for the presence of HA-specific antibodies. HA-specific T-cells were measured in IFNγ Elispot assays. The efficiency of the influenza vaccine candidates were evaluated in a challenge model by measuring viral titer in lung and nasal turbinate 3 days after inoculation of a homologous H1N1 virus. Conclusions/Significance A single immunization resulted in robust cellular and humoral immune response. Remarkably, the intensity of the immune response was substantially enhanced with codon-optimized antigen, indicating the benefit of manipulating the genetic code of HA antigens in the context of recombinant influenza vaccine design. These results highlight the value of advanced technologies in vaccine development and deployment in response to infections with pandemic potential. Our study emphasizes the potential of an adenoviral-based influenza vaccine platform with the benefits of speed of manufacture and efficacy of a single dose immunization. PMID:20463955

  2. Vaccine Candidates against Nontypeable Haemophilus influenzae: a Review

    PubMed Central

    Behrouzi, Ava; Vaziri, Farzam; Rahimi-Jamnani, Fatemeh; Afrough, Parviz; Rahbar, Mohammad; Satarian, Fereshteh; Siadat, Seyed Davar

    2017-01-01

    Nonencapsulated, nontypeable Hemophilus influenzae (NTHi) remains an important cause of acute otitis and respiratory diseases in children and adults. NTHi bacteria are one of the major causes of respiratory tract infections, including acute otitis media, cystic fibrosis, and community-acquired pneumonia among children, especially in developing countries. The bacteria can also cause chronic diseases such as chronic bronchitis and chronic obstructive pulmonary disease in the lower respiratory tract of adults. Such bacteria express several outer membrane proteins, some of which have been studied as candidates for vaccine development. Due to the lack of effective vaccines as well as the spread and prevalence of NTHi worldwide, there is an urgent need to design and develop effective vaccine candidates against these strains. PMID:28088130

  3. In Silico Analysis of Epitope-Based Vaccine Candidates against Hepatitis B Virus Polymerase Protein

    PubMed Central

    Zheng, Juzeng; Lin, Xianfan; Wang, Xiuyan; Zheng, Liyu; Lan, Songsong; Jin, Sisi; Ou, Zhanfan; Wu, Jinming

    2017-01-01

    Hepatitis B virus (HBV) infection has persisted as a major public health problem due to the lack of an effective treatment for those chronically infected. Therapeutic vaccination holds promise, and targeting HBV polymerase is pivotal for viral eradication. In this research, a computational approach was employed to predict suitable HBV polymerase targeting multi-peptides for vaccine candidate selection. We then performed in-depth computational analysis to evaluate the predicted epitopes’ immunogenicity, conservation, population coverage, and toxicity. Lastly, molecular docking and MHC-peptide complex stabilization assay were utilized to determine the binding energy and affinity of epitopes to the HLA-A0201 molecule. Criteria-based analysis provided four predicted epitopes, RVTGGVFLV, VSIPWTHKV, YMDDVVLGA and HLYSHPIIL. Assay results indicated the lowest binding energy and high affinity to the HLA-A0201 molecule for epitopes VSIPWTHKV and YMDDVVLGA and epitopes RVTGGVFLV and VSIPWTHKV, respectively. Regions 307 to 320 and 377 to 387 were considered to have the highest probability to be involved in B cell epitopes. The T cell and B cell epitopes identified in this study are promising targets for an epitope-focused, peptide-based HBV vaccine, and provide insight into HBV-induced immune response. PMID:28509875

  4. Meta-analysis of variables affecting mouse protection efficacy of whole organism Brucella vaccines and vaccine candidates

    PubMed Central

    2013-01-01

    Background Vaccine protection investigation includes three processes: vaccination, pathogen challenge, and vaccine protection efficacy assessment. Many variables can affect the results of vaccine protection. Brucella, a genus of facultative intracellular bacteria, is the etiologic agent of brucellosis in humans and multiple animal species. Extensive research has been conducted in developing effective live attenuated Brucella vaccines. We hypothesized that some variables play a more important role than others in determining vaccine protective efficacy. Using Brucella vaccines and vaccine candidates as study models, this hypothesis was tested by meta-analysis of Brucella vaccine studies reported in the literature. Results Nineteen variables related to vaccine-induced protection of mice against infection with virulent brucellae were selected based on modeling investigation of the vaccine protection processes. The variable "vaccine protection efficacy" was set as a dependent variable while the other eighteen were set as independent variables. Discrete or continuous values were collected from papers for each variable of each data set. In total, 401 experimental groups were manually annotated from 74 peer-reviewed publications containing mouse protection data for live attenuated Brucella vaccines or vaccine candidates. Our ANOVA analysis indicated that nine variables contributed significantly (P-value < 0.05) to Brucella vaccine protection efficacy: vaccine strain, vaccination host (mouse) strain, vaccination dose, vaccination route, challenge pathogen strain, challenge route, challenge-killing interval, colony forming units (CFUs) in mouse spleen, and CFU reduction compared to control group. The other 10 variables (e.g., mouse age, vaccination-challenge interval, and challenge dose) were not found to be statistically significant (P-value > 0.05). The protection level of RB51 was sacrificed when the values of several variables (e.g., vaccination route, vaccine viability

  5. Vaccine candidates for leishmaniasis: a review.

    PubMed

    Nagill, Rajeev; Kaur, Sukhbir

    2011-10-01

    Leishmaniasis is a diverse group of clinical syndromes caused by protozoan parasites of the genus Leishmania. The clinical manifestation of the disease varies from self-limiting cutaneous lesions to progressive visceral disease. It is estimated that 350 million people are at risk in 88 countries, with a global incidence of 1-1.5 million cases of cutaneous and 500,000 cases of visceral leishmaniasis. The key control measures mainly rely on early case detection and chemotherapy which has been hampered by the toxicity of drugs, side-effects and by the emergence of drug resistance in parasites. Control of reservoir host and vector is difficult due to operational difficulties and frequent relapses in the host. Therefore, the development of effective and affordable vaccine against leishmaniasis is highly desirable. Although considerable progress has been made over the last decade in understanding immune mechanisms underlying potential candidate antigens, including killed, live attenuated parasites, crude parasites, pure or recombinant Leishmania proteins or DNA encoding leishmanial proteins, as well as immunomodulators from sand fly saliva, very few candidate vaccines have progressed beyond the experimental stage. As such there is no vaccine against any form of human leishmaniasis. In recent years, however, much interest has been stimulated towards vaccination against leishmaniasis focused mainly on cutaneous leishmaniasis with fewer attempts against visceral leishmaniasis. Copyright © 2011 Elsevier B.V. All rights reserved.

  6. Activation of chicken bone marrow-derived dendritic cells induced by a Salmonella Enteritidis ghost vaccine candidate.

    PubMed

    Kamble, N M; Jawale, C V; Lee, J H

    2016-10-01

    Bacterial Ghost-based vaccine development has been applied to a variety of gram-negative bacteria. Developed Salmonella Enteritidis (S. Enteritidis) ghost are promising vaccine candidates because of their immunogenic and enhanced biosafety potential. In this study, we aimed to evaluate the immunostimulatory effect of a S. Enteritidis ghost vaccine on the maturation of chicken bone marrow-derived dendritic cells (chBM-DCs) in vitro The immature chBM-DCs were stimulated with S. Enteritidis ghost vaccine candidate. The vaccine efficiently stimulated maturation events in chBM-DCs, indicated by up-regulated expression of CD40, CD80, and MHC-II molecules. Immature BM-DCs responded to stimulation with S. Enteritidis ghost by increased expression of IL-6 and IL-12p40 cytokines. Also, S. Enteritidis ghost stimulated chBM-DCs induced the significant expression of IFN-γ and IL-2 in co-cultured autologous CD4+ T cells. In conclusion, our data suggest that S. Enteritidis ghost vaccine candidate is capable of activating and interacting with chBM-DCs. The results from current study may help for rational designing of Salmonella ghost based heterologous antigen delivery platforms to dendritic cells. © 2016 Poultry Science Association Inc.

  7. Generation of a parvovirus B19 vaccine candidate.

    PubMed

    Chandramouli, Sumana; Medina-Selby, Angelica; Coit, Doris; Schaefer, Mary; Spencer, Terika; Brito, Luis A; Zhang, Pu; Otten, Gillis; Mandl, Christian W; Mason, Peter W; Dormitzer, Philip R; Settembre, Ethan C

    2013-08-20

    Parvovirus B19 is the causative agent of fifth disease in children, aplastic crisis in those with blood dyscrasias, and hydrops fetalis. Previous parvovirus B19 virus-like-particle (VLP) vaccine candidates were produced by co-infection of insect cells with two baculoviruses, one expressing wild-type VP1 and the other expressing VP2. In humans, the VLPs were immunogenic but reactogenic. We have developed new VLP-based parvovirus B19 vaccine candidates, produced by co-expressing VP2 and either wild-type VP1 or phospholipase-negative VP1 in a regulated ratio from a single plasmid in Saccharomyces cerevisiae. These VLPs are expressed efficiently, are very homogeneous, and can be highly purified. Although VP2 alone can form VLPs, in mouse immunizations, VP1 and the adjuvant MF59 are required to elicit a neutralizing response. Wild-type VLPs and those with phospholipase-negative VP1 are equivalently potent. The purity, homogeneity, yeast origin, and lack of phospholipase activity of these VLPs address potential causes of previously observed reactogenicity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  8. Stability and pre-formulation development of a plant-produced anthrax vaccine candidate.

    PubMed

    Jones, R Mark; Burke, Michael; Dubose, Devon; Chichester, Jessica A; Manceva, Slobodanka; Horsey, April; Streatfield, Stephen J; Breit, Jeff; Yusibov, Vidadi

    2017-10-04

    Second generation anthrax vaccines focus on the use of recombinant protective antigen (rPA) to elicit a strong, toxin neutralizing antibody responses in immunized subjects. The main difference between the rPA vaccines compared to the current licensed vaccine, anthrax vaccine absorbed (AVA), is the rPA vaccines are highly purified preparations of only rPA. These second generation rPA vaccines strive to elicit strong immune responses with substantially fewer doses than AVA while provoking less side effects. Many of the rPA candidates have shown to be effective in pre-clinical studies, but most of the second generation molecules have stability issues which reduce their efficacy over time. These stability issues are evident even under refrigerated conditions and thus emphasis has been directed to stabilizing the rPA molecule and determining an optimized final formulation. Stabilization of vaccines for long-term storage is a major challenge in the product development life cycle. The effort required to identify suitable formulations can be slow and expensive. The ideal storage for stockpiled vaccines would allow the candidate to withstand years of storage at ambient temperatures. The Fraunhofer Center for Molecular Biotechnology is developing a plant-produced rPA vaccine candidate that shows instability when stored under refrigerated conditions in a solution, as is typical for rPA vaccines. Increased stability of our plant-produced rPA vaccine candidate was achieved in a spray dried powder formulation that could eliminate the need for conventional cold chain allowing greater confidence to stockpile vaccine for civilian and military biodefense. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Safety and immunogenicity of pneumococcal protein vaccine candidates: monovalent choline-binding protein A (PcpA) vaccine and bivalent PcpA-pneumococcal histidine triad protein D vaccine.

    PubMed

    Bologa, Monica; Kamtchoua, Thierry; Hopfer, Robert; Sheng, Xiaohua; Hicks, Bryony; Bixler, Garvin; Hou, Victor; Pehlic, Vildana; Yuan, Tao; Gurunathan, Sanjay

    2012-12-14

    Pneumococcal vaccines based on protein antigens may provide expanded protection against Streptococcus pneumoniae. To evaluate safety and immunogenicity in adults of pneumococcal vaccine candidates comprising S. pneumoniae pneumococcal histidine triad protein D (PhtD) and pneumococcal choline-binding protein A (PcpA) in monovalent and bivalent formulations. This was a phase I, randomized, observer-blinded, placebo-controlled, step-wise dose-escalation study. Following a pilot safety study in which participants received one intramuscular injection of either aluminum hydroxide (AH)-adjuvanted PcpA (25 μg) or PhtD-PcpA (10 μg each), participants in the main study received AH-adjuvanted PcpA (25 μg), AH-adjuvanted PhtD-PcpA (10, 25, or 50 μg each), unadjuvanted PhtD-PcpA (25 μg each), or placebo as 2 injections 30 days apart. Assignment of successive dose cohorts was made after blinded safety reviews after each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD and anti-PcpA antibodies (ELISA). Six adults 18-50 years of age were included in the pilot study and 125 in the main study. No obvious increases in solicited reactions or unsolicited AEs were reported with escalating doses (adjuvanted vaccine) after either injection, or with repeated administration. Adjuvanted vaccine candidates were associated with a higher incidence of solicited reactions (particularly injection site reactions) than unadjuvanted vaccine candidates. However, no SAE or discontinuation due to an AE occurred. Geometric mean concentrations of anti-PhtD IgG and anti-PcpA IgG increased significantly after injection 2 compared with injection 1 at each dose level. No enhancement of immune responses was shown with adjuvanted vaccine candidates compared with the unadjuvanted vaccine candidate. In the dose

  10. Glycolysis-related proteins are broad spectrum vaccine candidates against aquacultural pathogens.

    PubMed

    Liu, Xiaohong; Sun, Jiamin; Wu, Haizhen

    2017-07-05

    Reverse vaccinology (RV) has become a popular method for developing vaccines. Although Edwardsiella tarda is deemed to be an important fish pathogen, so far, no reports have used a genome-based approach to screen vaccine candidates against E. tarda. In the current study, protective antigens of E. tarda were screened using RV. Large-scale cloning, expression and purification of potential candidates were carried out, and their immunoprotective potential was evaluated. A candidate fructose-bisphosphate aldolase (FBA) exhibited broad spectrum protection, as did another glycolysis-related protein glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which we reported previously, indicating the potential of other glycolysis-related proteins of E. tarda as broad spectrum protective antigens. In total, half (5 out 10) of these proteins showed prominent immunoprotective potential. Therefore, we suggest that glycolysis-related proteins are a class of potential broad spectrum protective antigens and that these proteins should be preferentially selected. Copyright © 2017 Elsevier Ltd. All rights reserved.

  11. Rational Design and Evaluation of an Artificial Escherichia coli K1 Protein Vaccine Candidate Based on the Structure of OmpA

    PubMed Central

    Gu, Hao; Liao, Yaling; Zhang, Jin; Wang, Ying; Liu, Zhiyong; Cheng, Ping; Wang, Xingyong; Zou, Quanming; Gu, Jiang

    2018-01-01

    Escherichia coli (E. coli) K1 causes meningitis and remains an unsolved problem in neonates, despite the application of antibiotics and supportive care. The cross-reactivity of bacterial capsular polysaccharides with human antigens hinders their application as vaccine candidates. Thus, protein antigens could be an alternative strategy for the development of an E. coli K1 vaccine. Outer membrane protein A (OmpA) of E. coli K1 is a potential vaccine candidate because of its predominant contribution to bacterial pathogenesis and sub-cellular localization. However, little progress has been made regarding the use of OmpA for this purpose due to difficulties in OmpA production. In the present study, we first investigated the immunogenicity of the four extracellular loops of OmpA. Using the structure of OmpA, we rationally designed and successfully generated the artificial protein OmpAVac, composed of connected loops from OmpA. Recombinant OmpAVac was successfully produced in E. coli BL21 and behaved as a soluble homogenous monomer in the aqueous phase. Vaccination with OmpAVac induced Th1, Th2, and Th17 immune responses and conferred effective protection in mice. In addition, OmpAVac-specific antibodies were able to mediate opsonophagocytosis and inhibit bacterial invasion, thereby conferring prophylactic protection in E. coli K1-challenged adult mice and neonatal mice. These results suggest that OmpAVac could be a good vaccine candidate for the control of E. coli K1 infection and provide an additional example of structure-based vaccine design. PMID:29876324

  12. Rational Design and Evaluation of an Artificial Escherichia coli K1 Protein Vaccine Candidate Based on the Structure of OmpA.

    PubMed

    Gu, Hao; Liao, Yaling; Zhang, Jin; Wang, Ying; Liu, Zhiyong; Cheng, Ping; Wang, Xingyong; Zou, Quanming; Gu, Jiang

    2018-01-01

    Escherichia coli ( E. coli ) K1 causes meningitis and remains an unsolved problem in neonates, despite the application of antibiotics and supportive care. The cross-reactivity of bacterial capsular polysaccharides with human antigens hinders their application as vaccine candidates. Thus, protein antigens could be an alternative strategy for the development of an E. coli K1 vaccine. Outer membrane protein A (OmpA) of E. coli K1 is a potential vaccine candidate because of its predominant contribution to bacterial pathogenesis and sub-cellular localization. However, little progress has been made regarding the use of OmpA for this purpose due to difficulties in OmpA production. In the present study, we first investigated the immunogenicity of the four extracellular loops of OmpA. Using the structure of OmpA, we rationally designed and successfully generated the artificial protein OmpAVac, composed of connected loops from OmpA. Recombinant OmpAVac was successfully produced in E. coli BL21 and behaved as a soluble homogenous monomer in the aqueous phase. Vaccination with OmpAVac induced Th1, Th2, and Th17 immune responses and conferred effective protection in mice. In addition, OmpAVac-specific antibodies were able to mediate opsonophagocytosis and inhibit bacterial invasion, thereby conferring prophylactic protection in E. coli K1-challenged adult mice and neonatal mice. These results suggest that OmpAVac could be a good vaccine candidate for the control of E. coli K1 infection and provide an additional example of structure-based vaccine design.

  13. 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.

  14. Jenner-predict server: prediction of protein vaccine candidates (PVCs) in bacteria based on host-pathogen interactions

    PubMed Central

    2013-01-01

    Background Subunit vaccines based on recombinant proteins have been effective in preventing infectious diseases and are expected to meet the demands of future vaccine development. Computational approach, especially reverse vaccinology (RV) method has enormous potential for identification of protein vaccine candidates (PVCs) from a proteome. The existing protective antigen prediction software and web servers have low prediction accuracy leading to limited applications for vaccine development. Besides machine learning techniques, those software and web servers have considered only protein’s adhesin-likeliness as criterion for identification of PVCs. Several non-adhesin functional classes of proteins involved in host-pathogen interactions and pathogenesis are known to provide protection against bacterial infections. Therefore, knowledge of bacterial pathogenesis has potential to identify PVCs. Results A web server, Jenner-Predict, has been developed for prediction of PVCs from proteomes of bacterial pathogens. The web server targets host-pathogen interactions and pathogenesis by considering known functional domains from protein classes such as adhesin, virulence, invasin, porin, flagellin, colonization, toxin, choline-binding, penicillin-binding, transferring-binding, fibronectin-binding and solute-binding. It predicts non-cytosolic proteins containing above domains as PVCs. It also provides vaccine potential of PVCs in terms of their possible immunogenicity by comparing with experimentally known IEDB epitopes, absence of autoimmunity and conservation in different strains. Predicted PVCs are prioritized so that only few prospective PVCs could be validated experimentally. The performance of web server was evaluated against known protective antigens from diverse classes of bacteria reported in Protegen database and datasets used for VaxiJen server development. The web server efficiently predicted known vaccine candidates reported from Streptococcus pneumoniae and

  15. Egg-Independent Influenza Vaccines and Vaccine Candidates

    PubMed Central

    Manini, Ilaria; Pozzi, Teresa; Rossi, Stefania; Montomoli, Emanuele

    2017-01-01

    Vaccination remains the principal way to control seasonal infections and is the most effective method of reducing influenza-associated morbidity and mortality. Since the 1940s, the main method of producing influenza vaccines has been an egg-based production process. However, in the event of a pandemic, this method has a significant limitation, as the time lag from strain isolation to final dose formulation and validation is six months. Indeed, production in eggs is a relatively slow process and production yields are both unpredictable and highly variable from strain to strain. In particular, if the next influenza pandemic were to arise from an avian influenza virus, and thus reduce the egg-laying hen population, there would be a shortage of embryonated eggs available for vaccine manufacturing. Although the production of egg-derived vaccines will continue, new technological developments have generated a cell-culture-based influenza vaccine and other more recent platforms, such as synthetic influenza vaccines. PMID:28718786

  16. Immunogenicity of Novel Mumps Vaccine Candidates Generated by Genetic Modification

    PubMed Central

    Xu, Pei; Chen, Zhenhai; Phan, Shannon; Pickar, Adrian

    2014-01-01

    Mumps is a highly contagious human disease, characterized by lateral or bilateral nonsuppurative swelling of the parotid glands and neurological complications that can result in aseptic meningitis or encephalitis. A mumps vaccination program implemented since the 1960s reduced mumps incidence by more than 99% and kept the mumps case numbers as low as hundreds of cases per year in the United States before 2006. However, a large mumps outbreak occurred in vaccinated populations in 2006 and again in 2009 in the United States, raising concerns about the efficacy of the vaccination program. Previously, we have shown that clinical isolate-based recombinant mumps viruses lacking expression of either the V protein (rMuVΔV) or the SH protein (rMuVΔSH) are attenuated in a neurovirulence test using newborn rat brains (P. Xu et al., Virology 417:126–136, 2011, http://dx.doi.org/10.1016/j.virol.2011.05.003; P. Xu et al., J. Virol. 86:1768–1776, 2012, http://dx.doi.org/10.1128/JVI.06019-11) and may be good candidates for vaccine development. In this study, we examined immunity induced by rMuVΔSH and rMuVΔV in mice. Furthermore, we generated recombinant mumps viruses lacking expression of both the V protein and the SH protein (rMuVΔSHΔV). Analysis of rMuVΔSHΔV indicated that it was stable in tissue culture cell lines. Importantly, rMuVΔSHΔV was immunogenic in mice, indicating that it is a promising candidate for mumps vaccine development. PMID:24352450

  17. Immunogenicity of novel mumps vaccine candidates generated by genetic modification.

    PubMed

    Xu, Pei; Chen, Zhenhai; Phan, Shannon; Pickar, Adrian; He, Biao

    2014-03-01

    Mumps is a highly contagious human disease, characterized by lateral or bilateral nonsuppurative swelling of the parotid glands and neurological complications that can result in aseptic meningitis or encephalitis. A mumps vaccination program implemented since the 1960s reduced mumps incidence by more than 99% and kept the mumps case numbers as low as hundreds of cases per year in the United States before 2006. However, a large mumps outbreak occurred in vaccinated populations in 2006 and again in 2009 in the United States, raising concerns about the efficacy of the vaccination program. Previously, we have shown that clinical isolate-based recombinant mumps viruses lacking expression of either the V protein (rMuVΔV) or the SH protein (rMuVΔSH) are attenuated in a neurovirulence test using newborn rat brains (P. Xu et al., Virology 417:126-136, 2011, http://dx.doi.org/10.1016/j.virol.2011.05.003; P. Xu et al., J. Virol. 86:1768-1776, 2012, http://dx.doi.org/10.1128/JVI.06019-11) and may be good candidates for vaccine development. In this study, we examined immunity induced by rMuVΔSH and rMuVΔV in mice. Furthermore, we generated recombinant mumps viruses lacking expression of both the V protein and the SH protein (rMuVΔSHΔV). Analysis of rMuVΔSHΔV indicated that it was stable in tissue culture cell lines. Importantly, rMuVΔSHΔV was immunogenic in mice, indicating that it is a promising candidate for mumps vaccine development.

  18. Reverse vaccinology as an approach for developing Histophilus somni vaccine candidates.

    PubMed

    Madampage, Claudia Avis; Rawlyk, Neil; Crockford, Gordon; Wang, Yejun; White, Aaron P; Brownlie, Robert; Van Donkersgoed, Joyce; Dorin, Craig; Potter, Andrew

    2015-11-01

    Histophilosis of cattle is caused by the Gram negative bacterial pathogen Histophilus somni (H. somni) which is also associated with the bovine respiratory disease (BRD) complex. Existing vaccines for H. somni include either killed cells or bacteria-free outer membrane proteins from the organism which have proven to be moderately successful. In this study, reverse vaccinology was used to predict potential H. somni vaccine candidates from genome sequences. In turn, these may protect animals against new strains circulating in the field. Whole genome sequencing of six recent clinical H. somni isolates was performed using an Illumina MiSeq and compared to six genomes from the 1980's. De novo assembly of crude whole genomes was completed using Geneious 6.1.7. Protein coding regions was predicted using Glimmer3. Scores from multiple web-based programs were utilized to evaluate the antigenicity of these predicted proteins which were finally ranked based on their surface exposure scores. A single new strain was selected for future vaccine development based on conservation of the protein candidates among all 12 isolates. A positive signal with convalescent serum for these antigens in western blots indicates in vivo recognition. In order to test the protective capacity of these antigens bovine animal trials are ongoing. Copyright © 2015 The International Alliance for Biological Standardization. Published by Elsevier Ltd. All rights reserved.

  19. 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.

  20. Dengue vaccines: recent developments, ongoing challenges and current candidates

    PubMed Central

    McArthur, Monica A.; Sztein, Marcelo B.; Edelman, Robert

    2013-01-01

    Summary Dengue is among the most prevalent and important arbovirus diseases of humans. In order to effectively control this rapidly spreading disease, control of the vector mosquito and a safe and efficacious vaccine are critical. Despite considerable efforts, the development of a successful vaccine has remained elusive. Multiple factors have complicated the creation of a successful vaccine, not the least of which are the complex, immune-mediated responses against four antigenically distinct serotypes necessitating a tetravalent vaccine providing long lasting protective immunity. Despite the multiple impediments, there are currently many promising vaccine candidates in pre-clinical and clinical development. Here we review the recent advances in dengue virus vaccine development and briefly discuss the challenges associated with the use of these vaccines as a public health tool. PMID:23984962

  1. Engineering and expression of a human rotavirus candidate vaccine in Nicotiana benthamiana.

    PubMed

    Pêra, Francisco F P G; Mutepfa, David L R; Khan, Ayesha M; Els, Johann H; Mbewana, Sandiswa; van Dijk, Alberdina A A; Rybicki, Edward P; Hitzeroth, Inga I

    2015-12-02

    Human rotaviruses are the main cause of severe gastroenteritis in children and are responsible for over 500 000 deaths annually. There are two live rotavirus vaccines currently available, one based on human rotavirus serotype G1P[8], and the other a G1-G4 P[8] pentavalent vaccine. However, the recent emergence of the G9 and other novel rotavirus serotypes in Africa and Asia has prompted fears that current vaccines might not be fully effective against these new varieties. We report an effort to develop an affordable candidate rotavirus vaccine against the new emerging G9P[6] (RVA/Human-wt/ZAF/GR10924/1999/G9P[6]) strain. The vaccine is based on virus-like particles which are both highly immunogenic and safe. The vaccine candidate was produced in Nicotiana benthamiana by transient expression, as plants allow rapid production of antigens at lower costs, without the risk of contamination by animal pathogens. Western blot analysis of plant extracts confirmed the successful expression of two rotavirus capsid proteins, VP2 and VP6. These proteins assembled into VLPs resembling native rotavirus particles when analysed by transmission electron microscopy (TEM). Expression of the rotavirus glycoprotein VP7 and the spike protein VP4 was also tried. However, VP7 expression caused plant wilting during the course of the time trial and expression could never be detected for either protein. We therefore created three fusion proteins adding the antigenic part of VP4 (VP8*) to VP6 in an attempt to produce more appropriately immunogenic particles. Fusion protein expression in tobacco plants was detected by western blot using anti-VP6 and anti-VP4 antibodies, but no regular particles were observed by TEM, even when co-expressed with VP2. Our results suggest that the rotavirus proteins produced in N. benthamiana are candidates for a subunit vaccine specifically for the G9P[6] rotavirus strain. This could be more effective in developing countries, thereby possibly providing a higher

  2. Evaluation of Three Live Attenuated H2 Pandemic Influenza Vaccine Candidates in Mice and Ferrets

    PubMed Central

    Chen, Grace L.; Lamirande, Elaine W.; Cheng, Xing; Torres-Velez, Fernando; Orandle, Marlene; Jin, Hong; Kemble, George

    2014-01-01

    ABSTRACT H2 influenza viruses have not circulated in humans since 1968, and therefore a significant portion of the population would be susceptible to infection should H2 influenza viruses reemerge. H2 influenza viruses continue to circulate in avian reservoirs worldwide, and these reservoirs are a potential source from which these viruses could emerge. Three reassortant cold-adapted (ca) H2 pandemic influenza vaccine candidates with hemagglutinin (HA) and neuraminidase (NA) genes derived from the wild-type A/Japan/305/1957 (H2N2) (Jap/57), A/mallard/6750/1978 (H2N2) (mal/78), or A/swine/MO/4296424/2006 (H2N3) (sw/06) viruses and the internal protein gene segments from the A/Ann Arbor/6/60 ca virus were generated by plasmid-based reverse genetics (Jap/57 ca, mal/78 ca, and sw/06 ca, respectively). The vaccine candidates exhibited the in vitro phenotypes of temperature sensitivity and cold adaptation and were restricted in replication in the respiratory tract of ferrets. In mice and ferrets, the vaccines elicited neutralizing antibodies and conferred protection against homologous wild-type virus challenge. Of the three candidates, the sw/06 ca vaccine elicited cross-reactive antibodies and provided significant protection against the greatest number of heterologous viruses. These observations suggest that the sw/06 ca vaccine should be further evaluated in a clinical trial as an H2 pandemic influenza vaccine candidate. IMPORTANCE Influenza pandemics arise when novel influenza viruses are introduced into a population with little prior immunity to the new virus and often result in higher rates of illness and death than annual seasonal influenza epidemics. An influenza H2 subtype virus caused a pandemic in 1957, and H2 viruses circulated in humans till 1968. H2 influenza viruses continue to circulate in birds, and the development of an H2 influenza vaccine candidate is therefore considered a priority in preparing for future pandemics. However, we cannot predict whether a

  3. Chlamydia vaccine candidates and tools for chlamydial antigen discovery.

    PubMed

    Rockey, Daniel D; Wang, Jie; Lei, Lei; Zhong, Guangming

    2009-10-01

    The failure of the inactivated Chlamydia-based vaccine trials in the 1960s has led researchers studying Chlamydia to take cautious and rational approaches to develop safe and effective chlamydial vaccines. Subsequent research efforts focused on three areas. The first is the analysis of the immunobiology of chlamydial infection in animal models, with supporting clinical studies, to identify the immune correlates of both protective immunity and pathological responses. Second, recent radical improvements in genomics, proteomics and associated technologies have assisted in the implementation of creative approaches to search for suitable vaccine candidates. Third, progress in the analysis of host response and adjuvanticity regulating both innate and adaptive immunity at the mucosal site of infection has led to progress in the design of optimal delivery and adjuvant systems for enhancing protective immunity. Considerable progress has been made in the first two areas but research efforts to better define the factors that regulate immunity at mucosal sites of infection and to develop strategies to boost protective immunity via immunomodulation, effective delivery systems and potent adjuvants, have remained elusive. In this article, we will summarize progress in these areas with a focus on chlamydial vaccine antigen discovery, and discuss future directions towards the development of a safe and effective chlamydial vaccine.

  4. Serologic response to hepatitis B vaccination among lung transplantation candidates.

    PubMed

    Galar, Alicia; Engelson, Brian A; Kubiak, David W; Licona, Jose H; Boukedes, Steve; Goldberg, Hilary J; Baden, Lindsey R; Marty, Francisco M; Issa, Nicolas C

    2014-09-27

    Optimal hepatitis B (HBV) vaccination strategies for lung transplantation (LT) candidates are not well established. LT candidates with negative anti-HBs and anti-HBc antibody titers at baseline who received standard-dose HBV vaccination (Recombivax-HB 10 mcg/mL or Engerix-B 20 mcg/mL) administered at months 0, 1, and 6 or an accelerated vaccination schedule on days 0, 7 to 14, and 21 to 28 between June 1988 and October 2012 were studied. Patients who were more likely to undergo LT within 6 months of evaluation received the accelerated vaccination schedule starting in August 2009. Ninety-six HBV-seronegative patients who completed the vaccination series and had postvaccination anti-HBs titers available were identified. Median age was 60 years; 55.2% were female, and 92.7% were white. Underlying lung diseases included COPD (44.8%), idiopathic pulmonary fibrosis (22.9%), interstitial lung disease (15.6%), and cystic fibrosis (8.3%). The overall anti-HBs response rate was 54.2%. There was no significant difference in vaccine responses between accelerated and standard vaccination schedules (54.2% vs. 54.1%; P=1.0). Patients who received steroids or other immunosuppressants before transplantation had lower response rates compared with those who did not (38.9% vs. 63.3%; P=0.03). Better vaccination strategies to improve response rate are needed in this population. The accelerated HBV vaccination schedule elicited similar anti-HBs responses as the standard schedule and could be advantageous in this population, given current organ allocation practices, and it could allow repeat vaccination series for initial nonresponders before transplantation.

  5. Distinct Immunogenicity and Efficacy of Poxvirus-Based Vaccine Candidates against Ebola Virus Expressing GP and VP40 Proteins.

    PubMed

    Lázaro-Frías, Adrián; Gómez-Medina, Sergio; Sánchez-Sampedro, Lucas; Ljungberg, Karl; Ustav, Mart; Liljeström, Peter; Muñoz-Fontela, César; Esteban, Mariano; García-Arriaza, Juan

    2018-06-01

    Zaire and Sudan ebolavirus species cause a severe disease in humans and nonhuman primates (NHPs) characterized by a high mortality rate. There are no licensed therapies or vaccines against Ebola virus disease (EVD), and the recent 2013 to 2016 outbreak in West Africa highlighted the need for EVD-specific medical countermeasures. Here, we generated and characterized head-to-head the immunogenicity and efficacy of five vaccine candidates against Zaire ebolavirus (EBOV) and Sudan ebolavirus (SUDV) based on the highly attenuated poxvirus vector modified vaccinia virus Ankara (MVA) expressing either the virus glycoprotein (GP) or GP together with the virus protein 40 (VP40) forming virus-like particles (VLPs). In a human monocytic cell line, the different MVA vectors (termed MVA-EBOVs and MVA-SUDVs) triggered robust innate immune responses, with production of beta interferon (IFN-β), proinflammatory cytokines, and chemokines. Additionally, several innate immune cells, such as dendritic cells, neutrophils, and natural killer cells, were differentially recruited in the peritoneal cavity of mice inoculated with MVA-EBOVs. After immunization of mice with a homologous prime/boost protocol (MVA/MVA), total IgG antibodies against GP or VP40 from Zaire and Sudan ebolavirus were differentially induced by these vectors, which were mainly of the IgG1 and IgG3 isotypes. Remarkably, an MVA-EBOV construct coexpressing GP and VP40 protected chimeric mice challenged with EBOV to a greater extent than a vector expressing GP alone. These results support the consideration of MVA-EBOVs and MVA-SUDVs expressing GP and VP40 and producing VLPs as best-in-class potential vaccine candidates against EBOV and SUDV. IMPORTANCE EBOV and SUDV cause a severe hemorrhagic fever affecting humans and NHPs. Since their discovery in 1976, they have caused several sporadic epidemics, with the recent outbreak in West Africa from 2013 to 2016 being the largest and most severe, with more than 11,000 deaths

  6. 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.

  7. Decrease in circulating CD25(hi)Foxp3(+) regulatory T cells following vaccination with the candidate malaria vaccine RTS,S.

    PubMed

    Parsons, Emily; Epstein, Judith; Sedegah, Martha; Villasante, Eileen; Stewart, Ann

    2016-08-31

    Regulatory T (Treg) cells have been shown in some cases to limit vaccine-specific immune responses and impact efficacy. Very little is known about the regulatory responses to the leading malaria vaccine candidate, RTS,S. The goal of this study was to begin to characterize the regulatory responses to the RTS,S vaccine. Using multi-parameter flow cytometry, we examined responses in 13 malaria naïve adult volunteers who received 2 doses of RTS,S given eight weeks apart. Five of these volunteers had previously received 3 doses of a candidate DNA-CSP vaccine, with the final dose given approximately one year prior to the first dose of the RTS,S vaccine. We found that the frequency of CD25(hi)Foxp3(+) Treg cells decreased following administration of RTS,S (p=0.0195), with no differences based on vaccine regimen. There was a concomitant decrease in CTLA-4 expression on CD25(hi)Foxp3(+) Treg cells (p=0.0093) and PD-1 levels on CD8(+) T cells (p=0.0002). Additionally, the frequency of anergic CTLA-4(+)CCR7(+) T cells decreased following vaccination. An inverse correlation was observed between the frequency of Plasmodium falciparum circumsporozoite protein (PfCSP)-specific IFN-γ and PfCSP-specific IL-10, as well as an inverse correlation between IL-10 induced by Hepatitis B surface antigen, the carrier of RTS,S, and PfCSP-specific IFN-γ, suggesting that immunity against the vaccine backbone could impact vaccine immunogenicity. These results have implications for future malaria vaccine design. Copyright © 2016. Published by Elsevier Ltd.

  8. Comparative Infectivity Determinations of Dengue Virus Vaccine Candidates in Rhesus Monkeys, Mosquitoes, and Cell Cultures

    DTIC Science & Technology

    1993-01-28

    34 are required for the evaluation of these vaccine candidates. RE: DAMDI7-89-C-9175 Page 16 REFERENCES 1. Sabin AB, Sclesinger RW, 1945. Production of...AD-A261 892 CONTRACT NO: DAMD17-89-C-9 175 \\II\\IllI\\I\\I1\\\\~il\\ TITLE: COMPARATIVE INFECTIVITY DETERMINATIONS OF DENGUE VIRUS VACCINE CANDIDATES IN... Vaccine Candidates in Rhesus Monkeys, 63002A Mosquitoes, and Cell Cultures 3M263002D870 AC 6. AUTHOR(S) DA335475 Edmundo Kraiselburd 7. PERFORMING

  9. Development of chimeric candidate vaccine against HPV18: a proof of concept.

    PubMed

    Wahiduzzaman, Mohammed; Sharma, Chandresh; Dey, Bindu; Bhatla, Neerja; Singh, Neeta

    2015-06-01

    Human papillomaviruses (HPVs) are prerequisite for the development of cervical cancer, with HPV16 and HPV18 being the most prevalent. Despite the fact that two prophylactic vaccines against HPVs are in the market, wide-scale application of the vaccine in developing countries is a major problem as far as cost of the vaccine and lack of therapeutic efficacy are concerned. Hence, the aim of our study was to develop HPV18 L1E7 chimeric virus-like particles (CVLPs) vaccine candidate possessing both, prophylactic and therapeutic potential against HPV18-associated cervical cancer. In this study, we have developed a potential candidate vaccine against HPV18 involving HPV18 L1E7 CVLPs, which was expressed in E. coli and assembled in vitro. These CVLPs were able to induce a neutralizing antibody response as well as a cell-mediated immune response in mice.

  10. Recombinant lipoprotein-based vaccine candidates against C. difficile infections.

    PubMed

    Huang, Jui-Hsin; Wu, Chia-Wei; Lien, Shu-Pei; Leng, Chih-Hsiang; Hsiao, Kuang-Nan; Liu, Shih-Jen; Chen, Hsin-Wei; Siu, Leung-Kei; Chong, Pele

    2015-08-07

    Opportunistically nosocomial infections in hospitalized patients are often related to Clostridium difficile infections (CDI) due to disruption of the intestinal micro-flora by antibiotic therapies during hospitalization. Clostridial exotoxins A and B (TcdA and TcdB) specifically bind to unknown glycoprotein(s) in the host intestine, disrupt the intestinal barrier leading to acute inflammation and diarrhea. The C-terminal receptor binding domain of TcdA (A-rRBD) has been shown to elicit antibody responses that neutralize TcdA toxicity in Vero cell cytotoxicity assays, but not effectively protect hamsters against a lethal dose challenge of C. difficile spores. To develop an effective recombinant subunit vaccine against CDI, A-rRBD was lipidated (rlipoA-RBD) as a rational design to contain an intrinsic adjuvant, a toll-like receptor 2 agonist and expressed in Escherichia coli. The purified rlipoA-RBD was characterized immunologically and found to have the following properties: (a) mice, hamsters and rabbits vaccinated with 3 μg of rlipoA-RBD produced strong antibody responses that neutralized TcdA toxicity in Vero cell cytotoxicity assays; furthermore, the neutralization titer was comparable to those obtained from antisera immunized either with 10 μg of TcdA toxoid or 30 μg of A-rRBD; (b) rlipoA-RBD elicited immune responses and protected mice from TcdA challenge, but offered insignificant protection (10 to 20 %) against C. difficile spores challenge in hamster models; (c) only rlipoA-RBD formulated with B-rRBD consistently confers protection (90 to 100 %) in the hamster challenge model; and (d) rlipoA-RBD was found to be 10-fold more potent than A-rRBD as an adjuvant to enhancing immune responses against a poor antigen such as ovalbumin. These results indicate that rlipoA-RBD formulated with B-rRBD could be an excellent vaccine candidate for preclinical studies and future clinical trials.

  11. High-yield production of a stable Vero cell-based vaccine candidate against the highly pathogenic avian influenza virus H5N1

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

    Zhou, Fangye; Zhou, Jian; Ma, Lei

    Highlights: Black-Right-Pointing-Pointer Vero cell-based HPAI H5N1 vaccine with stable high yield. Black-Right-Pointing-Pointer Stable high yield derived from the YNVa H3N2 backbone. Black-Right-Pointing-Pointer H5N1/YNVa has a similar safety and immunogenicity to H5N1delta. -- Abstract: Highly pathogenic avian influenza (HPAI) viruses pose a global pandemic threat, for which rapid large-scale vaccine production technology is critical for prevention and control. Because chickens are highly susceptible to HPAI viruses, the supply of chicken embryos for vaccine production might be depleted during a virus outbreak. Therefore, developing HPAI virus vaccines using other technologies is critical. Meeting vaccine demand using the Vero cell-based fermentation process hasmore » been hindered by low stability and yield. In this study, a Vero cell-based HPAI H5N1 vaccine candidate (H5N1/YNVa) with stable high yield was achieved by reassortment of the Vero-adapted (Va) high growth A/Yunnan/1/2005(H3N2) (YNVa) virus with the A/Anhui/1/2005(H5N1) attenuated influenza vaccine strain (H5N1delta) using the 6/2 method. The reassorted H5N1/YNVa vaccine maintained a high hemagglutination (HA) titer of 1024. Furthermore, H5N1/YNVa displayed low pathogenicity and uniform immunogenicity compared to that of the parent virus.« less

  12. Evaluation of novel oral vaccine candidates and validation of a caprine model of Johne's disease

    PubMed Central

    Hines, Murray E.; Turnquist, Sue E.; Ilha, Marcia R. S.; Rajeev, Sreekumari; Jones, Arthur L.; Whittington, Lisa; Bannantine, John P.; Barletta, Raúl G.; Gröhn, Yrjö T.; Katani, Robab; Talaat, Adel M.; Li, Lingling; Kapur, Vivek

    2014-01-01

    Johne's disease (JD) caused by Mycobacterium avium subspecies paratuberculosis (MAP) is a major threat to the dairy industry and possibly some cases of Crohn's disease in humans. A MAP vaccine that reduced of clinical disease and/or reduced fecal shedding would aid in the control of JD. The objectives of this study were (1) to evaluate the efficacy of 5 attenuated strains of MAP as vaccine candidates compared to a commercial control vaccine using the protocol proposed by the Johne's Disease Integrated Program (JDIP) Animal Model Standardization Committee (AMSC), and (2) to validate the AMSC Johne's disease goat challenge model. Eighty goat kids were vaccinated orally twice at 8 and 10 weeks of age with an experimental vaccine or once subcutaneously at 8 weeks with Silirum® (Zoetis), or a sham control oral vaccine at 8 and 10 weeks. Kids were challenged orally with a total of approximately 1.44 × 109 CFU divided in two consecutive daily doses using MAP ATCC-700535 (K10-like bovine isolate). All kids were necropsied at 13 months post-challenge. Results indicated that the AMSC goat challenge model is a highly efficient and valid model for JD challenge studies. None of the experimental or control vaccines evaluated prevented MAP infection or eliminated fecal shedding, although the 329 vaccine lowered the incidence of infection, fecal shedding, tissue colonization and reduced lesion scores, but less than the control vaccine. Based on our results the relative performance ranking of the experimental live-attenuated vaccines evaluated, the 329 vaccine was the best performer, followed by the 318 vaccine, then 316 vaccine, 315 vaccine and finally the 319 vaccine was the worst performer. The subcutaneously injected control vaccine outperformed the orally-delivered mutant vaccine candidates. Two vaccines (329 and 318) do reduce presence of JD gross and microscopic lesions, slow progression of disease, and one vaccine (329) reduced fecal shedding and tissue colonization. PMID

  13. Prediction of vaccine candidates against Pseudomonas aeruginosa: An integrated genomics and proteomics approach.

    PubMed

    Rashid, Muhammad Ibrahim; Naz, Anam; Ali, Amjad; Andleeb, Saadia

    2017-07-01

    Pseudomonas aeruginosa is among top critical nosocomial infectious agents due to its persistent infections and tendency for acquiring drug resistance mechanisms. To date, there is no vaccine available for this pathogen. We attempted to exploit the genomic and proteomic information of P. aeruginosa though reverse-vaccinology approaches to unveil the prospective vaccine candidates. P. aeruginosa strain PAO1 genome was subjected to sequential prioritization approach following genomic, proteomics and structural analyses. Among, the predicted vaccine candidates: surface components of antibiotic efflux pumps (Q9HY88, PA2837), chaperone-usher pathway components (CupC2, CupB3), penicillin binding protein of bacterial cell wall (PBP1a/mrcA), extracellular component of Type 3 secretory system (PscC) and three uncharacterized secretory proteins (PA0629, PA2822, PA0978) were identified as potential candidates qualifying all the set criteria. These proteins were then analyzed for potential immunogenic surface exposed epitopes. These predicted epitopes may provide a basis for development of a reliable subunit vaccine against P. aeruginosa. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Algae-based oral recombinant vaccines

    PubMed Central

    Specht, Elizabeth A.; Mayfield, Stephen P.

    2014-01-01

    Recombinant subunit vaccines are some of the safest and most effective vaccines available, but their high cost and the requirement of advanced medical infrastructure for administration make them impractical for many developing world diseases. Plant-based vaccines have shifted that paradigm by paving the way for recombinant vaccine production at agricultural scale using an edible host. However, enthusiasm for “molecular pharming” in food crops has waned in the last decade due to difficulty in developing transgenic crop plants and concerns of contaminating the food supply. Microalgae could be poised to become the next candidate in recombinant subunit vaccine production, as they present several advantages over terrestrial crop plant-based platforms including scalable and contained growth, rapid transformation, easily obtained stable cell lines, and consistent transgene expression levels. Algae have been shown to accumulate and properly fold several vaccine antigens, and efforts are underway to create recombinant algal fusion proteins that can enhance antigenicity for effective orally delivered vaccines. These approaches have the potential to revolutionize the way subunit vaccines are made and delivered – from costly parenteral administration of purified protein, to an inexpensive oral algae tablet with effective mucosal and systemic immune reactivity. PMID:24596570

  15. Leishmania genome analysis and high-throughput immunological screening identifies tuzin as a novel vaccine candidate against visceral leishmaniasis.

    PubMed

    Lakshmi, Bhavana Sethu; Wang, Ruobing; Madhubala, Rentala

    2014-06-24

    Leishmaniasis is a neglected tropical disease caused by Leishmania species. It is a major health concern affecting 88 countries and threatening 350 million people globally. Unfortunately, there are no vaccines and there are limitations associated with the current therapeutic regimens for leishmaniasis. The emerging cases of drug-resistance further aggravate the situation, demanding rapid drug and vaccine development. The genome sequence of Leishmania, provides access to novel genes that hold potential as chemotherapeutic targets or vaccine candidates. In this study, we selected 19 antigenic genes from about 8000 common Leishmania genes based on the Leishmania major and Leishmania infantum genome information available in the pathogen databases. Potential vaccine candidates thus identified were screened using an in vitro high throughput immunological platform developed in the laboratory. Four candidate genes coding for tuzin, flagellar glycoprotein-like protein (FGP), phospholipase A1-like protein (PLA1) and potassium voltage-gated channel protein (K VOLT) showed a predominant protective Th1 response over disease exacerbating Th2. We report the immunogenic properties and protective efficacy of one of the four antigens, tuzin, as a DNA vaccine against Leishmania donovani challenge. Our results show that administration of tuzin DNA protected BALB/c mice against L. donovani challenge and that protective immunity was associated with higher levels of IFN-γ and IL-12 production in comparison to IL-4 and IL-10. Our study presents a simple approach to rapidly identify potential vaccine candidates using the exhaustive information stored in the genome and an in vitro high-throughput immunological platform. Copyright © 2014. Published by Elsevier Ltd.

  16. Recent progress on sanofi pasteur's dengue vaccine candidate.

    PubMed

    Lang, Jean

    2009-10-01

    The sanofi pasteur candidate dengue tetravalent vaccine (TV) is a recombinant live attenuated vaccine. It is based on a backbone of yellow fever vaccine (YF 17D) replication genes and incorporates the envelope genes of the four dengue virus serotypes. Pre-clinical studies have demonstrated that dengue TV is genetically stable, non-hepatotropic, less neurovirulent than YF 17D and does not infect mosquitoes by the oral route. Dengue TV reactogenicity, viraemia induction and antibody responses were investigated in three Phase II trials in the USA, the Philippines and Mexico. Participants were randomised to receive a three-dose regimen of dengue TV over 12 months (given at baseline, 3-4 and 12 months) or a control vaccine/placebo at baseline followed by two injections of dengue TV. Results showed that the majority of adverse events were mild to moderate and transient in nature, while no evidence of induction of viraemia was reported after initial dengue TV administration. Seroconversion was 100% for all four serotypes in flavivirus-naive adults in the USA injected with dengue TV. Similarly, seroconversion was 88-100% following three administrations in flavivirus-naive Mexican children aged 2-5 years. Furthermore, the proportion of seropositive subjects increased with each dengue TV injection in the Philippines where baseline flavivirus immunity was high (80.1%). An extensive clinical development programme for dengue TV is underway including an efficacy trial in Ratchaburi province, Thailand (an area of high dengue incidence). Assuming continued successful outcomes, initial submissions to regulatory authorities are envisaged within a 5-year period.

  17. Immunogenicity of mumps virus vaccine candidates matching circulating genotypes in the United States and China.

    PubMed

    Zengel, James; Phan, Shannon I; Pickar, Adrian; Xu, Pei; He, Biao

    2017-07-13

    Mumps virus (MuV) causes acute infection in humans with characteristic swelling of the parotid gland. While vaccination has greatly reduced the incidence of MuV infection, there have been multiple large outbreaks of mumps virus (MuV) in highly vaccinated populations. The most common vaccine strain, Jeryl Lynn, belongs to genotype A, which is no longer a circulating genotype. We have developed two vaccine candidates that match the circulating genotypes in the United States (genotype G) and China (genotype F). We found that there was a significant decrease in the ability of the Jeryl Lynn vaccine to produce neutralizing antibody responses to non-matched viruses, when compared to either of our vaccine candidates. Our data suggests that an updated vaccine may allow for better immunity against the circulating MuV genotypes G and F. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Safety, immunogenicity and protective efficacy in mice of a new cell-cultured Lister smallpox vaccine candidate.

    PubMed

    Ferrier-Rembert, Audrey; Drillien, Robert; Meignier, Bernard; Garin, Daniel; Crance, Jean-Marc

    2007-11-28

    It is now difficult to manufacture the first-generation smallpox vaccine, as the process could not comply with current safety and manufacturing regulations. In this study, a candidate non-clonal second-generation smallpox vaccine developed by Sanofi-Pasteur from the Lister strain has been assessed using a cowpox virus challenge in mice. We have observed similar safety, immunogenicity and protection (from disease and death) after a short or long interval following vaccination, as well as similar virus clearance post-challenge, with the second-generation smallpox vaccine candidate as compared to the traditional vaccine used as a benchmark.

  19. An Approach to Identify and Characterize a Subunit Candidate Shigella Vaccine Antigen.

    PubMed

    Pore, Debasis; Chakrabarti, Manoj K

    2016-01-01

    Shigellosis remains a serious issue throughout the developing countries, particularly in children under the age of 5. Numerous strategies have been tested to develop vaccines targeting shigellosis; unfortunately despite several years of extensive research, no safe, effective, and inexpensive vaccine against shigellosis is available so far. Here, we illustrate in detail an approach to identify and establish immunogenic outer membrane proteins from Shigella flexneri 2a as subunit vaccine candidates.

  20. 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.

  1. Glycoprotein G deficient infectious laryngotracheitis virus is a candidate attenuated vaccine.

    PubMed

    Devlin, Joanne M; Browning, Glenn F; Hartley, Carol A; Gilkerson, James R

    2007-05-04

    Infectious laryngotracheitis virus (ILTV), an alphaherpesvirus, causes respiratory disease in chickens and is currently controlled by vaccination with conventionally attenuated virus strains. These vaccines have limitations because of residual pathogenicity and reversion to virulence, suggesting that a novel vaccine strain that lacks virulence gene(s) may enhance disease control. Glycoprotein G (gG) has recently been identified as a virulence factor in ILTV. In this study the immunogenicity and relative pathogenicity of gG deficient ILTV was investigated in SPF chickens. Birds vaccinated with gG deficient ILTV were protected against clinical signs of disease following challenge with virulent ILTV and gG deficient ILTV was also shown to be less pathogenic than currently available commercial vaccine strains. Thus gG deficient ILTV appears to have potential as a vaccine candidate.

  2. 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.

  3. Attenuation and efficacy of live-attenuated Rift Valley fever virus vaccine candidates in non-human primates.

    PubMed

    Smith, Darci R; Johnston, Sara C; Piper, Ashley; Botto, Miriam; Donnelly, Ginger; Shamblin, Joshua; Albariño, César G; Hensley, Lisa E; Schmaljohn, Connie; Nichol, Stuart T; Bird, Brian H

    2018-05-09

    Rift Valley fever virus (RVFV) is an important mosquito-borne veterinary and human pathogen that has caused large outbreaks of severe disease throughout Africa and the Arabian Peninsula. Currently, no licensed vaccine or therapeutics exists to treat this potentially deadly disease. The explosive nature of RVFV outbreaks and the severe consequences of its accidental or intentional introduction into RVFV-free areas provide the impetus for the development of novel vaccine candidates for use in both livestock and humans. Rationally designed vaccine candidates using reverse genetics have been used to develop deletion mutants of two known RVFV virulence factors, the NSs and NSm genes. These recombinant viruses were demonstrated to be protective and immunogenic in rats, mice, and sheep, without producing clinical illness in these animals. Here, we expand upon those findings and evaluate the single deletion mutant (ΔNSs rRVFV) and double deletion mutant (ΔNSs-ΔNSm rRVFV) vaccine candidates in the common marmoset (Callithrix jacchus), a non-human primate (NHP) model resembling severe human RVF disease. We demonstrate that both the ΔNSs and ΔNSs-ΔNSm rRVFV vaccine candidates were found to be safe and immunogenic in the current study. The vaccinated animals received a single dose of vaccine that led to the development of a robust antibody response. No vaccine-induced adverse reactions, signs of clinical illness or infectious virus were detected in the vaccinated marmosets. All vaccinated animals that were subsequently challenged with RVFV were protected against viremia and liver disease. In summary, our results provide the basis for further development of the ΔNSs and ΔNSs-ΔNSm rRVFV as safe and effective human RVFV vaccines for this significant public health threat.

  4. Protection and mechanism of action of a novel human respiratory syncytial virus vaccine candidate based on the extracellular domain of small hydrophobic protein

    PubMed Central

    Schepens, Bert; Sedeyn, Koen; Vande Ginste, Liesbeth; De Baets, Sarah; Schotsaert, Michael; Roose, Kenny; Houspie, Lieselot; Van Ranst, Marc; Gilbert, Brian; van Rooijen, Nico; Fiers, Walter; Piedra, Pedro; Saelens, Xavier

    2014-01-01

    Infections with human respiratory syncytial virus (HRSV) occur globally in all age groups and can have devastating consequences in young infants. We demonstrate that a vaccine based on the extracellular domain (SHe) of the small hydrophobic (SH) protein of HRSV, reduced viral replication in challenged laboratory mice and in cotton rats. We show that this suppression of viral replication can be transferred by serum and depends on a functional IgG receptor compartment with a major contribution of FcγRI and FcγRIII. Using a conditional cell depletion method, we provide evidence that alveolar macrophages are involved in the protection by SHe-specific antibodies. HRSV-infected cells abundantly express SH on the cell surface and are likely the prime target of the humoral immune response elicited by SHe-based vaccination. Finally, natural infection of humans and experimental infection of mice or cotton rats does not induce a strong immune response against HRSV SHe. Using SHe as a vaccine antigen induces immune protection against HRSV by a mechanism that differs from the natural immune response and from other HRSV vaccination strategies explored to date. Hence, HRSV vaccine candidates that aim at inducing protective neutralizing antibodies or T-cell responses could be complemented with a SHe-based antigen to further improve immune protection. PMID:25298406

  5. 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.

  6. Vaccination of dogs with six different candidate leishmaniasis vaccines composed of a chimerical recombinant protein containing ribosomal and histone protein epitopes in combination with different adjuvants.

    PubMed

    Poot, J; Janssen, L H M; van Kasteren-Westerneng, T J; van der Heijden-Liefkens, K H A; Schijns, V E J C; Heckeroth, A

    2009-07-16

    Chimerical protein "Q", composed of antigenic ribosomal and histone sequences, in combination with live BCG is a promising canine leishmaniasis vaccine candidate; one of the few vaccine candidates that have been tested successfully in dogs. Unfortunately, live BCG is not an appropriate adjuvant for commercial application due to safety problems in dogs. In order to find a safe adjuvant with similar efficacy to live BCG, muramyl dipeptide, aluminium hydroxide, Matrix C and killed Propionibacterium acnes in combination with either E. coli- or baculovirus-produced recombinant JPCM5_Q protein were tested. Groups of five or seven dogs were vaccinated with six different adjuvant-antigen combinations and challenged with a high dose intravenous injection of Leishmania infantum JPC strain promastigotes. All candidate vaccines proved to be safe, and both humoral and cellular responses to the recombinant proteins were detected at the end of the prime-boost vaccination scheme. However, clinical and parasitological data obtained during the 10 month follow-up period indicated that protection was not induced by either of the six candidate vaccines. Although no direct evidence was obtained, our data suggest that live BCG may have a significant protective effect against challenge with L. infantum in dogs.

  7. Heat-precipitation allows the efficient purification of a functional plant-derived malaria transmission-blocking vaccine candidate fusion protein.

    PubMed

    Beiss, Veronique; Spiegel, Holger; Boes, Alexander; Kapelski, Stephanie; Scheuermayer, Matthias; Edgue, Gueven; Sack, Markus; Fendel, Rolf; Reimann, Andreas; Schillberg, Stefan; Pradel, Gabriele; Fischer, Rainer

    2015-07-01

    Malaria is a vector-borne disease affecting more than two million people and accounting for more than 600,000 deaths each year, especially in developing countries. The most serious form of malaria is caused by Plasmodium falciparum. The complex life cycle of this parasite, involving pre-erythrocytic, asexual and sexual stages, makes vaccine development cumbersome but also offers a broad spectrum of vaccine candidates targeting exactly those stages. Vaccines targeting the sexual stage of P. falciparum are called transmission-blocking vaccines (TBVs). They do not confer protection for the vaccinated individual but aim to reduce or prevent the transmission of the parasite within a population and are therefore regarded as an essential tool in the fight against the disease. Malaria predominantly affects large populations in developing countries, so TBVs need to be produced in large quantities at low cost. Combining the advantages of eukaryotic expression with a virtually unlimited upscaling potential and a good product safety profile, plant-based expression systems represent a suitable alternative for the production of TBVs. We report here the high level (300 μg/g fresh leaf weight (FLW)) transient expression in Nicotiana benthamiana leaves of an effective TBV candidate based on a fusion protein F0 comprising Pfs25 and the C0-domain of Pfs230, and the implementation of a simple and cost-effective heat treatment step for purification that yields intact recombinant protein at >90% purity with a recovery rate of >70%. The immunization of mice clearly showed that antibodies raised against plant-derived F0 completely blocked the formation of oocysts in a malaria transmission-blocking assay (TBA) making F0 an interesting TBV candidate or a component of a multi-stage malaria vaccine cocktail. © 2015 Wiley Periodicals, Inc.

  8. Influenza vaccines based on virus-like particles

    PubMed Central

    Kang, Sang-Moo; Song, Jae-Min; Quan, Fu-Shi; Compans, Richard W.

    2009-01-01

    The simultaneous expression of structural proteins of virus can produce virus-like particles (VLPs) by a self-assembly process in a viral life cycle even in the absence of genomic material. Taking an advantage of structural and morphological similarities of VLPs to native virions, VLPs have been suggested as a promising platform for new viral vaccines. In the light of a pandemic threat, influenza VLPs have been recently developed as a new generation of non-egg based cell culture-derived vaccine candidates against influenza infection. Animals vaccinated with VLPs containing hemagglutinin (HA) or HA and neuraminidase (NA) were protected from morbidity and mortality resulting from lethal influenza infections. Influenza VLPs serve as an excellent model system of an enveloped virus for understanding the properties of VLPs in inducing protective immunity. In this review, we briefly describe the characteristics of influenza VLPs assembled with a lipid bilayer containing glycoproteins, and summarize the current progress on influenza VLPs as an alternative vaccine candidate against seasonal as well as pandemic influenza viruses. In addition, the protective immune correlates induced by vaccination with influenza VLPs are discussed. PMID:19374929

  9. In silico analysis to identify vaccine candidates common to multiple serotypes of Shigella and evaluation of their immunogenicity.

    PubMed

    Pahil, Sapna; Taneja, Neelam; Ansari, Hifzur Rahman; Raghava, G P S

    2017-01-01

    Shigellosis or bacillary dysentery is an important cause of diarrhea, with the majority of the cases occurring in developing countries. Considering the high disease burden, increasing antibiotic resistance, serotype-specific immunity and the post-infectious sequelae associated with shigellosis, there is a pressing need of an effective vaccine against multiple serotypes of the pathogen. In the present study, we used bio-informatics approach to identify antigens shared among multiple serotypes of Shigella spp. This approach led to the identification of many immunogenic peptides. The five most promising peptides based on MHC binding efficiency were a putative lipoprotein (EL PGI I), a putative heat shock protein (EL PGI II), Spa32 (EL PGI III), IcsB (EL PGI IV) and a hypothetical protein (EL PGI V). These peptides were synthesized and the immunogenicity was evaluated in BALB/c mice by ELISA and cytokine assays. The putative heat shock protein (HSP) and the hypothetical protein elicited good humoral response, whereas putative lipoprotein, Spa32 and IcsB elicited good T-cell response as revealed by increased IFN-γ and TNF-α cytokine levels. The patient sera from confirmed cases of shigellosis were also evaluated for the presence of peptide specific antibodies with significant IgG and IgA antibodies against the HSP and the hypothetical protein, bestowing them as potential future vaccine candidates. The antigens reported in this study are novel and have not been tested as vaccine candidates against Shigella. This study offers time and cost-effective way of identifying unprecedented immunogenic antigens to be used as potential vaccine candidates. Moreover, this approach should easily be extendable to find new potential vaccine candidates for other pathogenic bacteria.

  10. A multi-country study of dengue vaccination strategies with Dengvaxia and a future vaccine candidate in three dengue-endemic countries: Vietnam, Thailand, and Colombia.

    PubMed

    Lee, Jung-Seok; Lourenço, José; Gupta, Sunetra; Farlow, Andrew

    2018-04-19

    The dengue vaccination era began when Dengvaxia (CYD-TDV) became available in 2016. In addition, several second-generation vaccine candidates are currently in phase 3 trials, suggesting that a broader availability of dengue vaccines may be possible in the near future. Advancing on the recent WHO-SAGE recommendations for the safe and effective use of CYD-TDV at the regional level on average, this study investigates the vaccination impacts and cost-effectiveness of CYD-TDV and of a hypothetical new vaccine candidate (NVC) in a country-specific manner for three endemic countries: Vietnam, Thailand, and Colombia. The vaccination impacts of CYD-TDV and NVC were derived by fitting the empirical seroprevalence rates of 9 year olds into an individual-based meta-population transmission model, previously used for the WHO-SAGE working group. The disability-adjusted life years were estimated by applying country-specific parametric values. The cost-effectiveness analyses of four intervention strategies in combination with routine and catch-up campaigns were compared for both vaccines to inform decision makers regarding the most suitable immunization program in each of the three countries. Both CYD-TDV and NVC could be cost-effective at the DALY threshold cost of $2000 depending upon vaccination costs. With CYD-TDV, targeting 9 year olds in routine vaccination programs and 10-29 year olds as a one-off catch-up campaign was the most cost-effective strategy in all three countries. With NVC, while the most cost-effective strategy was to vaccinate 9-29 and 9-18 year olds in Vietnam and Thailand respectively, vaccinating younger age cohorts between 1 and 5 years old in Colombia was more cost-effective than other strategies. Given that three countries will soon face decisions regarding whether and how to incorporate CYD-TDV or future dengue vaccines into their budget-constrained national immunization programs, the current study outcomes can be used to help decision makers

  11. A new strategy based on SmRho protein loaded chitosan nanoparticles as a candidate oral vaccine against schistosomiasis.

    PubMed

    Oliveira, Carolina R; Rezende, Cíntia M F; Silva, Marina R; Pêgo, Ana Paula; Borges, Olga; Goes, Alfredo M

    2012-01-01

    Schistosomiasis is one of the most important neglected tropical diseases and an effective control is unlikely in the absence of improved sanitation and vaccination. A new approach of oral vaccination with alginate coated chitosan nanoparticles appears interesting because their great stability and the ease of target accessibility, besides of chitosan and alginate immunostimulatory properties. Here we propose a candidate vaccine based on the combination of chitosan-based nanoparticles containing the antigen SmRho and coated with sodium alginate. Our results showed an efficient performance of protein loading of nanoparticles before and after coating with alginate. Characterization of the resulting nanoparticles reported a size around 430 nm and a negative zeta potential. In vitro release studies of protein showed great stability of coated nanoparticles in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Further in vivo studies was performed with different formulations of chitosan nanoparticles and it showed that oral immunization was not able to induce high levels of antibodies, otherwise intramuscular immunization induced high levels of both subtypes IgG1 and IgG2a SmRho specific antibodies. Mice immunized with nanoparticles associated to CpG showed significant modulation of granuloma reaction. Mice from all groups immunized orally with nanoparticles presented significant levels of protection against infection challenge with S. mansoni worms, suggesting an important role of chitosan in inducing a protective immune response. Finally, mice immunized with nanoparticles associated with the antigen SmRho plus CpG had 38% of the granuloma area reduced and also presented 48% of protection against of S. mansoni infection. Taken together, this results support this new strategy as an efficient delivery system and a potential vaccine against schistosomiasis.

  12. Strategic evaluation of vaccine candidate antigens for the prevention of Visceral Leishmaniasis.

    PubMed

    Duthie, Malcolm S; Favila, Michelle; Hofmeyer, Kimberley A; Tutterrow, Yeung L; Reed, Steven J; Laurance, John D; Picone, Alessandro; Guderian, Jeffrey; Bailor, H Remy; Vallur, Aarthy C; Liang, Hong; Mohamath, Raodoh; Vergara, Julie; Howard, Randall F; Coler, Rhea N; Reed, Steven G

    2016-05-27

    Infection with Leishmania parasites results in a range of clinical manifestations and outcomes, the most severe of which is visceral leishmaniasis (VL). Vaccination will likely provide the most effective long-term control strategy, as the large number of vectors and potential infectious reservoirs renders sustained interruption of Leishmania parasite transmission extremely difficult. Selection of the best vaccine is complicated because, although several vaccine antigen candidates have been proposed, they have emerged following production in different platforms. To consolidate the information that has been generated into a single vaccine platform, we expressed seven candidates as recombinant proteins in E. coli. After verifying that each recombinant protein could be recognized by VL patients, we evaluated their protective efficacy against experimental L. donovani infection of mice. Administration in formulation with the Th1-potentiating adjuvant GLA-SE indicated that each antigen could elicit antigen-specific Th1 responses that were protective. Considering the ability to reduce parasite burden along with additional factors such as sequence identity across Leishmania species, we then generated a chimeric fusion protein comprising a combination of the 8E, p21 and SMT proteins. This E. coli -expressed fusion protein was also demonstrated to protect against L. donovani infection. These data indicate a novel recombinant vaccine antigen with the potential for use in VL control programs. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  13. Genetic stability of genome-scale deoptimized RNA virus vaccine candidates under selective pressure

    PubMed Central

    Le Nouën, Cyril; McCarty, Thomas; Brown, Michael; Smith, Melissa Laird; Lleras, Roberto; Dolan, Michael A.; Mehedi, Masfique; Yang, Lijuan; Luongo, Cindy; Liang, Bo; Munir, Shirin; DiNapoli, Joshua M.; Mueller, Steffen; Wimmer, Eckard; Collins, Peter L.; Buchholz, Ursula J.

    2017-01-01

    Recoding viral genomes by numerous synonymous but suboptimal substitutions provides live attenuated vaccine candidates. These vaccine candidates should have a low risk of deattenuation because of the many changes involved. However, their genetic stability under selective pressure is largely unknown. We evaluated phenotypic reversion of deoptimized human respiratory syncytial virus (RSV) vaccine candidates in the context of strong selective pressure. Codon pair deoptimized (CPD) versions of RSV were attenuated and temperature-sensitive. During serial passage at progressively increasing temperature, a CPD RSV containing 2,692 synonymous mutations in 9 of 11 ORFs did not lose temperature sensitivity, remained genetically stable, and was restricted at temperatures of 34 °C/35 °C and above. However, a CPD RSV containing 1,378 synonymous mutations solely in the polymerase L ORF quickly lost substantial attenuation. Comprehensive sequence analysis of virus populations identified many different potentially deattenuating mutations in the L ORF as well as, surprisingly, many appearing in other ORFs. Phenotypic analysis revealed that either of two competing mutations in the virus transcription antitermination factor M2-1, outside of the CPD area, substantially reversed defective transcription of the CPD L gene and substantially restored virus fitness in vitro and in case of one of these two mutations, also in vivo. Paradoxically, the introduction into Min L of one mutation each in the M2-1, N, P, and L proteins resulted in a virus with increased attenuation in vivo but increased immunogenicity. Thus, in addition to providing insights on the adaptability of genome-scale deoptimized RNA viruses, stability studies can yield improved synthetic RNA virus vaccine candidates. PMID:28049853

  14. Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein

    DOE PAGES

    Chen, Edwin; Salinas, Nichole D.; Huang, Yining; ...

    2016-05-18

    Plasmodium vivax Duffy Binding Protein (PvDBP) is the most promising vaccine candidate for P. vivax malaria. The polymorphic nature of PvDBP induces strain-specific immune responses, however, and the epitopes of broadly neutralizing antibodies are unknown. These features hamper the rational design of potent DBP-based vaccines and necessitate the identification of globally conserved epitopes. Using X-ray crystallography, small-angle X-ray scattering, hydrogen-deuterium exchange mass spectrometry, and mutational mapping, we have defined epitopes for three inhibitory mAbs (mAbs 2D10, 2H2, and 2C6) and one noninhibitory mAb (3D10) that engage DBP. These studies expand the currently known inhibitory epitope repertoire by establishing protective motifsmore » in subdomain three outside the receptor-binding and dimerization residues of DBP, and introduce globally conserved protective targets. All of the epitopes are highly conserved among DBP alleles. In conclusion, the identification of broadly conserved epitopes of inhibitory antibodies provides critical motifs that should be retained in the next generation of potent vaccines for P. vivax malaria.« less

  15. Broadly neutralizing epitopes in the Plasmodium vivax vaccine candidate Duffy Binding Protein

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

    Chen, Edwin; Salinas, Nichole D.; Huang, Yining

    Plasmodium vivax Duffy Binding Protein (PvDBP) is the most promising vaccine candidate for P. vivax malaria. The polymorphic nature of PvDBP induces strain-specific immune responses, however, and the epitopes of broadly neutralizing antibodies are unknown. These features hamper the rational design of potent DBP-based vaccines and necessitate the identification of globally conserved epitopes. Using X-ray crystallography, small-angle X-ray scattering, hydrogen-deuterium exchange mass spectrometry, and mutational mapping, we have defined epitopes for three inhibitory mAbs (mAbs 2D10, 2H2, and 2C6) and one noninhibitory mAb (3D10) that engage DBP. These studies expand the currently known inhibitory epitope repertoire by establishing protective motifsmore » in subdomain three outside the receptor-binding and dimerization residues of DBP, and introduce globally conserved protective targets. All of the epitopes are highly conserved among DBP alleles. In conclusion, the identification of broadly conserved epitopes of inhibitory antibodies provides critical motifs that should be retained in the next generation of potent vaccines for P. vivax malaria.« less

  16. Identification of Novel Pre-Erythrocytic Malaria Antigen Candidates for Combination Vaccines with Circumsporozoite Protein

    PubMed Central

    Sahu, Tejram; Malkov, Vlad; Morrison, Robert; Pei, Ying; Juompan, Laure; Milman, Neta; Zarling, Stasya; Anderson, Charles; Wong-Madden, Sharon; Wendler, Jason; Ishizuka, Andrew; MacMillen, Zachary W.; Garcia, Valentino; Kappe, Stefan H. I.; Krzych, Urszula; Duffy, Patrick E.

    2016-01-01

    Malaria vaccine development has been hampered by the limited availability of antigens identified through conventional discovery approaches, and improvements are needed to enhance the efficacy of the leading vaccine candidate RTS,S that targets the circumsporozoite protein (CSP) of the infective sporozoite. Here we report a transcriptome-based approach to identify novel pre-erythrocytic vaccine antigens that could potentially be used in combination with CSP. We hypothesized that stage-specific upregulated genes would enrich for protective vaccine targets, and used tiling microarray to identify P. falciparum genes transcribed at higher levels during liver stage versus sporozoite or blood stages of development. We prepared DNA vaccines for 21 genes using the predicted orthologues in P. yoelii and P. berghei and tested their efficacy using different delivery methods against pre-erythrocytic malaria in rodent models. In our primary screen using P. yoelii in BALB/c mice, we found that 16 antigens significantly reduced liver stage parasite burden. In our confirmatory screen using P. berghei in C57Bl/6 mice, we confirmed 6 antigens that were protective in both models. Two antigens, when combined with CSP, provided significantly greater protection than CSP alone in both models. Based on the observations reported here, transcriptional patterns of Plasmodium genes can be useful in identifying novel pre-erythrocytic antigens that induce protective immunity alone or in combination with CSP. PMID:27434123

  17. Identification of Novel Pre-Erythrocytic Malaria Antigen Candidates for Combination Vaccines with Circumsporozoite Protein.

    PubMed

    Speake, Cate; Pichugin, Alexander; Sahu, Tejram; Malkov, Vlad; Morrison, Robert; Pei, Ying; Juompan, Laure; Milman, Neta; Zarling, Stasya; Anderson, Charles; Wong-Madden, Sharon; Wendler, Jason; Ishizuka, Andrew; MacMillen, Zachary W; Garcia, Valentino; Kappe, Stefan H I; Krzych, Urszula; Duffy, Patrick E

    2016-01-01

    Malaria vaccine development has been hampered by the limited availability of antigens identified through conventional discovery approaches, and improvements are needed to enhance the efficacy of the leading vaccine candidate RTS,S that targets the circumsporozoite protein (CSP) of the infective sporozoite. Here we report a transcriptome-based approach to identify novel pre-erythrocytic vaccine antigens that could potentially be used in combination with CSP. We hypothesized that stage-specific upregulated genes would enrich for protective vaccine targets, and used tiling microarray to identify P. falciparum genes transcribed at higher levels during liver stage versus sporozoite or blood stages of development. We prepared DNA vaccines for 21 genes using the predicted orthologues in P. yoelii and P. berghei and tested their efficacy using different delivery methods against pre-erythrocytic malaria in rodent models. In our primary screen using P. yoelii in BALB/c mice, we found that 16 antigens significantly reduced liver stage parasite burden. In our confirmatory screen using P. berghei in C57Bl/6 mice, we confirmed 6 antigens that were protective in both models. Two antigens, when combined with CSP, provided significantly greater protection than CSP alone in both models. Based on the observations reported here, transcriptional patterns of Plasmodium genes can be useful in identifying novel pre-erythrocytic antigens that induce protective immunity alone or in combination with CSP.

  18. Recent mouse models and vaccine candidates for preventing chronic/latent tuberculosis infection and its reactivation.

    PubMed

    Pedroza-Roldán, César; Flores-Valdez, Mario Alberto

    2017-08-31

    Tuberculosis (TB) remains a major challenge in public health worldwide. Until today, the only widely used and approved vaccine is the Mycobacterium bovis bacille Calmette-Guerin (BCG). This vaccine provides a highly variable level of protection against the active, pulmonary form of tuberculosis, and practically none against the latent form of TB infection. This disparity in protection has been extensively studied, and for this reason, several groups have focused their research on the quest for attenuated vaccines based on M. tuberculosis or on the identification of latency-associated antigens that can be incorporated into modified BCG, or that can be used as adjuvanted subunit vaccines. In order to seek new potential antigens relevant for infection, some researchers have performed experiments with highly sensitive techniques such as transcriptomic and proteomic analyses using sputum samples from humans or by using mouse models resembling several aspects of TB. In this review, we focus on reports of new mouse models or mycobacterial antigens recently tested for developing vaccine candidates against chronic/latent tuberculosis and its reactivation.

  19. Carbohydrate-based vaccine adjuvants - discovery and development.

    PubMed

    Hu, Jing; Qiu, Liying; Wang, Xiaoli; Zou, Xiaopeng; Lu, Mengji; Yin, Jian

    2015-10-01

    The addition of a suitable adjuvant to a vaccine can generate significant effective adaptive immune responses. There is an urgent need for the development of novel po7tent and safe adjuvants for human vaccines. Carbohydrate molecules are promising adjuvants for human vaccines due to their high biocompatibility and good tolerability in vivo. The present review covers a few promising carbohydrate-based adjuvants, lipopolysaccharide, trehalose-6,6'-dibehenate, QS-21 and inulin as examples, which have been extensively studied in human vaccines in a number of preclinical and clinical studies. The authors discuss the current status, applications and strategies of development of each adjuvant and different adjuvant formulation systems. This information gives insight regarding the exciting prospect in the field of carbohydrate-based adjuvant research. Carbohydrate-based adjuvants are promising candidates as an alternative to the Alum salts for human vaccines development. Furthermore, combining two or more adjuvants in one formulation is one of the effective strategies in adjuvant development. However, further research efforts are needed to study and develop novel adjuvants systems, which can be more stable, potent and safe. The development of synthetic carbohydrate chemistry can improve the study of carbohydrate-based adjuvants.

  20. Surface display of Clonorchis sinensis enolase on Bacillus subtilis spores potentializes an oral vaccine candidate.

    PubMed

    Wang, Xiaoyun; Chen, Wenjun; Tian, Yanli; Mao, Qiang; Lv, Xiaoli; Shang, Mei; Li, Xuerong; Yu, Xinbing; Huang, Yan

    2014-03-10

    Clonorchis sinensis (C. sinensis) infections remain the common public health problem in freshwater fish consumption areas. New effective prevention strategies are still the urgent challenges to control this kind of foodborne infectious disease. The biochemical importance and biological relevance render C. sinensis enolase (Csenolase) as a potential vaccine candidate. In the present study, we constructed Escherichia coli/Bacillus subtilis shuttle genetic engineering system and investigated the potential of Csenolase as an oral vaccine candidate for C. sinensis prevention in different immunization routes. Our results showed that, compared with control groups, both recombinant Csenolase protein and nucleic acid could induce a mixed IgG1/IgG2a immune response when administrated subcutaneously (P<0.001), intraperitoneally (P<0.01) and intramuscularly (P<0.001) with worm reduction rate of 56.29%, 15.38% and 37.42%, respectively. More importantly, Csenolase could be successfully expressed as a fusion protein (55kDa) on B. subtilis spore indicated by immunoblot and immunofluorescence assays. Killed spores triggered reactive Th1/Th2 immune response and exhibited protective efficacy against C. sinensis infection. Csenolase derived oral vaccine conferred worm reduction rate and egg reduction rate at 60.07% (P<0.001) and 80.67% (P<0.001), respectively. The shuttle genetic engineering system facilitated the development of oral vaccine with B. subtilis stably overexpressing target protein. Comparably vaccinal trails with Csenolase in different immunization routes potentialize Csenolase an oral vaccine candidate in C. sinensis prevention. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. In vitro analysis of virus particle subpopulations in candidate live-attenuated influenza vaccines distinguishes effective from ineffective vaccines.

    PubMed

    Marcus, Philip I; Ngunjiri, John M; Sekellick, Margaret J; Wang, Leyi; Lee, Chang-Won

    2010-11-01

    Two effective (vac+) and two ineffective (vac-) candidate live-attenuated influenza vaccines (LAIVs) derived from naturally selected genetically stable variants of A/TK/OR/71-delNS1[1-124] (H7N3) that differed only in the length and kind of amino acid residues at the C terminus of the nonstructural NS1 protein were analyzed for their content of particle subpopulations. These subpopulations included total physical particles (measured as hemagglutinating particles [HAPs]) with their subsumed biologically active particles of infectious virus (plaque-forming particles [PFPs]) and different classes of noninfectious virus, namely, interferon-inducing particles (IFPs), noninfectious cell-killing particles (niCKPs), and defective interfering particles (DIPs). The vac+ variants were distinguished from the vac- variants on the basis of their content of viral subpopulations by (i) the capacity to induce higher quantum yields of interferon (IFN), (ii) the generation of an unusual type of IFN-induction dose-response curve, (iii) the presence of IFPs that induce IFN more efficiently, (iv) reduced sensitivity to IFN action, and (v) elevated rates of PFP replication that resulted in larger plaques and higher PFP and HAP titers. These in vitro analyses provide a benchmark for the screening of candidate LAIVs and their potential as effective vaccines. Vaccine design may be improved by enhancement of attributes that are dominant in the effective (vac+) vaccines.

  2. Identification and development of a promising novel mumps vaccine candidate strain.

    PubMed

    Liang, Yan; Ma, Shaohui; Liu, Longding; Zhao, Hongling; Wang, Lichun; Jiang, Li; Xie, Zhongping; Dong, Chenghong; Li, Qihan

    2010-12-01

    Mumps epidemics are usually caused by airborne transmission of mumps virus (MuV) and have high morbidity in non-immunized children. Epidemiological studies in many regions of China show that the genotype F viral strain is the most prevalent. However, the genotype A strain is currently used to prepare vaccines. Regional epidemiological MuV data suggest a significant application for the development of live attenuated mumps vaccines targeting specific genotypes. This article reports the isolation and culture of a genotype F MuV candidate strain that could be used to prepare a live attenuated mumps vaccine. This strain is shown to have good immunological efficacy and stability in neurovirulence evaluations. This work should facilitate the implementation of mumps vaccination in mainland China by targeting the most prevalent MuV genotype, genotype F. Copyright © 2010 Institut Pasteur. Published by Elsevier SAS. All rights reserved.

  3. Seroprevalence of antibodies against the three serotypes of poliovirus and IPV vaccine response in adult solid organ transplant candidates.

    PubMed

    Brandão, Luciana Gomes Pedro; Santoro-Lopes, Guilherme; Oliveira, Silas de Souza; da Silva, Edson Elias; do Brasil, Pedro Emmanuel Alvarenga Americano

    2018-06-21

    To assess the prevalence of protective antibody titers to polioviruses in adults candidates for solid organ transplant (SOT), and to assess the immunogenic response to inactivated polio vaccine in this population. The study included SOT candidates referred to Immunization Reference Centre of Evandro Chagas National Institute of Infectious Diseases from March 2013 to January 2016. It was conducted in 2 phases. The first one, a cross-sectional seroprevalence study, followed by an uncontrolled analysis of vaccine response among patients without protective antibody titers at baseline. Antibody titers to poliomyelitis were determined by microneutralization assay. Among 206 SOT candidates included, 156 (76%) had protective antibody titers to all poliovirus serotypes (95% CI: 70-81%). Proven history of oral vaccination in childhood was not associated with higher seroprevalence of protective antibody. In 97% of individuals without protective antibody titers at baseline, there was adequate vaccine response with one dose of inactivated polio vaccine. A relevant proportion of adult candidates for SOT does not have protective titers of antibodies to one or more poliovirus serotype. One dose of inactivated vaccine elicited protective antibody titers in 97% of these subjects and should be routinely prescribed prior to SOT. Copyright © 2018 Elsevier Ltd. All rights reserved.

  4. Modulation of autophagy as a strategy for development of new vaccine candidates against tuberculosis.

    PubMed

    Flores-Valdez, Mario Alberto; Segura-Cerda, Cristian Alfredo; Gaona-Bernal, Jorge

    2018-05-01

    Effective prevention of tuberculosis (Tb) would undoubtedly be of paramount relevance in the control of its global burden, which resulted in more than 6 million new cases in 2016. Research aimed to improve the current vaccine, Bacillus Calmette- Guérin (BCG), or directed to develop new candidates, has taken into account the interaction between the host and Mycobacterium tuberculosis (Mtb). Recently, autophagy, an intracellular process of the host, has been shown to act as a mechanism that contributes to bacilli clearance in vitro and in vivo. Stimulation of autophagy, if correctly balanced, is an approach that has the potential to enhance the immune response of the host, and offers new avenues for developing immunogens that may give an improved protection upon immunization, given that in fact, some recent rBCG vaccine candidates have been shown to modulate autophagy. In this Discussion, we analyze the role of autophagy in the context of mycobacterial infection, its modulation via mycobacterial elements, and the management of host response as an alternative to develop new, hopefully improved, Tb-vaccine candidates. Copyright © 2018 Elsevier Ltd. All rights reserved.

  5. Cellular Immune Responses to Nine Mycobacterium tuberculosis Vaccine Candidates following Intranasal Vaccination

    PubMed Central

    Sable, Suraj B.; Cheruvu, Mani; Nandakumar, Subhadra; Sharma, Sunita; Bandyopadhyay, Kakali; Kellar, Kathryn L.; Posey, James E.; Plikaytis, Bonnie B.; Amara, Rama Rao; Shinnick, Thomas M.

    2011-01-01

    Background The identification of Mycobacterium tuberculosis vaccines that elicit a protective immune response in the lungs is important for the development of an effective vaccine against tuberculosis. Methods and Principal Findings In this study, a comparison of intranasal (i.n.) and subcutaneous (s.c.) vaccination with the BCG vaccine demonstrated that a single moderate dose delivered intranasally induced a stronger and sustained M. tuberculosis-specific T-cell response in lung parenchyma and cervical lymph nodes of BALB/c mice than vaccine delivered subcutaneously. Both BCG and a multicomponent subunit vaccine composed of nine M. tuberculosis recombinant proteins induced strong antigen-specific T-cell responses in various local and peripheral immune compartments. Among the nine recombinant proteins evaluated, the alanine proline rich antigen (Apa, Rv1860) was highly antigenic following i.n. BCG and immunogenic after vaccination with a combination of the nine recombinant antigens. The Apa-induced responses included induction of both type 1 and type 2 cytokines in the lungs as evaluated by ELISPOT and a multiplexed microsphere-based cytokine immunoassay. Of importance, i.n. subunit vaccination with Apa imparted significant protection in the lungs and spleen of mice against M. tuberculosis challenge. Despite observed differences in the frequencies and location of specific cytokine secreting T cells both BCG vaccination routes afforded comparable levels of protection in our study. Conclusion and Significance Overall, our findings support consideration and further evaluation of an intranasally targeted Apa-based vaccine to prevent tuberculosis. PMID:21799939

  6. Combined semi-empirical screening and design of experiments (DOE) approach to identify candidate formulations of a lyophilized live attenuated tetravalent viral vaccine candidate.

    PubMed

    Patel, Ashaben; Erb, Steven M; Strange, Linda; Shukla, Ravi S; Kumru, Ozan S; Smith, Lee; Nelson, Paul; Joshi, Sangeeta B; Livengood, Jill A; Volkin, David B

    2018-05-24

    A combination experimental approach, utilizing semi-empirical excipient screening followed by statistical modeling using design of experiments (DOE), was undertaken to identify stabilizing candidate formulations for a lyophilized live attenuated Flavivirus vaccine candidate. Various potential pharmaceutical compounds used in either marketed or investigative live attenuated viral vaccine formulations were first identified. The ability of additives from different categories of excipients, either alone or in combination, were then evaluated for their ability to stabilize virus against freeze-thaw, freeze-drying, and accelerated storage (25°C) stresses by measuring infectious virus titer. An exploratory data analysis and predictive DOE modeling approach was subsequently undertaken to gain a better understanding of the interplay between the key excipients and stability of virus as well as to determine which combinations were interacting to improve virus stability. The lead excipient combinations were identified and tested for stabilizing effects using a tetravalent mixture of viruses in accelerated and real time (2-8°C) stability studies. This work demonstrates the utility of combining semi-empirical excipient screening and DOE experimental design strategies in the formulation development of lyophilized live attenuated viral vaccine candidates. Copyright © 2017 Elsevier Ltd. All rights reserved.

  7. MVA ROP2 vaccinia virus recombinant as a vaccine candidate for toxoplasmosis.

    PubMed

    Roque-Reséndiz, J L; Rosales, R; Herion, P

    2004-04-01

    Toxoplasma gondii is the aetiological agent of toxoplasmosis and is the most frequent and best known of the parasitic diseases. In the United States, a serological survey from the Third National Health and Nutrition Examination Survey found that an estimated 23% of adolescents and adults have laboratory evidence of infection with T. gondii. Although toxoplasmosis is asymptomatic or shows self-limited symptoms in adults, in pregnant women infections can cause severe health problems to the fetus if the parasites are transmitted. Also, in immunodeficient patients, chronic infection with T. gondii can reactivate and produce encephalitis, which is frequently lethal. In addition, in veterinary medicine, T. gondii infection is of economic importance due to abortion and neonatal loss in sheep and goats. Recently, the development of vaccines against toxoplasmosis has progressed considerably. The live attenuated S48 strain of Toxoplasma has been broadly used for veterinary purposes. DNA vaccines containing the full-length of SAG1/P30, ROP2 or ROP1 genes have proved to be a promising candidate to induce protection against toxoplasmosis. Viral vectors have proved to be the best candidates for vaccination in different diseases. A recombinant Herpes virus carrying the ROP2 gene is able to induce protective immunity in cats. In the present work we describe the potential of the MVA ROP2 recombinant vaccinia virus as a vaccine against toxoplasmosis. MVA ROP2 induces antibodies against the ROP2 protein in similar amount and types as the thermo-sensible strain ts-4 of T. gondii, which is able to fully protect mice against challenge with the virulent RH strain of T. gondii. Also, the life-span of mice is increased in MVA ROP2 vaccinated animals. We conclude that MVA ROP2 vaccine can possibly generate an immune response, which could be useful in protection against toxoplasmosis.

  8. A novel approach of virulome based reverse vaccinology for exploring and validating peptide-based vaccine candidates against the most troublesome nosocomial pathogen: Acinetobacter baumannii.

    PubMed

    Ahmad, Sajjad; Azam, Syed Sikander

    2018-05-05

    Acinetobacter baumannii is one of the major cause of nosocomial infections around the globe. The emergence of hyper-virulent strains of the pathogen greatly narrows down therapeutic options for patients infected with this red alert superbug. Development of a peptide-based vaccine can offers an alternative, attractive, and cost-effective remedy for multidrug-resistant A. baumannii associated complications. Herein, we introduced a novel virulome based Reverse Vaccinology for screening peptide based vaccine candidates against A. baumannii and its validation using a negative control. The pipeline screened "FYLNDQPVS" of polysaccharide export outer membrane protein (EpsA) and "LQNNTRRMK" of chaperone-usher pathway protein B (CsuB) as broad-spectrum peptides for induction of targeted immune responses. The 9-mer epitope of both proteins was rendered virulent, antigenic, non-allergen, and highly conserved among thirty-four completely annotated strains. Interactome examination unravels peptides protein direct and indirect interactions with biological significant pathways, essential for A. baumannii pathogenesis and survival. Protein-peptide docking aids in addition by unveiling deep binding of the epitopes in the active site of the most prevalent binding allele in the human population-the DRB1*0101. Both the proteins till to date are not characterized for immunoprotective efficacy and desirable to be deciphered experimentally. The designed series of in silico filters rejected few recently reported peptide and non-peptide vaccine targets and has delivered outcomes, which we believe will enrich the existing knowledge of vaccinology against this life-threatening human pathogen. Copyright © 2018 Elsevier Inc. All rights reserved.

  9. Construction and preliminary immunobiological characterization of a novel, non-reverting, intranasal live attenuated whooping cough vaccine candidate.

    PubMed

    Cornford-Nairns, Renee; Daggard, Grant; Mukkur, Trilochan

    2012-06-01

    We describe the construction and immunobiological properties of a novel whooping cough vaccine candidate, in which the aroQ gene, encoding 3-dehydroquinase, was deleted by insertional inactivation using the kanamycin resistance gene cassette and allelic exchange using a Bordetella suicide vector. The aroQ B. pertussis mutant required supplementation of media to grow but failed to grow on an unsupplemented medium. The aroQ B. pertussis mutant was undetectable in the trachea and lungs of mice at days 6 and 12 post-infection, respectively. Antigen-specific antibody isotypes IgG1 and IgG2a, were produced, and cell-mediated immunity [CMI], using interleukin-2 and interferon-gamma as indirect indicators, was induced in mice vaccinated with the aroQ B. pertussis vaccine candidate, which were substantially enhanced upon second exposure to virulent B. pertussis. Interleukin- 12 was also produced in the aroQ B. pertussis-vaccinated mice. On the other hand, neither IgG2a nor CMI-indicator cytokines were produced in DTaP-vaccinated mice, although the CMI-indicator cytokines became detectable post-challenge with virulent B. pertussis. Intranasal immunization with one dose of the aroQ B. pertussis mutant protected vaccinated mice against an intranasal challenge infection, with no pathogen being detected in the lungs of immunized mice by day 7 post-challenge. B. pertussis aroQ thus constitutes a safe, non-reverting, metabolite-deficient vaccine candidate that induces both humoral and cellmediated immune responses with potential for use as a single-dose vaccine in adolescents and adults, in the first instance, with a view to disrupting the transmission cycle of whooping cough to infants and the community.

  10. Vaccination Against Tuberculosis With Whole-Cell Mycobacterial Vaccines.

    PubMed

    Scriba, Thomas J; Kaufmann, Stefan H E; Henri Lambert, Paul; Sanicas, Melvin; Martin, Carlos; Neyrolles, Olivier

    2016-09-01

    Live attenuated and killed whole-cell vaccines (WCVs) offer promising vaccination strategies against tuberculosis. A number of WCV candidates, based on recombinant bacillus Calmette-Guerin (BCG), attenuated Mycobacterium tuberculosis, or related mycobacterial species are in various stages of preclinical or clinical development. In this review, we discuss the vaccine candidates and key factors shaping the development pathway for live and killed WCVs and provide an update on progress. © 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.

  11. Mucosal Immunization with a Candidate Universal Influenza Vaccine Reduces Virus Transmission in a Mouse Model

    PubMed Central

    Lo, Chia-Yun; Misplon, Julia A.; Epstein, Suzanne L.

    2014-01-01

    ABSTRACT Pandemic influenza is a major public health concern, but conventional strain-matched vaccines are unavailable early in a pandemic. Candidate “universal” vaccines targeting the viral antigens nucleoprotein (NP) and matrix 2 (M2), which are conserved among all influenza A virus strains and subtypes, could be manufactured in advance for use at the onset of a pandemic. These vaccines do not prevent infection but can reduce disease severity, deaths, and virus titers in the respiratory tract. We hypothesized that such immunization may reduce virus transmission from vaccinated, infected animals. To investigate this hypothesis, we studied mouse models for direct-contact and airborne transmission of H1N1 and H3N2 influenza viruses. We established conditions under which virus transmission occurs and showed that transmission efficiency is determined in part at the level of host susceptibility to infection. Our findings indicate that virus transmission between mice has both airborne and direct-contact components. Finally, we demonstrated that immunization with recombinant adenovirus vectors expressing NP and M2 significantly reduced the transmission of virus to cohoused, unimmunized mice in comparison to controls. These findings have broad implications for the impact of conserved-antigen vaccines, not only in protecting the vaccinated individual but also in protecting others by limiting influenza virus transmission and potentially reducing the size of epidemics. IMPORTANCE Using a mouse model of influenza A virus transmission, we demonstrate that a candidate “universal” influenza vaccine both protects vaccinated animals from lethal infection and reduces the transmission of virus from vaccinated to nonvaccinated mice. This vaccine induces immunity against proteins conserved among all known influenza A virus strains and subtypes, so it could be used early in a pandemic before conventional strain-matched vaccines are available and could potentially reduce the

  12. In silico identification of genetically attenuated vaccine candidate genes for Plasmodium liver stage.

    PubMed

    Kumar, Hirdesh; Frischknecht, Friedrich; Mair, Gunnar R; Gomes, James

    2015-12-01

    Genetically attenuated parasites (GAPs) that lack genes essential for the liver stage of the malaria parasite, and therefore cause developmental arrest, have been developed as live vaccines in rodent malaria models and recently been tested in humans. The genes targeted for deletion were often identified by trial and error. Here we present a systematic gene - protein and transcript - expression analyses of several Plasmodium species with the aim to identify candidate genes for the generation of novel GAPs. With a lack of liver stage expression data for human malaria parasites, we used data available for liver stage development of Plasmodium yoelii, a rodent malaria model, to identify proteins expressed in the liver stage but absent from blood stage parasites. An orthology-based search was then employed to identify orthologous proteins in the human malaria parasite Plasmodium falciparum resulting in a total of 310 genes expressed in the liver stage but lacking evidence of protein expression in blood stage parasites. Among these 310 possible GAP candidates, we further studied Plasmodium liver stage proteins by phyletic distribution and functional domain analyses and shortlisted twenty GAP-candidates; these are: fabB/F, fabI, arp, 3 genes encoding subunits of the PDH complex, dnaJ, urm1, rS5, ancp, mcp, arh, gk, lisp2, valS, palm, and four conserved Plasmodium proteins of unknown function. Parasites lacking one or several of these genes might yield new attenuated malaria parasites for experimental vaccination studies. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. A randomized trial of candidate inactivated quadrivalent influenza vaccine versus trivalent influenza vaccines in children aged 3-17 years.

    PubMed

    Domachowske, Joseph B; Pankow-Culot, Heidemarie; Bautista, Milagros; Feng, Yang; Claeys, Carine; Peeters, Mathieu; Innis, Bruce L; Jain, Varsha

    2013-06-15

    Two antigenically distinct influenza B lineages have cocirculated since 2001, yet trivalent influenza vaccines (TIVs) contain 1 influenza B antigen, meaning lineage mismatch with the vaccine is frequent. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages vs TIV in healthy children aged 3-17 years. Children were randomized 1:1:1 to receive QIV or 1 of 2 TIVs (either B/Victoria or B/Yamagata lineage; N = 2738). Hemagglutination-inhibition assays were performed 28 days after 1 or 2 doses in primed and unprimed children, respectively. Immunological noninferiority of QIV vs TIV against shared strains, and superiority against alternate-lineage B strains was based on geometric mean titers (GMTs) and seroconversion rates. Reactogenicity and safety were also assessed (Clinicaltrials.gov NCT01196988). Noninferiority against shared strains and superiority against alternate-lineage B strains was demonstrated for QIV vs TIV. QIV was highly immunogenic; seroconversion rates were 91.4%, 72.3%, 70.0%, and 72.5% against A/H1N1, A/H3N2, B/Victoria, and B/Yamagata, respectively. Reactogenicity and safety of QIV was consistent with TIV. QIV vs TIV showed superior immunogenicity for the additional B strain without interfering with immune responses to shared strains. QIV may offer improved protection against influenza B in children compared with current trivalent vaccines.

  14. The Vaccine Candidate Vibrio cholerae 638 Is Protective against Cholera in Healthy Volunteers

    PubMed Central

    García, Luis; Jidy, Manuel Díaz; García, Hilda; Rodríguez, Boris L.; Fernández, Roberto; Año, Gemma; Cedré, Bárbara; Valmaseda, Tania; Suzarte, Edith; Ramírez, Margarita; Pino, Yadira; Campos, Javier; Menéndez, Jorge; Valera, Rodrigo; González, Daniel; González, Irma; Pérez, Oliver; Serrano, Teresita; Lastre, Miriam; Miralles, Fernando; del Campo, Judith; Maestre, Jorge Luis; Pérez, José Luis; Talavera, Arturo; Pérez, Antonio; Marrero, Karen; Ledón, Talena; Fando, Rafael

    2005-01-01

    Vibrio cholerae 638 is a living candidate cholera vaccine strain attenuated by deletion of the CTXΦ prophage from C7258 (O1, El Tor Ogawa) and by insertion of the Clostridium thermocellum endoglucanase A gene into the hemagglutinin/protease coding sequence. This vaccine candidate was previously found to be well tolerated and immunogenic in volunteers. This article reports a randomized, double-blind, placebo-controlled trial conducted to test short-term protection conferred by 638 against subsequent V. cholerae infection and disease in volunteers in Cuba. A total of 45 subjects were enrolled and assigned to receive vaccine or placebo. The vaccine contained 109 CFU of freshly harvested 638 buffered with 1.3% NaHCO3, while the placebo was buffer alone. After vaccine but not after placebo intake, 96% of volunteers had at least a fourfold increase in vibriocidal antibody titers, and 50% showed a doubling of at least the lipopolysaccharide-specific immunoglobulin A titers in serum. At 1 month after vaccination, five volunteers from the vaccine group and five from the placebo group underwent an exploratory challenge study with 109 CFU of ΔCTXΦ attenuated mutant strain V. cholerae 81. Only two volunteers from the vaccine group shed strain 81 in their feces, but none of them experienced diarrhea; in the placebo group, all volunteers excreted the challenge strain, and three had reactogenic diarrhea. An additional 12 vaccinees and 9 placebo recipients underwent challenge with 7 × 105 CFU of virulent strain V. cholerae 3008 freshly harvested from a brain heart infusion agar plate and buffered with 1.3% NaHCO3. Three volunteers (25%) from the vaccine group and all from the placebo group shed the challenge agent in their feces. None of the 12 vaccinees but 7 volunteers from the placebo group had diarrhea, and 2 of the latter exhibited severe cholera (>5,000 g of diarrheal stool). These results indicate that at 1 month after ingestion of a single oral dose (109 CFU) of strain

  15. The vaccine candidate Vibrio cholerae 638 is protective against cholera in healthy volunteers.

    PubMed

    García, Luis; Jidy, Manuel Díaz; García, Hilda; Rodríguez, Boris L; Fernández, Roberto; Año, Gemma; Cedré, Bárbara; Valmaseda, Tania; Suzarte, Edith; Ramírez, Margarita; Pino, Yadira; Campos, Javier; Menéndez, Jorge; Valera, Rodrigo; González, Daniel; González, Irma; Pérez, Oliver; Serrano, Teresita; Lastre, Miriam; Miralles, Fernando; Del Campo, Judith; Maestre, Jorge Luis; Pérez, José Luis; Talavera, Arturo; Pérez, Antonio; Marrero, Karen; Ledón, Talena; Fando, Rafael

    2005-05-01

    Vibrio cholerae 638 is a living candidate cholera vaccine strain attenuated by deletion of the CTXPhi prophage from C7258 (O1, El Tor Ogawa) and by insertion of the Clostridium thermocellum endoglucanase A gene into the hemagglutinin/protease coding sequence. This vaccine candidate was previously found to be well tolerated and immunogenic in volunteers. This article reports a randomized, double-blind, placebo-controlled trial conducted to test short-term protection conferred by 638 against subsequent V. cholerae infection and disease in volunteers in Cuba. A total of 45 subjects were enrolled and assigned to receive vaccine or placebo. The vaccine contained 10(9) CFU of freshly harvested 638 buffered with 1.3% NaHCO(3), while the placebo was buffer alone. After vaccine but not after placebo intake, 96% of volunteers had at least a fourfold increase in vibriocidal antibody titers, and 50% showed a doubling of at least the lipopolysaccharide-specific immunoglobulin A titers in serum. At 1 month after vaccination, five volunteers from the vaccine group and five from the placebo group underwent an exploratory challenge study with 10(9) CFU of DeltaCTXPhi attenuated mutant strain V. cholerae 81. Only two volunteers from the vaccine group shed strain 81 in their feces, but none of them experienced diarrhea; in the placebo group, all volunteers excreted the challenge strain, and three had reactogenic diarrhea. An additional 12 vaccinees and 9 placebo recipients underwent challenge with 7 x 10(5) CFU of virulent strain V. cholerae 3008 freshly harvested from a brain heart infusion agar plate and buffered with 1.3% NaHCO(3). Three volunteers (25%) from the vaccine group and all from the placebo group shed the challenge agent in their feces. None of the 12 vaccinees but 7 volunteers from the placebo group had diarrhea, and 2 of the latter exhibited severe cholera (>5,000 g of diarrheal stool). These results indicate that at 1 month after ingestion of a single oral dose (10

  16. 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.

  17. Genome-based approaches to develop vaccines against bacterial pathogens.

    PubMed

    Serruto, Davide; Serino, Laura; Masignani, Vega; Pizza, Mariagrazia

    2009-05-26

    Bacterial infectious diseases remain the single most important threat to health worldwide. Although conventional vaccinology approaches were successful in conferring protection against several diseases, they failed to provide efficacious solutions against many others. The advent of whole-genome sequencing changed the way to think about vaccine development, enabling the targeting of possible vaccine candidates starting from the genomic information of a single bacterial isolate, with a process named reverse vaccinology. As the genomic era progressed, reverse vaccinology has evolved with a pan-genome approach and multi-strain genome analysis became fundamental for the design of universal vaccines. This review describes the applications of genome-based approaches in the development of new vaccines against bacterial pathogens.

  18. Identification of Plasmodium falciparum reticulocyte binding protein homologue 5-interacting protein, PfRipr, as a highly conserved blood-stage malaria vaccine candidate.

    PubMed

    Ntege, Edward H; Arisue, Nobuko; Ito, Daisuke; Hasegawa, Tomoyuki; Palacpac, Nirianne M Q; Egwang, Thomas G; Horii, Toshihiro; Takashima, Eizo; Tsuboi, Takafumi

    2016-11-04

    Genetic variability in Plasmodium falciparum malaria parasites hampers current malaria vaccine development efforts. Here, we hypothesize that to address the impact of genetic variability on vaccine efficacy in clinical trials, conserved antigen targets should be selected to achieve robust host immunity across multiple falciparum strains. Therefore, suitable vaccine antigens should be assessed for levels of polymorphism and genetic diversity. Using a total of one hundred and two clinical isolates from a region of high malaria transmission in Uganda, we analyzed extent of polymorphism and genetic diversity in four recently reported novel blood-stage malaria vaccine candidate proteins: Rh5 interacting protein (PfRipr), GPI anchored micronemal antigen (PfGAMA), rhoptry-associated leucine zipper-like protein 1 (PfRALP1) and Duffy binding-like merozoite surface protein 1 (PfMSPDBL1). In addition, utilizing the wheat germ cell-free system, we expressed recombinant proteins for the four candidates based on P. falciparum laboratory strain 3D7 sequences, immunized rabbits to obtain specific antibodies (Abs) and performed functional growth inhibition assay (GIA). The GIA activity of the raised Abs was demonstrated using both homologous 3D7 and heterologous FVO strains in vitro. Both pfripr and pfralp1 are less polymorphic but the latter is comparatively more diverse, with varied number of regions having insertions and deletions, asparagine and 6-mer repeats in the coding sequences. Pfgama and pfmspdbl1 are polymorphic and genetically diverse among the isolates with antibodies against the 3D7-based recombinant PfGAMA and PfMSPDBL1 inhibiting merozoite invasion only in the 3D7 but not FVO strain. Moreover, although Abs against the 3D7-based recombinant PfRipr and PfRALP1 proteins potently inhibited merozoite invasion of both 3D7 and FVO, the GIA activity of anti-PfRipr was much higher than that of anti-PfRALP1. Thus, PfRipr is regarded as a promising blood-stage vaccine

  19. Collaborative study to assess the suitability of a candidate International Standard for yellow fever vaccine.

    PubMed

    Ferguson, Morag; Heath, Alan

    2004-12-01

    Yellow fever vaccines are routinely assayed by plaque assay. However, the results of these assays are then converted into mouse LD(50) using correlations/conversion factors which, in many cases, were established many years ago. The minimum required potency in WHO Recommendations is 10(3) LD(50)/dose. Thirteen participants from 8 countries participated in a collaborative study whose aim was to assess the suitability of two candidate preparations to serve as an International Standard for yellow fever vaccine. In addition, the study investigated the relationship between the mouse LD(50) test and plaque forming units with a view to updating the WHO recommendations. Plaque assays were more reproducible than mouse assays, as expected. Differences in sensitivities of plaque assays were observed between laboratories but these differences appear to be consistent within a laboratory for all samples and the expression of potency relative to the candidate standard vaccine improved the reproducibility of assays between laboratories. However, the use of potencies had little effect on the between laboratory variability in mouse LD(50) assays. There appears to be a consistent relationship between overall mean LD(50) and plaques titre for all study preparations other than sample E. The slope of the correlation curve is >1 and it would appear that 10(3) LD(50) is approximately equivalent to 10(4) plaque forming units (PFU), based on the overall means of all laboratory results. The First International Standard for yellow fever vaccine, NIBSC Code 99/616, has been established as the First International Standard for yellow fever vaccine by the Expert Committee of Biological Standards of the World Health Organisation. The International Standard has been arbitrarily assigned a potency of 10(4.5) International Units (IU) per ampoule. Manufacturers and National Control Laboratories are including the First International Standard for yellow fever vaccine in routine assays so that the minimum

  20. Age Dependence of Immunity Induced by a Candidate Universal Influenza Vaccine in Mice

    PubMed Central

    García, Mayra; Misplon, Julia A.; Price, Graeme E.; Lo, Chia-Yun; Epstein, Suzanne L.

    2016-01-01

    Influenza has a major impact on the elderly due to increased susceptibility to infection with age and poor response to current vaccines. We have studied universal influenza vaccine candidates based on influenza A nucleoprotein and matrix 2 (A/NP+M2). Long-lasting protection against influenza virus strains of divergent subtypes is induced, especially with mucosal immunization. Here, we tested universal vaccination in BALB/c mice of different ages. Vaccination used intramuscular DNA priming to A/NP+M2 followed by intranasal (i.n.) boosting with recombinant adenoviruses (rAd) expressing the same antigens, or only A/NP+M2-rAd given i.n. Antigen-specific systemic antibody responses were induced in young, middle-aged, and elderly mice (2, 11–17, and 20 months old, respectively), but decreased with age. Antibody responses in bronchoalveolar lavage (BAL) were detected only in young mice. Antigen-specific T cell responses were seen in young and middle-aged but not elderly mice. A/NP+M2 vaccination by the two regimens above protected against stringent challenge in young and middle-aged mice, but not in elderly mice. However, mice vaccinated with A/NP-rAd or A/M2-rAd during their youth were partially protected against challenge 16 months later when they were elderly. In addition, a regimen of two doses of A/NP+M2-rAd given i.n. one month apart beginning in old age protected elderly mice against stringent challenge. This study highlights the potential benefit of cross-protective vaccines through middle age, and suggests that their performance might be enhanced in elderly individuals who had been exposed to influenza antigens early in life, as most humans have been, or by a two-dose rAd regimen given later in life. PMID:27055234

  1. Age Dependence of Immunity Induced by a Candidate Universal Influenza Vaccine in Mice.

    PubMed

    García, Mayra; Misplon, Julia A; Price, Graeme E; Lo, Chia-Yun; Epstein, Suzanne L

    2016-01-01

    Influenza has a major impact on the elderly due to increased susceptibility to infection with age and poor response to current vaccines. We have studied universal influenza vaccine candidates based on influenza A nucleoprotein and matrix 2 (A/NP+M2). Long-lasting protection against influenza virus strains of divergent subtypes is induced, especially with mucosal immunization. Here, we tested universal vaccination in BALB/c mice of different ages. Vaccination used intramuscular DNA priming to A/NP+M2 followed by intranasal (i.n.) boosting with recombinant adenoviruses (rAd) expressing the same antigens, or only A/NP+M2-rAd given i.n. Antigen-specific systemic antibody responses were induced in young, middle-aged, and elderly mice (2, 11-17, and 20 months old, respectively), but decreased with age. Antibody responses in bronchoalveolar lavage (BAL) were detected only in young mice. Antigen-specific T cell responses were seen in young and middle-aged but not elderly mice. A/NP+M2 vaccination by the two regimens above protected against stringent challenge in young and middle-aged mice, but not in elderly mice. However, mice vaccinated with A/NP-rAd or A/M2-rAd during their youth were partially protected against challenge 16 months later when they were elderly. In addition, a regimen of two doses of A/NP+M2-rAd given i.n. one month apart beginning in old age protected elderly mice against stringent challenge. This study highlights the potential benefit of cross-protective vaccines through middle age, and suggests that their performance might be enhanced in elderly individuals who had been exposed to influenza antigens early in life, as most humans have been, or by a two-dose rAd regimen given later in life.

  2. Specific memory B cell response and participation of CD4+ central and effector memory T cells in mice immunized with liposome encapsulated recombinant NE protein based Hepatitis E vaccine candidate.

    PubMed

    Kulkarni, Shruti P; Thanapati, Subrat; Arankalle, Vidya A; Tripathy, Anuradha S

    2016-11-21

    Liposome encapsulated neutralizing epitope protein of Hepatitis E virus (HEV), rNEp, our Hepatitis E vaccine candidate, was shown to be immunogenic and safe in pregnant and non-pregnant mice and yielded sterilizing immunity in rhesus monkeys. The current study in Balb/c mice assessed the levels and persistence of anti-HEV IgG antibodies by ELISA, frequencies of B, memory B, T and memory T cells by flow cytometry and HEV-specific IgG secreting memory B cells by ELISPOT till 420days post immunization (PI) with 5?g rNEp encapsulated in liposome based adjuvant (2 doses, 4weeks apart). Mice immunized with a lower dose (1?g) were assessed only for anamnestic response post booster dose. Vaccine candidate immunized mice (5?g dose) elicited strong anti-HEV IgG response that was estimated to persist for lifetime. At day 120 PI, frequency of memory B cells was higher in immunized mice than those receiving adjuvant alone. Anti-HEV IgG titers were lower in mice immunized with 1?g dose. A booster dose yielded a heightened antibody response in mice with both high (>800GMT, 5?g) and low (?100GMT, 1?g) anti-HEV IgG titers. At day 6th post booster dose, HEV-specific antibody secreting plasma cells (ASCs) were detected in 100% and 50% of mice with high and low anti-HEV IgG titers, respectively, whereas the frequencies of CD4 + central and effector memory T cells were high in mice with high anti-HEV IgG titers only. Taken together, the vaccine candidate effectively generates persistent and anamnestic antibody response, elicits participation of CD4 + memory T cells and triggers memory B cells to differentiate into ASCs upon boosting. This approach of assessing the immunogenicity of vaccine candidate could be useful to explore the longevity of HEV-specific memory response in future HEV vaccine trials in human. Copyright © 2016. Published by Elsevier Ltd.

  3. Development and evaluation of novel recombinant adenovirus-based vaccine candidates for infectious bronchitis virus and Mycoplasma gallisepticum in chickens.

    PubMed

    Zhang, Dongchao; Long, Yuqing; Li, Meng; Gong, Jianfang; Li, Xiaohui; Lin, Jing; Meng, Jiali; Gao, Keke; Zhao, Ruili; Jin, Tianming

    2018-04-01

    Avian infectious bronchitis caused by the infectious bronchitis virus (IBV), and mycoplasmosis caused by Mycoplasma gallisepticum (MG) are two major respiratory diseases in chickens that have resulted in severe economic losses in the poultry industry. We constructed a recombinant adenovirus that simultaneously expresses the S1 spike glycoprotein of IBV and the TM-1 protein of MG (pBH-S1-TM-1-EGFP). For comparison, we constructed two recombinant adenoviruses (pBH-S1-EGFP and pBH-TM-1-EGFP) that express either the S1 spike glycoprotein or the TM-1 protein alone. The protective efficacy of these three vaccine constructs against challenge with IBV and/or MG was evaluated in specific pathogen free chickens. Groups of seven-day-old specific pathogen free chicks were immunized twice, two weeks apart, via the oculonasal route with the pBH-S1-TM-1-EGFP, pBH-S1-EGFP, or pBH-TM-1-EGFP vaccine candidates or the commercial attenuated infectious bronchitis vaccine strain H52 and MG vaccine strain F-36 (positive controls), and challenged with virulent IBV or MG two weeks later. Interestingly, by days 7 and 14 after the booster immunization, pBH-S1-TM-1-EGFP-induced antibody titre was significantly higher (P < 0.01) compared to attenuated commercial IBV vaccine; however, there was no significant difference between the pBH-S1-TM-1-EGFP and attenuated commercial MG vaccine groups (P > 0.05). The clinical signs, the gross, and histopathological lesions scores of the adenovirus vaccine constructs were not significantly different from that of the attenuated commercial IBV or MG vaccines (positive controls) (P > 0.05). These results demonstrate the potential of the bivalent pBH-S1-TM-1-EGFP adenovirus construct as a combination vaccine against IB and mycoplasmosis.

  4. Towards functional antibody-based vaccines to prevent pre-erythrocytic malaria infection.

    PubMed

    Sack, Brandon; Kappe, Stefan H I; Sather, D Noah

    2017-05-01

    An effective malaria vaccine would be considered a milestone of modern medicine, yet has so far eluded research and development efforts. This can be attributed to the extreme complexity of the malaria parasites, presenting with a multi-stage life cycle, high genome complexity and the parasite's sophisticated immune evasion measures, particularly antigenic variation during pathogenic blood stage infection. However, the pre-erythrocytic (PE) early infection forms of the parasite exhibit relatively invariant proteomes, and are attractive vaccine targets as they offer multiple points of immune system attack. Areas covered: We cover the current state of and roadblocks to the development of an effective, antibody-based PE vaccine, including current vaccine candidates, limited biological knowledge, genetic heterogeneity, parasite complexity, and suboptimal preclinical models as well as the power of early stage clinical models. Expert commentary: PE vaccines will need to elicit broad and durable immunity to prevent infection. This could be achievable if recent innovations in studying the parasites' infection biology, rational vaccine selection and design as well as adjuvant formulation are combined in a synergistic and multipronged approach. Improved preclinical assays as well as the iterative testing of vaccine candidates in controlled human malaria infection trials will further accelerate this effort.

  5. A cell wall protein-based vaccine candidate induce protective immune response against Sporothrix schenckii infection.

    PubMed

    Portuondo, Deivys Leandro; Batista-Duharte, Alexander; Ferreira, Lucas Souza; Martínez, Damiana Téllez; Polesi, Marisa Campos; Duarte, Roberta Aparecida; de Paula E Silva, Ana Carolina Alves; Marcos, Caroline Maria; Almeida, Ana Marisa Fusco de; Carlos, Iracilda Zeppone

    2016-02-01

    Sporotrichosis is a subcutaneous mycosis caused by several closely related thermo-dimorphic fungi of the Sporothrix schenckii species complex, affecting humans and other mammals. In the last few years, new strategies have been proposed for controlling sporotrichosis owning to concerns about its growing incidence in humans, cats, and dogs in Brazil, as well as the toxicity and limited efficacy of conventional antifungal drugs. In this study, we assessed the immunogenicity and protective properties of two aluminum hydroxide (AH)-adsorbed S. schenckii cell wall protein (ssCWP)-based vaccine formulations in a mouse model of systemic S. schenckii infection. Fractioning by SDS-PAGE revealed nine protein bands, two of which were functionally characterized: a 44kDa peptide hydrolase and a 47kDa enolase, which was predicted to be an adhesin. Sera from immunized mice recognized the 47kDa enolase and another unidentified 71kDa protein, whereas serum from S. schenckii-infected mice recognized both these proteins plus another unidentified 9.4kDa protein. Furthermore, opsonization with the anti-ssCWP sera led to markedly increased phagocytosis and was able to strongly inhibit the fungus' adhesion to fibroblasts. Immunization with the higher-dose AH-adjuvanted formulation led to increased ex vivo release of IL-12, IFN-γ, IL-4, and IL-17, whereas only IL-12 and IFN-γ were induced by the higher-dose non-adjuvanted formulation. Lastly, passive transference of the higher-dose AH-adjuvanted formulation's anti-ssCWP serum was able to afford in vivo protection in a subsequent challenge with S. schenckii, becoming a viable vaccine candidate for further testing. Copyright © 2015 Elsevier GmbH. All rights reserved.

  6. 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

  7. A Rapid and Improved Method to Generate Recombinant Dengue Virus Vaccine Candidates

    PubMed Central

    Govindarajan, Dhanasekaran; Guan, Liming; Meschino, Steven; Fridman, Arthur; Bagchi, Ansu; Pak, Irene; ter Meulen, Jan; Casimiro, Danilo R.; Bett, Andrew J.

    2016-01-01

    Dengue is one of the most important mosquito-borne infections accounting for severe morbidity and mortality worldwide. Recently, the tetravalent chimeric live attenuated Dengue vaccine Dengvaxia® was approved for use in several dengue endemic countries. In general, live attenuated vaccines (LAV) are very efficacious and offer long-lasting immunity against virus-induced disease. Rationally designed LAVs can be generated through reverse genetics technology, a method of generating infectious recombinant viruses from full length cDNA contained in bacterial plasmids. In vitro transcribed (IVT) viral RNA from these infectious clones is transfected into susceptible cells to generate recombinant virus. However, the generation of full-length dengue virus cDNA clones can be difficult due to the genetic instability of viral sequences in bacterial plasmids. To circumvent the need for a single plasmid containing a full length cDNA, in vitro ligation of two or three cDNA fragments contained in separate plasmids can be used to generate a full-length dengue viral cDNA template. However, in vitro ligation of multiple fragments often yields low quality template for IVT reactions, resulting in inconsistent low yield RNA. These technical difficulties make recombinant virus recovery less efficient. In this study, we describe a simple, rapid and efficient method of using LONG-PCR to recover recombinant chimeric Yellow fever dengue (CYD) viruses as potential dengue vaccine candidates. Using this method, we were able to efficiently generate several viable recombinant viruses without introducing any artificial mutations into the viral genomes. We believe that the techniques reported here will enable rapid and efficient recovery of recombinant flaviviruses for evaluation as vaccine candidates and, be applicable to the recovery of other RNA viruses. PMID:27008550

  8. A Rapid and Improved Method to Generate Recombinant Dengue Virus Vaccine Candidates.

    PubMed

    Govindarajan, Dhanasekaran; Guan, Liming; Meschino, Steven; Fridman, Arthur; Bagchi, Ansu; Pak, Irene; ter Meulen, Jan; Casimiro, Danilo R; Bett, Andrew J

    2016-01-01

    Dengue is one of the most important mosquito-borne infections accounting for severe morbidity and mortality worldwide. Recently, the tetravalent chimeric live attenuated Dengue vaccine Dengvaxia® was approved for use in several dengue endemic countries. In general, live attenuated vaccines (LAV) are very efficacious and offer long-lasting immunity against virus-induced disease. Rationally designed LAVs can be generated through reverse genetics technology, a method of generating infectious recombinant viruses from full length cDNA contained in bacterial plasmids. In vitro transcribed (IVT) viral RNA from these infectious clones is transfected into susceptible cells to generate recombinant virus. However, the generation of full-length dengue virus cDNA clones can be difficult due to the genetic instability of viral sequences in bacterial plasmids. To circumvent the need for a single plasmid containing a full length cDNA, in vitro ligation of two or three cDNA fragments contained in separate plasmids can be used to generate a full-length dengue viral cDNA template. However, in vitro ligation of multiple fragments often yields low quality template for IVT reactions, resulting in inconsistent low yield RNA. These technical difficulties make recombinant virus recovery less efficient. In this study, we describe a simple, rapid and efficient method of using LONG-PCR to recover recombinant chimeric Yellow fever dengue (CYD) viruses as potential dengue vaccine candidates. Using this method, we were able to efficiently generate several viable recombinant viruses without introducing any artificial mutations into the viral genomes. We believe that the techniques reported here will enable rapid and efficient recovery of recombinant flaviviruses for evaluation as vaccine candidates and, be applicable to the recovery of other RNA viruses.

  9. Tuberculosis vaccine development at a divide.

    PubMed

    Kaufmann, Stefan H E

    2014-05-01

    Tuberculosis (TB) remains a major health threat that will only be defeated by a combination of better drugs, diagnostics and vaccines. The only licensed TB vaccine, bacille Calmette-Guérin (BCG), protects against extrapulmonary TB in infants. Novel vaccine candidates that could protect against pulmonary TB either in TB naïve or in latent TB-infected healthy individuals have been developed and are currently being assessed in clinical trials. Subunit booster vaccines are either based on viral vectors expressing TB-specific antigens or on TB-protein antigens in adjuvants. Subunit vaccines are administered on top of BCG. Replacement vaccines for BCG are recombinant viable BCG or Mycobacterium tuberculosis. Several candidates are undergoing, or will soon start, phase IIb assessment for efficacy. The first vaccine candidate, MVA85A, to complete a phase IIb trial, unfortunately failed to show protection against TB in infants. Therapeutic vaccines composed of killed mycobacterial preparations target patients with complicated TB in adjunct to drug treatment. With increasing numbers of TB vaccine candidates in clinical trials, financial, regulatory and infrastructural issues arise, which would be best tackled by a global strategy. In addition, selection of the most promising vaccine candidates for further clinical development gains increasing importance.

  10. Increased efficacy of inactivated vaccine candidates prepared with Salmonella enterica serovar Typhimurium strains of predominant genotypes in ducks.

    PubMed

    Youn, S Y; Kwon, Y K; Song, C S; Lee, H J; Jeong, O M; Choi, B K; Jung, S C; Kang, M S

    2016-08-01

    Salmonella enterica serovar Typhimurium has been a major causative agent of food-borne human disease, mainly due to consumption of contaminated food animal products. In particular, ducks serve as a reservoir of serovar Typhimurium, and are one of the common sources of human infection. To prevent infection of ducks, and therefore minimize human infection, it is critical to control the persistent epidemic strains in ducks. Here, we analyzed the genetic diversity and virulence of serovar Typhimurium isolates from ducks in Korea to identify the predominant strains that might be used as efficient vaccine candidates for ducks. Among the isolates, 2 representative isolates (ST26 and ST76) of predominant genotypes were selected as vaccine strains on the basis of genotypic analysis by pulsed-field gel electrophoresis and DNA microarrays. Two-week-old ducks were then injected intramuscularly with inactivated vaccine candidates prepared using ST26 or ST76 (10(8) cfu/0.5 mL/duck or 10(9) cfu/0.5 mL/duck), and oral challenge with a highly virulent serovar Typhimurium strain (10(9) cfu/0.5 mL/duck) was carried out 2 wk later. Shedding of the challenge strain was significantly decreased in group 2 after vaccination. The antibody levels by enzyme-linked immunosorbent assay in all vaccinated groups were enhanced significantly (P < 0.05) compared to the unvaccinated control group. Overall, vaccination with ST26 or ST76 reduced bacterial shedding and colonization in internal organs, and induced elevated antibody response. In particular, serovar Typhimurium ST26 (10(8) cfu/0.5 mL/duck) was the most effective vaccine candidate, which can provide efficient protection against serovar Typhimurium in ducks with higher effectiveness compared to a commercial vaccine currently used worldwide. © 2016 Poultry Science Association Inc.

  11. Single-cycle replicable Rift Valley fever virus mutants as safe vaccine candidates.

    PubMed

    Terasaki, Kaori; Tercero, Breanna R; Makino, Shinji

    2016-05-02

    Rift Valley fever virus (RVFV) is an arbovirus circulating between ruminants and mosquitoes to maintain its enzootic cycle. Humans are infected with RVFV through mosquito bites or direct contact with materials of infected animals. The virus causes Rift Valley fever (RVF), which was first recognized in the Great Rift Valley of Kenya in 1931. RVF is characterized by a febrile illness resulting in a high rate of abortions in ruminants and an acute febrile illness, followed by fatal hemorrhagic fever and encephalitis in humans. Initially, the virus was restricted to the eastern region of Africa, but the disease has now spread to southern and western Africa, as well as outside of the African continent, e.g., Madagascar, Saudi Arabia and Yemen. There is a serious concern that the virus may spread to other areas, such as North America and Europe. As vaccination is an effective tool to control RVFV epidemics, formalin-inactivated vaccines and live-attenuated RVFV vaccines have been used in endemic areas. The formalin-inactivated vaccines require boosters for effective protection, whereas the live-attenuated vaccines enable the induction of protective immunity by a single vaccination. However, the use of live-attenuated RVFV vaccines for large human populations having a varied health status is of concern, because of these vaccines' residual neuro-invasiveness and neurovirulence. Recently, novel vaccine candidates have been developed using replication-defective RVFV that can undergo only a single round of replication in infected cells. The single-cycle replicable RVFV does not cause systemic infection in immunized hosts, but enables the conferring of protective immunity. This review summarizes the properties of various RVFV vaccines and recent progress on the development of the single-cycle replicable RVFV vaccines. Copyright © 2015 Elsevier B.V. All rights reserved.

  12. Universal fungal vaccines

    PubMed Central

    Hamad, Mawieh

    2012-01-01

    The complex nature of fungal pathogens, the intricate host-pathogen relationship and the health status of subjects in need of antifungal vaccination continue to hamper efforts to develop fungal vaccines for clinical use. That said, the rise of the universal vaccine concept is hoped to revive fungal vaccine research by expanding the pool of vaccine candidates worthy of clinical evaluation. It can do so through antigenic commonality-based screening for vaccine candidates from a wide range of pathogens and by reassessing the sizable collection of already available experimental and approved vaccines. Development of experimental vaccines protective against multiple fungal pathogens is evidence of the utility of this concept in fungal vaccine research. However, universal fungal vaccines are not without difficulties; for instance, development of vaccines with differential effectiveness is an issue that should be addressed. Additionally, rationalizing the development of universal fungal vaccines on health or economic basis could be contentious. Herein, universal fungal vaccines are discussed in terms of their potential usefulness and possible drawbacks. PMID:22922769

  13. Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations.

    PubMed

    Leunda, Amaya; Baldo, Aline; Goossens, Martine; Huygen, Kris; Herman, Philippe; Romano, Marta

    2014-06-16

    Novel efficient vaccines are needed to control tuberculosis (TB), a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG) to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine). In this review we provide up to date information on novel tuberculosis (TB) vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO) which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed.

  14. An avirulent Micropterus salmoides rhabdovirus vaccine candidate protects Chinese perch against rhabdovirus infection.

    PubMed

    Lijuan, Zhang; Ningqiu, Li; Qiang, Lin; Lihui, Liu; Hongru, Liang; Zhibin, Huang; Xiaozhe, Fu

    2018-06-01

    In order to develop live vaccine against Siniperca chuatsi rhabdovirus (SCRV) disease, an avirulent virus strain, designed as Micropterus salmoides rhabdovirus Sanshui (MSRV-SS), was selected from six fish rhabdovirus isolates (SCRV-QY、SCRV-SS、SCRV-GM、CMRV-FS、OMBRV-JM、MSRV-SS) by fish challenge assay. When Chinese perch (Siniperca chuatsi) were intraperitoneally injected live virus strain MSRV-SS, they were completely protected from virulent SCRV-GM challenge with a relative percent survival (RPS) of 100% on 18th day post vaccination. Then, the wild type MSRV-SS was purified by plaque clone assays, and the biological characteristics of the clonal strain designed as MSRV-SS-7 were investigated. The MSRV-SS-7 was avirulent to Chinese perch and its growth characteristic was similar to the MSRV-SS. The immune protection effects of clonal MSRV-SS-7 against virulent SCRV-GM were evaluated by intraperitoneal injection (IP) vaccination and immersion (IM) vaccination, their RPSs were all 100%. Altogether, these results indicate that MSRV-SS-7 is a potential live vaccine candidate against SCRV disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. Maternal immunization with a DNA vaccine candidate elicits specific passive protection against post-natal Zika virus infection in immunocompetent BALB/c mice.

    PubMed

    Wang, Ran; Liao, Xianzheng; Fan, Dongying; Wang, Lei; Song, Ji; Feng, Kaihao; Li, Mingyuan; Wang, Peigang; Chen, Hui; An, Jing

    2018-06-07

    Zika virus (ZIKV) infection is closely associated in the fetus with microcephaly and in the adults with Guillain-Barré syndrome and even male infertility. It is an urgent international priority to develop a safe and effective vaccine that offers protection to both women of childbearing age and their children. In this study, female immunocompetent BALB/c mice were immunized with a DNA-based vaccine candidate, pVAX1-ZME, expressing the prM/E protein of ZIKV, and the immunogenicity for maternal mice and the post-natal protection for suckling mice were evaluated. It was found that administration with three doses of 50 μg pVAX1-ZME via in vivo electroporation induced robust ZIKV-specific cellular and long-term humoral immune responses with high and sustained neutralizing activity in adult mice. Moreover, using a maternal immunization protocol, neutralizing antibodies provided specific passive protection against ZIKV infection in neonatal mice and effectively inhibited the growth delay. This vaccine candidate is expected to be further evaluated in higher animals, and maternal vaccination shows great promise for protecting both women of childbearing age and their offspring against post-natal ZIKV infection. The vaccinated mothers and ZIKV-challenged pups provide key insight into Zika vaccine evaluation in an available fully immunocompetent animal model. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Single-cycle replicable Rift Valley fever virus mutants as safe vaccine candidates

    PubMed Central

    Terasaki, Kaori; Tercero, Breanna R.; Makino, Shinji

    2015-01-01

    Rift Valley fever virus (RVFV) is an arbovirus circulating between ruminants and mosquitoes to maintain its enzootic cycle. Humans are infected with RVFV through mosquito bites or direct contact with materials of infected animals. The virus causes Rift Valley fever, which was first recognized in the Great Rift Valley of Kenya in 1931. RVFV is characterized by a febrile illness resulting in a high rate of abortions in ruminants and an acute febrile illness, followed by fatal hemorrhagic fever and encephalitis in humans. Initially, the virus was restricted to the eastern region of Africa, but the disease has now spread to southern and western Africa, as well as outside of the African continent, e.g., Madagascar, Saudi Arabia and Yemen. There is a serious concern that the virus may spread to other areas, such as North America and Europe. As vaccination is an effective tool to control RVFV epidemics, formalin-inactivated vaccines and live-attenuated RVFV vaccines have been used in endemic areas. The formalin-inactivated vaccines require boosters for effective protection, whereas the live-attenuated vaccines enable the induction of protective immunity by a single vaccination. However, the use of live-attenuated RVFV vaccines for large human populations having a varied health status is of concern, because of these vaccines’ residual neuro-invasiveness and neurovirulence. Recently, novel vaccine candidates have been developed using replication-defective RVFV that can undergo only a single round of replication in infected cells. The single-cycle replicable RVFV does not cause systemic infection in immunized hosts, but enables the conferring of protective immunity. This review summarizes the properties of various RVFV vaccines and recent progress on the development of the single-cycle replicable RVFV vaccines. PMID:26022573

  17. Strain-specific reverse transcriptase PCR assay: means to distinguish candidate vaccine from wild-type strains of respiratory syncytial virus.

    PubMed Central

    Zheng, H; Peret, T C; Randolph, V B; Crowley, J C; Anderson, L J

    1996-01-01

    Candidate live-virus vaccines for respiratory syncytial virus are being developed and are beginning to be evaluated in clinical trials. To distinguish candidate vaccine strains from wild-type strains isolated during these trials, we developed PCR assays specific to two sets of candidate vaccine strains. The two sets were a group A strain (3A), its three attenuated, temperature-sensitive variant strains, a group B strain (2B), and its four attenuated, temperature-sensitive variant strains. The PCR assays were evaluated by testing 18 group A wild-type strains, the 3A strains, 9 group B wild-type strains, and the 2B strains. PCR specific to group A wild-type strains amplified only group A wild-type strains, and 3A-specific PCR amplified only 3A strains. PCR specific to group B wild-type strains amplified all group A and group B strains but gave a 688-bp product for group B wild-type strains, a 279-bp product for 2B strains, a 547-bp product for all group A strains, and an additional 688-bp product for some group A strains, including 3A strains. These types of PCR assays can, in conjunction with other methods, be used to efficiently distinguish candidate vaccine strains from other respiratory syncytial virus strains. PMID:8789010

  18. Novel GMO-Based Vaccines against Tuberculosis: State of the Art and Biosafety Considerations

    PubMed Central

    Leunda, Amaya; Baldo, Aline; Goossens, Martine; Huygen, Kris; Herman, Philippe; Romano, Marta

    2014-01-01

    Novel efficient vaccines are needed to control tuberculosis (TB), a major cause of morbidity and mortality worldwide. Several TB vaccine candidates are currently in clinical and preclinical development. They fall into two categories, the one of candidates designed as a replacement of the Bacille Calmette Guérin (BCG) to be administered to infants and the one of sub-unit vaccines designed as booster vaccines. The latter are designed as vaccines that will be administered to individuals already vaccinated with BCG (or in the future with a BCG replacement vaccine). In this review we provide up to date information on novel tuberculosis (TB) vaccines in development focusing on the risk assessment of candidates composed of genetically modified organisms (GMO) which are currently evaluated in clinical trials. Indeed, these vaccines administered to volunteers raise biosafety concerns with respect to human health and the environment that need to be assessed and managed. PMID:26344627

  19. Evaluation of hydrophobic chitosan-based particulate formulations of porcine reproductive and respiratory syndrome virus vaccine candidate T cell antigens.

    PubMed

    Mokhtar, Helen; Biffar, Lucia; Somavarapu, Satyanarayana; Frossard, Jean-Pierre; McGowan, Sarah; Pedrera, Miriam; Strong, Rebecca; Edwards, Jane C; Garcia-Durán, Margarita; Rodriguez, Maria Jose; Stewart, Graham R; Steinbach, Falko; Graham, Simon P

    2017-09-01

    PRRS control is hampered by the inadequacies of existing vaccines to combat the extreme diversity of circulating viruses. Since immune clearance of PRRSV infection may not be dependent on the development of neutralising antibodies and the identification of broadly-neutralising antibody epitopes have proven elusive, we hypothesised that conserved T cell antigens represent potential candidates for development of a novel PRRS vaccine. Previously we had identified the M and NSP5 proteins as well-conserved targets of polyfunctional CD8 and CD4 T cells. To assess their vaccine potential, peptides representing M and NSP5 were encapsulated in hydrophobically-modified chitosan particles adjuvanted by incorporation of a synthetic multi-TLR2/TLR7 agonist and coated with a model B cell PRRSV antigen. For comparison, empty particles and adjuvanted particles encapsulating inactivated PRRSV-1 were prepared. Vaccination with the particulate formulations induced antigen-specific antibody responses, which were most pronounced following booster immunisation. M and NSP5-specific CD4, but not CD8, T cell IFN-γ reactivity was measurable following the booster immunisation in a proportion of animals vaccinated with peptide-loaded particles. Upon challenge, CD4 and CD8 T cell reactivity was detected in all groups, with the greatest responses being detected in the peptide vaccinated group but with limited evidence of an enhanced control of viraemia. Analysis of the lungs during the resolution of infection showed significant M/NSP5 specific IFN-γ responses from CD8 rather than CD4 T cells. Vaccine primed CD8 T cell responses may therefore be required for protection and future work should focus on enhancing the cross-presentation of M/NSP5 to CD8 T cells. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

  20. Differing Efficacies of Lead Group A Streptococcal Vaccine Candidates and Full-Length M Protein in Cutaneous and Invasive Disease Models.

    PubMed

    Rivera-Hernandez, Tania; Pandey, Manisha; Henningham, Anna; Cole, Jason; Choudhury, Biswa; Cork, Amanda J; Gillen, Christine M; Ghaffar, Khairunnisa Abdul; West, Nicholas P; Silvestri, Guido; Good, Michael F; Moyle, Peter M; Toth, Istvan; Nizet, Victor; Batzloff, Michael R; Walker, Mark J

    2016-06-14

    Group A Streptococcus (GAS) is an important human pathogen responsible for both superficial infections and invasive diseases. Autoimmune sequelae may occur upon repeated infection. For this reason, development of a vaccine against GAS represents a major challenge, since certain GAS components may trigger autoimmunity. We formulated three combination vaccines containing the following: (i) streptolysin O (SLO), interleukin 8 (IL-8) protease (Streptococcus pyogenes cell envelope proteinase [SpyCEP]), group A streptococcal C5a peptidase (SCPA), arginine deiminase (ADI), and trigger factor (TF); (ii) the conserved M-protein-derived J8 peptide conjugated to ADI; and (iii) group A carbohydrate lacking the N-acetylglucosamine side chain conjugated to ADI. We compared these combination vaccines to a "gold standard" for immunogenicity, full-length M1 protein. Vaccines were adjuvanted with alum, and mice were immunized on days 0, 21, and 28. On day 42, mice were challenged via cutaneous or subcutaneous routes. High-titer antigen-specific antibody responses with bactericidal activity were detected in mouse serum samples for all vaccine candidates. In comparison with sham-immunized mice, all vaccines afforded protection against cutaneous challenge. However, only full-length M1 protein provided protection in the subcutaneous invasive disease model. This set of experiments demonstrates the inherent variability of mouse models for the characterization of GAS vaccine candidate protective efficacy. Such variability poses an important challenge for GAS vaccine development, as advancement of candidates to human clinical trials requires strong evidence of efficacy. This study highlights the need for an open discussion within the field regarding standardization of animal models for GAS vaccine development. Copyright © 2016 Rivera-Hernandez et al.

  1. Defining epitope coverage requirements for T cell-based HIV vaccines: Theoretical considerations and practical applications

    PubMed Central

    2011-01-01

    Background HIV vaccine development must address the genetic diversity and plasticity of the virus that permits the presentation of diverse genetic forms to the immune system and subsequent escape from immune pressure. Assessment of potential HIV strain coverage by candidate T cell-based vaccines (whether natural sequence or computationally optimized products) is now a critical component in interpreting candidate vaccine suitability. Methods We have utilized an N-mer identity algorithm to represent T cell epitopes and explore potential coverage of the global HIV pandemic using natural sequences derived from candidate HIV vaccines. Breadth (the number of T cell epitopes generated) and depth (the variant coverage within a T cell epitope) analyses have been incorporated into the model to explore vaccine coverage requirements in terms of the number of discrete T cell epitopes generated. Results We show that when multiple epitope generation by a vaccine product is considered a far more nuanced appraisal of the potential HIV strain coverage of the vaccine product emerges. By considering epitope breadth and depth several important observations were made: (1) epitope breadth requirements to reach particular levels of vaccine coverage, even for natural sequence-based vaccine products is not necessarily an intractable problem for the immune system; (2) increasing the valency (number of T cell epitope variants present) of vaccine products dramatically decreases the epitope requirements to reach particular coverage levels for any epidemic; (3) considering multiple-hit models (more than one exact epitope match with an incoming HIV strain) places a significantly higher requirement upon epitope breadth in order to reach a given level of coverage, to the point where low valency natural sequence based products would not practically be able to generate sufficient epitopes. Conclusions When HIV vaccine sequences are compared against datasets of potential incoming viruses important

  2. Decreased accumulation of subgenomic RNA in human cells infected with vaccine candidate DEN4Δ30 increases viral susceptibility to type I interferon.

    PubMed

    Bustos-Arriaga, José; Gromowski, Gregory D; Tsetsarkin, Konstantin A; Firestone, Cai-Yen; Castro-Jiménez, Tannya; Pletnev, Alexander G; Cedillo-Barrón, Leticia; Whitehead, Stephen S

    2018-06-07

    The NIH has developed live attenuated dengue virus (DENV) vaccine candidates by deletion of 30 nucleotides (Δ30) from the untranslated region of the viral genome. Although this attenuation strategy has proven to be effective in generating safe and immunogenic vaccine strains, the molecular mechanism of attenuation is largely unknown. To examine the mediators of the observed attenuation phenotype, differences in translation efficiency, genome replication, cytotoxicity, and type I interferon susceptibility were compared between wild type parental DENV and DENVΔ30 attenuated vaccine candidates. We observed that decreased accumulation of subgenomic RNA (sfRNA) from the vaccine candidates in infected human cells causes increased type I IFN susceptibility and propose this as one of the of attenuation mechanisms produced by the 3' UTR Δ30 mutation. Copyright © 2018 Elsevier Ltd. All rights reserved.

  3. An assessment of enterotoxigenic Escherichia coli and Shigella vaccine candidates for infants and children.

    PubMed

    Walker, Richard I

    2015-02-18

    Despite improvements to water quality, sanitation, and the implementation of current prevention and treatment interventions, diarrhea remains a major cause of illness and death, especially among children less than five years of age in the developing world. Rotavirus vaccines have already begun making a real impact on diarrhea, but several more enteric vaccines will be necessary to achieve broader reductions of illness and death. Among the many causes of diarrheal disease, enterotoxigenic Escherichia coli (ETEC) and Shigella are the two most important bacterial pathogens for which there are no currently licensed vaccines. Vaccines against these two pathogens could greatly reduce the impact of disease caused by these infections. This review describes the approaches to ETEC and Shigella vaccines that are currently under development, including a range of both cellular and subunit approaches for each pathogen. In addition, the review discusses strategies for maximizing the potential benefit of these vaccines, which includes the feasibility of co-administration, consolidation, and combination of vaccine candidates, as well as issues related to effective administration of enteric vaccines to infants. Recent impact studies indicate that ETEC and Shigella vaccines could significantly benefit global public health. Either vaccine, particularly if they could be combined together or with another enteric vaccine, would be an extremely valuable tool for saving lives and promoting the health of infants and children in the developing world, as well as potentially providing protection to travelers and military personnel visiting endemic areas. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Oral administration of live Shigella vaccine candidates in rhesus monkeys show no evidence of competition for colonization and immunogenicity between different serotypes.

    PubMed

    Ranallo, R T; Kaminski, R; Baqar, S; Dutta, M; Lugo-Roman, L A; Boren, T; Barnoy, S; Venkatesan, M M

    2014-03-26

    Live oral monovalent Shigella flexneri 2a vaccine candidates as well as bivalent formulations with Shigella sonnei were evaluated in a rhesus monkey model for colonization and immunogenicity. Freshly harvested suspensions of S. flexneri 2a vaccine candidates WRSf2G12 and WRSf2G15 as well as S. sonnei vaccine candidate WRSs3 were nasogastrically administered to groups of rhesus monkeys, Macaca mulatta, either in a monovalent form or when combined with each other. The animals were monitored daily for physical well-being, stools were subjected to quantitative colony immunoblot assays for bacterial excretion and blood and stools were evaluated for humoral and mucosal immune responses. No clinical symptoms were noted in any group of animals and the vaccine candidates were excreted robustly for 48-72h without significant changes in either the magnitude or duration of excretion when given as a monovalent or as bivalent mixtures. Similarly, immunological interferences were not apparent in the magnitude of humoral and mucosal immune responses observed toward Shigella-specific antigens when monkeys were fed monovalent or bivalent formulations. These results predict that a multivalent live oral vaccine of more than one serotype can have a favorable outcome for protection against shigellosis. Published by Elsevier Ltd.

  5. Comparative Genomics and Immunoinformatics Approach for the Identification of Vaccine Candidates for Enterohemorrhagic Escherichia coli O157:H7

    PubMed Central

    García-Angulo, Víctor A.; Kalita, Anjana; Kalita, Mridul; Lozano, Luis

    2014-01-01

    Enterohemorrhagic Escherichia coli (EHEC) O157:H7 strains are major human food-borne pathogens, responsible for bloody diarrhea and hemolytic-uremic syndrome worldwide. Thus far, there is no vaccine for humans against EHEC infections. In this study, a comparative genomics analysis was performed to identify EHEC-specific antigens useful as potential vaccines. The genes present in both EHEC EDL933 and Sakai strains but absent in nonpathogenic E. coli K-12 and HS strains were subjected to an in silico analysis to identify secreted or surface-expressed proteins. We obtained a total of 65 gene-encoding protein candidates, which were subjected to immunoinformatics analysis. Our criteria of selection aided in categorizing the candidates as high, medium, and low priority. Three members of each group were randomly selected and cloned into pVAX-1. Candidates were pooled accordingly to their priority group and tested for immunogenicity against EHEC O157:H7 using a murine model of gastrointestinal infection. The high-priority (HP) pool, containing genes encoding a Lom-like protein (pVAX-31), a putative pilin subunit (pVAX-12), and a fragment of the type III secretion structural protein EscC (pVAX-56.2), was able to induce the production of EHEC IgG and sIgA in sera and feces. HP candidate-immunized mice displayed elevated levels of Th2 cytokines and diminished cecum colonization after wild-type challenge. Individually tested HP vaccine candidates showed that pVAX-12 and pVAX-56.2 significantly induced Th2 cytokines and production of fecal EHEC sIgA, with pVAX-56.2 reducing EHEC cecum colonization. We describe here a bioinformatics approach able to identify novel vaccine candidates potentially useful for preventing EHEC O157:H7 infections. PMID:24595137

  6. Short- and long-term immunogenicity and protection induced by non-replicating smallpox vaccine candidates in mice and comparison with the traditional 1st generation vaccine.

    PubMed

    Ferrier-Rembert, Audrey; Drillien, Robert; Tournier, Jean-Nicolas; Garin, Daniel; Crance, Jean-Marc

    2008-03-25

    This study assessed three non-replicating smallpox vaccine candidates (modified vaccinia Ankara (MVA), NYVAC and HR) for their immunogenicity and ability to protect mice against an intranasal cowpox virus challenge and compared them with the traditional replicating vaccine. A single immunisation with the non-replicating vaccines induced a complete protection from death at short-term, but was not fully protective when mice were challenged 150 days post-vaccination with protection correlated with the specific neutralizing antibodies and CD4(+) T-cells responses. Prime-boost vaccination enabled effective long-term protection from death for mice vaccinated with MVA, but protection from disease and CD4(+) T-cell level were lower than the ones induced by the traditional vaccine over the long-term period. Further investigations are necessary with MVA to determine the optimal conditions of immunisation to induce at long-term immunogenicity and protection observed with the 1st generation smallpox vaccine.

  7. Construction and characterization of human rotavirus recombinant VP8* subunit parenteral vaccine candidates.

    PubMed

    Wen, Xiaobo; Cao, Dianjun; Jones, Ronald W; Li, Jianping; Szu, Shousun; Hoshino, Yasutaka

    2012-09-21

    Two currently licensed live oral rotavirus vaccines (Rotarix® and RotaTeq®) are highly efficacious against severe rotavirus diarrhea. However, the efficacy of such vaccines in selected low-income African and Asian countries is much lower than that in middle or high-income countries. Additionally, these two vaccines have recently been associated with rare case of intussusception in vaccinated infants. We developed a novel recombinant subunit parenteral rotavirus vaccine which may be more effective in low-income countries and also avert the potential problem of intussusception. Truncated recombinant VP8* (ΔVP8*) protein of human rotavirus strain Wa P[8], DS-1 P[4] or 1076 P[6] expressed in Escherichia coli was highly soluble and was generated in high yield. Guinea pigs hyperimmunized intramuscularly with each of the ΔVP8* proteins (i.e., P[8], P[4] or P[6]) developed high levels of homotypic as well as variable levels of heterotypic neutralizing antibodies. Moreover, the selected ΔVP8* proteins when administered to mice at a clinically relevant dosage, route and schedule, elicited high levels of serum anti-VP8* IgG and/or neutralizing antibodies. Our data indicated that the ΔVP8* proteins may be a plausible additional candidate as new parenteral rotavirus vaccines. Published by Elsevier Ltd.

  8. Construction and Characterization of Human Rotavirus Recombinant VP8* Subunit Parenteral Vaccine Candidates

    PubMed Central

    Wen, Xiaobo; Cao, Dianjun; Jones, Ronald W.; Li, Jianping; Szu, Shousun; Hoshino, Yasutaka

    2012-01-01

    Two currently licensed live oral rotavirus vaccines (Rotarix® and RotaTeq®) are highly efficacious against severe rotavirus diarrhea. However, the efficacy of such vaccines in selected low-income African and Asian countries is much lower than that in middle or high-income countries. Additionally, these two vaccines have recently been associated with rare case of intussusception in vaccinated infants. We developed a novel recombinant subunit parenteral rotavirus vaccine which may be more effective in low-income countries and also avert the potential problem of intussusception. Truncated recombinant VP8* (ΔVP8*) protein of human rotavirus strain Wa P[8], DS-1 P[4] or 1076 P[6] expressed in E. coli was highly soluble and was generated in high yield. Guinea pigs hyperimmunized intramuscularly with each of the ΔVP8* proteins (i.e., (P[8], P[4] or P[6]) developed high levels of homotypic as well as variable levels of heterotypic neutralizing antibodies. Moreover, the selected ΔVP8* proteins when administered to mice at a clinically relevant dosage, route and schedule, elicited high levels of serum anti-VP8* IgG and/or neutralizing antibodies. Our data indicated that the ΔVP8* proteins may be a plausible additional candidate as new parenteral rotavirus vaccines. PMID:22885016

  9. The Hard Way towards an Antibody-Based HIV-1 Env Vaccine: Lessons from Other Viruses

    PubMed Central

    Ringel, Oliver; Vieillard, Vincent; Debré, Patrice; Eichler, Jutta; Büning, Hildegard

    2018-01-01

    Although effective antibody-based vaccines have been developed against multiple viruses, such approaches have so far failed for the human immunodeficiency virus type 1 (HIV-1). Despite the success of anti-retroviral therapy (ART) that has turned HIV-1 infection into a chronic disease and has reduced the number of new infections worldwide, a vaccine against HIV-1 is still urgently needed. We discuss here the major reasons for the failure of “classical” vaccine approaches, which are mostly due to the biological properties of the virus itself. HIV-1 has developed multiple mechanisms of immune escape, which also account for vaccine failure. So far, no vaccine candidate has been able to induce broadly neutralizing antibodies (bnAbs) against primary patient viruses from different clades. However, such antibodies were identified in a subset of patients during chronic infection and were shown to protect from infection in animal models and to reduce viremia in first clinical trials. Their detailed characterization has guided structure-based reverse vaccinology approaches to design better HIV-1 envelope (Env) immunogens. Furthermore, conserved Env epitopes have been identified, which are promising candidates in view of clinical applications. Together with new vector-based technologies, considerable progress has been achieved in recent years towards the development of an effective antibody-based HIV-1 vaccine. PMID:29662026

  10. Serum-free microcarrier based production of replication deficient Influenza vaccine candidate virus lacking NS1 using Vero cells

    PubMed Central

    2011-01-01

    Background Influenza virus is a major health concern that has huge impacts on the human society, and vaccination remains as one of the most effective ways to mitigate this disease. Comparing the two types of commercially available Influenza vaccine, the live attenuated virus vaccine is more cross-reactive and easier to administer than the traditional inactivated vaccines. One promising live attenuated Influenza vaccine that has completed Phase I clinical trial is deltaFLU, a deletion mutant lacking the viral Nonstructural Protein 1 (NS1) gene. As a consequence of this gene deletion, this mutant virus can only propagate effectively in cells with a deficient interferon-mediated antiviral response. To demonstrate the manufacturability of this vaccine candidate, a batch bioreactor production process using adherent Vero cells on microcarriers in commercially available animal-component free, serum-free media is described. Results Five commercially available animal-component free, serum-free media (SFM) were evaluated for growth of Vero cells in agitated Cytodex 1 spinner flask microcarrier cultures. EX-CELL Vero SFM achieved the highest cell concentration of 2.6 × 10^6 cells/ml, whereas other SFM achieved about 1.2 × 10^6 cells/ml. Time points for infection between the late exponential and stationary phases of cell growth had no significant effect in the final virus titres. A virus yield of 7.6 Log10 TCID50/ml was achieved using trypsin concentration of 10 μg/ml and MOI of 0.001. The Influenza vaccine production process was scaled up to a 3 liter controlled stirred tank bioreactor to achieve a cell density of 2.7 × 10^6 cells/ml and virus titre of 8.3 Log10 TCID50/ml. Finally, the bioreactor system was tested for the production of the corresponding wild type H1N1 Influenza virus, which is conventionally used in the production of inactivated vaccine. High virus titres of up to 10 Log10 TCID50/ml were achieved. Conclusions We describe for the first time the production

  11. Towards clinical development of a Pfs48/45-based transmission blocking malaria vaccine.

    PubMed

    Theisen, Michael; Jore, Matthijs M; Sauerwein, Robert

    2017-04-01

    Malaria is a devastating vector-borne disease caused by the Plasmodium parasite, resulting in almost 0.5 million casualties per year. The parasite has a complex life-cycle that includes asexual replication in human red blood cells, causing symptomatic malaria, and sexual stages which are essential for the transmission to the mosquito vector. A vaccine targeting the sexual stages of the parasite and thus blocking transmission will be instrumental for the eradication of malaria. One of the leading transmission blocking vaccine candidates is the sexual stage antigen Pfs48/45. Areas covered: PubMed was searched to review the progress and future prospects for clinical development of a Pfs48/45-based subunit vaccine. We will focus on biological function, naturally acquired immunity, functional activity of specific antibodies, sequence diversity, production of recombinant protein and preclinical studies. Expert commentary: Pfs48/45 is one of the lead-candidates for a transmission blocking vaccine and should be further explored in clinical trials.

  12. Ebola virus vaccine: benefit and risks of adenovirus-based vectors.

    PubMed

    Mennechet, Franck J D; Tran, Thi Thu Phuong; Eichholz, Karsten; van de Perre, Philippe; Kremer, Eric J

    2015-01-01

    In 2014, an outbreak of Ebola virus spread rapidly in West Africa. The epidemic killed more than 10,000 people and resulted in transmissions outside the endemic countries. WHO hopes for effective vaccines by the end of 2015. Numerous vaccine candidates have been proposed, and several are currently being evaluated in humans. Among the vaccine candidates are vectors derived from adenovirus (Ad). Despite previous encouraging preclinical and Phase I/II trials, Ad vectors used in three Phase II trials targeting HIV were prematurely interrupted because of the lack of demonstrated efficacy. The vaccine was not only ineffective but also led to a higher rate of HIV acquisition. In this context, the authors discuss the potential benefits, risks and impact of using Ad-derived vaccines to control Ebola virus disease.

  13. 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.

  14. Evaluation of a genetically modified foot-and-mouth disease virus vaccine candidate generated by reverse genetics

    PubMed Central

    2012-01-01

    Background Foot-and-mouth disease (FMD) is the most economically important and highly contagious disease of cloven-hoofed animals worldwide. Control of the disease has been mainly based on large-scale vaccinations with whole-virus inactivated vaccines. In recent years, a series of outbreaks of type O FMD occurred in China (including Chinese Taipei, Chinese Hong Kong) posed a tremendous threat to Chinese animal husbandry. Its causative agent, type O FMDV, has evolved into three topotypes (East–South Asia (ME-SA), Southeast Asia (SEA), Cathay (CHY)) in these regions, which represents an important obstacle to disease control. The available FMD vaccine in China shows generally good protection against ME-SA and SEA topotype viruses infection, but affords insufficient protection against some variants of the CHY topotype. Therefore, the choice of a new vaccine strain is of fundamental importance. Results The present study describes the generation of a full-length infectious cDNA clone of FMDV vaccine strain and a genetically modified virus with some amino acid substitutions in antigenic sites 1, 3, and 4, based on the established infectious clone. The recombinant viruses had similar growth properties to the wild O/HN/CHA/93 virus. All swine immunized with inactivated vaccine prepared from the O/HN/CHA/93 were fully protected from challenge with the viruses of ME-SA and SEA topotypes and partially protected against challenge with the virus of CHY topotype at 28 days post-immunization. In contrast, the swine inoculated with the genetically modified vaccine were completely protected from the infection of viruses of the three topotypes. Conclusions Some amino acid substitutions in the FMDV vaccine strain genome did not have an effect on the ability of viral replication in vitro. The vaccine prepared from genetically modified FMDV by reverse genetics significantly improved the protective efficacy to the variant of the CHY topotype, compared with the wild O/HN/CHA/93 virus

  15. The study of H. pylori putative candidate factors for single- and multi-component vaccine development.

    PubMed

    Mirzaei, Nasrin; Poursina, Farkhondeh; Moghim, Sharareh; Rashidi, Niloufar; Ghasemian Safaei, Hajieh

    2017-09-01

    Helicobacter pylori has grown to colonize inside the stomach of nearly half of the world's population, turning into the most prevalent infections in the universe. Medical care failures noticeably confirm the need for a vaccine to hinder or deal with H. pylori. This review is planned to discuss the most known factors as a vaccine candidate, including single (AhpC, BG, CagA, KatA, Fla, Hsp, HWC, Lpp, LPS, NAP, OMP, OMV, SOD, Tpx, Urease, VacA) and multi-component vaccines. Many promising results in the field of single and multivalent vaccine can be seen, but there is no satisfactory outcome and neither a prophylactic nor a therapeutic vaccine to treat or eradicate the infection in human has been acquired. Hence, selecting suitable antigen is an important factor as an appropriate adjuvant. Taken all together, the development of efficient anti-H. pylori vaccines relies on the fully understanding of the interactions between H. pylori and its host immune system. Therefore, more work should be done on epitope mapping, analysis of molecular structure, and determination of the antigen determinant region as well due to design a vaccine, preferably a multi-component vaccine to elicit specific CD4 T-cell responses that are required for H. pylori vaccine efficacy.

  16. Assessment of the Plasmodium falciparum Preerythrocytic Antigen UIS3 as a Potential Candidate for a Malaria Vaccine.

    PubMed

    Longley, Rhea J; Halbroth, Benedict R; Salman, Ahmed M; Ewer, Katie J; Hodgson, Susanne H; Janse, Chris J; Khan, Shahid M; Hill, Adrian V S; Spencer, Alexandra J

    2017-03-01

    Efforts are under way to improve the efficacy of subunit malaria vaccines through assessments of new adjuvants, vaccination platforms, and antigens. In this study, we further assessed the Plasmodium falciparum antigen upregulated in infective sporozoites 3 (PfUIS3) as a vaccine candidate. PfUIS3 was expressed in the viral vectors chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) and used to immunize mice in a prime-boost regimen. We previously demonstrated that this regimen could provide partial protection against challenge with chimeric P. berghei parasites expressing PfUIS3. We now show that ChAd63-MVA PfUIS3 can also provide partial cross-species protection against challenge with wild-type P. berghei parasites. We also show that PfUIS3-specific cellular memory responses could be recalled in human volunteers exposed to P. falciparum parasites in a controlled human malaria infection study. When ChAd63-MVA PfUIS3 was coadministered with the vaccine candidate P. falciparum thrombospondin-related adhesion protein (PfTRAP) expressed in the ChAd63-MVA system, there was no significant change in immunogenicity to either vaccine. However, when mice were challenged with double chimeric P. berghei - P. falciparum parasites expressing both PfUIS3 and PfTRAP, vaccine efficacy was improved to 100% sterile protection. This synergistic effect was evident only when the two vaccines were mixed and administered at the same site. We have therefore demonstrated that vaccination with PfUIS3 can induce a consistent delay in patent parasitemia across mouse strains and against chimeric parasites expressing PfUIS3 as well as wild-type P. berghei ; when this vaccine is combined with another partially protective regimen (ChAd63-MVA PfTRAP), complete protection is induced. Copyright © 2017 Longley et al.

  17. Differential CD4+ versus CD8+ T-cell responses elicited by different poxvirus-based human immunodeficiency virus type 1 vaccine candidates provide comparable efficacies in primates.

    PubMed

    Mooij, Petra; Balla-Jhagjhoorsingh, Sunita S; Koopman, Gerrit; Beenhakker, Niels; van Haaften, Patricia; Baak, Ilona; Nieuwenhuis, Ivonne G; Kondova, Ivanela; Wagner, Ralf; Wolf, Hans; Gómez, Carmen E; Nájera, José L; Jiménez, Victoria; Esteban, Mariano; Heeney, Jonathan L

    2008-03-01

    Poxvirus vectors have proven to be highly effective for boosting immune responses in diverse vaccine settings. Recent reports reveal marked differences in the gene expression of human dendritic cells infected with two leading poxvirus-based human immunodeficiency virus (HIV) vaccine candidates, New York vaccinia virus (NYVAC) and modified vaccinia virus Ankara (MVA). To understand how complex genomic changes in these two vaccine vectors translate into antigen-specific systemic immune responses, we undertook a head-to-head vaccine immunogenicity and efficacy study in the pathogenic HIV type 1 (HIV-1) model of AIDS in Indian rhesus macaques. Differences in the immune responses in outbred animals were not distinguished by enzyme-linked immunospot assays, but differences were distinguished by multiparameter fluorescence-activated cell sorter analysis, revealing a difference between the number of animals with both CD4(+) and CD8(+) T-cell responses to vaccine inserts (MVA) and those that elicit a dominant CD4(+) T-cell response (NYVAC). Remarkably, vector-induced differences in CD4(+)/CD8(+) T-cell immune responses persisted for more than a year after challenge and even accompanied antigenic modulation throughout the control of chronic infection. Importantly, strong preexposure HIV-1/simian immunodeficiency virus-specific CD4(+) T-cell responses did not prove deleterious with respect to accelerated disease progression. In contrast, in this setting, animals with strong vaccine-induced polyfunctional CD4(+) T-cell responses showed efficacies similar to those with stronger CD8(+) T-cell responses.

  18. Generation and characterization of a novel candidate gene therapy and vaccination vector based on human species D adenovirus type 56.

    PubMed

    Duffy, Margaret R; Alonso-Padilla, Julio; John, Lijo; Chandra, Naresh; Khan, Selina; Ballmann, Monika Z; Lipiec, Agnieszka; Heemskerk, Evert; Custers, Jerome; Arnberg, Niklas; Havenga, Menzo; Baker, Andrew H; Lemckert, Angelique

    2018-01-01

    The vectorization of rare human adenovirus (HAdV) types will widen our knowledge of this family and their interaction with cells, tissues and organs. In this study we focus on HAdV-56, a member of human Ad species D, and create ease-of-use cloning systems to generate recombinant HAdV-56 vectors carrying foreign genes. We present in vitro transduction profiles for HAdV-56 in direct comparison to the most commonly used HAdV-5-based vector. In vivo characterizations demonstrate that when it is delivered intravenously (i.v.) HAdV-56 mainly targets the spleen and, to a lesser extent, the lungs, whilst largely bypassing liver transduction in mice. HAdV-56 triggered robust inflammatory and cellular immune responses, with higher induction of IFNγ, TNFα, IL5, IL6, IP10, MCP1 and MIG1 compared to HAdV-5 following i.v. administration. We also investigated its potential as a vaccine vector candidate by performing prime immunizations in mice with HAdV-56 encoding luciferase (HAdV-56-Luc). Direct comparisons were made to HAdV-26, a highly potent human vaccine vector currently in phase II clinical trials. HAdV-56-Luc induced luciferase 'antigen'-specific IFNγ-producing cells and anti-HAdV-56 neutralizing antibodies in Balb/c mice, demonstrating a near identical profile to that of HAdV-26. Taken together, the data presented provides further insight into human Ad receptor/co-receptor usage, and the first report on HAdV-56 vectors and their potential for gene therapy and vaccine applications.

  19. Evaluation of two mutants of Mycobacterium avium subsp. paratuberculosis as candidates for a live attenuated vaccine for Johne's disease

    USDA-ARS?s Scientific Manuscript database

    Efforts to control Johne’s disease (JD), caused by Mycobacterium avium subsp. paratuberculosis (Map), has been difficult because of a lack of an effective vaccine. To address this problem we examined the potential of targeted gene disruption as a method to develop candidate vaccines with impaired c...

  20. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines.

    PubMed

    Richie, Thomas L; Billingsley, Peter F; Sim, B Kim Lee; James, Eric R; Chakravarty, Sumana; Epstein, Judith E; Lyke, Kirsten E; Mordmüller, Benjamin; Alonso, Pedro; Duffy, Patrick E; Doumbo, Ogobara K; Sauerwein, Robert W; Tanner, Marcel; Abdulla, Salim; Kremsner, Peter G; Seder, Robert A; Hoffman, Stephen L

    2015-12-22

    Sanaria Inc. has developed methods to manufacture, purify and cryopreserve aseptic Plasmodium falciparum (Pf) sporozoites (SPZ), and is using this platform technology to develop an injectable PfSPZ-based vaccine that provides high-grade, durable protection against infection with Pf malaria. Several candidate vaccines are being developed and tested, including PfSPZ Vaccine, in which the PfSPZ are attenuated by irradiation, PfSPZ-CVac, in which fully infectious PfSPZ are attenuated in vivo by concomitant administration of an anti-malarial drug, and PfSPZ-GA1, in which the PfSPZ are attenuated by gene knockout. Forty-three research groups in 15 countries, organized as the International PfSPZ Consortium (I-PfSPZ-C), are collaborating to advance this program by providing intellectual, clinical, and financial support. Fourteen clinical trials of these products have been completed in the USA, Europe and Africa, two are underway and at least 12 more are planned for 2015-2016 in the US (four trials), Germany (2 trials), Tanzania, Kenya, Mali, Burkina Faso, Ghana and Equatorial Guinea. Sanaria anticipates application to license a first generation product as early as late 2017, initially to protect adults, and a year later to protect all persons >6 months of age for at least six months. Improved vaccine candidates will be advanced as needed until the following requirements have been met: long-term protection against natural transmission, excellent safety and tolerability, and operational feasibility for population-wide administration. Here we describe the three most developed whole PfSPZ vaccine candidates, associated clinical trials, initial plans for licensure and deployment, and long-term objectives for a final product suitable for mass administration to achieve regional malaria elimination and eventual global eradication. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  1. Progress with Plasmodium falciparum sporozoite (PfSPZ)-based malaria vaccines

    PubMed Central

    Richie, Thomas L.; Billingsley, Peter F.; Sim, B. Kim Lee; James, Eric R.; Chakravarty, Sumana; Epstein, Judith E.; Lyke, Kirsten E.; Mordmüller, Benjamin; Alonso, Pedro; Duffy, Patrick E.; Doumbo, Ogobara K.; Sauerwein, Robert W.; Tanner, Marcel; Abdulla, Salim; Kremsner, Peter G.; Seder, Robert A.; Hoffman, Stephen L.

    2016-01-01

    Sanaria Inc. has developed methods to manufacture, purify and cryopreserve aseptic Plasmodium falciparum (Pf) sporozoites (SPZ), and is using this platform technology to develop an injectable PfSPZ-based vaccine that provides high-grade, durable protection against infection with Pf malaria. Several candidate vaccines are being developed and tested, including PfSPZ Vaccine, in which the PfSPZ are attenuated by irradiation, PfSPZ-CVac, in which fully infectious PfSPZ are attenuated in vivo by concomitant administration of an anti-malarial drug, and PfSPZ-GA1, in which the PfSPZ are attenuated by gene knockout. Forty-three research groups in 15 countries, organized as the International PfSPZ Consortium (I-PfSPZ-C), are collaborating to advance this program by providing intellectual, clinical, and financial support. Fourteen clinical trials of these products have been completed in the USA, Europe and Africa, two are underway and at least 12 more are planned for 2015–2016 in the US (four trials), Germany (2 trials), Tanzania, Kenya, Mali, Burkina Faso, Ghana and Equatorial Guinea. Sanaria anticipates application to license a first generation product as early as late 2017, initially to protect adults, and a year later to protect all persons >6 months of age for at least six months. Improved vaccine candidates will be advanced as needed until the following requirements have been met: long-term protection against natural transmission, excellent safety and tolerability, and operational feasibility for population-wide administration. Here we describe the three most developed whole PfSPZ vaccine candidates, associated clinical trials, initial plans for licensure and deployment, and long-term objectives for a final product suitable for mass administration to achieve regional malaria elimination and eventual global eradication. PMID:26469720

  2. Current ebola vaccines.

    PubMed

    Hoenen, Thomas; Groseth, Allison; Feldmann, Heinz

    2012-07-01

    Ebolaviruses cause severe viral hemorrhagic fever in humans and non-human primates (NHPs), with case fatality rates of up to 90%. Currently, neither a specific treatment nor a vaccine licensed for use in humans is available. However, a number of vaccine candidates have been developed in the last decade that are highly protective in NHPs, the gold standard animal model for ebola hemorrhagic fever. This review analyzes a number of scenarios for the use of ebolavirus vaccines, discusses the requirements for ebolavirus vaccines in these scenarios and describes current ebolavirus vaccines. Among these vaccines are recombinant adenoviruses, recombinant vesicular stomatitis viruses (VSVs), recombinant human parainfluenza viruses and virus-like particles. Interestingly, one of these vaccine platforms, based on recombinant VSVs, has also demonstrated post-exposure protection in NHPs. The most pressing remaining challenge is now to move these vaccine candidates forward into human trials and toward licensure. In order to achieve this, it will be necessary to establish the mechanisms and correlates of protection for these vaccines, and to continue to demonstrate their safety, particularly in potentially immunocompromised populations. However, already now there is sufficient evidence that, from a scientific perspective, a vaccine protective against ebolaviruses is possible.

  3. Plant-Produced Subunit Vaccine Candidates against Yellow Fever Induce Virus Neutralizing Antibodies and Confer Protection against Viral Challenge in Animal Models.

    PubMed

    Tottey, Stephen; Shoji, Yoko; Jones, R Mark; Chichester, Jessica A; Green, Brian J; Musiychuk, Konstantin; Si, Huaxin; Manceva, Slobodanka D; Rhee, Amy; Shamloul, Moneim; Norikane, Joey; Guimarães, Rosane C; Caride, Elena; Silva, Andrea N M R; Simões, Marisol; Neves, Patricia C C; Marchevsky, Renato; Freire, Marcos S; Streatfield, Stephen J; Yusibov, Vidadi

    2018-02-01

    Yellow fever (YF) is a viral disease transmitted by mosquitoes and endemic mostly in South America and Africa with 20-50% fatality. All current licensed YF vaccines, including YF-Vax ® (Sanofi-Pasteur, Lyon, France) and 17DD-YFV (Bio-Manguinhos, Rio de Janeiro, Brazil), are based on live attenuated virus produced in hens' eggs and have been widely used. The YF vaccines are considered safe and highly effective. However, a recent increase in demand for YF vaccines and reports of rare cases of YF vaccine-associated fatal adverse events have provoked interest in developing a safer YF vaccine that can be easily scaled up to meet this increased global demand. To this point, we have engineered the YF virus envelope protein (YFE) and transiently expressed it in Nicotiana benthamiana as a stand-alone protein (YFE) or as fusion to the bacterial enzyme lichenase (YFE-LicKM). Immunogenicity and challenge studies in mice demonstrated that both YFE and YFE-LicKM elicited virus neutralizing (VN) antibodies and protected over 70% of mice from lethal challenge infection. Furthermore, these two YFE-based vaccine candidates induced VN antibody responses with high serum avidity in nonhuman primates and these VN antibody responses were further enhanced after challenge infection with the 17DD strain of YF virus. These results demonstrate partial protective efficacy in mice of YFE-based subunit vaccines expressed in N. benthamiana . However, their efficacy is inferior to that of the live attenuated 17DD vaccine, indicating that formulation development, such as incorporating a more suitable adjuvant, may be required for product development.

  4. Live, Attenuated Influenza A H5N1 Candidate Vaccines Provide Broad Cross-Protection in Mice and Ferrets

    PubMed Central

    Mills, Kimberly L; Jin, Hong; Duke, Greg; Lu, Bin; Luke, Catherine J; Murphy, Brian; Swayne, David E; Kemble, George; Subbarao, Kanta

    2006-01-01

    Background Recent outbreaks of highly pathogenic influenza A H5N1 viruses in humans and avian species that began in Asia and have spread to other continents underscore an urgent need to develop vaccines that would protect the human population in the event of a pandemic. Methods and Findings Live, attenuated candidate vaccines possessing genes encoding a modified H5 hemagglutinin (HA) and a wild-type (wt) N1 neuraminidase from influenza A H5N1 viruses isolated in Hong Kong and Vietnam in 1997, 2003, and 2004, and remaining gene segments derived from the cold-adapted (ca) influenza A vaccine donor strain, influenza A/Ann Arbor/6/60 ca (H2N2), were generated by reverse genetics. The H5N1 ca vaccine viruses required trypsin for efficient growth in vitro, as predicted by the modification engineered in the gene encoding the HA, and possessed the temperature-sensitive and attenuation phenotypes specified by the internal protein genes of the ca vaccine donor strain. More importantly, the candidate vaccines were immunogenic in mice. Four weeks after receiving a single dose of 106 50% tissue culture infectious doses of intranasally administered vaccines, mice were fully protected from lethality following challenge with homologous and antigenically distinct heterologous wt H5N1 viruses from different genetic sublineages (clades 1, 2, and 3) that were isolated in Asia between 1997 and 2005. Four weeks after receiving two doses of the vaccines, mice and ferrets were fully protected against pulmonary replication of homologous and heterologous wt H5N1 viruses. Conclusions The promising findings in these preclinical studies of safety, immunogenicity, and efficacy of the H5N1 ca vaccines against antigenically diverse H5N1 vaccines provide support for their careful evaluation in Phase 1 clinical trials in humans. PMID:16968127

  5. Enhanced Neutralizing Antibody Response Induced by Respiratory Syncytial Virus Prefusion F Protein Expressed by a Vaccine Candidate

    PubMed Central

    Liang, Bo; Surman, Sonja; Amaro-Carambot, Emerito; Kabatova, Barbora; Mackow, Natalie; Lingemann, Matthias; Yang, Lijuan; McLellan, Jason S.; Graham, Barney S.; Kwong, Peter D.; Schaap-Nutt, Anne; Collins, Peter L.

    2015-01-01

    ABSTRACT Respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (HPIV3) are the first and second leading viral agents of severe respiratory tract disease in infants and young children worldwide. Vaccines are not available, and an RSV vaccine is particularly needed. A live attenuated chimeric recombinant bovine/human PIV3 (rB/HPIV3) vector expressing the RSV fusion (F) glycoprotein from an added gene has been under development as a bivalent vaccine against RSV and HPIV3. Previous clinical evaluation of this vaccine candidate suggested that increased genetic stability and immunogenicity of the RSV F insert were needed. This was investigated in the present study. RSV F expression was enhanced 5-fold by codon optimization and by modifying the amino acid sequence to be identical to that of an early passage of the original clinical isolate. This conferred a hypofusogenic phenotype that presumably reflects the original isolate. We then compared vectors expressing stabilized prefusion and postfusion versions of RSV F. In a hamster model, prefusion F induced increased quantity and quality of RSV-neutralizing serum antibodies and increased protection against wild-type (wt) RSV challenge. In contrast, a vector expressing the postfusion F was less immunogenic and protective. The genetic stability of the RSV F insert was high and was not affected by enhanced expression or the prefusion or postfusion conformation of RSV F. These studies provide an improved version of the previously well-tolerated rB/HPIV3-RSV F vaccine candidate that induces a superior RSV-neutralizing serum antibody response. IMPORTANCE Respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (HPIV3) are two major causes of pediatric pneumonia and bronchiolitis. The rB/HPIV3 vector expressing RSV F protein is a candidate bivalent live vaccine against HPIV3 and RSV. Previous clinical evaluation indicated the need to increase the immunogenicity and genetic stability of the RSV F

  6. Safety and tolerability of a live oral Salmonella typhimurium vaccine candidate in SIV-infected nonhuman primates.

    PubMed

    Ault, Alida; Tennant, Sharon M; Gorres, J Patrick; Eckhaus, Michael; Sandler, Netanya G; Roque, Annelys; Livio, Sofie; Bao, Saran; Foulds, Kathryn E; Kao, Shing-Fen; Roederer, Mario; Schmidlein, Patrick; Boyd, Mary Adetinuke; Pasetti, Marcela F; Douek, Daniel C; Estes, Jacob D; Nabel, Gary J; Levine, Myron M; Rao, Srinivas S

    2013-12-02

    Nontyphoidal Salmonella (NTS) serovars are a common cause of acute food-borne gastroenteritis worldwide and can cause invasive systemic disease in young infants, the elderly, and immunocompromised hosts, accompanied by high case fatality. Vaccination against invasive NTS disease is warranted where the disease incidence and mortality are high and multidrug resistance is prevalent, as in sub-Saharan Africa. Live-attenuated vaccines that mimic natural infection constitute one strategy to elicit protection. However, they must particularly be shown to be adequately attenuated for consideration of immunocompromised subjects. Accordingly, we examined the safety and tolerability of an oral live attenuated Salmonella typhimurium vaccine candidate, CVD 1921, in an established chronic simian immunodeficiency virus (SIV)-infected rhesus macaque model. We evaluated clinical parameters, histopathology, and measured differences in mucosal permeability to wild-type and vaccine strains. Compared to the wild-type S. typhimurium strain I77 in both SIV-infected and SIV-uninfected nonhuman primate hosts, this live-attenuated vaccine shows reduced shedding and systemic spread, exhibits limited pathological disease manifestations in the digestive tract, and induces low levels of cellular infiltration in tissues. Furthermore, wild-type S. typhimurium induces increased intestinal epithelial damage and permeability, with infiltration of neutrophils and macrophages in both SIV-infected and SIV-uninfected nonhuman primates compared to the vaccine strain. Based on shedding, systemic spread, and histopathology, the live-attenuated S. typhimurium strain CVD 1921 appears to be safe and well-tolerated in the nonhuman primate model, including chronically SIV-infected rhesus macaques. Copyright © 2013. Published by Elsevier Ltd.

  7. Ebola Virus Disease Candidate Vaccines Under Evaluation in Clinical Trials

    PubMed Central

    Martins, Karen A.; Jahrling, Peter B.; Bavari, Sina; Kuhn, Jens H.

    2016-01-01

    Summary Filoviruses are the etiological agents of two human illnesses: Ebola virus disease and Marburg virus disease. Until 2013, medical countermeasure development against these afflictions was limited to only a few research institutes worldwide as both infections were considered exotic due to very low case numbers. Together with the high case-fatality rate of both diseases, evaluation of any candidate countermeasure in properly controlled clinical trials seemed impossible. However, in 2013, Ebola virus was identified as the etiological agent of a large disease outbreak in Western Africa including almost 30,000 infections and more than 11,000 deaths, including case exportations to Europe and North America. These large case numbers resulted in medical countermeasure development against Ebola virus disease becoming a global public-health priority. This review summarizes the status quo of candidate vaccines against Ebola virus disease, with a focus on those that are currently under evaluation in clinical trials. PMID:27160784

  8. Limited antigenic variation in the Trypanosoma cruzi candidate vaccine antigen TSA-1.

    PubMed

    Knight, J M; Zingales, B; Bottazzi, M E; Hotez, P; Zhan, B

    2014-12-01

    Chagas disease (American trypanosomiasis caused by Trypanosoma cruzi) is one of the most important neglected tropical diseases in the Western Hemisphere. The toxicities and limited efficacies of current antitrypanosomal drugs have prompted a search for alternative technologies such as a therapeutic vaccine comprised of T. cruzi antigens, including a recombinant antigen encoding the N-terminal 65 kDa portion of Trypomastigote surface antigen-1 (TSA-1). With at least six known genetically distinct T. cruzi lineages, variability between the different lineages poses a unique challenge for the development of broadly effective therapeutic vaccine. The variability across the major lineages in the current vaccine candidate antigen TSA-1 has not previously been addressed. To assess the variation in TSA-1, we cloned and sequenced TSA-1 from several different T. cruzi strains representing three of the most clinically relevant lineages. Analysis of the different alleles showed limited variation in TSA-1 across the different strains and fit with the current theory for the evolution of the different lineages. Additionally, minimal variation in known antigenic epitopes for the HLA-A 02 allele suggests that interlineage variation in TSA-1 would not impair the range and efficacy of a vaccine containing TSA-1. © 2014 John Wiley & Sons Ltd.

  9. Pre-Clinical Efficacy and Safety of Experimental Vaccines Based on Non-Replicating Vaccinia Vectors against Yellow Fever

    PubMed Central

    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

    Background 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. Methodology/Principal Findings 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 105 TCID50. 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. Conclusions/Significance 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. PMID:21931732

  10. Dynamic profiles of neutralizing antibody responses elicited in rhesus monkeys immunized with a combined tetravalent DTaP-Sabin IPV candidate vaccine.

    PubMed

    Sun, Mingbo; Ma, Yan; Xu, Yinhua; Yang, Huijuan; Shi, Li; Che, Yanchun; Liao, Guoyang; Jiang, Shude; Zhang, Shumin; Li, Qihan

    2014-02-19

    The World Health Organization has recommended that a Sabin inactivated polio vaccine (IPV) should gradually and synchronously replace oral polio vaccines for routine immunizations because its benefits in eliminating vaccine-associated paralytic poliomyelitis have been reported in different phases of clinical trials. It is also considered important to explore new tetravalent diphtheria, tetanus, and acellular pertussis-Sabin IPV (DTaP-sIPV) candidate vaccines for possible use in developing countries. In this study, the immunogenicity of a combined tetravalent DTaP-sIPV candidate vaccine was investigated in primates by evaluating the neutralizing antibody responses it induced. The dynamic profiles of the antibody responses to each of the separate antigenic components and serotypes of Sabin IPV were determined and their corresponding geometric mean titers were similar to those generated by the tetravalent diphtheria, tetanus, and acellular pertussis-conventional IPV (DTaP-cIPV), the tetravalent diphtheria, tetanus, and acellular pertussis (DTaP), and Sabin IPV vaccines in the control groups. This implies that protective immunogenic effects are conferred by this combined tetravalent formulation. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Exoproteome and Secretome Derived Broad Spectrum Novel Drug and Vaccine Candidates in Vibrio cholerae Targeted by Piper betel Derived Compounds

    PubMed Central

    Barh, Debmalya; Barve, Neha; Gupta, Krishnakant; Chandra, Sudha; Jain, Neha; Tiwari, Sandeep; Leon-Sicairos, Nidia; Canizalez-Roman, Adrian; Rodrigues dos Santos, Anderson; Hassan, Syed Shah; Almeida, Síntia; Thiago Jucá Ramos, Rommel; Augusto Carvalho de Abreu, Vinicius; Ribeiro Carneiro, Adriana; de Castro Soares, Siomar; Luiz de Paula Castro, Thiago; Miyoshi, Anderson; Silva, Artur; Kumar, Anil; Narayan Misra, Amarendra; Blum, Kenneth; Braverman, Eric R.; Azevedo, Vasco

    2013-01-01

    Vibrio cholerae is the causal organism of the cholera epidemic, which is mostly prevalent in developing and underdeveloped countries. However, incidences of cholera in developed countries are also alarming. Because of the emergence of new drug-resistant strains, even though several generic drugs and vaccines have been developed over time, Vibrio infections remain a global health problem that appeals for the development of novel drugs and vaccines against the pathogen. Here, applying comparative proteomic and reverse vaccinology approaches to the exoproteome and secretome of the pathogen, we have identified three candidate targets (ompU, uppP and yajC) for most of the pathogenic Vibrio strains. Two targets (uppP and yajC) are novel to Vibrio, and two targets (uppP and ompU) can be used to develop both drugs and vaccines (dual targets) against broad spectrum Vibrio serotypes. Using our novel computational approach, we have identified three peptide vaccine candidates that have high potential to induce both B- and T-cell-mediated immune responses from our identified two dual targets. These two targets were modeled and subjected to virtual screening against natural compounds derived from Piper betel. Seven compounds were identified first time from Piper betel to be highly effective to render the function of these targets to identify them as emerging potential drugs against Vibrio. Our preliminary validation suggests that these identified peptide vaccines and betel compounds are highly effective against Vibrio cholerae. Currently we are exhaustively validating these targets, candidate peptide vaccines, and betel derived lead compounds against a number of Vibrio species. PMID:23382822

  12. The preventive phase I trial with the HIV-1 Tat-based vaccine.

    PubMed

    Ensoli, Barbara; Fiorelli, Valeria; Ensoli, Fabrizio; Lazzarin, Adriano; Visintini, Raffaele; Narciso, Pasquale; Di Carlo, Aldo; Tripiciano, Antonella; Longo, Olimpia; Bellino, Stefania; Francavilla, Vittorio; Paniccia, Giovanni; Arancio, Angela; Scoglio, Arianna; Collacchi, Barbara; Ruiz Alvarez, Maria Josè; Tambussi, Giuseppe; Tassan Din, Chiara; Palamara, Guido; Latini, Alessandra; Antinori, Andrea; D'Offizi, Gianpiero; Giuliani, Massimo; Giulianelli, Marina; Carta, Maria; Monini, Paolo; Magnani, Mauro; Garaci, Enrico

    2009-12-11

    The native HIV-1 Tat protein was chosen as vaccine candidate for phase I clinical trials based on its role in the natural infection and AIDS pathogenesis, on the association of Tat-specific immune response with the asymptomatic stage as well as on its sequence conservation among HIV clades. A randomized, double blind, placebo-controlled phase I study (ISS P-001) was conducted in healthy adult volunteers without identifiable risk of HIV infection. Tat was administered 5 times monthly, subcute in alum or intradermic alone at 7.5 microg, 15 microg or 30 microg, respectively (ClinicalTrials.gov identifier: NCT00529698). Vaccination with Tat resulted to be safe and well tolerated (primary endpoint) both locally and systemically. In addition, Tat induced both Th1 and Th2 type specific immune responses in all subjects (secondary endpoint) with a wide spectrum of functional antibodies that are rarely seen in natural infection, providing key information for further clinical development of the Tat vaccine candidate.

  13. Construction and Characterization of a Nonproliferative El Tor Cholera Vaccine Candidate Derived from Strain 638

    PubMed Central

    Valle, Edgar; Ledón, Talena; Cedré, Bárbara; Campos, Javier; Valmaseda, Tania; Rodríguez, Boris; García, Luis; Marrero, Karen; Benítez, Jorge; Rodríguez, Sandra; Fando, Rafael

    2000-01-01

    In recent clinical assays, our cholera vaccine candidate strain, Vibrio cholerae 638 El Tor Ogawa, was well tolerated and immunogenic in Cuban volunteers. In this work we describe the construction of 638T, a thymidine auxotrophic version of improved environmental biosafety. In so doing, the thyA gene from V. cholerae was cloned, sequenced, mutated in vitro, and used to replace the wild-type allele. Except for its dependence on thymidine for growth in minimal medium, 638T is essentially indistinguishable from 638 in the rate of growth and morphology in complete medium. The two strains showed equivalent phenotypes with regard to motility, expression of the celA marker, colonization capacity in the infant mouse cholera model, and immunogenicity in the adult rabbit cholera model. However, the ability of this new strain to survive environmental starvation was limited with respect to that of 638. Taken together, these results suggest that this live, attenuated, but nonproliferative strain is a new, promising cholera vaccine candidate. PMID:11035753

  14. Candidate mosaic proteins for a pan-filoviral cytotoxic T-Cell lymphocyte vaccine

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

    Fenimore, Paul W; Fischer, William M; Kuiken, Carla

    vaccine than is possible with a wild-type protein, (2) reducing the number of low-prevalence k-mers minimizes the likelihood of undesirable immunodominance, and (3) excluding exogenous k-mers will result in mosaic proteins whose processing for presentation is close to what occurs with wild-type proteins. The first and second applications of the mosaic method were to HIV and Hepatitis C Virus (HCV). HIV is the virus with the largest number of known sequences, and consequently a plethora of information for the CTL vaccine designer to incorporate into their mosaics. Experience with HIV and HCV mosaics supports the validity of the three conjectures above. The available FILV sequences are probably closer to the minimum amount of information needed to make a meaningful mosaic vaccine candidate. There were 532 protein sequences in the National Institutes of Health GenPept database in November 2007 when our reference set was downloaded. These sequences come from both Ebola and Marburg viruses (EBOV and MARV), representing transcripts of all 7 genes. The coverage of viral diversity by the 7 genes is variable, with genes 1 (nucleoprotein, NP), 4 (glycoprotein, GP; soluble glycoprotein, sGP) and 7 (polymerase, L) giving the best coverage. Broadly-protective vaccine candidates for diverse viruses, such as HIV or Hepatitis C virus (HCV) have required pools of antigens. FILV is similar in this regard. While we have designed CTL mosaic proteins using all 7 types of filoviral proteins, only NP, GP and L proteins are reported here. If it were important to include other proteins in a mosaic CTL vaccine, additional sequences would be required to cover the space of known viral diversity.« less

  15. Vesicular stomatitis virus-based vaccines protect nonhuman primates against aerosol challenge with Ebola and Marburg viruses.

    PubMed

    Geisbert, Thomas W; Daddario-Dicaprio, Kathleen M; Geisbert, Joan B; Reed, Douglas S; Feldmann, Friederike; Grolla, Allen; Ströher, Ute; Fritz, Elizabeth A; Hensley, Lisa E; Jones, Steven M; Feldmann, Heinz

    2008-12-09

    Considerable progress has been made over the last decade in developing candidate preventive vaccines that can protect nonhuman primates against Ebola and Marburg viruses. A vaccine based on recombinant vesicular stomatitis virus (VSV) seems to be particularly robust as it can also confer protection when administered as a postexposure treatment. While filoviruses are not thought to be transmitted by aerosol in nature the inhalation route is among the most likely portals of entry in the setting of a bioterrorist event. At present, all candidate filoviral vaccines have been evaluated against parenteral challenges but none have been tested against an aerosol exposure. Here, we evaluated our recombinant VSV-based Zaire ebolavirus (ZEBOV) and Marburg virus (MARV) vaccines against aerosol challenge in cynomolgus macaques. All monkeys vaccinated with a VSV vector expressing the glycoprotein of ZEBOV were completely protected against an aerosol exposure of ZEBOV. Likewise, all monkeys vaccinated with a VSV vector expressing the glycoprotein of MARV were completely protected against an aerosol exposure of MARV. All control animals challenged by the aerosol route with either ZEBOV or MARV succumbed. Interestingly, disease in control animals appeared to progress slower than previously seen in macaques exposed to comparable doses by intramuscular injection.

  16. Human Vaccines & Immunotherapeutics

    PubMed Central

    Riedmann, Eva M.

    2012-01-01

    Two therapeutic HPV vaccine candidates successful in phase 1 Flu shot may prevent heart attacks and stroke CDX-1401 combined with TLR agonist: Positive phase 1 results Three MRSA vaccines in early clincial trials Ovarian cancer vaccine candidate DPX-Survivac: Positive interim results from phase 1 Chinese biotech partnership brings first hepatitis E vaccine to the market Therapeutic vaccine for treatment of genital herpes enters phase 2 Visionary concept: Printable vaccines PMID:23817319

  17. Identification of Mutations in a Candidate Dengue 4 Vaccine Strain 341750 PDK20 and Construction of a Full-Length eDNA Clone of the PDK20 Vaccine Candidate

    DTIC Science & Technology

    2010-01-01

    comply with a collection of information if it does not display a currently valid OMB control number . 1. REPORT DATE OCT 2009 2. REPORT TYPE 3. DATES...construction of a full-length eDNA clone of the PDK20 vaccine candidate 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d...PROJECT NUMBER 5e. TASK NUMBER 5f. WORK UNIT NUMBER 7. PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) Naval Medical Research Center,Infectious

  18. Current Ebola vaccines

    PubMed Central

    Hoenen, Thomas; Groseth, Allison; Feldmann, Heinz

    2012-01-01

    Introduction Ebolaviruses cause severe viral hemorrhagic fever in humans and non-human primates, with case fatality rates of up to 90%. Currently, neither a specific treatment nor a vaccine licensed for use in humans is available. However, a number of vaccine candidates have been developed in the last decade that are highly protective in non-human primates, the gold standard animal model for Ebola hemorrhagic fever. Areas covered This review analyzes a number of scenarios for the use of ebolavirus vaccines, discusses the requirements for ebolavirus vaccines in these scenarios, and describes current ebolavirus vaccines. Among these vaccines are recombinant Adenoviruses, recombinant Vesicular Stomatitis viruses, recombinant Human Parainfluenza viruses and virus-like particles. Interestingly, one of these vaccine platforms, based on recombinant Vesicular Stomatitis viruses, has also demonstrated post-exposure protection in non-human primates. Expert opinion The most pressing remaining challenge is now to move these vaccine candidates forward into human trials and towards licensure. In order to achieve this, it will be necessary to establish the mechanisms and correlates of protection for these vaccines, and to continue to demonstrate their safety, particularly in potentially immunocompromised populations. However, already now there is sufficient evidence that, from a scientific perspective, a vaccine protective against ebolaviruses is possible. PMID:22559078

  19. Subcutaneous administration CpG-ODNs acts as a potent adjuvant for an HIV-1-tat-based vaccine candidate to elicit cellular immunity in BALB/c mice.

    PubMed

    Panahi, Zeinab; Abdoli, Asghar; Mosayebi, Ghasem; Mahdavi, Mehdi; Bahrami, Fariborz

    2018-03-01

    To evaluate the combined effects of CpG oligodeoxynucleotides (CpG-ODNs) adjuvant and subcutaneous injection route on efficacy of a HIV-1-tat DNA vaccine candidate using BALB/c mice as an animal model. Evaluation of cellular and humoral immunity of mice injected subcutaneously with HIV-1-tat gene cloned into a pcDNA3.1 vector indicated that significant levels of IFN-γ cytokine secretion (900 pg/ml), lymphocyte proliferation (2.5 stimulation index) and IgG 2a (1.45 absorbance 450 nm) production could be achieved. These indicators of stimulated cellular immunity were elicited 2 weeks after the last injection (P < 0.05). Formulation of HIV-1-tat DNA vaccine candidate with CpG-ODNs as an adjuvant while administrated subcutaneously are a promising approach to induce effective cellular immunity responses against HIV-1 infection.

  20. Virus like particle-based vaccines against emerging infectious disease viruses.

    PubMed

    Liu, Jinliang; Dai, Shiyu; Wang, Manli; Hu, Zhihong; Wang, Hualin; Deng, Fei

    2016-08-01

    Emerging infectious diseases are major threats to human health. Most severe viral disease outbreaks occur in developing regions where health conditions are poor. With increased international travel and business, the possibility of eventually transmitting infectious viruses between different countries is increasing. The most effective approach in preventing viral diseases is vaccination. However, vaccines are not currently available for numerous viral diseases. Virus-like particles (VLPs) are engineered vaccine candidates that have been studied for decades. VLPs are constructed by viral protein expression in various expression systems that promote the selfassembly of proteins into structures resembling virus particles. VLPs have antigenicity similar to that of the native virus, but are non-infectious as they lack key viral genetic material. VLP vaccines have attracted considerable research interest because they offer several advantages over traditional vaccines. Studies have shown that VLP vaccines can stimulate both humoral and cellular immune responses, which may offer effective antiviral protection. Here we review recent developments with VLP-based vaccines for several highly virulent emerging or re-emerging infectious diseases. The infectious agents discussed include RNA viruses from different virus families, such as the Arenaviridae, Bunyaviridae, Caliciviridae, Coronaviridae, Filoviridae, Flaviviridae, Orthomyxoviridae, Paramyxoviridae, and Togaviridae families.

  1. Group A Streptococcal vaccine candidate: contribution of epitope to size, antigen presenting cell interaction and immunogenicity.

    PubMed

    Zaman, Mehfuz; Chandrudu, Saranya; Giddam, Ashwini K; Reiman, Jennifer; Skwarczynski, Mariusz; McPhun, Virginia; Moyle, Peter M; Batzloff, Michael R; Good, Michael F; Toth, Istvan

    2014-12-01

    Utilize lipopeptide vaccine delivery system to develop a vaccine candidate against Group A Streptococcus. Lipopeptides synthesized by solid-phase peptide synthesis-bearing carboxyl (C)-terminal and amino (N)-terminal Group A Streptococcus peptide epitopes. Nanoparticles formed were evaluated in vivo. Immune responses were induced in mice without additional adjuvant. We demonstrated for the first time that incorporation of the C-terminal epitope significantly enhanced the N-terminal epitope-specific antibody response and correlated with forming smaller nanoparticles. Antigen-presenting cells had increased uptake and maturation by smaller, more immunogenic nanoparticles. Antibodies raised by vaccination recognized isolates. Demonstrated the lipopeptidic nanoparticles to induce an immune response which can be influenced by the combined effect of epitope choice and size.

  2. 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

  3. 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.

  4. Identification of L. infantum chagasi proteins in VL patients' urine: a promising antigen discovery approach of vaccine candidates

    PubMed Central

    Kashino, Suely S.; Abeijon, Claudia; Qin, Lizeng; Kanunfre, Kelly A.; Kubrusly, Flávia S.; Silva, Fernando O.; Costa, Dorcas L.; Campos, Dioclécio; Costa, Carlos H.N.; Raw, Isaias; Campos-Neto, Antonio

    2012-01-01

    Visceral leishmaniasis (VL) is a serious lethal parasitic disease caused by Leishmania donovani in Asia and by Leishmania infantum chagasi in Southern Europe and South America. VL is endemic in 47 countries with an annual incidence estimated to be 500,000 cases. This high incidence is due in part to the lack of an efficacious vaccine. Here, we introduce an innovative approach to directly identify parasite vaccine candidate antigens that are abundantly produced in vivo in humans with VL. We combined RP-HPLC and mass spectrometry and categorized three L. infantum chagasi proteins, presumably produced in spleen, liver, and bone marrow lesions and excreted in the patients’ urine. Specifically, these proteins were the following: Li-isd1 (XP_001467866.1), Li-txn1 (XP_001466642.1), and Li-ntf2 (XP_001463738.1). Initial vaccine validation studies were performed with the rLi-ntf2 protein produced in E. coli mixed with the adjuvant BpMPLA-SE. This formulation stimulated potent Th1 response in BALB/c mice. Compared to control animals, mice immunized with Li-ntf2 + BpMPLASE had a marked parasite burden reduction in spleens at 40 days post-challenge with virulent L. infantum chagasi. These results strongly support the proposed antigen discovery strategy of vaccine candidates to kala-azar and opens novel possibilities for vaccine development to other serious infectious diseases. PMID:22443237

  5. Characterization of Two Metal Binding Lipoproteins as Vaccine Candidates for Enterococcal Infections

    PubMed Central

    Romero-Saavedra, Felipe; Laverde, Diana; Budin-Verneuil, Aurélie; Muller, Cécile; Bernay, Benoit; Benachour, Abdellah; Hartke, Axel; Huebner, Johannes

    2015-01-01

    Background Enterococcus faecium and faecalis are Gram-positive opportunistic pathogens that have become leading causes of nosocomial infections over the last decades. Especially multidrug resistant enterococci have become a challenging clinical problem worldwide. Therefore, new treatment options are needed and the identification of alternative targets for vaccine development has emerged as a feasible alternative to fight the infections caused by these pathogens. Results We extrapolate the transcriptomic data from a mice peritonitis infection model in E. faecalis to identify putative up-regulated surface proteins under infection conditions in E. faecium. After the bionformatic analyses two metal binding lipoproteins were identified to have a high homology (>72%) between the two species, the manganese ABC transporter substrate-binding lipoprotein (PsaAfm,) and the zinc ABC transporter substrate-binding lipoprotein (AdcAfm). These candidate lipoproteins were overexpressed in Escherichia coli and purified. The recombinant proteins were used to produce rabbit polyclonal antibodies that were able to induce specific opsonic antibodies that mediated killing of the homologous strain E. faecium E155 as well as clinical strains E. faecium E1162, Enterococcus faecalis 12030, type 2 and type 5. Mice were passively immunized with the antibodies raised against recombinant lipoproteins, showing significant reduction of colony counts in mice livers after the bacterial challenge and demonstrating the efficacy of these metal binding lipoproteins as promising vaccine candidates to treat infections caused by these enterococcal pathogens. Conclusion Overall, our results demonstrate that these two metal binding lipoproteins elicited specific, opsonic and protective antibodies, with an extensive cross-reactivity and serotype-independent coverage among these two important nocosomial pathogens. Pointing these two protein antigens as promising immunogens, that can be used as single

  6. Enhanced Neutralizing Antibody Response Induced by Respiratory Syncytial Virus Prefusion F Protein Expressed by a Vaccine Candidate.

    PubMed

    Liang, Bo; Surman, Sonja; Amaro-Carambot, Emerito; Kabatova, Barbora; Mackow, Natalie; Lingemann, Matthias; Yang, Lijuan; McLellan, Jason S; Graham, Barney S; Kwong, Peter D; Schaap-Nutt, Anne; Collins, Peter L; Munir, Shirin

    2015-09-01

    Respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (HPIV3) are the first and second leading viral agents of severe respiratory tract disease in infants and young children worldwide. Vaccines are not available, and an RSV vaccine is particularly needed. A live attenuated chimeric recombinant bovine/human PIV3 (rB/HPIV3) vector expressing the RSV fusion (F) glycoprotein from an added gene has been under development as a bivalent vaccine against RSV and HPIV3. Previous clinical evaluation of this vaccine candidate suggested that increased genetic stability and immunogenicity of the RSV F insert were needed. This was investigated in the present study. RSV F expression was enhanced 5-fold by codon optimization and by modifying the amino acid sequence to be identical to that of an early passage of the original clinical isolate. This conferred a hypofusogenic phenotype that presumably reflects the original isolate. We then compared vectors expressing stabilized prefusion and postfusion versions of RSV F. In a hamster model, prefusion F induced increased quantity and quality of RSV-neutralizing serum antibodies and increased protection against wild-type (wt) RSV challenge. In contrast, a vector expressing the postfusion F was less immunogenic and protective. The genetic stability of the RSV F insert was high and was not affected by enhanced expression or the prefusion or postfusion conformation of RSV F. These studies provide an improved version of the previously well-tolerated rB/HPIV3-RSV F vaccine candidate that induces a superior RSV-neutralizing serum antibody response. Respiratory syncytial virus (RSV) and human parainfluenza virus type 3 (HPIV3) are two major causes of pediatric pneumonia and bronchiolitis. The rB/HPIV3 vector expressing RSV F protein is a candidate bivalent live vaccine against HPIV3 and RSV. Previous clinical evaluation indicated the need to increase the immunogenicity and genetic stability of the RSV F insert. Here, we

  7. Evaluation of Live Recombinant Nonpathogenic Leishmania tarentolae Expressing Cysteine Proteinase and A2 Genes as a Candidate Vaccine against Experimental Canine Visceral Leishmaniasis.

    PubMed

    Shahbazi, Mehdi; Zahedifard, Farnaz; Taheri, Tahereh; Taslimi, Yasaman; Jamshidi, Shahram; Shirian, Sadegh; Mahdavi, Niousha; Hassankhani, Mehdi; Daneshbod, Yahya; Zarkesh-Esfahani, Sayyed Hamid; Papadopoulou, Barbara; Rafati, Sima

    2015-01-01

    Canine Visceral Leishmaniasis (CVL) is a major veterinary and public health problem caused by Leishmania infantum (L. infantum) in many endemic countries. It is a severe chronic disease with generalized parasite spread to the reticuloendothelial system, such as spleen, liver and bone marrow and is often fatal when left untreated. Control of VL in dogs would dramatically decrease infection pressure of L. infantum for humans, since dogs are the main domestic reservoir. In the past decade, various subunits and DNA antigens have been identified as potential vaccine candidates in experimental animal models, but none has been approved for human use so far. In this study, we vaccinated outbreed dogs with a prime-boost regimen based on recombinant L. tarentolae expressing the L. donovani A2 antigen along with cysteine proteinase genes (CPA and CPB without its unusual C-terminal extension (CPB-CTE) and evaluated its immunogenicity and protective immunity against L. infantum infectious challenge. We showed that vaccinated animals produced significantly higher levels of IgG2, but not IgG1, and also IFN-γ and TNF-α, but low IL-10 levels, before and after challenge as compared to control animals. Protection in dogs was also correlated with a strong DTH response and low parasite burden in the vaccinated group. Altogether, immunization with recombinant L. tarentolae A2-CPA-CPB-CTE was proven to be immunogenic and induced partial protection in dogs, hence representing a promising live vaccine candidate against CVL.

  8. Evaluation of Live Recombinant Nonpathogenic Leishmania tarentolae Expressing Cysteine Proteinase and A2 Genes as a Candidate Vaccine against Experimental Canine Visceral Leishmaniasis

    PubMed Central

    Shahbazi, Mehdi; Zahedifard, Farnaz; Taheri, Tahereh; Taslimi, Yasaman; Jamshidi, Shahram; Shirian, Sadegh; Mahdavi, Niousha; Hassankhani, Mehdi; Daneshbod, Yahya; Zarkesh-Esfahani, Sayyed Hamid; Papadopoulou, Barbara; Rafati, Sima

    2015-01-01

    Canine Visceral Leishmaniasis (CVL) is a major veterinary and public health problem caused by Leishmania infantum (L. infantum) in many endemic countries. It is a severe chronic disease with generalized parasite spread to the reticuloendothelial system, such as spleen, liver and bone marrow and is often fatal when left untreated. Control of VL in dogs would dramatically decrease infection pressure of L. infantum for humans, since dogs are the main domestic reservoir. In the past decade, various subunits and DNA antigens have been identified as potential vaccine candidates in experimental animal models, but none has been approved for human use so far. In this study, we vaccinated outbreed dogs with a prime-boost regimen based on recombinant L. tarentolae expressing the L. donovani A2 antigen along with cysteine proteinase genes (CPA and CPB without its unusual C-terminal extension (CPB-CTE) and evaluated its immunogenicity and protective immunity against L. infantum infectious challenge. We showed that vaccinated animals produced significantly higher levels of IgG2, but not IgG1, and also IFN-γ and TNF-α, but low IL-10 levels, before and after challenge as compared to control animals. Protection in dogs was also correlated with a strong DTH response and low parasite burden in the vaccinated group. Altogether, immunization with recombinant L. tarentolae A2-CPA-CPB-CTE was proven to be immunogenic and induced partial protection in dogs, hence representing a promising live vaccine candidate against CVL. PMID:26197085

  9. Comparative genomics study for the identification of drug and vaccine targets in Staphylococcus aureus: MurA ligase enzyme as a proposed candidate.

    PubMed

    Ghosh, Soma; Prava, Jyoti; Samal, Himanshu Bhusan; Suar, Mrutyunjay; Mahapatra, Rajani Kanta

    2014-06-01

    Now-a-days increasing emergence of antibiotic-resistant pathogenic microorganisms is one of the biggest challenges for management of disease. In the present study comparative genomics, metabolic pathways analysis and additional parameters were defined for the identification of 94 non-homologous essential proteins in Staphylococcus aureus genome. Further study prioritized 19 proteins as vaccine candidates where as druggability study reports 34 proteins suitable as drug targets. Enzymes from peptidoglycan biosynthesis, folate biosynthesis were identified as candidates for drug development. Furthermore, bacterial secretory proteins and few hypothetical proteins identified in our analysis fulfill the criteria of vaccine candidates. As a case study, we built a homology model of one of the potential drug target, MurA ligase, using MODELLER (9v12) software. The model has been further selected for in silico docking study with inhibitors from the DrugBank database. Results from this study could facilitate selection of proteins for entry into drug design and vaccine production pipelines. Copyright © 2014 Elsevier B.V. All rights reserved.

  10. 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

  11. Proteomic analysis of Brucella abortus cell envelope and identification of immunogenic candidate proteins for vaccine development.

    PubMed

    Connolly, Joseph P; Comerci, Diego; Alefantis, Timothy G; Walz, Alexander; Quan, Marian; Chafin, Ryan; Grewal, Paul; Mujer, Cesar V; Ugalde, Rodolfo A; DelVecchio, Vito G

    2006-07-01

    Brucella abortus is the etiologic agent of bovine brucellosis and causes a chronic disease in humans known as undulant fever. In livestock the disease is characterized by abortion and sterility. Live, attenuated vaccines such as S19 and RB51 have been used to control the spread of the disease in animals; however, they are considered unsafe for human use and they induce abortion in pregnant cattle. For the development of a safer and equally efficacious vaccine, immunoproteomics was utilized to identify novel candidate proteins from B. abortus cell envelope (CE). A total of 163 proteins were identified using 2-DE with MALDI-TOF MS and LC-MS/MS. Some of the major protein components include outer-membrane protein (OMP) 25, OMP31, Omp2b porin, and 60 kDa chaperonin GroEL. 2-DE Western blot analyses probed with antiserum from bovine and a human patient infected with Brucella identified several new immunogenic proteins such as fumarate reductase flavoprotein subunit, F0F1-type ATP synthase alpha subunit, and cysteine synthase A. The elucidation of the immunome of B. abortus CE identified a number of candidate proteins for developing vaccines against Brucella infection in bovine and humans.

  12. Correlates of Protection for M Protein-Based Vaccines against Group A Streptococcus

    PubMed Central

    Smeesters, Pierre R.; Frost, Hannah R. C.; Steer, Andrew C.

    2015-01-01

    Group A streptococcus (GAS) is known to cause a broad spectrum of illness, from pharyngitis and impetigo, to autoimmune sequelae such as rheumatic heart disease, and invasive diseases. It is a significant cause of infectious disease morbidity and mortality worldwide, but no efficacious vaccine is currently available. Progress in GAS vaccine development has been hindered by a number of obstacles, including a lack of standardization in immunoassays and the need to define human correlates of protection. In this review, we have examined the current immunoassays used in both GAS and other organisms, and explored the various challenges in their implementation in order to propose potential future directions to identify a correlate of protection and facilitate the development of M protein-based vaccines, which are currently the main GAS vaccine candidates. PMID:26101780

  13. In silico epitope mapping and experimental evaluation of the Merozoite Adhesive Erythrocytic Binding Protein (MAEBL) as a malaria vaccine candidate.

    PubMed

    Cravo, Pedro; Machado, Renato B; Leite, Juliana A; Leda, Taizy; Suwanarusk, Rossarin; Bittencourt, Najara; Albrecht, Letusa; Judice, Carla; Lopes, Stefanie C P; Lacerda, Marcus V G; Ferreira, Marcelo U; Soares, Irene S; Goh, Yun Shan; Bargieri, Daniel Y; Nosten, François; Russell, Bruce; Rénia, Laurent; Costa, Fabio T M

    2018-01-10

    Technical limitations for culturing the human malaria parasite Plasmodium vivax have impaired the discovery of vaccine candidates, challenging the malaria eradication agenda. The immunogenicity of the M2 domain of the Merozoite Adhesive Erythrocytic Binding Protein (MAEBL) antigen cloned from the Plasmodium yoelii murine parasite, has been previously demonstrated. Detailed epitope mapping of MAEBL through immunoinformatics identified several MHCI, MHCII and B cell epitopes throughout the peptide, with several of these lying in the M2 domain and being conserved between P. vivax, P. yoelii and Plasmodium falciparum, hinting that the M2-MAEBL is pan-reactive. This hypothesis was tested through functional assays, showing that P. yoelii M2-MAEBL antisera are able to recognize and inhibit erythrocyte invasion from both P. falciparum and P. vivax parasites isolated from Thai patients, in ex vivo assays. Moreover, the sequence of the M2-MAEBL is shown to be highly conserved between P. vivax isolates from the Amazon and Thailand, indicating that the MAEBL antigen may constitute a vaccine candidate outwitting strain-specific immunity. The MAEBL antigen is promising candidate towards the development of a malaria vaccine.

  14. Top Down Tandem Mass Spectrometric Analysis of a Chemically Modified Rough-Type Lipopolysaccharide Vaccine Candidate.

    PubMed

    Oyler, Benjamin L; Khan, Mohd M; Smith, Donald F; Harberts, Erin M; Kilgour, David P A; Ernst, Robert K; Cross, Alan S; Goodlett, David R

    2018-06-01

    Recent advances in lipopolysaccharide (LPS) biology have led to its use in drug discovery pipelines, including vaccine and vaccine adjuvant discovery. Desirable characteristics for LPS vaccine candidates include both the ability to produce a specific antibody titer in patients and a minimal host inflammatory response directed by the innate immune system. However, in-depth chemical characterization of most LPS extracts has not been performed; hence, biological activities of these extracts are unpredictable. Additionally, the most widely adopted workflow for LPS structure elucidation includes nonspecific chemical decomposition steps before analyses, making structures inferred and not necessarily biologically relevant. In this work, several different mass spectrometry workflows that have not been previously explored were employed to show proof-of-principle for top down LPS primary structure elucidation, specifically for a rough-type mutant (J5) E. coli-derived LPS component of a vaccine candidate. First, ion mobility filtered precursor ions were subjected to collision induced dissociation (CID) to define differences in native J5 LPS v. chemically detoxified J5 LPS (dLPS). Next, ultra-high mass resolving power, accurate mass spectrometry was employed for unequivocal precursor and product ion empirical formulae generation. Finally, MS 3 analyses in an ion trap instrument showed that previous knowledge about dissociation of LPS components can be used to reconstruct and sequence LPS in a top down fashion. A structural rationale is also explained for differential inflammatory dose-response curves, in vitro, when HEK-Blue hTLR4 cells were administered increasing concentrations of native J5 LPS v. dLPS, which will be useful in future drug discovery efforts. Graphical Abstract ᅟ.

  15. Top Down Tandem Mass Spectrometric Analysis of a Chemically Modified Rough-Type Lipopolysaccharide Vaccine Candidate

    NASA Astrophysics Data System (ADS)

    Oyler, Benjamin L.; Khan, Mohd M.; Smith, Donald F.; Harberts, Erin M.; Kilgour, David P. A.; Ernst, Robert K.; Cross, Alan S.; Goodlett, David R.

    2018-02-01

    Recent advances in lipopolysaccharide (LPS) biology have led to its use in drug discovery pipelines, including vaccine and vaccine adjuvant discovery. Desirable characteristics for LPS vaccine candidates include both the ability to produce a specific antibody titer in patients and a minimal host inflammatory response directed by the innate immune system. However, in-depth chemical characterization of most LPS extracts has not been performed; hence, biological activities of these extracts are unpredictable. Additionally, the most widely adopted workflow for LPS structure elucidation includes nonspecific chemical decomposition steps before analyses, making structures inferred and not necessarily biologically relevant. In this work, several different mass spectrometry workflows that have not been previously explored were employed to show proof-of-principle for top down LPS primary structure elucidation, specifically for a rough-type mutant (J5) E. coli-derived LPS component of a vaccine candidate. First, ion mobility filtered precursor ions were subjected to collision induced dissociation (CID) to define differences in native J5 LPS v. chemically detoxified J5 LPS (dLPS). Next, ultra-high mass resolving power, accurate mass spectrometry was employed for unequivocal precursor and product ion empirical formulae generation. Finally, MS3 analyses in an ion trap instrument showed that previous knowledge about dissociation of LPS components can be used to reconstruct and sequence LPS in a top down fashion. A structural rationale is also explained for differential inflammatory dose-response curves, in vitro, when HEK-Blue hTLR4 cells were administered increasing concentrations of native J5 LPS v. dLPS, which will be useful in future drug discovery efforts. [Figure not available: see fulltext.

  16. 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.

  17. 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.

  18. Conjugating recombinant proteins to Pseudomonas aeruginosa ExoProtein A: a strategy for enhancing immunogenicity of malaria vaccine candidates.

    PubMed

    Qian, Feng; Wu, Yimin; Muratova, Olga; Zhou, Hong; Dobrescu, Gelu; Duggan, Peter; Lynn, Lambert; Song, Guanhong; Zhang, Yanling; Reiter, Karine; MacDonald, Nicholas; Narum, David L; Long, Carole A; Miller, Louis H; Saul, Allan; Mullen, Gregory E D

    2007-05-16

    Conjugation of polysaccharides to carrier proteins has been a successful approach for producing safe and effective vaccines. In an attempt to increase the immunogenicity of two malarial vaccine candidate proteins of Plasmodium falciparum, apical membrane antigen 1 (AMA1) to a blood stage vaccine candidate and surface protein 25 (Pfs25) a mosquito stage vaccine candidate, were each independently chemically conjugated to the mutant, nontoxic Pseudomonas aeruginosa ExoProtein A (rEPA). AMA1 is a large (66kD) relatively good immunogen in mice; Pfs25 is a poorly immunogenic protein when presented on alum to mice. Mice were immunized on days 0 and 28 with AMA1- or Pfs25-rEPA conjugates or unconjugated AMA1 or Pfs25, all formulated on Alhydrogel. Remarkably, sera from mice 14 days after the second immunization with Pfs25-rEPA conjugates displayed over a 1000-fold higher antibody titers as compared to unconjugated Pfs25. In contrast, AMA1 conjugated under the same conditions induced only a three-fold increase in antibody titers. When tested for functional activity, antibodies elicited by the AMA1-rEPA inhibited invasion of erythrocytes by blood-stage parasites and antibodies elicited by the Pfs25-rEPA conjugates blocked the development of the sexual stage parasites in the mosquito midgut. These results demonstrate that conjugation to rEPA induces a marked improvement in the antibody titer in mice for the poor immunogen (Pfs25) and for the larger protein (AMA1). These conjugates now need to be tested in humans to determine if mice are predictive of the response in humans.

  19. G-protein based ELISA as a potency test for rabies vaccines.

    PubMed

    Chabaud-Riou, Martine; Moreno, Nadège; Guinchard, Fabien; Nicolai, Marie Claire; Niogret-Siohan, Elisabeth; Sève, Nicolas; Manin, Catherine; Guinet-Morlot, Françoise; Riou, Patrice

    2017-03-01

    The NIH test is currently used to assess the potency of rabies vaccine, a key criterion for vaccine release. This test is based on mice immunization followed by intracerebral viral challenge. As part of global efforts to reduce animal experimentation and in the framework of the development of Sanofi Pasteur next generation, highly-purified vaccine, produced without any material of human or animal origin, we developed an ELISA as an alternative to the NIH test. This ELISA is based on monoclonal antibodies recognizing specifically the native form of the viral G-protein, the major antigen that induces neutralizing antibody response to rabies virus. We show here that our ELISA is able to distinguish between potent and different types of sub-potent vaccine lots. Satisfactory agreement was observed between the ELISA and the NIH test in the determination of the vaccine titer and their capacity to discern conform from non-conform batches. Our ELISA meets the criteria for a stability-indicating assay and has been successfully used to develop the new generation of rabies vaccine candidates. After an EPAA international pre-collaborative study, this ELISA was selected as the assay of choice for the EDQM collaborative study aimed at replacing the rabies vaccine NIH in vivo potency test. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  20. Co-expression of tetanus toxin fragment C in Escherichia coli with thioredoxin and its evaluation as an effective subunit vaccine candidate.

    PubMed

    Yu, Yun-Zhou; Gong, Zheng-Wei; Ma, Yao; Zhang, Shu-Ming; Zhu, Heng-Qi; Wang, Wen-Bing; Du, Yun; Wang, Shuang; Yu, Wei-Yuan; Sun, Zhi-Wei

    2011-08-11

    The receptor-binding domain of tetanus toxin (THc), which mediates the binding of the toxin to the nerve cells, is a candidate subunit vaccine against tetanus. In this study one synthetic gene encoding the THc was constructed and highly expressed in Escherichia coli by co-expression with thioredoxin (Trx). The purified THc-vaccinated mice were completely protected against an active toxin challenge in mouse models of disease and the potency of two doses of THc was comparable to that of three doses of toxoid vaccine. And a solid-phase assay showed that the anti-THc sera inhibited the binding of THc or toxoid to the ganglioside GT1b as the anti-tetanus toxoid sera. Furthermore, mice were vaccinated once or twice at four different dosages of THc and a dose-response was observed in both the antibody titer and protective efficacy with increasing dosage of THc and number of vaccinations. The data presented in the report showed that the recombinant THc expressed in E. coli is efficacious in protecting mice against challenge with tetanus toxin suggesting that the THc protein may be developed into a human subunit vaccine candidate designed for the prevention of tetanus. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. African Green Monkeys Recapitulate the Clinical Experience with Replication of Live Attenuated Pandemic Influenza Virus Vaccine Candidates

    PubMed Central

    Matsuoka, Yumiko; Suguitan, Amorsolo; Orandle, Marlene; Paskel, Myeisha; Boonnak, Kobporn; Gardner, Donald J.; Feldmann, Friederike; Feldmann, Heinz; Marino, Michael; Jin, Hong; Kemble, George

    2014-01-01

    ABSTRACT Live attenuated cold-adapted (ca) H5N1, H7N3, H6N1, and H9N2 influenza vaccine viruses replicated in the respiratory tract of mice and ferrets, and 2 doses of vaccines were immunogenic and protected these animals from challenge infection with homologous and heterologous wild-type (wt) viruses of the corresponding subtypes. However, when these vaccine candidates were evaluated in phase I clinical trials, there were inconsistencies between the observations in animal models and in humans. The vaccine viruses did not replicate well and immune responses were variable in humans, even though the study subjects were seronegative with respect to the vaccine viruses before vaccination. Therefore, we sought a model that would better reflect the findings in humans and evaluated African green monkeys (AGMs) as a nonhuman primate model. The distribution of sialic acid (SA) receptors in the respiratory tract of AGMs was similar to that in humans. We evaluated the replication of wt and ca viruses of avian influenza (AI) virus subtypes H5N1, H6N1, H7N3, and H9N2 in the respiratory tract of AGMs. All of the wt viruses replicated efficiently, while replication of the ca vaccine viruses was restricted to the upper respiratory tract. Interestingly, the patterns and sites of virus replication differed among the different subtypes. We also evaluated the immunogenicity and protective efficacy of H5N1, H6N1, H7N3, and H9N2 ca vaccines. Protection from wt virus challenge correlated well with the level of serum neutralizing antibodies. Immune responses were slightly better when vaccine was delivered by both intranasal and intratracheal delivery than when it was delivered intranasally by sprayer. We conclude that live attenuated pandemic influenza virus vaccines replicate similarly in AGMs and human subjects and that AGMs may be a useful model to evaluate the replication of ca vaccine candidates. IMPORTANCE Ferrets and mice are commonly used for preclinical evaluation of influenza

  2. Phase 1/2a Trial of Plasmodium vivax Malaria Vaccine Candidate VMP001/AS01B in Malaria-Naive Adults: Safety, Immunogenicity, and Efficacy.

    PubMed

    Bennett, Jason W; Yadava, Anjali; Tosh, Donna; Sattabongkot, Jetsumon; Komisar, Jack; Ware, Lisa A; McCarthy, William F; Cowden, Jessica J; Regules, Jason; Spring, Michele D; Paolino, Kristopher; Hartzell, Joshua D; Cummings, James F; Richie, Thomas L; Lumsden, Joanne; Kamau, Edwin; Murphy, Jittawadee; Lee, Cynthia; Parekh, Falgunee; Birkett, Ashley; Cohen, Joe; Ballou, W Ripley; Polhemus, Mark E; Vanloubbeeck, Yannick F; Vekemans, Johan; Ockenhouse, Christian F

    2016-02-01

    A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use. We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15 μg, 30 μg, or 60 μg respectively of VMP001, all formulated in 500 μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls. The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period. This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials.

  3. Phase 1/2a Trial of Plasmodium vivax Malaria Vaccine Candidate VMP001/AS01B in Malaria-Naive Adults: Safety, Immunogenicity, and Efficacy

    PubMed Central

    Bennett, Jason W.; Yadava, Anjali; Tosh, Donna; Sattabongkot, Jetsumon; Komisar, Jack; Ware, Lisa A.; McCarthy, William F.; Cowden, Jessica J.; Regules, Jason; Spring, Michele D.; Paolino, Kristopher; Hartzell, Joshua D.; Cummings, James F.; Richie, Thomas L.; Lumsden, Joanne; Kamau, Edwin; Murphy, Jittawadee; Lee, Cynthia; Parekh, Falgunee; Birkett, Ashley; Cohen, Joe; Ballou, W. Ripley; Polhemus, Mark E.; Vanloubbeeck, Yannick F.; Vekemans, Johan; Ockenhouse, Christian F.

    2016-01-01

    Background A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use. Methods We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15μg, 30μg, or 60μg respectively of VMP001, all formulated in 500μL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls. Results The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period. Significance This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for

  4. 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.

  5. The clinical development process for a novel preventive vaccine: An overview.

    PubMed

    Singh, K; Mehta, S

    2016-01-01

    Each novel vaccine candidate needs to be evaluated for safety, immunogenicity, and protective efficacy in humans before it is licensed for use. After initial safety evaluation in healthy adults, each vaccine candidate follows a unique development path. This article on clinical development gives an overview on the development path based on the expectations of various guidelines issued by the World Health Organization (WHO), the European Medicines Agency (EMA), and the United States Food and Drug Administration (USFDA). The manuscript describes the objectives, study populations, study designs, study site, and outcome(s) of each phase (Phase I-III) of a clinical trial. Examples from the clinical development of a malaria vaccine candidate, a rotavirus vaccine, and two vaccines approved for human papillomavirus (HPV) have also been discussed. The article also tabulates relevant guidelines, which can be referred to while drafting the development path of a novel vaccine candidate.

  6. A human dendritic cell-based in vitro model to assess Mycobacterium tuberculosis SO2 vaccine immunogenicity.

    PubMed

    Etna, Marilena P; Giacomini, Elena; Severa, Martina; Pardini, Manuela; Aguilo, Nacho; Martin, Carlos; Coccia, Eliana M

    2014-01-01

    Among the tuberculosis (TB) vaccine candidates, SO2 is the prototype of the first live-attenuated vaccine that recently entered into clinical trials. To investigate the capacity of SO2 to stimulate an appropriate immune response in vitro within a human immunological context, a comparative analysis of the effects promoted by SO2, the current Bacille Calmette-Guerin (BCG) vaccine and Mycobacterium tuberculosis (Mtb) was conducted in human primary dendritic cells (DC), which are critical modulators of vaccine-induced immunity. In particular, we found that SO2 promotes the expression of maturation markers similarly to BCG but at a lower extent than Mtb. Moreover, SO2-infected DC released higher levels of interleukin (IL)-23 than BCG-infected cells, which account for the expansion of interferon (IFN)-γ-producing T cells in an IL-12-independent manner. In the autologous mixed leukocyte reaction setting, the expansion of IL-17-producing T cells was also observed in response to SO2 infection. Interestingly, apoptosis and autophagic flux, events required for the antigen presentation within MHC class II complex, were not affected in DC infected with SO2, conversely to what observed upon Mtb stimulation. Collectively, our results indicate that SO2 represents a promising TB vaccine candidate, which displays an attenuated phenotype and promotes in DC a stronger capacity to stimulate the Th response than BCG vaccine. Interestingly, the data obtained by using the human DC-based experimental setting mirrored the results derived from studies in animal models, suggesting that this system could be used for an efficient and rapid down-selection of new TB vaccine candidates, contributing to achieve the "3Rs" objective.

  7. Generation of transgenic corn-derived Actinobacillus pleuropneumoniae ApxIIA fused with the cholera toxin B subunit as a vaccine candidate

    PubMed Central

    Shin, Min-Kyoung; Jung, Myung Hwan; Lee, Won-Jung; Choi, Pil Son; Jang, Yong-Suk

    2011-01-01

    Corn, one of the most important forage crops worldwide, has proven to be a useful expression vehicle due to the availability of established transformation procedures for this well-studied plant. The exotoxin Apx, a major virulence factor, is recognized as a common antigen of Actinobacillus (A.) pleuropneumoniae, the causative agent of porcine pleuropneumonia. In this study, a cholera toxin B (CTB)-ApxIIA#5 fusion protein and full-size ApxIIA expressed in corn seed, as a subunit vaccine candidate, were observed to induce Apx-specific immune responses in mice. These results suggest that transgenic corn-derived ApxIIA and CTB-ApxIIA#5 proteins are potential vaccine candidates against A. pleuropneumoniae infection. PMID:22122907

  8. In Vitro Analysis of Virus Particle Subpopulations in Candidate Live-Attenuated Influenza Vaccines Distinguishes Effective from Ineffective Vaccines▿

    PubMed Central

    Marcus, Philip I.; Ngunjiri, John M.; Sekellick, Margaret J.; Wang, Leyi; Lee, Chang-Won

    2010-01-01

    Two effective (vac+) and two ineffective (vac−) candidate live-attenuated influenza vaccines (LAIVs) derived from naturally selected genetically stable variants of A/TK/OR/71-delNS1[1-124] (H7N3) that differed only in the length and kind of amino acid residues at the C terminus of the nonstructural NS1 protein were analyzed for their content of particle subpopulations. These subpopulations included total physical particles (measured as hemagglutinating particles [HAPs]) with their subsumed biologically active particles of infectious virus (plaque-forming particles [PFPs]) and different classes of noninfectious virus, namely, interferon-inducing particles (IFPs), noninfectious cell-killing particles (niCKPs), and defective interfering particles (DIPs). The vac+ variants were distinguished from the vac− variants on the basis of their content of viral subpopulations by (i) the capacity to induce higher quantum yields of interferon (IFN), (ii) the generation of an unusual type of IFN-induction dose-response curve, (iii) the presence of IFPs that induce IFN more efficiently, (iv) reduced sensitivity to IFN action, and (v) elevated rates of PFP replication that resulted in larger plaques and higher PFP and HAP titers. These in vitro analyses provide a benchmark for the screening of candidate LAIVs and their potential as effective vaccines. Vaccine design may be improved by enhancement of attributes that are dominant in the effective (vac+) vaccines. PMID:20739541

  9. A low-toxic site-directed mutant of Clostridium perfringens ε-toxin as a potential candidate vaccine against enterotoxemia.

    PubMed

    Li, Qing; Xin, Wenwen; Gao, Shan; Kang, Lin; Wang, Jinglin

    2013-11-01

    Clostridium perfringens epsilon toxin (ETX), one of the most potent toxins known, is a potential biological weapon; therefore, the development of an effective vaccine is important for preventing intoxication or disease by ETX. In this study, genetically detoxified epsilon toxin mutants were developed as candidate vaccines. We used site-directed mutagenesis to mutate the essential amino acid residues (His106, Ser111 and Phe199). Six site-directed mutants of ETX (mETX (H106P) , mETX (S111H) , mETX (S111Y) , mETX (F199H) , mETX (F199E) , mETX (S111YF199E) ) were generated and then expressed in Escherichia coli. Both mETX (F199E) and mETX (H106P) with low or non-cytotoxicity that retained their immunogenicity were selected to immunize mice 3 times, and the mouse survival data were recorded after challenging with recombinant wild-type ETX. mETX (F199E) induces the same protection as mETX (H106P) , which was reported previously as a promising toxin mutant for vaccine, and both of them could protect immunized mice against a 100× LD₅₀ dose of active wild-type recombinant ETX. This work showed that mETX (F199E) is another promising candidate vaccine against enterotoxemia and other diseases caused by ETX.

  10. Dendritic cell-targeting DNA-based mucosal adjuvants for the development of mucosal vaccines

    PubMed Central

    Kataoka, Kosuke; Fujihashi, Kohtaro

    2009-01-01

    In order to establish effective mucosal immunity against various mucosal pathogens, vaccines must be delivered via the mucosal route and contain effective adjuvant(s). Since mucosal adjuvants can simply mix with the antigen, it is relatively easy to adapt them for different types of vaccine development. Even in simple admixture vaccines, the adjuvant itself must be prepared without any complications. Thus, CpG oligodeoxynucleotides or plasmids encoding certain cDNA(s) would be potent mucosal adjuvant candidates when compared with other substances that can be used as mucosal adjuvants. The strategy of a DNA-based mucosal adjuvant facilitates the targeting of mucosal dendritic cells, and thus is an effective and safe approach. It would also provide great flexibility for the development of effective vaccines for various mucosal pathogens. PMID:19722892

  11. Correction to: Top Down Tandem Mass Spectrometric Analysis of a Chemically Modified Rough-Type Lipopolysaccharide Vaccine Candidate

    NASA Astrophysics Data System (ADS)

    Oyler, Benjamin L.; Khan, Mohd M.; Smith, Donald F.; Harberts, Erin M.; Kilgour, David P. A.; Ernst, Robert K.; Cross, Alan S.; Goodlett, David R.

    2018-04-01

    In the preceding article "Top Down Tandem Mass Spectrometric Analysis of a Chemically Modified Rough-Type Lipopolysaccharide Vaccine Candidate" by Oyler et al., an error in the J5 E. coli LPS chemical structure (Figs. 2 and 4) was introduced and propagated into the final revision.

  12. 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.

  13. HIV-1 Immunogen: an overview of almost 30 years of clinical testing of a candidate therapeutic vaccine.

    PubMed

    Graziani, Gina M; Angel, Jonathan B

    2016-07-01

    Although current antiretroviral therapy (ART) has transformed HIV infection into a chronic, manageable disease, ART does not cure HIV infection. Furthermore, the majority of the world's infected individuals live in resource-limited countries in which access to ART is limited. Thus, the development of an effective therapeutic HIV vaccine would be an invaluable treatment alternative. Developed by the late Dr. Jonas Salk, HIV-1 Immunogen (Remune®) is a candidate therapeutic vaccine that has been studied in thousands of HIV-infected individuals in more than a dozen clinical trials during almost three decades. This Drug Evaluation, which summarizes the results of these trials that have shown the vaccine to be safe and immunogenic, also discusses the contradictory and controversial conclusions drawn from the phases 2, 2/3 and 3 trials that assessed the clinical efficacy of this vaccine. Given the lack of unequivocal clinical benefits of HIV-1 Immunogen despite almost 30 years of extensive testing, it does not appear, in our view, that this vaccine is a clinically effective immunotherapy. However, inclusion of this vaccine in the newly proposed 'Kick/Shock and Kill' strategy for HIV eradication, or use as a prophylactic vaccine, could be considered for future trials.

  14. Status of research and development of vaccines for Streptococcus pyogenes.

    PubMed

    Steer, Andrew C; Carapetis, Jonathan R; Dale, James B; Fraser, John D; Good, Michael F; Guilherme, Luiza; Moreland, Nicole J; Mulholland, E Kim; Schodel, Florian; Smeesters, Pierre R

    2016-06-03

    Streptococcus pyogenes is an important global pathogen, causing considerable morbidity and mortality, especially in low and middle income countries where rheumatic heart disease and invasive infections are common. There is a number of promising vaccine candidates, most notably those based on the M protein, the key virulence factor for the bacterium. Vaccines against Streptococcus pyogenes are considered as impeded vaccines because of a number of crucial barriers to development. Considerable effort is needed by key players to bring current vaccine candidates through phase III clinical trials and there is a clear need to develop a roadmap for future development of current and new candidates. Copyright © 2016 World Health Organization. Published by Elsevier Ltd.. All rights reserved.

  15. Phase I Clinical Trial of a Recombinant Blood Stage Vaccine Candidate for Plasmodium falciparum Malaria Based on MSP1 and EBA175

    PubMed Central

    Chitnis, Chetan E.; Mukherjee, Paushali; Mehta, Shantanu; Yazdani, Syed Shams; Dhawan, Shikha; Shakri, Ahmad Rushdi; Bharadwaj, Rukmini; Gupta, Puneet Kumar; Hans, Dhiraj; Mazumdar, Suman; Singh, Bijender; Kumar, Sanjeev; Pandey, Gaurav; Parulekar, Varsha; Imbault, Nathalie; Shivyogi, Preethi; Godbole, Girish; Mohan, Krishna; Leroy, Odile; Singh, Kavita; Chauhan, Virander S.

    2015-01-01

    Background A phase I randomised, controlled, single blind, dose escalation trial was conducted to evaluate safety and immunogenicity of JAIVAC-1, a recombinant blood stage vaccine candidate against Plasmodium falciparum malaria, composed of a physical mixture of two recombinant proteins, PfMSP-119, the 19 kD conserved, C-terminal region of PfMSP-1 and PfF2 the receptor-binding F2 domain of EBA175. Method Healthy malaria naïve Indian male subjects aged 18–45 years were recruited from the volunteer database of study site. Fifteen subjects in each cohort, randomised in a ratio of 2:1 and meeting the protocol specific eligibility criteria, were vaccinated either with three doses (10μg, 25μg and 50μg of each antigen) of JAIVAC-1 formulated with adjuvant Montanide ISA 720 or with standard dosage of Hepatitis B vaccine. Each subject received the assigned vaccine in the deltoid muscle of the upper arms on Day 0, Day 28 and Day 180. Results JAIVAC-1 was well tolerated and no serious adverse event was observed. All JAIVAC-1 subjects sero-converted for PfF2 but elicited poor immune response to PfMSP-119. Dose-response relationship was observed between vaccine dose of PfF2 and antibody response. The antibodies against PfF2 were predominantly of IgG1 and IgG3 isotype. Sera from JAIVAC-1 subjects reacted with late schizonts in a punctate pattern in immunofluorescence assays. Purified IgG from JAIVAC-1 sera displayed significant growth inhibitory activity against Plasmodium falciparum CAMP strain. Conclusion Antigen PfF2 should be retained as a component of a recombinant malaria vaccine but PfMSP-119 construct needs to be optimised to improve its immunogenicity. Trial Registration Clinical Trial Registry, India CTRI/2010/091/000301 PMID:25927360

  16. The use of mutant mycobacteria as new vaccines to prevent tuberculosis.

    PubMed

    Hernàndez Pando, R; Aguilar, L D; Infante, E; Cataldi, A; Bigi, F; Martin, C; Gicquel, B

    2006-01-01

    Given the variable protective efficacy generated by Mycobacterium bovis BCG (Bacillus Calmette-Guérin), there is a concerted effort worldwide to develop better vaccines that could be used to reduce the burden of tuberculosis. Rational attenuated mutants of Mycobacterium tuberculosis are vaccine candidates that offer some potential in this area. In this paper, we will discuss the molecular methods used to generate mutant mycobacteria, as well as the results obtained with some of these strains, in terms of attenuation, immunogenicity and level of protection, when compared with the conventional BCG vaccine in diverse animal models. Tuberculosis vaccine candidates based on safe and live mycobacterial mutants could be promising candidates.

  17. Live vaccines for human metapneumovirus designed by reverse genetics.

    PubMed

    Buchholz, Ursula J; Nagashima, Kunio; Murphy, Brian R; Collins, Peter L

    2006-10-01

    Human metapneumovirus (HMPV) was first described in 2001 and has quickly become recognized as an important cause of respiratory tract disease worldwide, especially in the pediatric population. A vaccine against HMPV is required to prevent severe disease associated with infection in infancy. The primary strategy is to develop a live-attenuated virus for intranasal immunization, which is particularly well suited against a respiratory virus. Reverse genetics provides a means of developing highly characterized 'designer' attenuated vaccine candidates. To date, several promising vaccine candidates have been developed, each using a different mode of attenuation. One candidate involves deletion of the G glycoprotein, providing attenuation that is probably based on reduced efficiency of attachment. A second candidate involves deletion of the M2-2 protein, which participates in regulating RNA synthesis and whose deletion has the advantageous property of upregulating transcription and increasing antigen synthesis. A third candidate involves replacing the P protein gene of HMPV with its counterpart from the related avian metapneumovirus, thereby introducing attenuation owing to its chimeric nature and host range restriction. Another live vaccine strategy involves using an attenuated parainfluenza virus as a vector to express HMPV protective antigens, providing a bivalent pediatric vaccine. Additional modifications to provide improved vaccines will also be discussed.

  18. Formulation and Immunogenicity studies of Type III Secretion System needle antigens as Vaccine Candidates

    PubMed Central

    Barrett, Brooke S.; Markham, Aaron P.; Esfandiary, Reza; Picking, Wendy L.; Picking, William D.; Joshi, Sangeeta B.; Middaugh, C. Russell

    2013-01-01

    Bacterial infections caused by Shigella flexneri, Salmonella typhimurium and Burkholderia pseudomallei are currently difficult to prevent due to the lack of a licensed vaccine. Here we present formulation and immunogenicity studies for the three type III secretion system (TTSS) needle proteins MxiHΔ5, PrgIΔ5 and BsaLΔ5 (each truncated by five residues at its C terminus) as potential candidates for vaccine development. These antigens are found to be thermally stabilized by the presence of carbohydrates and polyols. Additionally, all adsorb readily to aluminum hydroxide apparently through a combination of hydrogen bonds and/or Van der Waals forces. The interaction of these proteins with the aluminum-based adjuvant changes with time to resulting in varying degrees of irreversible binding. Peptide maps of desorbed protein, however, suggest that chemical changes are not responsible for this irreversible association. The ability of MxiHΔ5 and PrgIΔ5 to elicit strong humoral immune responses was tested in a murine model. When administered intramuscularly as monomers, the needle components exhibited dose dependent immunogenic behavior. The polymerized version of MxiH was exceptionally immunogenic even at low doses. The responses of both monomeric and polymerized forms were boosted by adsorption to an aluminum salt adjuvant. PMID:20845448

  19. Protection against Multiple Influenza A Virus Strains Induced by Candidate Recombinant Vaccine Based on Heterologous M2e Peptides Linked to Flagellin

    PubMed Central

    Kovaleva, Anna A.; Potapchuk, Marina V.; Korotkov, Alexandr V.; Sergeeva, Mariia V.; Kasianenko, Marina A.; Kuprianov, Victor V.; Ravin, Nikolai V.; Tsybalova, Liudmila M.; Skryabin, Konstantin G.; Kiselev, Oleg I.

    2015-01-01

    Matrix 2 protein ectodomain (M2e) is considered a promising candidate for a broadly protective influenza vaccine. M2e-based vaccines against human influenza A provide only partial protection against avian influenza viruses because of differences in the M2e sequences. In this work, we evaluated the possibility of obtaining equal protection and immune response by using recombinant protein on the basis of flagellin as a carrier of the M2e peptides of human and avian influenza A viruses. Recombinant protein was generated by the fusion of two tandem copies of consensus M2e sequence from human influenza A and two copies of M2e from avian A/H5N1 viruses to flagellin (Flg-2M2eh2M2ek). Intranasal immunisation of Balb/c mice with recombinant protein significantly elicited anti-M2e IgG in serum, IgG and sIgA in BAL. Antibodies induced by the fusion protein Flg-2M2eh2M2ek bound efficiently to synthetic peptides corresponding to the human consensus M2e sequence as well as to the M2e sequence of A/Chicken/Kurgan/05/05 RG (H5N1) and recognised native M2e epitopes exposed on the surface of the MDCK cells infected with A/PR/8/34 (H1N1) and A/Chicken/Kurgan/05/05 RG (H5N1) to an equal degree. Immunisation led to both anti-M2e IgG1 and IgG2a response with IgG1 prevalence. We observed a significant intracellular production of IL-4, but not IFN-γ, by CD4+ T-cells in spleen of mice following immunisation with Flg-2M2eh2M2ek. Immunisation with the Flg-2M2eh2M2ek fusion protein provided similar protection from lethal challenge with human influenza A viruses (H1N1, H3N2) and avian influenza virus (H5N1). Immunised mice experienced significantly less weight loss and decreased lung viral titres compared to control mice. The data obtained show the potential for the development of an M2e-flagellin candidate influenza vaccine with broad spectrum protection against influenza A viruses of various origins. PMID:25799221

  20. Preclinical immunogenicity and safety of a Group A streptococcal M protein-based vaccine candidate.

    PubMed

    Batzloff, Michael R; Fane, Anne; Gorton, Davina; Pandey, Manisha; Rivera-Hernandez, Tania; Calcutt, Ainslie; Yeung, Grace; Hartas, Jon; Johnson, Linda; Rush, Catherine M; McCarthy, James; Ketheesan, Natkunam; Good, Michael F

    2016-12-01

    Streptococcus pyogenes (group A streptococcus, GAS) causes a wide range of clinical manifestations ranging from mild self-limiting pyoderma to invasive diseases such as sepsis. Also of concern are the post-infectious immune-mediated diseases including rheumatic heart disease. The development of a vaccine against GAS would have a large health impact on populations at risk of these diseases. However, there is a lack of suitable models for the safety evaluation of vaccines with respect to post-infectious complications. We have utilized the Lewis Rat model for cardiac valvulitis to evaluate the safety of the J8-DT vaccine formulation in parallel with a rabbit toxicology study. These studies demonstrated that the vaccine did not induce abnormal pathology. We also show that in mice the vaccine is highly immunogenic but that 3 doses are required to induce protection from a GAS skin challenge even though 2 doses are sufficient to induce a high antibody titer.

  1. Preclinical immunogenicity and safety of a Group A streptococcal M protein-based vaccine candidate

    PubMed Central

    Batzloff, Michael R.; Fane, Anne; Gorton, Davina; Pandey, Manisha; Rivera-Hernandez, Tania; Calcutt, Ainslie; Yeung, Grace; Hartas, Jon; Johnson, Linda; Rush, Catherine M.; McCarthy, James; Ketheesan, Natkunam; Good, Michael F.

    2016-01-01

    ABSTRACT Streptococcus pyogenes (group A streptococcus, GAS) causes a wide range of clinical manifestations ranging from mild self-limiting pyoderma to invasive diseases such as sepsis. Also of concern are the post-infectious immune-mediated diseases including rheumatic heart disease. The development of a vaccine against GAS would have a large health impact on populations at risk of these diseases. However, there is a lack of suitable models for the safety evaluation of vaccines with respect to post-infectious complications. We have utilized the Lewis Rat model for cardiac valvulitis to evaluate the safety of the J8-DT vaccine formulation in parallel with a rabbit toxicology study. These studies demonstrated that the vaccine did not induce abnormal pathology. We also show that in mice the vaccine is highly immunogenic but that 3 doses are required to induce protection from a GAS skin challenge even though 2 doses are sufficient to induce a high antibody titer. PMID:27541593

  2. Vaccine platforms to control Lassa fever.

    PubMed

    Lukashevich, Igor S; Pushko, Peter

    2016-09-01

    Lassa virus (LASV), the most prominent human pathogen of the Arenaviridae, is transmitted to humans from infected rodents and can cause Lassa Fever (LF). The sizeable disease burden in West Africa, numerous imported LF cases worldwide, and the possibility that LASV can be used as an agent of biological warfare make a strong case for vaccine development. There are no licensed LASV vaccines and the antiviral treatment is limited to an off-label use of ribavirin that is only partially effective. LASV vaccine development is hampered by high cost of biocontainment requirement, the absence of appropriate small animal models, genetic diversity of LASV species, and by high HIV-1 prevalence in LASV endemic areas. Over the past 15 years several vaccine platforms have been developed. Natural history of LASV and pathogenesis of the disease provide strong justification for replication-competent (RC) vaccine as one of the most feasible approaches to control LF. Development of LASV vaccine candidates based on reassortant, recombinant, and alphavirus replicon technologies is covered in this review. Expert commentary: Two lead RC vaccine candidates, reassortant ML29 and recombinant VSV/LASV, have been successfully tested in non-human primates and have been recommended by international vaccine experts for rapid clinical development. Both platforms have powerful molecular tools to further secure safety, improve immunogenicity, and cross-protection. These platforms are well positioned to design multivalent vaccines to protect against all LASV strains citculatrd in West Africa. The regulatory pathway of Candid #1, the first live-attenuated arenaviral vaccine against Argentine hemorrhagic, will be a reasonable guideline for LASV vaccine efficacy trials.

  3. Immunoinformatics Approach in Designing Epitope-based Vaccine Against Meningitis-inducing Bacteria (Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae Type b).

    PubMed

    Zahroh, Hilyatuz; Ma'rup, Ahmad; Tambunan, Usman Sumo Friend; Parikesit, Arli Aditya

    2016-01-01

    Meningitis infection is one of the major threats during Hajj season in Mecca. Meningitis vaccines are available, but their uses are limited in some countries due to religious reasons. Furthermore, they only give protection to certain serogroups, not to all types of meningitis-inducing bacteria. Recently, research on epitope-based vaccines has been developed intensively. Such vaccines have potential advantages over conventional vaccines in that they are safer to use and well responded to the antibody. In this study, we developed epitope-based vaccine candidates against various meningitis-inducing bacteria, including Streptococcus pneumoniae , Neisseria meningitidis , and Haemophilus influenzae type b. The epitopes were selected from their protein of polysaccharide capsule. B-cell epitopes were predicted by using BCPred, while T-cell epitope for major histocompatibility complex (MHC) class I was predicted using PAProC, TAPPred, and Immune Epitope Database. Immune Epitope Database was also used to predict T-cell epitope for MHC class II. Population coverage and molecular docking simulation were predicted against previously generated epitope vaccine candidates. The best candidates for MHC class I- and class II-restricted T-cell epitopes were MQYGDKTTF, MKEQNTLEI, ECTEGEPDY, DLSIVVPIY, YPMAMMWRNASNRAI, TLQMTLLGIVPNLNK, ETSLHHIPGISNYFI, and SLLYILEKNAEMEFD, which showed 80% population coverage. The complexes of class I T-cell epitopes-HLA-C*03:03 and class II T-cell epitopes-HLA-DRB1*11:01 showed better affinity than standards as evaluated from their Δ G binding value and the binding interaction between epitopes and HLA molecules. These peptide constructs may further be undergone in vitro and in vivo testings for the development of targeted vaccine against meningitis infection.

  4. Recombinant Mip-PilE-FlaA dominant epitopes vaccine candidate against Legionella pneumophila.

    PubMed

    He, Jinlei; Huang, Fan; Chen, Han; Chen, Qiwei; Zhang, Junrong; Li, Jiao; Chen, Dali; Chen, Jianping

    2017-06-01

    Legionella pneumophila is the main causative agent of Legionnaires' disease, which is a severe multi-system disease with pneumonia as the primary manifestation. We designed a recombinant Mip-PilE-FlaA dominant epitopes vaccine against Legionella pneumophila to prevent the disease and evaluated its immunogenicity and protective immunity. The protein structures of Mip, PilE and FlaA were analyzed using a computer, and the gene sequences of the dominant epitopes of the three proteins were selected to construct and optimize the vaccine. The optimized mip, pilE, flaA and recombinant mip-pilE-flaA gene sequences were cloned, expressed and purified. The purified proteins were used as dominant epitopes vaccines to immunize BALB/c mice and determine the protective immunity and immunogenicity of these purified proteins. The identification confirmed that the recombinant mip-pilE-flaA was successfully cloned and expressed. ELISA revealed that the Mip-PilE-FlaA group produced the highest IgG response, and this protein may considerably improve the production of some cytokines in BALB/c mice. Histopathology analyses of lungs from mice immunized with Mip-PilE-FlaA revealed a certain protective effect. Our work demonstrated that the recombinant dominant epitopes of Mip-PilE-FlaA exhibited strong immunogenicity and immune protection, and this protein may be an efficient epitopes vaccine candidate against Legionella pneumophila. Copyright © 2017 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.

  5. A Recombinant Respiratory Syncytial Virus Vaccine Candidate Attenuated by a Low-Fusion F Protein Is Immunogenic and Protective against Challenge in Cotton Rats

    PubMed Central

    Rostad, Christina A.; Stobart, Christopher C.; Gilbert, Brian E.; Pickles, Ray J.; Hotard, Anne L.; Meng, Jia; Blanco, Jorge C. G.; Moin, Syed M.; Graham, Barney S.; Piedra, Pedro A.

    2016-01-01

    ABSTRACT Although respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants, a safe and effective vaccine is not yet available. Live-attenuated vaccines (LAVs) are the most advanced vaccine candidates in RSV-naive infants. However, designing an LAV with appropriate attenuation yet sufficient immunogenicity has proven challenging. In this study, we implemented reverse genetics to address these obstacles with a multifaceted LAV design that combined the codon deoptimization of genes for nonstructural proteins NS1 and NS2 (dNS), deletion of the small hydrophobic protein (ΔSH) gene, and replacement of the wild-type fusion (F) protein gene with a low-fusion RSV subgroup B F consensus sequence of the Buenos Aires clade (BAF). This vaccine candidate, RSV-A2-dNS-ΔSH-BAF (DB1), was attenuated in two models of primary human airway epithelial cells and in the upper and lower airways of cotton rats. DB1 was also highly immunogenic in cotton rats and elicited broadly neutralizing antibodies against a diverse panel of recombinant RSV strains. When vaccinated cotton rats were challenged with wild-type RSV A, DB1 reduced viral titers in the upper and lower airways by 3.8 log10 total PFU and 2.7 log10 PFU/g of tissue, respectively, compared to those in unvaccinated animals (P < 0.0001). DB1 was thus attenuated, highly immunogenic, and protective against RSV challenge in cotton rats. DB1 is the first RSV LAV to incorporate a low-fusion F protein as a strategy to attenuate viral replication and preserve immunogenicity. IMPORTANCE RSV is a leading cause of infant hospitalizations and deaths. The development of an effective vaccine for this high-risk population is therefore a public health priority. Although live-attenuated vaccines have been safely administered to RSV-naive infants, strategies to balance vaccine attenuation with immunogenicity have been elusive. In this study, we introduced a novel strategy to attenuate a recombinant RSV

  6. European Vaccine Initiative: lessons from developing malaria vaccines.

    PubMed

    Geels, Mark J; Imoukhuede, Egeruan B; Imbault, Nathalie; van Schooten, Harry; McWade, Terry; Troye-Blomberg, Marita; Dobbelaer, Roland; Craig, Alister G; Leroy, Odile

    2011-12-01

    For over 10 years, the European Vaccine Initiative (EVI; European Malaria Vaccine Initiative until 2009) has contributed to the development of 24 malaria candidate vaccine antigens with 13 vaccine candidates being advanced into Phase I clinical trials, two of which have been transitioned for further clinical development in sub-Saharan Africa. Since its inception the EVI organization has operated as a funding agency, but with a clear service-oriented strategy. The scientific successes and difficulties encountered during these years and how these efforts have led to standardization and harmonization in vaccine development through large-scale European consortia are discussed. In the future, the EVI will remain instrumental in the pharmaceutical and clinical development of vaccines against 'diseases of poverty' with a continued focus on malaria. EVI will continue to focus on funding and managing preclinical evaluation up to Phase I/II clinical trials and strengthening the vaccine-development infrastructure in Europe, albeit with a global orientation.

  7. Optimization of HIV-1 Envelope DNA Vaccine Candidates within Three Different Animal Models, Guinea Pigs, Rabbits and Cynomolgus Macaques.

    PubMed

    Borggren, Marie; Vinner, Lasse; Andresen, Betina Skovgaard; Grevstad, Berit; Repits, Johanna; Melchers, Mark; Elvang, Tara Laura; Sanders, Rogier W; Martinon, Frédéric; Dereuddre-Bosquet, Nathalie; Bowles, Emma Joanne; Stewart-Jones, Guillaume; Biswas, Priscilla; Scarlatti, Gabriella; Jansson, Marianne; Heyndrickx, Leo; Grand, Roger Le; Fomsgaard, Anders

    2013-07-19

    HIV-1 DNA vaccines have many advantageous features. Evaluation of HIV-1 vaccine candidates often starts in small animal models before macaque and human trials. Here, we selected and optimized DNA vaccine candidates through systematic testing in rabbits for the induction of broadly neutralizing antibodies (bNAb). We compared three different animal models: guinea pigs, rabbits and cynomolgus macaques. Envelope genes from the prototype isolate HIV-1 Bx08 and two elite neutralizers were included. Codon-optimized genes, encoded secreted gp140 or membrane bound gp150, were modified for expression of stabilized soluble trimer gene products, and delivered individually or mixed. Specific IgG after repeated i.d. inoculations with electroporation confirmed in vivo expression and immunogenicity. Evaluations of rabbits and guinea pigs displayed similar results. The superior DNA construct in rabbits was a trivalent mix of non-modified codon-optimized gp140 envelope genes. Despite NAb responses with some potency and breadth in guinea pigs and rabbits, the DNA vaccinated macaques displayed less bNAb activity. It was concluded that a trivalent mix of non-modified gp140 genes from rationally selected clinical isolates was, in this study, the best option to induce high and broad NAb in the rabbit model, but this optimization does not directly translate into similar responses in cynomolgus macaques.

  8. Optimization of HIV-1 Envelope DNA Vaccine Candidates within Three Different Animal Models, Guinea Pigs, Rabbits and Cynomolgus Macaques

    PubMed Central

    Borggren, Marie; Vinner, Lasse; Andresen, Betina Skovgaard; Grevstad, Berit; Repits, Johanna; Melchers, Mark; Elvang, Tara Laura; Sanders, Rogier W; Martinon, Frédéric; Dereuddre-Bosquet, Nathalie; Bowles, Emma Joanne; Stewart-Jones, Guillaume; Biswas, Priscilla; Scarlatti, Gabriella; Jansson, Marianne; Heyndrickx, Leo; Le Grand, Roger; Fomsgaard, Anders

    2013-01-01

    HIV-1 DNA vaccines have many advantageous features. Evaluation of HIV-1 vaccine candidates often starts in small animal models before macaque and human trials. Here, we selected and optimized DNA vaccine candidates through systematic testing in rabbits for the induction of broadly neutralizing antibodies (bNAb). We compared three different animal models: guinea pigs, rabbits and cynomolgus macaques. Envelope genes from the prototype isolate HIV-1 Bx08 and two elite neutralizers were included. Codon-optimized genes, encoded secreted gp140 or membrane bound gp150, were modified for expression of stabilized soluble trimer gene products, and delivered individually or mixed. Specific IgG after repeated i.d. inoculations with electroporation confirmed in vivo expression and immunogenicity. Evaluations of rabbits and guinea pigs displayed similar results. The superior DNA construct in rabbits was a trivalent mix of non-modified codon-optimized gp140 envelope genes. Despite NAb responses with some potency and breadth in guinea pigs and rabbits, the DNA vaccinated macaques displayed less bNAb activity. It was concluded that a trivalent mix of non-modified gp140 genes from rationally selected clinical isolates was, in this study, the best option to induce high and broad NAb in the rabbit model, but this optimization does not directly translate into similar responses in cynomolgus macaques. PMID:26344115

  9. Cellular and humoral immune responses in sheep vaccinated with candidate antigens MAP2698c and MAP3567 from Mycobacterium avium subspecies paratuberculosis

    PubMed Central

    Gurung, Ratna B.; Purdie, Auriol C.; Whittington, Richard J.; Begg, Douglas J.

    2014-01-01

    Control of Johne's disease, caused by Mycobacterium avium subspecies paratuberculosis (MAP) in ruminants using commercially available vaccine reduces production losses, mortality, fecal shedding and histopathological lesions but does not provide complete protection from infection and interferes with serological diagnosis of Johne's disease and bovine tuberculosis. At this time no recombinant antigens have been found to provide superior protection compared to whole killed or live-attenuated MAP vaccines. Therefore, there is a need to evaluate more candidate MAP antigens. In this study recombinant MAP antigens MAP2698c and MAP3567 were formulated with four different MONTANIDE™ (ISA 50V2, 61VG, 71VG, and 201VG) adjuvants and evaluated for their ability to produce specific immune responses in vaccinated sheep. The cellular immune response was measured with an interferon-gamma (IFN-γ) release assay and the humoral immune response was measured by antibody detection enzyme linked immunosorbent assay. Recombinant vaccine formulation with the antigen MAP2698c and MONTANIDE™ ISA 201VG adjuvant produced strong whole-MAP as well as MAP2698c-specific IFN-γ responses in a high proportion of the vaccinated sheep. The formulation caused less severe injection site lesions in comparison to other formulations. The findings from this study suggest that the MAP2698c + 201VG should be evaluated in a challenge trial to determine the efficacy of this vaccine candidate. PMID:25077074

  10. A Systematic Approach Toward Stabilization of CagL, a Protein Antigen from Helicobacter pylori That Is a Candidate Subunit Vaccine

    PubMed Central

    Choudhari, Shyamal P.; Pendleton, Kirk P.; Ramsey, Joshua D.; Blanchard, Thomas G.; Picking, William D.

    2013-01-01

    An important consideration in the development of subunit vaccines is loss of activity caused by physical instability of the protein. Such instability often results from suboptimal solution conditions related to pH and temperature. Excipients can help to stabilize vaccines, but it is important to screen and identify excipients that adequately contribute to stabilization of a given formulation. CagL is a protein present in strains of Helicobacter pylori that possess type IV secretion systems. It contributes to bacterial adherence via α5β1 integrin, thereby making it an attractive subunit vaccine candidate. We characterized the stability of CagL in different pH and temperature conditions using a variety of spectroscopic techniques. Stability was assessed in terms of transition temperature (Tm) with the accumulated data then incorporated into an empirical phase diagram (EPD) that provided an overview of CagL physical stability. These analyses indicated maximum CagL stability at pH 4–6 up to 40 °C in the absence of excipient. Using this EPD analysis, aggregation assays were developed to screen a panel of excipients with some found to inhibit CagL aggregation. Candidate stabilizers were selected to confirm their enhanced stabilizing effect. These analyses will help in the formulation of a stable vaccine against H. pylori. PMID:23794457

  11. 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

  12. Vaccines in a hurry.

    PubMed

    Søborg, Christian; Mølbak, Kåre; Doherty, T Mark; Ulleryd, Peter; Brooks, Tim; Coenen, Claudine; van der Zeijst, Ben

    2009-05-26

    Preparing populations for health threats, including threats from new or re-emerging infectious diseases is recognised as an important public health priority. The development, production and application of emergency vaccinations are the important measures against such threats. Vaccines are cost-effective tools to prevent disease, and emergency vaccines may be the only means to prevent a true disaster for global society in the event of a new pandemic with potential to cause morbidity and mortality comparable to the Spanish flu, the polio epidemics in the 1950s, or the SARS outbreak in 2003 if its spread had not been contained in time. Given the early recognition of a new threat, and given the advances of biotechnology, vaccinology and information systems, it is not an unrealistic goal to have promising prototype vaccine candidates available in a short time span following the identification of a new infectious agent; this is based on the assumption that the emerging infection is followed by natural immunity. However, major bottlenecks for the deployment of emergency vaccine are lack of established systems for fast-track regulatory approval of such candidates and limited international vaccine production capacity. In the present discussion paper, we propose mechanisms to facilitate development of emergency vaccines in Europe by focusing on public-private scientific partnerships, fast-track approval of emergency vaccine by regulatory agencies and proposing incentives for emergency vaccine production in private vaccine companies.

  13. 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

  14. Identification of Leishmania infantum chagasi proteins in urine of patients with visceral leishmaniasis: a promising antigen discovery approach of vaccine candidates.

    PubMed

    Kashino, S S; Abeijon, C; Qin, L; Kanunfre, K A; Kubrusly, F S; Silva, F O; Costa, D L; Campos, D; Costa, C H N; Raw, I; Campos-Neto, A

    2012-07-01

    Visceral leishmaniasis (VL) is a serious lethal parasitic disease caused by Leishmania donovani in Asia and by Leishmania infantum chagasi in southern Europe and South America. VL is endemic in 47 countries with an annual incidence estimated to be 500,000 cases. This high incidence is due in part to the lack of an efficacious vaccine. Here, we introduce an innovative approach to directly identify parasite vaccine candidate antigens that are abundantly produced in vivo in humans with VL. We combined RP-HPLC and mass spectrometry and categorized three L. infantum chagasi proteins, presumably produced in spleen, liver and bone marrow lesions and excreted in the patients' urine. Specifically, these proteins were the following: Li-isd1 (XP_001467866.1), Li-txn1 (XP_001466642.1) and Li-ntf2 (XP_001463738.1). Initial vaccine validation studies were performed with the rLi-ntf2 protein produced in Escherichia coli mixed with the adjuvant BpMPLA-SE. This formulation stimulated potent Th1 response in BALB/c mice. Compared to control animals, mice immunized with Li-ntf2+ BpMPLA-SE had a marked parasite burden reduction in spleens at 40 days post-challenge with virulent L. infantum chagasi. These results strongly support the proposed antigen discovery strategy of vaccine candidates to VL and opens novel possibilities for vaccine development to other serious infectious diseases. © 2012 Blackwell Publishing Ltd.

  15. Emerging human papillomavirus vaccines

    PubMed Central

    Ma, Barbara; Maraj, Bharat; Tran, Nam Phuong; Knoff, Jayne; Chen, Alexander; Alvarez, Ronald D; Hung, Chien-Fu; Wu, T.-C.

    2013-01-01

    Introduction Identification of human papillomavirus (HPV) as the etiologic factor of cervical, anogenital, and a subset of head and neck cancers has stimulated the development of preventive and therapeutic HPV vaccines to control HPV-associated malignancies. Excitement has been generated by the commercialization of two preventive L1-based vaccines, which use HPV virus-like particles (VLPs) to generate capsid-specific neutralizing antibodies. However, factors such as high cost and requirement for cold chain have prevented widespread implementation where they are needed most. Areas covered Next generation preventive HPV vaccine candidates have focused on cost-effective stable alternatives and generating broader protection via targeting multivalent L1 VLPs, L2 capsid protein, and chimeric L1/L2 VLPs. Therapeutic HPV vaccine candidates have focused on enhancing T cell-mediated killing of HPV-transformed tumor cells, which constitutively express HPV-encoded proteins, E6 and E7. Several therapeutic HPV vaccines are in clinical trials. Expert opinion Although progress is being made, cost remains an issue inhibiting the use of preventive HPV vaccines in countries that carry the majority of the cervical cancer burden. In addition, progression of therapeutic HPV vaccines through clinical trials may require combination strategies employing different therapeutic modalities. As research in the development of HPV vaccines continues, we may generate effective strategies to control HPV-associated malignancies. PMID:23163511

  16. Identification of novel Haemophilus parasuis serovar 5 vaccine candidates using an immunoproteomic approach.

    PubMed

    Li, Gang; Xie, Fang; Li, Jianjun; Liu, Jiao; Li, Dapeng; Zhang, Yanhe; Langford, Paul R; Li, Yanwen; Liu, Siguo; Wang, Chunlai

    2017-06-23

    Haemophilus parasuis is the aetiological agent of Glässer's disease, which is responsible for cases of fibrinous polyserositis, polyarthritis and meningitis. No vaccine is known that provides cross-protection against all serovars. The identification of novel immunoprotective antigens would undoubtedly contribute to the development of efficient subunit vaccines. In the present study, an immunoproteomic approach was used to analyze secreted proteins of H. parasuis and six proteins with high immunogenicity were identified. Five of them were successfully expressed, and their immunogenicity and protective efficacy were assessed in a mouse challenge model. All five proteins elicited strong humoral antibody and cellular immune responses in mice. They all effectively reduced the growth of H. parasuis in mouse organs and conferred different levels of protection (40-80%) against challenge. IgG subtype analysis revealed that the five proteins induce a bias toward a Th1-type immune response, and a significant increase was observed in the cytokine levels of IL-2, IFN-γ and Th2-specific IL-4 in the culture supernatants of splenocytes isolated from immunized mice. The results suggest that both Th1 and Th2 responses are involved in mediating protection. These data suggest that the five proteins could be potential subunit vaccine candidates for use to prevent H. parasuis infection. Haemophilus parasuis can cause huge financial loss in the swine industry worldwide. There are still no vaccines which can provide cross-protection against all serovars. To address this need, we applied an immunoproteomic approach involving 2-DE, MALDI-TOF/TOF MS and Western-blot to identify the secreted proteins which may be able to provide immunoprotection to this disease. We identified six immunogenic proteins, and the immunogenicity and protective efficacy were validated. This result provides a foundation for developing novel subunit vaccines against Haemophilus parasuis. Copyright © 2017

  17. Construction of a Salmonella Gallinarum ghost as a novel inactivated vaccine candidate and its protective efficacy against fowl typhoid in chickens

    PubMed Central

    2012-01-01

    In order to develop a novel, safe and immunogenic fowl typhoid (FT) vaccine candidate, a Salmonella Gallinarum ghost with controlled expression of the bacteriophage PhiX174 lysis gene E was constructed using pMMP99 plasmid in this study. The formation of the Salmonella Gallinarum ghost with tunnel formation and loss of cytoplasmic contents was observed by scanning electron microscopy and transmission electron microscopy. No viable cells were detectable 24 h after the induction of gene E expression by an increase in temperature from 37 °C to 42 °C. The safety and protective efficacy of the Salmonella Gallinarum ghost vaccine was tested in chickens that were divided into four groups: group A (non-immunized control), group B (orally immunized), group C (subcutaneously immunized) and group D (intramuscularly immunized). The birds were immunized at day 7 of age. None of the immunized animals showed any adverse reactions such as abnormal behavior, mortality, or signs of FT such as anorexia, depression, or diarrhea. These birds were subsequently challenged with a virulent Salmonella Gallinarum strain at 3 weeks post-immunization (wpi). Significant protection against the virulent challenge was observed in all immunized groups based on mortality and post-mortem lesions compared to the non-immunized control group. In addition, immunization with the Salmonella Gallinarum ghosts induced significantly high systemic IgG response in all immunized groups. Among the groups, orally-vaccinated group B showed significantly higher levels of secreted IgA. A potent antigen-specific lymphocyte activation response along with significantly increased percentages of CD4+ and CD8+ T lymphocytes found in all immunized groups clearly indicate the induction of cellular immune responses. Overall, these findings suggest that the newly constructed Salmonella Gallinarum ghost appears to be a safe, highly immunogenic, and efficient non-living bacterial vaccine candidate that protects against

  18. Safety and efficacy of the RTS,S/AS01E candidate malaria vaccine given with expanded-programme-on-immunisation vaccines: 19 month follow-up of a randomised, open-label, phase 2 trial.

    PubMed

    Asante, Kwaku Poku; Abdulla, Salim; Agnandji, Selidji; Lyimo, John; Vekemans, Johan; Soulanoudjingar, Solange; Owusu, Ruth; Shomari, Mwanajaa; Leach, Amanda; Jongert, Erik; Salim, Nahya; Fernandes, Jose F; Dosoo, David; Chikawe, Maria; Issifou, Saadou; Osei-Kwakye, Kingsley; Lievens, Marc; Paricek, Maria; Möller, Tina; Apanga, Stephen; Mwangoka, Grace; Dubois, Marie-Claude; Madi, Tigani; Kwara, Evans; Minja, Rose; Hounkpatin, Aurore B; Boahen, Owusu; Kayan, Kingsley; Adjei, George; Chandramohan, Daniel; Carter, Terrell; Vansadia, Preeti; Sillman, Marla; Savarese, Barbara; Loucq, Christian; Lapierre, Didier; Greenwood, Brian; Cohen, Joe; Kremsner, Peter; Owusu-Agyei, Seth; Tanner, Marcel; Lell, Bertrand

    2011-10-01

    The RTS,S/AS01(E) candidate malaria vaccine is being developed for immunisation of infants in Africa through the expanded programme on immunisation (EPI). 8 month follow-up data have been reported for safety and immunogenicity of RTS,S/AS01(E) when integrated into the EPI. We report extended follow-up to 19 months, including efficacy results. We did a randomised, open-label, phase 2 trial of safety and efficacy of the RTS,S/AS01(E) candidate malaria vaccine given with EPI vaccines between April 30, 2007, and Oct 7, 2009, in Ghana, Tanzania, and Gabon. Eligible children were 6-10 weeks of age at first vaccination, without serious acute or chronic illness. All children received the EPI diphtheria, tetanus, pertussis (inactivated whole-cell), and hepatitis-B vaccines, Haemophilus influenzae type b vaccine, and oral polio vaccine at study months 0, 1, and 2, and measles vaccine and yellow fever vaccines at study month 7. Participants were randomly assigned (1:1:1) to receive three doses of RTS,S/AS01(E) at 6, 10, and 14 weeks (0, 1, 2 month schedule) or at 6 weeks, 10 weeks, and 9 months (0, 2, 7 month schedule) or placebo. Randomisation was according to a predefined block list with a computer-generated randomisation code. Detection of serious adverse events and malaria was by passive case detection. Antibodies against Plasmodium falciparum circumsporozoite protein and HBsAg were monitored for 19 months. This study is registered with ClinicalTrials.gov, number NCT00436007. 511 children were enrolled. Serious adverse events occurred in 57 participants in the RTS,S/AS01(E) 0, 1, 2 month group (34%, 95% CI 27-41), 47 in the 0, 1, 7 month group (28%, 21-35), and 49 (29%, 22-36) in the control group; none were judged to be related to study vaccination. At month 19, anticircumsporozoite immune responses were significantly higher in the RTS,S/AS01(E) groups than in the control group. Vaccine efficacy for the 0, 1, 2 month schedule (2 weeks after dose three to month 19, site

  19. Exploitation of stable nanostructures based on the mouse polyomavirus for development of a recombinant vaccine against porcine circovirus 2

    PubMed Central

    Fraiberk, Martin; Hájková, Michaela; Krulová, Magdaléna; Kojzarová, Martina; Drda Morávková, Alena; Pšikal, Ivan

    2017-01-01

    The aim of this study was to develop a suitable vaccine antigen against porcine circovirus 2 (PCV2), the causative agent of post-weaning multi-systemic wasting syndrome, which causes significant economic losses in swine breeding. Chimeric antigens containing PCV2b Cap protein sequences based on the mouse polyomavirus (MPyV) nanostructures were developed. First, universal vectors for baculovirus-directed production of chimeric MPyV VLPs or pentamers of the major capsid protein, VP1, were designed for their exploitation as vaccines against other pathogens. Various strategies were employed based on: A) exposure of selected immunogenic epitopes on the surface of MPyV VLPs by insertion into a surface loop of the VP1 protein, B) insertion of foreign protein molecules inside the VLPs, or C) fusion of a foreign protein or its part with the C-terminus of VP1 protein, to form giant pentamers of a chimeric protein. We evaluated these strategies by developing a recombinant vaccine against porcine circovirus 2. All candidate vaccines induced the production of antibodies against the capsid protein of porcine circovirus after immunization of mice. The candidate vaccine, Var C, based on fusion of mouse polyomavirus and porcine circovirus capsid proteins, could induce the production of antibodies with the highest PCV2 neutralizing capacity. Its ability to induce the production of neutralization antibodies was verified after immunization of pigs. The advantage of this vaccine, apart from its efficient production in insect cells and easy purification, is that it represents a DIVA (differentiating infected from vaccinated animals) vaccine, which also induces an immune response against the mouse polyoma VP1 protein and is thus able to distinguish between vaccinated and naturally infected animals. PMID:28922413

  20. Preclinical and clinical development of YFV 17D-based chimeric vaccines against dengue, West Nile and Japanese encephalitis viruses.

    PubMed

    Guy, Bruno; Guirakhoo, Farshad; Barban, Veronique; Higgs, Stephen; Monath, Thomas P; Lang, Jean

    2010-01-08

    Dengue viruses (DENV), West Nile virus (WNV) and Japanese encephalitis virus (JEV) are major global health and growing medical problems. While a live-attenuated vaccine exists since decades against the prototype flavivirus, yellow fever virus (YFV), there is an urgent need for vaccines against dengue or West Nile diseases, and for improved vaccines against Japanese encephalitis. Live-attenuated chimeric viruses were constructed by replacing the genes coding for Premembrane (prM) and Envelope (E) proteins from YFV 17D vaccine strain with those of heterologous flaviviruses (ChimeriVax technology). This technology has been used to produce vaccine candidates for humans, for construction of a horse vaccine for West Nile fever, and as diagnostic reagents for dengue, Japanese encephalitis, West Nile and St. Louis encephalitis infections. This review focuses on human vaccines and their characterization from the early stages of research through to clinical development. Phenotypic and genetic properties and stability were examined, preclinical evaluation through in vitro or animal models, and clinical testing were carried out. Theoretical environmental concerns linked to the live and genetically modified nature of these vaccines have been carefully addressed. Results of the extensive characterizations are in accordance with the immunogenicity and excellent safety profile of the ChimeriVax-based vaccine candidates, and support their development towards large-scale efficacy trials and registration.

  1. Clinical experience with respiratory syncytial virus vaccines.

    PubMed

    Piedra, Pedro A

    2003-02-01

    Respiratory syncytial virus (RSV) infection is at times associated with life-threatening lower respiratory tract illness in infancy. Severe infection during the first year of life may be an important risk factor or indicator for the development of asthma in early childhood. Severe infections primarily occur in healthy infants, and young infants and children with specific risk factors. However, RSV causes respiratory infections in all age groups. Indeed it is now recognized that RSV disease is responsible for significant morbidity and mortality in the geriatric population. RSV infection remains difficult to treat, and prevention is a worldwide goal. For this reason there has been an intensive effort to develop an effective and safe RSV vaccine. Initial infection with RSV affords limited protection to reinfection, yet repeated episodes decrease the risk for lower respiratory tract illness. In the 20 years from 1960 to 1980, trials of several candidate RSV vaccines failed to attain the desired safety and protection against natural infection. Some vaccine types either failed to elicit immunogenicity, as with the live subcutaneous vaccine, or resulted in exaggerated disease on natural exposure to the virus, as with the formalin-inactivated (FI) type. Currently vaccine candidates are being developed based on the molecular virology of RSV. Recent formulations of candidate RSV vaccines have focused on subunit vaccines [such as purified fusion protein (PFP)], subunit vaccines combined with nonspecific immune activating adjuvants, live attenuated vaccines (including cold passaged, temperature-sensitive or cpts mutants), genetically engineered live attenuated vaccines and polypeptide vaccines.

  2. Applications and challenges of multivalent recombinant vaccines

    PubMed Central

    Naim, Hussein Y.

    2013-01-01

    The exceptional discoveries of antigen/gene delivery systems have allowed the development of novel prophylactic and therapeutic vaccine candidates. The vaccine candidates employ various antigen-delivery systems, particularly recombinant viral vectors. Recombinant viral vectors are experimental vaccines similar to DNA vaccines, but they use attenuated viruses or bacterium as a carrier “vector” to introduce microbial DNA to cells of the body. They closely mimic a natural infection and therefore can efficiently stimulate the immune system. Although such recombinant vectors may face extensive preclinical testing and will possibly have to meet stringent regulatory requirements, some of these vectors (e.g. measles virus vectors) may benefit from the profound industrial and clinical experience of the parent vaccine. Most notably, novel vaccines based on live attenuated viruses combine the induction of broad, strong and persistent immune responses with acceptable safety profiles. We assess certain technologies in light of their use against human immunodeficiency virus (HIV). PMID:23249651

  3. Multilayer engineered nanoliposomes as a novel tool for oral delivery of lipopeptide-based vaccines against group A Streptococcus.

    PubMed

    Marasini, Nirmal; Giddam, Ashwini K; Ghaffar, Khairunnisa A; Batzloff, Michael R; Good, Michael F; Skwarczynski, Mariusz; Toth, Istvan

    2016-05-01

    To develop an oral nanovaccine delivery system for lipopeptide-based vaccine candidate against group A Streptococcus. Lipid-core peptide-1-loaded nanoliposomes were prepared as a template and coated with opposite-charged polyelectrolytes to produce particles with size <200 nm. Efficacy of this oral nanovaccine delivery system was evaluated in mice model. Polymer-coated liposomes produced significantly higher antigen-specific mucosal IgA and systemic IgG titers in comparison to vaccine formulated with a strong mucosal adjuvant upon oral immunization in mice. Moreover, high levels of systemic antibody titers were retained even at day 185 postprimary immunization. Efficient oral delivery platform for lipopeptide-based vaccines has been developed.

  4. Immunoproteomics Approach for Screening of Vaccine Candidates against Intestinal Botulism.

    PubMed

    Sharma, Arti; Rani, Sarita; Alam, Syed Imteyaz; Ponmariappan, Sarkaraisamy

    2017-01-01

    Intestinal botulism is an infectious form of botulism in which disease results from ingesting spores, which is followed by spore germination and intraluminal production of botulinum neurotoxins over an extended period. Botulinum neurotoxin is produced by endospore forming bacteria called C. botulinum. Immunoproteomic study was used to screen the cross reactive immunogenic proteins of Clostridium botulinum type B using C. botulinum type B live spore antiserum. The whole cell proteins were separated by two dimensional gel electrophoresis and transferred to polyvinylidene difluoride membranes. Further, the Western blotting was performed with mouse pups immune serum against C. botulinum type B live spores. Eight predominant cross immunoreactive proteins were identified by mass spectrometry. These immunogenic proteins might be used to develop novel subunit vaccine candidates against the intestinal botulism. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Tuberculosis vaccine candidate: Characterization of H4-IC31 formulation and H4 antigen conformation.

    PubMed

    Deshmukh, Sasmit S; Magcalas, Federico Webster; Kalbfleisch, Kristen N; Carpick, Bruce W; Kirkitadze, Marina D

    2018-08-05

    Tuberculosis (TB) is one of the leading causes of death worldwide, making the development of effective TB vaccines a global priority. A TB vaccine consisting of a recombinant fusion protein, H4, combined with a novel synthetic cationic adjuvant, IC31 ® , is currently being developed. The H4 fusion protein consists of two immunogenic mycobacterial antigens, Ag85 B and TB10.4, and the IC31 ® adjuvant is a mixture of KLK, a leucine-rich peptide (KLKL5KLK), and the oligodeoxynucleotide ODN1a, a TLR9 ligand. However, efficient and robust methods for assessing these formulated components are lacking. Here, we developed and optimized phase analysis light scattering (PALS), electrical sensing zone (ESZ), and Raman, FTIR, and CD spectroscopy methods to characterize the H4-IC31 vaccine formulation. PALS-measured conductivity and zeta potential values could differentiate between the similarly sized particles of IC31 ® adjuvant and the H4-IC31 vaccine candidate and could thereby serve as a control during vaccine formulation. In addition, zeta potential is indicative of the adjuvant to antigen ratio which is the key in the immunomodulatory response of the vaccine. ESZ was used as an orthogonal method to measure IC31 ® and H4-IC31 particle sizes. Raman, FTIR, and CD spectroscopy revealed structural changes in H4 protein and IC31 ® adjuvant, inducing an increase in both the β-sheet and random coil content as a result of adsorption. Furthermore, nanoDSF showed changes in the tertiary structure of H4 protein as a result of adjuvantation to IC31 ® . Our findings demonstrate the applicability of biophysical methods to characterize vaccine components in the final H4-IC31 drug product without the requirement for desorption. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  6. Vaccines to prevent severe acute respiratory syndrome coronavirus-induced disease

    PubMed Central

    Enjuanes, Luis; DeDiego, Marta L.; Álvarez, Enrique; Deming, Damon; Sheahan, Tim; Baric, Ralph

    2009-01-01

    An important effort has been performed after the emergence of severe acute respiratory syndrome (SARS) epidemic in 2003 to diagnose and prevent virus spreading. Several types of vaccines have been developed including inactivated viruses, subunit vaccines, virus-like particles (VLPs), DNA vaccines, heterologous expression systems, and vaccines derived from SARS-CoV genome by reverse genetics. This review describes several aspects essential to develop SARS-CoV vaccines, such as the correlates of protection, virus serotypes, vaccination side effects, and bio-safeguards that can be engineered into recombinant vaccine approaches based on the SARS-CoV genome. The production of effective and safe vaccines to prevent SARS has led to the development of promising vaccine candidates, in contrast to the design of vaccines for other coronaviruses, that in general has been less successful. After preclinical trials in animal models, efficacy and safety evaluation of the most promising vaccine candidates described has to be performed in humans. PMID:17416434

  7. 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.

  8. A Recombinant Respiratory Syncytial Virus Vaccine Candidate Attenuated by a Low-Fusion F Protein Is Immunogenic and Protective against Challenge in Cotton Rats.

    PubMed

    Rostad, Christina A; Stobart, Christopher C; Gilbert, Brian E; Pickles, Ray J; Hotard, Anne L; Meng, Jia; Blanco, Jorge C G; Moin, Syed M; Graham, Barney S; Piedra, Pedro A; Moore, Martin L

    2016-08-15

    Although respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants, a safe and effective vaccine is not yet available. Live-attenuated vaccines (LAVs) are the most advanced vaccine candidates in RSV-naive infants. However, designing an LAV with appropriate attenuation yet sufficient immunogenicity has proven challenging. In this study, we implemented reverse genetics to address these obstacles with a multifaceted LAV design that combined the codon deoptimization of genes for nonstructural proteins NS1 and NS2 (dNS), deletion of the small hydrophobic protein (ΔSH) gene, and replacement of the wild-type fusion (F) protein gene with a low-fusion RSV subgroup B F consensus sequence of the Buenos Aires clade (BAF). This vaccine candidate, RSV-A2-dNS-ΔSH-BAF (DB1), was attenuated in two models of primary human airway epithelial cells and in the upper and lower airways of cotton rats. DB1 was also highly immunogenic in cotton rats and elicited broadly neutralizing antibodies against a diverse panel of recombinant RSV strains. When vaccinated cotton rats were challenged with wild-type RSV A, DB1 reduced viral titers in the upper and lower airways by 3.8 log10 total PFU and 2.7 log10 PFU/g of tissue, respectively, compared to those in unvaccinated animals (P < 0.0001). DB1 was thus attenuated, highly immunogenic, and protective against RSV challenge in cotton rats. DB1 is the first RSV LAV to incorporate a low-fusion F protein as a strategy to attenuate viral replication and preserve immunogenicity. RSV is a leading cause of infant hospitalizations and deaths. The development of an effective vaccine for this high-risk population is therefore a public health priority. Although live-attenuated vaccines have been safely administered to RSV-naive infants, strategies to balance vaccine attenuation with immunogenicity have been elusive. In this study, we introduced a novel strategy to attenuate a recombinant RSV vaccine by

  9. 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

  10. Zika virus-like particle (VLP) based vaccine

    PubMed Central

    Boigard, Hélène; Alimova, Alexandra; Martin, George R.; Katz, Al; Gottlieb, Paul

    2017-01-01

    The newly emerged mosquito-borne Zika virus poses a major public challenge due to its ability to cause significant birth defects and neurological disorders. The impact of sexual transmission is unclear but raises further concerns about virus dissemination. No specific treatment or vaccine is currently available, thus the development of a safe and effective vaccine is paramount. Here we describe a novel strategy to assemble Zika virus-like particles (VLPs) by co-expressing the structural (CprME) and non-structural (NS2B/NS3) proteins, and demonstrate their effectiveness as vaccines. VLPs are produced in a suspension culture of mammalian cells and self-assembled into particles closely resembling Zika viruses as shown by electron microscopy studies. We tested various VLP vaccines and compared them to analogous compositions of an inactivated Zika virus (In-ZIKV) used as a reference. VLP immunizations elicited high titers of antibodies, as did the In-ZIKV controls. However, in mice the VLP vaccine stimulated significantly higher virus neutralizing antibody titers than comparable formulations of the In-ZIKV vaccine. The serum neutralizing activity elicited by the VLP vaccine was enhanced using a higher VLP dose and with the addition of an adjuvant, reaching neutralizing titers greater than those detected in the serum of a patient who recovered from a Zika infection in Brazil in 2015. Discrepancies in neutralization levels between the VLP vaccine and the In-ZIKV suggest that chemical inactivation has deleterious effects on neutralizing epitopes within the E protein. This along with the inability of a VLP vaccine to cause infection makes it a preferable candidate for vaccine development. PMID:28481898

  11. Yeast-expressed recombinant protein of the receptor-binding domain in SARS-CoV spike protein with deglycosylated forms as a SARS vaccine candidate

    PubMed Central

    Chen, Wen-Hsiang; Du, Lanying; Chag, Shivali M; Ma, Cuiqing; Tricoche, Nancy; Tao, Xinrong; Seid, Christopher A; Hudspeth, Elissa M; Lustigman, Sara; Tseng, Chien-Te K; Bottazzi, Maria Elena; Hotez, Peter J; Zhan, Bin; Jiang, Shibo

    2014-01-01

    Development of vaccines for preventing a future pandemic of severe acute respiratory syndrome (SARS) caused by SARS coronavirus (SARS-CoV) and for biodefense preparedness is urgently needed. Our previous studies have shown that a candidate SARS vaccine antigen consisting of the receptor-binding domain (RBD) of SARS-CoV spike protein can induce potent neutralizing antibody responses and protection against SARS-CoV challenge in vaccinated animals. To optimize expression conditions for scale-up production of the RBD vaccine candidate, we hypothesized that this could be potentially achieved by removing glycosylation sites in the RBD protein. In this study, we constructed two RBD protein variants: 1) RBD193-WT (193-aa, residues 318–510) and its deglycosylated forms (RBD193-N1, RBD193-N2, RBD193-N3); 2) RBD219-WT (219-aa, residues 318–536) and its deglycosylated forms (RBD219-N1, RBD219-N2, and RBD219-N3). All constructs were expressed as recombinant proteins in yeast. The purified recombinant proteins of these constructs were compared for their antigenicity, functionality and immunogenicity in mice using alum as the adjuvant. We found that RBD219-N1 exhibited high expression yield, and maintained its antigenicity and functionality. More importantly, RBD219-N1 induced significantly stronger RBD-specific antibody responses and a higher level of neutralizing antibodies in immunized mice than RBD193-WT, RBD193-N1, RBD193-N3, or RBD219-WT. These results suggest that RBD219-N1 could be selected as an optimal SARS vaccine candidate for further development. PMID:24355931

  12. Yeast-expressed recombinant protein of the receptor-binding domain in SARS-CoV spike protein with deglycosylated forms as a SARS vaccine candidate.

    PubMed

    Chen, Wen-Hsiang; Du, Lanying; Chag, Shivali M; Ma, Cuiqing; Tricoche, Nancy; Tao, Xinrong; Seid, Christopher A; Hudspeth, Elissa M; Lustigman, Sara; Tseng, Chien-Te K; Bottazzi, Maria Elena; Hotez, Peter J; Zhan, Bin; Jiang, Shibo

    2014-01-01

    Development of vaccines for preventing a future pandemic of severe acute respiratory syndrome (SARS) caused by SARS coronavirus (SARS-CoV) and for biodefense preparedness is urgently needed. Our previous studies have shown that a candidate SARS vaccine antigen consisting of the receptor-binding domain (RBD) of SARS-CoV spike protein can induce potent neutralizing antibody responses and protection against SARS-CoV challenge in vaccinated animals. To optimize expression conditions for scale-up production of the RBD vaccine candidate, we hypothesized that this could be potentially achieved by removing glycosylation sites in the RBD protein. In this study, we constructed two RBD protein variants: 1) RBD193-WT (193-aa, residues 318-510) and its deglycosylated forms (RBD193-N1, RBD193-N2, RBD193-N3); 2) RBD219-WT (219-aa, residues 318-536) and its deglycosylated forms (RBD219-N1, RBD219-N2, and RBD219-N3). All constructs were expressed as recombinant proteins in yeast. The purified recombinant proteins of these constructs were compared for their antigenicity, functionality and immunogenicity in mice using alum as the adjuvant. We found that RBD219-N1 exhibited high expression yield, and maintained its antigenicity and functionality. More importantly, RBD219-N1 induced significantly stronger RBD-specific antibody responses and a higher level of neutralizing antibodies in immunized mice than RBD193-WT, RBD193-N1, RBD193-N3, or RBD219-WT. These results suggest that RBD219-N1 could be selected as an optimal SARS vaccine candidate for further development.

  13. Protection against Fasciola gigantica using paramyosin antigen as a candidate for vaccine production.

    PubMed

    Abou-Elhakam, H; Rabee, I; El Deeb, S; El Amir, A

    2013-11-15

    Yet no vaccine to protect ruminants against liver fluke infection has been commercialized. In an attempt to develop a suitable vaccine against Fasciola gigantica (F. gigantica) infection in rabbits, using 97 kDa Pmy antigen. It was found that, the mean worm burdens and bile egg count after challenge were reduced significantly by 58.40 and 61.40%, respectively. On the other hand, immunization of rabbits with Pmy induced a significant expression of humoral antibodies (IgM, total IgG, IgG1, IgG2 and IgG4) and different cytokines (IL-6, IL-10, L-12 and TNF-alpha). Among Ig isotypes, IgG2 and IgG4 were most dominant Post-infection (PI) while, recording a low IgG1 level. The dominance of IgG2 and IgG4 suggested late T helper1 (Th1) involvement in rabbit's cellular response. While, the low IgG1 level suggested Th2 response to adult F. gigantica worm Pmy. Among all cytokines, IL-10 was the highest in rabbits immunized with Pmy PI suggesting also the enhancement of Th2 response. It was clear that the native F. gigantica Pmy is considered as a relevant candidate for vaccination against fascioliasis. Also, these data suggested the immunoprophylactic effect of the native F. gigantica Pmy which is mediated by a mixed Th1/Th2 response.

  14. Safety, Protective Immunity, and DIVA Capability of a Rough Mutant Salmonella Pullorum Vaccine Candidate in Broilers.

    PubMed

    Guo, Rongxian; Jiao, Yang; Li, Zhuoyang; Zhu, Shanshan; Fei, Xiao; Geng, Shizhong; Pan, Zhiming; Chen, Xiang; Li, Qiuchun; Jiao, Xinan

    2017-01-01

    Salmonella enterica subsp. enterica serovar Gallinarum biovar Pullorum ( Salmonella Pullorum) is highly adapted to chickens causing an acute systemic disease that results in high mortality. Vaccination represents one approach for promoting animal health, food safety and reducing environmental persistence in Salmonella control. An important consideration is that Salmonella vaccination in poultry should not interfere with the salmonellosis monitoring program. This is the basis of the DIVA (Differentiation of Infected and Vaccinated Animals) program. In order to achieve this goal, waaL mutant was developed on a spiC mutant that was developed previously. The safety, efficacy, and DIVA features of this vaccine candidate ( Salmonella Pullorum Δ spiC Δ waaL ) were evaluated in broilers. Our results show that the truncated LPS in the vaccine strain has a differentiating use as both a bacteriological marker (rough phenotype) and also as a serological marker facilitating the differentiation between infected and vaccinated chickens. The rough mutant showed adequate safety being avirulent in the host chicks and showed increased sensitivity to environmental stresses. Single intramuscular immunization of day-old broiler chicks with the mutant confers ideal protection against lethal wild type challenge by significantly stimulating both humoral and cellular immune responses as well as reducing the colonization of the challenge strain. Significantly lower mean pathology scores were observed in the vaccination group compared to the control group. Additionally, the mutant strain generated cross-protection against challenge with the wild type Salmonella Gallinarum thereby improving survival and with the wild type Salmonella Enteritidis thereby reducing colonization. These results suggest that the double-mutant strain may be a safe, effective, and cross-protective vaccine against Salmonella infection in chicks while conforming to the requirements of the DIVA program.

  15. Pulmonary immunity and durable protection induced by the ID93/GLA-SE vaccine candidate against the hyper-virulent Korean Beijing Mycobacterium tuberculosis strain K.

    PubMed

    Cha, Seung Bin; Kim, Woo Sik; Kim, Jong-Seok; Kim, Hongmin; Kwon, Kee Woong; Han, Seung Jung; Cho, Sang-Nae; Coler, Rhea N; Reed, Steven G; Shin, Sung Jae

    2016-04-27

    The majority of tuberculosis (TB) vaccine candidates advanced to clinical trials have been evaluated preclinically using laboratory-adapted strains. However, it has been proposed that challenge with clinical isolates in preclinical vaccine testing could provide further and more practical validation. Here, we tested the ID93/GLA-SE TB vaccine candidate against the clinical Mycobacterium tuberculosis (Mtb) strain K (Mtb K) belonging to the Beijing family, the most prevalent Mtb strain in South Korea. Mice immunized with ID93/GLA-SE exhibited a significant reduction in bacteria and reduced lung inflammation against Mtb K when compared to non-immunized controls. In addition, we analyzed the immune responses in the lungs of ID93/GLA-SE-immunized mice, and showed that ID93/GLA-SE was able to elicit sustained Th1-biased immune responses including antigen-specific multifunctional CD4(+) T cell co-producing IFN-γ, TNF-α, and IL-2 as well as a high magnitude of IFN-γ response for up to 10 weeks post-challenge. Notably, further investigation of T cell subsets in the lung following challenge showed remarkable generation of CD8(+) central memory T cells by ID93/GLA-SE-immunization. Our findings showed that ID93/GLA-SE vaccine confers a high level of robust protection against the hypervirulent Mtb Beijing infection which was characterized by pulmonary Th1-polarized T-cell immune responses. These findings may also provide relevant information for potential utility of this vaccine candidate in East-Asian countries where the Beijing genotype is highly prevalent. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Autoimmune diseases and vaccinations.

    PubMed

    Vial, Thierry; Descotes, Jacques

    2004-01-01

    The potential association between vaccination and autoimmune diseases has been largely questioned in the past few years, but this assumption has mostly been based on case reports. The available evidence derived from several negative epidemiological studies is reassuring and at least indicates that vaccines are not a major cause of autoimmune diseases. However, there are still uncertainties as to whether a susceptible subpopulation may be at a higher risk of developing an autoimmune disease without causing an overall increase in the disease incidence. Based on selected examples, this review highlights the difficulties in assessing this issue. We suggest that a potential link between vaccines and autoimmune diseases cannot be definitely ruled out and should be carefully explored during the development of new candidate vaccines. Copyright John Libbey Eurotext 2003.

  17. Why does the world need another rotavirus vaccine?

    PubMed Central

    Ward, Richard L; McNeal, Monica M; Steele, A Duncan

    2008-01-01

    A “Meeting on Upstream Rotavirus Vaccines and Emerging Vaccine Producers” was held at the World Health Organization in Geneva, Switzerland on March 28–30, 2006. The purpose was to discuss, evaluate, and weigh the importance of additional rotavirus vaccine candidates following the successful international licensure of rotavirus vaccines by two major pharmaceutical companies (GlaxoSmithKline and Merck) that had been in development for many years. Both licensed vaccines are composed of live rotaviruses that are delivered orally as have been all candidate rotavirus vaccines evaluated in humans. Each is built on the experience gained with previous candidates whose development had either been discontinued or, in the case of the previously licensed rhesus rotavirus reassortant vaccine (Rotashield), was withdrawn by its manufacturer after the discovery of a rare association with intussusception. Although which alternative candidate vaccines should be supported for development and where this should be done are controversial topics, there was general agreement expressed at the Geneva meeting that further development of alternative candidates is a high priority. This development will help insure that the most safe, effective and economic vaccines are available to children in Third World nations where the vast majority of the >600,000 deaths due to rotavirus occur each year. This review is intended to provide the history and present status of rotavirus vaccines as well as a perspective on the future development of candidate vaccines as a means of promulgating plans suggested at the Geneva meeting. PMID:18728720

  18. 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.

  19. Respiratory syncytial virus vaccines: an update on those in the immediate pipeline.

    PubMed

    Esposito, Susanna; Pietro, Giada Di

    2016-10-01

    Respiratory syncytial virus (RSV) is among the most common causes of lower respiratory tract infection among infants and the elderly worldwide. Despite its long history, no licensed vaccine is available. Recently, advances in the knowledge of RSV biology and pathology as well as the development of new techniques to generate vaccine candidates have increased the number of promising vaccines. The aim of this review is to analyze RSV characteristics, to consider the history of RSV vaccines and to discuss RSV vaccines currently in development. Among the candidates in clinical trials, nanoparticle and subunit vaccines seem to be the most promising for pregnant women and the elderly, whereas live-attenuated or vector-based vaccines appear to be optimal for the pediatric population.

  20. Recombinant α-actinin subunit antigens of Trichomonas vaginalis as potential vaccine candidates in protecting against trichomoniasis.

    PubMed

    Xie, Yi-Ting; Gao, Jiang-Mei; Wu, Ya-Ping; Tang, Petrus; Hide, Geoff; Lai, De-Hua; Lun, Zhao-Rong

    2017-02-16

    Human trichomoniasis caused by Trichomonas vaginalis is one of the most common sexually transmitted diseases with more than 200 million cases worldwide. It has caused a series of health problems to patients. For prevention and control of infectious diseases, vaccines are usually considered as one of the most cost-efficient tools. However, until now, work on the development of T. vaginalis vaccines is still mainly focused on the screening of potential immunogens. Alpha-actinin characterized by high immunogenicity in T. vaginalis was suggested as a promising candidate. Therefore, the purpose of this study was to evaluate the protective potency of recombinant α-actinin against T. vaginalis infection in a mouse intraperitoneal model. Two selected coding regions of α-actinin (ACT-F, 14-469 aa and ACT-T, 462-844 aa) amplified from cDNA were cloned into pET-32a (+) expression vector and transfected into BL21 cells. After induction with IPTG and purification with electroelution, the two recombinant fusion proteins were emulsified in Freund's adjuvant (FA) and used to immunize BALB/C mice. Following intraperitoneal inoculation with T. vaginalis, the survival rate of mice was monitored for the assessment of protective potency. After immunization, the antibody level in mouse serum was assessed by ELISA, splenocyte proliferation response was detected with CCK8 and cytokines in the supernatant of splenocytes were quantified with a cytometric bead-based assay. We successfully obtained purified ACT-F (70.33 kDa) and ACT-T (61.7kDa). Both recombinant proteins could provide significant protection against T. vaginalis challenge, especially ACT-T (with 100% protection within one month). Meanwhile, high levels of specific total IgG and subtypes (IgG1 > IgG2a) were detected in sera from the immunized mice. Our results also revealed a statistically significant increase in splenocyte proliferation and related cytokine (IFN-γ, IL-6, IL-17A and IL-10) production after repeated

  1. GapA, a potential vaccine candidate antigen against Streptococcus agalactiae in Nile tilapia (Oreochromis niloticus).

    PubMed

    Zhang, Ze; Yu, Angen; Lan, Jiangfeng; Zhang, Hua; Hu, Minqiang; Cheng, Jiewei; Zhao, Lijuan; Lin, Li; Wei, Shun

    2017-04-01

    Streptococcosis due to the bacterium Streptococcus agalactiae (S. agalactiae) has resulted in enormous economic losses in aquaculture worldwide, especially in the tilapia culture industry. Previously, there were limited vaccines that could be employed against streptococcosis in tilapia. This study aimed to develop a vaccine candidate using the glyceraldehyde-phosphate dehydrogenase protein (GapA) of S. agalactiae encoded by the gapA gene. Tilapia were intraperitoneally injected with PBS, PBS + Freund's adjuvant, PBS + Montanide's adjuvant, GapA + Freund's adjuvant, GapA + Montanide's adjuvant, killed S. agalactiae whole cells (WC)+Freund's adjuvant, or killed S. agalactiae whole cells (WC)+ Montanide's adjuvant. They were then challenged with S. agalactiae, and the relative percentage survival (RPS) was monitored 14 days after the challenge. The highest RPSs were observed in the WC groups, with 76.7% in WC + Freund's adjuvant and 74.4% in WC + Montanide's adjuvant groups; these were followed by the GapA groups, with 63.3% in GapA + Freund's adjuvant and 45.6% in GapA + Montanide's adjuvant groups. The RPS of the PBS group was 0%, and those of PBS + Freund's adjuvant and PBS + Montanide's adjuvant groups were 6.7% and 3.3%, respectively. Additionally, the IgM antibody responses elicited in GapA groups and WC groups were significantly higher than those in PBS groups. Furthermore, the expressions of cytokine (IL-1β and TNF-α) mRNAs in the GapA groups and WC groups were significantly higher than those in the PBS groups. Taken together, these results reveal that the GapA protein is a promising vaccine candidate that could be used to prevent streptococcosis in tilapia. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Type 1 diabetes vaccine candidates promote human Foxp3+Treg induction in humanized mice

    PubMed Central

    Serr, Isabelle; Fürst, Rainer W.; Achenbach, Peter; Scherm, Martin G.; Gökmen, Füsun; Haupt, Florian; Sedlmeier, Eva-Maria; Knopff, Annette; Shultz, Leonard; Willis, Richard A.; Ziegler, Anette-Gabriele; Daniel, Carolin

    2016-01-01

    Immune tolerance is executed partly by Foxp3+regulatory T (Treg) cells, which suppress autoreactive T cells. In autoimmune type 1 diabetes (T1D) impaired tolerance promotes destruction of insulin-producing β-cells. The development of autoantigen-specific vaccination strategies for Foxp3+Treg-induction and prevention of islet autoimmunity in patients is still in its infancy. Here, using human haematopoietic stem cell-engrafted NSG-HLA-DQ8 transgenic mice, we provide direct evidence for human autoantigen-specific Foxp3+Treg-induction in vivo. We identify HLA-DQ8-restricted insulin-specific CD4+T cells and demonstrate efficient human insulin-specific Foxp3+Treg-induction upon subimmunogenic vaccination with strong agonistic insulin mimetopes in vivo. Induced human Tregs are stable, show increased expression of Treg signature genes such as Foxp3, CTLA4, IL-2Rα and TIGIT and can efficiently suppress effector T cells. Such Foxp3+Treg-induction does not trigger any effector T cells. These T1D vaccine candidates could therefore represent an expedient improvement in the challenge to induce human Foxp3+Tregs and to develop novel precision medicines for prevention of islet autoimmunity in children at risk of T1D. PMID:26975663

  3. Oral vaccination with an adenovirus-vectored vaccine protects against botulism

    PubMed Central

    Chen, Shan; Xu, Qingfu; Zeng, Mingtao

    2013-01-01

    We have previously shown that an adenovirus vectored vaccine delivered intramuscularly or intranasally was effective in protection against botulism in a mouse model. The adenoviral vector encodes a human codon-optimized heavy chain C-fragment (HC50) of botulinum neurotoxin type C (BoNT/C). Here, we evaluate the same vaccine candidate as an oral vaccine against BoNT/C in a mouse model. To elicit protective immunity, the mice were orally vaccinated with a single dose of 1×104 to 1×107 plaque forming units (pfu) of the adenoviral vector. The immune sera, collected six weeks after oral vaccination with 2×107 pfu adenovirus, has shown an ability to neutralize the biological activity of BoNT/C in vitro. Additionally, animals receiving a single dose of 2×106 pfu adenovirus or greater were completely protected against challenge with 100×MLD50 of BoNT/C. The data demonstrated the feasibility to develop an adenovirus-based oral vaccine against botulism. PMID:23295065

  4. Safety and Immunogenicity of Adenovirus 35 Tuberculosis Vaccine Candidate in Adults with Active or Previous Tuberculosis. A Randomized Trial.

    PubMed

    van Zyl-Smit, Richard N; Esmail, Aliasgar; Bateman, Mary E; Dawson, Rodney; Goldin, Jonathan; van Rikxoort, Eva; Douoguih, Macaya; Pau, Maria Grazia; Sadoff, Jerald C; McClain, J Bruce; Snowden, Margaret Ann; Benko, Jacqueline; Hokey, David A; Rutkowski, Kathryn Tucker; Graves, Andrew; Shepherd, Barbara; Ishmukhamedov, Sadritdin; Kagina, Benjamin M N; Abel, Brian; Hanekom, Willem A; Scriba, Thomas J; Bateman, Eric D

    2017-05-01

    Administration of tuberculosis (TB) vaccines in participants with previous or current pulmonary TB may have the potential for causing harmful postvaccination immunologic (Koch-type) reactions. To assess the safety and immunogenicity of three dose levels of the AERAS-402 live, replication-deficient adenovirus 35-vectored TB candidate vaccine, containing three mycobacterial antigens, in individuals with current or previous pulmonary TB. We performed a phase II randomized, placebo-controlled, double-blinded dose-escalation study in an HIV-negative adult South African cohort (n = 72) with active pulmonary TB (on treatment for 1-4 mo) or pulmonary TB treated at least 12 months before study entry and considered cured. Safety endpoints included clinical assessment, flow volume curves, diffusing capacity of the lung for carbon monoxide, pulse oximetry, chest radiograph, and high-resolution thoracic computerized tomography scans. Cytokine expression by CD4 and CD8 T cells, after stimulation with Ag85A, Ag85B, and TB10.4 peptide pools, was examined by intracellular cytokine staining. No apparent temporal or dose-related changes in clinical status (specifically acute, Koch phenomenon-like reactions), lung function, or radiology attributable to vaccine were observed. Injection site reactions were mild or moderate. Hematuria (by dipstick only) occurred in 25 (41%) of 61 AERAS-402 recipients and 3 (27%) of 11 placebo recipients, although no gross hematuria was reported. AERAS-402 induced robust CD8 + and moderate CD4 + T-cell responses, mainly to Ag85B in both vaccine groups. Administration of the AERAS-402 candidate TB vaccine to participants with current or previous pulmonary TB induced a robust immune response and is not associated with clinically significant pulmonary complications. Clinical trial registered with www.clinicaltrials.gov (NCT 02414828) and in the South African National Clinical Trials Register ( www.sanctr.gov.za DOH 27-0808-2060).

  5. 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

  6. Vaccines. An Ebola whole-virus vaccine is protective in nonhuman primates.

    PubMed

    Marzi, Andrea; Halfmann, Peter; Hill-Batorski, Lindsay; Feldmann, Friederike; Shupert, W Lesley; Neumann, Gabriele; Feldmann, Heinz; Kawaoka, Yoshihiro

    2015-04-24

    Zaire ebolavirus is the causative agent of the current outbreak of hemorrhagic fever disease in West Africa. Previously, we showed that a whole Ebola virus (EBOV) vaccine based on a replication-defective EBOV (EBOVΔVP30) protects immunized mice and guinea pigs against lethal challenge with rodent-adapted EBOV. Here, we demonstrate that EBOVΔVP30 protects nonhuman primates against lethal infection with EBOV. Although EBOVΔVP30 is replication-incompetent, we additionally inactivated the vaccine with hydrogen peroxide; the chemically inactivated vaccine remained antigenic and protective in nonhuman primates. EBOVΔVP30 thus represents a safe, efficacious, whole-EBOV vaccine candidate that differs from other EBOV vaccine platforms in that it presents all viral proteins and the viral RNA to the host immune system, which might contribute to protective immune responses. Copyright © 2015, American Association for the Advancement of Science.

  7. Detection of antigenic proteins expressed by lymphocystis virus as vaccine candidates in olive flounder, Paralichthys olivaceus (Temminck & Schlegel).

    PubMed

    Jang, H B; Kim, Y R; Cha, I S; Noh, S W; Park, S B; Ohtani, M; Hikima, J; Aoki, T; Jung, T S

    2011-07-01

    Although the major capsid proteins (MCPs) of lymphocystis disease virus (LCDV) have been characterized, little is known about the host-derived immune response to MCPs and other LCDV antigenic proteins. To identify antigenic proteins of LCDV that could be used as vaccine candidates in olive flounder, Paralichthys olivaceus, we analysed the viral proteins responsible for its virulence by applying immuno-proteomics. LCDV proteins were separated by one-dimensional gel electrophoresis, transferred to polyvinylidene difluoride membrane, and probed with homogeneous P. olivaceus antisera elicited by LCDV natural infection and vaccination with formalin-killed LCDV. Four immune-reactive proteins were obtained at 68-, 51-, 41- and 21 kDa using antisera collected from natural infection while two proteins at 51- and 21 kDa exhibited response to antisera from vaccinated fish, indicating that the latter two proteins have vaccine potential. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and nanoelectrospray MS/MS, the 51 and 21 kDa proteins were identified as MCP and an unknown protein, respectively. © 2011 Blackwell Publishing Ltd.

  8. Candid No. 1 Argentine Hemorrhagic Fever Vaccine Protects against Lethal Junin Virus Challenge in Rhesus Macaques

    DTIC Science & Technology

    1992-01-01

    HeLra Fever Vaccine Anna L. Kuhne Hemorrhagic Joan A. Spisso Protects against Lethal Junin Virus B.G. Mahlandt United States Army Medical Challenge in...live-attenuated vac- cine against Argentine hemorrhagic fever (AH F), was evaluated om in non-human primates. Twenty rhesus macaques immunized 3 months...nees that had received 3 logl,• PFU Candid No. I or fewer: all Argentine hemorrhagic fever others, including those receiving 127,200 PFU, maintained

  9. 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.

  10. Transcriptional changes induced by candidate malaria vaccines and correlation with protection against malaria in a human challenge model

    PubMed Central

    Dunachie, Susanna; Berthoud, Tamara; Hill, Adrian V.S.; Fletcher, Helen A.

    2015-01-01

    Introduction The complexity of immunity to malaria is well known, and clear correlates of protection against malaria have not been established. A better understanding of immune markers induced by candidate malaria vaccines would greatly enhance vaccine development, immunogenicity monitoring and estimation of vaccine efficacy in the field. We have previously reported complete or partial efficacy against experimental sporozoite challenge by several vaccine regimens in healthy malaria-naïve subjects in Oxford. These include a prime-boost regimen with RTS,S/AS02A and modified vaccinia virus Ankara (MVA) expressing the CSP antigen, and a DNA-prime, MVA-boost regimen expressing the ME TRAP antigens. Using samples from these trials we performed transcriptional profiling, allowing a global assessment of responses to vaccination. Methods We used Human RefSeq8 Bead Chips from Illumina to examine gene expression using PBMC (peripheral blood mononuclear cells) from 16 human volunteers. To focus on antigen-specific changes, comparisons were made between PBMC stimulated with CSP or TRAP peptide pools and unstimulated PBMC post vaccination. We then correlated gene expression with protection against malaria in a human Plasmodium falciparum malaria challenge model. Results Differentially expressed genes induced by both vaccine regimens were predominantly in the IFN-γ pathway. Gene set enrichment analysis revealed antigen-specific effects on genes associated with IFN induction and proteasome modules after vaccination. Genes associated with IFN induction and antigen presentation modules were positively enriched in subjects with complete protection from malaria challenge, while genes associated with haemopoietic stem cells, regulatory monocytes and the myeloid lineage modules were negatively enriched in protected subjects. Conclusions These results represent novel insights into the immune repertoires involved in malaria vaccination. PMID:26256523

  11. Current status of meningococcal group B vaccine candidates: capsular or noncapsular?

    PubMed

    Diaz Romero, J; Outschoorn, I M

    1994-10-01

    Meningococcal meningitis is a severe, life-threatening infection for which no adequate vaccine exists. Current vaccines, based on the group-specific capsular polysaccharides, provide short-term protection in adults against serogroups A and C but are ineffective in infants and do not induce protection against group B strains, the predominant cause of infection in western countries, because the purified serogroup B polysaccharide fails to elicit human bactericidal antibodies. Because of the poor immunogenicity of group B capsular polysaccharide, different noncapsular antigens have been considered for inclusion in a vaccine against this serogroup: outer membrane proteins, lipooligosaccharides, iron-regulated proteins, Lip, pili, CtrA, and the immunoglobulin A proteases. Alternatively, attempts to increase the immunogenicity of the capsular polysaccharide have been made by using noncovalent complexes with outer membrane proteins, chemical modifications, and structural analogs. Here, we review the strategies employed for the development of a vaccine for Neisseria meningitidis serogroup B; the difficulties associated with the different approaches are discussed.

  12. Current status of meningococcal group B vaccine candidates: capsular or noncapsular?

    PubMed Central

    Diaz Romero, J; Outschoorn, I M

    1994-01-01

    Meningococcal meningitis is a severe, life-threatening infection for which no adequate vaccine exists. Current vaccines, based on the group-specific capsular polysaccharides, provide short-term protection in adults against serogroups A and C but are ineffective in infants and do not induce protection against group B strains, the predominant cause of infection in western countries, because the purified serogroup B polysaccharide fails to elicit human bactericidal antibodies. Because of the poor immunogenicity of group B capsular polysaccharide, different noncapsular antigens have been considered for inclusion in a vaccine against this serogroup: outer membrane proteins, lipooligosaccharides, iron-regulated proteins, Lip, pili, CtrA, and the immunoglobulin A proteases. Alternatively, attempts to increase the immunogenicity of the capsular polysaccharide have been made by using noncovalent complexes with outer membrane proteins, chemical modifications, and structural analogs. Here, we review the strategies employed for the development of a vaccine for Neisseria meningitidis serogroup B; the difficulties associated with the different approaches are discussed. PMID:7834605

  13. 6-O-Branched Oligo-β-glucan-Based Antifungal Glycoconjugate Vaccines.

    PubMed

    Liao, Guochao; Zhou, Zhifang; Liao, Jun; Zu, Luning; Wu, Qiuye; Guo, Zhongwu

    2016-02-12

    With the rapid growth in fungal infections and drug-resistant fungal strains, antifungal vaccines have become an especially attractive strategy to tackle this important health problem. β-Glucans, a class of extracellular carbohydrate antigens abundantly and consistently expressed on fungal cell surfaces, are intriguing epitopes for antifungal vaccine development. β-Glucans have a conserved β-1,3-glucan backbone with sporadic β-1,3- or β-1,6-linked short glucans as branches at the 6-O-positions, and the branches may play a critical role in their immunologic functions. To study the immunologic properties of branched β-glucans and develop β-glucan-based antifungal vaccines, three branched β-glucan oligosaccharides with 6-O-linked β-1,6-tetraglucose, β-1,3-diglucose, and β-1,3-tetraglucose branches on a β-1,3-nonaglucan backbone, which mimic the structural epitopes of natural β-glucans, were synthesized and coupled with keyhole limpet hemocyanin (KLH) to form novel synthetic conjugate vaccines. These glycoconjugates were proved to elicit strong IgG antibody responses in mice. It was also discovered that the number, size, and structure of branches linked to the β-glucan backbone had a significant impact on the immunologic property. Moreover, antibodies induced by the synthetic oligosaccharide-KLH conjugates were able to recognize and bind to natural β-glucans and fungal cells. Most importantly, these conjugates elicited effective protection against systemic Candida albicans infection in mice. Thus, branched oligo-β-glucans were identified as functional epitopes for antifungal vaccine design and the corresponding protein conjugates as promising antifungal vaccine candidates.

  14. Next-generation dengue vaccines: novel strategies currently under development.

    PubMed

    Durbin, Anna P; Whitehead, Stephen S

    2011-10-01

    Dengue has become the most important arboviral infection worldwide with more than 30 million cases of dengue fever estimated to occur each year. The need for a dengue vaccine is great and several live attenuated dengue candidate vaccines are proceeding through clinical evaluation. The need to induce a balanced immune response against all four DENV serotypes with a single vaccine has been a challenge for dengue vaccine developers. A live attenuated DENV chimeric vaccine produced by Sanofi Pasteur has recently entered Phase III evaluation in numerous dengue-endemic regions of the world. Viral interference between serotypes contained in live vaccines has required up to three doses of the vaccine be given over a 12-month period of time. For this reason, novel DENV candidate vaccines are being developed with the goal of achieving a protective immune response with an immunization schedule that can be given over the course of a few months. These next-generation candidates include DNA vaccines, recombinant adenovirus vectored vaccines, alphavirus replicons, and sub-unit protein vaccines. Several of these novel candidates will be discussed.

  15. Prevention of bubonic and pneumonic plague using plant-derived vaccines.

    PubMed

    Alvarez, M Lucrecia; Cardineau, Guy A

    2010-01-01

    Yersinia pestis, the causative agent of bubonic and pneumonic plague, is an extremely virulent bacterium but there are currently no approved vaccines for protection against this organism. Plants represent an economical and safer alternative to fermentation-based expression systems for the production of therapeutic proteins. The recombinant plague vaccine candidates produced in plants are based on the two most immunogenic antigens of Y. pestis: the fraction-1 capsular antigen (F1) and the low calcium response virulent antigen (V) either in combination or as a fusion protein (F1-V). These antigens have been expressed in plants using all three known possible strategies: nuclear transformation, chloroplast transformation and plant-virus-based expression vectors. These plant-derived plague vaccine candidates were successfully tested in animal models using parenteral, oral, or prime/boost immunization regimens. This review focuses on the recent research accomplishments towards the development of safe and effective pneumonic and bubonic plague vaccines using plants as bioreactors.

  16. 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…

  17. Virus-like particle-based vaccine against coxsackievirus A6 protects mice against lethal infections.

    PubMed

    Shen, Chaoyun; Ku, Zhiqiang; Zhou, Yu; Li, Dapeng; Wang, Lili; Lan, Ke; Liu, Qingwei; Huang, Zhong

    2016-07-25

    Coxsackievirus A6 (CA6) is emerging as one of the major causative agents of hand, foot, and mouth disease (HFMD) worldwide. However, no vaccine is currently available for preventing CA6 infection. Here, we report the development of a virus-like particle (VLP)-based recombinant vaccine for CA6. We produced CA6 VLPs in insect cells by infecting the cells with a baculovirus coexpressing the genes encoding CA6 P1 and 3CD. Biochemical analyses showed that the produced VLPs consisted of VP0, VP1, and VP3 capsid subunit proteins generated by the cleavage of P1 by 3CD. Mice immunized with these VLPs produced CA6-specific serum antibodies. Passive transfer of antisera from CA6 VLP-immunized mice protected recipient mice from lethal infections caused by homologous and heterologous CA6 strains. Moreover, active immunization of mice with CA6 VLPs efficiently conferred protection against both homologous and heterologous CA6 infections. These results suggested that CA6 VLP-based recombinant vaccine is a promising candidate vaccine for preventing CA6 infection and can be incorporated into a multivalent HFMD vaccine formulation to achieve broad-spectrum and effective prevention of this disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. 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.

  19. 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.

  20. 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.

  1. Brucellosis vaccines based on the open reading frames from genomic island 3 of Brucella abortus.

    PubMed

    Gómez, Leonardo; Alvarez, Francisco; Betancur, Daniel; Oñate, Angel

    2018-05-17

    Brucella abortus is the etiological agent of brucellosis, a zoonotic disease affecting cattle and humans. This disease has been partially controlled in cattle by immunization with live attenuated B. abortus S19 and RB51 strains. However, use of these vaccine strains has been associated with safety issues in animals and humans. New vaccines have since emerged in the prevention of brucellosis, particularly DNA vaccines, which have shown effectiveness and a good safety profile. Their protection efficacy in mice is associated with the induction of Th1 type and cytotoxic T cell mediated immune response against structural antigens and virulence factors expressed during B. abortus infection. Some antigenic candidate for vaccine design against brucellosis (mainly DNA vaccines) have been obtained from genomic island 3 (GI-3) of B. abortus, which encodes several open reading frames (ORFs) involved in the intracellular survival and virulence of this pathogen. The immunogenicity and protection conferred by these DNA vaccines in a murine model is reviewed in this article, suggesting that some of them could be safe and effective vaccine candidates against to prevent B. abortus infection. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. Safety and immunogenicity of an AS01-adjuvanted varicella-zoster virus subunit candidate vaccine against herpes zoster in adults >=50 years of age.

    PubMed

    Chlibek, Roman; Bayas, José M; Collins, Harry; de la Pinta, Maria Luisa Rodriguez; Ledent, Edouard; Mols, Johann F; Heineman, Thomas C

    2013-12-15

    An adjuvanted varicella-zoster virus glycoprotein E (gE) subunit vaccine candidate for herpes zoster is in development. In this trial we compared the safety, reactogenicity, and immunogenicity of the vaccine antigen combined with different adjuvant doses. This was a phase II, observer-blind, randomized, multinational study. Adults ≥50 years old were randomized 4:4:2:1 to be vaccinated at months 0 and 2 with gE combined with a higher (AS01B) or lower (AS01E) dose adjuvant, unadjuvanted gE, or saline. Following each dose, solicited events were recorded for 7 days and unsolicited adverse events for 30 days. Serious adverse events were collected for 1 year. Cell-mediated and humoral immune responses were assessed at baseline and following each dose. No vaccine-related severe adverse events were reported. Solicited adverse events were generally mild to moderate and transient. For all gE-based vaccines, pain was the most common local symptom and fatigue the most common general symptom. Immune responses were significantly enhanced by AS01B and AS01E compared to unadjuvanted gE and were significantly stronger for gE/AS01B than for gE/AS01E. AS01 improved the immunogenicity of gE while retaining acceptable safety and reactogenicity profiles. The enhancement of gE-specific cellular and humoral responses was adjuvant dose dependent. NCT00802464.

  3. Vaccines for viral and bacterial pathogens causing acute gastroenteritis: Part I: Overview, vaccines for enteric viruses and Vibrio cholerae.

    PubMed

    O'Ryan, Miguel; Vidal, Roberto; del Canto, Felipe; Salazar, Juan Carlos; Montero, David

    2015-01-01

    Efforts to develop vaccines for prevention of acute diarrhea have been going on for more than 40 y with partial success. The myriad of pathogens, more than 20, that have been identified as a cause of acute diarrhea throughout the years pose a significant challenge for selecting and further developing the most relevant vaccine candidates. Based on pathogen distribution as identified in epidemiological studies performed mostly in low-resource countries, rotavirus, Cryptosporidium, Shigella, diarrheogenic E. coli and V. cholerae are predominant, and thus the main targets for vaccine development and implementation. Vaccination against norovirus is most relevant in middle/high-income countries and possibly in resource-deprived countries, pending a more precise characterization of disease impact. Only a few licensed vaccines are currently available, of which rotavirus vaccines have been the most outstanding in demonstrating a significant impact in a short time period. This is a comprehensive review, divided into 2 articles, of nearly 50 vaccine candidates against the most relevant viral and bacterial pathogens that cause acute gastroenteritis. In order to facilitate reading, sections for each pathogen are organized as follows: i) a discussion of the main epidemiological and pathogenic features; and ii) a discussion of vaccines based on their stage of development, moving from current licensed vaccines to vaccines in advanced stage of development (in phase IIb or III trials) to vaccines in early stages of clinical development (in phase I/II) or preclinical development in animal models. In this first article we discuss rotavirus, norovirus and Vibrio cholerae. In the following article we will discuss Shigella, Salmonella (non-typhoidal), diarrheogenic E. coli (enterotoxigenic and enterohemorragic), and Campylobacter jejuni.

  4. Vaccines for viral and bacterial pathogens causing acute gastroenteritis: Part I: Overview, vaccines for enteric viruses and Vibrio cholerae

    PubMed Central

    O’Ryan, Miguel; Vidal, Roberto; del Canto, Felipe; Salazar, Juan Carlos; Montero, David

    2015-01-01

    Efforts to develop vaccines for prevention of acute diarrhea have been going on for more than 40 y with partial success. The myriad of pathogens, more than 20, that have been identified as a cause of acute diarrhea throughout the years pose a significant challenge for selecting and further developing the most relevant vaccine candidates. Based on pathogen distribution as identified in epidemiological studies performed mostly in low-resource countries, rotavirus, Cryptosporidium, Shigella, diarrheogenic E. coli and V. cholerae are predominant, and thus the main targets for vaccine development and implementation. Vaccination against norovirus is most relevant in middle/high-income countries and possibly in resource-deprived countries, pending a more precise characterization of disease impact. Only a few licensed vaccines are currently available, of which rotavirus vaccines have been the most outstanding in demonstrating a significant impact in a short time period. This is a comprehensive review, divided into 2 articles, of nearly 50 vaccine candidates against the most relevant viral and bacterial pathogens that cause acute gastroenteritis. In order to facilitate reading, sections for each pathogen are organized as follows: i) a discussion of the main epidemiological and pathogenic features; and ii) a discussion of vaccines based on their stage of development, moving from current licensed vaccines to vaccines in advanced stage of development (in phase IIb or III trials) to vaccines in early stages of clinical development (in phase I/II) or preclinical development in animal models. In this first article we discuss rotavirus, norovirus and Vibrio cholerae. In the following article we will discuss Shigella, Salmonella (non-typhoidal), diarrheogenic E. coli (enterotoxigenic and enterohemorragic), and Campylobacter jejuni. PMID:25715048

  5. Prophylactic Hepatitis E Vaccine.

    PubMed

    Zhang, Jun; Zhao, Qinjian; Xia, Ningshao

    2016-01-01

    Hepatitis E has been increasingly recognized as an underestimated global disease burden in recent years. Subpopulations with more serious infection-associated damage or death include pregnant women, patients with basic liver diseases, and elderly persons. Vaccine would be the most effective means for prevention of HEV infection. The lack of an efficient cell culture system for HEV makes the development of classic inactive or attenuated vaccine infeasible. Hence, the recombinant vaccine approaches are explored deeply. The neutralizing sites are located almost exclusively in the capsid protein, pORF2, of the virion. Based on pORF2, many vaccine candidates showed potential of protecting primate animals; two of them were tested in human and evidenced to be well tolerated in adults and highly efficacious in preventing hepatitis E. The world's first hepatitis E vaccine, Hecolin ® (HEV 239 vaccine), was licensed in China and launched in 2012.

  6. Current State in the Development of Candidate Therapeutic HPV Vaccines

    PubMed Central

    Yang, Andrew; Jeang, Jessica; Cheng, Kevin; Cheng, Ting; Yang, Benjamin; Wu, T.-C.; Hung, Chien-Fu

    2016-01-01

    Summary The identification of human papillomavirus (HPV) as an etiological factor for HPV-associated malignancies creates the opportunity to control these cancers through vaccination. Currently, available preventive HPV vaccines have not yet demonstrated strong evidences for therapeutic effects against established HPV infections and lesions. Furthermore, HPV infections remain extremely common. Thus, there is urgent need for therapeutic vaccines to treat existing HPV infections and HPV-associated diseases. Therapeutic vaccines differ from preventive vaccines in that they are aimed at generating cell-mediated immunity rather than neutralizing antibodies. The HPV-encoded early proteins, especially oncoproteins E6 and E7, form ideal targets for therapeutic HPV vaccines since they are consistently expressed in HPV-associated malignancies and precancerous lesions, playing crucial roles in the generation and maintenance of HPV-associated disease. Our review will cover various therapeutic vaccines in development for the treatment of HPV-associated lesions and cancers. Furthermore, we review strategies to enhance vaccine efficacy and the latest clinical trials on therapeutic HPV vaccines. PMID:26901118

  7. Pathogenicity testing of influenza candidate vaccine viruses in the ferret model.

    PubMed

    Belser, Jessica A; Johnson, Adam; Pulit-Penaloza, Joanna A; Pappas, Claudia; Pearce, Melissa B; Tzeng, Wen-Pin; Hossain, M Jaber; Ridenour, Callie; Wang, Li; Chen, Li-Mei; Wentworth, David E; Katz, Jacqueline M; Maines, Taronna R; Tumpey, Terrence M

    2017-11-01

    The development of influenza candidate vaccine viruses (CVVs) for pre-pandemic vaccine production represents a critical step in pandemic preparedness. The multiple subtypes and clades of avian or swine origin influenza viruses circulating world-wide at any one time necessitates the continuous generation of CVVs to provide an advanced starting point should a novel zoonotic virus cross the species barrier and cause a pandemic. Furthermore, the evolution and diversity of novel influenza viruses that cause zoonotic infections requires ongoing monitoring and surveillance, and, when a lack of antigenic match between circulating viruses and available CVVs is identified, the production of new CVVs. Pandemic guidelines developed by the WHO Global Influenza Program govern the design and preparation of reverse genetics-derived CVVs, which must undergo numerous safety and quality tests prior to human use. Confirmation of reassortant CVV attenuation of virulence in ferrets relative to wild-type virus represents one of these critical steps, yet there is a paucity of information available regarding the relative degree of attenuation achieved by WHO-recommended CVVs developed against novel viruses with pandemic potential. To better understand the degree of CVV attenuation in the ferret model, we examined the relative virulence of six A/Puerto Rico/8/1934-based CVVs encompassing five different influenza A subtypes (H2N3, H5N1, H5N2, H5N8, and H7N9) compared with the respective wild-type virus in ferrets. Despite varied virulence of wild-type viruses in the ferret, all CVVs examined showed reductions in morbidity and viral shedding in upper respiratory tract tissues. Furthermore, unlike the wild-type counterparts, none of the CVVs spread to extrapulmonary tissues during the acute phase of infection. While the magnitude of virus attenuation varied between virus subtypes, collectively we show the reliable and reproducible attenuation of CVVs that have the A/Puerto Rico/9/1934 backbone

  8. Pathogenicity testing of influenza candidate vaccine viruses in the ferret model

    PubMed Central

    Belser, Jessica A.; Johnson, Adam; Pulit-Penaloza, Joanna A.; Pappas, Claudia; Pearce, Melissa B.; Tzeng, Wen-Pin; Hossain, M. Jaber; Ridenour, Callie; Wang, Li; Chen, Li-Mei; Wentworth, David E.; Katz, Jacqueline M.; Maines, Taronna R.; Tumpey, Terrence M.

    2018-01-01

    The development of influenza candidate vaccine viruses (CVVs) for pre-pandemic vaccine production represents a critical step in pandemic preparedness. The multiple subtypes and clades of avian or swine origin influenza viruses circulating world-wide at any one time necessitates the continuous generation of CVVs to provide an advanced starting point should a novel zoonotic virus cross the species barrier and cause a pandemic. Furthermore, the evolution and diversity of novel influenza viruses that cause zoonotic infections requires ongoing monitoring and surveillance, and, when a lack of antigenic match between circulating viruses and available CVVs is identified, the production of new CVVs. Pandemic guidelines developed by the WHO Global Influenza Program govern the design and preparation of reverse genetics-derived CVVs, which must undergo numerous safety and quality tests prior to human use. Confirmation of reassortant CVV attenuation of virulence in ferrets relative to wild-type virus represents one of these critical steps, yet there is a paucity of information available regarding the relative degree of attenuation achieved by WHO-recommended CVVs developed against novel viruses with pandemic potential. To better understand the degree of CVV attenuation in the ferret model, we examined the relative virulence of six A/Puerto Rico/8/1934-based CVVs encompassing five different influenza A subtypes (H2N3, H5N1, H5N2, H5N8, and H7N9) compared with the respective wild-type virus in ferrets. Despite varied virulence of wild-type viruses in the ferret, all CVVs examined showed reductions in morbidity and viral shedding in upper respiratory tract tissues. Furthermore, unlike the wild-type counterparts, none of the CVVs spread to extrapulmonary tissues during the acute phase of infection. While the magnitude of virus attenuation varied between virus subtypes, collectively we show the reliable and reproducible attenuation of CVVs that have the A/Puerto Rico/9/1934 backbone

  9. Tuberculosis vaccine development: strength lies in tenacity.

    PubMed

    Kaufmann, Stefan H E

    2012-07-01

    The past decade has witnessed a tremendous increase in the development of novel vaccines against tuberculosis (TB). In mice, each of these vaccine candidates stimulates an immune response that reduces the bacillary load, reflecting control but not sterilization of infection. Yet, the immune mechanisms underlying vaccine efficacy are only partially understood. In parallel to clinical assessment of current candidates, the next generation of vaccine candidates still needs to be developed. This requires basic research on how to induce the most efficacious immune response. Equally important is the dissection of immune responses in patients, latently infected healthy individuals, and participants of clinical vaccine trials. Amalgamation of this information will foster the way towards more efficacious vaccination strategies that not only prevent disease, but prevent or abolish infection. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Transcriptional changes induced by candidate malaria vaccines and correlation with protection against malaria in a human challenge model.

    PubMed

    Dunachie, Susanna; Berthoud, Tamara; Hill, Adrian V S; Fletcher, Helen A

    2015-09-29

    The complexity of immunity to malaria is well known, and clear correlates of protection against malaria have not been established. A better understanding of immune markers induced by candidate malaria vaccines would greatly enhance vaccine development, immunogenicity monitoring and estimation of vaccine efficacy in the field. We have previously reported complete or partial efficacy against experimental sporozoite challenge by several vaccine regimens in healthy malaria-naïve subjects in Oxford. These include a prime-boost regimen with RTS,S/AS02A and modified vaccinia virus Ankara (MVA) expressing the CSP antigen, and a DNA-prime, MVA-boost regimen expressing the ME TRAP antigens. Using samples from these trials we performed transcriptional profiling, allowing a global assessment of responses to vaccination. We used Human RefSeq8 Bead Chips from Illumina to examine gene expression using PBMC (peripheral blood mononuclear cells) from 16 human volunteers. To focus on antigen-specific changes, comparisons were made between PBMC stimulated with CSP or TRAP peptide pools and unstimulated PBMC post vaccination. We then correlated gene expression with protection against malaria in a human Plasmodium falciparum malaria challenge model. Differentially expressed genes induced by both vaccine regimens were predominantly in the IFN-γ pathway. Gene set enrichment analysis revealed antigen-specific effects on genes associated with IFN induction and proteasome modules after vaccination. Genes associated with IFN induction and antigen presentation modules were positively enriched in subjects with complete protection from malaria challenge, while genes associated with haemopoietic stem cells, regulatory monocytes and the myeloid lineage modules were negatively enriched in protected subjects. These results represent novel insights into the immune repertoires involved in malaria vaccination. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  11. Surface proteome mining for identification of potential vaccine candidates against Campylobacter jejuni: an in silico approach.

    PubMed

    Mehla, Kusum; Ramana, Jayashree

    2017-01-01

    Campylobacter jejuni remains a major cause of human gastroenteritis with estimated annual incidence rate of 450 million infections worldwide. C. jejuni is a major burden to public health in both socioeconomically developing and industrialized nations. Virulence determinants involved in C. jejuni pathogenesis are multifactorial in nature and not yet fully understood. Despite the completion of the first C. jejuni genome project in 2000, there are currently no vaccines in the market against this pathogen. Traditional vaccinology approach is an arduous and time extensive task. Omics techniques coupled with sequencing data have engaged researcher's attention to reduce the time and resources applied in the process of vaccine development. Recently, there has been remarkable increase in development of in silico analysis tools for efficiently mining biological information obscured in the genome. In silico approaches have been crucial for combating infectious diseases by accelerating the pace of vaccine development. This study employed a range of bioinformatics approaches for proteome scale identification of peptide vaccine candidates. Whole proteome of C. jejuni was investigated for varied properties like antigenicity, allergenicity, major histocompatibility class (MHC)-peptide interaction, immune cell processivity, HLA distribution, conservancy, and population coverage. Predicted epitopes were further tested for binding in MHC groove using computational docking studies. The predicted epitopes were conserved; covered more than 80 % of the world population and were presented by MHC-I supertypes. We conclude by underscoring that the epitopes predicted are believed to expedite the development of successful vaccines to control or prevent C. jejuni infections albeit the results need to be experimentally validated.

  12. Comparative preclinical evaluation of AS01 versus other Adjuvant Systems in a candidate herpes zoster glycoprotein E subunit vaccine.

    PubMed

    Fochesato, Michel; Dendouga, Najoua; Boxus, Mathieu

    2016-08-02

    The candidate vaccine HZ/su is being developed to prevent herpes-zoster disease (HZ). HZ occurrence is attributed to declines in varicella-zoster virus (VZV) specific T-cell immunity. HZ/su contains VZV antigen, gE, and Adjuvant System AS01 B (liposome-based formulation of MPL and QS-21). In clinical trials, AS01 B enhances CD4 + T-cell responses to gE. In clinical trials of other vaccines, Adjuvant Systems AS03 and AS04 also enhance antigen-specific CD4 + T-cell responses. Hence the purpose of this study was to evaluate gE formulated with AS01 B , AS01 E (50% less MPL and QS-21 than AS01 B ), AS03 or AS04 in C57BL6 mice primed with live-attenuated VZV. Four-weeks post-vaccination, the gE-specific CD4 + T-cell response to gE/AS01 B was 5.4, 2.8 and 2.2-fold greater than those to gE/AS03, gE/AS04 and gE/AS03, respectively (p<0.001). Therefore in the VZV-primed mouse model, CD4 + T-cell responses to gE appeared most enhanced by AS01 B , and adds further support for the use of AS01 B in the HZ/su formulation.

  13. [Comparison of protective properties of the smallpox DNA-vaccine based on the variola virus A30L gene and its variant with modified codon usage].

    PubMed

    Maksiutov, R A; Shchelkunov, S N

    2011-01-01

    Efficacy of candidate DNA-vaccines based on the variola virus natural gene A30L and artificial gene A30Lopt with modified codon usage, optimized for expression in mammalian cells, was tested. The groups of mice were intracutaneously immunized three times with three-week intervals with candidate DNA-vaccines: pcDNA_A30L or pcDNA_A30Lopt, and in three weeks after the last immunization all mice in the groups were intraperitoneally infected by the ectromelia virus K1 strain in 10 LD50 dose for the estimation of protection. It was shown that the DNA-vaccines based on natural gene A30L and codon-optimized gene A30Lopt elicited virus, thereby neutralizing the antibody response and protected mice from lethal intraperitoneal challenge with the ectromelia virus with lack of statistically significant difference.

  14. Identifying gnostic predictors of the vaccine response

    PubMed Central

    Haining, W. Nicholas; Pulendran, Bali

    2012-01-01

    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 for 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 outcome classification. 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. PMID:22633886

  15. Safety and immunogenicity of candidate vaccine M72/AS01E in adolescents in a TB endemic setting.

    PubMed

    Penn-Nicholson, Adam; Geldenhuys, Hennie; Burny, Wivine; van der Most, Robbert; Day, Cheryl L; Jongert, Erik; Moris, Philippe; Hatherill, Mark; Ofori-Anyinam, Opokua; Hanekom, Willem; Bollaerts, Anne; Demoitie, Marie-Ange; Kany Luabeya, Angelique Kany; De Ruymaeker, Evi; Tameris, Michele; Lapierre, Didier; Scriba, Thomas J

    2015-07-31

    Vaccination that prevents tuberculosis (TB) disease, particularly in adolescents, would have the greatest impact on the global TB epidemic. Safety, reactogenicity and immunogenicity of the vaccine candidate M72/AS01E was evaluated in healthy, HIV-negative adolescents in a TB endemic region, regardless of Mycobacterium tuberculosis (M.tb) infection status. In a phase II, double-blind randomized, controlled study (NCT00950612), two doses of M72/AS01E or placebo were administered intramuscularly, one month apart. Participants were followed-up post-vaccination, for 6 months. M72-specific immunogenicity was evaluated by intracellular cytokine staining analysis of T cells and NK cells by flow cytometry. No serious adverse events were recorded. M72/AS01E induced robust T cell and antibody responses, including antigen-dependent NK cell IFN-γ production. CD4 and CD8 T cell responses were sustained at 6 months post vaccination. Irrespective of M.tb infection status, vaccination induced a high frequency of M72-specific CD4 T cells expressing multiple combinations of Th1 cytokines, and low level IL-17. We observed rapid boosting of immune responses in M.tb-infected participants, suggesting natural infection acts as a prime to vaccination. The clinically acceptable safety and immunogenicity profile of M72/AS01E in adolescents living in an area with high TB burden support the move to efficacy trials. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  16. Safety and immunogenicity of candidate vaccine M72/AS01E in adolescents in a TB endemic setting

    PubMed Central

    Penn-Nicholson, Adam; Geldenhuys, Hennie; Burny, Wivine; van der Most, Robbert; Day, Cheryl L.; Jongert, Erik; Moris, Philippe; Hatherill, Mark; Ofori-Anyinam, Opokua; Hanekom, Willem

    2018-01-01

    Background Vaccination that prevents tuberculosis (TB) disease, particularly in adolescents, would have the greatest impact on the global TB epidemic. Safety, reactogenicity and immunogenicity of the vaccine candidate M72/AS01E was evaluated in healthy, HIV-negative adolescents in a TB endemic region, regardless of Mycobacterium tuberculosis (M.tb) infection status. Methods In a phase II, double-blind randomized, controlled study (NCT00950612), two doses of M72/AS01E or placebo were administered intramuscularly, one month apart. Participants were followed-up post-vaccination, for 6 months. M72-specific immunogenicity was evaluated by intracellular cytokine staining analysis of T cells and NK cells by flow cytometry. Results No serious adverse events were recorded. M72/AS01E induced robust T cell and antibody responses, including antigen-dependent NK cell IFN-γ production. CD4 and CD8 T cell responses were sustained at 6 months post vaccination. Irrespective of M.tb infection status, vaccination induced a high frequency of M72-specific CD4 T cells expressing multiple combinations of Th1 cytokines, and low level IL-17. We observed rapid boosting of immune responses in M.tb-infected participants, suggesting natural infection acts as a prime to vaccination. Conclusions The clinically acceptable safety and immunogenicity profile of M72/AS01E in adolescents living in an area with high TB burden support the move to efficacy trials. PMID:26072017

  17. Correlation between anthrax lethal toxin neutralizing antibody levels and survival in guinea pigs and nonhuman primates vaccinated with the AV7909 anthrax vaccine candidate.

    PubMed

    Savransky, Vladimir; Shearer, Jeffry D; Gainey, Melicia R; Sanford, Daniel C; Sivko, Gloria S; Stark, Gregory V; Li, Na; Ionin, Boris; Lacy, Michael J; Skiadopoulos, Mario H

    2017-09-05

    The anthrax vaccine candidate AV7909 is being developed as a next generation vaccine for a post-exposure prophylaxis (PEP) indication against anthrax. AV7909 consists of the Anthrax Vaccine Adsorbed (AVA, BioThrax®) bulk drug substance adjuvanted with the immunostimulatory oligodeoxynucleotide (ODN) compound, CPG 7909. The addition of CPG 7909 to AVA enhances both the magnitude and the kinetics of antibody responses in animals and human subjects, making AV7909 a suitable next-generation vaccine for use in a PEP setting. The studies described here provide initial information on AV7909-induced toxin-neutralizing antibody (TNA) levels associated with the protection of animals from lethal Bacillus anthracis challenge. Guinea pigs or nonhuman primates (NHPs) were immunized on Days 0 and 28 with various dilutions of AV7909, AVA or a saline or Alhydrogel+CPG 7909 control. Animals were challenged via the inhalational route with a lethal dose of aerosolized B. anthracis (Ames strain) spores and observed for clinical signs of disease and mortality. The relationship between pre-challenge serum TNA levels and survival following challenge was determined in order to calculate a threshold TNA level associated with protection. Immunisation with AV7909 induced a rapid, highly protective TNA response in guinea pigs and NHPs. Surprisingly, the TNA threshold associated with a 70% probability of survival for AV7909 immunized animals was substantially lower than the threshold which has been established for the licensed AVA vaccine. The results of this study suggest that the TNA threshold of protection against anthrax could be modified by the addition of an immune stimulant such as CPG 7909 and that the TNA levels associated with protection may be vaccine-specific. Copyright © 2017. Published by Elsevier Ltd.

  18. 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.

  19. Current status of Zika vaccine development: Zika vaccines advance into clinical evaluation.

    PubMed

    Barrett, Alan D T

    2018-01-01

    Zika virus (ZIKV), a mosquito-borne flavivirus, was first identified in the 1940s in Uganda in Africa and emerged in the Americas in Brazil in May 2015. In the 30 months since ZIKV emerged as a major public health problem, spectacular progress has been made with vaccine development cumulating with the publication of three reports of phase 1 clinical trials in the 4th quarter of 2017. Clinical trials involving candidate DNA and purified inactivated virus vaccines showed all were safe and well-tolerated in the small number of volunteers and all induced neutralizing antibodies, although these varied by vaccine candidate and dosing regimen. These results suggest that a Zika vaccine can be developed and that phase 2 clinical trials are warranted. However, it is difficult to compare the results from the different phase 1 studies or with neutralizing antibodies induced by licensed flavivirus vaccines (Japanese encephalitis, tick-borne encephalitis, and yellow fever) as neutralizing antibody assays vary and, unfortunately, there are no standards for Zika virus neutralizing antibodies. In addition to clinical studies, substantial progress continues to be made in nonclinical development, particularly in terms of the ability of candidate vaccines to protect reproductive tissues, and the potential use of monoclonal antibodies for passive prophylaxis.

  20. Protective effects of a Modified Vaccinia Ankara-based vaccine candidate against Crimean-Congo Haemorrhagic Fever virus require both cellular and humoral responses.

    PubMed

    Dowall, Stuart D; Graham, Victoria A; Rayner, Emma; Hunter, Laura; Watson, Robert; Taylor, Irene; Rule, Antony; Carroll, Miles W; Hewson, Roger

    2016-01-01

    Crimean-Congo Haemorrhagic Fever (CCHF) is a severe tick-borne disease, endemic in many countries in Africa, the Middle East, Eastern Europe and Asia. There is no approved vaccine currently available against CCHF. The most promising candidate, which has previously been shown to confer protection in the small animal model, is a modified Vaccinia Ankara virus vector expressing the CCHF viral glycoprotein (MVA-GP). It has been shown that MVA-GP induces both humoral and cellular immunogenicity. In the present study, sera and T-lymphocytes were passively and adoptively transferred into recipient mice prior to challenge with CCHF virus. Results demonstrated that mediators from both arms of the immune system were required to demonstrate protective effects against lethal challenge.

  1. Assessment of Lactobacillus gasseri as a candidate oral vaccine vector.

    PubMed

    Stoeker, Laura; Nordone, Shila; Gunderson, Sara; Zhang, Lin; Kajikawa, Akinobu; LaVoy, Alora; Miller, Michael; Klaenhammer, Todd R; Dean, Gregg A

    2011-11-01

    Lactobacillus species are commensal bacteria that have long been recognized as probiotic microbes and are generally regarded as safe (GRAS) for human consumption. We have investigated the use of L. gasseri as a vaccine vector for oral immunization against mucosal pathogens. Recent research has shown that the immune response to different lactobacilli can vary widely depending on the species or subspecies of Lactobacillus being studied. While some lactobacilli seem to induce oral tolerance, others induce an adaptive immune response. This study characterized the systemic and mucosal immune response to wild-type and genetically modified L. gasseri. L. gasseri primarily activates TLR2/6, with additional activation through the TLR2 homodimer. To expand the Toll-like receptor (TLR) activation profile of L. gasseri and the immunogenicity of the vector, a plasmid containing fliC, the gene encoding bacterial flagellin, was introduced which resulted in the strong activation of TLR5. The treatment of human myeloid dendritic cells with recombinant lactobacilli expressing flagellin triggered phenotypic maturation and the release of proinflammatory cytokines. In contrast, bacterial treatment also resulted in a statistically significant increase in IL-10 production. In vivo studies established that treatment with L. gasseri led to a diversification of B-cell populations in the lamina propria of the murine colon. Furthermore, treatment with genetically modified L. gasseri led to a significant decrease in the percentage of FoxP3(+) colonic lymphocytes. Taken together, these data clarify the interaction of L. gasseri with the host immune system and support further investigation of the in vivo immunogenicity of L. gasseri expressing both flagellin and candidate vaccine antigens.

  2. New vaccines against otitis media: projected benefits and cost-effectiveness.

    PubMed

    O'Brien, Megan A; Prosser, Lisa A; Paradise, Jack L; Ray, G Thomas; Kulldorff, Martin; Kurs-Lasky, Marcia; Hinrichsen, Virginia L; Mehta, Jyotsna; Colborn, D Kathleen; Lieu, Tracy A

    2009-06-01

    New vaccines that offer protection against otitis media caused by nontypeable Haemophilus influenzae and by Moraxella catarrhalis are under development. However, the potential health benefits and economic effects of such candidate vaccines have not been systematically assessed. We created a computerized model to compare the projected benefits and costs of (1) the currently available 7-valent pneumococcal conjugate vaccine, (2) a candidate pneumococcal-nontypeable H influenzae vaccine that has been tested in Europe, (3) a hypothetical pneumococcal-nontypeable H influenzae-Moraxella vaccine, and (4) no vaccination. The clinical probabilities of acute otitis media and of otitis media with effusion were generated from multivariate analyses of data from 2 large health maintenance organizations and from the Pittsburgh Child Development/Otitis Media Study cohort. Other probabilities, costs, and quality-of-life values were derived from published and unpublished sources. The base-case analysis assumed vaccine dose costs of $65 for the 7-valent pneumococcal conjugate vaccine, $100 for the pneumococcal-nontypeable H influenzae vaccine, and $125 for the pneumococcal-nontypeable H influenzae-Moraxella vaccine. With no vaccination, we projected that 13.7 million episodes of acute otitis media would occur annually in US children aged 0 to 4 years, at an annual cost of $3.8 billion. The 7-valent pneumococcal conjugate vaccine was projected to prevent 878,000 acute otitis media episodes, or 6.4% of those that would occur with no vaccination; the corresponding value for the pneumococcal-nontypeable H influenzae vaccine was 3.7 million (27%) and for the pneumococcal-nontypeable H influenzae-Moraxella vaccine was 4.2 million (31%). Using the base-case vaccine costs, pneumococcal-nontypeable H influenzae vaccine use would result in net savings compared with nontypeable 7-valent pneumococcal conjugate use. Conversely, pneumococcal-nontypeable H influenzae-Moraxella vaccine use would not

  3. Human papillomavirus vaccines and vaccine implementation.

    PubMed

    de Sanjosé, Silvia; Alemany, Laia; Castellsagué, Xavier; Bosch, F Xavier

    2008-11-01

    Countries are now challenged by the rapid development of vaccines aimed at the primary prevention of infections. In the years to come, several vaccines will need to be considered as potential candidates in routine immunization programs. Recently, two new vaccines against two/four types of human papillomavirus (HPV) have been commercialized. Bivalent HPV 16 and 18 (Cervarix) and quadrivalent HPV 6, 11, 16 and 18 (Gardasil) vaccines are now extensively used in some countries. These vaccines will prevent infection and long-running complications, such as cervical cancer, other HPV-related cancers and genital warts (for the quadrivalent vaccine). The beneficial effect of these vaccines will be largely observed in women. This article summarizes the burden of HPV preventable disease worldwide and briefly describes the impact of secondary prevention and the most relevant aspects of the current available vaccines, their efficacy and safety. Finally, some major aspects that are likely to impact the introduction of these vaccines around the world are outlined, with particular emphasis on developing countries.

  4. Differing Efficacies of Lead Group A Streptococcal Vaccine Candidates and Full-Length M Protein in Cutaneous and Invasive Disease Models

    PubMed Central

    Rivera-Hernandez, Tania; Pandey, Manisha; Henningham, Anna; Cole, Jason; Choudhury, Biswa; Cork, Amanda J.; Gillen, Christine M.; Ghaffar, Khairunnisa Abdul; West, Nicholas P.; Silvestri, Guido; Good, Michael F.; Moyle, Peter M.; Toth, Istvan; Nizet, Victor; Batzloff, Michael R.

    2016-01-01

    ABSTRACT Group A Streptococcus (GAS) is an important human pathogen responsible for both superficial infections and invasive diseases. Autoimmune sequelae may occur upon repeated infection. For this reason, development of a vaccine against GAS represents a major challenge, since certain GAS components may trigger autoimmunity. We formulated three combination vaccines containing the following: (i) streptolysin O (SLO), interleukin 8 (IL-8) protease (Streptococcus pyogenes cell envelope proteinase [SpyCEP]), group A streptococcal C5a peptidase (SCPA), arginine deiminase (ADI), and trigger factor (TF); (ii) the conserved M-protein-derived J8 peptide conjugated to ADI; and (iii) group A carbohydrate lacking the N-acetylglucosamine side chain conjugated to ADI. We compared these combination vaccines to a “gold standard” for immunogenicity, full-length M1 protein. Vaccines were adjuvanted with alum, and mice were immunized on days 0, 21, and 28. On day 42, mice were challenged via cutaneous or subcutaneous routes. High-titer antigen-specific antibody responses with bactericidal activity were detected in mouse serum samples for all vaccine candidates. In comparison with sham-immunized mice, all vaccines afforded protection against cutaneous challenge. However, only full-length M1 protein provided protection in the subcutaneous invasive disease model. PMID:27302756

  5. 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.

  6. Immunogenicity and in vitro Protective Efficacy of a Recombinant Multistage Plasmodium falciparum Candidate Vaccine

    NASA Astrophysics Data System (ADS)

    Shi, Ya Ping; Hasnain, Seyed E.; Sacci, John B.; Holloway, Brian P.; Fujioka, Hisashi; Kumar, Nirbhay; Wohlhueter, Robert; Hoffman, Stephen L.; Collins, William E.; Lal, Altaf A.

    1999-02-01

    Compared with a single-stage antigen-based vaccine, a multistage and multivalent Plasmodium falciparum vaccine would be more efficacious by inducing "multiple layers" of immunity. We have constructed a synthetic gene that encodes for 12 B cell, 6 T cell proliferative, and 3 cytotoxic T lymphocyte epitopes derived from 9 stage-specific P. falciparum antigens corresponding to the sporozoite, liver, erythrocytic asexual, and sexual stages. The gene was expressed in the baculovirus system, and a 41-kDa antigen, termed CDC/NIIMALVAC-1, was purified. Immunization in rabbits with the purified protein in the presence of different adjuvants generated antibody responses that recognized vaccine antigen, linear peptides contained in the vaccine, and all stages of P. falciparum. In vitro assays of protection revealed that the vaccine-elicited antibodies strongly inhibited sporozoite invasion of hepatoma cells and growth of blood-stage parasites in the presence of monocytes. These observations demonstrate that a multicomponent, multistage malaria vaccine can induce immune responses that inhibit parasite development at multiple stages. The rationale and approach used in the development of a multicomponent P. falciparum vaccine will be useful in the development of a multispecies human malaria vaccine and vaccines against other infectious diseases.

  7. Malaria vaccines: past, present and future.

    PubMed

    von Seidlein, Lorenz; Bejon, Philip

    2013-12-01

    The currently available malaria control tools have allowed malaria elimination in many regions but there remain many regions where malaria control has made little progress. A safe and protective malaria vaccine would be a huge asset for malaria control. Despite the many challenges, efforts continue to design and evaluate malaria vaccine candidates. These candidates target different stages in the life cycle of Plasmodia. The most advanced vaccine candidates target the pre-erythrocytic stages in the life cycle of the parasite and include RTS,S/AS01, which has progressed through clinical development to the stage that it may be licensed in 2015. Attenuated whole-parasite vaccine candidates are highly protective, but there are challenges to manufacture and to administration. Cellular immunity is targeted by the prime-boost approach. Priming vectors trigger only modest responses but these are focused on the recombinant antigen. Boosting vectors trigger strong but broad non-specific responses. The heterologous sequence produces strong immunological responses to the recombinant antigen. Candidates that target the blood stages of the parasite have to result in an immune response that is more effective than the response to an infection to abort or control the infection of merozoites and hence disease. Finally, the sexual stages of the parasite offer another target for vaccine development, which would prevent the transmission of malaria. Today it seems unlikely that any candidate targeting a single antigen will provide complete protection against an organism of the complexity of Plasmodium. A systematic search for vaccine targets and combinations of antigens may be a more promising approach.

  8. Status of prophylactic and therapeutic genital herpes vaccines.

    PubMed

    Awasthi, Sita; Friedman, Harvey M

    2014-06-01

    A half billion people have genital herpes infections worldwide. Approximately one-fifth of American women between ages 14 and 49 are HSV-2 seropositive. The development of an effective genital herpes vaccine is a global health necessity based on the mental anguish genital herpes causes for some individuals, the fact that pregnant women with genital herpes risk transmitting infection to their newborn children, and the observation that HSV-2 infection is associated with a 3-fold to 4-fold increased probability of HIV acquisition. We review the strengths and limitations of preclinical animal models used to assess genital herpes vaccine candidates and the goals of prophylactic and therapeutic vaccines. We also discuss the current pipeline of vaccine candidates and lessons learned from past clinical trials that serve as a stimulus for new strategies, study designs and endpoint determinations. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Vaccine strategies against Babesia bovis based on prime-boost immunizations in mice with modified vaccinia Ankara vector and recombinant proteins.

    PubMed

    Jaramillo Ortiz, José Manuel; Del Médico Zajac, María Paula; Zanetti, Flavia Adriana; Molinari, María Paula; Gravisaco, María José; Calamante, Gabriela; Wilkowsky, Silvina Elizabeth

    2014-08-06

    In this study, a recombinant modified vaccinia virus Ankara vector expressing a chimeric multi-antigen was obtained and evaluated as a candidate vaccine in homologous and heterologous prime-boost immunizations with a recombinant protein cocktail. The chimeric multi-antigen comprises immunodominant B and T cell regions of three Babesia bovis proteins. Humoral and cellular immune responses were evaluated in mice to compare the immunogenicity induced by different immunization schemes. The best vaccination scheme was achieved with a prime of protein cocktail and a boost with the recombinant virus. This scheme induced high level of specific IgG antibodies and secreted IFN and a high degree of activation of IFNγ(+) CD4(+) and CD8(+) specific T cells. This is the first report in which a novel vaccine candidate was constructed based on a rationally designed multi-antigen and evaluated in a prime-boost regime, optimizing the immune response necessary for protection against bovine babesiosis. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Deletion of nuoG from the Vaccine Candidate Mycobacterium bovis BCG ΔureC::hly Improves Protection against Tuberculosis

    PubMed Central

    Gengenbacher, Martin; Nieuwenhuizen, Natalie; Vogelzang, Alexis; Liu, Haipeng; Kaiser, Peggy; Schuerer, Stefanie; Lazar, Doris; Wagner, Ina; Mollenkopf, Hans-Joachim

    2016-01-01

    ABSTRACT The current tuberculosis (TB) vaccine, Mycobacterium bovis Bacillus Calmette-Guérin (BCG), provides insufficient protection against pulmonary TB. Previously, we generated a listeriolysin-expressing recombinant BCG strain, which to date has successfully completed phase I and phase IIa clinical trials. In an attempt to further improve efficacy, we deleted the antiapoptotic virulence gene nuoG, encoding NADH dehydrogenase 1 subunit G, from BCG ΔureC::hly. In vitro, deletion of nuoG unexpectedly led to strongly increased recruitment of the autophagosome marker LC3 to the engulfed vaccine, suggesting that nuoG also affects xenophagic pathways. In mice, BCG ΔureC::hly ΔnuoG vaccination was safer than BCG and improved protection over that of parental BCG ΔureC::hly, significantly reducing TB load in murine lungs, ameliorating pulmonary pathology, and enhancing immune responses. Transcriptome analysis of draining lymph nodes after vaccination with either BCG ΔureC::hly or BCG ΔureC::hly ΔnuoG demonstrated earlier and stronger induction of immune responses than that with BCG SSI and suggested upregulation of inflammasome activation and interferon-induced GTPases. In summary, BCG ΔureC::hly ΔnuoG is a promising next-generation TB vaccine candidate with excellent efficacy and safety. PMID:27222470

  11. 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.

  12. Gene constellation of influenza A virus reassortants with high growth phenotype prepared as seed candidates for vaccine production.

    PubMed

    Fulvini, Andrew A; Ramanunninair, Manojkumar; Le, Jianhua; Pokorny, Barbara A; Arroyo, Jennifer Minieri; Silverman, Jeanmarie; Devis, Rene; Bucher, Doris

    2011-01-01

    Influenza A virus vaccines undergo yearly reformulations due to the antigenic variability of the virus caused by antigenic drift and shift. It is critical to the vaccine manufacturing process to obtain influenza A seed virus that is antigenically identical to circulating wild type (wt) virus and grows to high titers in embryonated chicken eggs. Inactivated influenza A seasonal vaccines are generated by classical reassortment. The classical method takes advantage of the ability of the influenza virus to reassort based on the segmented nature of its genome. In ovo co-inoculation of a high growth or yield (hy) donor virus and a low yield wt virus with antibody selection against the donor surface antigens results in progeny viruses that grow to high titers in ovo with wt origin hemagglutinin (HA) and neuraminidase (NA) glycoproteins. In this report we determined the parental origin of the remaining six genes encoding the internal proteins that contribute to the hy phenotype in ovo. The genetic analysis was conducted using reverse transcription-polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP). The characterization was conducted to determine the parental origin of the gene segments (hy donor virus or wt virus), gene segment ratios and constellations. Fold increase in growth of reassortant viruses compared to respective parent wt viruses was determined by hemagglutination assay titers. In this study fifty-seven influenza A vaccine candidate reassortants were analyzed for the presence or absence of correlations between specific gene segment ratios, gene constellations and hy reassortant phenotype. We found two gene ratios, 6:2 and 5:3, to be the most prevalent among the hy reassortants analyzed, although other gene ratios also conferred hy in certain reassortants.

  13. Gene Constellation of Influenza A Virus Reassortants with High Growth Phenotype Prepared as Seed Candidates for Vaccine Production

    PubMed Central

    Fulvini, Andrew A.; Ramanunninair, Manojkumar; Le, Jianhua; Pokorny, Barbara A.; Arroyo, Jennifer Minieri; Silverman, Jeanmarie; Devis, Rene; Bucher, Doris

    2011-01-01

    Background Influenza A virus vaccines undergo yearly reformulations due to the antigenic variability of the virus caused by antigenic drift and shift. It is critical to the vaccine manufacturing process to obtain influenza A seed virus that is antigenically identical to circulating wild type (wt) virus and grows to high titers in embryonated chicken eggs. Inactivated influenza A seasonal vaccines are generated by classical reassortment. The classical method takes advantage of the ability of the influenza virus to reassort based on the segmented nature of its genome. In ovo co-inoculation of a high growth or yield (hy) donor virus and a low yield wt virus with antibody selection against the donor surface antigens results in progeny viruses that grow to high titers in ovo with wt origin hemagglutinin (HA) and neuraminidase (NA) glycoproteins. In this report we determined the parental origin of the remaining six genes encoding the internal proteins that contribute to the hy phenotype in ovo. Methodology The genetic analysis was conducted using reverse transcription-polymerase chain reaction (RT-PCR) and restriction fragment length polymorphism (RFLP). The characterization was conducted to determine the parental origin of the gene segments (hy donor virus or wt virus), gene segment ratios and constellations. Fold increase in growth of reassortant viruses compared to respective parent wt viruses was determined by hemagglutination assay titers. Significance In this study fifty-seven influenza A vaccine candidate reassortants were analyzed for the presence or absence of correlations between specific gene segment ratios, gene constellations and hy reassortant phenotype. We found two gene ratios, 6∶2 and 5∶3, to be the most prevalent among the hy reassortants analyzed, although other gene ratios also conferred hy in certain reassortants. PMID:21695145

  14. Prescreening of Nicotine Hapten Linkers in Vitro To Select Hapten-Conjugate Vaccine Candidates for Pharmacokinetic Evaluation in Vivo.

    PubMed

    Arutla, Viswanath; Leal, Joseph; Liu, Xiaowei; Sokalingam, Sriram; Raleigh, Michael; Adaralegbe, Adejimi; Liu, Li; Pentel, Paul R; Hecht, Sidney M; Chang, Yung

    2017-05-08

    Since the demonstration of nicotine vaccines as a possible therapeutic intervention for the effects of tobacco smoke, extensive effort has been made to enhance nicotine specific immunity. Linker modifications of nicotine haptens have been a focal point for improving the immunogenicity of nicotine, in which the evaluation of these modifications usually relies on in vivo animal models, such as mice, rats or nonhuman primates. Here, we present two in vitro screening strategies to estimate and predict the immunogenic potential of our newly designed nicotine haptens. One utilizes a competition enzyme-linked immunoabsorbent assay (ELISA) to profile the interactions of nicotine haptens or hapten-protein conjugates with nicotine specific antibodies, both polyclonal and monoclonal. Another relies on computational modeling of the interactions between haptens and amino acid residues near the conjugation site of the carrier protein to infer linker-carrier protein conjugation effect on antinicotine antibody response. Using these two in vitro methods, we ranked the haptens with different linkers for their potential as viable vaccine candidates. The ELISA-based hapten ranking was in an agreement with the results obtained by in vivo nicotine pharmacokinetic analysis. A correlation was found between the average binding affinity (IC 50 ) of the haptens to an anti-Nic monoclonal antibody and the average brain nicotine concentration in the immunized mice. The computational modeling of hapten and carrier protein interactions helps exclude conjugates with strong linker-carrier conjugation effects and low in vivo efficacy. The simplicity of these in vitro screening strategies should facilitate the selection and development of more effective nicotine conjugate vaccines. In addition, these data highlight a previously under-appreciated contribution of linkers and hapten-protein conjugations to conjugate vaccine immunogenicity by virtue of their inclusion in the epitope that binds and

  15. Melioidosis Vaccines: A Systematic Review and Appraisal of the Potential to Exploit Biodefense Vaccines for Public Health Purposes

    PubMed Central

    Lubell, Yoel; Koh, Gavin C. K. W.; White, Lisa J.; Day, Nicholas P. J.; Titball, Richard W.

    2012-01-01

    Background Burkholderia pseudomallei is a Category B select agent and the cause of melioidosis. Research funding for vaccine development has largely considered protection within the biothreat context, but the resulting vaccines could be applicable to populations who are at risk of naturally acquired melioidosis. Here, we discuss target populations for vaccination, consider the cost-benefit of different vaccination strategies and review potential vaccine candidates. Methods and Findings Melioidosis is highly endemic in Thailand and northern Australia, where a biodefense vaccine might be adopted for public health purposes. A cost-effectiveness analysis model was developed, which showed that a vaccine could be a cost-effective intervention in Thailand, particularly if used in high-risk populations such as diabetics. Cost-effectiveness was observed in a model in which only partial immunity was assumed. The review systematically summarized all melioidosis vaccine candidates and studies in animal models that had evaluated their protectiveness. Possible candidates included live attenuated, whole cell killed, sub-unit, plasmid DNA and dendritic cell vaccines. Live attenuated vaccines were not considered favorably because of possible reversion to virulence and hypothetical risk of latent infection, while the other candidates need further development and evaluation. Melioidosis is acquired by skin inoculation, inhalation and ingestion, but routes of animal inoculation in most published studies to date do not reflect all of this. We found a lack of studies using diabetic models, which will be central to any evaluation of a melioidosis vaccine for natural infection since diabetes is the most important risk factor. Conclusion Vaccines could represent one strand of a public health initiative to reduce the global incidence of melioidosis. PMID:22303489

  16. Epitope mapping of PfCP-2.9, an asexual blood-stage vaccine candidate of Plasmodium falciparum.

    PubMed

    Li, Changling; Wang, Rui; Wu, Yuan; Zhang, Dongmei; He, Zhicheng; Pan, Weiqing

    2010-04-12

    Apical membrane antigen 1 (AMA-1) and merozoite surface protein 1 (MSP1) of Plasmodium falciparum are two leading blood-stage malaria vaccine candidates. A P. falciparum chimeric protein 2.9 (PfCP-2.9) has been constructed as a vaccine candidate, by fusing AMA-1 domain III (AMA-1 (III)) with a C-terminal 19 kDa fragment of MSP1 (MSP1-19) via a 28-mer peptide hinge. PfCP-2.9 was highly immunogenic in animal studies, and antibodies elicited by the PfCP-2.9 highly inhibited parasite growth in vitro. This study focused on locating the distribution of epitopes on PfCP-2.9. A panel of anti-PfCP-2.9 monoclonal antibodies (mAbs) were produced and their properties were examined by Western blot as well as in vitro growth inhibition assay (GIA). In addition, a series of PfCP-2.9 mutants containing single amino acid substitution were produced in Pichia pastoris. Interaction of the mAbs with the PfCP-2.9 mutants was measured by both Western blot and enzyme-linked immunosorbent assay (ELISA). Twelve mAbs recognizing PfCP-2.9 chimeric protein were produced. Of them, eight mAbs recognized conformational epitopes and six mAbs showed various levels of inhibitory activities on parasite growth in vitro. In addition, seventeen PfCP-2.9 mutants with single amino acid substitution were produced in Pichia pastoris for interaction with mAbs. Reduced binding of an inhibitory mAb (mAb7G), was observed in three mutants including M62 (Phe491-->Ala), M82 (Glu511-->Gln) and M84 (Arg513-->Lys), suggesting that these amino acid substitutions are critical to the epitope corresponding to mAb7G. The binding of two non-inhibitory mAbs (mAbG11.12 and mAbW9.10) was also reduced in the mutants of either M62 or M82. The substitution of Leu31 to Arg resulted in completely abolishing the binding of mAb1E1 (a blocking antibody) to M176 mutant, suggesting that the Leu residue at this position plays a crucial role in the formation of the epitope. In addition, the Asn15 residue may also play an important role

  17. Report of a consultation on the optimization of clinical challenge trials for evaluation of candidate blood stage malaria vaccines, 18-19 March 2009, Bethesda, MD, USA.

    PubMed

    Moorthy, V S; Diggs, C; Ferro, S; Good, M F; Herrera, S; Hill, A V; Imoukhuede, E B; Kumar, S; Loucq, C; Marsh, K; Ockenhouse, C F; Richie, T L; Sauerwein, R W

    2009-09-25

    Development and optimization of first generation malaria vaccine candidates has been facilitated by the existence of a well-established Plasmodium falciparum clinical challenge model in which infectious sporozoites are administered to human subjects via mosquito bite. While ideal for testing pre-erythrocytic stage vaccines, some researchers believe that the sporozoite challenge model is less appropriate for testing blood stage vaccines. Here we report a consultation, co-sponsored by PATH MVI, USAID, EMVI and WHO, where scientists from all institutions globally that have conducted such clinical challenges in recent years and representatives from regulatory agencies and funding agencies met to discuss clinical malaria challenge models. Participants discussed strengthening and harmonizing the sporozoite challenge model and considered the pros and cons of further developing a blood stage challenge possibly better suited for evaluating the efficacy of blood stage vaccines. This report summarizes major findings and recommendations, including an update on the Plasmodium vivax clinical challenge model, the prospects for performing experimental challenge trials in malaria endemic countries and an update on clinical safety data. While the focus of the meeting was on the optimization of clinical challenge models for evaluation of blood stage candidate malaria vaccines, many of the considerations are relevant for the application of challenge trials to other purposes.

  18. Conventional influenza vaccines influence the performance of a universal influenza vaccine in mice.

    PubMed

    Rowell, Janelle; Lo, Chia-Yun; Price, Graeme E; Misplon, Julia A; Epstein, Suzanne L; Garcia, Mayra

    2018-02-08

    Universal influenza vaccines are designed to protect against diverse strains of influenza virus. Preclinical testing of new vaccine candidates is usually done in naïve animals, despite intended use in the human population with its varied immune history including responses to previous vaccinations. As an approach more relevant to human use, we tested a candidate universal influenza vaccine in mice with a history of conventional vaccination. Female BALB/c mice were given two intramuscular doses of inactivated influenza vaccine (IIV) or diphtheria and tetanus toxoids vaccine (DT), one month apart. Another group was given two intranasal doses of live attenuated influenza virus (LAIV). One month after the second dose, mice were given the universal influenza vaccine: recombinant adenoviruses expressing influenza A nucleoprotein (A/NP) and matrix 2 (M2) (A/NP + M2-rAd). Immune responses to universal vaccine antigens A/NP and M2 were assessed by ELISA and interferon-γ ELISPOT. Protection was tested by challenge with mouse-adapted A/FM/1/47 (H1N1) and monitoring for weight loss and survival. Universal vaccine performance was enhanced, inhibited or unaffected by particular prior vaccinations. Mice given Afluria IIV and LAIV had greater antibody and T-cell response to A/NP than mice without prior vaccination, providing examples of enhanced A/NP + M2-rAd performance. Though Fluvirin IIV partially inhibited, the universal vaccine still provided considerable protection unlike conventional vaccination. Fluzone IIV and DT had no effect on A/NP + M2-rAd performance. Thus our results demonstrate that universal vaccine candidate A/NP + M2-rAd was at least partially effective in mice with diverse prior histories. However, the degree of protection and nature of the immune responses may be affected by a history of conventional vaccination and suggests that performance in humans would be influenced by immune history. Published by Elsevier Ltd.

  19. Virus-like particles as nanovaccine candidates

    NASA Astrophysics Data System (ADS)

    Guillen, G.; Aguilar, J. C.; Dueñas, S.; Hermida, L.; Iglesias, E.; Penton, E.; Lobaina, Y.; Lopez, M.; Mussachio, A.; Falcon, V.; Alvarez, L.; Martinez, G.; Gil, L.; Valdes, I.; Izquierdo, A.; Lazo, L.; Marcos, E.; Guzman, G.; Muzio, V.; Herrera, L.

    2013-03-01

    The existing vaccines are mainly limited to the microorganisms we are able to culture and produce and/or to those whose killing is mediated by humoral response (antibody mediated). It has been more difficult to develop vaccines capable of inducing a functional cellular response needed to prevent or cure chronic diseases. New strategies should be taken into account in the improvement of cell-based immune responses in order to prevent and control the infections and eventually clear the virus. Preclinical and clinical results with vaccine candidates developed as a vaccine platform based on virus-like particles (VLPs) evidenced their ability to stimulate mucosal as well as systemic immunity. Particles based on envelope, membrane or nucleocapsid microbial proteins induce a strong immune response after nasal or parenteral administration in mice, non-human primates and humans. In addition, the immune response obtained was modulated in a Th1 sense. The VLPs were also able to immunoenhance the humoral and cellular immune responses against several viral pathogens. Studies in animals and humans with nasal and systemic formulations evidenced that it is possible to induce functional immune response against HBV, HCV, HIV and dengue virus. Invited talk at the 6th International Workshop on Advanced Materials Science and Nanotechnology, 30 October - 2 November 2012, Ha Long, Vietnam.

  20. Immunogenicity and protective efficacy of Semliki forest virus replicon-based DNA vaccines encoding goatpox virus structural proteins

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

    Zheng Min; Guangxi Center for Animal Disease Control and Prevention, Nanning 530001; College of Animal Science and Veterinary Medicine, Jilin University, Changchun 130062

    Goatpox, caused by goatpox virus (GTPV), is an acute feverish and contagious disease in goats often associated with high morbidity and high mortality. To resolve potential safety risks and vaccination side effects of existing live attenuated goatpox vaccine (AV41), two Semliki forest virus (SFV) replicon-based bicistronic expression DNA vaccines (pCSm-AAL and pCSm-BAA) which encode GTPV structural proteins corresponding to the Vaccinia virus proteins A27, L1, A33, and B5, respectively, were constructed. Then, theirs ability to induce humoral and cellular response in mice and goats, and protect goats against virulent virus challenge were evaluated. The results showed that, vaccination with pCSm-AALmore » and pCSm-BAA in combination could elicit strong humoral and cellular responses in mice and goats, provide partial protection against viral challenge in goats, and reduce disease symptoms. Additionally, priming vaccination with the above-mentioned DNA vaccines could significantly reduce the goats' side reactions from boosting vaccinations with current live vaccine (AV41), which include skin lesions at the inoculation site and fevers. Data obtained in this study could not only facilitate improvement of the current goatpox vaccination strategy, but also provide valuable guidance to suitable candidates for evaluation and development of orthopoxvirus vaccines.« less

  1. Consensus on the Development of Vaccines against Naturally Acquired Melioidosis

    PubMed Central

    Funnell, Simon G.P.; Torres, Alfredo G.; Morici, Lisa A.; Brett, Paul J.; Dunachie, Susanna; Atkins, Timothy; Altmann, Daniel M.; Bancroft, Gregory; Peacock, Sharon J.

    2015-01-01

    Several candidates for a vaccine against Burkholderia pseudomallei, the causal bacterium of melioidosis, have been developed, and a rational approach is now needed to select and advance candidates for testing in relevant nonhuman primate models and in human clinical trials. Development of such a vaccine was the topic of a meeting in the United Kingdom in March 2014 attended by international candidate vaccine developers, researchers, and government health officials. The focus of the meeting was advancement of vaccines for prevention of natural infection, rather than for protection from the organism’s known potential for use as a biological weapon. A direct comparison of candidate vaccines in well-characterized mouse models was proposed. Knowledge gaps requiring further research were identified. Recommendations were made to accelerate the development of an effective vaccine against melioidosis. PMID:25992835

  2. Vaccine Platforms to Control Arenaviral Hemorrhagic Fevers.

    PubMed

    Carrion, Ricardo; Bredenbeek, Peter; Jiang, Xiaohong; Tretyakova, Irina; Pushko, Peter; Lukashevich, Igor S

    2012-11-20

    Arenaviruses are rodent-borne emerging human pathogens. Diseases caused by these viruses, e.g., Lassa fever (LF) in West Africa and South American hemorrhagic fevers (HFs), are serious public health problems in endemic areas. We have employed replication-competent and replication-deficient strategies to design vaccine candidates potentially targeting different groups "at risk". Our leader LF vaccine candidate, the live reassortant vaccine ML29, is safe and efficacious in all tested animal models including non-human primates. In this study we showed that treatment of fatally infected animals with ML29 two days after Lassa virus (LASV) challenge protected 80% of the treated animals. In endemic areas, where most of the target population is poor and many live far from health care facilities, a single-dose vaccination with ML29 would be ideal solution. Once there is an outbreak, a fast-acting vaccine or post-exposure prophylaxis would be best. The 2(nd) vaccine technology is based on Yellow Fever (YF) 17D vaccine. We designed YF17D-based recombinant viruses expressing LASV glycoproteins (GP) and showed protective efficacy of these recombinants. In the current study we developed a novel technology to clone LASV nucleocapsid within YF17D C gene. Low immunogenicity and stability of foreign inserts must be addressed to design successful LASV/YFV bivalent vaccines to control LF and YF in overlapping endemic areas of West Africa. The 3(rd) platform is based on the new generation of alphavirus replicon virus-like-particle vectors (VLPV). Using this technology we designed VLPV expressing LASV GP with enhanced immunogenicity and bivalent VLPV expressing cross-reactive GP of Junin virus (JUNV) and Machupo virus (MACV), causative agents of Argentinian and Bolivian HF, respectively. A prime-boost regimen required for VLPV immunization might be practical for medical providers, military, lab personnel, and visitors in endemic areas.

  3. 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

  4. B cells from knock-in mice expressing broadly neutralizing HIV antibody b12 carry an innocuous B cell receptor responsive to HIV vaccine candidates.

    PubMed

    Ota, Takayuki; Doyle-Cooper, Colleen; Cooper, Anthony B; Doores, Katherine J; Aoki-Ota, Miyo; Le, Khoa; Schief, William R; Wyatt, Richard T; Burton, Dennis R; Nemazee, David

    2013-09-15

    Broadly neutralizing Abs against HIV protect from infection, but their routine elicitation by vaccination has not been achieved. To generate small animal models to test vaccine candidates, we have generated targeted transgenic ("knock-in") mice expressing, in the physiological Ig H and L chain loci, two well-studied broadly neutralizing Abs: 4E10, which interacts with the membrane proximal external region of gp41, and b12, which binds to the CD4 binding site on gp120. 4E10HL mice are described in the companion article (Doyle-Cooper et al., J. Immunol. 191: 3186-3191). In this article, we describe b12 mice. B cells in b12HL mice, in contrast to the case in 4E10 mice, were abundant and essentially monoclonal, retaining the b12 specificity. In cell culture, b12HL B cells responded avidly to HIV envelope gp140 trimers and to BCR ligands. Upon transfer to wild-type recipients, b12HL B cells responded robustly to vaccination with gp140 trimers. Vaccinated b12H mice, although generating abundant precursors and Abs with affinity for Env, were unable to rapidly generate neutralizing Abs, highlighting the importance of developing Ag forms that better focus responses to neutralizing epitopes. The b12HL and b12H mice should be useful in optimizing HIV vaccine candidates to elicit a neutralizing response while avoiding nonprotective specificities.

  5. Progress and challenges in TB vaccine development

    PubMed Central

    Voss, Gerald; Casimiro, Danilo; Neyrolles, Olivier; Williams, Ann; Kaufmann, Stefan H.E.; McShane, Helen; Hatherill, Mark; Fletcher, Helen A

    2018-01-01

    The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development.  To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our “failed” trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models.  However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development. PMID:29568497

  6. Progress and challenges in TB vaccine development.

    PubMed

    Voss, Gerald; Casimiro, Danilo; Neyrolles, Olivier; Williams, Ann; Kaufmann, Stefan H E; McShane, Helen; Hatherill, Mark; Fletcher, Helen A

    2018-01-01

    The Bacille Calmette Guerin (BCG) vaccine can provide decades of protection against tuberculosis (TB) disease, and although imperfect, BCG is proof that vaccine mediated protection against TB is a possibility. A new TB vaccine is, therefore, an inevitability; the question is how long will it take us to get there? We have made substantial progress in the development of vaccine platforms, in the identification of antigens and of immune correlates of risk of TB disease. We have also standardized animal models to enable head-to-head comparison and selection of candidate TB vaccines for further development.  To extend our understanding of the safety and immunogenicity of TB vaccines we have performed experimental medicine studies to explore route of administration and have begun to develop controlled human infection models. Driven by a desire to reduce the length and cost of human efficacy trials we have applied novel approaches to later stage clinical development, exploring alternative clinical endpoints to prevention of disease outcomes. Here, global leaders in TB vaccine development discuss the progress made and the challenges that remain. What emerges is that, despite scientific progress, few vaccine candidates have entered clinical trials in the last 5 years and few vaccines in clinical trials have progressed to efficacy trials. Crucially, we have undervalued the knowledge gained from our "failed" trials and fostered a culture of risk aversion that has limited new funding for clinical TB vaccine development. The unintended consequence of this abundance of caution is lack of diversity of new TB vaccine candidates and stagnation of the clinical pipeline. We have a variety of new vaccine platform technologies, mycobacterial antigens and animal and human models.  However, we will not encourage progression of vaccine candidates into clinical trials unless we evaluate and embrace risk in pursuit of vaccine development.

  7. Enhanced mucosal immune responses induced by a combined candidate mucosal vaccine based on Hepatitis A virus and Hepatitis E virus structural proteins linked to tuftsin.

    PubMed

    Gao, Yan; Su, Qiudong; Yi, Yao; Jia, Zhiyuan; Wang, Hao; Lu, Xuexin; Qiu, Feng; Bi, Shengli

    2015-01-01

    Hepatitis A virus (HAV) and Hepatitis E virus (HEV) are the most common causes of infectious hepatitis. These viruses are spread largely by the fecal-oral route and lead to clinically important disease in developing countries. To evaluate the potential of targeting hepatitis A and E infection simultaneously, a combined mucosal candidate vaccine was developed with the partial open reading frame 2 (ORF2) sequence (aa 368-607) of HEV (HE-ORF2) and partial virus protein 1 (VP1) sequence (aa 1-198) of HAV (HA-VP1), which included the viral neutralization epitopes. Tuftsin is an immunostimulatory peptide which can enhance the immunogenicity of a protein by targeting it to macrophages and dendritic cells. Here, we developed a novel combined protein vaccine by conjugating tuftsin to HE-ORF2 and HA-VP1 and used synthetic CpG oligodeoxynucleotides (ODNs) as the adjuvant. Subsequent experiments in BALB/c mice demonstrated that tuftsin enhanced the serum-specific IgG and IgA antibodies against HEV and HAV at the intestinal, vaginal and pulmonary interface when delivered intranasally. Moreover, mice from the intranasally immunized tuftsin group (HE-ORF2-tuftsin + HA-VP1-tuftsin + CpG) showed higher levels of IFN-γ-secreting splenocytes (Th1 response) and ratio of CD4+/CD8+ T cells than those of the no-tuftsin group (HE-ORF2 + HA-VP1 + CpG). Thus, the tuftsin group generated stronger humoral and cellular immune responses compared with the no-tuftsin group. Moreover, enhanced responses to the combined protein vaccine were obtained by intranasal immunization compared with intramuscular injection. By integrating HE-ORF2, HA-VP1 and tuftsin in a vaccine, this study validated an important concept for further development of a combined mucosal vaccine against hepatitis A and E infection.

  8. Reducing empiricism in malaria vaccine design.

    PubMed

    Moorthy, Vasee S; Kieny, Marie Paule

    2010-03-01

    Gains in the control of malaria and the promising progress of a malaria vaccine that is partly efficacious do not reduce the need for a high-efficacy vaccine in the longer term. Evidence supports the feasibility of developing a highly efficacious malaria vaccine. However, design of candidate malaria vaccines remains empirical and is necessarily based on many unproven assumptions because much of the knowledge needed to design vaccines and to predict efficacy is not available. Data to inform key questions of vaccine science might allow the design of vaccines to progress to a less empirical stage, for example through availability of assay results associated with vaccine efficacy. We discuss six strategic gaps in knowledge that contribute to empiricism in the design of vaccines. Comparative evaluation, assay and model standardisation, greater sharing of information, collaboration and coordination between groups, and rigorous evaluation of existing datasets are steps that can be taken to enable reductions in empiricism over time. 2010 Elsevier Ltd. All rights reserved.

  9. The ΔfbpA attenuated candidate vaccine from Mycobacterium tuberculosis, H37Rv primes for a stronger T-bet dependent Th1 immunity in mice.

    PubMed

    Roche, Cherie M; Smith, Amanda; Lindsey, Devin R; Meher, Akshay; Schluns, Kimberly; Arora, Ashish; Armitige, Lisa Y; Jagannath, Chinnaswamy

    2011-12-01

    The ΔfbpA candidate vaccine derived from Mycobacterium tuberculosis (H37Rv) (Mtb) protects mice better than BCG against tuberculosis, and we investigated the hypothesis that ΔfbpA may induce a stronger Th1 immunity. Since T-bet transcription factor regulates Th1 immunity, mice infected with ΔfbpA, BCG vaccine and related mycobacteria were analyzed for T-bet positive T cells. Mouse dendritic cells (DCs) or macrophages were also pulsed with excretory-secreted antigens (ES; Antigen-85B, ESAT-6 and CFP10) and cocultured with T cells from immunized or naïve mice and tested for in vitro induction of T-bet and IFN-γ. In both models, ΔfbpA mutant induced a stronger response of T-bet(+)CD4 T cells, which correlated with an increased expansion of IFN-γ(+)CD4 T cells in vivo and in vitro. When DCs pulsed with ES antigens were allowed to stimulate T cells, ESAT-6 and CFP-10 failed to induce a recall expansion of T-bet(+)IFN-γ(+)CD4 T cells from BCG vaccinated mice. Thus, deletion of RD1 in BCG seems to reduce its ability to induce T-bet and induce stronger Th1 immunity. Finally, mice were vaccinated with ΔfbpA and BCG and challenged with virulent Mtb for evaluation of protection and T cell expansion. ΔfbpA vaccinated mice showed a rapid and stronger expansion of CD4(+)CXCR3(+) IFN-γ(+) T cells in the lungs of Mtb challenged mice, compared to those which had BCG vaccine. ΔfbpA immunized mice also showed a better decline of the Mtb bacterial counts of the lungs. Mtb derived ΔfbpA candidate vaccine therefore induces qualitatively better T-bet dependent Th1 immunity than BCG vaccine. Copyright © 2011 Elsevier Ltd. All rights reserved.

  10. A Library of Plasmodium vivax Recombinant Merozoite Proteins Reveals New Vaccine Candidates and Protein-Protein Interactions

    PubMed Central

    Hostetler, Jessica B.; Sharma, Sumana; Bartholdson, S. Josefin; Wright, Gavin J.; Fairhurst, Rick M.; Rayner, Julian C.

    2015-01-01

    Background A vaccine targeting Plasmodium vivax will be an essential component of any comprehensive malaria elimination program, but major gaps in our understanding of P. vivax biology, including the protein-protein interactions that mediate merozoite invasion of reticulocytes, hinder the search for candidate antigens. Only one ligand-receptor interaction has been identified, that between P. vivax Duffy Binding Protein (PvDBP) and the erythrocyte Duffy Antigen Receptor for Chemokines (DARC), and strain-specific immune responses to PvDBP make it a complex vaccine target. To broaden the repertoire of potential P. vivax merozoite-stage vaccine targets, we exploited a recent breakthrough in expressing full-length ectodomains of Plasmodium proteins in a functionally-active form in mammalian cells and initiated a large-scale study of P. vivax merozoite proteins that are potentially involved in reticulocyte binding and invasion. Methodology/Principal Findings We selected 39 P. vivax proteins that are predicted to localize to the merozoite surface or invasive secretory organelles, some of which show homology to P. falciparum vaccine candidates. Of these, we were able to express 37 full-length protein ectodomains in a mammalian expression system, which has been previously used to express P. falciparum invasion ligands such as PfRH5. To establish whether the expressed proteins were correctly folded, we assessed whether they were recognized by antibodies from Cambodian patients with acute vivax malaria. IgG from these samples showed at least a two-fold change in reactivity over naïve controls in 27 of 34 antigens tested, and the majority showed heat-labile IgG immunoreactivity, suggesting the presence of conformation-sensitive epitopes and native tertiary protein structures. Using a method specifically designed to detect low-affinity, extracellular protein-protein interactions, we confirmed a predicted interaction between P. vivax 6-cysteine proteins P12 and P41, further

  11. Candidate hepatitis C vaccine trials and people who inject drugs: Challenges and opportunities

    PubMed Central

    Maher, Lisa; White, Bethany; Hellard, Margaret; Madden, Annie; Prins, Maria; Kerr, Thomas; Page, Kimberly

    2013-01-01

    This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues. Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited. In most cases authors are permitted to post their version of the article (e.g. in Word or Tex form) to their personal website or institutional repository. Authors requiring further information regarding Elsevier's archiving and manuscript policies are encouraged to visit: http://www.elsevier.com/copyright People who inject drugs (PWID) are at high risk of HCV. Limited evidence of the effectiveness of prevention interventions and low uptake of treatment in this group highlight the need for increased investment in biomedical interventions, notably safe and efficacious vaccines. While several candidates are currently in development, field trials in PWID present challenges, including ethical issues associated with trial literacy, informed consent and standards of care. Significant biological and social factors and differences between HIV and HCV suggest that HCV warrants targeted vaccine preparedness research to lay the groundwork for successful implementation of future trials. PMID:20831914

  12. A prime-boost immunization regimen based on a simian adenovirus 36 vectored multi-stage malaria vaccine induces protective immunity in mice.

    PubMed

    Fonseca, Jairo A; McCaffery, Jessica N; Kashentseva, Elena; Singh, Balwan; Dmitriev, Igor P; Curiel, David T; Moreno, Alberto

    2017-05-31

    Malaria remains a considerable burden on public health. In 2015, the WHO estimates there were 212 million malaria cases causing nearly 429,000 deaths globally. A highly effective malaria vaccine is needed to reduce the burden of this disease. We have developed an experimental vaccine candidate (PyCMP) based on pre-erythrocytic (CSP) and erythrocytic (MSP1) stage antigens derived from the rodent malaria parasite P. yoelii. Our protein-based vaccine construct induces protective antibodies and CD4 + T cell responses. Based on evidence that viral vectors increase CD8 + T cell-mediated immunity, we also have tested heterologous prime-boost immunization regimens that included human adenovirus serotype 5 vector (Ad5), obtaining protective CD8 + T cell responses. While Ad5 is commonly used for vaccine studies, the high prevalence of pre-existing immunity to Ad5 severely compromises its utility. Here, we report the use of the novel simian adenovirus 36 (SAd36) as a candidate for a vectored malaria vaccine since this virus is not known to infect humans, and it is not neutralized by anti-Ad5 antibodies. Our study shows that the recombinant SAd36PyCMP can enhance specific CD8 + T cell response and elicit similar antibody titers when compared to an immunization regimen including the recombinant Ad5PyCMP. The robust immune responses induced by SAd36PyCMP are translated into a lower parasite load following P. yoelii infectious challenge when compared to mice immunized with Ad5PyCMP. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Prime-boost and recombinant protein vaccination strategies using Sm-p80 protects against Schistosoma mansoni infection in the mouse model to levels previously attainable only by the irradiated cercarial vaccine

    PubMed Central

    Ahmad, Gul; Zhang, Weidong; Torben, Workineh; Haskins, Chad; Diggs, Sue; Noor, Zahid; Le, Loc

    2009-01-01

    Advent of an effective schistosome vaccine would contribute significantly toward reducing the disease spectrum and transmission of schistosomiasis. We have targeted a functionally important antigen, Sm-p80, as a vaccine candidate because of its consistent immunogenicity, protective and antifecundity potentials, and important role in the immune evasion process. In this study, we report that using two vaccination approaches (prime boost and recombinant protein), Sm-p80-based vaccine formulation(s) confer up to 70% reduction in worm burden in mice. Animals immunized with the vaccine exhibited a decrease in egg production by up to 75%. The vaccine elicited strong immune responses that included IgM, IgA, and IgG (IgG1, IgG2a, IgG2b, and IgG3) in vaccinated animals. Splenocytes proliferated in response to Sm-p80 produced Th1 and Th17 response enhancing cytokines. These results again emphasize the potential of Sm-p80 as a viable vaccine candidate for schistosomiasis. PMID:19809833

  14. The Epstein-Barr virus lytic protein BZLF1 as a candidate target antigen for vaccine development1

    PubMed Central

    Hartlage, Alex S.; Liu, Tom; Patton, John T.; Garman, Sabrina L.; Zhang, Xiaoli; Kurt, Habibe; Lozanski, Gerard; Lustberg, Mark E.; Caligiuri, Michael A.; Baiocchi, Robert A.

    2015-01-01

    The Epstein-Barr virus (EBV) is an oncogenic, γ-herpesvirus associated with a broad spectrum of disease. While most immune-competent individuals can effectivley develop efficient adaptive immune responses to EBV, immunocompromised individuals are at serious risk for developing life threatening diseases such as Hodgkin’s lymphoma and post-transplant lymphoproliferative disorder (PTLD). Given the significant morbidity associated with EBV infection in high-risk populations, there is a need to develop vaccine strategies that restore or enhance EBV-specific immune responses. Here, we identify the EBV immediate-early protein BZLF1 as a potential target antigen for vaccine development. Primary tumors from patients with PTLD and a chimeric human-murine model of EBV-driven lymphoproliferative disorder (EBV-LPD) express BZLF1 protein. Pulsing human dendritic cells (DC) with recombinant BZLF1 followed by incubation with autologous mononuclear cells led to expansion of BZLF1-specific CD8(+) T cells in vitro and primed BZLF1-specific T-cell responses in vivo. In addition, vaccination of hu-PBL-SCID mice with BZLF1-transduced DCs induced specific cellular immunity and significantly prolonged survival from fatal EBV-LPD. These findings identify BZLF1 as a candidate target protein in the immunosurveillance of EBV and provide rationale for considering BZLF1 in vaccine strategies to enhance primary and recall immune responses and potentially prevent EBV-associated diseases. PMID:25735952

  15. Protective effects of a Modified Vaccinia Ankara-based vaccine candidate against Crimean-Congo Haemorrhagic Fever virus require both cellular and humoral responses

    PubMed Central

    Dowall, Stuart D.; Graham, Victoria A.; Rayner, Emma; Hunter, Laura; Watson, Robert; Taylor, Irene; Rule, Antony; Carroll, Miles W.; Hewson, Roger

    2016-01-01

    Crimean-Congo Haemorrhagic Fever (CCHF) is a severe tick-borne disease, endemic in many countries in Africa, the Middle East, Eastern Europe and Asia. There is no approved vaccine currently available against CCHF. The most promising candidate, which has previously been shown to confer protection in the small animal model, is a modified Vaccinia Ankara virus vector expressing the CCHF viral glycoprotein (MVA-GP). It has been shown that MVA-GP induces both humoral and cellular immunogenicity. In the present study, sera and T-lymphocytes were passively and adoptively transferred into recipient mice prior to challenge with CCHF virus. Results demonstrated that mediators from both arms of the immune system were required to demonstrate protective effects against lethal challenge. PMID:27272940

  16. Biophysical characterization and immunization studies of dominant negative inhibitor (DNI), a candidate anthrax toxin subunit vaccine.

    PubMed

    Iyer, Vidyashankara; Hu, Lei; Schanté, Carole E; Vance, David; Chadwick, Chrystal; Jain, Nishant Kumar; Brey, Robert N; Joshi, Sangeeta B; Volkin, David B; Andra, Kiran K; Bann, James G; Mantis, Nicholas J; Middaugh, C Russell

    2013-11-01

    Dominant Negative Inhibitor (DNI) is a translocation-deficient homolog of recombinant protective antigen of Bacillus anthracis that is a candidate for a next generation anthrax vaccine. This study demonstrates that the biophysical characteristics of the DNI protein stored in lyophilized form at 4°C for 8 y were similar to recombinant Protective Antigen (rPA). To provide information on the accelerated stability of DNI, samples in the lyophilized form were subjected to thermal stress (40°C and 70°C for up to 4 weeks) and thoroughly evaluated using various biophysical and chemical characterization techniques. Results demonstrate preserved structural stability of the DNI protein under extreme conditions, suggesting long-term stability can be achieved for a vaccine that employs DNI, as desired for a biodefense countermeasure. Furthermore, the biological activity of the stressed DNI bound to the adjuvant Alhydrogel (®) was evaluated in mice and it was found that the immunogenicity DNI was not affected by thermal stress.

  17. Successes and failures in human tuberculosis vaccine development.

    PubMed

    Zenteno-Cuevas, Roberto

    2017-12-01

    Tuberculosis (TB) is an infectious disease caused mainly by Mycobacterium tuberculosis. In 2016, the WHO estimated 10.5 million new cases and 1.8 million deaths, making this disease the leading cause of death by an infectious agent. The current and projected TB situation necessitates the development of new vaccines with improved attributes compared to the traditional BCG method. Areas covered: In this review, the authors describe the most promising candidate vaccines against TB and discuss additional key elements in vaccine development, such as animal models, new adjuvants and immunization routes and new strategies for the identification of candidate vaccines. Expert opinion: At present, around 13 candidate vaccines for TB are in the clinical phase of evaluation; however, there is still no substitute for the BCG vaccine. One major impediment to developing an effective vaccine is our lack of understanding of several of the mechanisms associated with infection and the immune response against TB. However, the recent implementation of an entirely new set of technological advances will facilitate the proposal of new candidates. Finally, development of a new vaccine will require a major coordination of effort in order to achieve its effective administration to the people most in need of it.

  18. A 52 Kilodalton Protein Vaccine Candidate for Francisella tularensis

    DTIC Science & Technology

    2004-12-01

    du vaccin vivant F. tularensis (LVS). Soixante pourcent (60%) des souris vaccindes ont survdcu la dose ltale multiple alors que toutes les souris non...le lysat des cellules de cultures vivantes du vaccin vivant F. tularensis. Plusieurs composants de Francisella tularensis ont dt6 identifids par cet...antiserum. Le s6rum de souris provenant de souris vaccin6es avec F. tularensis non- vivant n’a pas identifid ces composants. A partir de ces prot6ines

  19. Vaccinations in pediatric kidney transplant recipients.

    PubMed

    Fox, Thomas G; Nailescu, Corina

    2018-04-18

    Pediatric kidney transplant (KT) candidates should be fully immunized according to routine childhood schedules using age-appropriate guidelines. Unfortunately, vaccination rates in KT candidates remain suboptimal. With the exception of influenza vaccine, vaccination after transplantation should be delayed 3-6 months to maximize immunogenicity. While most vaccinations in the KT recipient are administered by primary care physicians, there are specific schedule alterations in the cases of influenza, hepatitis B, pneumococcal, and meningococcal vaccinations; consequently, these vaccines are usually administered by transplant physicians. This article will focus on those deviations from the normal vaccine schedule important in the care of pediatric KT recipients. The article will also review human papillomavirus vaccine due to its special importance in cancer prevention. Live vaccines are generally contraindicated in KT recipients. However, we present a brief review of live vaccines in organ transplant recipients, as there is evidence that certain live virus vaccines may be safe and effective in select groups. Lastly, we review vaccination of pediatric KT recipients prior to international travel.

  20. The recent progress in RSV vaccine technology.

    PubMed

    Fretzayas, Andrew; Papadopoulou, Anna; Kotzia, Doxa; Moustaki, Maria

    2012-12-01

    The most effective way to control RSV infection would be the development of an expedient and safe vaccine. Subunit vaccines, live attenuated RSV vaccines, plasmid DNA vaccines have been tested either in human or in mouse models without reaching the ultimate goal of efficacy and safety, at least in humans. Viruses such as adenovirus, sendai virus, measles virus were also used as vectors for the generation of RSV vaccines with promising results in animal models. Recent patents describe new techniques for the generation of candidate vaccines. These patents include virus like particles as vaccine platforms, recombinant RSVs or modified RSV F protein as component of the vaccine. Despite the number of the candidate vaccines, the new RSV vaccines should overcome many obstacles before being established as effective vaccines for the control of RSV infections especially for the young infants who are more susceptible to the virus.

  1. Preliminary aggregate safety and immunogenicity results from three trials of a purified inactivated Zika virus vaccine candidate: phase 1, randomised, double-blind, placebo-controlled clinical trials.

    PubMed

    Modjarrad, Kayvon; Lin, Leyi; George, Sarah L; Stephenson, Kathryn E; Eckels, Kenneth H; De La Barrera, Rafael A; Jarman, Richard G; Sondergaard, Erica; Tennant, Janice; Ansel, Jessica L; Mills, Kristin; Koren, Michael; Robb, Merlin L; Barrett, Jill; Thompson, Jason; Kosel, Alison E; Dawson, Peter; Hale, Andrew; Tan, C Sabrina; Walsh, Stephen R; Meyer, Keith E; Brien, James; Crowell, Trevor A; Blazevic, Azra; Mosby, Karla; Larocca, Rafael A; Abbink, Peter; Boyd, Michael; Bricault, Christine A; Seaman, Michael S; Basil, Anne; Walsh, Melissa; Tonwe, Veronica; Hoft, Daniel F; Thomas, Stephen J; Barouch, Dan H; Michael, Nelson L

    2018-02-10

    A safe, effective, and rapidly scalable vaccine against Zika virus infection is needed. We developed a purified formalin-inactivated Zika virus vaccine (ZPIV) candidate that showed protection in mice and non-human primates against viraemia after Zika virus challenge. Here we present the preliminary results in human beings. We did three phase 1, placebo-controlled, double-blind trials of ZPIV with aluminium hydroxide adjuvant. In all three studies, healthy adults were randomly assigned by a computer-generated list to receive 5 μg ZPIV or saline placebo, in a ratio of 4:1 at Walter Reed Army Institute of Research, Silver Spring, MD, USA, or of 5:1 at Saint Louis University, Saint Louis, MO, USA, and Beth Israel Deaconess Medical Center, Boston, MA, USA. Vaccinations were given intramuscularly on days 1 and 29. The primary objective was safety and immunogenicity of the ZPIV candidate. We recorded adverse events and Zika virus envelope microneutralisation titres up to day 57. These trials are registered at ClinicalTrials.gov, numbers NCT02963909, NCT02952833, and NCT02937233. We enrolled 68 participants between Nov 7, 2016, and Jan 25, 2017. One was excluded and 67 participants received two injections of Zika vaccine (n=55) or placebo (n=12). The vaccine caused only mild to moderate adverse events. The most frequent local effects were pain (n=40 [60%]) or tenderness (n=32 [47%]) at the injection site, and the most frequent systemic reactogenic events were fatigue (29 [43%]), headache (26 [39%]), and malaise (15 [22%]). By day 57, 52 (92%) of vaccine recipients had seroconverted (microneutralisation titre ≥1:10), with peak geometric mean titres seen at day 43 and exceeding protective thresholds seen in animal studies. The ZPIV candidate was well tolerated and elicited robust neutralising antibody titres in healthy adults. Departments of the Army and Defense and National Institute of Allergy and Infectious Diseases. Copyright © 2018 Elsevier Ltd. All rights reserved.

  2. Identification and evaluation of vaccine candidate antigens from the poultry red mite (Dermanyssus gallinae)

    PubMed Central

    Bartley, Kathryn; Wright, Harry W.; Huntley, John F.; Manson, Erin D.T.; Inglis, Neil F.; McLean, Kevin; Nath, Mintu; Bartley, Yvonne; Nisbet, Alasdair J.

    2015-01-01

    An aqueous extract of the haematophagous poultry ectoparasite, Dermanyssus gallinae, was subfractionated using anion exchange chromatography. Six of these subfractions were used to immunise hens and the blood from these hens was fed, in vitro, to poultry red mites. Mite mortality following these feeds was indicative of protective antigens in two of the subfractions, with the risks of mites dying being 3.1 and 3.7 times higher than in the control group (P < 0.001). A combination of two-dimensional immunoblotting and immunoaffinity chromatography, using IgY from hens immunised with these subfractions, was used in concert with proteomic analyses to identify the strongest immunogenic proteins in each of these subfractions. Ten of the immunoreactive proteins were selected for assessment as vaccine candidates using the following criteria: intensity of immune recognition; likelihood of exposure of the antigen to the antibodies in a blood meal; proposed function and known vaccine potential of orthologous molecules. Recombinant versions of each of these 10 proteins were produced in Escherichia coli and were used to immunise hens. Subsequent in vitro feeding of mites on blood from these birds indicated that immunisation with Deg-SRP-1 (serpin), Deg-VIT-1 (vitellogenin), Deg-HGP-1 (hemelipoglycoprotein) or Deg-PUF-1 (a protein of unknown function) resulted in significantly increased risk of mite death (1.7–2.8 times higher than in mites fed blood from control hens immunised with adjuvant only, P < 0.001). The potential for using these antigens in a recombinant vaccine is discussed. PMID:26296690

  3. Identification and evaluation of vaccine candidate antigens from the poultry red mite (Dermanyssus gallinae).

    PubMed

    Bartley, Kathryn; Wright, Harry W; Huntley, John F; Manson, Erin D T; Inglis, Neil F; McLean, Kevin; Nath, Mintu; Bartley, Yvonne; Nisbet, Alasdair J

    2015-11-01

    An aqueous extract of the haematophagous poultry ectoparasite, Dermanyssus gallinae, was subfractionated using anion exchange chromatography. Six of these subfractions were used to immunise hens and the blood from these hens was fed, in vitro, to poultry red mites. Mite mortality following these feeds was indicative of protective antigens in two of the subfractions, with the risks of mites dying being 3.1 and 3.7 times higher than in the control group (P<0.001). A combination of two-dimensional immunoblotting and immunoaffinity chromatography, using IgY from hens immunised with these subfractions, was used in concert with proteomic analyses to identify the strongest immunogenic proteins in each of these subfractions. Ten of the immunoreactive proteins were selected for assessment as vaccine candidates using the following criteria: intensity of immune recognition; likelihood of exposure of the antigen to the antibodies in a blood meal; proposed function and known vaccine potential of orthologous molecules. Recombinant versions of each of these 10 proteins were produced in Escherichia coli and were used to immunise hens. Subsequent in vitro feeding of mites on blood from these birds indicated that immunisation with Deg-SRP-1 (serpin), Deg-VIT-1 (vitellogenin), Deg-HGP-1 (hemelipoglycoprotein) or Deg-PUF-1 (a protein of unknown function) resulted in significantly increased risk of mite death (1.7-2.8times higher than in mites fed blood from control hens immunised with adjuvant only, P<0.001). The potential for using these antigens in a recombinant vaccine is discussed. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  4. Construction and comparison of different source neuraminidase candidate vaccine strains for human infection with Eurasian avian-like influenza H1N1 virus.

    PubMed

    Liu, Liqi; Lu, Jian; Zhou, Jianfang; Li, Zi; Zhang, Heng; Wang, Dayan; Shu, Yuelong

    2017-12-01

    Human infections with Eurasian avian-like swine influenza H1N1 viruses have been reported in China in past years. One case resulted in death and others were mild case. In 2016, the World Health Organization recommended the use of A/Hunan/42443/2015(H1N1) virus to construct the first candidate vaccine strain for Eurasian avian-like swine influenza H1N1 viruses. Previous reports showed that the neuraminidase of A/Puerto Rico/8/34(H1N1) might improve the viral yield of reassortant viruses. Therefore, we constructed two reassortant candidate vaccine viruses of A/Hunan/42443/2015(H1N1) by reverse genetic technology, with (6+2) and (7+1) gene constitution, respectively. The (6+2) virus had hemagglutinin and neuraminidase from A/Hunan/42443/2015, and the (7+1) one had hemagglutinin from A/Hunan/42443/2015, while all the other genes were from A/Puerto Rico/8/34. Our data revealed that although the neuraminidase of the (7+1) virus was from high yield A/Puerto Rico/8/34, the hemagglutination titer and the hemagglutinin protein content of the (7+1) virus was not higher than that of the (6+2) virus. Both of the (7+1) and (6+2) viruses reached a similar level to that of A/Puerto Rico/8/34 at the usual harvest time in vitro. Therefore, both reassortant viruses are potential candidate vaccine viruses, which could contribute to pandemic preparedness. Copyright © 2017. Published by Elsevier Masson SAS.

  5. Development of vaccines against meningococcal disease.

    PubMed

    Jódar, Luis; Feavers, Ian M; Salisbury, David; Granoff, Dan M

    2002-04-27

    Neisseria meningitidis is a major cause of bacterial meningitis and sepsis. Polysaccharide-protein conjugate vaccines for prevention of group C disease have been licensed in Europe. Such vaccines for prevention of disease caused by groups A (which is associated with the greatest disease burden worldwide), Y, and W135 are being developed. However, conventional approaches to develop a vaccine for group B strains, which are responsible for most cases in Europe and the USA, have been largely unsuccessful. Capsular polysaccharide-based vaccines can elicit autoantibodies to host polysialic acid, whereas the ability of most non-capsular antigens to elicit broad-based immunity is limited by their antigenic diversity. Many new membrane proteins have been discovered during analyses of genomic sequencing data. These antigens are highly conserved and, in mice, elicit serum bactericidal antibodies, which are the serological hallmark of protective immunity in man. Therefore, there are many promising new vaccine candidates, and improved prospects for development of a broadly protective vaccine for group B disease, and for control of all meningococcal disease.

  6. A Recombinant Vesicular Stomatitis Virus Ebola Vaccine.

    PubMed

    Regules, Jason A; Beigel, John H; Paolino, Kristopher M; Voell, Jocelyn; Castellano, Amy R; Hu, Zonghui; Muñoz, Paula; Moon, James E; Ruck, Richard C; Bennett, Jason W; Twomey, Patrick S; Gutiérrez, Ramiro L; Remich, Shon A; Hack, Holly R; Wisniewski, Meagan L; Josleyn, Matthew D; Kwilas, Steven A; Van Deusen, Nicole; Mbaya, Olivier Tshiani; Zhou, Yan; Stanley, Daphne A; Jing, Wang; Smith, Kirsten S; Shi, Meng; Ledgerwood, Julie E; Graham, Barney S; Sullivan, Nancy J; Jagodzinski, Linda L; Peel, Sheila A; Alimonti, Judie B; Hooper, Jay W; Silvera, Peter M; Martin, Brian K; Monath, Thomas P; Ramsey, W Jay; Link, Charles J; Lane, H Clifford; Michael, Nelson L; Davey, Richard T; Thomas, Stephen J

    2017-01-26

    The worst Ebola virus disease (EVD) outbreak in history has resulted in more than 28,000 cases and 11,000 deaths. We present the final results of two phase 1 trials of an attenuated, replication-competent, recombinant vesicular stomatitis virus (rVSV)-based vaccine candidate designed to prevent EVD. We conducted two phase 1, placebo-controlled, double-blind, dose-escalation trials of an rVSV-based vaccine candidate expressing the glycoprotein of a Zaire strain of Ebola virus (ZEBOV). A total of 39 adults at each site (78 participants in all) were consecutively enrolled into groups of 13. At each site, volunteers received one of three doses of the rVSV-ZEBOV vaccine (3 million plaque-forming units [PFU], 20 million PFU, or 100 million PFU) or placebo. Volunteers at one of the sites received a second dose at day 28. Safety and immunogenicity were assessed. The most common adverse events were injection-site pain, fatigue, myalgia, and headache. Transient rVSV viremia was noted in all the vaccine recipients after dose 1. The rates of adverse events and viremia were lower after the second dose than after the first dose. By day 28, all the vaccine recipients had seroconversion as assessed by an enzyme-linked immunosorbent assay (ELISA) against the glycoprotein of the ZEBOV-Kikwit strain. At day 28, geometric mean titers of antibodies against ZEBOV glycoprotein were higher in the groups that received 20 million PFU or 100 million PFU than in the group that received 3 million PFU, as assessed by ELISA and by pseudovirion neutralization assay. A second dose at 28 days after dose 1 significantly increased antibody titers at day 56, but the effect was diminished at 6 months. This Ebola vaccine candidate elicited anti-Ebola antibody responses. After vaccination, rVSV viremia occurred frequently but was transient. These results support further evaluation of the vaccine dose of 20 million PFU for preexposure prophylaxis and suggest that a second dose may boost antibody responses

  7. 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.

  8. 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

  9. 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

  10. Assessment of Lactobacillus gasseri as a Candidate Oral Vaccine Vector ▿

    PubMed Central

    Stoeker, Laura; Nordone, Shila; Gunderson, Sara; Zhang, Lin; Kajikawa, Akinobu; LaVoy, Alora; Miller, Michael; Klaenhammer, Todd R.; Dean, Gregg A.

    2011-01-01

    Lactobacillus species are commensal bacteria that have long been recognized as probiotic microbes and are generally regarded as safe (GRAS) for human consumption. We have investigated the use of L. gasseri as a vaccine vector for oral immunization against mucosal pathogens. Recent research has shown that the immune response to different lactobacilli can vary widely depending on the species or subspecies of Lactobacillus being studied. While some lactobacilli seem to induce oral tolerance, others induce an adaptive immune response. This study characterized the systemic and mucosal immune response to wild-type and genetically modified L. gasseri. L. gasseri primarily activates TLR2/6, with additional activation through the TLR2 homodimer. To expand the Toll-like receptor (TLR) activation profile of L. gasseri and the immunogenicity of the vector, a plasmid containing fliC, the gene encoding bacterial flagellin, was introduced which resulted in the strong activation of TLR5. The treatment of human myeloid dendritic cells with recombinant lactobacilli expressing flagellin triggered phenotypic maturation and the release of proinflammatory cytokines. In contrast, bacterial treatment also resulted in a statistically significant increase in IL-10 production. In vivo studies established that treatment with L. gasseri led to a diversification of B-cell populations in the lamina propria of the murine colon. Furthermore, treatment with genetically modified L. gasseri led to a significant decrease in the percentage of FoxP3+ colonic lymphocytes. Taken together, these data clarify the interaction of L. gasseri with the host immune system and support further investigation of the in vivo immunogenicity of L. gasseri expressing both flagellin and candidate vaccine antigens. PMID:21900526

  11. Design of different strategies of multivalent DNA-based vaccination against rabies and canine distemper in mice and dogs.

    PubMed

    Touihri, Leila; Ahmed, Sami Belhaj; Chtourou, Yacine; Daoud, Rahma; Bahloul, Chokri

    2012-12-27

    During the vaccination campaigns, puppies younger than 3 months old are not targeted and remain unvaccinated for at least the first year of their lives. Almost half of the reported rabid dogs are 6 months or younger. Hence, we should recommend the vaccination against rabies of young puppies. Unfortunately, owing to the exposure of puppies to infections with either canine parvovirus (CPV) or distemper virus (CDV) after the intervention of the vaccinators, owners are reluctant to vaccinate puppies against rabies. Therefore, it is necessary to include the CPV and CDV valences in the vaccine against rabies. Multivalent DNA-based vaccination in dogs, including rabies and distemper valences, could help in raising vaccine coverage. We have designed monovalent and multivalent DNA-based vaccine candidates for in vitro and in vivo assays. These plasmids encode to the rabies virus glycoprotein and/or the canine distemper virus hemagglutinin. The first strategy of multivalent DNA-based vaccination is by mixing plasmids encoding to a single antigen each. The second is by simply fusing the genes of the antigens together. The third is by adding the foot and mouth disease virus (FMDV) 2A oligopeptide gene into the antigen genes. The last strategy is by the design and use of a bicistronic plasmid with an "Internal Ribosome Entry Site" (IRES) domain. The monovalent construct against canine distemper was efficiently validated by inducing higher humoral immune responses compared to cell-culture-derived vaccine both in mice and dogs. All multivalent plasmids efficiently expressed both valences after in vitro transfection of BHK-21 cells. In BALB/c mice, the bicistronic IRES-dependant construct was the most efficient inducer of virus-neutralizing antibodies against both valences. It was able to induce better humoral immune responses compared to the administration of either cell-culture-derived vaccines or monovalent plasmids. The FMDV 2A was also efficient in the design of multivalent

  12. Reverse Vaccinology: An Approach for Identifying Leptospiral Vaccine Candidates

    PubMed Central

    Dellagostin, Odir A.; Grassmann, André A.; Rizzi, Caroline; Schuch, Rodrigo A.; Jorge, Sérgio; Oliveira, Thais L.; McBride, Alan J. A.; Hartwig, Daiane D.

    2017-01-01

    Leptospirosis is a major public health problem with an incidence of over one million human cases each year. It is a globally distributed, zoonotic disease and is associated with significant economic losses in farm animals. Leptospirosis is caused by pathogenic Leptospira spp. that can infect a wide range of domestic and wild animals. Given the inability to control the cycle of transmission among animals and humans, there is an urgent demand for a new vaccine. Inactivated whole-cell vaccines (bacterins) are routinely used in livestock and domestic animals, however, protection is serovar-restricted and short-term only. To overcome these limitations, efforts have focused on the development of recombinant vaccines, with partial success. Reverse vaccinology (RV) has been successfully applied to many infectious diseases. A growing number of leptospiral genome sequences are now available in public databases, providing an opportunity to search for prospective vaccine antigens using RV. Several promising leptospiral antigens were identified using this approach, although only a few have been characterized and evaluated in animal models. In this review, we summarize the use of RV for leptospirosis and discuss the need for potential improvements for the successful development of a new vaccine towards reducing the burden of human and animal leptospirosis. PMID:28098813

  13. Universal influenza vaccines: Shifting to better vaccines.

    PubMed

    Berlanda Scorza, Francesco; Tsvetnitsky, Vadim; Donnelly, John J

    2016-06-03

    Influenza virus causes acute upper and lower respiratory infections and is the most likely, among known pathogens, to cause a large epidemic in humans. Influenza virus mutates rapidly, enabling it to evade natural and vaccine-induced immunity. Furthermore, influenza viruses can cross from animals to humans, generating novel, potentially pandemic strains. Currently available influenza vaccines induce a strain specific response and may be ineffective against new influenza viruses. The difficulty in predicting circulating strains has frequently resulted in mismatch between the annual vaccine and circulating viruses. Low-resource countries remain mostly unprotected against seasonal influenza and are particularly vulnerable to future pandemics, in part, because investments in vaccine manufacturing and stockpiling are concentrated in high-resource countries. Antibodies that target conserved sites in the hemagglutinin stalk have been isolated from humans and shown to confer protection in animal models, suggesting that broadly protective immunity may be possible. Several innovative influenza vaccine candidates are currently in preclinical or early clinical development. New technologies include adjuvants, synthetic peptides, virus-like particles (VLPs), DNA vectors, messenger RNA, viral vectors, and attenuated or inactivated influenza viruses. Other approaches target the conserved exposed epitope of the surface exposed membrane matrix protein M2e. Well-conserved influenza proteins, such as nucleoprotein and matrix protein, are mainly targeted for developing strong cross-protective T cell responses. With multiple vaccine candidates moving along the testing and development pipeline, the field is steadily moving toward a product that is more potent, durable, and broadly protective than previously licensed vaccines. Copyright © 2016 World Health Organization. Published by Elsevier Ltd.. All rights reserved.

  14. Case study for a vaccine against leishmaniasis.

    PubMed

    Alvar, Jorge; Croft, Simon L; Kaye, Paul; Khamesipour, Ali; Sundar, Shyam; Reed, Steven G

    2013-04-18

    Leishmaniasis in many ways offers a unique vaccine case study. Two reasons for this are that leishmaniasis is a disease complex caused by several different species of parasite that are highly related, thus raising the possibility of developing a single vaccine to protect against multiple diseases. Another reason is the demonstration that a leishmaniasis vaccine may be used therapeutically as well as prophylactically. Although there is no registered human leishmaniasis vaccine today, immunization approaches using live or killed organisms, as well as defined vaccine candidates, have demonstrated at least some degree of efficacy in humans to prevent and to treat some forms of leishmaniasis, and there is a vigorous pipeline of candidates in development. Current approaches include using individual or combined antigens of the parasite or of salivary gland extract of the parasites' insect vector, administered with or without formulation in adjuvant. Animal data obtained with several vaccine candidates are promising and some have been or will be entered into clinical testing in the near future. There is sufficient scientific and epidemiological justification to continue to invest in the development of vaccines against leishmaniasis. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. A semi-synthetic whole parasite vaccine designed to protect against blood stage malaria.

    PubMed

    Giddam, Ashwini Kumar; Reiman, Jennifer M; Zaman, Mehfuz; Skwarczynski, Mariusz; Toth, Istvan; Good, Michael F

    2016-10-15

    Although attenuated malaria parasitized red blood cells (pRBCs) are promising vaccine candidates, their application in humans may be restricted for ethical and regulatory reasons. Therefore, we developed an organic microparticle-based delivery platform as a whole parasite malaria-antigen carrier to mimic pRBCs. Killed blood stage parasites were encapsulated within liposomes that are targeted to antigen presenting cells (APCs). Mannosylated lipid core peptides (MLCPs) were used as targeting ligands for the liposome-encapsulated parasite antigens. MLCP-liposomes, but not unmannosylated liposomes, were taken-up efficiently by APCs which then significantly upregulated expression of MHC-ll and costimulatory molecules, CD80 and CD86. Two such vaccines using rodent model systems were constructed - one with Plasmodium chabaudi and the other with P. yoelii. MLCP-liposome vaccines were able to control the parasite burden and extended the survival of mice. Thus, we have demonstrated an alternative delivery system to attenuated pRBCs with similar vaccine efficacy and added clinical advantages. Such liposomes are promising candidates for a human malaria vaccine. Attenuated whole parasite-based vaccines, by incorporating all parasite antigens, are very promising candidates, but issues relating to production, storage and safety concerns are significantly slowing their development. We therefore developed a semi-synthetic whole parasite malaria vaccine that is easily manufactured and stored. Two such prototype vaccines (a P. chabaudi and a P. yoelii vaccine) have been constructed. They are non-infectious, highly immunogenic and give good protection profiles. This semi-synthetic delivery platform is an exciting strategy to accelerate the development of a licensed malaria vaccine. Moreover, this strategy can be potentially applied to a wide range of pathogens. Copyright © 2016 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  16. 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

  17. 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

  18. A consultation on the optimization of controlled human malaria infection by mosquito bite for evaluation of candidate malaria vaccines.

    PubMed

    Laurens, Matthew B; Duncan, Christopher J; Epstein, Judith E; Hill, Adrian V; Komisar, Jack L; Lyke, Kirsten E; Ockenhouse, Christian F; Richie, Thomas L; Roestenberg, Meta; Sauerwein, Robert W; Spring, Michele D; Talley, Angela K; Moorthy, Vasee S

    2012-08-03

    Early clinical investigations of candidate malaria vaccines and antimalarial medications increasingly employ an established model of controlled human malaria infection (CHMI). Study results are used to guide further clinical development of vaccines and antimalarial medications as CHMI results to date are generally predictive of efficacy in malaria-endemic areas. The urgency to rapidly develop an efficacious malaria vaccine has increased demand for efficacy studies that include CHMI and the need for comparability of study results among the different centres conducting CHMI. An initial meeting with the goal to optimize and standardise CHMI procedures was held in 2009 with follow-up meetings in March and June 2010 to harmonise methods used at different centres. The end result is a standardised document for the design and conduct of CHMI and a second document for the microscopy methods used to determine the patency endpoint. These documents will facilitate high accuracy and comparability of CHMI studies and will be revised commensurate with advances in the field. Copyright © 2012. Published by Elsevier Ltd.. All rights reserved.

  19. 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.

  20. Evaluation of candidate vaccine approaches for MERS-CoV

    DOE PAGES

    Wang, Lingshu; Shi, Wei; Joyce, M. Gordon; ...

    2015-07-28

    The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development. Efforts focused solely on the receptor-binding domain (RBD) of the viral Spike (S) glycoprotein may not optimize neutralizing antibody (NAb) responses. Here we show that immunogens based on full-length S DNA and S1 subunit protein elicit robust serum-neutralizing activity against several MERS-CoV strains in mice and non-human primates. Serological analysis and isolation of murine monoclonal antibodies revealed that immunization elicits NAbs to RBD and, non-RBD portions of S1 and S2 subunit. Multiple neutralization mechanismsmore » were demonstrated by solving the atomic structure of a NAb-RBD complex, through sequencing of neutralization escape viruses and by constructing MERS-CoV S variants for serological assays. Immunization of rhesus macaques confers protection against MERS-CoV-induced radiographic pneumonia, as assessed using computerized tomography, supporting this strategy as a promising approach for MERS-CoV vaccine development.« less

  1. Evaluation of candidate vaccine approaches for MERS-CoV

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

    Wang, Lingshu; Shi, Wei; Joyce, M. Gordon

    The emergence of Middle East respiratory syndrome coronavirus (MERS-CoV) as a cause of severe respiratory disease highlights the need for effective approaches to CoV vaccine development. Efforts focused solely on the receptor-binding domain (RBD) of the viral Spike (S) glycoprotein may not optimize neutralizing antibody (NAb) responses. Here we show that immunogens based on full-length S DNA and S1 subunit protein elicit robust serum-neutralizing activity against several MERS-CoV strains in mice and non-human primates. Serological analysis and isolation of murine monoclonal antibodies revealed that immunization elicits NAbs to RBD and, non-RBD portions of S1 and S2 subunit. Multiple neutralization mechanismsmore » were demonstrated by solving the atomic structure of a NAb-RBD complex, through sequencing of neutralization escape viruses and by constructing MERS-CoV S variants for serological assays. Immunization of rhesus macaques confers protection against MERS-CoV-induced radiographic pneumonia, as assessed using computerized tomography, supporting this strategy as a promising approach for MERS-CoV vaccine development.« less

  2. H5N1 vaccines in humans

    PubMed Central

    Baz, Mariana; Luke, Catherine J; Cheng, Xing; Jin, Hong; Subbarao, Kanta

    2013-01-01

    The spread of highly pathogenic avian H5N1 influenza viruses since 1997 and their virulence for poultry and humans has raised concerns about their potential to cause an influenza pandemic. Vaccines offer the most viable means to combat a pandemic threat. However, it will be a challenge to produce, distribute and implement a new vaccine if a pandemic spreads rapidly. Therefore, efforts are being undertaken to develop pandemic vaccines that use less antigen and induce cross-protective and long-lasting responses, that can be administered as soon as a pandemic is declared or possibly even before, in order to prime the population and allow for a rapid and protective antibody response. In the last few years, several vaccine manufacturers have developed candidate pandemic and pre-pandemic vaccines, based on reverse genetics and have improved the immunogenicity by formulating these vaccines with different adjuvants. Some of the important and consistent observations from clinical studies with H5N1 vaccines are as follows: two doses of inactivated vaccine are generally necessary to elicit the level of immunity required to meet licensure criteria, less antigen can be used if an oil-in-water adjuvant is included, in general antibody titers decline rapidly but can be boosted with additional doses of vaccine and if high titers of antibody are elicited, cross-reactivity against other clades is observed. Prime-boost strategies elicit a more robust immune response. In this review, we discuss data from clinical trials with a variety of H5N1 influenza vaccines. We also describe studies conducted in animal models to explore the possibility of reassortment between pandemic live attenuated vaccine candidates and seasonal influenza viruses, since this is an important consideration for the use of live vaccines in a pandemic setting. PMID:23726847

  3. 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.

  4. An interferon inducing porcine reproductive and respiratory syndrome virus vaccine candidate elicits protection against challenge with the heterologous virulent type 2 strain VR-2385 in pigs.

    PubMed

    Fontanella, Eve; Ma, Zexu; Zhang, Yanjin; de Castro, Alessandra M M G; Shen, Huigang; Halbur, Patrick G; Opriessnig, Tanja

    2017-01-03

    Achieving consistent protection by vaccinating pigs against porcine reproductive and respiratory syndrome virus (PRRSV) remains difficult. Recently, an interferon-inducing PRRSV vaccine candidate strain A2MC2 was demonstrated to be attenuated and induced neutralizing antibodies. The objective of this study was to determine the efficacy of passage 90 of A2MC2 (A2P90) to protect pigs against challenge with moderately virulent PRRSV strain VR-2385 (92.3% nucleic acid identity with A2MC2) and highly virulent atypical PRRSV MN184 (84.5% nucleic acid identity with A2MC2). Forty 3-week old pigs were randomly assigned to five groups including a NEG-CONTROL group (non-vaccinated, non-challenged), VAC-VR2385 (vaccinated, challenged with strain VR-2385), VR2385 (challenged with strain VR-2385), VAC-MN184 (vaccinated, challenged with strain MN184) and a MN184 group (challenged with MN184 virus). Vaccination was done at 3weeks of age followed by challenge at 8weeks of age. No viremia was detectable in any of the vaccinated pigs; however, by the time of challenge, 15/16 vaccinated pigs had seroconverted based on ELISA and had neutralizing antibodies against a homologous strain with titers ranging from 8 to 128. Infection with VR-2385 resulted in mild-to-moderate clinical disease and lesions. For VR-2385 infected pigs, vaccination significantly lowered PRRSV viremia and nasal shedding by 9days post challenge (dpc), significantly reduced macroscopic lung lesions, and significantly increased the average daily weight gain compared to the non-vaccinated pigs. Infection with MN184 resulted in moderate-to-severe clinical disease and lesions regardless of vaccination status; however, vaccinated pigs had significantly less nasal shedding by dpc 5 compared to non-vaccinated pigs. Under the study conditions, the A2P90 vaccine strain was attenuated without detectable shedding, improved weight gain, and offered protection to the pigs challenged with VR-2385 by reduction of virus load and

  5. Optimizing expression of the pregnancy malaria vaccine candidate, VAR2CSA in Pichia pastoris.

    PubMed

    Avril, Marion; Hathaway, Marianne J; Cartwright, Megan M; Gose, Severin O; Narum, David L; Smith, Joseph D

    2009-06-29

    VAR2CSA is the main candidate for a vaccine against pregnancy-associated malaria, but vaccine development is complicated by the large size and complex disulfide bonding pattern of the protein. Recent X-ray crystallographic information suggests that domain boundaries of VAR2CSA Duffy binding-like (DBL) domains may be larger than previously predicted and include two additional cysteine residues. This study investigated whether longer constructs would improve VAR2CSA recombinant protein secretion from Pichia pastoris and if domain boundaries were applicable across different VAR2CSA alleles. VAR2CSA sequences were bioinformatically analysed to identify the predicted C11 and C12 cysteine residues at the C-termini of DBL domains and revised N- and C-termimal domain boundaries were predicted in VAR2CSA. Multiple construct boundaries were systematically evaluated for protein secretion in P. pastoris and secreted proteins were tested as immunogens. From a total of 42 different VAR2CSA constructs, 15 proteins (36%) were secreted. Longer construct boundaries, including the predicted C11 and C12 cysteine residues, generally improved expression of poorly or non-secreted domains and permitted expression of all six VAR2CSA DBL domains. However, protein secretion was still highly empiric and affected by subtle differences in domain boundaries and allelic variation between VAR2CSA sequences. Eleven of the secreted proteins were used to immunize rabbits. Antibodies reacted with CSA-binding infected erythrocytes, indicating that P. pastoris recombinant proteins possessed native protein epitopes. These findings strengthen emerging data for a revision of DBL domain boundaries in var-encoded proteins and may facilitate pregnancy malaria vaccine development.

  6. Optimizing expression of the pregnancy malaria vaccine candidate, VAR2CSA in Pichia pastoris

    PubMed Central

    Avril, Marion; Hathaway, Marianne J; Cartwright, Megan M; Gose, Severin O; Narum, David L; Smith, Joseph D

    2009-01-01

    Background VAR2CSA is the main candidate for a vaccine against pregnancy-associated malaria, but vaccine development is complicated by the large size and complex disulfide bonding pattern of the protein. Recent X-ray crystallographic information suggests that domain boundaries of VAR2CSA Duffy binding-like (DBL) domains may be larger than previously predicted and include two additional cysteine residues. This study investigated whether longer constructs would improve VAR2CSA recombinant protein secretion from Pichia pastoris and if domain boundaries were applicable across different VAR2CSA alleles. Methods VAR2CSA sequences were bioinformatically analysed to identify the predicted C11 and C12 cysteine residues at the C-termini of DBL domains and revised N- and C-termimal domain boundaries were predicted in VAR2CSA. Multiple construct boundaries were systematically evaluated for protein secretion in P. pastoris and secreted proteins were tested as immunogens. Results From a total of 42 different VAR2CSA constructs, 15 proteins (36%) were secreted. Longer construct boundaries, including the predicted C11 and C12 cysteine residues, generally improved expression of poorly or non-secreted domains and permitted expression of all six VAR2CSA DBL domains. However, protein secretion was still highly empiric and affected by subtle differences in domain boundaries and allelic variation between VAR2CSA sequences. Eleven of the secreted proteins were used to immunize rabbits. Antibodies reacted with CSA-binding infected erythrocytes, indicating that P. pastoris recombinant proteins possessed native protein epitopes. Conclusion These findings strengthen emerging data for a revision of DBL domain boundaries in var-encoded proteins and may facilitate pregnancy malaria vaccine development. PMID:19563628

  7. Progress and prospects for blood-stage malaria vaccines.

    PubMed

    Miura, Kazutoyo

    2016-06-01

    There have been significant decreases in malaria mortality and morbidity in the last 10-15 years, and the most advanced pre-erythrocytic malaria vaccine, RTS,S, received a positive opinion from European regulators in July 2015. However, no blood-stage vaccine has reached a phase III trial. The first part of this review summarizes the pros and cons of various assays and models that have been and will be used to predict the efficacy of blood-stage vaccines. In the second part, blood-stage vaccine candidates that showed some efficacy in human clinical trials or controlled human malaria infection models are discussed. Then, candidates under clinical investigation are described in the third part, and other novel candidates and strategies are reviewed in the last part.

  8. Fact and fiction in tuberculosis vaccine research: 10 years later.

    PubMed

    Kaufmann, Stefan H E

    2011-08-01

    Tuberculosis is one of the most deadly infectious diseases. The situation is worsening because of co-infection with HIV and increased occurrence of drug resistance. Although the BCG vaccine has been in use for 90 years, protection is insufficient; new vaccine candidates are therefore needed. 12 potential vaccines have gone into clinical trials. Ten are aimed at prevention of tuberculosis and, of these, seven are subunit vaccines either as adjuvanted or viral-vectored antigens. These vaccines would be boosters of BCG-prime vaccination. Three vaccines are recombinant BCG constructs-possible replacements for BCG. Additional vaccine candidates will enter clinical trials in the near future, including postexposure vaccines for individuals with latent infection. In the long term, vaccines that prevent or eradicate infection with Mycobacterium tuberculosis would be the best possible option. Improved knowledge of immunology, molecular microbiology, cell biology, biomics, and biotechnology has paved the way towards an effective and safe vaccine against tuberculosis. The pipeline of new vaccine candidates from preclinical to clinical testing could be accelerated by development of biomarkers that can predict the clinical outcome of tuberculosis. Copyright © 2011 Elsevier Ltd. All rights reserved.

  9. Aerosol Delivery of a Candidate Universal Influenza Vaccine Reduces Viral Load in Pigs Challenged with Pandemic H1N1 Virus

    PubMed Central

    Morgan, Sophie B.; Hemmink, Johanneke D.; Porter, Emily; Harley, Ross; Shelton, Holly; Aramouni, Mario; Everett, Helen E.; Brookes, Sharon M.; Bailey, Michael; Townsend, Alain M.; Charleston, Bryan

    2016-01-01

    Influenza A viruses are a major health threat to livestock and humans, causing considerable mortality, morbidity, and economic loss. Current inactivated influenza vaccines are strain specific and new vaccines need to be produced at frequent intervals to combat newly arising influenza virus strains, so that a universal vaccine is highly desirable. We show that pandemic H1N1 influenza virus in which the hemagglutinin signal sequence has been suppressed (S-FLU), when administered to pigs by aerosol can induce CD4 and CD8 T cell immune responses in blood, bronchoalveolar lavage (BAL), and tracheobronchial lymph nodes. Neutralizing Ab was not produced. Detection of a BAL response correlated with a reduction in viral titer in nasal swabs and lungs, following challenge with H1N1 pandemic virus. Intratracheal immunization with a higher dose of a heterologous H5N1 S-FLU vaccine induced weaker BAL and stronger tracheobronchial lymph node responses and a lesser reduction in viral titer. We conclude that local cellular immune responses are important for protection against influenza A virus infection, that these can be most efficiently induced by aerosol immunization targeting the lower respiratory tract, and that S-FLU is a promising universal influenza vaccine candidate. PMID:27183611

  10. Challenges in reducing dengue burden; diagnostics, control measures and vaccines.

    PubMed

    Lam, Sai Kit

    2013-09-01

    Dengue is a major public health concern worldwide, with the number of infections increasing globally. The illness imposes the greatest economic and human burden on developing countries that have limited resources to deal with the scale of the problem. No cure for dengue exists; treatment is limited to rehydration therapy, and with vector control strategies proving to be relatively ineffective, a vaccine is an urgent priority. Despite the numerous challenges encountered in the development of a dengue vaccine, several vaccine candidates have shown promise in clinical development and it is believed that a vaccination program would be at least as cost-effective as current vector control programs. The lead candidate vaccine is a tetravalent, live attenuated, recombinant vaccine, which is currently in Phase III clinical trials. Vaccine introduction is a complex process that requires consideration and is discussed here. This review discusses the epidemiology, burden and pathogenesis of dengue, as well as the vaccine candidates currently in clinical development.

  11. Advances and challenges in malaria vaccine development.

    PubMed

    Crompton, Peter D; Pierce, Susan K; Miller, Louis H

    2010-12-01

    Malaria caused by Plasmodium falciparum remains a major public health threat, especially among children and pregnant women in Africa. An effective malaria vaccine would be a valuable tool to reduce the disease burden and could contribute to elimination of malaria in some regions of the world. Current malaria vaccine candidates are directed against human and mosquito stages of the parasite life cycle, but thus far, relatively few proteins have been studied for potential vaccine development. The most advanced vaccine candidate, RTS,S, conferred partial protection against malaria in phase II clinical trials and is currently being evaluated in a phase III trial in Africa. New vaccine targets need to be identified to improve the chances of developing a highly effective malaria vaccine. A better understanding of the mechanisms of naturally acquired immunity to malaria may lead to insights for vaccine development.

  12. Investigation into the misincorporation of norleucine into a recombinant protein vaccine candidate.

    PubMed

    Ni, Joyce; Gao, Meg; James, Andrew; Yao, Jiansheng; Yuan, Tao; Carpick, Bruce; D'Amore, Tony; Farrell, Patrick

    2015-06-01

    A high level of norleucine misincorporation was detected in a recombinant methionine-rich protein vaccine candidate expressed in E. coli K12. An investigation was conducted to evaluate a simple remediation strategy to reduce norleucine misincorporation and to determine if the phenomenon was either (a) due to the depletion of methionine during fermentation, (b) a result of the cultivation environment, or (c) a strain-specific effect. While supplementation with exogenous methionine improved product quality, the undesirable biosynthesis of non-standard amino acids such as norleucine and norvaline persisted. In contrast, non-standard amino acid biosynthesis was quickly minimized upon selection of an appropriate fed-batch process control strategy, fermentation medium, and nutrient feed. By expressing the same protein in E. coli BL21(DE3), it was determined that the biosynthesis of norleucine and norvaline, and the misincorporation of norleucine into the protein were primarily attributed to the use of E. coli K12 as the host for protein expression.

  13. Induction of long-lasting multi-specific CD8+ T cells by a four-component DNA-MVA/HIVA-RENTA candidate HIV-1 vaccine in rhesus macaques.

    PubMed

    Im, Eung-Jun; Nkolola, Joseph P; di Gleria, Kati; McMichael, Andrew J; Hanke, Tomás

    2006-10-01

    As a part of a long-term effort to develop vaccine against HIV-1 clade A inducing protective T cell responses in humans, we run mutually complementing studies in humans and non-human primates (NHP) with the aim to maximize vaccine immunogenicity. The candidate vaccine under development has four components, pTHr.HIVA and pTH.RENTA DNA, and modified vaccinia virus Ankara (MVA).HIVA and MVA.RENTA, delivered in a heterologous DNA prime-MVA boost regimen. While the HIVA (Gag/epitopes) components have been tested in NHP and over 300 human subjects, we plan to test in humans the RENTA (reverse transcriptase, gp41, Nef, Tat) vaccines designed to broaden HIVA-induced responses in year 2007. Here, we investigated the four-component vaccine long-term immunogenicity in Mamu-A*01-positive rhesus macaques and demonstrated that the vaccine-induced T cells were multi-specific, multi-functional, readily proliferated to recall peptides and were circulating in the peripheral blood of vaccine recipients over 1 year after vaccine administration. The consensus clade A-elicited T cells recognized 50% of tested epitope variants from other HIV-1 clades. Thus, the DNA-MVA/HIVA-RENTA vaccine induced memory T cells of desirable characteristics and similarities to those induced in humans by HIVA vaccines alone; however, single-clade vaccines may not elicit sufficiently cross-reactive responses.

  14. Potency assay design for adjuvanted recombinant proteins as malaria vaccines.

    PubMed

    Giersing, Birgitte K; Dubovsky, Filip; Saul, Allan; Denamur, Francoise; Minor, Philip; Meade, Bruce

    2006-05-15

    Many licensed vaccines are composed of live, attenuated or inactivated whole-cell microorganisms, or they comprise purified components from whole-cell extracts or culture supernatants. For some diseases, pathology is fairly well understood, and there may be known correlates of protection that provide obvious parameters for assessment of vaccine potency. However, this is not always the case, and some effective vaccines are routinely used even though the mechanisms or correlates of protection are unknown. Some more modern vaccine approaches employ purified recombinant proteins, based on molecules that appear on the surface of the pathogen. This is one of the strategies that has been adopted in the quest to develop a malaria vaccine. Use of these parasite antigens as vaccine candidates is supported by substantial epidemiological data, and some have demonstrated the ability to elicit protective responses in animal models of malaria infection. However, there is as yet no immunological correlate of protection and no functional assays or animal models that have demonstrated the ability to predict efficacy in humans. There is little precedence for the most appropriate and practical method for assessing potency of vaccines based on these recombinant molecules for malaria vaccines. This is likely because the majority of malaria vaccine candidates have only recently entered clinical evaluation. The PATH Malaria Vaccine Initiative (MVI) convened a panel with expertise in potency assay design from industry, governmental institutions, and regulatory bodies to discuss and review the rationale, available methods, and best approaches for assessing the potency of recombinant proteins, specifically for their use as malarial vaccines. The aim of this meeting was to produce a discussion document on the practical potency assessment of recombinant protein malaria vaccines, focusing on early phase potency assay development.

  15. Protection against Experimental Cryptococcosis following Vaccination with Glucan Particles Containing Cryptococcus Alkaline Extracts

    PubMed Central

    Lee, Chrono K.; Huang, Haibin; Shen, Zu T.; Lodge, Jennifer K.; Leszyk, John; Ostroff, Gary R.

    2015-01-01

    ABSTRACT A vaccine capable of protecting at-risk persons against infections due to Cryptococcus neoformans and Cryptococcus gattii could reduce the substantial global burden of human cryptococcosis. Vaccine development has been hampered though, by lack of knowledge as to which antigens are immunoprotective and the need for an effective vaccine delivery system. We made alkaline extracts from mutant cryptococcal strains that lacked capsule or chitosan. The extracts were then packaged into glucan particles (GPs), which are purified Saccharomyces cerevisiae cell walls composed primarily of β-1,3-glucans. Subcutaneous vaccination with the GP-based vaccines provided significant protection against subsequent pulmonary infection with highly virulent strains of C. neoformans and C. gattii. The alkaline extract derived from the acapsular strain was analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS), and the most abundant proteins were identified. Separation of the alkaline extract by size exclusion chromatography revealed fractions that conferred protection when loaded in GP-based vaccines. Robust Th1- and Th17-biased CD4+ T cell recall responses were observed in the lungs of vaccinated and infected mice. Thus, our preclinical studies have indicated promising cryptococcal vaccine candidates in alkaline extracts delivered in GPs. Ongoing studies are directed at identifying the individual components of the extracts that confer protection and thus would be promising candidates for a human vaccine. PMID:26695631

  16. Use of an Sm-p80–Based Therapeutic Vaccine to Kill Established Adult Schistosome Parasites in Chronically Infected Baboons

    PubMed Central

    Karmakar, Souvik; Zhang, Weidong; Ahmad, Gul; Torben, Workineh; Alam, Mayeen U.; Le, Loc; Damian, Raymond T.; Wolf, Roman F.; White, Gary L.; Carey, David W.; Carter, Darrick; Reed, Steven G.; Siddiqui, Afzal A.

    2014-01-01

    No vaccines are available for human use for any parasitic infections, including the helminthic disease schistosomiasis. Sm-p80, the large subunit of Schistosoma mansoni calpain, is a leading antigen candidate for a schistosomiasis vaccine. Prophylactic and antifecundity efficacies of Sm-p80 have been tested using a variety of vaccine approaches in both rodent and nonhuman primate models. However, the therapeutic efficacy of a Sm-p80–based vaccine had not been determined. In this study, we evaluated the therapeutic efficacy of Sm-p80 by using 2 different strategies and 3 Sm-p80–based vaccine formulations in baboons. Vaccine formulations were able to decrease established adult worms by 10%–36%, reduce retention of eggs in tissues by 10%–57%, and decrease egg excretion in feces by 13%–33%, compared with control formulations. Marked differences were observed in B and T cell immune correlates between vaccinated and control animals. This is the first report of killing of established adult schistosome worms by a vaccine. In addition to distinct prophylactic efficacy of Sm-p80, this study adds to the evidence that Sm-p80 is a potentially important antigen with both substantial prophylactic and therapeutic efficacies. These data reinforce that Sm-p80 should be moved forward along the path toward human clinical trials. PMID:24436452

  17. Technical Transformation of Biodefense Vaccines

    PubMed Central

    Lu, Shan; Wang, Shixia

    2013-01-01

    Biodefense vaccines are developed against a diverse group of pathogens. Vaccines were developed for some of these pathogens a long time ago but they are facing new challenges to move beyond the old manufacturing technologies. New vaccines to be developed against other pathogens have to determine whether to follow traditional vaccination strategies or to seek new approaches. Advances in basic immunology and recombinant DNA technology have fundamentally transformed the process of formulating a vaccine concept, optimizing protective antigens, and selecting the most effective vaccine delivery approach for candidate biodefense vaccines. PMID:19837293

  18. 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.

  19. DNA vaccine against visceral leishmaniasis: a promising approach for prevention and control.

    PubMed

    Kumar, A; Samant, M

    2016-05-01

    The visceral leishmaniasis (VL) caused by Leishmania donovani parasite severely affects large populations in tropical and subtropical regions of the world. The arsenal of drugs available is limited, and resistance is common in clinical field isolates. Therefore, vaccines could be an important alternative for prevention against VL. Recently, some investigators advocated the protective efficacy of DNA vaccines, which induces the T cell-based immunity against VL. The vaccine antigens are selected as conserved in various Leishmania species and provide a viable strategy for DNA vaccine development. Our understanding for DNA vaccine development against VL is not enough and much technological advancement is required. Improved formulations and methods of delivery are required, which increase the uptake of DNA vaccine by cells; optimization of vaccine vectors/encoded antigens to augment and direct the host immune response in VL. Despite the many genes identified as vaccine candidates, the disappointing potency of the DNA vaccines in VL underscores the challenges encountered in the efforts to translate efficacy in preclinical models into clinical realities. This review will provide a brief background of DNA vaccines including the insights gained about the design, strategy, safety issues, varied candidates, progress and challenges that play a role in their ability against VL. © 2016 John Wiley & Sons Ltd.

  20. Live Respiratory Syncytial Virus (RSV) Vaccine Candidate Containing Stabilized Temperature-Sensitivity Mutations Is Highly Attenuated in RSV-Seronegative Infants and Children.

    PubMed

    Buchholz, Ursula J; Cunningham, Coleen K; Muresan, Petronella; Gnanashanmugam, Devasena; Sato, Paul; Siberry, George K; Rexroad, Vivian; Valentine, Megan; Perlowski, Charlotte; Schappell, Elizabeth; Thumar, Bhagvinji; Luongo, Cindy; Barr, Emily; Aziz, Mariam; Yogev, Ram; Spector, Stephen A; Collins, Peter L; McFarland, Elizabeth J; Karron, Ruth A

    2018-04-11

    Respiratory syncytial virus (RSV) is the most important viral cause of severe respiratory illness in young children and lacks a vaccine. RSV cold-passage/stabilized 2 (RSVcps2) is a modification of a previously evaluated vaccine candidate in which 2 major attenuating mutations have been stabilized against deattenuation. RSV-seronegative 6-24-month-old children received an intranasal dose of 105.3 plaque-forming units (PFU) of RSVcps2 (n = 34) or placebo (n = 16) (International Maternal Pediatric Adolescent AIDS Clinical Trials protocol P1114 and companion protocol CIR285). RSV serum neutralizing antibody titers before and 56 days after vaccination, vaccine virus infectivity (defined as vaccine virus shedding detectable in nasal wash and/or a ≥4-fold rise in serum antibodies), reactogenicity, and genetic stability were assessed. During the following RSV transmission season, participants were monitored for respiratory illness, with serum antibody titers measured before and after the season. A total of 85% of vaccinees were infected with RSVcps2 (median peak titer, 0.5 log10 PFU/mL by culture and 2.9 log10 copies/mL by polymerase chain reaction analysis); 77% shed vaccine virus, and 59% developed a ≥4-fold rise in RSV-serum neutralizing antibody titers. Respiratory tract and/or febrile illness occurred at the same rate (50%) in the vaccine and placebo groups. Deattenuation was not detected at either of 2 stabilized mutation sites. RSVcps2 was well tolerated and moderately immunogenic and had increased genetic stability in 6-24-month-old RSV-seronegative children. NCT01852266 and NCT01968083.

  1. Micro/nanoparticle adjuvants for antileishmanial vaccines: present and future trends.

    PubMed

    Badiee, Ali; Heravi Shargh, Vahid; Khamesipour, Ali; Jaafari, Mahmoud Reza

    2013-01-21

    Leishmania infection continues to have a major impact on public health inducing significant morbidity and mortality mostly in the poorest populations. Drug resistance, toxicity and side effects associated with expensive chemotherapeutic treatments and difficult reservoir control emphasize the need for a safe and effective vaccine which is not available yet. Although, Leishmanization (LZ) was shown to be effective against cutaneous leishmaniasis, standardization and safety are the main problems of LZ. First generation killed parasites demonstrated limited efficacy in phase 3 trials and moreover well defined molecules have not reached to phase 3 yet. Limited efficacy in vaccines against leishmaniasis is partly due to lack of an appropriate adjuvant. Hence, the use of particulate delivery systems as carriers for antigen and/or immunostimulatory adjuvants for effective delivery to the antigen-presenting cells (APCs) is a valuable strategy to enhance vaccine efficacies. Particle-based delivery systems such as emulsions, liposomes, virosomes, and polymeric microspheres have the potential for successfully delivering antigens, which can then be further improved via incorporation of additional antigenic or immustimulatory adjuvant components in or onto the particle carrier system. In this review, we have attempted to provide a list of particulate vaccine delivery systems involved in the production of candidate leishmaniasis vaccines and introduced some potentially useful vaccine delivery systems for leishmaniasis in future experiments. In conclusion, combination vaccines (adjuvant systems) composed of candidate antigens and more importantly well-developed particulate delivery systems, such as lipid-based particles containing immunostimulatory adjuvants, have a chance to succeed as antileishmanial vaccines. Copyright © 2012 Elsevier Ltd. All rights reserved.

  2. Therapeutic vaccination to treat chronic infectious diseases

    PubMed Central

    Boukhebza, Houda; Bellon, Nadine; Limacher, Jean Marc; Inchauspé, Geneviève

    2012-01-01

    A famous milestone in the vaccine field has been the first successful vaccination against smallpox, in 1798, by Edward Jenner. Using the vaccinia cowpox virus, Jenner was able to protect vaccinees from variola or smallpox. The Modified Virus Ankara (MVA) poxvirus strain has been one of the vaccines subsequently developed to prevent smallpox infection and was selected by the US government in their Biodefense strategy. Progress in molecular biology and immunology associated with MVA infection has led to the development of MVA as vaccine platform, both in the field of preventive and therapeutic vaccines. This later class of therapeutics has witnessed growing interest that has translated into an increasing number of vaccine candidates reaching the clinics. Among those, MVA-based therapeutic vaccines have addressed four major chronic infections including viral hepatitis, AIDS, human papillomavirus-linked pathologies and tuberculosis. Clinical trials encompass phase 1 and 2 and have started to show significant results and promises. PMID:22894957

  3. IMOJEV(®): a Yellow fever virus-based novel Japanese encephalitis vaccine.

    PubMed

    Appaiahgari, Mohan Babu; Vrati, Sudhanshu

    2010-12-01

    Japanese encephalitis (JE) is a disease of the CNS caused by Japanese encephalitis virus (JEV). The disease appears in the form of frequent outbreaks in most south- and southeast Asian countries and the virus has become endemic in several areas. There is no licensed therapy available and disease control by vaccination is considered to be most effective. Mouse brain-derived inactivated JE vaccines, although immunogenic, have several limitations in terms of safety, availability and requirement for multiple doses. Owing to these drawbacks, the WHO called for the development of novel, safe and more efficacious JE vaccines. Several candidate vaccines have been developed and at least three of them that demonstrated strong immunogenicity after one or two doses of the vaccine in animal models were subsequently tested in various clinical trials. One of these vaccines, IMOJEV(®) (JE-CV and previously known as ChimeriVax™-JE), is a novel recombinant chimeric virus vaccine, developed using the Yellow fever virus (YFV) vaccine vector YFV17D, by replacing the cDNA encoding the envelope proteins of YFV with that of an attenuated JEV strain SA14-14-2. IMOJEV was found to be safe, highly immunogenic and capable of inducing long-lasting immunity in both preclinical and clinical trials. Moreover, a single dose of IMOJEV was sufficient to induce protective immunity, which was similar to that induced in adults by three doses of JE-VAX(®), a mouse brain-derived inactivated JE vaccine. Recently, Phase III trials evaluating the immunogenicity and safety of the chimeric virus vaccine have been successfully completed in some JE-endemic countries and the vaccine manufacturers have filed an application for vaccine registration. IMOJEV may thus be licensed for use in humans as an improved alternative to the currently licensed JE vaccines.

  4. Progress and prospects for blood-stage malaria vaccines

    PubMed Central

    Miura, Kazutoyo

    2016-01-01

    ABSTRACT There have been significant decreases in malaria mortality and morbidity in the last 10-15 years, and the most advanced pre-erythrocytic malaria vaccine, RTS,S, received a positive opinion from European regulators in July 2015. However, no blood-stage vaccine has reached a phase III trial. The first part of this review summarizes the pros and cons of various assays and models that have been and will be used to predict the efficacy of blood-stage vaccines. In the second part, blood-stage vaccine candidates that showed some efficacy in human clinical trials or controlled human malaria infection models are discussed. Then, candidates under clinical investigation are described in the third part, and other novel candidates and strategies are reviewed in the last part. PMID:26760062

  5. A School-Based Human Papillomavirus Vaccination Program in Barretos, Brazil: Final Results of a Demonstrative Study

    PubMed Central

    Fregnani, José Humberto Tavares Guerreiro; Carvalho, André Lopes; Eluf-Neto, José; Ribeiro, Karina de Cássia Braga; Kuil, Larissa de Melo; da Silva, Tauana Arcadepani; Rodrigues, Silvia Lapola; Mauad, Edmundo Carvalho; Longatto-Filho, Adhemar; Villa, Luisa Lina

    2013-01-01

    Introduction The implementation of a public HPV vaccination program in several developing countries, especially in Latin America, is a great challenge for health care specialists. Aim To evaluate the uptake and the three-dose completion rates of a school-based HPV vaccination program in Barretos (Brazil). Methods The study included girls who were enrolled in public and private schools and who regularly attended the sixth and seventh grades of elementary school (mean age: 11.9 years). A meeting with the parents or guardians occurred approximately one week before the vaccination in order to explain the project and clarify the doubts. The quadrivalent vaccine was administered using the same schedule as in the product package (0–2–6 months). The school visits for regular vaccination occurred on previously scheduled dates. The vaccine was also made available at Barretos Cancer Hospital for the girls who could not be vaccinated on the day when the team visited the school. Results Among the potential candidates for vaccination (n = 1,574), the parents or guardians of 1,513 girls (96.1%) responded to the invitation to participate in the study. A total of 1,389 parents or guardians agreed to participate in the program (acceptance rate = 91.8%). The main reason for refusing to participate in the vaccination program was fear of adverse events. The vaccine uptake rates for the first, second, and third doses were 87.5%, 86.3% and 85.0%, respectively. The three-dose completion rate was 97.2%. Conclusions This demonstrative study achieved high rates of vaccination uptake and completion of three vaccine doses in children 10–16 years old from Brazil. The feasibility and success of an HPV vaccination program for adolescents in a developing country may depend on the integration between the public health and schooling systems. PMID:23638130

  6. A tetravalent alphavirus-vector based Dengue vaccine provides effective immunity in an early life mouse model

    PubMed Central

    Khalil, Syed Muaz; Tonkin, Daniel R.; Mattocks, Melissa D.; Snead, Andrew T.; Johnston, Robert E.; White, Laura J.

    2014-01-01

    Dengue viruses (DENV1-4) cause 390 million clinical infections every year, several hundred thousand of which progress to severe hemorrhagic and shock syndromes. Preexisting immunity resulting from a previous DENV infection is the major risk factor for severe dengue during secondary heterologous infections. During primary infections in infants, maternal antibodies pose an analogous risk. At the same time, maternal antibodies are likely to prevent induction of endogenous anti-DENV antibodies in response to current live, attenuated virus (LAV) vaccine candidates. Any effective early life dengue vaccine has to overcome maternal antibody interference (leading to ineffective vaccination) and poor induction of antibody responses (increasing the risk of severe dengue disease upon primary infection). In a previous study, we demonstrated that a non-propagating Venezuelan equine encephalitis virus replicon expression vector (VRP), expressing the ectodomain of DENV E protein (E85), overcomes maternal interference in a BALB/c mouse model. We report here that a single immunization with a tetravalent VRP vaccine induced NAb and T-cell responses to each serotype at a level equivalent to the monovalent vaccine components, suggesting that this vaccine modality can overcome serotype interference. Furthermore, neonatal immunization was durable and could be boosted later in life to further increase NAb and T-cell responses. Although the neonatal immune response was lower in magnitude than responses in adult BALB/c mice, we demonstrate that VRP vaccines generated protective immunity from a lethal challenge after a single neonatal immunization. In summary, VRP vaccines expressing DENV antigens were immunogenic and protective in neonates, and hence are promising candidates for safe and effective vaccination in early life. PMID:24882043

  7. Immunogenicity of sanofi pasteur tetravalent dengue vaccine.

    PubMed

    Guy, Bruno

    2009-10-01

    A candidate tetravalent (TV) dengue vaccine based on the yellow fever (YF) 17D vaccine has been developed by sanofi pasteur. This dengue TV vaccine induced a controlled dendritic cell stimulation in vitro. In clinical trials, Th1 and CD8 responses were induced with an IFN-gamma/TNF-alpha ratio favouring IFN-gamma in both cases, regardless of whether the vaccine recipients were flavivirus naive or not. There was an absence of Th2 response in all cases. The Th1 response was dominated by the D4 serotype in flavivirus naive individuals after initial vaccination but broadened to include all serotypes after second vaccination. This broadened response was also observed after primary dengue TV vaccination in subjects previously administered monovalent live-attenuated dengue 1 and dengue 2 vaccines. Notably, virtually no cross-reactivity between YF 17D and dengue NS3 antigens at the CD8 level was observed. Clinical and pre-clinical results support the favourable immunogenicity and short-term safety of the dengue TV. Future studies will establish the longevity of the vaccine-induced immunity and requirements for boosters.

  8. Novel formulations enhance the thermal stability of live-attenuated flavivirus vaccines

    PubMed Central

    Wiggan, O’Neil; Silengo, Shawn J.; Kinney, Richard M.; Osorio, Jorge E.; Huang, Claire Y.-H.; Stinchcomb, Dan T.

    2011-01-01

    Thermal stability is important for the manufacture, distribution and administration of vaccines, especially in tropical developing countries, where particularly adverse field conditions exist. Current live-attenuated flavivirus vaccines exhibit relatively poor liquid stability in clinical settings, and clinicians are instructed to discard the yellow fever vaccine 1h after reconstitution. We have identified novel combinations of excipients that greatly enhance the thermal stability of live-attenuated DEN-2 PDK-53-based flavivirus vaccine candidates. Liquid formulations comprising a sugar, albumin and a pluronic polymer minimized the loss of flavivirus infectious titer to less than 0.5log(10)pfu after storage for at least 8h at 37°C, 7 days at room temperature or at least 11 weeks at 4°C. Additionally, these formulations prevented reduction of viral infectivity after two freeze-thaw cycles of virus. Formulated candidate vaccines were readily lyophilized and reconstituted with minimal loss of viral titers. In mice, the formulations were safe and did not hinder the ability of the vaccine virus to generate a potent, protective immune response. These formulations provided significantly greater liquid-phase stability than has been reported previously for other flavivirus vaccine formulations. The enhanced thermal stability provided by the formulations described here will facilitate the effective distribution of flavivirus vaccines worldwide. PMID:21803103

  9. The state-of-the-art of approved and under-development cholera vaccines.

    PubMed

    Pastor, M; Pedraz, J L; Esquisabel, A

    2013-08-28

    Cholera remains a huge public health problem. Although in 1894, the first cholera vaccination was reported, an ideal vaccine that meets all the requirements of the WHO has not yet been produced. Among the different approaches used for cholera vaccination, attenuated vaccines represent a major category; these vaccines are beneficial in being able to induce a strong protective response after a single administration. However, they have possible negative effects on immunocompromised patient populations. Both the licensed CVD103-HgR and other vaccine approaches under development are detailed in this article, such as the Vibrio cholerae 638 vaccine candidate, Peru-15 or CholeraGarde(®) and the VA1.3, VA1.4, IEM 108 VCUSM2 and CVD 112 vaccine candidates. In another strategy, killed V. cholerae vaccines have been developed, including Dukoral(®), mORCAX(®) and Sanchol™. The killed vaccines are already sold, and they have successfully demonstrated their potential to protect populations in endemic areas or after natural disasters. However, these vaccines do not fulfill all the requirements of the WHO because they fail to confer long-term protection, are not suitable for children under two years, require more than a single dose and require a distribution chain with cold storage. Lastly, other vaccine strategies under development are summarized in this review. Among these strategies, vaccine candidates based on alternative drug delivery systems that have been reported lately in the literature are discussed, such as microparticles, proteoliposomes, LPS subunits, DNA vaccines and rice seeds containing toxin subunits. Preliminary results reported by many groups working on alternative delivery systems for cholera vaccines demonstrate the importance of new technologies in addressing old problems such as cholera. Although a fully ideal vaccine has not yet been designed, promising steps have been reported in the literature resulting in hope for the fight against cholera

  10. A Novel Immunogenic Spore Coat-Associated Protein in Bacillus Anthracis: Characterization via Proteomics Approaches and a Vector-Based Vaccine System

    PubMed Central

    Liu, Yu-Tsueng; Lin, Shwu-Bin; Huang, Cheng-Po; Huang, Chun-Ming

    2007-01-01

    New generation anthrax vaccines have been actively explored with the aim of enhancing efficacies and decreasing undesirable side effects that could be caused by licensed vaccines. Targeting novel antigens and/or eliminating the requirements for multiple needle injections and adjuvants are major objectives in the development of new anthrax vaccines. Using proteomics approaches, we identified a spore coat-associated protein (SCAP) in Bacillus anthracis. An E. coli vector-based vaccine system was used to determine the immunogenicity of SCAP. Mice generated detectable SCAP antibodies three weeks after intranasal immunization with an intact particle of ultraviolet (UV)-irradiated E. coli vector overproducing SCAP. The production of SCAP antibodies was detected via western blotting and SCAP-spotted antigen-arrays. The adjuvant effect of a UV-irradiated E. coli vector eliminates the necessity of boosting and the use of other immunomodulators which will foster the screening and manufacturing of new generation anthrax vaccines. More importantly, the immunogenic SCAP may potentially be a new candidate for the development of anthrax vaccines. PMID:18029197

  11. Deciphering the Function of New Gonococcal Vaccine Antigens Using Phenotypic Microarrays

    PubMed Central

    Baarda, Benjamin I.; Emerson, Sarah; Proteau, Philip J.

    2017-01-01

    ABSTRACT The function and extracellular location of cell envelope proteins make them attractive candidates for developing vaccines against bacterial diseases, including challenging drug-resistant pathogens, such as Neisseria gonorrhoeae. A proteomics-driven reverse vaccinology approach has delivered multiple gonorrhea vaccine candidates; however, the biological functions of many of them remain to be elucidated. Herein, the functions of six gonorrhea vaccine candidates—NGO2121, NGO1985, NGO2054, NGO2111, NGO1205, and NGO1344—in cell envelope homeostasis were probed using phenotype microarrays under 1,056 conditions and a ΔbamE mutant (Δngo1780) as a reference of perturbed outer membrane integrity. Optimal growth conditions for an N. gonorrhoeae phenotype microarray assay in defined liquid medium were developed, which can be useful in other applications, including rapid and thorough antimicrobial susceptibility assessment. Our studies revealed 91 conditions having uniquely positive or negative effects on one of the examined mutants. A cluster analysis of 37 and 57 commonly beneficial and detrimental compounds, respectively, revealed three separate phenotype groups: NGO2121 and NGO1985; NGO1344 and BamE; and the trio of NGO1205, NGO2111, and NGO2054, with the last protein forming an independent branch of this cluster. Similar phenotypes were associated with loss of these vaccine candidates in the highly antibiotic-resistant WHO X strain. Based on their extensive sensitivity phenomes, NGO1985 and NGO2121 appear to be the most promising vaccine candidates. This study establishes the principle that phenotype microarrays can be successfully applied to a fastidious bacterial organism, such as N. gonorrhoeae. IMPORTANCE Innovative approaches are required to develop vaccines against prevalent and neglected sexually transmitted infections, such as gonorrhea. Herein, we have utilized phenotype microarrays in the first such investigation into Neisseria gonorrhoeae to

  12. Preclinical profiling of the immunogenicity of a two-component subunit malaria vaccine candidate based on virosome technology.

    PubMed

    Okitsu, Shinji L; Mueller, Markus S; Amacker, Mario; Vogel, Denise; Westerfeld, Nicole; Robinson, John A; Zurbriggen, Rinaldo; Pluschke, Gerd

    2008-01-01

    Presentation of synthetic peptides on immunopotentiating reconstituted influenza virosomes is a promising technology for subunit vaccine development. An optimized virosomally delivered peptide representing 5 NPNA repeats of P. falciparum circumsporozoite protein is highly immunogenic in mice. Antibodies against this peptide (UK-39) inhibit sporozoite invasion of human hepatocytes. A second peptide (AMA49-C1) based on domain III of apical membrane antigen 1, induces antibodies that inhibit blood-stage parasite growth in vitro. Here we show a detailed pre-clinical profiling of these virosomally formulated peptides alone and in combination in mice and rabbits. Two immunizations with virosomally formulated UK-39 or AMA49-C1 were enough to elicit high titers of parasite cross-reactive antibodies in both species. A low dose of 10 microg UK-39 was enough to induce maximal titers in rabbits. Higher doses of peptide did not increase antibody titers. In contrast, AMA49-C1 induced higher antibody titers with 25 and 50 microg peptide. Combination of UK-39 and AMA49- C1 on separate virosomes did not have any negative effect on anti-peptide antibody titers in mice or rabbits. No MHC restriction was observed in the development of humoral responses in outbred rabbits with different immunogenetic backgrounds. All vaccine formulations were safe in toxicity studies in rabbits and rats. Taken together, low amounts of synthetic peptides delivered on virosomes induced high antibody titers in mice and rabbits. Moreover, different peptides could be combined without interfering with individual anti-peptide responses, augmenting the value of this system for the development of a multivalent malaria vaccine.

  13. Working towards dengue as a vaccine-preventable disease: challenges and opportunities.

    PubMed

    Shrivastava, Ambuj; Tripathi, Nagesh K; Dash, Paban K; Parida, Manmohan

    2017-10-01

    Dengue is an emerging viral disease that affects the human population around the globe. Recent advancements in dengue virus research have opened new avenues for the development of vaccines against dengue. The development of a vaccine against dengue is a challenging task because any of the four serotypes of dengue viruses can cause disease. The development of a dengue vaccine aims to provide balanced protection against all the serotypes. Several dengue vaccine candidates are in the developmental stages such as inactivated, live attenuated, recombinant subunit, and plasmid DNA vaccines. Area covered: The authors provide an overview of the progress made in the development of much needed dengue vaccines. The authors include their expert opinion and their perspectives for future developments. Expert opinion: Human trials of a live attenuated tetravalent chimeric vaccine have clearly demonstrated its potential as a dengue vaccine. Other vaccine candidate molecules such as DENVax, a recombinant chimeric vaccine andTetraVax, are at different stages of development at this time. The authors believe that the novel strategies for testing and improving the immune response of vaccine candidates in humans will eventually lead to the development of a successful dengue vaccine in future.

  14. 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

  15. 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.

  16. Novel vaccination approach for dengue infection based on recombinant immune complex universal platform.

    PubMed

    Kim, Mi-Young; Reljic, Rajko; Kilbourne, Jacquelyn; Ceballos-Olvera, Ivonne; Yang, Moon-Sik; Reyes-del Valle, Jorge; Mason, Hugh S

    2015-04-08

    Dengue infection is on the rise in many endemic areas of the tropics. Vaccination remains the most realistic strategy for prevention of this potentially fatal viral disease but there is currently no effective vaccine that could protect against all four known serotypes of the dengue virus. This study describes the generation and testing of a novel vaccination approach against dengue based on recombinant immune complexes (RIC). We modelled the dengue RIC on the existing Ebola RIC (Phoolcharoen, et al. Proc Natl Acad Sci USA 2011;108(Dec (51)):20695) but with a key modification that allowed formation of a universal RIC platform that can be easily adapted for use for other pathogens. This was achieved by retaining only the binding epitope of the 6D8 ant-Ebola mAb, which was then fused to the consensus dengue E3 domain (cEDIII), resulting in a hybrid dengue-Ebola RIC (DERIC). We expressed human and mouse versions of these molecules in tobacco plants using a geminivirus-based expression system. Following purification from the plant extracts by protein G affinity chromatography, DERIC bound to C1q component of complement, thus confirming functionality. Importantly, following immunization of mice, DERIC induced a potent, virus-neutralizing anti-cEDIII humoral immune response without exogenous adjuvants. We conclude that these self-adjuvanting immunogens have the potential to be developed as a novel vaccine candidate for dengue infection, and provide the basis for a universal RIC platform for use with other antigens. Copyright © 2015 Elsevier Ltd. All rights reserved.

  17. Status of vaccine research and development of vaccines for leishmaniasis.

    PubMed

    Gillespie, Portia M; Beaumier, Coreen M; Strych, Ulrich; Hayward, Tara; Hotez, Peter J; Bottazzi, Maria Elena

    2016-06-03

    A number of leishmaniasis vaccine candidates are at various stages of pre-clinical and clinical development. Leishmaniasis is a vector-borne neglected tropical disease (NTD) caused by a protozoan parasite of the genus Leishmania and transmitted to humans by the bite of a sand fly. Visceral leishmaniasis (VL, kala-azar) is a high mortality NTD found mostly in South Asia and East Africa, while cutaneous leishmaniasis (CL) is a disfiguring NTD highly endemic in the Middle East, Central Asia, North Africa, and the Americas. Estimates attribute 50,000 annual deaths and 3.3 million disability-adjusted life years to leishmaniasis. There are only a few approved drug treatments, no prophylactic drug and no vaccine. Ideally, an effective vaccine against leishmaniasis will elicit long-lasting immunity and protect broadly against VL and CL. Vaccines such as Leish-F1, F2 and F3, developed at IDRI and designed based on selected Leishmania antigen epitopes, have been in clinical trials. Other groups, including the Sabin Vaccine Institute in collaboration with the National Institutes of Health are investigating recombinant Leishmania antigens in combination with selected sand fly salivary gland antigens in order to augment host immunity. To date, both VL and CL vaccines have been shown to be cost-effective in economic modeling studies. Copyright © 2016 World Health Organization. Published by Elsevier Ltd.. All rights reserved.

  18. Dengue vaccine: come let's fight the menace.

    PubMed

    Chawla, Sumit; Sahoo, Soumya Swaroop; Singh, Inderjeet; Verma, Madhur; Gupta, Vikas; Kumari, Sneh

    2015-01-01

    Although dengue has a global distribution, the World Health Organization (WHO) South-East Asia region together with Western Pacific region bears nearly 75% of the current global disease burden. Globally, the societal burden has been estimated to be approximately 528 to 1300 disability-adjusted life years (DALY) per million to populations in endemic regions Dengue is believed to infect 50 to 100 million people worldwide a year with half a million life-threatening infections requiring hospitalization, resulting in approximately 12,500 to 25,000 deaths. Despite being known for decades and nearly half the world's population is at risk for infection with as many as 100 million cases occurring annually, the pitiable state is that we still have no antiviral drugs to treat it and no vaccines to prevent it. In recent years, however, the development of dengue vaccines has accelerated dramatically in tandem with the burgeoning dengue problem with a rejuvenated vigour. However, recent progress in molecular-based vaccine strategies, as well as a renewed commitment by the World Health Organization (WHO) to co-ordinate global efforts on vaccine development, finally provides hope that control of this serious disease may be at hand. Today, several vaccines are in various stages of advanced development, with clinical trials currently underway on 5 candidate vaccines. Trials in the most advanced stages are showing encouraging preliminary data, and the leading candidate could be licensed as early as 2015.

  19. 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

    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.

  20. 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

    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

  1. Zika virus vaccines.

    PubMed

    Abbink, Peter; Stephenson, Kathryn E; Barouch, Dan H

    2018-06-19

    The recent epidemic of Zika virus (ZIKV) in the Americas has revealed the devastating consequences of ZIKV infection, particularly in pregnant women. Congenital Zika syndrome, characterized by malformations and microcephaly in neonates as well as developmental challenges in children, highlights the need for the development of a safe and effective vaccine. Multiple vaccine candidates have been developed and have shown promising results in both animal models and phase I clinical trials. However, important challenges remain for the clinical development of these vaccines. In this Progress article, we discuss recent preclinical studies and lessons learned from first-in-human clinical trials with ZIKV vaccines.

  2. Post-Genomics and Vaccine Improvement for Leishmania

    PubMed Central

    Seyed, Negar; Taheri, Tahereh; Rafati, Sima

    2016-01-01

    Leishmaniasis is a parasitic disease that primarily affects Asia, Africa, South America, and the Mediterranean basin. Despite extensive efforts to develop an effective prophylactic vaccine, no promising vaccine is available yet. However, recent advancements in computational vaccinology on the one hand and genome sequencing approaches on the other have generated new hopes in vaccine development. Computational genome mining for new vaccine candidates is known as reverse vaccinology and is believed to further extend the current list of Leishmania vaccine candidates. Reverse vaccinology can also reduce the intrinsic risks associated with live attenuated vaccines. Individual epitopes arranged in tandem as polytopes are also a possible outcome of reverse genome mining. Here, we will briefly compare reverse vaccinology with conventional vaccinology in respect to Leishmania vaccine, and we will discuss how it influences the aforementioned topics. We will also introduce new in vivo models that will bridge the gap between human and laboratory animal models in future studies. PMID:27092123

  3. A first-in-human phase 1 trial to evaluate the safety and immunogenicity of the candidate tuberculosis vaccine MVA85A-IMX313, administered to BCG-vaccinated adults

    PubMed Central

    Minhinnick, Alice; Satti, Iman; Harris, Stephanie; Wilkie, Morven; Sheehan, Sharon; Stockdale, Lisa; Thomas, Zita-Rose Manjaly; Lopez-Ramon, Raquel; Poulton, Ian; Lawrie, Alison; Vermaak, Samantha; Le Vert, Alexandre; Del Campo, Judith; Hill, Fergal; Moss, Paul; McShane, Helen

    2016-01-01

    Introduction There is an urgent need for a new and effective tuberculosis vaccine because BCG does not sufficiently prevent pulmonary disease. IMX313 is a novel carrier protein designed to improve cellular and humoral immunity. MVA85A-IMX313 is a novel vaccine candidate designed to boost immunity primed by bacillus Calmette-Guérin (BCG) that has been immunogenic in pre-clinical studies. This is the first evaluation of IMX313 delivered as MVA85A-IMX313 in humans. Methods In this phase 1, open-label first-in-human trial, 30 healthy previously BCG-vaccinated adults were enrolled into three treatment groups and vaccinated with low dose MVA85A-IMX313 (group A), standard dose MVA85A-IMX313 (group B), or MVA85A (group C). Volunteers were followed up for 6 months for safety and immunogenicity assessment. Results The majority of adverse events were mild and there were no vaccine-related serious AEs. Both MVA85A-IMX313 and MVA85A induced a significant increase in IFN-γ ELISpot responses. There were no significant differences between the Ag85A ELISpot and intracellular cytokine responses between the two study groups B (MVA85A-IMX313) and C (MVA85A) at any time point post-vaccination. Conclusion MVA85A-IMX313 was well tolerated and immunogenic. There was no significant difference in the number of vaccine-related, local or systemic adverse reactions between MVA85A and MVA85A-IMX313 groups. The mycobacteria-specific cellular immune responses induced by MVA85A-IMX313 were not significantly different to those detected in the MVA85A group. In light of this encouraging safety data, further work to improve the potency of molecular adjuvants like IMX313 is merited. This trial was registered on clinicatrials.gov ref. NCT01879163. PMID:26854906

  4. Cloned cDNA of A/swine/Iowa/15/1930 internal genes as a candidate backbone for reverse genetics vaccine against influenza A viruses

    PubMed Central

    Lekcharoensuk, Porntippa; Wiriyarat, Witthawat; Petcharat, Nuntawan; Lekcharoensuk, Chalermpol; Auewarakul, Prasert; Richt, Juergen A

    2012-01-01

    Reverse genetics viruses for influenza vaccine production usually utilize the internal genes of the egg-adapted A/Puerto Rico/8/34 (PR8) strain. This egg-adapted strain provides high production yield in embryonated eggs but does not necessarily give the best yield in mammalian cell culture. In order to generate a reverse genetics viral backbone that is well-adapted to high growth in mammalian cell culture, a swine influenza isolate (A/swine/Iowa/15/30 (H1N1) (rg1930) that was shown to give high yield in Madin-Darby Canine Kidney (MDCK) cells was used as the internal gene donor for reverse genetics plasmids. In this report, the internal genes from rg1930 were used for construction of reverse genetics viruses carrying a cleavage site-modified hemagglutinin (HA) gene and neuraminidase (NA) gene from a highly pathogenic H5N1 virus. The resulting virus (rg1930H5N1) was low pathogenic in vivo. Inactivated rg1930H5N1 vaccine completely protected chickens from morbidity and mortality after challenge with highly pathogenic H5N1. Protective immunity was obtained when chickens were immunized with an inactivated vaccine consisting of at least 29 HA units of the rg1930H5N1 virus. In comparison to the PR8-based reverse genetics viruses carrying the same HA and NA genes from an H5N1 virus, rg1930 based viruses yielded higher viral titers in MDCK and Vero cells. In addition, the reverse genetics derived H3N2 and H5N2 viruses with the rg1930 backbone replicated in MDCK cells better than the cognate viruses with the rgPR8 backbone. It is concluded that this newly established reverse genetics backbone system could serve as a candidate for a master donor strain for development of inactivated influenza vaccines in cell-based systems. PMID:22230579

  5. Cloned cDNA of A/swine/Iowa/15/1930 internal genes as a candidate backbone for reverse genetics vaccine against influenza A viruses.

    PubMed

    Lekcharoensuk, Porntippa; Wiriyarat, Witthawat; Petcharat, Nantawan; Lekcharoensuk, Chalermpol; Auewarakul, Prasert; Richt, Juergen A

    2012-02-14

    Reverse genetics viruses for influenza vaccine production usually utilize the internal genes of the egg-adapted A/Puerto Rico/8/34 (PR8) strain. This egg-adapted strain provides high production yield in embryonated eggs but does not necessarily give the best yield in mammalian cell culture. In order to generate a reverse genetics viral backbone that is well-adapted to high growth in mammalian cell culture, a swine influenza isolate A/swine/Iowa/15/30 (H1N1) (rg1930) that was shown to give high yield in Madin-Darby canine kidney (MDCK) cells was used as the internal gene donor for reverse genetics plasmids. In this report, the internal genes from rg1930 were used for construction of reverse genetics viruses carrying a cleavage site-modified hemagglutinin (HA) gene and neuraminidase (NA) gene from a highly pathogenic H5N1 virus. The resulting virus (rg1930H5N1) was low pathogenic in vivo. Inactivated rg1930H5N1 vaccine completely protected chickens from morbidity and mortality after challenge with highly pathogenic H5N1. Protective immunity was obtained when chickens were immunized with an inactivated vaccine consisting of at least 2(9) HA units of the rg1930H5N1 virus. In comparison to the PR8-based reverse genetics viruses carrying the same HA and NA genes from an H5N1 virus, rg1930 based viruses yielded higher viral titers in MDCK and Vero cells. In addition, the reverse genetics derived H3N2 and H5N2 viruses with the rg1930 backbone replicated in MDCK cells better than the cognate viruses with the rgPR8 backbone. It is concluded that this newly established reverse genetics backbone system could serve as a candidate for a master donor strain for development of inactivated influenza vaccines in cell-based systems. Copyright © 2011 Elsevier Ltd. All rights reserved.

  6. Improving rotavirus vaccine coverage: Can newer-generation and locally produced vaccines help?

    PubMed Central

    Kanungo, Suman; Anh, Dang Duc; Grais, Rebecca F.

    2018-01-01

    ABSTRACT There are two internationally available WHO-prequalified oral rotavirus vaccines (Rotarix and RotaTeq), two rotavirus vaccines licensed in India (Rotavac and Rotasiil), one in China (Lanzhou lamb rotavirus vaccine) and one in Vietnam (Rotavin-M1), and several candidates in development. Rotavirus vaccination has been rolled out in Latin American countries and is beginning to be deployed in sub-Saharan African countries but middle- and low-income Asian countries have lagged behind in rotavirus vaccine introduction. We provide a mini-review of the leading newer-generation rotavirus vaccines and compare them with Rotarix and RotaTeq. We discuss how the development and future availability of newer-generation rotavirus vaccines that address the programmatic needs of poorer countries may help scale-up rotavirus vaccination where it is needed. PMID:29135339

  7. Preclinical development of a vaccine against oligomeric alpha-synuclein based on virus-like particles.

    PubMed

    Doucet, Marika; El-Turabi, Aadil; Zabel, Franziska; Hunn, Benjamin H M; Bengoa-Vergniory, Nora; Cioroch, Milena; Ramm, Mauricio; Smith, Amy M; Gomes, Ariane Cruz; Cabral de Miranda, Gustavo; Wade-Martins, Richard; Bachmann, Martin F

    2017-01-01

    Parkinson's disease (PD) is a progressive and currently incurable neurological disorder characterised by the loss of midbrain dopaminergic neurons and the accumulation of aggregated alpha-synuclein (a-syn). Oligomeric a-syn is proposed to play a central role in spreading protein aggregation in the brain with associated cellular toxicity contributing to a progressive neurological decline. For this reason, a-syn oligomers have attracted interest as therapeutic targets for neurodegenerative conditions such as PD and other alpha-synucleinopathies. In addition to strategies using small molecules, neutralisation of the toxic oligomers by antibodies represents an attractive and highly specific strategy for reducing disease progression. Emerging active immunisation approaches using vaccines are already being trialled to induce such antibodies. Here we propose a novel vaccine based on the RNA bacteriophage (Qbeta) virus-like particle conjugated with short peptides of human a-syn. High titres of antibodies were successfully and safely generated in wild-type and human a-syn over-expressing (SNCA-OVX) transgenic mice following vaccination. Antibodies from vaccine candidates targeting the C-terminal regions of a-syn were able to recognise Lewy bodies, the hallmark aggregates in human PD brains. Furthermore, antibodies specifically targeted oligomeric and aggregated a-syn as they exhibited 100 times greater affinity for oligomeric species over monomer a-syn proteins in solution. In the SNCA-OVX transgenic mice used, vaccination was, however, unable to confer significant changes to oligomeric a-syn bioburden. Similarly, there was no discernible effect of vaccine treatment on behavioural phenotype as compared to control groups. Thus, antibodies specific for oligomeric a-syn induced by vaccination were unable to treat symptoms of PD in this particular mouse model.

  8. Preclinical development of a vaccine against oligomeric alpha-synuclein based on virus-like particles

    PubMed Central

    Zabel, Franziska; Hunn, Benjamin H.M.; Bengoa-Vergniory, Nora; Cioroch, Milena; Ramm, Mauricio; Smith, Amy M.; Gomes, Ariane Cruz; Cabral de Miranda, Gustavo; Wade-Martins, Richard; Bachmann, Martin F.

    2017-01-01

    Parkinson's disease (PD) is a progressive and currently incurable neurological disorder characterised by the loss of midbrain dopaminergic neurons and the accumulation of aggregated alpha-synuclein (a-syn). Oligomeric a-syn is proposed to play a central role in spreading protein aggregation in the brain with associated cellular toxicity contributing to a progressive neurological decline. For this reason, a-syn oligomers have attracted interest as therapeutic targets for neurodegenerative conditions such as PD and other alpha-synucleinopathies. In addition to strategies using small molecules, neutralisation of the toxic oligomers by antibodies represents an attractive and highly specific strategy for reducing disease progression. Emerging active immunisation approaches using vaccines are already being trialled to induce such antibodies. Here we propose a novel vaccine based on the RNA bacteriophage (Qbeta) virus-like particle conjugated with short peptides of human a-syn. High titres of antibodies were successfully and safely generated in wild-type and human a-syn over-expressing (SNCA-OVX) transgenic mice following vaccination. Antibodies from vaccine candidates targeting the C-terminal regions of a-syn were able to recognise Lewy bodies, the hallmark aggregates in human PD brains. Furthermore, antibodies specifically targeted oligomeric and aggregated a-syn as they exhibited 100 times greater affinity for oligomeric species over monomer a-syn proteins in solution. In the SNCA-OVX transgenic mice used, vaccination was, however, unable to confer significant changes to oligomeric a-syn bioburden. Similarly, there was no discernible effect of vaccine treatment on behavioural phenotype as compared to control groups. Thus, antibodies specific for oligomeric a-syn induced by vaccination were unable to treat symptoms of PD in this particular mouse model. PMID:28797124

  9. Radiation and Anti-Cancer Vaccines: A Winning Combination.

    PubMed

    Cadena, Alexandra; Cushman, Taylor R; Anderson, Clark; Barsoumian, Hampartsoum B; Welsh, James W; Cortez, Maria Angelica

    2018-01-30

    The emerging combination of radiation therapy with vaccines is a promising new treatment plan in the fight against cancer. While many cancer vaccines such as MUC1, p53 CpG oligodeoxynucleotide, and SOX2 may be great candidates for antitumor vaccination, there still remain many investigations to be done into possible vaccine combinations. One fruitful partnership that has emerged are anti-tumor vaccines in combination with radiation. Radiation therapy was previously thought to be only a tool for directly or indirectly damaging DNA and therefore causing cancer cell death. Now, with much preclinical and clinical data, radiation has taken on the role of an in situ vaccine. With both cancer vaccines and radiation at our disposal, more and more studies are looking to combining vaccine types such as toll-like receptors, viral components, dendritic-cell-based, and subunit vaccines with radiation. While the outcomes of these combinatory efforts are promising, there is still much work to be covered. This review sheds light on the current state of affairs in cancer vaccines and how radiation will bring its story into the future.

  10. Isolation and Characterization of Vaccine Candidate Genes Including CSP and MSP1 in Plasmodium yoelii.

    PubMed

    Kim, Seon-Hee; Bae, Young-An; Seoh, Ju-Young; Yang, Hyun-Jong

    2017-06-01

    Malaria is an infectious disease affecting humans, which is transmitted by the bite of Anopheles mosquitoes harboring sporozoites of parasitic protozoans belonging to the genus Plasmodium . Despite past achievements to control the protozoan disease, malaria still remains a significant health threat up to now. In this study, we cloned and characterized the full-unit Plasmodium yoelii genes encoding merozoite surface protein 1 (MSP1), circumsporozoite protein (CSP), and Duffy-binding protein (DBP), each of which can be applied for investigations to obtain potent protective vaccines in the rodent malaria model, due to their specific expression patterns during the parasite life cycle. Recombinant fragments corresponding to the middle and C-terminal regions of PyMSP1 and PyCSP, respectively, displayed strong reactivity against P. yoelii -infected mice sera. Specific native antigens invoking strong humoral immune response during the primary and secondary infections of P. yoelii were also abundantly detected in experimental ICR mice. The low or negligible parasitemia observed in the secondary infected mice was likely to result from the neutralizing action of the protective antibodies. Identification of these antigenic proteins might provide the necessary information and means to characterize additional vaccine candidate antigens, selected solely on their ability to produce the protective antibodies.

  11. Vaccination against group B streptococcus.

    PubMed

    Heath, Paul T; Feldman, Robert G

    2005-04-01

    Streptococcus agalactiae (Group B streptococcus) is an important cause of disease in infants, pregnant women, the elderly and in immunosuppressed adults. An effective vaccine is likely to prevent the majority of infant disease (both early and late onset), as well as Group B streptococcus-related stillbirths and prematurity, to avoid the current real and theoretical limitations of intrapartum antibiotic prophylaxis, and to be cost effective. The optimal time to administer such a vaccine would be in the third trimester of pregnancy. The main limitations on the production of a Group B streptococcus vaccine are not technical or scientific, but regulatory and legal. A number of candidates including capsular conjugate vaccines using traditional carrier proteins such as tetanus toxoid and mutant diphtheria toxin CRM197, as well as Group B streptococcus-specific proteins such as C5a peptidase, protein vaccines using one or more Group B streptococcus surface proteins and mucosal vaccines, have the potential to be successful vaccines. The capsular conjugate vaccines using tetanus and CRM197 carrier proteins are the most advanced candidates, having already completed Phase II human studies including use in the target population of pregnant women (tetanus toxoid conjugate), however, no definitive protein conjugates have yet been trialed. However, unless the regulatory environment is changed specifically to allow the development of a Group B streptococcus vaccine, it is unlikely that one will ever reach the market.

  12. Dengue vaccine development: strategies and challenges.

    PubMed

    Ramakrishnan, Lakshmy; Pillai, Madhavan Radhakrishna; Nair, Radhakrishnan R

    2015-03-01

    Infection with dengue virus may result in dengue fever or a more severe outcome, such as dengue hemorrhagic syndrome/shock. Dengue virus infection poses a threat to endemic regions for four reasons: the presence of four serotypes, each with the ability to cause a similar disease outcome, including fatality; difficulties related to vector control; the lack of specific treatment; and the nonavailability of a suitable vaccine. Vaccine development is considered challenging due to the severity of the disease observed in individuals who have acquired dengue-specific immunity, either passively or actively. Therefore, the presence of vaccine-induced immunity against a particular serotype may prime an individual to severe disease on exposure to dengue virus. Vaccine development strategies include live attenuated vaccines, chimeric, DNA-based, subunit, and inactivated vaccines. Each of the candidates is in various stages of preclinical and clinical development. Issues pertaining to selection pressures, viral interaction, and safety still need to be evaluated in order to induce a complete protective immune response against all four serotypes. This review highlights the various strategies that have been employed in vaccine development, and identifies the obstacles to producing a safe and effective vaccine.

  13. A live attenuated H7N7 candidate vaccine virus induces neutralizing antibody that confers protection from challenge in mice, ferrets and monkeys

    USDA-ARS?s Scientific Manuscript database

    A live attenuated H7N7 candidate vaccine virus was generated by reverse genetics using the modified hemagglutinin (HA) and neuraminidase (NA) genes of HP A/Netherlands/219/03 (NL/03) (H7N7) wild-type (wt) virus and the six internal protein genes of the cold-adapted (ca) A/Ann Arbor/6/60 ca (AA ca) (...

  14. Prediction and analysis of promiscuous T cell-epitopes derived from the vaccine candidate antigens of Leishmania donovani binding to MHC class-II alleles using in silico approach.

    PubMed

    Kashyap, Manju; Jaiswal, Varun; Farooq, Umar

    2017-09-01

    Visceral leishmaniasis is a dreadful infectious disease and caused by the intracellular protozoan parasites, Leishmania donovani and Leishmania infantum. Despite extensive efforts for developing effective prophylactic vaccine, still no vaccine is available against leishmaniasis. However, advancement in immunoinformatics methods generated new dimension in peptide based vaccine development. The present study was aimed to identify T-cell epitopes from the vaccine candidate antigens like Lipophosphogylcan-3(LPG-3) and Nucleoside hydrolase (NH) from the L. donovani using in silico methods. Available best tools were used for the identification of promiscuous peptides for MHC class-II alleles. A total of 34 promiscuous peptides from LPG-3, 3 from NH were identified on the basis of their 100% binding affinity towards all six HLA alleles, taken in this study. These peptides were further checked computationally to know their IFN-γ and IL4 inducing potential and nine peptides were identified. Peptide binding interactions with predominant HLA alleles were done by docking. Out of nine docked promiscuous peptides, only two peptides (QESRILRVIKKKLVR, RILRVIKKKLVRKTL), from LPG-3 and one peptide (FDKFWCLVIDALKRI) from NH showed lowest binding energy with all six alleles. These promiscuous T-cell epitopes were predicted on the basis of their antigenicity, hydrophobicity, potential immune response and docking scores. The immunogenicity of predicted promiscuous peptides might be used for subunit vaccine development with immune-modulating adjuvants. Copyright © 2017 Elsevier B.V. All rights reserved.

  15. Efficacy assessment of an inactivated Tembusu virus vaccine candidate in ducks.

    PubMed

    Zhang, Lijiao; Li, Zhanhong; Zhang, Qingshui; Sun, Mengxu; Li, Shuang; Su, Wenliang; Hu, Xueying; He, Weiyong; Su, Jingliang

    2017-02-01

    Duck Tembusu virus (TMUV) is a recently identified pathogen that causes severe egg drop and neurological disease in domestic duck and goose flocks. The infection has spread across the China mainland since its outbreak in 2010. Effective vaccines are needed to fight the disease. In this work, we describe the development and laboratory assessment of a cell culture-derived, inactivated duck TMUV vaccine. The TMUV-JXSP strain was successfully propagated on a baby hamster kidney cell line (BHK-21), inactivated with beta-propiolactone (BPL) and emulsified with mineral oil. The efficacy of different vaccination schedules was assessed in laying ducks and table ducks using virus challenge experiments. Two doses of vaccine provided efficient protection against the virus challenge to avoid the egg production drop in laying ducks. An ELISA demonstrated that 97% (39/40) of ducks seroconverted on day 21 after one dose of the inactivated vaccine and that significant increases in antibody titers against the virus were induced after the second immunization. For table ducks, a single dose of vaccine immunization resulted in a protection index of 87% and significant reduction of viral loads in tissues. Sterilizing immunity can be attained after second immunization. Our results demonstrate that BHK-21 cell culture is suitable for duck TMUV propagation and that BPL-inactivated TMUV vaccine can provide a high level of protection from virus challenge in laying ducks and table ducks. These data provide a scientific basis for the development of an inactivated vaccine for the prevention of duck TMUV infection. Copyright © 2016 Elsevier Ltd. All rights reserved.

  16. Dengue Fever: Causes, Complications, and Vaccine Strategies

    PubMed Central

    Khanna, Ira

    2016-01-01

    Dengue is a highly endemic infectious disease of the tropical countries and is rapidly becoming a global burden. It is caused by any of the 4 serotypes of dengue virus and is transmitted within humans through female Aedes mosquitoes. Dengue disease varies from mild fever to severe conditions of dengue hemorrhagic fever and shock syndrome. Globalization, increased air travel, and unplanned urbanization have led to increase in the rate of infection and helped dengue to expand its geographic and demographic distribution. Dengue vaccine development has been a challenging task due to the existence of four antigenically distinct dengue virus serotypes, each capable of eliciting cross-reactive and disease-enhancing antibody response against the remaining three serotypes. Recently, Sanofi Pasteur's chimeric live-attenuated dengue vaccine candidate has been approved in Mexico, Brazil, and Philippines for usage in adults between 9 and 45 years of age. The impact of its limited application to the public health system needs to be evaluated. Simultaneously, the restricted application of this vaccine candidate warrants continued efforts in developing a dengue vaccine candidate which is additionally efficacious for infants and naïve individuals. In this context, alternative strategies of developing a designed vaccine candidate which does not allow production of enhancing antibodies should be explored, as it may expand the umbrella of efficacy to include infants and naïve individuals. PMID:27525287

  17. Status of vaccine research and development of vaccines for GBS.

    PubMed

    Heath, Paul T

    2016-06-03

    Streptococcus agalactiae (group B streptococcus (GBS)) is the leading cause of neonatal sepsis and meningitis in many countries. Intrapartum antibiotic strategies have reduced the incidence of early-onset neonatal GBS in a number of countries but have had no impact on late onset GBS infection (LOD). In low/middle income settings, the disease burden remains uncertain although in several countries of Southern Africa appears comparable to or higher than that of high-income countries. As disease may be rapidly fulminating cases can be missed before appropriate samples are obtained and this may lead to underestimation of the true burden. Given the rapid onset and progression within hours of birth as well as the deficiencies in IAP strategies and absence of a solution for preventing LOD, it is clear that administration of a suitable vaccine in pregnancy could provide a better solution in all settings; it should also be cost effective. The current leading vaccine candidates are CPS-protein conjugate vaccines but protein-based vaccines are also in development and one has recently commenced clinical trials. Copyright © 2016 World Health Organization. Published by Elsevier Ltd.. All rights reserved.

  18. Malaria vaccine clinical trials: what’s on the horizon

    PubMed Central

    Moreno, Alberto; Joyner, Chester

    2015-01-01

    Significant progress towards a malaria vaccine, specifically for Plasmodium falciparum, has been made in the past few years with the completion of numerous clinical trials. Each trial has utilized a unique combination of antigens, delivery platforms, and adjuvants, and the data that has been obtained provides critical information that has poises the research community for the development of next generation malaria vaccines. Despite the progress towards a P. falciparum vaccine, P. vivax vaccine research requires more momentum and additional investigations to identify novel vaccine candidates. In this review, recently completed and ongoing malaria vaccine clinical trials as well as vaccine candidates that are in the development pipeline are reviewed. Perspectives for future research using post-genomic mining, nonhuman primate models, and systems biology are also discussed. PMID:26172291

  19. 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

  20. Particle-based vaccines for HIV-1 infection.

    PubMed

    Young, Kelly R; Ross, Ted M

    2003-06-01

    The use of live-attenuated viruses as vaccines has been successful for the control of viral infections. However, the development of an effective vaccine against the human immunodeficiency virus (HIV) has proven to be a challenge. HIV infects cells of the immune system and results in a severe immunodeficiency. In addition, the ability of the virus to adapt to immune pressure and the ability to reside in an integrated form in host cells present hurdles for vaccinologists to overcome. A particle-based vaccine strategy has promise for eliciting high titer, long-lived, immune responses to a diverse number of viral epitopes from different HIV antigens. Live-attenuated viruses are effective at generating both cellular and humoral immunity, however, a live-attenuated vaccine for HIV is problematic. The possibility of a live-attenuated vaccine to revert to a pathogenic form or recombine with a wild-type or defective virus in an infected individual is a drawback to this approach. Therefore, these vaccines are currently only being tested in non-human primate models. Live-attenuated vaccines are effective in stimulating immunity, however challenged animals rarely clear viral infection and the degree of attenuation directly correlates with the protection of animals from disease. Another particle-based vaccine approach for HIV involves the use of virus-like particles (VLPs). VLPs mimic the viral particle without causing an immunodeficiency disease. HIV-like particles (HIV-LP) are defined as self-assembling, non-replicating, nonpathogenic, genomeless particles that are similar in size and conformation to intact virions. A variety of VLPs for both HIV and SIV are currently in pre-clinical and clinical trials. This review focuses on the current knowledge regarding the immunogenicity and safety of particle-based vaccine strategies for HIV-1.

  1. Status of vaccine research and development of vaccines for Staphylococcus aureus.

    PubMed

    Giersing, Birgitte K; Dastgheyb, Sana S; Modjarrad, Kayvon; Moorthy, Vasee

    2016-06-03

    Staphylococcus aureus is a highly versatile gram positive bacterium that is resident as an asymptomatic colonizer on the skin and in the nasopharynx of approximately 30% of individuals. Nasopharyngeal colonization is a risk for acquiring S. aureus infections, which can cause a range of clinical symptoms that are commonly associated with skin and soft-tissue infections. The emergence of S. aureus strains that are highly resistant to antimicrobials has recently become a major public health concern. In low-income countries the incidence of S. aureus disease is highest in neonates and children up to one year of age and mortality rates are estimated to be up to 50%. In the United States, S. aureus infection accounts for approximately 300,000 hospitalizations per year. A vaccine against multi-drug resistant S. aureus, therefore, is urgently needed. Two vaccine candidates have previously been evaluated in late-stage clinical trials but have not demonstrated efficacy. At present, one vaccine candidate and two monoclonal antibody are undergoing clinical evaluation in target groups at high risk for S. aureus infection. This review provides an overview of current vaccine development efforts and presents the major technical and regulatory challenges to developing a licensed S. aureus vaccine. Copyright © 2016 World Health Organization. Published by Elsevier Ltd.. All rights reserved.

  2. Characterization of Inherent Particles and Mechanism of Thermal Stress Induced Particle Formation in HSV-2 Viral Vaccine Candidate.

    PubMed

    Li, Lillian; Kirkitadze, Marina; Bhandal, Kamaljit; Roque, Cristopher; Yang, Eric; Carpick, Bruce; Rahman, Nausheen

    2017-11-10

    Vaccine formulations may contain visible and/or subvisible particles, which can vary in both size and morphology. Extrinsic particles, which are particles not part of the product such as foreign contaminants, are generally considered undesirable and should be eliminated or controlled in injectable products. However, biological products, in particular vaccines, may also contain particles that are inherent to the product. Here we focus on the characterization of visible and subvisible particles in a live, replication-deficient viral vaccine candidate against HSV genital herpes in an early developmental stage. HSV-2 viral vaccine was characterized using a panel of analytical methods, including Fourier transform infrared spectroscopy (FTIR), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), Western blot, liquid chromatography-mass spectrometry (LC-MS), light microscopy, transmission electron microscopy (TEM), micro-flow imaging (MFI), dynamic light scattering (DLS), right angle light scattering (RALS), and intrinsic fluorescence. Particles in HSV-2 vaccine typically ranged from hundreds of nanometers to hundreds of micrometers in size and were determined to be inherent to the product. The infectious titer did not correlate with any trend in subvisible particle concentration and size distribution as shown by DLS, MFI, and TEM under stressed conditions. This suggested that particle changes in the submicron range were related to HSV-2 virion structure and had direct impact on biological activity. It was also observed that subvisible and visible particles could induce aggregation in the viral product. The temperature induced aggregation was observed by RALS, intrinsic fluorescence, and DLS. The increase of subvisible particle size with temperature could be fitted to a two-step thermokinetic model. Visible and subvisible particles were found to be inherent to the HSV-2 viral vaccine product. The mechanism of protein aggregation was discussed and a two

  3. Safety and Immunogenicity of a Candidate Parvovirus B19 Vaccine

    PubMed Central

    Bernstein, David I; El Sahly, Hana M; Keitel, Wendy A; Wolff, Mark; Simone, Gina; Segawa, Claire; Wong, Susan; Shelly, Daniel; Young, Neal S; Dempsey, Walla

    2011-01-01

    Parvovirus B19 is an important human pathogen causing erythema infectiosum, transient aplastic crisis in individuals with underlying hemolytic disorders and hydrops fetalis. We therefore evaluated a parvovirus B19 virus like particle (VLP) vaccine. The safety and immunogenicity of a 25 μg dose of parvovirus B19 recombinant capsid; 2.5 and 25 μg doses of the recombinant capsid given with MF59; and saline placebo were assessed in healthy adults. Because of 3 unexplained cutaneous events the study was halted after enrollment of 43 subjects and before any subject received their third scheduled dose. The rashes developed 5-9 days after the first or second injection and were seen in one placebo recipient (without an injection site lesion) and two vaccine recipients (with injection site reactions). No clear cause was established. Other safety evaluations revealed mostly injection site reactions that were mild to moderate with an increase in pain in subjects receiving vaccine and MF59. After dose 2 the majority of vaccine recipients developed ELISA and neutralizing antibody to parvovirus B19. Given the possible severe consequences of parvovirus B19 infection, further development of a safe and effective vaccine continues to be important. PMID:21807052

  4. Safety and immunogenicity of a candidate parvovirus B19 vaccine.

    PubMed

    Bernstein, David I; El Sahly, Hana M; Keitel, Wendy A; Wolff, Mark; Simone, Gina; Segawa, Claire; Wong, Susan; Shelly, Daniel; Young, Neal S; Dempsey, Walla

    2011-10-06

    Parvovirus B19 is an important human pathogen causing erythema infectiosum, transient aplastic crisis in individuals with underlying hemolytic disorders and hydropsfetalis. We therefore evaluated a parvovirus B19 virus like particle (VLP) vaccine. The safety and immunogenicity of a 25 μg dose of parvovirus B19 recombinant capsid; 2.5 and 25 μg doses of the recombinant capsid given with MF59; and saline placebo were assessed in healthy adults. Because of 3 unexplained cutaneous events the study was halted after enrollment of 43 subjects and before any subject received their third scheduled dose. The rashes developed 5-9 days after the first or second injection and were seen in one placebo recipient (without an injection site lesion) and two vaccine recipients (with injection site reactions). No clear cause was established. Other safety evaluations revealed mostly injection site reactions that were mild to moderate with an increase in pain in subjects receiving vaccine and MF59. After dose 2 the majority of vaccine recipients developed ELISA and neutralizing antibody to parvovirus B19. Given the possible severe consequences of parvovirus B19 infection, further development of a safe and effective vaccine continues to be important. Copyright © 2011 Elsevier Ltd. All rights reserved.

  5. Current biodefense vaccine programs and challenges.

    PubMed

    Wolfe, Daniel N; Florence, William; Bryant, Paula

    2013-07-01

    The Defense Threat Reduction Agency's Joint Science and Technology Office manages the Chemical and Biological Defense Program's Science and Technology portfolio. The Joint Science and Technology Office's mission is to invest in transformational ideas, innovative people and actionable technology development for Chemical and Biological Defense solutions, with the primary goal to deliver Science and Technology products and capabilities to the warfighter and civilian population that outpace the threat. This commentary focuses on one thrust area within this mission: the Vaccine program of the Joint Science and Technology Office's Translational Medical Division. Here, we will describe candidate vaccines currently in the S&T pipeline, enabling technologies that should facilitate advanced development of these candidates into FDA licensed vaccines, and how the ever-changing biological threat landscape impacts the future of biodefense vaccines.

  6. Efficacy of severe acute respiratory syndrome vaccine based on a nonhuman primate adenovirus in the presence of immunity against human adenovirus.

    PubMed

    Zhi, Yan; Figueredo, Joanita; Kobinger, Gary P; Hagan, Heather; Calcedo, Roberto; Miller, James R; Gao, Guangping; Wilson, James M

    2006-05-01

    Replication-deficient human adenovirus type 5 (AdH5) vectors can induce strong transgene product-specific cellular and humoral responses. However, many adult humans have neutralizing antibodies (NAbs) against AdH5 as a result of natural infection with this virus. Therefore, a chimpanzee adenovirus C7 (AdC7) vector was developed to circumvent interference by preexisting immunity to AdH5. This study evaluated the impact of preexisting immunity to human adenovirus on the efficacy of adenovirus-based vaccines against the coronavirus that causes severe acute respiratory syndrome (SARS-CoV). Efficacy was assessed after intramuscular injection of the vector into mice and was measured as the frequency of SARS-CoV-specific T cells and NAbs against SARS-CoV. Immunogenicity of the AdH5-based vaccine was significantly attenuated or completely abolished when the preexisting anti-AdH5 NAb titer was higher than 40. Because 27% of human serum samples from the United States tested so far have an anti-AdH5 NAb titer higher than 40, our results suggested that a significant percentage of humans with preexisting anti-AdH5 immunity would not be candidates for vaccination with an AdH5-based genetic vaccine. In contrast, preexisting anti-AdH5 NAbs have a minimal effect on the potency of the AdC7-based genetic vaccine. Taken together, our studies warrant the further development of AdC7 as a vaccine carrier for human trials.

  7. 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

  8. 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

  9. 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.

  10. Ricin vaccine development.

    PubMed

    Smallshaw, Joan E; Vitetta, Ellen S

    2012-01-01

    In this chapter we discuss vaccines to protect against the highly toxic plant-derived toxin, ricin. Due to its prevalence, ease of use, and stability it has been used in sporadic incidents of espionage. There is also concern that it will be used as an agent of bioterrorism. As a result there has been a great deal of interest in developing a safe vaccine or antidote to protect humans, and in particular soldiers and first responders. Although multiple types of vaccines have been tested, at this time two recombinant vaccines are the leading candidates for the national vaccine stockpile. In terms of passive post-exposure protection, monoclonal neutralizing antibodies that passively protect animals are also under development. These vaccines and antibodies are discussed in the context of the toxicity and structure of ricin.

  11. Immunogenicity of next-generation HPV vaccines in non-human primates: Measles-vectored HPV vaccine versus Pichia pastoris recombinant protein vaccine.

    PubMed

    Gupta, Gaurav; Giannino, Viviana; Rishi, Narayan; Glueck, Reinhard

    2016-09-07

    Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide. HPVs are oncogenic small double-stranded DNA viruses that are the primary causal agent of cervical cancer and other types of cancers, including in the anus, oropharynx, vagina, vulva, and penis. Prophylactic vaccination against HPV is an attractive strategy for preventing cervical cancer and some other types of cancers. However, there are few safe and effective vaccines against HPV infections. Current first-generation commercial HPV vaccines are expensive to produce and deliver. The goal of this study was to develop an alternate potent HPV recombinant L1-based vaccines by producing HPV virus-like particles into a vaccine that is currently used worldwide. Live attenuated measles virus (MV) vaccines have a well-established safety and efficacy record, and recombinant MV (rMV) produced by reverse genetics may be useful for generating candidate HPV vaccines to meet the needs of the developing world. We studied in non-human primate rMV-vectored HPV vaccine in parallel with a classical alum adjuvant recombinant HPV16L1 and 18L1 protein vaccine produced in Pichia pastoris. A combined prime-boost approach using both vaccines was evaluated, as well as immune interference due to pre-existing immunity against the MV. The humoral immune response induced by the MV, Pichia-expressed vaccine, and their combination as priming and boosting approaches was found to elicit HPV16L1 and 18L1 specific total IgG and neutralizing antibody titres. Pre-existing antibodies against measles did not prevent the immune response against HPV16L1 and 18L1. Copyright © 2016 Elsevier Ltd. All rights reserved.

  12. Overcoming Antigenic Diversity by Enhancing the Immunogenicity of Conserved Epitopes on the Malaria Vaccine Candidate Apical Membrane Antigen-1

    PubMed Central

    Dutta, Sheetij; Dlugosz, Lisa S.; Drew, Damien R.; Ge, Xiopeng; Ababacar, Diouf; Rovira, Yazmin I.; Moch, J. Kathleen; Shi, Meng; Long, Carole A.; Foley, Michael; Beeson, James G.; Anders, Robin F.; Miura, Kazutoyo; Haynes, J. David; Batchelor, Adrian H.

    2013-01-01

    Malaria vaccine candidate Apical Membrane Antigen-1 (AMA1) induces protection, but only against parasite strains that are closely related to the vaccine. Overcoming the AMA1 diversity problem will require an understanding of the structural basis of cross-strain invasion inhibition. A vaccine containing four diverse allelic proteins 3D7, FVO, HB3 and W2mef (AMA1 Quadvax or QV) elicited polyclonal rabbit antibodies that similarly inhibited the invasion of four vaccine and 22 non-vaccine strains of P. falciparum. Comparing polyclonal anti-QV with antibodies against a strain-specific, monovalent, 3D7 AMA1 vaccine revealed that QV induced higher levels of broadly inhibitory antibodies which were associated with increased conserved face and domain-3 responses and reduced domain-2 response. Inhibitory monoclonal antibodies (mAb) raised against the QV reacted with a novel cross-reactive epitope at the rim of the hydrophobic trough on domain-1; this epitope mapped to the conserved face of AMA1 and it encompassed the 1e-loop. MAbs binding to the 1e-loop region (1B10, 4E8 and 4E11) were ∼10-fold more potent than previously characterized AMA1-inhibitory mAbs and a mode of action of these 1e-loop mAbs was the inhibition of AMA1 binding to its ligand RON2. Unlike the epitope of a previously characterized 3D7-specific mAb, 1F9, the 1e-loop inhibitory epitope was partially conserved across strains. Another novel mAb, 1E10, which bound to domain-3, was broadly inhibitory and it blocked the proteolytic processing of AMA1. By itself mAb 1E10 was weakly inhibitory but it synergized with a previously characterized, strain-transcending mAb, 4G2, which binds close to the hydrophobic trough on the conserved face and inhibits RON2 binding to AMA1. Novel inhibition susceptible regions and epitopes, identified here, can form the basis for improving the antigenic breadth and inhibitory response of AMA1 vaccines. Vaccination with a few diverse antigenic proteins could provide universal

  13. Particle-based platforms for malaria vaccines.

    PubMed

    Wu, Yimin; Narum, David L; Fleury, Sylvain; Jennings, Gary; Yadava, Anjali

    2015-12-22

    Recombinant subunit vaccines in general are poor immunogens likely due to the small size of peptides and proteins, combined with the lack or reduced presentation of repetitive motifs and missing complementary signal(s) for optimal triggering of the immune response. Therefore, recombinant subunit vaccines require enhancement by vaccine delivery vehicles in order to attain adequate protective immunity. Particle-based delivery platforms, including particulate antigens and particulate adjuvants, are promising delivery vehicles for modifying the way in which immunogens are presented to both the innate and adaptive immune systems. These particle delivery platforms can also co-deliver non-specific immunostimodulators as additional adjuvants. This paper reviews efforts and advances of the Particle-based delivery platforms in development of vaccines against malaria, a disease that claims over 600,000 lives per year, most of them are children under 5 years of age in sub-Sahara Africa. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Rift Valley Fever vaccines: An overview of the safety and efficacy of the live-attenuated MP-12 vaccine candidate

    PubMed Central

    Ikegami, Tetsuro

    2017-01-01

    Introduction Rift Valley fever (RVF) is a mosquito-borne zoonotic viral disease endemic to Africa and the Arabian Peninsula. High rates of abortion among infected ruminants and hemorrhagic fever in infected humans are major public health concerns. Commercially available veterinary RVF vaccines are important for preventing the spread of the Rift Valley fever virus (RVFV) in endemic countries; however, RVFV outbreaks continue to occur frequently in endemic countries in the 21st century. In the U.S., the live-attenuated MP-12 vaccine has been developed for both animal and human vaccination. This vaccine strain is well attenuated, and a single dose induces neutralizing antibodies in both ruminants and humans. Areas covered This review describes scientific evidences of MP-12 vaccine efficacy and safety, as well as MP-12 variants recently developed by reverse genetics, in comparison with other RVF vaccines. Expert commentary The containment of active RVF outbreaks and long-term protection from RVF exposure to infected mosquitoes are important goals for RVF vaccination. MP-12 vaccine will allow immediate vaccination of susceptible animals in case of an unexpected RVF outbreak in the U.S., whereas MP-12 vaccine may be also useful for the RVF control in endemic regions. PMID:28425834

  15. Rift Valley fever vaccines: an overview of the safety and efficacy of the live-attenuated MP-12 vaccine candidate.

    PubMed

    Ikegami, Tetsuro

    2017-06-01

    Rift Valley fever (RVF) is a mosquito-borne zoonotic viral disease endemic to Africa and the Arabian Peninsula. High rates of abortion among infected ruminants and hemorrhagic fever in infected humans are major public health concerns. Commercially available veterinary RVF vaccines are important for preventing the spread of the Rift Valley fever virus (RVFV) in endemic countries; however, RVFV outbreaks continue to occur frequently in endemic countries in the 21st century. In the U.S., the live-attenuated MP-12 vaccine has been developed for both animal and human vaccination. This vaccine strain is well attenuated, and a single dose induces neutralizing antibodies in both ruminants and humans. Areas covered: This review describes scientific evidences of MP-12 vaccine efficacy and safety, as well as MP-12 variants recently developed by reverse genetics, in comparison with other RVF vaccines. Expert commentary: The containment of active RVF outbreaks and long-term protection from RVF exposure to infected mosquitoes are important goals for RVF vaccination. MP-12 vaccine will allow immediate vaccination of susceptible animals in case of an unexpected RVF outbreak in the U.S., whereas MP-12 vaccine may be also useful for the RVF control in endemic regions.

  16. Protective effect of enterovirus‑71 (EV71) virus‑like particle vaccine against lethal EV71 infection in a neonatal mouse model.

    PubMed

    Cao, Lei; Mao, Fengfeng; Pang, Zheng; Yi, Yao; Qiu, Feng; Tian, Ruiguang; Meng, Qingling; Jia, Zhiyuan; Bi, Shengli

    2015-08-01

    Enterovirus-71 (EV71) is a viral pathogen that causes severe cases of hand, foot and mouth disease (HFMD) among young children, with significant mortality. Effective vaccines against HFMD are urgently required. Several EV71 virus-like particle (VLP) vaccine candidates were found to be protective in the neonatal mouse EV71 challenge model. However, to what extent the VLP vaccine protects susceptible organs against EV71 infection in vivo has remained elusive. In the present study, the comprehensive immunogenicity of a potential EV71 vaccine candidate based on VLPs was evaluated in a neonatal mouse model. Despite lower levels of neutralizing antibodies to EV71 in the sera of VLP-immunized mice compared with those in mice vaccinated with inactivated EV71, the VLP-based vaccine was shown to be able to induce immunoglobulin (Ig)G and IgA memory-associated cellular immune responses to EV71. Of note, the EV71 VLP vaccine candidate was capable of inhibiting viral proliferation in cardiac muscle, skeletal muscle, lung and intestine of immunized mice and provided effective protection against the pathological damage caused by viral attack. In particular, the VLP vaccine was able to inhibit the transportation of EV71 from the central nervous system to the muscle tissue and greatly protected muscle tissue from infection, along with recovery from the viral infection. This led to nearly 100% immunoprotective efficacy, enabling neonatal mice delivered by VLP-immunized female adult mice to survive and grow with good health. The present study provided valuable additional knowledge of the specific protective efficacy of the EV71 VLP vaccine in vivo, which also indicated that it is a promising potential candidate for being developed into an EV71 vaccine.

  17. Toward the development of effective transmission-blocking vaccines for malaria.

    PubMed

    Nikolaeva, Daria; Draper, Simon J; Biswas, Sumi

    2015-05-01

    The continued global burden of malaria can in part be attributed to a complex lifecycle, with both human hosts and mosquito vectors serving as transmission reservoirs. In preclinical models of vaccine-induced immunity, antibodies to parasite sexual-stage antigens, ingested in the mosquito blood meal, can inhibit parasite survival in the insect midgut as judged by ex vivo functional studies such as the membrane feeding assay. In an era of renewed political momentum for malaria elimination and eradication campaigns, such observations have fueled support for the development and implementation of so-called transmission-blocking vaccines. While leading candidates are being evaluated using a variety of promising vaccine platforms, the field is also beginning to capitalize on global '-omics' data for the rational genome-based selection and unbiased characterization of parasite and mosquito proteins to expand the candidate list. This review covers the progress and prospects of these recent developments.

  18. Development of a multicomponent Staphylococcus aureus vaccine designed to counter multiple bacterial virulence factors

    PubMed Central

    Anderson, Annaliesa S.; Miller, Alita A.; Donald, Robert G.K.; Scully, Ingrid L.; Nanra, Jasdeep S.; Cooper, David; Jansen, Kathrin U.

    2012-01-01

    Staphylococcus aureus is a major cause of healthcare-associated infections and is responsible for a substantial burden of disease in hospitalized patients. Despite increasingly rigorous infection control guidelines, the prevalence and corresponding negative impact of S. aureus infections remain considerable. Difficulties in controlling S. aureus infections as well as the associated treatment costs are exacerbated by increasing rates of resistance to available antibiotics. Despite ongoing efforts over the past 20 years, no licensed S. aureus vaccine is currently available. However, learnings from past clinical failures of vaccine candidates and a better understanding of the immunopathology of S. aureus colonization and infection have aided in the design of new vaccine candidates based on multiple important bacterial pathogenesis mechanisms. This review outlines important considerations in designing a vaccine for the prevention of S. aureus disease in healthcare settings. PMID:22922765

  19. Recombinant protein vaccines produced in insect cells.

    PubMed

    Cox, Manon M J

    2012-02-27

    The baculovirus-insect cell expression system is a well known tool for the production of complex proteins. The technology is also used for commercial manufacture of various veterinary and human vaccines. This review paper provides an overview of how this technology can be applied to produce a multitude of vaccine candidates. The key advantage of this recombinant protein manufacturing platform is that a universal "plug and play" process may be used for producing a broad range of protein-based prophylactic and therapeutic vaccines for both human and veterinary use while offering the potential for low manufacturing costs. Large scale mammalian cell culture facilities previously established for the manufacturing of monoclonal antibodies that have now become obsolete due to yield improvement could be deployed for the manufacturing of these vaccines. Alternatively, manufacturing capacity could be established in geographic regions that do not have any vaccine production capability. Dependent on health care priorities, different vaccines could be manufactured while maintaining the ability to rapidly convert to producing pandemic influenza vaccine when the need arises. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Live attenuated tetravalent dengue vaccine.

    PubMed

    Bhamarapravati, N; Sutee, Y

    2000-05-26

    The development of a live attenuated tetravalent dengue vaccine is currently the best strategy to obtain a vaccine against dengue viruses. The Mahidol University group developed candidate live attenuated vaccines by attenuation through serial passages in certified primary cell cultures. Dengue serotype 1, 2 and 4 viruses were developed in primary dog kidney cells, whereas dengue serotype 3 was serially passaged in primary African green monkey kidney cells. Tissue culture passaged strain viruses were subjected to biological marker studies. Candidate vaccines have been tested as monovalent (single virus), bivalent (two viruses), trivalent (three viruses) and tetravalent (all four serotype viruses) vaccines in Thai volunteers. They were found to be safe and immunogenic in both adults and children. The Mahidol live attenuated dengue 2 virus was also tested in American volunteers and resulted in good immune response indistinguishable from those induced in Thai volunteers. The master seeds from the four live attenuated virus strains developed were provided to Pasteur Merieux Connaught of France for production on an industrial scale following good manufacturing practice guidelines.

  1. Limited variation in vaccine candidate Plasmodium falciparum Merozoite Surface Protein-6 over multiple transmission seasons.

    PubMed

    Neal, Aaron T; Jordan, Stephen J; Oliveira, Ana L; Hernandez, Jean N; Branch, Oralee H; Rayner, Julian C

    2010-05-24

    sequence level, with no SNPs detected in the 506 samples analysed. This limited diversity supports further investigation of PfMSP6 as a blood stage vaccine candidate, with the clear caveat that any such vaccine must either contain both alleles or generate cross-protective responses that react against both allele classes. Detailed immunoepidemiology studies are needed to establish the viability of these approaches before PfMSP6 advances further down the vaccine development pipeline.

  2. Flying vaccinator; a transgenic mosquito delivers a Leishmania vaccine via blood feeding.

    PubMed

    Yamamoto, D S; Nagumo, H; Yoshida, S

    2010-06-01

    'Flying vaccinator' is the concept of using genetically engineered hematophagous insects to deliver vaccines. Here we show the generation of a transgenic anopheline mosquito that expresses the Leishmania vaccine candidate, SP15, fused to monomeric red fluorescent protein (mDsRed) in its salivary glands. Importantly, mice bitten repeatedly by the transgenic mosquitoes raised anti-SP15 antibodies, indicating delivery of SP15 via blood feeding with its immunogenicity intact. Thus, this technology makes possible the generation of transgenic mosquitoes that match the original concept of a 'flying vaccinator'. However, medical safety issues and concerns about informed consent mitigate the use of the 'flying vaccinator' as a method to deliver vaccines. We propose that this expression system could be applied to elucidate saliva-malaria sporozoite interactions.

  3. Comparative Evaluation of Two Vaccine Candidates against Experimental Leishmaniasis Due to Leishmania major Infection in Four Inbred Mouse Strains▿

    PubMed Central

    Benhnini, Fouad; Chenik, Mehdi; Laouini, Dhafer; Louzir, Hechmi; Cazenave, Pierre André; Dellagi, Koussay

    2009-01-01

    Experimental leishmaniasis in BALB/c and C57BL/6 mice are the most investigated murine models that were used for the preclinical evaluation of Leishmania vaccine candidates. We have previously described two new inbred mouse strains named PWK and MAI issued from feral founders that also support the development of experimental leishmaniasis due to L. major. In this study, we sought to determine whether different mouse inbred strains generate concordant or discordant results when used to evaluate the potential of Leishmania proteins to protect against experimental leishmaniasis. To this end, two Leishmania proteins, namely, LACK (for Leishmania homolog of receptor for activated C kinase) and LmPDI (for L. major protein disulfide isomerase) were compared for their capacity to protect against experimental leishmaniasis in PWK, MAI, BALB/c, and C57BL/6 inbred mouse strains. Our data show that the capacity of Leishmania proteins to confer protection depends on the mouse strain used, stressing the important role played by the genetic background in shaping the immune response against the pathogen. These results may have important implications for the preclinical evaluation of candidate Leishmania vaccines: rather than using a single mouse strain, a panel of different inbred strains of various genetic backgrounds should be tested in parallel. The antigen that confers protection in the larger range of inbred strains may have better chances to be also protective in outbred human populations and should be selected for clinical trials. PMID:19726616

  4. Comparative evaluation of two vaccine candidates against experimental leishmaniasis due to Leishmania major infection in four inbred mouse strains.

    PubMed

    Benhnini, Fouad; Chenik, Mehdi; Laouini, Dhafer; Louzir, Hechmi; Cazenave, Pierre André; Dellagi, Koussay

    2009-11-01

    Experimental leishmaniasis in BALB/c and C57BL/6 mice are the most investigated murine models that were used for the preclinical evaluation of Leishmania vaccine candidates. We have previously described two new inbred mouse strains named PWK and MAI issued from feral founders that also support the development of experimental leishmaniasis due to L. major. In this study, we sought to determine whether different mouse inbred strains generate concordant or discordant results when used to evaluate the potential of Leishmania proteins to protect against experimental leishmaniasis. To this end, two Leishmania proteins, namely, LACK (for Leishmania homolog of receptor for activated C kinase) and LmPDI (for L. major protein disulfide isomerase) were compared for their capacity to protect against experimental leishmaniasis in PWK, MAI, BALB/c, and C57BL/6 inbred mouse strains. Our data show that the capacity of Leishmania proteins to confer protection depends on the mouse strain used, stressing the important role played by the genetic background in shaping the immune response against the pathogen. These results may have important implications for the preclinical evaluation of candidate Leishmania vaccines: rather than using a single mouse strain, a panel of different inbred strains of various genetic backgrounds should be tested in parallel. The antigen that confers protection in the larger range of inbred strains may have better chances to be also protective in outbred human populations and should be selected for clinical trials.

  5. Tuberculosis vaccine development: recent progress.

    PubMed

    Orme, I M; McMurray, D N; Belisle, J T

    2001-03-01

    Recent years have seen a renewed effort to develop new vaccines against tuberculosis. As a result, several promising avenues of research have developed, including the production of recombinant vaccines, auxotrophic vaccines, DNA vaccines and subunit vaccines. In this article we briefly review this work, as well as consider the pros and cons of the animal models needed to test these new vaccines. Screening to date has been carried out in mouse and guinea pig models, which have been used to obtain basic information such as the effect of the vaccine on bacterial load, and whether the vaccine can prevent or reduce lung pathology. The results to date lead us to be optimistic that new candidate vaccines could soon be considered for evaluation in clinical trials.

  6. Vaccination Against Dengue: Challenges and Current Developments.

    PubMed

    Guy, Bruno; Lang, Jean; Saville, Melanie; Jackson, Nicholas

    2016-01-01

    Dengue is a growing threat worldwide, and the development of a vaccine is a public health priority. The completion of the active phase of two pivotal efficacy studies conducted in Asia and Latin America by Sanofi Pasteur has constituted an important step. Several other approaches are under development, and whichever technology is used, vaccine developers face several challenges linked to the particular nature and etiology of dengue disease. We start our review by defining questions and potential issues linked to dengue pathology and presenting the main types of vaccine approaches that have explored these questions; some of these candidates are in a late stage of clinical development. In the second part of the review, we focus on the Sanofi Pasteur dengue vaccine candidate, describing the steps from research to phase III efficacy studies. Finally, we discuss what could be the next steps, before and after vaccine introduction, to ensure that the vaccine will provide the best benefit with an acceptable safety profile to the identified target populations.

  7. From brain passage to cell adaptation: the road of human rabies vaccine development.

    PubMed

    Wu, Xianfu; Smith, Todd G; Rupprecht, Charles E

    2011-11-01

    A major challenge for global rabies prevention and control is the lack of sufficient and affordable high quality vaccines. Such candidates should be pure, potent, safe, effective and economical to produce, with broad cross-reactivity against viral variants of public health and veterinary importance. The history of licensed human vaccines reviewed herein demonstrates clearly how the field has evolved to the current state of more passive development and postexposure management. Modern cell culture techniques provide adequate viral substrates for production of representative verified virus seeds. In contrast to outdated nervous tissue-based rabies vaccines, once a suitable substrate is identified, production of high titer virus results in a major qualitative and quantitative difference. Given the current scenario of only inactivated vaccines for humans, highly cell-adapted and stable, attenuated rabies viruses are ideal candidates for consideration to meet the need for seed viruses in the future.

  8. 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.

  9. 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

  10. 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.

  11. Tuberculosis vaccines in clinical trials

    PubMed Central

    Rowland, Rosalind; McShane, Helen

    2011-01-01

    Effective prophylactic and/or therapeutic vaccination is a key strategy for controlling the global TB epidemic. The partial effectiveness of the existing TB vaccine, bacille Calmette–Guérin (BCG), suggests effective vaccination is possible and highlights the need for an improved vaccination strategy. Clinical trials are evaluating both modifications to the existing BCG immunization methods and also novel TB vaccines, designed to replace or boost BCG. Candidate vaccines in clinical development include live mycobacterial vaccines designed to replace BCG, subunit vaccines designed to boost BCG and therapeutic vaccines designed as an adjunct to chemotherapy. There is a great need for validated animal models, identification of immunological biomarkers of protection and field sites with the capacity for large-scale efficacy testing in order to develop and license a novel TB vaccine or regimen. PMID:21604985

  12. [Approaches and problems in vaccine development against leishmaniasis].

    PubMed

    Allahverdiyev, Adil; Bağirova, Melahat; Cakir Koç, Rabia; Oztel, Olga Nehir; Elçıçek, Serhat; Ateş, Sezen Canım; Karaca, Tuğçe Deniz

    2010-01-01

    Leishmaniasis is a major public health problem of the world and Turkey. Recently there has been increasing interest in vaccine studies among strategies for control of leishmaniasis. Recently the increase of interest in vaccine studies among leishmaniasis control strategies makes the subject more up to date. So the aim of this review is to present information about recent vaccine studies, problems and new strategies for vaccine development studies. There are 3 generations of vaccine against leishmaniasis. First-generation vaccines are killed or live attenuated parasites; second-generation vaccines are recombinant or native antigens and live genetically modified parasites (knock out and suicidal cassettes), third generation vaccines are DNA vaccines. Also vector salivary proteins, dendritic cells and non-pathogenic L. tarentolae have been used as vaccine candidates. However there is still no effective vaccine against leishmaniasis. Since polymer conjugates considerably increase immunogenicity, polymer based vaccine studies have gained importance in recent years. However, there has not been such a study for an antileishmanial vaccine yet. LPG, surface antigen of Leishmania promastigotes, and polymer conjugates may be promising in antileishmanial vaccine studies so we are carrying out a TUBITAK Project on this subject which has been given the number, 1085170SBAG-4007.

  13. Immunogenicity and protective efficacy of DMT liposome-adjuvanted tuberculosis subunit CTT3H vaccine

    PubMed Central

    Teng, Xindong; Tian, Maopeng; Li, Jianrong; Tan, Songwei; Yuan, Xuefeng; Yu, Qi; Jing, Yukai; Zhang, Zhiping; Yue, Tingting; Zhou, Lei; Fan, Xionglin

    2015-01-01

    Different strategies have been proposed for the development of protein subunit vaccine candidates for tuberculosis (TB), which shows better safety than other types of candidates and the currently used Bacillus Calmette-Guérin (BCG) vaccine. In order to develop more effective protein subunits depending on the mechanism of cell-mediated immunity against TB, a polyprotein CTT3H, based on 5 immunodominant antigens (CFP10, TB10.4, TB8.4, Rv3615c, and HBHA) with CD8+ epitopes of Mycobacterium tuberculosis, was constructed in this study. We vaccinated C57BL/6 mice with a TB subunit CTT3H protein in an adjuvant of dimethyldioctadecylammonium/monophosphoryl lipid A/trehalose 6,6′-dibehenate (DDA/MPL/TDB, DMT) liposome to investigate the immunogenicity and protective efficacy of this novel vaccine. Our results demonstrated that DMT liposome-adjuvanted CTT3H vaccine not only induced an antigen-specific CD4+ Th1 response, but also raised the number of PPD- and CTT3H-specific IFN-γ+ CD8+ T cells and elicited strong CTL responses against TB10.4, which provided more effective protection against a 60 CFU M. tuberculosis aerosol challenge than PBS control and DMT adjuvant alone. Our findings indicate that DMT-liposome is an effective adjuvant to stimulate CD8+ T cell responses and the DMT-adjuvanted subunit CTT3H vaccine is a promising candidate for the next generation of TB vaccine. PMID:25905680

  14. Immunogenicity and protective efficacy of DMT liposome-adjuvanted tuberculosis subunit CTT3H vaccine.

    PubMed

    Teng, Xindong; Tian, Maopeng; Li, Jianrong; Tan, Songwei; Yuan, Xuefeng; Yu, Qi; Jing, Yukai; Zhang, Zhiping; Yue, Tingting; Zhou, Lei; Fan, Xionglin

    2015-01-01

    Different strategies have been proposed for the development of protein subunit vaccine candidates for tuberculosis (TB), which shows better safety than other types of candidates and the currently used Bacillus Calmette-Guérin (BCG) vaccine. In order to develop more effective protein subunits depending on the mechanism of cell-mediated immunity against TB, a polyprotein CTT3H, based on 5 immunodominant antigens (CFP10, TB10.4, TB8.4, Rv3615c, and HBHA) with CD8(+) epitopes of Mycobacterium tuberculosis, was constructed in this study. We vaccinated C57BL/6 mice with a TB subunit CTT3H protein in an adjuvant of dimethyldioctadecylammonium/monophosphoryl lipid A/trehalose 6,6'-dibehenate (DDA/MPL/TDB, DMT) liposome to investigate the immunogenicity and protective efficacy of this novel vaccine. Our results demonstrated that DMT liposome-adjuvanted CTT3H vaccine not only induced an antigen-specific CD4(+) Th1 response, but also raised the number of PPD- and CTT3H-specific IFN-γ(+) CD8(+) T cells and elicited strong CTL responses against TB10.4, which provided more effective protection against a 60 CFU M. tuberculosis aerosol challenge than PBS control and DMT adjuvant alone. Our findings indicate that DMT-liposome is an effective adjuvant to stimulate CD8(+) T cell responses and the DMT-adjuvanted subunit CTT3H vaccine is a promising candidate for the next generation of TB vaccine.

  15. Multi-walled carbon nanotubes increase antibody-producing B cells in mice immunized with a tetravalent vaccine candidate for dengue virus.

    PubMed

    Calegari, Luan P; Dias, Roberto S; de Oliveira, Michelle D; Pessoa, Carine Ribeiro; de Oliveira, André S; Oliveira, Ana F C S; da Silva, Cynthia C; Fonseca, Flavio G; Versiani, Alice F; De Paula, Sérgio O

    2016-07-27

    In recent times, studies have demonstrated that carbon nanotubes are good candidates for use as vehicles for transfection of exogenous material into the cells. However, there are few studies evaluating the behavior of carbon nanotubes as DNA vectors and few of these studies have used multi-walled carbon nanotubes (MWCNTs) or carboxylated MWCNTs. Thus, this study aims to assess the MWCNTs' (carboxylated or not) efficiency in the increase in expression of the tetravalent vaccine candidate (TVC) plasmid vector for dengue virus in vitro using Vero cells, and in vivo, through the intramuscular route, to evaluate the immunological response profile. Multi-walled carbon nanotubes internalized by Vero cells, have been found in the cytoplasm and nucleus associated with the plasmid. However, it was not efficient to increase the messenger ribonucleic acid (mRNA) compared to the pure vaccine candidate associated with Lipofectamine(®) 2000. The in vivo experiments showed that the use of intramuscular injection of the TVC in combination with MWCNTs reduced the immune response compared to pure TVC, in a general way, although an increase was observed in the population of the antibody-producing B cells, as compared to pure TVC. The results confirm the data found by other authors, which demonstrate the ability of nanotubes to penetrate target cells and reach both the cytoplasm and the cell nucleus. The cytotoxicity values are also in accordance with the literature, which range from 5 to 20 µg/mL. This has been found to be 10 µg/mL in this study. Although the expression levels are higher in cells that receive the pure TVC transfected using Lipofectamine(®) 2000, the nanotubes show an increase in B-cells producing antibodies.

  16. Vaccines: an ongoing promise?

    PubMed

    Alsahli, M; Farrell, R J; Michetti, P

    2001-01-01

    Over the past decade, intensive research has focused on developing a vaccine therapy for Helicobacter pylori. Substantial unresolved questions cloud the current approach, and the development of a vaccine against this unique organism has proved very challenging. Many candidate vaccines have been tested in animal models. The immunogenicity and the safety of some vaccine formulations have been recently evaluated through clinical trials, and the efficacy of these vaccine therapies in humans will be determined in the near future. This article will provide an overview of the current knowledge of natural and vaccine-induced immune responses to H. pylori infection. It will also review past vaccine successes and failures in animal models and the limited experience to date in using vaccine therapy in humans. Several obstacles to H. pylori vaccine development efforts along with the future direction of these efforts will be discussed. Copyright 2001 S. Karger AG, Basel

  17. New Kids on the Block: RNA-Based Influenza Virus Vaccines.

    PubMed

    Scorza, Francesco Berlanda; Pardi, Norbert

    2018-04-01

    RNA-based immunization strategies have emerged as promising alternatives to conventional vaccine approaches. A substantial body of published work demonstrates that RNA vaccines can elicit potent, protective immune responses against various pathogens. Consonant with its huge impact on public health, influenza virus is one of the best studied targets of RNA vaccine research. Currently licensed influenza vaccines show variable levels of protection against seasonal influenza virus strains but are inadequate against drifted and pandemic viruses. In recent years, several types of RNA vaccines demonstrated efficacy against influenza virus infections in preclinical models. Additionally, comparative studies demonstrated the superiority of some RNA vaccines over the currently used inactivated influenza virus vaccines in animal models. Based on these promising preclinical results, clinical trials have been initiated and should provide valuable information about the translatability of the impressive preclinical data to humans. This review briefly describes RNA-based vaccination strategies, summarizes published preclinical and clinical data, highlights the roadblocks that need to be overcome for clinical applications, discusses the landscape of industrial development, and shares the authors' personal perspectives about the future of RNA-based influenza virus vaccines.

  18. Efficacy of phase 3 trial of RTS, S/AS01 malaria vaccine: The need for an alternative development plan.

    PubMed

    Mahmoudi, Shima; Keshavarz, Hossein

    2017-09-02

    Although vaccines would be the ideal tool for control, prevention, elimination, and eradication of many infectious diseases, developing of parasites vaccines such as malaria vaccine is very complex. The most advanced malaria vaccine candidate RTS,S, a pre-erythrocytic vaccine, has been recommended for licensure by EMEA. The results of this phase III trial suggest that this candidate malaria vaccine has relatively little efficacy, and the vaccine apparently will not meet the goal of malaria eradication by itself. Since there are many vaccine candidates in the pipeline 1 that are being evaluated in vaccine trials, further study on using of alternative parasite targets and vaccination strategies are highly recommended.

  19. Chitosan microspheres as candidate plasmid vaccine carrier for oral immunisation of Japanese flounder (Paralichthys olivaceus).

    PubMed

    Tian, Jiyuan; Yu, Juan; Sun, Xiuqin

    2008-12-15

    Oral DNA-based immunotherapy is a new treatment option for fish immunisation in intensive culture. However, because of the existence of the nucleases and severe gastrointestinal conditions, DNA-based vaccines can be hydrolyzed or denatured. In our laboratory, a plasmid DNA (pDNA) containing major capsid protein (MCP) gene of lymphocystis disease virus (LCDV) was prepared, and then pDNA was encapsulated in chitosan microspheres through an emulsion-based methodology. The yield, loading percent and encapsulation efficiency of microspheres were 93.6%, 0.3% and 94.5%, respectively. Scanning electron microscopy (SEM) showed that pDNA-loaded microspheres yielded a spherical shape with smooth surfaces. The disproportion of super-coiled to open circle and linear pDNA suggested that high transfection efficiencies of pDNA in microspheres were retained. The cumulative release of pDNA showed that chitosan microspheres were resistant to degradation in simulated gastrointestinal tract environment. The release profile at PBS buffer (pH 7.4) displayed that pDNA-loaded chitosan microspheres had a release up to 42 days after intestinal imbibition. RT-PCR showed that RNA containing information of MCP gene existed in various tissues 10-90 days post-vaccination. SDS-PAGE and immunofluorescent images indicated that pDNA expressed MCP in tissues of fish 10-90 days after oral administration. In addition, indirect ELISA displayed that the immune responses of sera were positive (O.D.> or =0.3) from week 1 to week 16 for fish vaccinated with microspheres, in comparison with fish vaccinated with naked pDNA. Data obtained suggested that chitosan microspheres were promising carriers for oral pDNA vaccine. Because this encapsulation technique was easy to operate and immunisation efficacy of microspheres loaded with pDNA was significant, it had potential to be used in drug delivery applications.

  20. Evaluation of the Schistosoma mansoni Y-box-binding protein (SMYB1) potential as a vaccine candidate against schistosomiasis.

    PubMed

    Dias, Sílvia R C; Boroni, Mariana; Rocha, Elizângela A; Dias, Thomaz L; de Laet Souza, Daniela; Oliveira, Fabrício M S; Bitar, Mainá; Macedo, Andrea M; Machado, Carlos R; Caliari, Marcelo V; Franco, Glória R

    2014-01-01

    Schistosomiasis is a neglected tropical disease, and after malaria, is the second most important tropical disease in public health. A vaccine that reduces parasitemia is desirable to achieve mass treatment with a low cost. Although potential antigens have been identified and tested in clinical trials, no effective vaccine against schistosomiasis is available. Y-box-binding proteins (YBPs) regulate gene expression and participate in a variety of cellular processes, including transcriptional and translational regulation, DNA repair, cellular proliferation, drug resistance, and stress responses. The Schistosoma mansoni ortholog of the human YB-1, SMYB1, is expressed in all stages of the parasite life cycle. Although SMYB1 binds to DNA or RNA oligonucleotides, immunohistochemistry assays demonstrated that it is primarily localized in the cytoplasm of parasite cells. In addition, SMYB1 interacts with a protein involved in mRNA processing, suggesting that SMYB1 functions in the turnover, transport, and/or stabilization of RNA molecules during post-transcriptional gene regulation. Here we report the potential of SMYB1 as a vaccine candidate. We demonstrate that recombinant SMYB1 stimulates the production of high levels of specific IgG1 antibodies in a mouse model. The observed levels of specific IgG1 and IgG2a antibodies indicate an actual protection against cercariae challenge. Animals immunized with rSMYB1 exhibited a 26% reduction in adult worm burden and a 28% reduction in eggs retained in the liver. Although proteins from the worm tegument are considered optimal targets for vaccine development, this study demonstrates that unexposed cytoplasmic proteins can reduce the load of intestinal worms and the number of eggs retained in the liver.

  1. Peri-exposure protection against Nipah virus disease using a single-dose recombinant vesicular stomatitis virus-based vaccine

    PubMed Central

    DeBuysscher, Blair L; Scott, Dana; Thomas, Tina; Feldmann, Heinz; Prescott, Joseph

    2016-01-01

    Nipah virus is a zoonotic paramyxovirus that causes severe disease in humans and animals. Due to almost yearly outbreaks in Bangladesh, and a large outbreak in Malaysia that lead to the shutdown of swine export, Nipah virus is both a threat to public health and the economy. Infection is associated with respiratory distress, encephalitis and human-to-human transmission, resulting in high case fatality rates during outbreaks. This study aims to address the amount of time needed until protection from a recombinant vesicular stomatitis virus-based vaccine candidate expressing the Nipah virus glycoprotein (G), which we have previously shown to protect hamsters and non-human primates when administered 28 days before challenge. We found that a single-dose vaccination, when administered 1 day before challenge, reduced viral load, limited pathology and fully protected hamsters from Nipah virus infection. The vaccine was even partially protective when administered at early time points following challenge with Nipah virus. These data indicate that a single administration of this vaccine to high-risk individuals, such as family members and health-care workers of infected patients, could be protective and useful for reducing human-to-human transmission and curbing an outbreak. PMID:28706736

  2. Peri-exposure protection against Nipah virus disease using a single-dose recombinant vesicular stomatitis virus-based vaccine.

    PubMed

    DeBuysscher, Blair L; Scott, Dana; Thomas, Tina; Feldmann, Heinz; Prescott, Joseph

    2016-01-01

    Nipah virus is a zoonotic paramyxovirus that causes severe disease in humans and animals. Due to almost yearly outbreaks in Bangladesh, and a large outbreak in Malaysia that lead to the shutdown of swine export, Nipah virus is both a threat to public health and the economy. Infection is associated with respiratory distress, encephalitis and human-to-human transmission, resulting in high case fatality rates during outbreaks. This study aims to address the amount of time needed until protection from a recombinant vesicular stomatitis virus-based vaccine candidate expressing the Nipah virus glycoprotein (G), which we have previously shown to protect hamsters and non-human primates when administered 28 days before challenge. We found that a single-dose vaccination, when administered 1 day before challenge, reduced viral load, limited pathology and fully protected hamsters from Nipah virus infection. The vaccine was even partially protective when administered at early time points following challenge with Nipah virus. These data indicate that a single administration of this vaccine to high-risk individuals, such as family members and health-care workers of infected patients, could be protective and useful for reducing human-to-human transmission and curbing an outbreak.

  3. Current status and future prospects of yellow fever vaccines.

    PubMed

    Beck, Andrew S; Barrett, Alan D T

    2015-01-01

    Yellow fever 17D vaccine is one of the oldest live-attenuated vaccines in current use that is recognized historically for its immunogenic and safe properties. These unique properties of 17D are presently exploited in rationally designed recombinant vaccines targeting not only flaviviral antigens but also other pathogens of public health concern. Several candidate vaccines based on 17D have advanced to human trials, and a chimeric recombinant Japanese encephalitis vaccine utilizing the 17D backbone has been licensed. The mechanism(s) of attenuation for 17D are poorly understood; however, recent insights from large in silico studies have indicated particular host genetic determinants contributing to the immune response to the vaccine, which presumably influences the considerable durability of protection, now in many cases considered to be lifelong. The very rare occurrence of severe adverse events for 17D is discussed, including a recent fatal case of vaccine-associated viscerotropic disease.

  4. Current Status and Future Prospects of Yellow Fever Vaccines

    PubMed Central

    Beck, Andrew S.; Barrett, Alan D.T.

    2017-01-01

    Summary Yellow fever 17D vaccine is one of the oldest live-attenuated vaccines in current use that is recognized for historically immunogenic and safe properties. These unique properties of 17D are presently exploited in rationally designed recombinant vaccines targeting not only flaviviral antigens but also other pathogens of public health concern. Several candidate vaccines based on 17D have advanced to human trials, and a chimeric recombinant Japanese encephalitis vaccine utilizing the 17D backbone has been licensed. The mechanism(s) of attenuation for 17D are poorly understood; however, recent insights from large in silico studies have indicated particular host genetic determinants contributing to the immune response to the vaccine, which presumably influences the considerable durability of protection, now in many cases considered to be life-long. The very rare occurrence of severe adverse events for 17D is discussed, including a recent fatal case of vaccine-associated viscerotropic disease. PMID:26366673

  5. Immunogenicity and Safety of Yellow Fever Vaccine (Stamaril) When Administered Concomitantly With a Tetravalent Dengue Vaccine Candidate in Healthy Toddlers at 12-13 Months of Age in Colombia and Peru: A Randomized Trial.

    PubMed

    López, Pio; Lanata, Claudio F; Zambrano, Betzana; Cortés, Margarita; Andrade, Teresa; Amemiya, Isabel; Terrones, Cynthia; Gil, Ana I; Verastegui, Hector; Marquez, Viviana; Crevat, Denis; Jezorwski, John; Noriega, Fernando

    2016-10-01

    Dengue and yellow fever (YF) viruses are closely related members of the Flaviviridae family. Given the inherent similarities between the YF vaccine and dengue vaccine (CYD-TDV) candidate, it is possible that the latter could interfere with the response to the licensed YF vaccine when coadministered. In this randomized, observer-blind, controlled, phase III trial, conducted in Colombia and Peru, 787 toddlers were administered YF vaccine concomitantly with CYD-TDV (group 1) or placebo (group 2), followed by CYD-TDV after 6 and 12 months. YF and dengue neutralizing antibody titers were determined using a 50% plaque reduction neutralization test. Noninferiority was demonstrated if the lower limit of the 2-sided 95% confidence interval of the difference in seroconversion rates [(YF + CYD-TDV) - YF alone] was greater than -10%. The safety of both vaccines was also assessed. Concomitant administration of YF with either CYD-TDV or placebo yielded YF seroconversion rates of 100.0% and 99.7%, respectively. The difference in YF seroconversion rates between the 2 groups was 0.33% (95% confidence interval:0.98; 1.87), demonstrating that the immune response against YF administered concomitantly with CYD-TDV was noninferior to YF administered with placebo. After 2 injections of CYD-TDV, the percentage of participants with dengue titres ≥10 (1/dil) for the 4 dengue serotypes were 91.2%-100% for group 1 and 97.2%-100% in group 2. There were no safety concerns during the study period. Concomitant administration of YF vaccine with CYD-TDV has no relevant impact on the immunogenicity or safety profile of the YF vaccine.

  6. [Recombinant Vp2 protein of infectious bursal disease virus AH1 strain expressed in insect cells: a vaccine candidate].

    PubMed

    Ouyang, Wei; Wang, Yongshan; Zhou, Yu; Zhang, Haibin; Tang, Yude

    2010-05-01

    Protective immune response of the available IBD vaccine is insufficient to fully protect against the prevailing strain of the infectious bursal disease virus (IBDV). Such a vaccination escape IBDV field isolate idenfied from Anhui province of China in December 2007, where IBD broke out at 2 weeks post vaccination. The IBDV vp2 gene was cloned into pFastBacHTA donor plasmid, followed by generation of the recombinant bacmid DNA pBac-VP2. The latter was used to transfect insect cell Sf9 with Lipofectamine to produce recombinant baculovirus vBac-VP2. The Sf9 cells infected with vBac-VP2 were stained positive against IBDV antibody using the indirect immunofluorescence assay (IFA), which was also confirmed by the detection of IBDV Vp2 protein in the infected Sf9 cells by IBDV sandwich ELISA. Western blotting revealed that the calculated protein of approximately 53 kDa was in the expressed in the insect cells. Moreover, virus-like particles (VLPs) and "inclusion body-like"structure in the infected Sf9 cells were observed under electron microscopy. We further developed an indirect ELISA for the detection of the IBDV antibodies, which was specific and sensitive. In addition, the lysates of vBac-VP2 infected cells was used to immunize 2-week-old SPF chickens, followed by challenging with the virulent IBDV, the survival rate was 30% at 14 days post primary immunization, however, the survival rate was 100% at 14 d after the booster vaccination. The ELISA antibody titers was up to 3.2 x 10(3) and neutralization antibody titer was 2536, significantly higher than those of one-shot vaccination, 8 x 10(2) and 1106, respectively. The immunized chickens did not show any clinical signs and histopathological changes of infection in 7-days trial time. The bursa/body-weight ratios were higher than those of the unimmunized control (P < 0.05). The virus-like-particle recombinant Vp2 protein expressed in insect cells promises to be a novel subunit vaccine and diagnostic reagent candidate

  7. Optimization and scale-up of cell culture and purification processes for production of an adenovirus-vectored tuberculosis vaccine candidate.

    PubMed

    Shen, Chun Fang; Jacob, Danielle; Zhu, Tao; Bernier, Alice; Shao, Zhongqi; Yu, Xuefeng; Patel, Mehul; Lanthier, Stephane; Kamen, Amine

    2016-06-17

    Tuberculosis (TB) is the second leading cause of death by infectious disease worldwide. The only available TB vaccine is the Bacille Calmette-Guerin (BCG). However, parenterally administered Mycobacterium bovis BCG vaccine confers only limited immune protection from pulmonary tuberculosis in humans. There is a need for developing effective boosting vaccination strategies. AdAg85A, an adenoviral vector expressing the mycobacterial protein Ag85A, is a new tuberculosis vaccine candidate, and has shown promising results in pre-clinical studies and phase I trial. This adenovirus vectored vaccine is produced using HEK 293 cell culture. Here we report on the optimization of cell culture conditions, scale-up of production and purification of the AdAg85A at different scales. Four commercial serum-free media were evaluated under various conditions for supporting the growth of HEK293 cell and production of AdAg85A. A culturing strategy was employed to take advantages of two culture media with respective strengths in supporting the cell growth and virus production, which enabled to maintain virus productivity at higher cell densities and resulted in more than two folds of increases in culture titer. The production of AdAg85A was successfully scaled up and validated at 60L bioreactor under the optimal conditions. The AdAg85A generated from the 3L and 60L bioreactor runs was purified through several purification steps. More than 98% of total cellular proteins was removed, over 60% of viral particles was recovered after the purification process, and purity of AdAg85A was similar to that of the ATCC VR-1516 Ad5 standard. Vaccination of mice with the purified AdAg85A demonstrated a very good level of Ag85A-specific antibody responses. The optimized production and purification conditions were transferred to a GMP facility for manufacturing of AdAg85A for generation of clinical grade material to support clinical trials. Crown Copyright © 2016. Published by Elsevier Ltd. All rights

  8. What's new in tuberculosis vaccines?

    PubMed Central

    Ginsberg, Ann M.

    2002-01-01

    Over the past 10 years, tuberculosis (TB) vaccine development has resurged as an active area of investigation. The renewed interest has been stimulated by the recognition that, although BCG is delivered to approximately 90% of all neonates globally through the Expanded Programme on Immunization, Mycobacterium tuberculosis continues to cause over 8 million new cases of TB and over 2 million deaths annually. Over one hundred TB vaccine candidates have been developed, using different approaches to inducing protective immunity. Candidate vaccines are typically screened in small animal models of primary TB disease for their ability to protect against a virulent strain of M. tuberculosis. The most promising are now beginning to enter human safety trials, marking real progress in this field for the first time in 80 years. PMID:12132007

  9. From bench to almost bedside: the long road to a licensed Ebola virus vaccine.

    PubMed

    Wong, Gary; Mendoza, Emelissa J; Plummer, Francis A; Gao, George F; Kobinger, Gary P; Qiu, Xiangguo

    2018-02-01

    The Ebola virus (EBOV) disease epidemic during 2014-16 in West Africa has accelerated the clinical development of several vaccine candidates that have demonstrated efficacy in the gold standard nonhuman primate (NHP) model, namely cynomolgus macaques. Areas covered: This review discusses the pre-clinical research and if available, clinical evaluation of the currently available EBOV vaccine candidates, while emphasizing the translatability of pre-clinical data generated in the NHP model to clinical data in humans. Expert opinion: Despite the existence of many successful EBOV vaccine candidates in the pre-clinical stages, only two platforms became the focus of Phase 2/3 efficacy trials in Liberia, Sierra Leone, and Guinea near the peak of the epidemic: the Vesicular stomatitis virus (VSV)-vectored vaccine and the chimpanzee adenovirus type 3 (ChAd3)-vectored vaccine. The results of three distinct clinical trials involving these candidates may soon pave the way for a licensed, safe and efficacious EBOV vaccine to help combat future epidemics.

  10. From bench to almost bedside: The long road to a licensed Ebola virus vaccine

    PubMed Central

    Wong, Gary; Mendoza, Emelissa J.; Plummer, Francis A.; Gao, George F.; Kobinger, Gary P.; Qiu, Xiangguo

    2018-01-01

    Introduction The Ebola virus (EBOV) disease epidemic during 2014-16 in West Africa has accelerated the clinical development of several vaccine candidates that have demonstrated efficacy in the gold standard nonhuman primate (NHP) model, namely cynomolgus macaques. Areas covered This review discusses the pre-clinical research and if available, clinical evaluation of the currently available EBOV vaccine candidates, while emphasizing the translatability of pre-clinical data generated in the NHP model to clinical data in humans. Expert opinion Despite the existence of many successful EBOV vaccine candidates in the pre-clinical stages, only two platforms became the focus of Phase 2/3 efficacy trials in Liberia, Sierra Leone, and Guinea near the peak of the epidemic: the Vesicular stomatitis virus (VSV)-vectored vaccine and the chimpanzee adenovirus type 3 (ChAd3)-vectored vaccine. The results of three distinct clinical trials involving these candidates may soon pave the way for a licensed, safe and efficacious EBOV vaccine to help combat future epidemics. PMID:29148858

  11. Force Spectroscopy of the Plasmodium falciparum Vaccine Candidate Circumsporozoite Protein Suggests a Mechanically Pliable Repeat Region.

    PubMed

    Patra, Aditya Prasad; Sharma, Shobhona; Ainavarapu, Sri Rama Koti

    2017-02-10

    The most effective vaccine candidate of malaria is based on the Plasmodium falciparum circumsporozoite protein (CSP), a major surface protein implicated in the structural strength, motility, and immune evasion properties of the infective sporozoites. It is suspected that reversible conformational changes of CSP are required for infection of the mammalian host, but the detailed structure and dynamic properties of CSP remain incompletely understood, limiting our understanding of its function in the infection. Here, we report the structural and mechanical properties of the CSP studied using single-molecule force spectroscopy on several constructs, one including the central region of CSP, which is rich in NANP amino acid repeats (CSP rep ), and a second consisting of a near full-length sequence without the signal and anchor hydrophobic domains (CSP ΔHP ). Our results show that the CSP rep is heterogeneous, with 40% of molecules requiring virtually no mechanical force to unfold (<10 piconewtons (pN)), suggesting that these molecules are mechanically compliant and perhaps act as entropic springs, whereas the remaining 60% are partially structured with low mechanical resistance (∼70 pN). CSP ΔHP having multiple force peaks suggests specifically folded domains, with two major populations possibly indicating the open and collapsed forms. Our findings suggest that the overall low mechanical resistance of the repeat region, exposed on the outer surface of the sporozoites, combined with the flexible full-length conformations of CSP, may provide the sporozoites not only with immune evasion properties, but also with lubricating capacity required during its navigation through the mosquito and vertebrate host tissues. We anticipate that these findings would further assist in the design and development of future malarial vaccines. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Development of designed site-directed pseudopeptide-peptido-mimetic immunogens as novel minimal subunit-vaccine candidates for malaria.

    PubMed

    Lozano, José Manuel; Lesmes, Liliana P; Carreño, Luisa F; Gallego, Gina M; Patarroyo, Manuel Elkin

    2010-12-06

    Synthetic vaccines constitute the most promising tools for controlling and preventing infectious diseases. When synthetic immunogens are designed from the pathogen native sequences, these are normally poorly immunogenic and do not induce protection, as demonstrated in our research. After attempting many synthetic strategies for improving the immunogenicity properties of these sequences, the approach consisting of identifying high binding motifs present in those, and then performing specific changes on amino-acids belonging to such motifs, has proven to be a workable strategy. In addition, other strategies consisting of chemically introducing non-natural constraints to the backbone topology of the molecule and modifying the α-carbon asymmetry are becoming valuable tools to be considered in this pursuit. Non-natural structural constraints to the peptide backbone can be achieved by introducing peptide bond isosters such as reduced amides, partially retro or retro-inverso modifications or even including urea motifs. The second can be obtained by strategically replacing L-amino-acids with their enantiomeric forms for obtaining both structurally site-directed designed immunogens as potential vaccine candidates and their Ig structural molecular images, both having immuno-therapeutic effects for preventing and controlling malaria.

  13. Engineering Enhanced Vaccine Cell Lines To Eradicate Vaccine-Preventable Diseases: the Polio End Game

    PubMed Central

    van der Sanden, Sabine M. G.; Wu, Weilin; Dybdahl-Sissoko, Naomi; Weldon, William C.; Brooks, Paula; O'Donnell, Jason; Jones, Les P.; Brown, Cedric; Tompkins, S. Mark; Karpilow, Jon; Tripp, Ralph A.

    2015-01-01

    ABSTRACT Vaccine manufacturing costs prevent a significant portion of the world's population from accessing protection from vaccine-preventable diseases. To enhance vaccine production at reduced costs, a genome-wide RNA interference (RNAi) screen was performed to identify gene knockdown events that enhanced poliovirus replication. Primary screen hits were validated in a Vero vaccine manufacturing cell line using attenuated and wild-type poliovirus strains. Multiple single and dual gene silencing events increased poliovirus titers >20-fold and >50-fold, respectively. Host gene knockdown events did not affect virus antigenicity, and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9-mediated knockout of the top candidates dramatically improved viral vaccine strain production. Interestingly, silencing of several genes that enhanced poliovirus replication also enhanced replication of enterovirus 71, a clinically relevant virus to which vaccines are being targeted. The discovery that host gene modulation can markedly increase virus vaccine production dramatically alters mammalian cell-based vaccine manufacturing possibilities and should facilitate polio eradication using the inactivated poliovirus vaccine. IMPORTANCE Using a genome-wide RNAi screen, a collection of host virus resistance genes was identified that, upon silencing, increased poliovirus and enterovirus 71 production by from 10-fold to >50-fold in a Vero vaccine manufacturing cell line. This report provides novel insights into enterovirus-host interactions and describes an approach to developing the next generation of vaccine manufacturing through engineered vaccine cell lines. The results show that specific gene silencing and knockout events can enhance viral titers of both attenuated (Sabin strain) and wild-type polioviruses, a finding that should greatly facilitate global implementation of inactivated polio vaccine as well as further reduce costs for live-attenuated oral polio vaccines

  14. Engineering Enhanced Vaccine Cell Lines To Eradicate Vaccine-Preventable Diseases: the Polio End Game.

    PubMed

    van der Sanden, Sabine M G; Wu, Weilin; Dybdahl-Sissoko, Naomi; Weldon, William C; Brooks, Paula; O'Donnell, Jason; Jones, Les P; Brown, Cedric; Tompkins, S Mark; Oberste, M Steven; Karpilow, Jon; Tripp, Ralph A

    2016-02-15

    Vaccine manufacturing costs prevent a significant portion of the world's population from accessing protection from vaccine-preventable diseases. To enhance vaccine production at reduced costs, a genome-wide RNA interference (RNAi) screen was performed to identify gene knockdown events that enhanced poliovirus replication. Primary screen hits were validated in a Vero vaccine manufacturing cell line using attenuated and wild-type poliovirus strains. Multiple single and dual gene silencing events increased poliovirus titers >20-fold and >50-fold, respectively. Host gene knockdown events did not affect virus antigenicity, and clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9-mediated knockout of the top candidates dramatically improved viral vaccine strain production. Interestingly, silencing of several genes that enhanced poliovirus replication also enhanced replication of enterovirus 71, a clinically relevant virus to which vaccines are being targeted. The discovery that host gene modulation can markedly increase virus vaccine production dramatically alters mammalian cell-based vaccine manufacturing possibilities and should facilitate polio eradication using the inactivated poliovirus vaccine. Using a genome-wide RNAi screen, a collection of host virus resistance genes was identified that, upon silencing, increased poliovirus and enterovirus 71 production by from 10-fold to >50-fold in a Vero vaccine manufacturing cell line. This report provides novel insights into enterovirus-host interactions and describes an approach to developing the next generation of vaccine manufacturing through engineered vaccine cell lines. The results show that specific gene silencing and knockout events can enhance viral titers of both attenuated (Sabin strain) and wild-type polioviruses, a finding that should greatly facilitate global implementation of inactivated polio vaccine as well as further reduce costs for live-attenuated oral polio vaccines. This work

  15. A plant-produced protective antigen vaccine confers protection in rabbits against a lethal aerosolized challenge with Bacillus anthracis Ames spores.

    PubMed

    Chichester, Jessica A; Manceva, Slobodanka D; Rhee, Amy; Coffin, Megan V; Musiychuk, Konstantin; Mett, Vadim; Shamloul, Moneim; Norikane, Joey; Streatfield, Stephen J; Yusibov, Vidadi

    2013-03-01

    The potential use of Bacillus anthracis as a bioterrorism weapon threatens the security of populations globally, requiring the immediate availability of safe, efficient and easily delivered anthrax vaccine for mass vaccination. Extensive research efforts have been directed toward the development of recombinant subunit vaccines based on protective antigen (PA), the principal virulence factor of B. anthracis. Among the emerging technologies for the production of these vaccine antigens is our launch vector-based plant transient expression system. Using this system, we have successfully engineered, expressed, purified and characterized full-length PA (pp-PA83) in Nicotiana benthamiana plants using agroinfiltration. This plant-produced antigen elicited high toxin neutralizing antibody titers in mice and rabbits after two vaccine administrations with Alhydrogel. In addition, immunization with this vaccine candidate protected 100% of rabbits from a lethal aerosolized B. anthracis challenge. The vaccine effects were dose-dependent and required the presence of Alhydrogel adjuvant. In addition, the vaccine antigen formulated with Alhydrogel was stable and retained immunogenicity after two-week storage at 4°C, the conditions intended for clinical use. These results support the testing of this vaccine candidate in human volunteers and the utility of our plant expression system for the production of a recombinant anthrax vaccine.

  16. A novel Sin Nombre virus DNA vaccine and its inclusion in a candidate pan-hantavirus vaccine against hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS).

    PubMed

    Hooper, Jay W; Josleyn, Matthew; Ballantyne, John; Brocato, Rebecca

    2013-09-13

    Sin Nombre virus (SNV; family Bunyaviridae, genus Hantavirus) causes a hemorrhagic fever known as hantavirus pulmonary syndrome (HPS) in North America. There have been approximately 200 fatal cases of HPS in the United States since 1993, predominantly in healthy working-age males (case fatality rate 35%). There are no FDA-approved vaccines or drugs to prevent or treat HPS. Previously, we reported that hantavirus vaccines based on the full-length M gene segment of Andes virus (ANDV) for HPS in South America, and Hantaan virus (HTNV) and Puumala virus (PUUV) for hemorrhagic fever with renal syndrome (HFRS) in Eurasia, all elicited high-titer neutralizing antibodies in animal models. HFRS is more prevalent than HPS (>20,000 cases per year) but less pathogenic (case fatality rate 1-15%). Here, we report the construction and testing of a SNV full-length M gene-based DNA vaccine to prevent HPS. Rabbits vaccinated with the SNV DNA vaccine by muscle electroporation (mEP) developed high titers of neutralizing antibodies. Furthermore, hamsters vaccinated three times with the SNV DNA vaccine using a gene gun were completely protected against SNV infection. This is the first vaccine of any kind that specifically elicits high-titer neutralizing antibodies against SNV. To test the possibility of producing a pan-hantavirus vaccine, rabbits were vaccinated by mEP with an HPS mix (ANDV and SNV plasmids), or HFRS mix (HTNV and PUUV plasmids), or HPS/HFRS mix (all four plasmids). The HPS mix and HFRS mix elicited neutralizing antibodies predominantly against ANDV/SNV and HTNV/PUUV, respectively. Furthermore, the HPS/HFRS mix elicited neutralizing antibodies against all four viruses. These findings demonstrate a pan-hantavirus vaccine using a mixed-plasmid DNA vaccine approach is feasible and warrants further development. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

  17. Strategic priorities for respiratory syncytial virus (RSV) vaccine development

    PubMed Central

    Anderson, L.J.; Dormitzer, P.R.; Nokes, D.J.; Rappuoli, R.; Roca, A.; Graham, B.S.

    2013-01-01

    Although RSV has been a high priority for vaccine development, efforts to develop a safe and effective vaccine have yet to lead to a licensed product. Clinical and epidemiologic features of RSV disease suggest there are at least 4 distinct target populations for vaccines, the RSV naïve young infant, the RSV naïve child ≥6 months of age, pregnant women (to provide passive protection to newborns), and the elderly. These target populations raise different safety and efficacy concerns and may require different vaccination strategies. The highest priority target population is the RSV naïve child. The occurrence of serious adverse events associated with the first vaccine candidate for young children, formalin inactivated RSV (FI-RSV), has focused vaccine development for the young RSV naïve child on live virus vaccines. Enhanced disease is not a concern for persons previously primed by a live virus infection. A variety of live-attenuated viruses have been developed with none yet achieving licensure. New live-attenuated RSV vaccines are being developed and evaluated that maybe sufficiently safe and efficacious to move to licensure. A variety of subunit vaccines are being developed and evaluated primarily for adults in whom enhanced disease is not a concern. An attenuated parainfluenza virus 3 vector expressing the RSV F protein was evaluated in RSV naïve children. Most of these candidate vaccines have used the RSV F protein in various vaccine platforms including virus-like particles, nanoparticles, formulated with adjuvants, and expressed by DNA or virus vectors. The other surface glycoprotein, the G protein, has also been used in candidate vaccines. We now have tools to make and evaluate a wide range of promising vaccines. Costly clinical trials in the target population are needed to evaluate and select candidate vaccines for advancement to efficacy trials. Better data on RSV-associated mortality in developing countries, better estimates of the risk of long term

  18. Development of male contraceptive vaccine--a perspective.

    PubMed

    Moudgal, N R; Jeyakumar, M; Krishnamurthy, H N; Sridhar, S; Krishnamurthy, H; Martin, F

    1997-01-01

    This paper reviews the recent advances that have occurred in the area of development of a male contraceptive vaccine. The vaccine candidates considered for review are hormone/hormone receptor-based proteins including luteinizing hormone-releasing hormone (LHRH)/LH, follicle stimulating hormone (FSH), as well as LH and FSH receptor proteins. The review also highlights the advances in our basic understanding of gonadotrophin action which have led to development of these vaccines. Focus is mainly on studies in the non-human primate which may be directly relevant to projected studies in the human. The data indicate that the vaccines are well tolerated by the primate (including the human based on limited data) and do not give rise to any known toxic symptoms or immediate health hazards. The response to the immunogen has been uniform and it may be possible to increase antibody titres as well as prolong the immune response by adding acceptable immune stimulators to the adjuvant cocktail and developing better immunization schedules or immunogen delivery systems. Contraceptive vaccines for the male are a feasible proposition and attention should now be focussed on evaluating carefully the bioefficacy of antibodies raised to recombinant ovine FSHbeta or FSH receptor protein fragments in both human and non-human primates. The advantage of the FSH/FSH receptor over the LHRH/LH-based vaccine lies in the fact that the former does not require an exogenous testosterone supplement to maintain accessory gland function, libido etc. The LHRH/LH-based vaccine results in azoospermia, while the FSH vaccine causes the production of low numbers of poor quality spermatozoa which are incapable of impregnating cycling females.

  19. Latest development on RNA-based drugs and vaccines.

    PubMed

    Lundstrom, Kenneth

    2018-06-01

    Drugs and vaccines based on mRNA and RNA viruses show great potential and direct translation in the cytoplasm eliminates chromosomal integration. Limitations are associated with delivery and stability issues related to RNA degradation. Clinical trials on RNA-based drugs have been conducted in various disease areas. Likewise, RNA-based vaccines for viral infections and various cancers have been subjected to preclinical and clinical studies. RNA delivery and stability improvements include RNA structure modifications, targeting dendritic cells and employing self-amplifying RNA. Single-stranded RNA viruses possess self-amplifying RNA, which can provide extreme RNA replication in the cytoplasm to support RNA-based drug and vaccine development. Although oligonucleotide-based approaches have demonstrated potential, the focus here is on mRNA- and RNA virus-based methods.

  20. Vaccines to combat river blindness: expression, selection and formulation of vaccines against infection with Onchocerca volvulus in a mouse model

    PubMed Central

    Hess, Jessica A.; Zhan, Bin; Bonne-Année, Sandra; Deckman, Jessica M.; Bottazzi, Maria Elena; Hotez, Peter J.; Klei, Thomas R.; Lustigman, Sara; Abraham, David

    2014-01-01

    Human onchocerciasis is a neglected tropical disease caused by Onchocerca volvulus and an important cause of blindness and chronic disability in the developing world. Although mass drug administration of ivermectin has had a profound effect on control of the disease, additional tools are critically needed including the need for a vaccine against onchocerciasis. The objectives of the present study were to: (i) select antigens with known vaccine pedigrees as components of a vaccine; (ii) produce the selected vaccine antigens under controlled conditions, using two expression systems and in one laboratory and (iii) evaluate their vaccine efficacy using a single immunization protocol in mice. In addition, we tested the hypothesis that joining protective antigens as a fusion protein or in combination, into a multivalent vaccine, would improve the ability of the vaccine to induce protective immunity. Out of eight vaccine candidates tested in this study, Ov-103, Ov-RAL-2 and Ov-CPI-2M were shown to reproducibly induce protective immunity when administered individually, as fusion proteins or in combination. Although there was no increase in the level of protective immunity induced by combining the antigens into one vaccine, these antigens remain strong candidates for inclusion in a vaccine to control onchocerciasis in humans. PMID:24907553

  1. National Institute of Allergy and Infectious Diseases workshop report: "Chlamydia vaccines: The way forward".

    PubMed

    Zhong, Guangming; Brunham, Robert C; de la Maza, Luis M; Darville, Toni; Deal, Carolyn

    2017-10-31

    Chlamydia trachomatis (Ct), an intracellular pathogen, is the most common bacterial sexually transmitted infection. In addition to acute cervicitis and urethritis, Ct can lead to serious sequelae of significant public health burden including pelvic inflammatory disease (PID) and infertility. Ct control efforts have not resulted in desired outcomes such as reduced incidence and reinfection, and this highlights the need for the development of an effective Ct vaccine. To this end, NIAID organized a workshop to consider the current status of Ct vaccine research and address critical questions in Ct vaccine design and clinical testing. Topics included the goal(s) of a vaccine and the feasibility of achieving these goals, animal models of infection including mouse and nonhuman primate (NHP) models, and correlates of protection to guide vaccine design. Decades of research have provided both whole cell-based and subunit vaccine candidates for development. At least one is currently in clinical development and efforts now need to be directed toward further development of the most attractive candidates. Overall, the discussions and presentations from the workshop highlighted optimism about the current status of Ct vaccine research and detailed the remaining gaps and questions needed to move vaccines forward. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. 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.

  3. Animal Models for Salmonellosis: Applications in Vaccine Research

    PubMed Central

    Higginson, Ellen E.; Simon, Raphael

    2016-01-01

    Salmonellosis remains an important cause of human disease worldwide. While there are several licensed vaccines for Salmonella enterica serovar Typhi, these vaccines are generally ineffective against other Salmonella serovars. Vaccines that target paratyphoid and nontyphoidal Salmonella serovars are very much in need. Preclinical evaluation of candidate vaccines is highly dependent on the availability of appropriate scientific tools, particularly animal models. Many different animal models exist for various Salmonella serovars, from whole-animal models to smaller models, such as those recently established in insects. Here, we discuss various mouse, rat, rabbit, calf, primate, and insect models for Salmonella infection, all of which have their place in research. However, choosing the right model is imperative in selecting the best vaccine candidates for further clinical testing. In this minireview, we summarize the various animal models that are used to assess salmonellosis, highlight some of the advantages and disadvantages of each, and discuss their value in vaccine development. PMID:27413068

  4. Respiratory syncytial virus subunit vaccine based on a recombinant fusion protein expressed transiently in mammalian cells.

    PubMed

    Nallet, Sophie; Amacker, Mario; Westerfeld, Nicole; Baldi, Lucia; König, Iwo; Hacker, David L; Zaborosch, Christiane; Zurbriggen, Rinaldo; Wurm, Florian M

    2009-10-30

    Although respiratory syncytial virus (RSV) causes severe lower respiratory tract infection in infants and adults at risk, no RSV vaccine is currently available. In this report, efforts toward the generation of an RSV subunit vaccine using recombinant RSV fusion protein (rRSV-F) are described. The recombinant protein was produced by transient gene expression (TGE) in suspension-adapted human embryonic kidney cells (HEK-293E) in 4 L orbitally shaken bioreactors. It was then purified and formulated in immunostimulating reconstituted influenza virosomes (IRIVs). The candidate vaccine induced anti-RSV-F neutralizing antibodies in mice, and challenge studies in cotton rats are ongoing. If successful in preclinical and clinical trials, this will be the first recombinant subunit vaccine produced by large-scale TGE in mammalian cells.

  5. Correlates of protection for enteric vaccines.

    PubMed

    Holmgren, Jan; Parashar, Umesh D; Plotkin, Stanley; Louis, Jacques; Ng, Su-Peing; Desauziers, Eric; Picot, Valentina; Saadatian-Elahi, Mitra

    2017-06-08

    An immunological Correlate of Protection (CoP) is an immune response that is statistically interrelated with protection. Identification of CoPs for enteric vaccines would help design studies to improve vaccine performance of licensed vaccines in low income settings, and would facilitate the testing of future vaccines in development that might be more affordable. CoPs are lacking today for most existing and investigational enteric vaccines. In order to share the latest information on CoPs for enteric vaccines and to discuss novel approaches to correlate mucosal immune responses in humans with protection, the Foundation Mérieux organized an international conference of experts where potential CoPs for vaccines were examined using case-studies for both bacterial and viral enteric pathogens. Experts on the panel concluded that to date, all established enteric vaccine CoPs, such as those for hepatitis A, Vi typhoid and poliovirus vaccines, are based on serological immune responses even though these may poorly reflect the relevant gut immune responses or predict protective efficacy. Known CoPs for cholera, norovirus and rotavirus could be considered as acceptable for comparisons of similarly composed vaccines while more work is still needed to establish CoPs for the remaining enteric pathogens and their candidate vaccines. Novel approaches to correlate human mucosal immune responses with protection include the investigation of gut-originating antibody-secreting cells (ASCs), B memory cells and follicular helper T cells from samples of peripheral blood during their recirculation. Copyright © 2017.

  6. 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.

  7. Development and approval of live attenuated influenza vaccines based on Russian master donor viruses: Process challenges and success stories.

    PubMed

    Rudenko, Larisa; Yeolekar, Leena; Kiseleva, Irina; Isakova-Sivak, Irina

    2016-10-26

    Influenza is a viral infection that affects much of the global population each year. Vaccination remains the most effective tool for preventing the disease. Live attenuated influenza vaccine (LAIV) has been used since the 1950s to protect humans against seasonal influenza. LAIVs developed by the Institute of Experimental Medicine (IEM), Saint Petersburg, Russia, have been successfully used in Russia since 1987. In 2006, the World Health Organization (WHO) announced a Global action plan for influenza vaccines (GAP). WHO, recognizing potential advantages of LAIV over the inactivated influenza vaccine in a pandemic situation, included LAIV in the GAP. BioDiem Ltd., a vaccine development company based in Melbourne, Australia which held the rights for the Russian LAIV, licensed this technology to WHO in 2009. WHO was permitted to grant sub-licenses to vaccine manufacturers in newly industrialized and developing countries to use the Russian LAIV for the development, manufacture, use and sale of pandemic and seasonal LAIVs. To date, WHO has granted sub-licenses to vaccine manufacturers in China (Changchun BCHT Biotechnology Co., Ltd.), India (Serum Institute of India Pvt. Ltd.) and Thailand (Government Pharmaceutical Organization). In parallel, in 2009, IEM signed an agreement with WHO, under which IEM committed to supply pandemic and seasonal candidate vaccine viruses to the sub-licensees. This paper describes the progress made by collaborators from China, India, Russia and Thailand in developing preventive measures, including LAIV against pandemic influenza. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. Progress with new malaria vaccines.

    PubMed Central

    Webster, Daniel; Hill, Adrian V. S.

    2003-01-01

    Malaria is a parasitic disease of major global health significance that causes an estimated 2.7 million deaths each year. In this review we describe the burden of malaria and discuss the complicated life cycle of Plasmodium falciparum, the parasite responsible for most of the deaths from the disease, before reviewing the evidence that suggests that a malaria vaccine is an attainable goal. Significant advances have recently been made in vaccine science, and we review new vaccine technologies and the evaluation of candidate malaria vaccines in human and animal studies worldwide. Finally, we discuss the prospects for a malaria vaccine and the need for iterative vaccine development as well as potential hurdles to be overcome. PMID:14997243

  9. Atypical antibody responses in dengue vaccine recipients.

    PubMed

    Kanesa-Thasan, N; Sun, W; Ludwig, G V; Rossi, C; Putnak, J R; Mangiafico, J A; Innis, B L; Edelman, R

    2003-12-01

    Eight of 69 (12%) healthy adult volunteers vaccinated with monovalent live-attenuated dengue virus (DENV) vaccine candidates had atypical antibody responses, with depressed IgM:IgG antibody ratios and induction of high-titer hemagglutination-inhibiting and neutralizing (NT) antibodies to all four DENV serotypes. These features suggested flavivirus exposure prior to DENV vaccination, yet no volunteer had a history of previous flavivirus infection, flavivirus vaccination, or antibody to flaviviruses evident before DENV vaccination. Moreover, production of antibody to DENV by atypical responders (AR) was not accelerated compared with antibody responses in the 61 flavivirus-naive responders (NR). Further evaluation revealed no differences in sex, age, race, DENV vaccine candidate received, or clinical signs and symptoms following vaccination between AR and NR. However, viremia was delayed at the onset in AR compared with NR. A comparative panel of all AR and five randomly selected NR found flavivirus cross-reactive antibody after vaccination only in AR. Unexpectedly, six of eight AR had NT antibodies to yellow fever virus (YFV) > 1:10 before vaccination while NR had none (P = 0.04). The AR also universally demonstrated YFV NT antibody titers > or = 1:160 after DENV vaccination, whereas four of five NR failed to seroconvert (P = 0.02). Yellow fever virus priming broadens the antibody response to monovalent DENV vaccination. The effect of flavivirus priming on the clinical and immunologic response to tetravalent DENV vaccine remains to be determined.

  10. An α-Gal-containing neoglycoprotein-based vaccine partially protects against murine cutaneous leishmaniasis caused by Leishmania major

    PubMed Central

    Iniguez, Eva; Schocker, Nathaniel S.; Subramaniam, Krishanthi; Portillo, Susana; Montoya, Alba L.; Al-Salem, Waleed S.; Torres, Caresse L.; Rodriguez, Felipe; Moreira, Otacilio C.; Acosta-Serrano, Alvaro; Michael, Katja; Maldonado, Rosa A.

    2017-01-01

    Background Protozoan parasites from the genus Leishmania cause broad clinical manifestations known as leishmaniases, which affect millions of people worldwide. Cutaneous leishmaniasis (CL), caused by L. major, is one the most common forms of the disease in the Old World. There is no preventive or therapeutic human vaccine available for L. major CL, and existing drug treatments are expensive, have toxic side effects, and resistant parasite strains have been reported. Hence, further therapeutic interventions against the disease are necessary. Terminal, non-reducing, and linear α-galactopyranosyl (α-Gal) epitopes are abundantly found on the plasma membrane glycolipids of L. major known as glycoinositolphospholipids. The absence of these α-Gal epitopes in human cells makes these glycans highly immunogenic and thus potential targets for vaccine development against CL. Methodology/Principal findings Here, we evaluated three neoglycoproteins (NGPs), containing synthetic α-Gal epitopes covalently attached to bovine serum albumin (BSA), as vaccine candidates against L. major, using α1,3-galactosyltransferase-knockout (α1,3GalT-KO) mice. These transgenic mice, similarly to humans, do not express nonreducing, linear α-Gal epitopes in their cells and are, therefore, capable of producing high levels of anti-α-Gal antibodies. We observed that Galα(1,6)Galβ-BSA (NGP5B), but not Galα(1,4)Galβ-BSA (NGP12B) or Galα(1,3)Galα-BSA (NGP17B), was able to significantly reduce the size of footpad lesions by 96% in comparison to control groups. Furthermore, we observed a robust humoral and cellular immune response with production of high levels of protective lytic anti-α-Gal antibodies and induction of Th1 cytokines. Conclusions/Significance We propose that NGP5B is an attractive candidate for the study of potential synthetic α-Gal-neoglycoprotein-based vaccines against L. major infection. PMID:29069089

  11. An α-Gal-containing neoglycoprotein-based vaccine partially protects against murine cutaneous leishmaniasis caused by Leishmania major.

    PubMed

    Iniguez, Eva; Schocker, Nathaniel S; Subramaniam, Krishanthi; Portillo, Susana; Montoya, Alba L; Al-Salem, Waleed S; Torres, Caresse L; Rodriguez, Felipe; Moreira, Otacilio C; Acosta-Serrano, Alvaro; Michael, Katja; Almeida, Igor C; Maldonado, Rosa A

    2017-10-01

    Protozoan parasites from the genus Leishmania cause broad clinical manifestations known as leishmaniases, which affect millions of people worldwide. Cutaneous leishmaniasis (CL), caused by L. major, is one the most common forms of the disease in the Old World. There is no preventive or therapeutic human vaccine available for L. major CL, and existing drug treatments are expensive, have toxic side effects, and resistant parasite strains have been reported. Hence, further therapeutic interventions against the disease are necessary. Terminal, non-reducing, and linear α-galactopyranosyl (α-Gal) epitopes are abundantly found on the plasma membrane glycolipids of L. major known as glycoinositolphospholipids. The absence of these α-Gal epitopes in human cells makes these glycans highly immunogenic and thus potential targets for vaccine development against CL. Here, we evaluated three neoglycoproteins (NGPs), containing synthetic α-Gal epitopes covalently attached to bovine serum albumin (BSA), as vaccine candidates against L. major, using α1,3-galactosyltransferase-knockout (α1,3GalT-KO) mice. These transgenic mice, similarly to humans, do not express nonreducing, linear α-Gal epitopes in their cells and are, therefore, capable of producing high levels of anti-α-Gal antibodies. We observed that Galα(1,6)Galβ-BSA (NGP5B), but not Galα(1,4)Galβ-BSA (NGP12B) or Galα(1,3)Galα-BSA (NGP17B), was able to significantly reduce the size of footpad lesions by 96% in comparison to control groups. Furthermore, we observed a robust humoral and cellular immune response with production of high levels of protective lytic anti-α-Gal antibodies and induction of Th1 cytokines. We propose that NGP5B is an attractive candidate for the study of potential synthetic α-Gal-neoglycoprotein-based vaccines against L. major infection.

  12. 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.

  13. First generation leishmaniasis vaccines: a review of field efficacy trials.

    PubMed

    Noazin, Sassan; Modabber, Farrokh; Khamesipour, Ali; Smith, Peter G; Moulton, Lawrence H; Nasseri, Kiumarss; Sharifi, Iraj; Khalil, Eltahir A G; Bernal, Ivan Dario Velez; Antunes, Carlos M F; Kieny, Marie Paule; Tanner, Marcel

    2008-12-09

    First generation candidate vaccines against leishmaniasis, prepared using inactivated whole parasites as their main ingredient, were considered as promising because of their relative ease of production and low cost. These vaccines have been the subject of many investigations over several decades and are the only leishmaniasis vaccine candidates which have undergone phase 3 clinical trial evaluation. Although the studies demonstrated the safety of the vaccines and several studies showed reasonable immunogenicity and some indication of protection, an efficacious prophylactic vaccine is yet to be identified. Despite this overall failure, these trials contributed significantly to increasing knowledge on human leishmaniasis immunology. To provide a collective view, this review discusses the methods and findings of field efficacy trials of first generation leishmaniasis vaccine clinical trials conducted in the Old and New Worlds.

  14. From genomes to vaccines: Leishmania as a model.

    PubMed Central

    Almeida, Renata; Norrish, Alan; Levick, Mark; Vetrie, David; Freeman, Tom; Vilo, Jaak; Ivens, Alasdair; Lange, Uta; Stober, Carmel; McCann, Sharon; Blackwell, Jenefer M

    2002-01-01

    The 35 Mb genome of Leishmania should be sequenced by late 2002. It contains approximately 8500 genes that will probably translate into more than 10 000 proteins. In the laboratory we have been piloting strategies to try to harness the power of the genome-proteome for rapid screening of new vaccine candidate. To this end, microarray analysis of 1094 unique genes identified using an EST analysis of 2091 cDNA clones from spliced leader libraries prepared from different developmental stages of Leishmania has been employed. The plan was to identify amastigote-expressed genes that could be used in high-throughput DNA-vaccine screens to identify potential new vaccine candidates. Despite the lack of transcriptional regulation that polycistronic transcription in Leishmania dictates, the data provide evidence for a high level of post-transcriptional regulation of RNA abundance during the developmental cycle of promastigotes in culture and in lesion-derived amastigotes of Leishmania major. This has provided 147 candidates from the 1094 unique genes that are specifically upregulated in amastigotes and are being used in vaccine studies. Using DNA vaccination, it was demonstrated that pooling strategies can work to identify protective vaccines, but it was found that some potentially protective antigens are masked by other disease-exacerbatory antigens in the pool. A total of 100 new vaccine candidates are currently being tested separately and in pools to extend this analysis, and to facilitate retrospective bioinformatic analysis to develop predictive algorithms for sequences that constitute potentially protective antigens. We are also working with other members of the Leishmania Genome Network to determine whether RNA expression determined by microarray analyses parallels expression at the protein level. We believe we are making good progress in developing strategies that will allow rapid translation of the sequence of Leishmania into potential interventions for disease

  15. Ebolavirus Vaccines for Humans and Apes

    PubMed Central

    Fausther-Bovendo, Hugues; Mulangu, Sabue

    2012-01-01

    Due to high case fatality proportions, person-to-person transmission, and potential use in bioterrorism, the development of a vaccine against ebolavirus remains a top priority. Although no licensed vaccine or treatment against ebolavirus is currently available, progress in preclinical testing of countermeasures has been made. Here, we will review ebolavirus vaccine candidates and considerations for their use in humans and wild apes. PMID:22560007

  16. Strain Selection for Generation of O-Antigen-Based Glycoconjugate Vaccines against Invasive Nontyphoidal Salmonella Disease

    PubMed Central

    Saul, Allan; MacLennan, Calman A.; Micoli, Francesca; Rondini, Simona

    2015-01-01

    Nontyphoidal Salmonellae, principally S. Typhimurium and S. Enteritidis, are a major cause of invasive bloodstream infections in sub-Saharan Africa with no vaccine currently available. Conjugation of lipopolysaccharide O-antigen to a carrier protein constitutes a promising vaccination strategy. Here we describe a rational process to select the most appropriate isolates of Salmonella as source of O-antigen for developing a bivalent glycoconjugate vaccine. We screened a library of 30 S. Typhimurium and 21 S. Enteritidis in order to identify the most suitable strains for large scale O-antigen production and generation of conjugate vaccines. Initial screening was based on growth characteristics, safety profile of the isolates, O-antigen production, and O-antigen characteristics in terms of molecular size, O-acetylation and glucosylation level and position, as determined by phenol sulfuric assay, NMR, HPLC-SEC and HPAEC-PAD. Three animal isolates for each serovar were identified and used to synthesize candidate glycoconjugate vaccines, using CRM197 as carrier protein. The immunogenicity of these conjugates and the functional activity of the induced antibodies was investigated by ELISA, serum bactericidal assay and flow cytometry. S. Typhimurium O-antigen showed high structural diversity, including O-acetylation of rhamnose in a Malawian invasive strain generating a specific immunodominant epitope. S. Typhimurium conjugates provoked an anti-O-antigen response primarily against the O:5 determinant. O-antigen from S. Enteritidis was structurally more homogeneous than from S. Typhimurium, and no idiosyncratic antibody responses were detected for the S. Enteritidis conjugates. Of the three initially selected isolates, two S. Typhimurium (1418 and 2189) and two S. Enteritidis (502 and 618) strains generated glycoconjugates able to induce high specific antibody levels with high breadth of serovar-specific strain coverage, and were selected for use in vaccine production. The

  17. Dengue human infection models to advance dengue vaccine development.

    PubMed

    Larsen, Christian P; Whitehead, Stephen S; Durbin, Anna P

    2015-12-10

    Dengue viruses (DENV) currently infect approximately 400 million people each year causing millions to seek care and overwhelming the health care infrastructure in endemic areas. Vaccines to prevent dengue and therapeutics to treat dengue are not currently available. The efficacy of the most advanced candidate vaccine against symptomatic dengue in general and DENV-2 in particular was much lower than expected, despite the ability of the vaccine to induce neutralizing antibody against all four DENV serotypes. Because seroconversion to the DENV serotypes following vaccination was thought to be indicative of induced protection, these results have made it more difficult to assess which candidate vaccines should or should not be evaluated in large studies in endemic areas. A dengue human infection model (DHIM) could be extremely valuable to down-select candidate vaccines or therapeutics prior to engaging in efficacy trials in endemic areas. Two DHIM have been developed to assess the efficacy of live attenuated tetravalent (LATV) dengue vaccines. The first model, developed by the Laboratory of Infectious Diseases at the U. S. National Institutes of Health, utilizes a modified DENV-2 strain DEN2Δ30. This virus was derived from the DENV-2 Tonga/74 that caused only very mild clinical infection during the outbreak from which it was recovered. DEN2Δ30 induced viremia in 100%, rash in 80%, and neutropenia in 27% of the 30 subjects to whom it was given. The Walter Reed Army Institute of Research (WRAIR) is developing a DHIM the goal of which is to identify DENV that cause symptomatic dengue fever. WRAIR has evaluated seven viruses and has identified two that meet dengue fever criteria. Both of these models may be very useful in the evaluation and down-selection of candidate dengue vaccines and therapeutics. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  18. Combination vaccines against diarrheal diseases

    PubMed Central

    Venkatesan, Malabi M; Van de Verg, Lillian L

    2015-01-01

    Abstract Diarrheal diseases remain a leading cause of global childhood mortality and morbidity. Several recent epidemiological studies highlight the rate of diarrheal diseases in different parts of the world and draw attention to the impact on childhood growth and survival. Despite the well-documented global burden of diarrheal diseases, currently there are no combination diarrheal vaccines, only licensed vaccines for rotavirus and cholera, and Salmonella typhi-based vaccines for typhoid fever. The recognition of the impact of diarrheal episodes on infant growth, as seen in resource-poor countries, has spurred action from governmental and non-governmental agencies to accelerate research toward affordable and effective vaccines against diarrheal diseases. Both travelers and children in endemic countries will benefit from a combination diarrheal vaccine, but it can be argued that the greater proportion of any positive impact will be on the public health status of the latter. The history of combination pediatric vaccines indicate that monovalent or single disease vaccines are typically licensed first prior to formulation in a combination vaccine, and that the combinations themselves undergo periodic revision in response to need for improvement in safety or potential for wider coverage of important pediatric pathogens. Nevertheless combination pediatric vaccines have proven to be an effective tool in limiting or eradicating communicable childhood diseases worldwide. The landscape of diarrheal vaccine candidates indicates that there now several in active development that offer options for potential testing of combinations to combat those bacterial and viral pathogens responsible for the heaviest disease burden—rotavirus, ETEC, Shigella, Campylobacter, V. cholera and Salmonella. PMID:25891647

  19. Newer Vaccines against Mosquito-borne Diseases.

    PubMed

    Aggarwal, Anju; Garg, Neha

    2018-02-01

    Mosquitos are responsible for a number of protozoal and viral diseases. Malaria, dengue, Japanese encephalitis (JE) and chikungunya epidemics occur commonly all over the world, leading to marked mortality and morbidity in children. Zika, Yellow fever and West Nile fever are others requiring prevention. Environmental control and mosquito bite prevention are useful in decreasing the burden of disease but vaccination has been found to be most cost-effective and is the need of the hour. RTS,S/AS01 vaccine is the first malaria vaccine being licensed for use against P. falciparum malaria. Dengvaxia (CYD-TDV) against dengue was licensed first in Mexico in 2015. A Vero-cell derived, inactivated and alum-adjuvanted JE vaccine based on the SA14-14-2 strain was approved in 2009 in North America, Australia and various European countries. It can be used from 2 mo of age. In India, immunization is carried out in endemic regions at 1 y of age. Another inactivated Vero-cell culture derived Kolar strain, 821564XY, JE vaccine is being used in India. Candidate vaccines against dengue, chikungunya and West Nile fever are been discussed. A continued research and development of new vaccines are required for controlling these mosquito-borne diseases.

  20. Optimization and revision of the production process of the Necator americanus glutathione S-transferase 1 (Na-GST-1), the lead hookworm vaccine recombinant protein candidate

    PubMed Central

    Curti, Elena; Seid, Christopher A; Hudspeth, Elissa; Center, Lori; Rezende, Wanderson; Pollet, Jeroen; Kwityn, Cliff; Hammond, Molly; Matsunami, Rise K; Engler, David A; Hotez, Peter J; Elena Bottazzi, Maria

    2014-01-01

    Infection by the human hookworm Necator americanus is a leading cause of anemia and disability in the developing countries of Africa, Asia, and the Americas. In order to prevent childhood hookworm disease in resource poor settings, a recombinant vaccine is under development by the Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, a Product Development Partnership (PDP). Previously, we reported on the expression and purification of a highly promising hookworm vaccine candidate, Na-GST-1, an N. americanus glutathione s-transferase expressed in Pichia pastoris (yeast), which led to production of 1.5 g of 95% pure recombinant protein at a 20L scale.1, 2, 3 This yield and purity of Na-GST-1 was sufficient for early pilot manufacturing and initial phase 1 clinical testing. However, based on the number of doses which would be required to allow mass vaccination and a potential goal to deliver a vaccine as inexpensively as possible, a higher yield of expression of the recombinant antigen at the lowest possible cost is highly desirable. Here we report on modifications to the fermentation (upstream process) of the antigen expressed in P. pastoris, and to the purification (downstream process) of the recombinant protein that allowed for a 2–3-fold improvement in the final yield of Na-GST-1 purified protein. The major improvements included upstream process changes such as the addition of a sorbitol pulse and co-feed during methanol induction as well as an extension of the induction stage to approximately 96 hours; downstream process changes included modifying the UFDF to flat sheet with a 10 kDa Molecular Weight cut-off (MWCO), adjusting the capacity of an ion-exchange chromatography step utilizing a gradient elution as opposed to the original step elution, and altering the hydrophobic interaction chromatography conditions. The full process, as well as the purity and stability profiles of the target Na-GST-1, and its formulation on

  1. 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.

  2. Ebola Virus Disease Candidate Vaccines Under Evaluation in Clinical Trials

    DTIC Science & Technology

    2016-06-02

    studies in HPIV-3-immune guinea pigs with EBOV GP1,2-expressing HPIV-3 have suggested that while pre-existing immunity to the vector suppressed... guinea pigs and nonhuman primates against infection with multiple Marburg viruses. Expert Rev Vaccines, 7(4), 417-429 (2008). 98. Warfield KL...Swenson DL, Negley DL et al. Marburg virus-like particles protect guinea pigs from lethal Marburg virus infection. Vaccine, 22(25-26), 3495-3502 (2004

  3. 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.

  4. Construction and Evaluation of Novel Rhesus Monkey Adenovirus Vaccine Vectors

    PubMed Central

    Abbink, Peter; Maxfield, Lori F.; Ng'ang'a, David; Borducchi, Erica N.; Iampietro, M. Justin; Bricault, Christine A.; Teigler, Jeffrey E.; Blackmore, Stephen; Parenteau, Lily; Wagh, Kshitij; Handley, Scott A.; Zhao, Guoyan; Virgin, Herbert W.; Korber, Bette

    2014-01-01

    ABSTRACT Adenovirus vectors are widely used as vaccine candidates for a variety of pathogens, including HIV-1. To date, human and chimpanzee adenoviruses have been explored in detail as vaccine vectors. The phylogeny of human and chimpanzee adenoviruses is overlapping, and preexisting humoral and cellular immunity to both are exhibited in human populations worldwide. More distantly related adenoviruses may therefore offer advantages as vaccine vectors. Here we describe the primary isolation and vectorization of three novel adenoviruses from rhesus monkeys. The seroprevalence of these novel rhesus monkey adenovirus vectors was extremely low in sub-Saharan Africa human populations, and these vectors proved to have immunogenicity comparable to that of human and chimpanzee adenovirus vaccine vectors in mice. These rhesus monkey adenoviruses phylogenetically clustered with the poorly described adenovirus species G and robustly stimulated innate immune responses. These novel adenoviruses represent a new class of candidate vaccine vectors. IMPORTANCE Although there have been substantial efforts in the development of vaccine vectors from human and chimpanzee adenoviruses, far less is known about rhesus monkey adenoviruses. In this report, we describe the isolation and vectorization of three novel rhesus monkey adenoviruses. These vectors exhibit virologic and immunologic characteristics that make them attractive as potential candidate vaccine vectors for both HIV-1 and other pathogens. PMID:25410856

  5. 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

  6. Development of high-yield influenza B virus vaccine viruses

    PubMed Central

    Ping, Jihui; Lopes, Tiago J. S.; Neumann, Gabriele; Kawaoka, Yoshihiro

    2016-01-01

    The burden of human infections with influenza A and B viruses is substantial, and the impact of influenza B virus infections can exceed that of influenza A virus infections in some seasons. Over the past few decades, viruses of two influenza B virus lineages (Victoria and Yamagata) have circulated in humans, and both lineages are now represented in influenza vaccines, as recommended by the World Health Organization. Influenza B virus vaccines for humans have been available for more than half a century, yet no systematic efforts have been undertaken to develop high-yield candidates. Therefore, we screened virus libraries possessing random mutations in the six “internal” influenza B viral RNA segments [i.e., those not encoding the major viral antigens, hemagglutinin (HA) and neuraminidase NA)] for mutants that confer efficient replication. Candidate viruses that supported high yield in cell culture were tested with the HA and NA genes of eight different viruses of the Victoria and Yamagata lineages. We identified combinations of mutations that increased the titers of candidate vaccine viruses in mammalian cells used for human influenza vaccine virus propagation and in embryonated chicken eggs, the most common propagation system for influenza viruses. These influenza B virus vaccine backbones can be used for improved vaccine virus production. PMID:27930325

  7. Development of high-yield influenza B virus vaccine viruses.

    PubMed

    Ping, Jihui; Lopes, Tiago J S; Neumann, Gabriele; Kawaoka, Yoshihiro

    2016-12-20

    The burden of human infections with influenza A and B viruses is substantial, and the impact of influenza B virus infections can exceed that of influenza A virus infections in some seasons. Over the past few decades, viruses of two influenza B virus lineages (Victoria and Yamagata) have circulated in humans, and both lineages are now represented in influenza vaccines, as recommended by the World Health Organization. Influenza B virus vaccines for humans have been available for more than half a century, yet no systematic efforts have been undertaken to develop high-yield candidates. Therefore, we screened virus libraries possessing random mutations in the six "internal" influenza B viral RNA segments [i.e., those not encoding the major viral antigens, hemagglutinin (HA) and neuraminidase NA)] for mutants that confer efficient replication. Candidate viruses that supported high yield in cell culture were tested with the HA and NA genes of eight different viruses of the Victoria and Yamagata lineages. We identified combinations of mutations that increased the titers of candidate vaccine viruses in mammalian cells used for human influenza vaccine virus propagation and in embryonated chicken eggs, the most common propagation system for influenza viruses. These influenza B virus vaccine backbones can be used for improved vaccine virus production.

  8. Assessment of the potential public health impact of Herpes Zoster vaccination in Germany.

    PubMed

    Curran, Desmond; Van Oorschot, Desirée; Varghese, Lijoy; Oostvogels, Lidia; Mrkvan, Tomas; Colindres, Romulo; von Krempelhuber, Alfred; Anastassopoulou, Anastassia

    2017-10-03

    The aim of this study was to compare the public health impact of introducing 2 Herpes Zoster (HZ) vaccines, Zoster Vaccine Live (ZVL) versus a non-live adjuvanted subunit candidate vaccine (HZ/su), in the German population aged 50+ years split into 3 age cohorts, i.e. 50-59, 60-69 and 70+ years, respectively. A multi-cohort static Markov model was developed following age cohorts over their lifetime. Demographic data were obtained from the German federal statistical office. HZ incidence and the proportion of HZ individuals developing post-herpetic neuralgia (PHN) were derived from German specific sources. Age-specific vaccine efficacy and waning rates were based on published clinical trial data. Vaccine coverage for both vaccines was assumed to be 40%, with compliance of the second dose of the HZ/su vaccine of 70%. Sensitivity analyses were performed to assess the robustness of the results. It was estimated that, over the remaining lifetime since vaccination, the HZ/su vaccine would reduce the number of HZ cases by 725,233, 533,162 and 486,794 in the 3 age cohorts, respectively, compared with 198,477, 196,000 and 104,640, using ZVL. The number needed to vaccinate (NNV) to prevent one HZ case ranged from 8 to 11 using the HZ/su vaccine compared with 20 to 50 using ZVL. Corresponding NNV to prevent one PHN case ranged from 39 to 53 using the HZ/su vaccine compared with 94 to 198 using ZVL. Due to the higher, sustained vaccine efficacy, the candidate HZ/su vaccine demonstrated superior public health impact compared with ZVL.

  9. High-Density Peptide Arrays for Malaria Vaccine Development.

    PubMed

    Loeffler, Felix F; Pfeil, Johannes; Heiss, Kirsten

    2016-01-01

    The development of an efficacious and practicable vaccine conferring sterile immunity towards a Plasmodium infection represents a not yet achieved goal. A crucial factor for the impact of a given anti-plasmodial subunit vaccine is the identification of the most potent parasitic components required to induce protection from both infection and disease. Here, we present a method based on a novel high-density peptide array technology that allows for a flexible readout of malaria antibodies. Peptide arrays applied as a screening method can be used to identify novel immunogenic antibody epitopes under a large number of potential antigens/peptides. Ultimately, discovered antigen candidates and/or epitope sequences can be translated into vaccine prototype design. The technology can be further utilized to unravel antibody-mediated immune responses (e.g., involved in the establishment of semi-immunity) and moreover to confirm vaccine potency during the process of clinical development by verifying the induced antibody responses following vaccination.

  10. [Legal Bases Of Vaccination In Ukraine].

    PubMed

    Terzi, Olena O

    2018-01-01

    Introduction: Despite the extraordinary progress made in the field of vaccination, a large number of children in the last decade, 24 million children, or nearly 20% of children born every year, do not receive a full plan for vaccination during their first year of life. The aim: The purpose of the article is to analyze the legal framework of vaccination in Ukraine, comparing the approach of the domestic legislator to the vaccination with foreign experience. Materials and methods: Methods of research are selected based on the goal of the study. In order to establish the objectivity and validity of scientific statements and conclusions, during the conducted research a complex of general scientific and special scientific methods was used, in particular such as: the formal legal method; comparative legal method; the method of forecasting and modeling; historical-legal method. Review: In countries with epidemics, a state of emergency can be established and quarantine measures and vaccination to exercise the right to collective health, which may limit the right to individual health by limiting the right to consent to vaccination. Conclusions: It is concluded that in world practice there is no single approach to the recognition of the right to vaccination, as a human right, or as a duty to preserve the epidemiological security of the state. It has been proved that infectious diseases evolve, change their form, the only effective means of preventing pandemics, which may question the existence of man as a biological species, is the vaccination system.

  11. New approaches for Helicobacter vaccine development--difficulties and progress.

    PubMed

    Jagusztyn-Krynicka, Elzbieta K; Godlewska, Renata

    2008-01-01

    Despite the enormous progress in understanding the process of bacterial pathogenesis and interactions of pathogens with eucaryotic cells the infectious diseases still remain the main cause of human premature deaths. It is now recognized that Helicobacter pylori infects about half of the world's population. Based on results of clinical studies the World Health Organization has assigned H. pylori as a class I carcinogen. The review presents new achievements aimed at construction efficient and safe anti-Helicobacter vaccine. We discuss the new global technologies such as immunoproteomics employed for selecting new candidates for vaccine construction as well as new vaccine delivery systems. The review presents also our knowledge concerning H. pylori interaction with immune system which might facilitate modulation of the host immune system by specific adjuvant included into vaccine.

  12. M2e-Based Universal Influenza A Vaccines

    PubMed Central

    Deng, Lei; Cho, Ki Joon; Fiers, Walter; Saelens, Xavier

    2015-01-01

    The successful isolation of a human influenza virus in 1933 was soon followed by the first attempts to develop an influenza vaccine. Nowadays, vaccination is still the most effective method to prevent human influenza disease. However, licensed influenza vaccines offer protection against antigenically matching viruses, and the composition of these vaccines needs to be updated nearly every year. Vaccines that target conserved epitopes of influenza viruses would in principle not require such updating and would probably have a considerable positive impact on global human health in case of a pandemic outbreak. The extracellular domain of Matrix 2 (M2e) protein is an evolutionarily conserved region in influenza A viruses and a promising epitope for designing a universal influenza vaccine. Here we review the seminal and recent studies that focused on M2e as a vaccine antigen. We address the mechanism of action and the clinical development of M2e-vaccines. Finally, we try to foresee how M2e-based vaccines could be implemented clinically in the future. PMID:26344949

  13. Rhesus macaque and mouse models for down-selecting circumsporozoite protein based malaria vaccines differ significantly in immunogenicity and functional outcomes.

    PubMed

    Phares, Timothy W; May, Anthony D; Genito, Christopher J; Hoyt, Nathan A; Khan, Farhat A; Porter, Michael D; DeBot, Margot; Waters, Norman C; Saudan, Philippe; Dutta, Sheetij

    2017-03-13

    Non-human primates, such as the rhesus macaques, are the preferred model for down-selecting human malaria vaccine formulations, but the rhesus model is expensive and does not allow for direct efficacy testing of human malaria vaccines. Transgenic rodent parasites expressing genes of human Plasmodium are now routinely used for efficacy studies of human malaria vaccines. Mice have however rarely predicted success in human malaria trials and there is scepticism whether mouse studies alone are sufficient to move a vaccine candidate into the clinic. A comparison of immunogenicity, fine-specificity and functional activity of two Alum-adjuvanted Plasmodium falciparum circumsporozoite protein (CSP)-based vaccines was conducted in mouse and rhesus models. One vaccine was a soluble recombinant protein (CSP) and the other was the same CSP covalently conjugated to the Qβ phage particle (Qβ-CSP). Mice showed different kinetics of antibody responses and different sensitivity to the NANP-repeat and N-terminal epitopes as compared to rhesus. While mice failed to discern differences between the protective efficacy of CSP versus Qβ-CSP vaccine following direct challenge with transgenic Plasmodium berghei parasites, rhesus serum from the Qβ-CSP-vaccinated animals induced higher in vivo sporozoite neutralization activity. Despite some immunologic parallels between models, these data demonstrate that differences between the immune responses induced in the two models risk conflicting decisions regarding potential vaccine utility in humans. In combination with historical observations, the data presented here suggest that although murine models may be useful for some purposes, non-human primate models may be more likely to predict the human response to investigational vaccines.

  14. Effects of sex, parity, and sequence variation on seroreactivity to candidate pregnancy malaria vaccine antigens.

    PubMed

    Oleinikov, Andrew V; Rossnagle, Eddie; Francis, Susan; Mutabingwa, Theonest K; Fried, Michal; Duffy, Patrick E

    2007-07-01

    Plasmodium falciparum-infected erythrocytes adhere to chondroitin sulfate A (CSA) to sequester in the human placenta, and pregnancy malaria (PM) is associated with the development of disease in and the death of both mother and child. A PM vaccine appears to be feasible, because women become protected as they develop antibodies against placental infected erythrocytes (IEs). Two IE surface molecules, VAR1CSA and VAR2CSA, bind CSA in vitro and are potential vaccine candidates. We expressed all domains of VAR1CSA and VAR2CSA as mammalian cell surface proteins, using a novel approach that allows rapid purification, immobilization, and quantification of target antigen. For serum samples from East Africa, we measured reactivity to all domains, and we examined the effects of host sex and parity, as well as the effects of parasite antigenic variation. Serum samples obtained from multigravid women had a higher reactivity to all VAR2CSA domains than did those obtained from primigravid women or from men. Conversely, serum samples obtained from men had consistently higher reactivity to VAR1CSA domains than did those obtained from gravid women. Seroreactivity was strongly influenced by antigenic variation of VAR2CSA Duffy binding-like domains. Women acquire antibodies to VAR2CSA over successive pregnancies, but they lose reactivity to VAR1CSA. Serum reactivity to VAR2CSA is variant specific, and future studies should examine the degree to which functional antibodies, such as binding-inhibition antibodies, are variant specific.

  15. Molecular Basis of Allele-Specific Efficacy of a Blood-Stage Malaria Vaccine: Vaccine Development Implications

    PubMed Central

    Ouattara, Amed; Takala-Harrison, Shannon; Thera, Mahamadou A.; Coulibaly, Drissa; Niangaly, Amadou; Saye, Renion; Tolo, Youssouf; Dutta, Sheetij; Heppner, D. Gray; Soisson, Lorraine; Diggs, Carter L.; Vekemans, Johan; Cohen, Joe; Blackwelder, William C.; Dube, Tina; Laurens, Matthew B.; Doumbo, Ogobara K.; Plowe, Christopher V.

    2013-01-01

    The disappointing efficacy of blood-stage malaria vaccines may be explained in part by allele-specific immune responses that are directed against polymorphic epitopes on blood-stage antigens. FMP2.1/AS02A, a blood-stage candidate vaccine based on apical membrane antigen 1 (AMA1) from the 3D7 strain of Plasmodium falciparum, had allele-specific efficacy against clinical malaria in a phase II trial in Malian children. We assessed the cross-protective efficacy of the malaria vaccine and inferred which polymorphic amino acid positions in AMA1 were the targets of protective allele-specific immune responses. FMP2.1/AS02A had the highest efficacy against AMA1 alleles that were identical to the 3D7 vaccine-type allele at 8 highly polymorphic amino acid positions in the cluster 1 loop (c1L) but differed from 3D7 elsewhere in the molecule. Comparison of the incidence of vaccine-type alleles before and after vaccination in the malaria vaccine and control groups and examination of the patterns of allele change at polymorphic positions in consecutive malaria episodes suggest that the highly polymorphic amino acid position 197 in c1L was the most critical determinant of allele-specific efficacy. These results indicate that a multivalent AMA1 vaccine with broad efficacy could include only a limited set of key alleles of this extremely polymorphic antigen. PMID:23204168

  16. A thermostable messenger RNA based vaccine against rabies.

    PubMed

    Stitz, Lothar; Vogel, Annette; Schnee, Margit; Voss, Daniel; Rauch, Susanne; Mutzke, Thorsten; Ketterer, Thomas; Kramps, Thomas; Petsch, Benjamin

    2017-12-01

    Although effective rabies virus vaccines have been existing for decades, each year, rabies virus infections still cause around 50.000 fatalities worldwide. Most of these cases occur in developing countries, where these vaccines are not available. The reasons for this are the prohibitive high costs of cell culture or egg grown rabies virus vaccines and the lack of a functional cold chain in many regions in which rabies virus is endemic. Here, we describe the excellent temperature resistance of a non-replicating mRNA based rabies virus vaccine encoding the rabies virus glycoprotein (RABV-G). Prolonged storage of the vaccine from -80°C to up to +70°C for several months did not impact the protective capacity of the mRNA vaccine. Efficacy after storage was demonstrated by the induction of rabies specific virus neutralizing antibodies and protection in mice against lethal rabies infection. Moreover, storing the vaccine at oscillating temperatures between +4° and +56°C for 20 cycles in order to simulate interruptions of the cold chain during vaccine transport, did not affect the vaccine's immunogenicity and protective characteristics, indicating that maintenance of a cold chain is not essential for this vaccine.

  17. 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

  18. Mucosal Vaccine Development Based on Liposome Technology

    PubMed Central

    Norling, Karin; Bally, Marta; Höök, Fredrik

    2016-01-01

    Immune protection against infectious diseases is most effective if located at the portal of entry of the pathogen. Hence, there is an increasing demand for vaccine formulations that can induce strong protective immunity following oral, respiratory, or genital tract administration. At present, only few mucosal vaccines are found on the market, but recent technological advancements and a better understanding of the principles that govern priming of mucosal immune responses have contributed to a more optimistic view on the future of mucosal vaccines. Compared to live attenuated vaccines, subcomponent vaccines, most often protein-based, are considered safer, more stable, and less complicated to manufacture, but they require the addition of nontoxic and clinically safe adjuvants to be effective. In addition, another limiting factor is the large antigen dose that usually is required for mucosal vaccines. Therefore, the combination of mucosal adjuvants with the recent progress in nanoparticle technology provides an attractive solution to these problems. In particular, the liposome technology is ideal for combining protein antigen and adjuvant into an effective mucosal vaccine. Here, we describe and discuss recent progress in nanoparticle formulations using various types of liposomes that convey strong promise for the successful development of the next generation of mucosal vaccines. PMID:28127567

  19. Ebolavirus vaccines for humans and apes.

    PubMed

    Fausther-Bovendo, Hugues; Mulangu, Sabue; Sullivan, Nancy J

    2012-06-01

    Because of high case fatality proportions, person-to-person transmission, and potential use in bioterrorism, the development of a vaccine against ebolavirus remains a top priority. Although no licensed vaccine or treatment against ebolavirus is currently available, progress in preclinical testing of countermeasures has been made. Here, we will review ebolavirus vaccine candidates and considerations for their use in humans and wild apes. Published by Elsevier B.V.

  20. Single-dose replication-defective VSV-based Nipah virus vaccines provide protection from lethal challenge in Syrian hamsters.

    PubMed

    Lo, Michael K; Bird, Brian H; Chattopadhyay, Anasuya; Drew, Clifton P; Martin, Brock E; Coleman, Joann D; Rose, John K; Nichol, Stuart T; Spiropoulou, Christina F

    2014-01-01

    Nipah virus (NiV) continues to cause outbreaks of fatal human encephalitis due to spillover from its bat reservoir. We determined that a single dose of replication-defective vesicular stomatitis virus (VSV)-based vaccine vectors expressing either the NiV fusion (F) or attachment (G) glycoproteins protected hamsters from over 1000 times LD50 NiV challenge. This highly effective single-dose protection coupled with an enhanced safety profile makes these candidates ideal for potential use in livestock and humans. Published by Elsevier B.V.