The NLRP3 Inflammasome Suppresses Protective Immunity to Gastrointestinal Helminth Infection.

PubMed

Alhallaf, Rafid; Agha, Zainab; Miller, Catherine M; Robertson, Avril A B; Sotillo, Javier; Croese, John; Cooper, Matthew A; Masters, Seth L; Kupz, Andreas; Smith, Nicholas C; Loukas, Alex; Giacomin, Paul R

2018-04-24

Inflammasomes promote immunity to microbial pathogens by regulating the function of IL-1-family cytokines such as IL-18 and IL-1β. However, the roles for inflammasomes during parasitic helminth infections remain unclear. We demonstrate that mice and humans infected with gastrointestinal nematodes display increased IL-18 secretion, which in Trichuris-infected or worm antigen-treated mice and in macrophages co-cultured with Trichuris antigens or exosome-like vesicles was dependent on the NLRP3 inflammasome. NLRP3-deficient mice displayed reduced pro-inflammatory type 1 cytokine responses and augmented protective type 2 immunity, which was reversed by IL-18 administration. NLRP3-dependent suppression of immunity partially required CD4 + cells but was apparent even in Rag1 -/- mice that lack adaptive immune cells, suggesting that NLRP3 influences both innate and adaptive immunity. These data highlight a role for NLRP3 in limiting protective immunity to helminths, suggesting that targeting the NLRP3 inflammasome may be an approach for limiting the disease burden associated with helminth infections. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Preparation for emergence of an Eastern European porcine reproductive and respiratory syndrome virus (PRRSV) strain in Western Europe: Immunization with modified live virus vaccines or a field strain confers partial protection.

PubMed

Renson, P; Fablet, C; Le Dimna, M; Mahé, S; Touzain, F; Blanchard, Y; Paboeuf, F; Rose, N; Bourry, O

2017-05-01

The porcine reproductive and respiratory syndrome virus (PRRSV) causes huge economic losses for the swine industry worldwide. In the past several years, highly pathogenic strains that lead to even greater losses have emerged. For the Western European swine industry, one threat is the possible introduction of Eastern European PRRSV strains (example Lena genotype 1.3) which were shown to be more virulent than common Western resident strains under experimental conditions. To prepare for the possible emergence of this strain in Western Europe, we immunized piglets with a Western European PRRSV field strain (Finistere: Fini, genotype 1.1), a new genotype 1 commercial modified live virus (MLV) vaccine (MLV1) or a genotype 2 commercial MLV vaccine (MLV2) to evaluate and compare the level of protection that these strains conferred upon challenge with the Lena strain 4 weeks later. Results show that immunization with Fini, MLV1 or MLV2 strains shortened the Lena-induced hyperthermia. In the Fini group, a positive effect was also demonstrated in growth performance. The level of Lena viremia was reduced for all immunized groups (significantly so for Fini and MLV2). This reduction in Lena viremia was correlated with the level of Lena-specific IFNγ-secreting cells. In conclusion, we showed that a commercial MLV vaccine of genotype 1 or 2, as well as a field strain of genotype 1.1 may provide partial clinical and virological protection upon challenge with the Lena strain. The cross-protection induced by these immunizing strains was not related with the level of genetic similarity to the Lena strain. The slightly higher level of protection established with the field strain is attributed to a better cell-mediated immune response. Copyright © 2017 Elsevier B.V. All rights reserved.

Oral vaccination with different antigens from Yersinia pestis KIM delivered by live attenuated Salmonella typhimurium elicits a protective immune response against plague.

PubMed

Branger, Christine G; Fetherston, Jacqueline D; Perry, Robert D; Curtiss, Roy

2007-01-01

The use of live recombinant Salmonella attenuated vaccine (RASV) encoding Yersinia proteins is a promising new approach for the vaccination against Yersinia pestis. We have tested the efficacy of 2 proteins, Psn and a portion of LcrV in protecting mice against virulent Yersinia pestis challenge. To remove the immunosuppressive properties of LcrV protein, the lcrV gene, without the TLR2 receptor sequence, was cloned into a beta-lactamase secretion vector. Immunizations were performed with RSAV expressing LcrV or Psn. Challenge with a virulent Y. pestis strain was performed 4 weeks after the last immunization. Our results show that the truncated LcrV protein delivered by RASV is sufficient to afford a full protective immune response in a mouse model of bubonic plague and the Psn protein afforded partial protection in a non-optimized system. This finding should facilitate the design and development of a new generation of vaccines against Y. pestis.

The 17D-204 Vaccine Strain-Induced Protection against Virulent Yellow Fever Virus Is Mediated by Humoral Immunity and CD4+ but not CD8+ T Cells.

PubMed

Watson, Alan M; Lam, L K Metthew; Klimstra, William B; Ryman, Kate D

2016-07-01

A gold standard of antiviral vaccination has been the safe and effective live-attenuated 17D-based yellow fever virus (YFV) vaccines. Among more than 500 million vaccinees, only a handful of cases have been reported in which vaccinees developed a virulent wild type YFV infection. This efficacy is presumed to be the result of both neutralizing antibodies and a robust T cell response. However, the particular immune components required for protection against YFV have never been evaluated. An understanding of the immune mechanisms that underlie 17D-based vaccine efficacy is critical to the development of next-generation vaccines against flaviviruses and other pathogens. Here we have addressed this question for the first time using a murine model of disease. Similar to humans, vaccination elicited long-term protection against challenge, characterized by high neutralizing antibody titers and a robust T cell response that formed long-lived memory. Both CD4+ and CD8+ T cells were polyfunctional and cytolytic. Adoptive transfer of immune sera or CD4+ T cells provided partial protection against YFV, but complete protection was achieved by transfer of both immune sera and CD4+ T cells. Thus, robust CD4+ T cell activity may be a critical contributor to protective immunity elicited by highly effective live attenuated vaccines.

The 17D-204 Vaccine Strain-Induced Protection against Virulent Yellow Fever Virus Is Mediated by Humoral Immunity and CD4+ but not CD8+ T Cells

PubMed Central

Lam, L. K. Metthew; Klimstra, William B.

2016-01-01

A gold standard of antiviral vaccination has been the safe and effective live-attenuated 17D-based yellow fever virus (YFV) vaccines. Among more than 500 million vaccinees, only a handful of cases have been reported in which vaccinees developed a virulent wild type YFV infection. This efficacy is presumed to be the result of both neutralizing antibodies and a robust T cell response. However, the particular immune components required for protection against YFV have never been evaluated. An understanding of the immune mechanisms that underlie 17D-based vaccine efficacy is critical to the development of next-generation vaccines against flaviviruses and other pathogens. Here we have addressed this question for the first time using a murine model of disease. Similar to humans, vaccination elicited long-term protection against challenge, characterized by high neutralizing antibody titers and a robust T cell response that formed long-lived memory. Both CD4+ and CD8+ T cells were polyfunctional and cytolytic. Adoptive transfer of immune sera or CD4+ T cells provided partial protection against YFV, but complete protection was achieved by transfer of both immune sera and CD4+ T cells. Thus, robust CD4+ T cell activity may be a critical contributor to protective immunity elicited by highly effective live attenuated vaccines. PMID:27463517

Protective Efficacy of a Single Dose of Baculovirus Hemagglutinin-Based Vaccine in Chickens and Ducks Against Homologous and Heterologous H5N1 Virus Infections

PubMed Central

Park, Eun Hye; Song, Byung Min; Yum, Jung; Kim, Ji An; Oh, Seung Kyoo; Kim, Hyun Soo; Cho, Gil Jae

2014-01-01

Abstract Outbreaks of the highly pathogenic H5N1 virus in poultry and humans are ongoing. Vaccination is an efficient method for prevention of H5N1 infection. Using chickens and ducks, we assessed the efficacy of a vaccine comprising H5N1 hemagglutinin (HA) protein produced in a baculovirus expression system. The immunized chickens and ducks were protected against lethal infection by H5N1 in an antigen dose-dependent manner. Complete protection against homologous challenge and partial protection against heterologous challenge were achieved in chickens immunized with 5 μg HA protein and in ducks immunized with 10 μg HA protein. The IgG antibody subtype was mainly detected in the sera and tissues, including the lungs. The neuraminidase (NA) inhibition assay was negative in immunized chickens and ducks. Our results indicated that the expressed HA protein by baculovirus was immunogenic to both chickens and ducks, and the immunized chickens and ducks were protected from the lethal infections of highly pathogenic H5N1 influenza virus, though ducks required more HA protein than chickens to be protected. Also, baculovirus HA-vaccinated poultry can be differentiated from infected poultry by NA inhibition assay. PMID:25211640

Successful passive and active immunization of cynomolgus monkeys against hepatitis E.

PubMed Central

Tsarev, S A; Tsareva, T S; Emerson, S U; Govindarajan, S; Shapiro, M; Gerin, J L; Purcell, R H

1994-01-01

Virtually full protection against hepatitis E and partial or complete protection against infection with hepatitis E virus (HEV) were achieved in passively or actively immunized cynomolgus monkeys. Hepatitis, viremia, and shedding of the virus in feces were detected in all nonimmunized animals that were challenged with HEV. HEV titers detected by reverse transcriptase PCR were higher in feces than in serum of nonimmunized animals. Anti-HEV antibody titers at the time of challenge ranged between 1:40 and 1:200 in animals passively immunized with convalescent plasma from a cynomolgus monkey previously infected with HEV and between 1:100 and 1:10,000 in animals actively immunized with a recombinant 55-kDa open reading frame 2 protein. The estimated 50% protective titer of passively acquired anti-HEV antibodies was 1:40. Although only one of four passively immunized animals showed histopathologic evidence of hepatitis, all four were infected after challenge; however, the titers of HEV in serum and feces were lower in the passively immunized animals than in the nonimmunized group. The actively immunized animals developed neither hepatitis nor viremia when challenged with HEV and virus was either not detected or was present in low titer in feces. The protective response was a function of the ELISA anti-HEV antibody titer at the time of challenge and the immunization schedule. PMID:7937861

Modelling Risk to US Military Populations from Stopping Blanket Mandatory Polio Vaccination.

PubMed

Burgess, Colleen; Burgess, Andrew; McMullen, Kellie

2017-01-01

Transmission of polio poses a threat to military forces when deploying to regions where such viruses are endemic. US-born soldiers generally enter service with immunity resulting from childhood immunization against polio; moreover, new recruits are routinely vaccinated with inactivated poliovirus vaccine (IPV), supplemented based upon deployment circumstances. Given residual protection from childhood vaccination, risk-based vaccination may sufficiently protect troops from polio transmission. This analysis employed a mathematical system for polio transmission within military populations interacting with locals in a polio-endemic region to evaluate changes in vaccination policy. Removal of blanket immunization had no effect on simulated polio incidence among deployed military populations when risk-based immunization was employed; however, when these individuals reintegrated with their base populations, risk of transmission to nondeployed personnel increased by 19%. In the absence of both blanket- and risk-based immunization, transmission to nondeployed populations increased by 25%. The overall number of new infections among nondeployed populations was negligible for both scenarios due to high childhood immunization rates, partial protection against transmission conferred by IPV, and low global disease incidence levels. Risk-based immunization driven by deployment to polio-endemic regions is sufficient to prevent transmission among both deployed and nondeployed US military populations.

Evaluation of formalin-inactivated Clostridium difficile vaccines administered by parenteral and mucosal routes of immunization in hamsters.

PubMed Central

Torres, J F; Lyerly, D M; Hill, J E; Monath, T P

1995-01-01

Clostridium difficile produces toxins that cause inflammation, necrosis, and fluid in the intestine and is the most important cause of nosocomial antibiotic-associated diarrhea and colitis. We evaluated C. difficile antigens as vaccines to protect against systemic and intestinal disease in a hamster model of clindamycin colitis. Formalin-inactivated culture filtrates from a highly toxigenic strain were administered by mucosal routes (intranasal, intragastric, and rectal) with cholera toxin as a mucosal adjuvant. A preparation of culture filtrate and killed whole cells was also tested rectally. The toxoid was also tested parenterally (subcutaneously and intraperitoneally) and by a combination of three intranasal immunizations followed by a combined intranasal-intraperitoneal boost. Serum antibodies against toxins A and B and whole-cell antigen were measured by enzyme-linked immunosorbent assay, neutralization of cytotoxic activity, and bacterial agglutination. The two rectal immunization regimens induced low antibody responses and protected only 20% of hamsters against death and 0% against diarrhea. The intragastric regimen induced high antibody responses but low protection, 40% against death and 0% against diarrhea. Hamsters immunized by the intranasal, intraperitoneal, and subcutaneous routes were 100% protected against death and partially protected (40, 40, and 20%, respectively) against diarrhea. Among the latter groups, intraperitoneally immunized animals had the highest serum anticytotoxic activity and the highest agglutinating antibody responses. Hamsters immunized intranasally and revaccinated intraperitoneally were 100% protected against both death and diarrhea. Protection against death and diarrhea correlated with antibody responses to all antigens tested. The results indicate that optimal protection against C. difficile disease can be achieved with combined parenteral and mucosal immunization. PMID:7591115

Immune protection of chickens conferred by a vaccine consisting of attenuated strains of Salmonella Enteritidis, Typhimurium and Infantis.

PubMed

Varmuzova, Karolina; Faldynova, Marcela; Elsheimer-Matulova, Marta; Sebkova, Alena; Polansky, Ondrej; Havlickova, Hana; Sisak, Frantisek; Rychlik, Ivan

2016-10-15

The colonization of poultry with different Salmonella enterica serovars poses an issue throughout the world. In this study we therefore tested the efficacy of a vaccine consisting of attenuated strains of Salmonella enterica serovars Enteritidis, Typhimurium and Infantis against challenge with the same serovars and with S. Agona, Dublin and Hadar. We tested oral and aerosol administration of the vaccine, with or without co-administration of cecal microbiota from adult hens. The protective effect was determined by bacterial counts of the challenge strains up to week 18 of life and by characterizing the immune response using real-time PCR specific for 16 different genes. We have shown that a vaccine consisting of attenuated S. Enteritidis, S. Typhimurium and S. Infantis protected chickens against challenge with the wild type strains of the same serovars and partially protected chickens also against challenge with isolates belonging to serovars Dublin or Hadar. Aerosol vaccination was more effective at inducing systemic immunity whilst oral vaccination stimulated a local immune response in the gut. Co-administration of cecal microbiota increased the protectiveness in the intestinal tract but slightly decreased the systemic immune response. Adjusting the vaccine composition and changing the administration route therefore affects vaccine efficacy.

Vaccine and Monoclonal Antibody That Enhance Mouse Resistance to Candidiasis ▿

PubMed Central

Xin, Hong; Cutler, Jim E.

2011-01-01

Previously we showed that antibodies specific for the glycan β-1,2-mannotriose [β-(Man)3] on the cell surface of Candida albicans protect mice against disseminated candidiasis (H. Xin, S. Dziadek, D. R. Bundle, and J. E. Cutler, Proc. Natl. Acad. Sci. U. S. A. 105:13526–13531, 2008). Furthermore, six 14-mer peptides that are within the N-terminal portion of C. albicans wall proteins were conjugated to the glycan in an attempt to create immunogenic glycopeptide conjugates. By a dendritic cell (DC)-based immunization approach, all were immunogenic and three of the six conjugates induced a high degree of protection in mice. Interestingly, whereas all six peptides induced antibody responses when used alone to pulse DCs for subsequent immunizations, three peptides induced protection, and one in particular, peptide Fba (derived from fructose-bisphosphate aldolase), induced robust protective responses and is the focus of the current work. Fba peptide is not restricted by the major histocompatibility complex class II (MHC-II), as it induced anti-Fba antibodies in mice of different H-2 haplotypes and in rabbits. Furthermore, the peptide induced protection against disease caused by different C. albicans strains. Partial protection was achieved when alum was used in place of DCs for Fba immunizations. The passive transfer of immune sera from Fba-vaccinated mice, but not immune serum preabsorbed with fungal cells, conferred protection in naïve mice. This result, along with our finding that a monoclonal antibody specific for the peptide, E2-9 (IgM), protected mice against candidiasis, provide strong evidence that antibodies contribute to protection. Our work demonstrates the utility of cell wall peptides alone or as glycopeptides in vaccines designed for the induction of immunity against candidiasis and monoclonal antibodies as a rapid immunoprotective approach against the disease. PMID:21832099

Role of CD4+ T cells in a protective immune response against Cryptococcus neoformans in the central nervous system.

PubMed

Uicker, William C; McCracken, James P; Buchanan, Kent L

2006-02-01

Cryptococcosis is a life-threatening disease caused by the encapsulated yeast, Cryptococcus neoformans. Although infection with C. neoformans is initiated in the lungs, morbidity and mortality is mostly associated with infections of the central nervous system (CNS). Individuals with deficiencies in cell-mediated immunity, such as patients with AIDS, are more susceptible to disseminated cryptococcosis, highlighting the importance of cell-mediated immunity and CD4+ T cells in host resistance against C. neoformans. Using a mouse model of cryptococcal meningoencephalitis, we have shown that immunization of mice with a cryptococcal antigen induced a protective immune response that crossed the blood-brain barrier and initiated an immune response directly in the CNS if C. neoformans was present. The regional protective response was characteristic of a Type-1 (Th1) response in the types of cells present at the site of infection and in the cytokines and chemokines expressed. Here, we extend those findings and report that CD4+ T cells are required for survival of immune mice infected directly in the brain with C. neoformans and sensitized CD4 + T cells can transfer partial protection to naive mice infected intracerebrally with C. neoformans. Furthermore, CD4 + T cells were also important for optimal infiltration of inflammatory cells at the site of infection and in the expression of cytokines and chemokines associated with protection in the brain. Lastly, CD4+ T cells were required for optimal regional production and secretion of IFNgamma and in the significantly increased expression of iNOS in C. neoformans-infected brains of immune mice.

Postchallenge Administration of Brincidofovir Protects Healthy and Immune-Deficient Mice Reconstituted with Limited Numbers of T Cells from Lethal Challenge with IHD-J-Luc Vaccinia Virus

PubMed Central

McCullough, Kevin Tyler; Cruz, Stephanie; Thomas, Antonia; Diaz, Claudia G.; Keilholz, Laurie; Grossi, Irma M.; Trost, Lawrence C.; Golding, Hana

2015-01-01

ABSTRACT Protection from lethality by postchallenge administration of brincidofovir (BCV, CMX001) was studied in normal and immune-deficient (nude, nu/nu) BALB/c mice infected with vaccinia virus (VACV). Whole-body bioluminescence imaging was used to record total fluxes in the nasal cavity, lungs, spleen, and liver and to enumerate pox lesions on tails of mice infected via the intranasal route with 105 PFU of recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve (AUCs) were calculated for individual mice to assess viral loads. A three-dose regimen of 20 mg/kg BCV administered every 48 h starting either on day 1 or day 2 postchallenge protected 100% of mice. Initiating BCV treatment earlier was more efficient in reducing viral loads and in providing protection from pox lesion development. All BCV-treated mice that survived challenge were also protected from rechallenge with IHD-J-Luc or WRvFire VACV without additional treatment. In immune-deficient mice, BCV protected animals from lethality and reduced viral loads while animals were on the drug. Viral recrudescence occurred within 4 to 9 days, and mice succumbed ∼10 to 20 days after treatment termination. Nude mice reconstituted with 105 T cells prior to challenge with 104 PFU of IHD-J-Luc and treated with BCV postchallenge survived the infection, cleared the virus from all organs, and survived rechallenge with 105 PFU of IHD-J-Luc VACV without additional BCV treatment. Together, these data suggest that BCV protects immunocompetent and partially T cell-reconstituted immune-deficient mice from lethality, reduces viral dissemination in organs, prevents pox lesion development, and permits generation of VACV-specific memory. IMPORTANCE Mass vaccination is the primary element of the public health response to a smallpox outbreak. In addition to vaccination, however, antiviral drugs are required for individuals with uncertain exposure status to smallpox or for whom vaccination is contraindicated. Whole-body bioluminescence imaging was used to study the effect of brincidofovir (BCV) in normal and immune-deficient (nu/nu) mice infected with vaccinia virus, a model of smallpox. Postchallenge administration of 20 mg/kg BCV rescued normal and immune-deficient mice partially reconstituted with T cells from lethality and significantly reduced viral loads in organs. All BCV-treated mice that survived infection were protected from rechallenge without additional treatment. In immune-deficient mice, BCV extended survival. The data show that BCV controls viral replication at the site of challenge and reduces viral dissemination to internal organs, thus providing a shield for the developing adaptive immunity that clears the host of virus and builds virus-specific immunological memory. PMID:25589648

Cross protective immune responses in nursing piglets infected with a US spike-insertion deletion porcine epidemic diarrhea virus strain and challenged with an original US PEDV strain.

PubMed

Annamalai, Thavamathi; Lin, Chun-Ming; Gao, Xiang; Liu, Xinsheng; Lu, Zhongyan; Saif, Linda J; Wang, Qiuhong

2017-10-06

We investigated cross-protective immunity of a US spike-insertion deletion porcine epidemic diarrhea virus (PEDV) Iowa106 (S-INDEL) strain against the original US PEDV (PC21A) strain in nursing piglets. Piglets were inoculated orally with S-INDEL, PC21A or mock. At 20-29 days post-inoculation (dpi), all pigs were challenged with the PC21A strain. The S-INDEL-inoculated pigs had lower ileal IgA antibody secreting cells, serum IgA and neutralizing antibody titers compared with PC21A-inoculated pigs. No pigs in the PC21A-group developed diarrhea, whereas 81 and 100% of pigs in the S-INDEL and mock-groups had diarrhea post challenge, respectively. S-INDEL induced partial protective immunity against the original US PEDV strain.

Modelling Risk to US Military Populations from Stopping Blanket Mandatory Polio Vaccination

PubMed Central

Burgess, Andrew

2017-01-01

Objectives Transmission of polio poses a threat to military forces when deploying to regions where such viruses are endemic. US-born soldiers generally enter service with immunity resulting from childhood immunization against polio; moreover, new recruits are routinely vaccinated with inactivated poliovirus vaccine (IPV), supplemented based upon deployment circumstances. Given residual protection from childhood vaccination, risk-based vaccination may sufficiently protect troops from polio transmission. Methods This analysis employed a mathematical system for polio transmission within military populations interacting with locals in a polio-endemic region to evaluate changes in vaccination policy. Results Removal of blanket immunization had no effect on simulated polio incidence among deployed military populations when risk-based immunization was employed; however, when these individuals reintegrated with their base populations, risk of transmission to nondeployed personnel increased by 19%. In the absence of both blanket- and risk-based immunization, transmission to nondeployed populations increased by 25%. The overall number of new infections among nondeployed populations was negligible for both scenarios due to high childhood immunization rates, partial protection against transmission conferred by IPV, and low global disease incidence levels. Conclusion Risk-based immunization driven by deployment to polio-endemic regions is sufficient to prevent transmission among both deployed and nondeployed US military populations. PMID:29104608

Monophosphoryl Lipid A Enhances Efficacy of a Francisella tularensis LVS-Catanionic Nanoparticle Subunit Vaccine against F. tularensis Schu S4 Challenge by Augmenting both Humoral and Cellular Immunity

PubMed Central

Richard, Katharina; Mann, Barbara J.; Qin, Aiping; Barry, Eileen M.; Ernst, Robert K.

2017-01-01

ABSTRACT Francisella tularensis, a bacterial biothreat agent, has no approved vaccine in the United States. Previously, we showed that incorporating lysates from partially attenuated F. tularensis LVS or fully virulent F. tularensis Schu S4 strains into catanionic surfactant vesicle (V) nanoparticles (LVS-V and Schu S4-V, respectively) protected fully against F. tularensis LVS intraperitoneal (i.p.) challenge in mice. However, we achieved only partial protection against F. tularensis Schu S4 intranasal (i.n.) challenge, even when employing heterologous prime-boost immunization strategies. We now extend these findings to show that both LVS-V and Schu S4-V immunization (i.p./i.p.) elicited similarly high titers of anti-F. tularensis IgG and that the titers could be further increased by adding monophosphoryl lipid A (MPL), a nontoxic Toll-like receptor 4 (TLR4) adjuvant that is included in several U.S. FDA-approved vaccines. LVS-V+MPL immune sera also detected more F. tularensis antigens than LVS-V immune sera and, after passive transfer to naive mice, significantly delayed the time to death against F. tularensis Schu S4 subcutaneous (s.c.) but not i.n. challenge. Active immunization with LVS-V+MPL (i.p./i.p.) also increased the frequency of gamma interferon (IFN-γ)-secreting activated helper T cells, IFN-γ production, and the ability of splenocytes to control intramacrophage F. tularensis LVS replication ex vivo. Active LVS-V+MPL immunization via heterologous routes (i.p./i.n.) significantly elevated IgA and IgG levels in bronchoalveolar lavage fluid and significantly enhanced protection against i.n. F. tularensis Schu S4 challenge (to ∼60%). These data represent a significant step in the development of a subunit vaccine against the highly virulent type A strains. PMID:28077440

Protection of Mice against Plasmodium yoelii Sporozoite Challenge with P. yoelii Merozoite Surface Protein 1 DNA Vaccines

PubMed Central

Becker, Sylvia I.; Wang, Ruobing; Hedstrom, Richard C.; Aguiar, Joao C.; Jones, Trevor R.; Hoffman, Stephen L.; Gardner, Malcolm J.

1998-01-01

Immunization of mice with DNA vaccines encoding the full-length form and C and N termini of Plasmodium yoelii merozoite surface protein 1 provided partial protection against sporozoite challenge and resulted in boosting of antibody titers after challenge. In C57BL/6 mice, two DNA vaccines provided protection comparable to that of recombinant protein consisting of the C terminus in Freund’s adjuvant. PMID:9632624

Allicin enhances host pro-inflammatory immune responses and protects against acute murine malaria infection

PubMed Central

2012-01-01

Background During malaria infection, multiple pro-inflammatory mediators including IFN-γ, TNF and nitric oxide (NO) play a crucial role in the protection against the parasites. Modulation of host immunity is an important strategy to improve the outcome of malaria infection. Allicin is the major biologically active component of garlic and shows anti-microbial activity. Allicin is also active against protozoan parasites including Plasmodium, which is thought to be mediated by inhibiting cysteine proteases. In this study, the immunomodulatory activities of allicin were assessed during acute malaria infection using a rodent malaria model Plasmodium yoelii 17XL. Methods To determine whether allicin modulates host immune responses against malaria infection, mice were treated with allicin after infection with P. yoelii 17XL. Mortality was checked daily and parasitaemia was determined every other day. Pro-inflammatory mediators and IL-4 were quantified by ELISA, while NO level was determined by the Griess method. The populations of dendritic cells (DCs), macrophages, CD4+ T and regulatory T cells (Treg) were assessed by FACS. Results Allicin reduced parasitaemia and prolonged survival of the host in a dose-dependent manner. This effect is at least partially due to improved host immune responses. Results showed that allicin treatment enhanced the production of pro-inflammatory mediators such as IFN-γ, TNF, IL-12p70 and NO. The absolute numbers of CD4+ T cells, DCs and macrophages were significantly higher in allicin-treated mice. In addition, allicin promoted the maturation of CD11c+ DCs, whereas it did not cause major changes in IL-4 and the level of anti-inflammatory cytokine IL-10. Conclusions Allicin could partially protect host against P. yoelii 17XL through enhancement of the host innate and adaptive immune responses. PMID:22873687

Allicin enhances host pro-inflammatory immune responses and protects against acute murine malaria infection.

PubMed

Feng, Yonghui; Zhu, Xiaotong; Wang, Qinghui; Jiang, Yongjun; Shang, Hong; Cui, Liwang; Cao, Yaming

2012-08-08

During malaria infection, multiple pro-inflammatory mediators including IFN-γ, TNF and nitric oxide (NO) play a crucial role in the protection against the parasites. Modulation of host immunity is an important strategy to improve the outcome of malaria infection. Allicin is the major biologically active component of garlic and shows anti-microbial activity. Allicin is also active against protozoan parasites including Plasmodium, which is thought to be mediated by inhibiting cysteine proteases. In this study, the immunomodulatory activities of allicin were assessed during acute malaria infection using a rodent malaria model Plasmodium yoelii 17XL. To determine whether allicin modulates host immune responses against malaria infection, mice were treated with allicin after infection with P. yoelii 17XL. Mortality was checked daily and parasitaemia was determined every other day. Pro-inflammatory mediators and IL-4 were quantified by ELISA, while NO level was determined by the Griess method. The populations of dendritic cells (DCs), macrophages, CD4+ T and regulatory T cells (Treg) were assessed by FACS. Allicin reduced parasitaemia and prolonged survival of the host in a dose-dependent manner. This effect is at least partially due to improved host immune responses. Results showed that allicin treatment enhanced the production of pro-inflammatory mediators such as IFN-γ, TNF, IL-12p70 and NO. The absolute numbers of CD4+ T cells, DCs and macrophages were significantly higher in allicin-treated mice. In addition, allicin promoted the maturation of CD11c+ DCs, whereas it did not cause major changes in IL-4 and the level of anti-inflammatory cytokine IL-10. Allicin could partially protect host against P. yoelii 17XL through enhancement of the host innate and adaptive immune responses.

The relative contribution of antibody and CD8+ T cells to vaccine immunity against West Nile encephalitis virus.

PubMed

Shrestha, Bimmi; Ng, Terry; Chu, Hsien-Jue; Noll, Michelle; Diamond, Michael S

2008-04-07

West Nile virus (WNV) is a mosquito borne, neurotropic flavivirus that causes a severe central nervous system (CNS) infection in humans and animals. Although commercial vaccines are available for horses, none is currently approved for human use. In this study, we evaluated the efficacy and mechanism of immune protection of two candidate WNV vaccines in mice. A formalin-inactivated WNV vaccine induced higher levels of specific and neutralizing antibodies compared to a DNA plasmid vaccine that produces virus-like particles. Accordingly, partial and almost complete protection against a highly stringent lethal intracranial WNV challenge were observed in mice 60 days after single dose immunization with the DNA plasmid and inactivated virus vaccines, respectively. In mice immunized with a single dose of DNA plasmid or inactivated vaccine, antigen-specific CD8(+) T cells were induced and contributed to protective immunity as acquired or genetic deficiencies of CD8(+) T cells lowered the survival rates. In contrast, in boosted animals, WNV-specific antibody titers were higher, survival rates after challenge were greater, and an absence of CD8(+) T cells did not appreciably affect mortality. Overall, our experiments suggest that in mice, both inactivated WNV and DNA plasmid vaccines are protective after two doses, and the specific contribution of antibody and CD8(+) T cells to vaccine immunity against WNV is modulated by the prime-boost strategy.

A recombinant chimeric Ad5/3 vector expressing a multi-stage Plasmodium antigen induces protective immunity in mice using heterologous prime-boost immunization regimens1

PubMed Central

Cabrera-Mora, Monica; Fonseca, Jairo Andres; Singh, Balwan; Zhao, Chunxia; Makarova, Natalia; Dmitriev, Igor; Curiel, David T.; Blackwell, Jerry; Moreno, Alberto

2016-01-01

An ideal malaria vaccine should target several stages of the parasite life cycle and induce anti-parasite and anti-disease immunity. We have reported a Plasmodium yoelii chimeric multi-stage recombinant protein (PyLPC/RMC), engineered to express several autologous T cell epitopes and sequences derived from the circumsporozoite protein (CSP) and the merozoite surface protein 1 (MSP-1). This chimeric protein elicits protective immunity, mediated by CD4+ T cells and neutralizing antibodies. However, experimental evidence from pre-erythrocytic vaccine candidates and irradiated sporozoites has shown that CD8+ T cells play a significant role in protection. Recombinant viral vectors have been used as a vaccine platform to elicit effective CD8+ T cell responses. The human adenovirus serotype 5 (Ad5) has been tested in malaria vaccine clinical trials with excellent safety profile. Nevertheless, a major concern for the use of Ad5 is the high prevalence of anti-vector neutralizing antibodies in humans, hampering its immunogenicity. To minimize the impact of anti-vector pre-existing immunity we developed a chimeric Ad5/3 vector in which the knob region of Ad5 was replaced with that of Ad3, conferring partial resistance to anti-Ad5 neutralizing antibodies. Furthermore, we implemented heterologous adenovirus/protein immunization regimens which include a single immunization with recombinant Ad vectors. Our data show that immunization with the recombinant Ad5/3 vector induces protective efficacy indistinguishable from that elicited by Ad5. Our study also demonstrate that the dose of the Ad vectors has an impact on the memory profile and protective efficacy. The results support further studies with Ad5/3 for malaria vaccine development. PMID:27574299

Multimodality vaccination against clade C SHIV: partial protection against mucosal challenges with a heterologous tier 2 virus.

PubMed

Lakhashe, Samir K; Byrareddy, Siddappa N; Zhou, Mingkui; Bachler, Barbara C; Hemashettar, Girish; Hu, Shiu-Lok; Villinger, Francois; Else, James G; Stock, Shannon; Lee, Sandra J; Vargas-Inchaustegui, Diego A; Cofano, Egidio Brocca; Robert-Guroff, Marjorie; Johnson, Welkin E; Polonis, Victoria R; Forthal, Donald N; Loret, Erwann P; Rasmussen, Robert A; Ruprecht, Ruth M

2014-11-12

We sought to test whether vaccine-induced immune responses could protect rhesus macaques (RMs) against upfront heterologous challenges with an R5 simian-human immunodeficiency virus, SHIV-2873Nip. This SHIV strain exhibits many properties of transmitted HIV-1, such as tier 2 phenotype (relatively difficult to neutralize), exclusive CCR5 tropism, and gradual disease progression in infected RMs. Since no human AIDS vaccine recipient is likely to encounter an HIV-1 strain that exactly matches the immunogens, we immunized the RMs with recombinant Env proteins heterologous to the challenge virus. For induction of immune responses against Gag, Tat, and Nef, we explored a strategy of immunization with overlapping synthetic peptides (OSP). The immune responses against Gag and Tat were finally boosted with recombinant proteins. The vaccinees and a group of ten control animals were given five low-dose intrarectal (i.r.) challenges with SHIV-2873Nip. All controls and seven out of eight vaccinees became systemically infected; there was no significant difference in viremia levels of vaccinees vs. controls. Prevention of viremia was observed in one vaccinee which showed strong boosting of virus-specific cellular immunity during virus exposures. The protected animal showed no challenge virus-specific neutralizing antibodies in the TZM-bl or A3R5 cell-based assays and had low-level ADCC activity after the virus exposures. Microarray data strongly supported a role for cellular immunity in the protected animal. Our study represents a case of protection against heterologous tier 2 SHIV-C by vaccine-induced, virus-specific cellular immune responses. Copyright © 2014 Elsevier Ltd. All rights reserved.

Strategies and challenges for eliciting immunity against avian influenza virus in birds.

PubMed

Swayne, David E; Kapczynski, Darrell

2008-10-01

Vaccines and vaccination have emerged during the past two decades as essential tools in avian influenza (AI) control for poultry, because they increase resistance to infection, prevent illness and death, reduce virus replication and shed from respiratory and alimentary tracts, and reduce virus transmission to birds and mammals, including humans. Such protection in birds is primarily mediated by homosubtypic humoral immunity against the hemagglutinin protein, but cell-mediated and innate immunity contribute to protection in some bird species. The immune response to the neuraminidase protein can contribute to protection, but immunity to the viral internal proteins is generally not protective. Although, some preliminary studies with M2e protein in chickens suggest partial protection may be achievable. Historically, the H5 subtype AI vaccines have demonstrated broad homosubtypic protection, primarily against H5 high-pathogenicity (HP) AI viruses isolated in the early stages of outbreaks. However, as H5 viruses have become endemic and outbreaks prolonged, some drift variants with resistance to earlier H5 AI vaccines have emerged in Central America, China, Egypt, and Indonesia. How widespread such drift variants are will remain unknown until more detailed genetic and antigenic analyses are conducted on field isolates. Future vaccines will utilize biotechnology to produce new AI vaccine seed strains using HA genes more closely matching circulating field viruses. In addition, newer technologies for AI vaccines will improve vaccine coverage by using mass application technologies for example by drinking water, by spray, or via injection in ovo or at the hatchery.

Intranasal Immunization with Influenza Virus-Like Particles Containing Membrane-Anchored Cholera Toxin B or Ricin Toxin B Enhances Adaptive Immune Responses and Protection against an Antigenically Distinct Virus.

PubMed

Ji, Xianliang; Ren, Zhiguang; Xu, Na; Meng, Lingnan; Yu, Zhijun; Feng, Na; Sang, Xiaoyu; Li, Shengnan; Li, Yuanguo; Wang, Tiecheng; Zhao, Yongkun; Wang, Hualei; Zheng, Xuexing; Jin, Hongli; Li, Nan; Yang, Songtao; Cao, Jinshan; Liu, Wensen; Gao, Yuwei; Xia, Xianzhu

2016-04-21

Vaccination is the most effective means to prevent influenza virus infection, although current approaches are associated with suboptimal efficacy. Here, we generated virus-like particles (VLPs) composed of the hemagglutinin (HA), neuraminidase (NA) and matrix protein (M1) of A/Changchun/01/2009 (H1N1) with or without either membrane-anchored cholera toxin B (CTB) or ricin toxin B (RTB) as molecular adjuvants. The intranasal immunization of mice with VLPs containing membrane-anchored CTB or RTB elicited stronger humoral and cellular immune responses when compared to mice immunized with VLPs alone. Administration of VLPs containing CTB or RTB significantly enhanced virus-specific systemic and mucosal antibody responses, hemagglutination inhibiting antibody titers, virus neutralizing antibody titers, and the frequency of virus-specific IFN-γ and IL-4 secreting splenocytes. VLPs with and without CTB or RTB conferred complete protection against lethal challenge with a mouse-adapted homologous virus. When challenged with an antigenically distinct H1N1 virus, all mice immunized with VLPs containing CTB or RTB survived whereas mice immunized with VLPs alone showed only partial protection (80% survival). Our results suggest that membrane-anchored CTB and RTB possess strong adjuvant properties when incorporated into an intranasally-delivered influenza VLP vaccine. Chimeric influenza VLPs containing CTB or RTB may represent promising vaccine candidates for improved immunological protection against homologous and antigenically distinct influenza viruses.

Intranasal Immunization with Influenza Virus-Like Particles Containing Membrane-Anchored Cholera Toxin B or Ricin Toxin B Enhances Adaptive Immune Responses and Protection against an Antigenically Distinct Virus

PubMed Central

Ji, Xianliang; Ren, Zhiguang; Xu, Na; Meng, Lingnan; Yu, Zhijun; Feng, Na; Sang, Xiaoyu; Li, Shengnan; Li, Yuanguo; Wang, Tiecheng; Zhao, Yongkun; Wang, Hualei; Zheng, Xuexing; Jin, Hongli; Li, Nan; Yang, Songtao; Cao, Jinshan; Liu, Wensen; Gao, Yuwei; Xia, Xianzhu

2016-01-01

Vaccination is the most effective means to prevent influenza virus infection, although current approaches are associated with suboptimal efficacy. Here, we generated virus-like particles (VLPs) composed of the hemagglutinin (HA), neuraminidase (NA) and matrix protein (M1) of A/Changchun/01/2009 (H1N1) with or without either membrane-anchored cholera toxin B (CTB) or ricin toxin B (RTB) as molecular adjuvants. The intranasal immunization of mice with VLPs containing membrane-anchored CTB or RTB elicited stronger humoral and cellular immune responses when compared to mice immunized with VLPs alone. Administration of VLPs containing CTB or RTB significantly enhanced virus-specific systemic and mucosal antibody responses, hemagglutination inhibiting antibody titers, virus neutralizing antibody titers, and the frequency of virus-specific IFN-γ and IL-4 secreting splenocytes. VLPs with and without CTB or RTB conferred complete protection against lethal challenge with a mouse-adapted homologous virus. When challenged with an antigenically distinct H1N1 virus, all mice immunized with VLPs containing CTB or RTB survived whereas mice immunized with VLPs alone showed only partial protection (80% survival). Our results suggest that membrane-anchored CTB and RTB possess strong adjuvant properties when incorporated into an intranasally-delivered influenza VLP vaccine. Chimeric influenza VLPs containing CTB or RTB may represent promising vaccine candidates for improved immunological protection against homologous and antigenically distinct influenza viruses. PMID:27110810

Virus-like particles vaccine containing Clonorchis sinensis tegumental protein induces partial protection against Clonorchis sinensis infection.

PubMed

Lee, Dong-Hun; Kim, Ah-Ra; Lee, Su-Hwa; Quan, Fu-Shi

2017-12-29

Human clonorchiasis, caused by the infection of Clonorchis sinensis, is one of the major health problems in Southeast Asia. However, vaccine efficacy against C. sinensis infection remains largely unknown. In this study, for the first time, we generated virus-like particles (VLPs) vaccine containing the C. sinensis tegumental protein 22.3 kDa (CsTP 22.3) and the influenza matrix protein (M1) as a core protein, and investigated the vaccine efficacy in Sprague-Dawley rats. Intranasal immunization of VLPs vaccine induced C. sinensis-specific IgG, IgG2a and IgG2c in the sera and IgA responses in the feces and intestines. Notably, upon challenge infection with C. sinensis metacercariae, significantly lower adult worm loads (70.2%) were measured in the liver of rats immunized with VLPs, compared to those of naïve rats. Furthermore, VLPs immunization induced antibody secreting cells (ASC) responses and CD4+/CD8+ T cell responses in the spleen. Our results indicated that VLPs vaccine containing C. sinensis CsTP 22.3 kDa provided partial protection against C. sisnensis infection. Thus, VLPs could be a potential vaccine candidate against C. sinensis.

Evaluation of the Newcastle Disease Virus F and HN Proteins in Protective Immunity by Using a Recombinant Avian Paramyxovirus Type 3 Vector in Chickens▿

PubMed Central

Kumar, Sachin; Nayak, Baibaswata; Collins, Peter L.; Samal, Siba K.

2011-01-01

Newcastle disease virus (NDV) belongs to serotype 1 of the avian paramyxoviruses (APMV-1) and causes severe disease in chickens. Current live attenuated NDV vaccines are not fully satisfactory. An alternative is to use a viral vector vaccine that infects chickens but does not cause disease. APMV serotype 3 infects a wide variety of avian species but does not cause any apparent disease in chickens. In this study, we constructed a reverse-genetics system for recovery of infectious APMV-3 strain Netherlands from cloned cDNAs. Two recombinant viruses, rAPMV3-F and rAPMV3-HN, were generated expressing the NDV fusion (F) and hemagglutinin-neuraminidase (HN) proteins, respectively, from added genes. These viruses were used to immunize 2-week-old chickens by the oculonasal route in order to evaluate the contribution of each protein to the induction of NDV-specific neutralizing antibodies and protective immunity. Each virus induced high titers of NDV-specific hemagglutination inhibition and serum neutralizing antibodies, but the response to F protein was greater. Protective immunity was evaluated by challenging the immunized birds 21 days later with virulent NDV via the oculonasal, intramuscular, or intravenous route. With oculonasal or intramuscular challenge, all three recombinant viruses (rAPMV3, rAPMV3-F, and rAPMV3-HN) were protective, while all unvaccinated birds succumbed to death. These results indicated that rAPMV3 alone can provide cross-protection against NDV challenge. However, with intravenous challenge, birds immunized with rAPMV3 were not protected, whereas birds immunized with rAPMV3-F alone or in combination with rAPMV3-HN were completely protected, and birds immunized with rAPMV3-HN alone were partially protected. These results indicate that the NDV F and HN proteins are independent neutralization and protective antigens, but the contribution by F is greater. rAMPV3 represents an avirulent vaccine vector that can be used against NDV and other poultry pathogens. PMID:21525340

Immune Mechanisms Responsible for Vaccination against and Clearance of Mucosal and Lymphatic Norovirus Infection

PubMed Central

Chachu, Karen A.; LoBue, Anna D.; Strong, David W.; Baric, Ralph S.; Virgin, Herbert W.

2008-01-01

Two cardinal manifestations of viral immunity are efficient clearance of acute infection and the capacity to vaccinate against secondary viral exposure. For noroviruses, the contributions of T cells to viral clearance and vaccination have not been elucidated. We report here that both CD4 and CD8 T cells are required for efficient clearance of primary murine norovirus (MNV) infection from the intestine and intestinal lymph nodes. Further, long-lasting protective immunity was generated by oral live virus vaccination. Systemic vaccination with the MNV capsid protein also effectively protected against mucosal challenge, while vaccination with the capsid protein of the distantly related human Lordsdale virus provided partial protection. Fully effective vaccination required a broad immune response including CD4 T cells, CD8 T cells, and B cells, but the importance of specific immune cell types varied between the intestine and intestinal lymph nodes. Perforin, but not interferon gamma, was required for clearance of MNV infection by adoptively transferred T lymphocytes from vaccinated hosts. These studies prove the feasibility of both mucosal and systemic vaccination against mucosal norovirus infection, demonstrate tissue specificity of norovirus immune cells, and indicate that efficient vaccination strategies should induce potent CD4 and CD8 T cell responses. PMID:19079577

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.

Vaccinia virus recombinants encoding the truncated structural gene region of Venezuelan equine encephalitis virus (VEEV) give solid protection against peripheral challenge but only partial protection against airborne challenge with virulent VEEV.

PubMed

Phillpotts, R J; Lescott, T L; Jacobs, S C

2000-10-01

Vaccinia virus (VV) recombinants that contain the genes encoding the Venezuelan equine encephalitis virus (VEEV) structural gene region (C-E3-E2-6 K-E1) solidly protect mice against peripheral challenge with virulent VEEV, but provide only partial protection against airborne challenge. To improve upon these results we focussed on the principal antigens involved in protection. VV recombinants encoding the structural genes E3-E2-6 K-E1, E3-E2-6 K or 6 K-E1 were prepared and evaluated for their ability to protect Balb/c mice after a single dorsal scarification with 10(8) PFU against peripheral or airborne challenge with virulent VEEV. The antibody response was also examined. Our experiments provide new evidence that truncates of the VEEV structural region (E3-E2-6 K-E1, E3-E2-6 K), cloned and expressed in VV, protect against challenge with virulent virus. They also confirm the important role of E2 in protection. However, we were unable to improve upon previously reported levels of protection against airborne challenge. A substantial level of circulating antibodies and the presence of local IgA (not always induced by mucosal immunization) (Greenway et al., 1992) appear essential for protection against the airborne virus. Current VV-VEEV recombinants seem unable to elicit this level of immune response and further improvements are therefore required to increase the immunogenicity of VV-VEEV vaccines.

A prophylactic multivalent vaccine against different filovirus species is immunogenic and provides protection from lethal infections with Ebolavirus and Marburgvirus species in non-human primates.

PubMed

Callendret, Benoit; Vellinga, Jort; Wunderlich, Kerstin; Rodriguez, Ariane; Steigerwald, Robin; Dirmeier, Ulrike; Cheminay, Cedric; Volkmann, Ariane; Brasel, Trevor; Carrion, Ricardo; Giavedoni, Luis D; Patterson, Jean L; Mire, Chad E; Geisbert, Thomas W; Hooper, Jay W; Weijtens, Mo; Hartkoorn-Pasma, Jutta; Custers, Jerome; Grazia Pau, Maria; Schuitemaker, Hanneke; Zahn, Roland

2018-01-01

The search for a universal filovirus vaccine that provides protection against multiple filovirus species has been prompted by sporadic but highly lethal outbreaks of Ebolavirus and Marburgvirus infections. A good prophylactic vaccine should be able to provide protection to all known filovirus species and as an upside potentially protect from newly emerging virus strains. We investigated the immunogenicity and protection elicited by multivalent vaccines expressing glycoproteins (GP) from Ebola virus (EBOV), Sudan virus (SUDV), Taï Forest virus (TAFV) and Marburg virus (MARV). Immune responses against filovirus GP have been associated with protection from disease. The GP antigens were expressed by adenovirus serotypes 26 and 35 (Ad26 and Ad35) and modified Vaccinia virus Ankara (MVA) vectors, all selected for their strong immunogenicity and good safety profile. Using fully lethal NHP intramuscular challenge models, we assessed different vaccination regimens for immunogenicity and protection from filovirus disease. Heterologous multivalent Ad26-Ad35 prime-boost vaccination regimens could give full protection against MARV (range 75%-100% protection) and EBOV (range 50% to 100%) challenge, and partial protection (75%) against SUDV challenge. Heterologous multivalent Ad26-MVA prime-boost immunization gave full protection against EBOV challenge in a small cohort study. The use of such multivalent vaccines did not show overt immune interference in comparison with monovalent vaccines. Multivalent vaccines induced GP-specific antibody responses and cellular IFNγ responses to each GP expressed by the vaccine, and cross-reactivity to TAFV GP was detected in a trivalent vaccine expressing GP from EBOV, SUDV and MARV. In the EBOV challenge studies, higher humoral EBOV GP-specific immune responses (p = 0.0004) were associated with survival from EBOV challenge and less so for cellular immune responses (p = 0.0320). These results demonstrate that it is feasible to generate a multivalent filovirus vaccine that can protect against lethal infection by multiple members of the filovirus family.

A prophylactic multivalent vaccine against different filovirus species is immunogenic and provides protection from lethal infections with Ebolavirus and Marburgvirus species in non-human primates

PubMed Central

Callendret, Benoit; Vellinga, Jort; Wunderlich, Kerstin; Steigerwald, Robin; Dirmeier, Ulrike; Cheminay, Cedric; Volkmann, Ariane; Brasel, Trevor; Carrion, Ricardo; Giavedoni, Luis D.; Patterson, Jean L.; Mire, Chad E.; Geisbert, Thomas W.; Hooper, Jay W.; Weijtens, Mo; Hartkoorn-Pasma, Jutta; Custers, Jerome; Grazia Pau, Maria; Schuitemaker, Hanneke

2018-01-01

The search for a universal filovirus vaccine that provides protection against multiple filovirus species has been prompted by sporadic but highly lethal outbreaks of Ebolavirus and Marburgvirus infections. A good prophylactic vaccine should be able to provide protection to all known filovirus species and as an upside potentially protect from newly emerging virus strains. We investigated the immunogenicity and protection elicited by multivalent vaccines expressing glycoproteins (GP) from Ebola virus (EBOV), Sudan virus (SUDV), Taï Forest virus (TAFV) and Marburg virus (MARV). Immune responses against filovirus GP have been associated with protection from disease. The GP antigens were expressed by adenovirus serotypes 26 and 35 (Ad26 and Ad35) and modified Vaccinia virus Ankara (MVA) vectors, all selected for their strong immunogenicity and good safety profile. Using fully lethal NHP intramuscular challenge models, we assessed different vaccination regimens for immunogenicity and protection from filovirus disease. Heterologous multivalent Ad26-Ad35 prime-boost vaccination regimens could give full protection against MARV (range 75%-100% protection) and EBOV (range 50% to 100%) challenge, and partial protection (75%) against SUDV challenge. Heterologous multivalent Ad26-MVA prime-boost immunization gave full protection against EBOV challenge in a small cohort study. The use of such multivalent vaccines did not show overt immune interference in comparison with monovalent vaccines. Multivalent vaccines induced GP-specific antibody responses and cellular IFNγ responses to each GP expressed by the vaccine, and cross-reactivity to TAFV GP was detected in a trivalent vaccine expressing GP from EBOV, SUDV and MARV. In the EBOV challenge studies, higher humoral EBOV GP-specific immune responses (p = 0.0004) were associated with survival from EBOV challenge and less so for cellular immune responses (p = 0.0320). These results demonstrate that it is feasible to generate a multivalent filovirus vaccine that can protect against lethal infection by multiple members of the filovirus family. PMID:29462200

Preventative Vaccines for Zika Virus Outbreak: Preliminary Evaluation.

PubMed

Kim, Eun; Erdos, Geza; Huang, Shaohua; Kenniston, Thomas; Falo, Louis D; Gambotto, Andrea

2016-11-01

Since it emerged in Brazil in May 2015, the mosquito-borne Zika virus (ZIKV) has raised global concern due to its association with a significant rise in the number of infants born with microcephaly and neurological disorders such as Guillain-Barré syndrome. We developed prototype subunit and adenoviral-based Zika vaccines encoding the extracellular portion of the ZIKV envelope gene (E) fused to the T4 fibritin foldon trimerization domain (Efl). The subunit vaccine was delivered intradermally through carboxymethyl cellulose microneedle array (MNA). The immunogenicity of these two vaccines, named Ad5.ZIKV-Efl and ZIKV-rEfl, was tested in C57BL/6 mice. Prime/boost immunization regimen was associated with induction of a ZIKV-specific antibody response, which provided neutralizing immunity. Moreover, protection was evaluated in seven-day-old pups after virulent ZIKV intraperitoneal challenge. Pups born to mice immunized with Ad5.ZIKV-Efl were all protected against lethal challenge infection without weight loss or neurological signs, while pups born to dams immunized with MNA-ZIKV-rEfl were partially protected (50%). No protection was seen in pups born to phosphate buffered saline-immunized mice. This study illustrates the preliminary efficacy of the E ZIKV antigen vaccination in controlling ZIKV infectivity, providing a promising candidate vaccine and antigen format for the prevention of Zika virus disease. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Improvement of the Trivalent Inactivated Flu Vaccine Using PapMV Nanoparticles

PubMed Central

Savard, Christian; Guérin, Annie; Drouin, Karine; Bolduc, Marilène; Laliberté-Gagné, Marie-Eve; Dumas, Marie-Christine; Majeau, Nathalie; Leclerc, Denis

2011-01-01

Commercial seasonal flu vaccines induce production of antibodies directed mostly towards hemaglutinin (HA). Because HA changes rapidly in the circulating virus, the protection remains partial. Several conserved viral proteins, e.g., nucleocapsid (NP) and matrix proteins (M1), are present in the vaccine, but are not immunogenic. To improve the protection provided by these vaccines, we used nanoparticles made of the coat protein of a plant virus (papaya mosaic virus; PapMV) as an adjuvant. Immunization of mice and ferrets with the adjuvanted formulation increased the magnitude and breadth of the humoral response to NP and to highly conserved regions of HA. They also triggered a cellular mediated immune response to NP and M1, and long-lasting protection in animals challenged with a heterosubtypic influenza strain (WSN/33). Thus, seasonal flu vaccine adjuvanted with PapMV nanoparticles can induce universal protection to influenza, which is a major advancement when facing a pandemic. PMID:21747909

Passive Immunization with a Polyclonal Antiserum to the Hemoglobin Receptor of Haemophilus ducreyi Confers Protection against a Homologous Challenge in the Experimental Swine Model of Chancroid▿

PubMed Central

Leduc, Isabelle; Fusco, William G.; Choudhary, Neelima; Routh, Patty A.; Cholon, Deborah M.; Hobbs, Marcia M.; Almond, Glen W.; Orndorff, Paul E.; Elkins, Christopher

2011-01-01

Haemophilus ducreyi, the etiologic agent of chancroid, has an obligate requirement for heme. Heme is acquired by H. ducreyi from its human host via TonB-dependent transporters expressed at its bacterial surface. Of 3 TonB-dependent transporters encoded in the genome of H. ducreyi, only the hemoglobin receptor, HgbA, is required to establish infection during the early stages of the experimental human model of chancroid. Active immunization with a native preparation of HgbA (nHgbA) confers complete protection in the experimental swine model of chancroid, using either Freund's or monophosphoryl lipid A as adjuvants. To determine if transfer of anti-nHgbA serum is sufficient to confer protection, a passive immunization experiment using pooled nHgbA antiserum was conducted in the experimental swine model of chancroid. Pigs receiving this pooled nHgbA antiserum were protected from a homologous, but not a heterologous, challenge. Passively transferred polyclonal antibodies elicited to nHgbA bound the surface of H. ducreyi and partially blocked hemoglobin binding by nHgbA, but were not bactericidal. Taken together, these data suggest that the humoral immune response to the HgbA vaccine is protective against an H. ducreyi infection, possibly by preventing acquisition of the essential nutrient heme. PMID:21646451

Passive immunization with a polyclonal antiserum to the hemoglobin receptor of Haemophilus ducreyi confers protection against a homologous challenge in the experimental swine model of chancroid.

PubMed

Leduc, Isabelle; Fusco, William G; Choudhary, Neelima; Routh, Patty A; Cholon, Deborah M; Hobbs, Marcia M; Almond, Glen W; Orndorff, Paul E; Elkins, Christopher

2011-08-01

Haemophilus ducreyi, the etiologic agent of chancroid, has an obligate requirement for heme. Heme is acquired by H. ducreyi from its human host via TonB-dependent transporters expressed at its bacterial surface. Of 3 TonB-dependent transporters encoded in the genome of H. ducreyi, only the hemoglobin receptor, HgbA, is required to establish infection during the early stages of the experimental human model of chancroid. Active immunization with a native preparation of HgbA (nHgbA) confers complete protection in the experimental swine model of chancroid, using either Freund's or monophosphoryl lipid A as adjuvants. To determine if transfer of anti-nHgbA serum is sufficient to confer protection, a passive immunization experiment using pooled nHgbA antiserum was conducted in the experimental swine model of chancroid. Pigs receiving this pooled nHgbA antiserum were protected from a homologous, but not a heterologous, challenge. Passively transferred polyclonal antibodies elicited to nHgbA bound the surface of H. ducreyi and partially blocked hemoglobin binding by nHgbA, but were not bactericidal. Taken together, these data suggest that the humoral immune response to the HgbA vaccine is protective against an H. ducreyi infection, possibly by preventing acquisition of the essential nutrient heme.

Immune correlates of protection against yellow fever determined by passive immunization and challenge in the hamster model.

PubMed

Julander, Justin G; Trent, Dennis W; Monath, Thomas P

2011-08-11

Live, attenuated yellow fever (YF) 17D vaccine is highly efficacious but causes rare, serious adverse events resulting from active replication in the host and direct viral injury to vital organs. We recently reported development of a potentially safer β-propiolactone-inactivated whole virion YF vaccine (XRX-001), which was highly immunogenic in mice, hamsters, monkeys, and humans [10,11]. To characterize the protective efficacy of neutralizing antibodies stimulated by the inactivated vaccine, graded doses of serum from hamsters immunized with inactivated XRX-001 or live 17D vaccine were transferred to hamsters by the intraperitoneal (IP) route 24h prior to virulent, viscerotropic YF virus challenge. Neutralizing antibody (PRNT(50)) titers were determined in the sera of treated animals 4h before challenge and 4 and 21 days after challenge. Neutralizing antibodies were shown to mediate protection. Animals having 50% plaque reduction neutralization test (PRNT(50)) titers of ≥40 4h before challenge were completely protected from disease as evidenced by viremia, liver enzyme elevation, and protection against illness (weight change) and death. Passive titers of 10-20 were partially protective. Immunization with the XRX-001 vaccine stimulated YF neutralizing antibodies that were equally effective (based on dose response) as antibodies stimulated by live 17D vaccine. The results will be useful in defining the level of seroprotection in clinical studies of new yellow fever vaccines. Copyright © 2011 Elsevier Ltd. All rights reserved.

The immune response against Chlamydia suis genital tract infection partially protects against re-infection.

PubMed

De Clercq, Evelien; Devriendt, Bert; Yin, Lizi; Chiers, Koen; Cox, Eric; Vanrompay, Daisy

2014-09-25

The aim of the present study was to reveal the characteristic features of genital Chlamydia suis infection and re-infection in female pigs by studying the immune response, pathological changes, replication of chlamydial bacteria in the genital tract and excretion of viable bacteria. Pigs were intravaginally infected and re-infected with C. suis strain S45, the type strain of this species. We demonstrated that S45 is pathogenic for the female urogenital tract. Chlamydia replication occurred throughout the urogenital tract, causing inflammation and pathology. Furthermore, genital infection elicited both cellular and humoral immune responses. Compared to the primo-infection of pigs with C. suis, re-infection was characterized by less severe macroscopic lesions and less chlamydial elementary bodies and inclusions in the urogenital tract. This indicates the development of a certain level of protection following the initial infection. Protective immunity against re-infection coincided with higher Chlamydia-specific IgG and IgA antibody titers in sera and vaginal secretions, higher proliferative responses of peripheral blood mononuclear cells (PBMC), higher percentages of blood B lymphocytes, monocytes and CD8⁺ T cells and upregulated production of IFN-γ and IL-10 by PBMC.

Systemic Immunization with Papillomavirus L1 Protein Completely Prevents the Development of Viral Mucosal Papillomas

NASA Astrophysics Data System (ADS)

Suzich, Joann A.; Ghim, Shin-Je; Palmer-Hill, Frances J.; White, Wendy I.; Tamura, James K.; Bell, Judith A.; Newsome, Joseph A.; Bennett Jenson, A.; Schlegel, Richard

1995-12-01

Infection of mucosal epithelium by papillomaviruses is responsible for the induction of genital and oral warts and plays a critical role in the development of human cervical and oropharyngeal cancer. We have employed a canine model to develop a systemic vaccine that completely protects against experimentally induced oral mucosal papillomas. The major capsid protein, L1, of canine oral papillomavirus (COPV) was expressed in Sf9 insect cells in native conformation. L1 protein, which self-assembled into virus-like particles, was purified on CsCl gradients and injected intradermally into the foot pad of beagles. Vaccinated animals developed circulating antibodies against COPV and became completely resistant to experimental challenge with COPV. Successful immunization was strictly dependent upon native L1 protein conformation and L1 type. Partial protection was achieved with as little as 0.125 ng of L1 protein, and adjuvants appeared useful for prolonging the host immune response. Serum immunoglobulins passively transferred from COPV L1-immunized beagles to naive beagles conferred protection from experimental infection with COPV. Our results indicate the feasibility of developing a human vaccine to prevent mucosal papillomas, which can progress to malignancy.

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.

Immunity against Helminths: Interactions with the Host and the Intercurrent Infections

PubMed Central

Moreau, Emmanuelle; Chauvin, Alain

2010-01-01

Helminth parasites are of considerable medical and economic importance. Studies of the immune response against helminths are of great interest in understanding interactions between the host immune system and parasites. Effector immune mechanisms against tissue-dwelling helminths and helminths localized in the lumen of organs, and their regulation, are reviewed. Helminth infections are characterized by an association of Th2-like and Treg responses. Worms are able to persist in the host and are mainly responsible for chronic infection despite a strong immune response developed by the parasitized host. Two types of protection against the parasite, namely, premune and partial immunities, have been described. Immune responses against helminths can also participate in pathogenesis. Th2/Treg-like immunomodulation allows the survival of both host and parasite by controlling immunopathologic disorders and parasite persistence. Consequences of the modified Th2-like responses on co-infection, vaccination, and inflammatory diseases are discussed. PMID:20150967

Mucosal immunization with PspA (Pneumococcal surface protein A)-adsorbed nanoparticles targeting the lungs for protection against pneumococcal infection

PubMed Central

Rodrigues, Tasson C.; Oliveira, Maria Leonor S.; Soares-Schanoski, Alessandra; Chavez-Rico, Stefanni L.; Figueiredo, Douglas B.; Gonçalves, Viviane M.; Ferreira, Daniela M.; Kunda, Nitesh K.; Saleem, Imran Y.

2018-01-01

Burden of pneumonia caused by Streptococcus pneumoniae remains high despite the availability of conjugate vaccines. Mucosal immunization targeting the lungs is an attractive alternative for the induction of local immune responses to improve protection against pneumonia. Our group had previously described the development of poly(glycerol adipate-co-ω-pentadecalactone) (PGA-co-PDL) polymeric nanoparticles (NPs) adsorbed with Pneumococcal surface protein A from clade 4 (PspA4Pro) within L-leucine microcarriers (nanocomposite microparticles—NCMPs) for mucosal delivery targeting the lungs (NP/NCMP PspA4Pro). NP/NCMP PspA4Pro was now used for immunization of mice. Inoculation of this formulation induced anti-PspA4Pro IgG antibodies in serum and lungs. Analysis of binding of serum IgG to intact bacteria showed efficient binding to bacteria expressing PspA from clades 3, 4 and 5 (family 2), but no binding to bacteria expressing PspA from clades 1 and 2 (family 1) was observed. Both mucosal immunization with NP/NCMP PspA4Pro and subcutaneous injection of the protein elicited partial protection against intranasal lethal pneumococcal challenge with a serotype 3 strain expressing PspA from clade 5 (PspA5). Although similar survival levels were observed for mucosal immunization with NP/NCMP PspA4Pro and subcutaneous immunization with purified protein, NP/NCMP PspA4Pro induced earlier control of the infection. Conversely, neither immunization with NP/NCMP PspA4Pro nor subcutaneous immunization with purified protein reduced bacterial burden in the lungs after challenge with a serotype 19F strain expressing PspA from clade 1 (PspA1). Mucosal immunization with NP/NCMP PspA4Pro targeting the lungs is thus able to induce local and systemic antibodies, conferring protection only against a strain expressing PspA from the homologous family 2. PMID:29360883

Protective efficacy of passive immunization with monoclonal antibodies in animal models of H5N1 highly pathogenic avian influenza virus infection.

PubMed

Itoh, Yasushi; Yoshida, Reiko; Shichinohe, Shintaro; Higuchi, Megumi; Ishigaki, Hirohito; Nakayama, Misako; Pham, Van Loi; Ishida, Hideaki; Kitano, Mitsutaka; Arikata, Masahiko; Kitagawa, Naoko; Mitsuishi, Yachiyo; Ogasawara, Kazumasa; Tsuchiya, Hideaki; Hiono, Takahiro; Okamatsu, Masatoshi; Sakoda, Yoshihiro; Kida, Hiroshi; Ito, Mutsumi; Quynh Mai, Le; Kawaoka, Yoshihiro; Miyamoto, Hiroko; Ishijima, Mari; Igarashi, Manabu; Suzuki, Yasuhiko; Takada, Ayato

2014-06-01

Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype often cause severe pneumonia and multiple organ failure in humans, with reported case fatality rates of more than 60%. To develop a clinical antibody therapy, we generated a human-mouse chimeric monoclonal antibody (MAb) ch61 that showed strong neutralizing activity against H5N1 HPAI viruses isolated from humans and evaluated its protective potential in mouse and nonhuman primate models of H5N1 HPAI virus infections. Passive immunization with MAb ch61 one day before or after challenge with a lethal dose of the virus completely protected mice, and partial protection was achieved when mice were treated 3 days after the challenge. In a cynomolgus macaque model, reduced viral loads and partial protection against lethal infection were observed in macaques treated with MAb ch61 intravenously one and three days after challenge. Protective effects were also noted in macaques under immunosuppression. Though mutant viruses escaping from neutralization by MAb ch61 were recovered from macaques treated with this MAb alone, combined treatment with MAb ch61 and peramivir reduced the emergence of escape mutants. Our results indicate that antibody therapy might be beneficial in reducing viral loads and delaying disease progression during H5N1 HPAI virus infection in clinical cases and combined treatment with other antiviral compounds should improve the protective effects of antibody therapy against H5N1 HPAI virus infection.

Effectiveness of pentavalent rotavirus vaccine in a large urban population in the United States.

PubMed

Boom, Julie A; Tate, Jacqueline E; Sahni, Leila C; Rench, Marcia A; Hull, Jennifer J; Gentsch, Jon R; Patel, Manish M; Baker, Carol J; Parashar, Umesh D

2010-02-01

The goal was to assess the effectiveness of complete (3-dose) or partial (1- or 2-dose) immunization with pentavalent rotavirus vaccine (RV5) against rotavirus acute gastroenteritis (AGE) in US clinical practice. A case-control evaluation was conducted in February through June 2008 at an emergency department in Houston, Texas. Case patients with rotavirus AGE (N = 90) were identified through testing for rotavirus in fecal specimens obtained from 205 children 15 days through 23 months of age presenting with AGE. Control groups included rotavirus-negative AGE patients (N = 115), concurrently enrolled patients with acute respiratory infection (ARI) (N = 228), and up to 10 age- and zip code-matched children sampled from the Houston-Harris County Immunization Registry (HHCIR) for each case patient >8 months of age. Immunization data were obtained from parent records, health care providers, and/or the HHCIR. Vaccine effectiveness was calculated as 1 minus odds of RV5 vaccination for case patients versus control patients, after adjustment for age at presentation and birth date. The vaccine effectiveness of a complete RV5 series was 89% (95% confidence interval [CI]: 70%-96%) and 85% (95% CI: 55%-95%) with rotavirus-negative AGE and ARI control patients, respectively. Immunization data were available for 44% of case patients (n = 40) from the HHCIR; the estimated 3-dose vaccine effectiveness with these HHCIR control patients was 82% (95% CI: 19%-96%). A complete RV5 series conferred 100% protection (95% CI: 71%-100%) against severe rotavirus disease requiring hospitalization and 96% protection (95% CI: 72%-99%) against disease requiring intravenous hydration. Vaccine effectiveness of 1 and 2 doses against hospitalization and emergency department visits was 69% (95% CI: 13%-89%) and 81% (95% CI: 13%-96%), respectively, using rotavirus-negative AGE and ARI control groups combined. In this setting, a complete series of RV5 was highly effective against severe rotavirus AGE. Partial immunization also conferred substantial protection.

Antibody-mediated protection against mucosal simian-human immunodeficiency virus challenge of macaques immunized with alphavirus replicon particles and boosted with trimeric envelope glycoprotein in MF59 adjuvant.

PubMed

Barnett, Susan W; Burke, Brian; Sun, Yide; Kan, Elaine; Legg, Harold; Lian, Ying; Bost, Kristen; Zhou, Fengmin; Goodsell, Amanda; Zur Megede, Jan; Polo, John; Donnelly, John; Ulmer, Jeffrey; Otten, Gillis R; Miller, Christopher J; Vajdy, Michael; Srivastava, Indresh K

2010-06-01

We have previously shown that rhesus macaques were partially protected against high-dose intravenous challenge with simian-human immunodeficiency virus SHIV(SF162P4) following sequential immunization with alphavirus replicon particles (VRP) of a chimeric recombinant VEE/SIN alphavirus (derived from Venezuelan equine encephalitis virus [VEE] and the Sindbis virus [SIN]) encoding human immunodeficiency virus type 1 HIV-1(SF162) gp140DeltaV2 envelope (Env) and trimeric Env protein in MF59 adjuvant (R. Xu, I. K. Srivastava, C. E. Greer, I. Zarkikh, Z. Kraft, L. Kuller, J. M. Polo, S. W. Barnett, and L. Stamatatos, AIDS Res. Hum. Retroviruses 22:1022-1030, 2006). The protection did not require T-cell immune responses directed toward simian immunodeficiency virus (SIV) Gag. We extend those findings here to demonstrate antibody-mediated protection against mucosal challenge in macaques using prime-boost regimens incorporating both intramuscular and mucosal routes of delivery. The macaques in the vaccination groups were primed with VRP and then boosted with Env protein in MF59 adjuvant, or they were given VRP intramuscular immunizations alone and then challenged with SHIV(SF162P4) (intrarectal challenge). The results demonstrated that these vaccines were able to effectively protect the macaques to different degrees against subsequent mucosal SHIV challenge, but most noteworthy, all macaques that received the intramuscular VRP prime plus Env protein boost were completely protected. A statistically significant association was observed between the titer of virus neutralizing and binding antibodies as well as the avidity of anti-Env antibodies measured prechallenge and protection from infection. These results highlight the merit of the alphavirus replicon vector prime plus Env protein boost vaccine approach for the induction of protective antibody responses and are of particular relevance to advancing our understanding of the potential correlates of immune protection against HIV infection at a relevant mucosal portal of entry.

ImprimatinC1, a novel plant immune-priming compound, functions as a partial agonist of salicylic acid

PubMed Central

Noutoshi, Yoshiteru; Jikumaru, Yusuke; Kamiya, Yuji; Shirasu, Ken

2012-01-01

Plant activators are agrochemicals that protect crops from pathogens. They confer durable resistance to a broad range of diseases by activating intrinsic immune mechanisms in plants. To obtain leads regarding useful compounds, we have screened a chemical library using an established method that allows selective identification of immune-priming compounds. Here, we report the characterisation of one of the isolated chemicals, imprimatinC1, and its structural derivative imprimatinC2. ImprimatinC1 functions as a weak analogue of salicylic acid (SA) and activates the expression of defence-related genes. However, it lacks antagonistic activity toward jasmonic acid. Structure-activity relationship analysis suggests that imprimatinC1 and C2 can be metabolised to 4-chlorobenzoic acid and 3,4-chlorobenzoic acid, respectively, to function in Arabidopsis. We also found that imprimatinC1 and C2 and their potential functional metabolites acted as partial agonists of SA. Thus, imprimatinC compounds could be useful tools for dissecting SA-dependent signal transduction pathways. PMID:23050089

ImprimatinC1, a novel plant immune-priming compound, functions as a partial agonist of salicylic acid.

PubMed

Noutoshi, Yoshiteru; Jikumaru, Yusuke; Kamiya, Yuji; Shirasu, Ken

2012-01-01

Plant activators are agrochemicals that protect crops from pathogens. They confer durable resistance to a broad range of diseases by activating intrinsic immune mechanisms in plants. To obtain leads regarding useful compounds, we have screened a chemical library using an established method that allows selective identification of immune-priming compounds. Here, we report the characterisation of one of the isolated chemicals, imprimatinC1, and its structural derivative imprimatinC2. ImprimatinC1 functions as a weak analogue of salicylic acid (SA) and activates the expression of defence-related genes. However, it lacks antagonistic activity toward jasmonic acid. Structure-activity relationship analysis suggests that imprimatinC1 and C2 can be metabolised to 4-chlorobenzoic acid and 3,4-chlorobenzoic acid, respectively, to function in Arabidopsis. We also found that imprimatinC1 and C2 and their potential functional metabolites acted as partial agonists of SA. Thus, imprimatinC compounds could be useful tools for dissecting SA-dependent signal transduction pathways.

Protective effects of broadly neutralizing immunoglobulin against homologous and heterologous equine infectious anemia virus infection in horses with severe combined immunodeficiency.

PubMed

Taylor, Sandra D; Leib, Steven R; Wu, Wuwei; Nelson, Robert; Carpenter, Susan; Mealey, Robert H

2011-07-01

Using the equine infectious anemia virus (EIAV) lentivirus model system, we previously demonstrated protective effects of broadly neutralizing immune plasma in young horses (foals) with severe combined immunodeficiency (SCID). However, in vivo selection of a neutralization-resistant envelope variant occurred. Here, we determined the protective effects of purified immunoglobulin with more potent broadly neutralizing activity. Overall, protection correlated with the breadth and potency of neutralizing activity in vitro. Four of five SCID foals were completely protected against homologous challenge, while partial protection occurred following heterologous challenge. These results support the inclusion of broadly neutralizing antibodies in lentivirus control strategies.

48 CFR 1852.228-81 - Insurance-Partial Immunity From Tort Liability.

Code of Federal Regulations, 2014 CFR

2014-10-01

... 48 Federal Acquisition Regulations System 6 2014-10-01 2014-10-01 false Insurance-Partial Immunity... Provisions and Clauses 1852.228-81 Insurance—Partial Immunity From Tort Liability. As prescribed in 1828.311-270(c), insert the following clause: Insurance—Partial Immunity From Tort Liability (SEP 2000) (a...

48 CFR 1852.228-81 - Insurance-Partial Immunity From Tort Liability.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 48 Federal Acquisition Regulations System 6 2010-10-01 2010-10-01 true Insurance-Partial Immunity... Provisions and Clauses 1852.228-81 Insurance—Partial Immunity From Tort Liability. As prescribed in 1828.311-270(c), insert the following clause: Insurance—Partial Immunity From Tort Liability (SEP 2000) (a...

48 CFR 1852.228-81 - Insurance-Partial Immunity From Tort Liability.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 48 Federal Acquisition Regulations System 6 2012-10-01 2012-10-01 false Insurance-Partial Immunity... Provisions and Clauses 1852.228-81 Insurance—Partial Immunity From Tort Liability. As prescribed in 1828.311-270(c), insert the following clause: Insurance—Partial Immunity From Tort Liability (SEP 2000) (a...

48 CFR 1852.228-81 - Insurance-Partial Immunity From Tort Liability.

Code of Federal Regulations, 2013 CFR

2013-10-01

... 48 Federal Acquisition Regulations System 6 2013-10-01 2013-10-01 false Insurance-Partial Immunity... Provisions and Clauses 1852.228-81 Insurance—Partial Immunity From Tort Liability. As prescribed in 1828.311-270(c), insert the following clause: Insurance—Partial Immunity From Tort Liability (SEP 2000) (a...

48 CFR 1852.228-81 - Insurance-Partial Immunity From Tort Liability.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 48 Federal Acquisition Regulations System 6 2011-10-01 2011-10-01 false Insurance-Partial Immunity... Provisions and Clauses 1852.228-81 Insurance—Partial Immunity From Tort Liability. As prescribed in 1828.311-270(c), insert the following clause: Insurance—Partial Immunity From Tort Liability (SEP 2000) (a...

A DNA vaccine co-expressing Trichinella spiralis MIF and MCD-1 with murine ubiquitin induces partial protective immunity in mice.

PubMed

Tang, F; Xu, L; Yan, R; Song, X; Li, X

2013-03-01

Co-expression of Trichinella spiralis macrophage migration inhibitory factor (TsMIF) with T. spiralis cystatin-like domain protein (TsMCD-1) in a DNA vaccine induces a Th1 immune response and partial protection against T. spiralis infection. The present study evaluated whether co-expression of mouse ubiquitin (Ub) with TsMIF and TsMCD-1 might improve the immune response against T. spiralis infection. Groups of BALB/c mice were immunized twice at 2-week intervals with 100 μg of plasmid DNA encoding either a TsMIF-TsMCD-1 fusion protein (pVAX1-Tsmif-Tsmcd-1) or an Ub-co-expressing triple fusion protein Ub-TsMIF-TsMCD-1 (pVAX1-Ub-Tsmif-Tsmcd-1). Control animals were immunized with pVAX1-Ub or blank vector plasmid. Specific antibody levels (IgG, IgG1, IgG2a, IgG2b, IgM, IgA, IgE) against the recombinant protein TsMIF-TsMCD-1, serum cytokines (interferon (IFN)-γ, interleukin (IL)-4, IL-5, transforming growth factor (TGF)-β1 and IL-17), CD4+/CD8+ T cells and cytotoxic T lymphocyte (CTL) responses were monitored. Challenge infection was performed 2 weeks after the second immunization and worm burden was assayed at 35 days post-challenge. Antibody responses induced by pVAX1-Ub-Tsmif-Tsmcd-1 were significantly lower than for TsMIF-TsMCD-1, but the vaccine induced increased levels of Th1 cytokine (IFN-γ) and increased T-cell cytotoxicity. The reduction of worm burden (37.95%) following immunization with pVAX1-Ub-Tsmif-Tsmcd-1 was significantly greater than that induced by the pVAX1-Tsmif-Tsmcd-1 vaccine (23.17%; P< 0.05).

Immunization with a DNA vaccine encoding Toxoplasma gondii Superoxide dismutase (TgSOD) induces partial immune protection against acute toxoplasmosis in BALB/c mice.

PubMed

Liu, Yuan; Cao, Aiping; Li, Yawen; Li, Xun; Cong, Hua; He, Shenyi; Zhou, Huaiyu

2017-06-07

Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan parasite that infects all warm-blooded animals including humans and causes toxoplasmosis. An effective vaccine could be an ideal choice for preventing and controlling toxoplasmosis. T. gondii Superoxide dismutase (TgSOD) might participate in affecting the intracellular growth of both bradyzoite and tachyzoite forms. In the present study, the TgSOD gene was used to construct a DNA vaccine (pEGFP-SOD). TgSOD gene was amplified and inserted into eukaryotic vector pEGFP-C1 and formed the DNA vaccine pEGFP-SOD. Then the BALB/c mice were immunized intramuscularly with the DNA vaccine and those injected with pEGFP-C1, PBS or nothing were treated as controls. Four weeks after the last immunization, all mouse groups followed by challenging intraperitoneally with tachyzoites of T. gondii ME49 strain. Results showed higher levels of total IgG, IgG2α in the sera and interferon gamma (IFN-γ) in the splenocytes from pEGFP-SOD inoculated mice than those unvaccinated, or inoculated with either empty plasmid vector or PBS. The proportions of CD4 + T cells and CD8 + T cells in the spleen from pEGFP-SOD inoculated mice were significantly (p < 0.05) increased compared to control groups. In addition, the survival time of mice immunized with pEGFP-SOD was significantly prolonged as compared to the controls (p < 0.05) although all the mice died. The present study revealed that the DNA vaccine triggered strong humoral and cellular immune responses, and aroused partial protective immunity against acute T. gondii infection in BALB/c mice. The collective data suggests the SOD may be a potential vaccine candidate for further development.

Progress with viral vectored malaria vaccines: A multi-stage approach involving "unnatural immunity".

PubMed

Ewer, Katie J; Sierra-Davidson, Kailan; Salman, Ahmed M; Illingworth, Joseph J; Draper, Simon J; Biswas, Sumi; Hill, Adrian V S

2015-12-22

Viral vectors used in heterologous prime-boost regimens are one of very few vaccination approaches that have yielded significant protection against controlled human malaria infections. Recently, protection induced by chimpanzee adenovirus priming and modified vaccinia Ankara boosting using the ME-TRAP insert has been correlated with the induction of potent CD8(+) T cell responses. This regimen has progressed to field studies where efficacy against infection has now been reported. The same vectors have been used pre-clinically to identify preferred protective antigens for use in vaccines against the pre-erythrocytic, blood-stage and mosquito stages of malaria and this work is reviewed here for the first time. Such antigen screening has led to the prioritization of the PfRH5 blood-stage antigen, which showed efficacy against heterologous strain challenge in non-human primates, and vectors encoding this antigen are in clinical trials. This, along with the high transmission-blocking activity of some sexual-stage antigens, illustrates well the capacity of such vectors to induce high titre protective antibodies in addition to potent T cell responses. All of the protective responses induced by these vectors exceed the levels of the same immune responses induced by natural exposure supporting the view that, for subunit vaccines to achieve even partial efficacy in humans, "unnatural immunity" comprising immune responses of very high magnitude will need to be induced. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

An engineered vaccine of the Plasmodium vivax Duffy binding protein enhances induction of broadly neutralizing antibodies.

PubMed

Ntumngia, Francis B; Pires, Camilla V; Barnes, Samantha J; George, Miriam T; Thomson-Luque, Richard; Kano, Flora S; Alves, Jessica R S; Urusova, Darya; Pereira, Dhelio B; Tolia, Niraj H; King, Christopher L; Carvalho, Luzia H; Adams, John H

2017-10-23

Plasmodium vivax invasion into human reticulocytes is a complex process. The Duffy binding protein (DBP) dimerization with its cognate receptor is vital for junction formation in the invasion process. Due to its functional importance, DBP is considered a prime vaccine candidate, but variation in B-cell epitopes at the dimer interface of DBP leads to induction of strain-limited immunity. We believe that the polymorphic residues tend to divert immune responses away from functionally conserved epitopes important for receptor binding or DBP dimerization. As a proof of concept, we engineered the vaccine DEKnull to ablate the dominant Bc epitope to partially overcome strain-specific immune antibody responses. Additional surface engineering on the next generation immunogen, DEKnull-2, provides an immunogenicity breakthrough to conserved protective epitopes. DEKnull-2 elicits a stronger broadly neutralizing response and reactivity with long-term persistent antibody responses of acquired natural immunity. By using novel engineered DBP immunogens, we validate that the prime targets of protective immunity are conformational epitopes at the dimer interface. These successful results indicate a potential approach that can be used generally to improve efficacy of other malaria vaccine candidates.

DNA Vaccination Partially Protects against African Swine Fever Virus Lethal Challenge in the Absence of Antibodies

PubMed Central

Argilaguet, Jordi M.; Pérez-Martín, Eva; Nofrarías, Miquel; Gallardo, Carmina; Accensi, Francesc; Lacasta, Anna; Mora, Mercedes; Ballester, Maria; Galindo-Cardiel, Ivan; López-Soria, Sergio; Escribano, José M.; Reche, Pedro A.; Rodríguez, Fernando

2012-01-01

The lack of available vaccines against African swine fever virus (ASFV) means that the evaluation of new immunization strategies is required. Here we show that fusion of the extracellular domain of the ASFV Hemagglutinin (sHA) to p54 and p30, two immunodominant structural viral antigens, exponentially improved both the humoral and the cellular responses induced in pigs after DNA immunization. However, immunization with the resulting plasmid (pCMV-sHAPQ) did not confer protection against lethal challenge with the virulent E75 ASFV-strain. Due to the fact that CD8+ T-cell responses are emerging as key components for ASFV protection, we designed a new plasmid construct, pCMV-UbsHAPQ, encoding the three viral determinants above mentioned (sHA, p54 and p30) fused to ubiquitin, aiming to improve Class I antigen presentation and to enhance the CTL responses induced. As expected, immunization with pCMV-UbsHAPQ induced specific T-cell responses in the absence of antibodies and, more important, protected a proportion of immunized-pigs from lethal challenge with ASFV. In contrast with control pigs, survivor animals showed a peak of CD8+ T-cells at day 3 post-infection, coinciding with the absence of viremia at this time point. Finally, an in silico prediction of CTL peptides has allowed the identification of two SLA I-restricted 9-mer peptides within the hemagglutinin of the virus, capable of in vitro stimulating the specific secretion of IFNγ when using PBMCs from survivor pigs. Our results confirm the relevance of T-cell responses in protection against ASF and open new expectations for the future development of more efficient recombinant vaccines against this disease. PMID:23049728

Vaccine potential of antigen cocktails composed of recombinant Toxoplasma gondii TgPI-1, ROP2 and GRA4 proteins against chronic toxoplasmosis in C3H mice.

PubMed

Picchio, Mariano S; Sánchez, Vanesa R; Arcon, Nadia; Soto, Ariadna S; Perrone Sibilia, Matías; Aldirico, María de Los Angeles; Urrutia, Mariela; Moretta, Rosalía; Fenoy, Ignacio M; Goldman, Alejandra; Martin, Valentina

2018-02-01

The development of an effective and safe vaccine to prevent Toxoplasma gondii infection is an important aim due to the great clinical and economic impact of this parasitosis. We have previously demonstrated that immunization with the serine protease inhibitor-1 (TgPI-1) confers partial protection to C3H/HeN and C57BL/6 mice. In order to improve the level of protection, in this work, we combined this novel antigen with ROP2 and/or GRA4 recombinant proteins (rTgPI-1+rROP2, rTgPI-1+rGRA4, rTgPI-1+rROP2+rGRA4) to explore the best combination against chronic toxoplasmosis in C3H/HeN mice. All tested vaccine formulations, administered following a homologous prime-boost protocol that combines intradermal and intranasal routes, conferred partial protection as measured by the reduction of brain cyst burden following oral challenge with tissue cysts of Me49 T. gondii strain. The highest level of protection was achieved by the mixture of rTgPI-1 and rROP2 proteins with an average parasite burden reduction of 50% compared to the unvaccinated control group. The vaccine-induced protective effect was related to the elicitation of systemic cellular and humoral immune responses that included antigen-specific spleen cell proliferation, the release of Th1/Th2 cytokines, and the generation of antigen-specific antibodies in serum. Additionally, mucosal immune responses were also induced, characterized by secretion of antigen-specific IgA antibodies in intestinal lavages and specific mesenteric lymph node cell proliferation. Our results demonstrate that rTgPI-1+rROP2 antigens seem a promising mixture to be combined with other immunogenic proteins in a multiantigenic vaccine formulation against toxoplasmosis. Copyright © 2018 Elsevier Inc. All rights reserved.

Protective Immunity to Ricin Toxin Conferred by Antibodies against the Toxin’s Binding Subunit (RTB)

PubMed Central

Yermakova, Anastasiya; Mantis, Nicholas J.

2011-01-01

The B subunit (RTB) of ricin toxin is a galactose-/N-acetyl galactosamine-specific lectin that promotes attachment and entry of ricin into host cells. RTB is also the archetype of the so-called R-type lectin family, whose members include haemagglutinins of botulinum neurotoxin (BoNT) progenitor toxins, as well as the binding subunits of cytolethal distending toxins. Although RTB is an appealing subunit vaccine candidate, as well as a potential target for immunotherapeutics, the degree to which RTB immunization elicits protective antibodies against ricin toxin remains unresolved. To address this issue, groups of mice were immunized with RTB and then challenged with 5xLD50s of ricin administered intraperitoneally. Despite high RTB-specific serum antibody titers, groups of RTB immunized mice were only partially immune to ricin challenge. Analysis of a collection of RTB-specific B cell hybridomas suggested that only a small fraction of antibodies against RTB have demonstrable neutralizing activity. Two RTB-specific neutralizing monoclonal IgG1 antibodies, 24B11 and SylH3, when passively administered to mice, were sufficient to protect the animals against a 5xLD50 dose of ricin. Both 24B11 and SylH3 blocked ricin attachment to terminal galactose residues and prevented toxin binding to the surfaces of bone marrow-derived macrophages (BMM), suggesting that they function by steric hindrance and recognize epitopes located on RTB’s carbohydrate recognition sub-domains (1α or 2γ). These data raise the possibility of using specific RTB sub-domains, rather than RTB itself, as antigens to more efficiently elicit neutralizing antibodies and protective immunity against ricin. PMID:21872634

Intranasal vaccination with Ad5-encoding influenza HA elicits sterilizing immunity to homologous challenge and partial protection to heterologous challenge in pigs

USDA-ARS?s Scientific Manuscript database

Vaccine availability during the 2009 H1N1 pandemic highlighted the lengthy production time of traditional vaccine. Replication defective adenovirus (Ad5) constructs with influenza genes have been investigated as candidate vaccines with rapid production potential. However, the primary model used for ...

An initial examination of the potential role of T-cell immunity in protection against feline immunodeficiency virus (FIV) infection.

PubMed

Aranyos, Alek M; Roff, Shannon R; Pu, Ruiyu; Owen, Jennifer L; Coleman, James K; Yamamoto, Janet K

2016-03-14

The importance of vaccine-induced T-cell immunity in conferring protection with prototype and commercial FIV vaccines is still unclear. Current studies performed adoptive transfer of T cells from prototype FIV-vaccinated cats to partial-to-complete feline leukocyte antigen (FLA)-matched cats a day before either homologous FIVPet or heterologous-subtype pathogenic FIVFC1 challenge. Adoptive-transfer (A-T) conferred a protection rate of 87% (13 of 15, p < 0.001) against FIVPet using the FLA-matched T cells, whereas all 12 control cats were unprotected. Furthermore, A-T conferred protection rate of 50% (6 of 12, p<0.023) against FIVFC1 using FLA-matched T cells, whereas all 8 control cats were unprotected. Transfer of FLA-matched T and B cells demonstrated that T cells are needed to confer A-T protection. In addition, complete FLA-matching and addition of T-cell numbers > 13 × 10(6) cells were required for A-T protection against FIVFC1 strain, reported to be a highly pathogenic virus resistant to vaccine-induced neutralizing-antibodies. The addition of FLA-matched B cells alone was not protective. The poor quality of the anti-FIV T-cell immunity induced by the vaccine likely contributed to the lack of protection in an FLA-matched recipient against FIVFC1. The quality of the immune response was determined by the presence of high mRNA levels of cytolysin (perforin) and cytotoxins (granzymes A, B, and H) and T helper-1 cytokines (interferon-γ [IFNγ] and IL2). Increased cytokine, cytolysin and cytotoxin production was detected in the donors which conferred protection in A-T studies. In addition, the CD4(+) and CD8(+) T-cell proliferation and/or IFNγ responses to FIV p24 and reverse transcriptase increased with each year in cats receiving 1X-3X vaccine boosts over 4 years. These studies demonstrate that anti-FIV T-cell immunity induced by vaccination with a dual-subtype FIV vaccine is essential for prophylactic protection against AIDS lentiviruses such as FIV and potentially HIV-1. Copyright © 2016 Elsevier Ltd. All rights reserved.

An initial examination of the potential role of T-cell immunity in protection against feline immunodeficiency virus (FIV) infection

PubMed Central

Aranyos, Alek M.; Roff, Shannon R.; Pu, Riuyu; Owen, Jennifer L.; Coleman, James K.; Yamamoto, Janet K.

2016-01-01

The importance of vaccine-induced T-cell immunity in conferring protection with prototype and commercial FIV vaccines is still unclear. Current studies performed adoptive transfer of T cells from prototype FIV-vaccinated cats to partial-to-complete feline leukocyte antigen (FLA)-matched cats a day before either homologous FIVPet or heterologous-subtype pathogenic FIVFC1 challenge. Adoptive-transfer (A–T) conferred a protection rate of 87% (13 of 15, p<0.001) against FIVPet using FLA-matched T cells, whereas all 12 control cats were unprotected. Furthermore, A-T conferred protection rate of 50% (6 of 12, p<0.023) against FIVFC1 using FLA-matched T cells, whereas all 8 control cats were unprotected. Transfer of FLA-matched T and B cells demonstrated that T cells are needed to confer A-T protection. In addition, complete FLA-matching and addition of T-cell numbers >13×106 cells were required for A-T protection against FIVFC1 strain, reported to be a highly pathogenic virus resistant to vaccine-induced neutralizing-antibodies. The addition of FLA-matched B cells alone was not protective. The poor quality of the anti-FIV T-cell immunity induced by the vaccine likely contributed to the lack of protection in an FLA-matched recipient against FIVFC1. The quality of the immune response was determined by the presence of high mRNA levels of cytolysin (perforin) and cytotoxins (granzymes A, B, and H) and T helper-1 cytokines (interferon-γ [IFNγ] and IL2). Increased cytokine, cytolysin and cytotoxin production was detected in the donors which conferred protection in A-T studies. In addition, the CD4+ and CD8+ T-cell proliferation and/or IFNγ responses to FIV p24 and reverse transcriptase increased with each year in cats receiving 1X-3X vaccine boosts over 4 years. These studies demonstrate that anti-FIV T-cell immunity induced by vaccination with a dual-subtype FIV vaccine is essential for prophylactic protection against AIDS lentiviruses such as FIV and potentially HIV-1. PMID:26802606

Anaplasma phagocytophilum MSP4 and HSP70 Proteins Are Involved in Interactions with Host Cells during Pathogen Infection

PubMed Central

Contreras, Marinela; Alberdi, Pilar; Mateos-Hernández, Lourdes; Fernández de Mera, Isabel G.; García-Pérez, Ana L.; Vancová, Marie; Villar, Margarita; Ayllón, Nieves; Cabezas-Cruz, Alejandro; Valdés, James J.; Stuen, Snorre; Gortazar, Christian; de la Fuente, José

2017-01-01

Anaplasma phagocytophilum transmembrane and surface proteins play a role during infection and multiplication in host neutrophils and tick vector cells. Recently, A. phagocytophilum Major surface protein 4 (MSP4) and Heat shock protein 70 (HSP70) were shown to be localized on the bacterial membrane, with a possible role during pathogen infection in ticks. In this study, we hypothesized that A. phagocytophilum MSP4 and HSP70 have similar functions in tick-pathogen and host-pathogen interactions. To address this hypothesis, herein we characterized the role of these bacterial proteins in interaction and infection of vertebrate host cells. The results showed that A. phagocytophilum MSP4 and HSP70 are involved in host-pathogen interactions, with a role for HSP70 during pathogen infection. The analysis of the potential protective capacity of MSP4 and MSP4-HSP70 antigens in immunized sheep showed that MSP4-HSP70 was only partially protective against pathogen infection. This limited protection may be associated with several factors, including the recognition of non-protective epitopes by IgG in immunized lambs. Nevertheless, these antigens may be combined with other candidate protective antigens for the development of vaccines for the control of human and animal granulocytic anaplasmosis. Focusing on the characterization of host protective immune mechanisms and protein-protein interactions at the host-pathogen interface may lead to the discovery and design of new effective protective antigens. PMID:28725639

Anaplasma phagocytophilum MSP4 and HSP70 Proteins Are Involved in Interactions with Host Cells during Pathogen Infection.

PubMed

Contreras, Marinela; Alberdi, Pilar; Mateos-Hernández, Lourdes; Fernández de Mera, Isabel G; García-Pérez, Ana L; Vancová, Marie; Villar, Margarita; Ayllón, Nieves; Cabezas-Cruz, Alejandro; Valdés, James J; Stuen, Snorre; Gortazar, Christian; de la Fuente, José

2017-01-01

Anaplasma phagocytophilum transmembrane and surface proteins play a role during infection and multiplication in host neutrophils and tick vector cells. Recently, A. phagocytophilum Major surface protein 4 (MSP4) and Heat shock protein 70 (HSP70) were shown to be localized on the bacterial membrane, with a possible role during pathogen infection in ticks. In this study, we hypothesized that A. phagocytophilum MSP4 and HSP70 have similar functions in tick-pathogen and host-pathogen interactions. To address this hypothesis, herein we characterized the role of these bacterial proteins in interaction and infection of vertebrate host cells. The results showed that A. phagocytophilum MSP4 and HSP70 are involved in host-pathogen interactions, with a role for HSP70 during pathogen infection. The analysis of the potential protective capacity of MSP4 and MSP4-HSP70 antigens in immunized sheep showed that MSP4-HSP70 was only partially protective against pathogen infection. This limited protection may be associated with several factors, including the recognition of non-protective epitopes by IgG in immunized lambs. Nevertheless, these antigens may be combined with other candidate protective antigens for the development of vaccines for the control of human and animal granulocytic anaplasmosis. Focusing on the characterization of host protective immune mechanisms and protein-protein interactions at the host-pathogen interface may lead to the discovery and design of new effective protective antigens.

Sialidase-Inhibiting Antibody Titers Correlate with Protection from Heterologous Influenza Virus Strains of the Same Neuraminidase Subtype.

PubMed

Walz, Lisa; Kays, Sarah-Katharina; Zimmer, Gert; von Messling, Veronika

2018-06-20

Immune responses induced by currently licensed inactivated influenza vaccines are mainly directed against the hemagglutinin (HA) glycoprotein, the immunodominant antigen of influenza viruses. The resulting antigenic drift of HA requires frequent updating of the vaccine composition and annual revaccination. On the other hand, the level of antibodies directed against the neuraminidase (NA) glycoprotein, the second major influenza virus antigen, vary greatly. To investigate the potential of the more conserved NA protein for the induction of a subtype-specific protection, vesicular stomatitis virus-based replicons expressing a panel of N1 proteins from prototypic seasonal and pandemic H1N1 strain and human H5N1 and H7N9 isolates were generated. Immunization of mice and ferrets with the replicon carrying the matched N1 protein resulted in robust humoral and cellular immune responses and protected against challenge with the homologous influenza virus with similar efficacy as the matched HA protein, illustrating the potential of the NA protein as vaccine antigen. The extent of protection after immunization with mismatched N1 proteins correlated with the level of cross-reactive sialidase-inhibiting antibody titers. Passive serum transfer experiments in mice confirmed that these functional antibodies determine subtype-specific cross-protection. Our findings illustrate the potential of NA-specific immunity for achieving broader protection against antigenic drift variants or newly emerging viruses carrying the same NA but a different HA subtype. IMPORTANCE Despite the availability of vaccines, annual influenza virus epidemics cause 250,000 to 500,000 deaths worldwide. Currently licensed inactivated vaccines, which are standardized for the amount of the hemagglutinin (HA) antigen, primarily induce strain-specific antibodies whereas the immune response to the neuraminidase (NA) antigen, which is also present on the viral surface, is usually low. Using NA-expressing single-cycle vesicular stomatitis virus replicons, we show that the NA antigen not only conferred protection of mice and ferrets to the matched influenza strains, but also against viruses carrying NA proteins from other strains of the same subtype. The extent of protection correlated with the level of cross-reactive NA-inhibiting antibodies. This highlights the potential of the NA antigen for the development of more broadly protective influenza vaccines. Such vaccines may also provide partial protection against newly emerging strains with the same NA but a different HA subtype. Copyright © 2018 American Society for Microbiology.

Immune response in bovine neosporosis: Protection or contribution to the pathogenesis of abortion.

PubMed

Almería, Sonia; Serrano-Pérez, Beatriz; López-Gatius, Fernando

2017-08-01

Neospora caninum is a protozoan parasite with a preference for cattle and dogs as hosts. When N. caninum infection occurs in cattle it induces abortion, bovine neosporosis being a main cause of abortion worldwide. In dairy cattle, the economic burden of neosporosis-associated abortion is so great that it might results in closure of a farm. However, not all infected cows abort and it is not yet understood why this occurs. At present there is no effective treatment or vaccine. This review provides insights on how immune response against the parasite determines protection or contribution to abortion. Aspects on markers of risk of abortion are also discussed. Humoral immune responses are not protective against N. caninum but seropositivity and antibody level can be good markers for a diagnosis of bovine neosporosis and its associated abortion risk. In addition, humoral mechanisms against N. caninum infection and abortion differ in pure-breed and cross-breed pregnant dairy and beef cattle. Concentrations of Pregnancy Associated glycoprotein -2 (PAG-2) can also be used to predict abortion. A partially protective immune response encompasses increased IFN-γ expression, which has to be counterbalanced by other cytokines such as IL-12 and IL-10, especially towards the end of pregnancy. Although IFN-γ is required to limit parasite proliferation a critical threshold of the IFN-γ response is also required to limit adverse effects on pregnancy. In clinical terms, it may be stated that IFN-γ production and cross-breed pregnancy can protect Neospora-infected dairy cows against abortion. Published by Elsevier Ltd.

Immune parameters to p67C antigen adjuvanted with ISA206VG correlate with protection against East Coast fever.

PubMed

Lacasta, Anna; Mwalimu, Stephen; Kibwana, Elisabeth; Saya, Rosemary; Awino, Elias; Njoroge, Thomas; Poole, Jane; Ndiwa, Nicholas; Pelle, Roger; Nene, Vishvanath; Steinaa, Lucilla

2018-03-07

East Coast fever (ECF) is a lymphoproliferative disease caused by the tick-transmitted protozoan parasite Theileria parva. ECF is one of the most serious cattle tick-borne diseases in Sub-Saharan Africa. We have previously demonstrated that three doses of the C-terminal part of the sporozoite protein p67 (p67C) adjuvanted with ISA206VG confers partial protection against ECF at a herd level. We have tested the efficacy of two doses of this experimental vaccine, as reducing the vaccination regimen would facilitate its deployment in the field. We reconfirm that three antigen doses gave a significant level of protection to severe disease (46%, ECF score < 6) when compared with the control group, while two doses did not (23%). Animals receiving three doses of p67C developed higher antibody titers and CD4 + T-cell proliferation indices, than those which received two doses. A new panel of immune parameters were tested in order to identify factors correlating with protection: CD4 + proliferation index, total IgG, IgG1, IgG2 and IgM half maximal titers and neutralization capacity of the sera with and without complement. We show that some of the cellular and humoral immune responses provide preliminary correlates of protection. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Killed but metabolically active Bacillus anthracis vaccines induce broad and protective immunity against anthrax.

PubMed

Skoble, Justin; Beaber, John W; Gao, Yi; Lovchik, Julie A; Sower, Laurie E; Liu, Weiqun; Luckett, William; Peterson, Johnny W; Calendar, Richard; Portnoy, Daniel A; Lyons, C Rick; Dubensky, Thomas W

2009-04-01

Bacillus anthracis is the causative agent of anthrax. We have developed a novel whole-bacterial-cell anthrax vaccine utilizing B. anthracis that is killed but metabolically active (KBMA). Vaccine strains that are asporogenic and nucleotide excision repair deficient were engineered by deleting the spoIIE and uvrAB genes, rendering B. anthracis extremely sensitive to photochemical inactivation with S-59 psoralen and UV light. We also introduced point mutations into the lef and cya genes, which allowed inactive but immunogenic toxins to be produced. Photochemically inactivated vaccine strains maintained a high degree of metabolic activity and secreted protective antigen (PA), lethal factor, and edema factor. KBMA B. anthracis vaccines were avirulent in mice and induced less injection site inflammation than recombinant PA adsorbed to aluminum hydroxide gel. KBMA B. anthracis-vaccinated animals produced antibodies against numerous anthrax antigens, including high levels of anti-PA and toxin-neutralizing antibodies. Vaccination with KBMA B. anthracis fully protected mice against challenge with lethal doses of toxinogenic unencapsulated Sterne 7702 spores and rabbits against challenge with lethal pneumonic doses of fully virulent Ames strain spores. Guinea pigs vaccinated with KBMA B. anthracis were partially protected against lethal Ames spore challenge, which was comparable to vaccination with the licensed vaccine anthrax vaccine adsorbed. These data demonstrate that KBMA anthrax vaccines are well tolerated and elicit potent protective immune responses. The use of KBMA vaccines may be broadly applicable to bacterial pathogens, especially those for which the correlates of protective immunity are unknown.

Identification of BALB/c Immune Markers Correlated with a Partial Protection to Leishmania infantum after Vaccination with a Rationally Designed Multi-epitope Cysteine Protease A Peptide-Based Nanovaccine

PubMed Central

Agallou, Maria; Margaroni, Maritsa; Athanasiou, Evita; Toubanaki, Dimitra K.; Kontonikola, Katerina; Karidi, Konstantina; Kammona, Olga; Kiparissides, Costas

2017-01-01

Background Through their increased potential to be engaged and processed by dendritic cells (DCs), nanovaccines consisting of Poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) loaded with both antigenic moieties and adjuvants are attractive candidates for triggering specific defense mechanisms against intracellular pathogens. The aim of the present study was to evaluate the immunogenicity and prophylactic potential of a rationally designed multi-epitope peptide of Leishmania Cysteine Protease A (CPA160-189) co-encapsulated with Monophosphoryl lipid A (MPLA) in PLGA NPs against L. infantum in BALB/c mice and identify immune markers correlated with protective responses. Methodology/Principal Findings The DCs phenotypic and functional features exposed to soluble (CPA160-189, CPA160-189+MPLA) or encapsulated in PLGA NPs forms of peptide and adjuvant (PLGA-MPLA, PLGA-CPA160-189, PLGA-CPA160-189+MPLA) was firstly determined using BALB/c bone marrow-derived DCs. The most potent signatures of DCs maturation were obtained with the PLGA-CPA160-189+MPLA NPs. Subcutaneous administration of PLGA-CPA160-189+MPLA NPs in BALB/c mice induced specific anti-CPA160-189 cellular and humoral immune responses characterized by T cells producing high amounts of IL-2, IFN-γ and TNFα and IgG1/IgG2a antibodies. When these mice were challenged with 2x107 stationary phase L. infantum promastigotes, they displayed significant reduced hepatic (48%) and splenic (90%) parasite load at 1 month post-challenge. This protective phenotype was accompanied by a strong spleen lymphoproliferative response and high levels of IL-2, IFN-γ and TNFα versus low IL-4 and IL-10 secretion. Although, at 4 months post-challenge, the reduced parasite load was preserved in the liver (61%), an increase was detected in the spleen (30%), indicating a partial vaccine-induced protection. Conclusions/Significance This study provide a basis for the development of peptide-based nanovaccines against leishmaniasis, since it reveals that vaccination with well-defined Leishmania MHC-restricted epitopes extracted from various immunogenic proteins co-encapsulated with the proper adjuvant or/and phlebotomine fly saliva multi-epitope peptides into clinically compatible PLGA NPs could be a promising approach for the induction of a strong and sustainable protective immunity. PMID:28114333

Prolonged Ischemia Triggers Necrotic Depletion of Tissue Resident Macrophages to Facilitate Inflammatory Immune Activation in Liver Ischemia Reperfusion Injury

PubMed Central

Yue, Shi; Zhou, Haoming; Wang, Xuehao; Busuttil, Ronald W.; Kupiec-Weglinski, Jerzy W.; Zhai, Yuan

2017-01-01

Although mechanisms of immune activation against liver ischemia reperfusion injury (IRI) have been studied extensively, questions regarding liver resident macrophages, i.e., Kupffer cells, remain controversial. Recent progress in the biology of tissue resident macrophages implicates homeostatic functions of KCs. This study aims to dissect responses and functions of KCs in liver IRI. In a murine liver partial warm ischemia model, we analyzed liver resident vs. infiltrating macrophages by fluorescence-activated cell sorting (FACS) and immunofluorescence staining. Our data showed that liver immune activation by IR was associated with not only infiltrations/activations of peripheral macrophages (iMØ), but also necrotic depletion of KCs. Inhibition of Receptor Interacting Protein 1 (RIP1) by necrostatin-1s protected KCs from ischemia-induce depletion, resulting in the reduction of iMØ infiltration, suppression of pro-inflammatory immune activation and protection of livers from IRI. The depletion of KCs by clodronate-liposomes abrogated these effects of Nec-1s. Additionally, liver reconstitutions with KCs post-ischemia exerted anti-inflammatory/cytoprotective effects against IRI. These results reveal a unique response of KCs against liver IR, i.e., RIP-1-dependent necrosis, which constitutes a novel mechanism of liver inflammatory immune activation in the pathogenesis of liver IRI. PMID:28289160

Prime-boost vaccination with heterologous live vectors encoding SIV gag and multimeric HIV-1 gp160 protein: efficacy against repeated mucosal R5 clade C SHIV challenges

PubMed Central

Lakhashe, Samir K.; Velu, Vijayakumar; Sciaranghella, Gaia; Siddappa, Nagadenahalli B.; DiPasquale, Janet M.; Hemashettar, Girish; Yoon, John K.; Rasmussen, Robert A.; Yang, Feng; Lee, Sandra J.; Montefiori, David C.; Novembre, Francis J.; Villinger, François; Amara, Rama Rao; Kahn, Maria; Hu, Shiu-Lok; Li, Sufen; Li, Zhongxia; Frankel, Fred R.; Robert-Guroff, Marjorie; Johnson, Welkin E.; Lieberman, Judy; Ruprecht, Ruth M.

2011-01-01

We sought to induce primate immunodeficiency virus-specific cellular and neutralizing antibody (nAb) responses in rhesus macaques (RM) through a bimodal vaccine approach. RM were immunized intragastrically (i.g.) with the live-attenuated Listeria monocytogenes (Lm) vector Lmdd-BdopSIVgag encoding SIVmac239 gag. SIV Gag-specific cellular responses were boosted by intranasal and intratracheal administration of replication-competent adenovirus (Ad5hr-SIVgag) encoding the same gag. To broaden antiviral immunity, the RM were immunized with multimeric HIV clade C (HIV-C) gp160 and HIV Tat. SIV Gag-specific cellular immune responses and HIV-1 nAb developed in some RM. The animals were challenged intrarectally with five low doses of R5 SHIV-1157ipEL-p, encoding a heterologous HIV-C Env (22.1% divergent to the Env immunogen). All five controls became viremic. One out of ten vaccinees was completely protected and another had low peak viremia. Sera from the completely and partially protected RM neutralized the challenge virus >90%; these RM also had strong SIV Gag-specific proliferation of CD8+ T cells. Peak and area under the curve of plasma viremia (during acute phase) among vaccinees was lower than for controls, but did not attain significance. The completely protected RM showed persistently low numbers of the α4β7-expressing CD4+ T cells; the latter have been implicated as preferential virus targets in-vivo. Thus, vaccine-induced immune responses and relatively lower numbers of potential target cells were associated with protection. PMID:21693155

Prime-boost vaccination with heterologous live vectors encoding SIV gag and multimeric HIV-1 gp160 protein: efficacy against repeated mucosal R5 clade C SHIV challenges.

PubMed

Lakhashe, Samir K; Velu, Vijayakumar; Sciaranghella, Gaia; Siddappa, Nagadenahalli B; Dipasquale, Janet M; Hemashettar, Girish; Yoon, John K; Rasmussen, Robert A; Yang, Feng; Lee, Sandra J; Montefiori, David C; Novembre, Francis J; Villinger, François; Amara, Rama Rao; Kahn, Maria; Hu, Shiu-Lok; Li, Sufen; Li, Zhongxia; Frankel, Fred R; Robert-Guroff, Marjorie; Johnson, Welkin E; Lieberman, Judy; Ruprecht, Ruth M

2011-08-05

We sought to induce primate immunodeficiency virus-specific cellular and neutralizing antibody (nAb) responses in rhesus macaques (RM) through a bimodal vaccine approach. RM were immunized intragastrically (i.g.) with the live-attenuated Listeria monocytogenes (Lm) vector Lmdd-BdopSIVgag encoding SIVmac239 gag. SIV Gag-specific cellular responses were boosted by intranasal and intratracheal administration of replication-competent adenovirus (Ad5hr-SIVgag) encoding the same gag. To broaden antiviral immunity, the RM were immunized with multimeric HIV clade C (HIV-C) gp160 and HIV Tat. SIV Gag-specific cellular immune responses and HIV-1 nAb developed in some RM. The animals were challenged intrarectally with five low doses of R5 SHIV-1157ipEL-p, encoding a heterologous HIV-C Env (22.1% divergent to the Env immunogen). All five controls became viremic. One out of ten vaccinees was completely protected and another had low peak viremia. Sera from the completely and partially protected RM neutralized the challenge virus > 90%; these RM also had strong SIV Gag-specific proliferation of CD8⁺ T cells. Peak and area under the curve of plasma viremia (during acute phase) among vaccinees was lower than for controls, but did not attain significance. The completely protected RM showed persistently low numbers of the α4β7-expressing CD4⁺ T cells; the latter have been implicated as preferential virus targets in vivo. Thus, vaccine-induced immune responses and relatively lower numbers of potential target cells were associated with protection. Copyright © 2011 Elsevier Ltd. All rights reserved.

BacMam immunization partially protects pigs against sublethal challenge with African swine fever virus.

PubMed

Argilaguet, Jordi M; Pérez-Martín, Eva; López, Sergio; Goethe, Martin; Escribano, J M; Giesow, Katrin; Keil, Günther M; Rodríguez, Fernando

2013-04-01

Lack of vaccines and efficient control measures complicate the control and eradication of African swine fever (ASF). Limitations of conventional inactivated and attenuated virus-based vaccines against African swine fever virus (ASFV) highlight the need to use new technologies to develop efficient and safe vaccines against this virus. With this aim in mind, in this study we have constructed BacMam-sHAPQ, a baculovirus based vector for gene transfer into mammalian cells, expressing a fusion protein comprising three in tandem ASFV antigens: p54, p30 and the extracellular domain of the viral hemagglutinin (secretory hemagglutinin, sHA), under the control of the human cytomegalovirus immediate early promoter (CMVie). Confirming its correct in vitro expression, BacMam-sHAPQ induced specific T-cell responses directly after in vivo immunization. Conversely, no specific antibody responses were detectable prior to ASFV challenge. The protective potential of this recombinant vaccine candidate was tested by a homologous sublethal challenge with ASFV following immunization. Four out of six immunized pigs remained viremia-free after ASFV infection, while the other two pigs showed similar viremic titres to control animals. The protection afforded correlated with the presence of a large number of virus-specific IFNγ-secreting T-cells in blood at 17 days post-infection. In contrast, the specific antibody levels observed after ASFV challenge in sera from BacMam-sHAPQ immunized pigs were indistinguishable from those found in control pigs. These results highlight the importance of the cellular responses in protection against ASFV and point towards BacMam vectors as potential tools for future vaccine development. Copyright © 2013 Elsevier B.V. All rights reserved.

Familial and temperamental predictors of resilience in children at risk for conduct disorder and depression

PubMed Central

Shannon, Katherine E.; Beauchaine, Theodore P.; Brenner, Sharon L.; Neuhaus, Emily; Gatzke-Kopp, Lisa

2009-01-01

In this study, we evaluated predictors of resilience among 8- to 12-year-old children recruited from primarily low socioeconomic status neighborhoods, 117 of whom suffered from clinical levels of conduct problems and/or depression, and 63 of whom suffered from no significant symptoms. Tests of interactions were conducted between (a) paternal antisocial behavior and maternal depression and (b) several physiological indices of child temperament and emotionality in predicting (c) children’s conduct problems and depression. Both internalizing and externalizing outcomes among children were associated specifically with maternal melancholic depression, and not with nonmelancholic depression. In addition, low levels of respiratory sinus arrhythmia (RSA) among children conferred significant risk for depression, regardless of maternal melancholia, whereas high RSA offered partial protection. Furthermore, high levels of maternal melancholia conferred significant risk for child depression, regardless of paternal antisocial behavior, whereas low levels of maternal melancholia offered partial protection. Finally, low levels of electrodermal responding (EDR) conferred significant risk for conduct problems, regardless of paternal antisocial behavior, whereas high EDR offered partial protection. None of the identified protective factors offered complete immunity from psychopathology. These findings underscore the complexity of resilience and resilience-related processes, and suggest several potential avenues for future longitudinal research. PMID:17705899

Gut immune deficits in LEW.1AR1-iddm rats partially overcome by feeding a diabetes-protective diet.

PubMed

Crookshank, Jennifer A; Patrick, Christopher; Wang, Gen-Sheng; Noel, J Ariana; Scott, Fraser W

2015-07-01

The gut immune system and its modification by diet have been implicated in the pathogenesis of type 1 diabetes (T1D). Therefore, we investigated gut immune status in non-diabetes-prone LEW.1AR1 and diabetes-prone LEW.1AR1-iddm rats and evaluated the effect of a low antigen, hydrolysed casein (HC)-based diet on gut immunity and T1D. Rats were weaned onto a cereal-based or HC-based diet and monitored for T1D. Strain and dietary effects on immune homeostasis were assessed in non-diabetic rats (50-60 days old) and rats with recent-onset diabetes using flow cytometry and immunohistochemistry. Immune gene expression was analysed in mesenteric lymph nodes (MLN) and jejunum using quantitative RT-PCR and PCR arrays. T1D was prevented in LEW.1AR1-iddm rats by feeding an HC diet. Diabetic LEW.1AR1-iddm rats had fewer lymphoid tissue T cells compared with LEW.1AR1 rats. The percentage of CD4(+)  Foxp3(+) regulatory T (Treg) cells was decreased in pancreatic lymph nodes (PLN) of diabetic rats. The jejunum of 50-day LEW.1AR1-iddm rats contained fewer CD3(+) T cells, CD163(+) M2 macrophages and Foxp3(+) Treg cells. Ifng expression was increased in MLN and Foxp3 expression was decreased in the jejunum of LEW.1AR1-iddm rats; Ifng/Il4 was decreased in jejunum of LEW.1AR1-iddm rats fed HC. PCR arrays revealed decreased expression of M2-associated macrophage factors in 50-day LEW.1AR1-iddm rats. Wheat peptides stimulated T-cell proliferation and activation in MLN and PLN cells from diabetic LEW.1AR1-iddm rats. LEW.1AR1-iddm rats displayed gut immune cell deficits and decreased immunoregulatory capacity, which were partially corrected in animals fed a low antigen, protective HC diet consistent with other models of T1D. © 2015 John Wiley & Sons Ltd.

Influenza Virus Vaccine Based on the Conserved Hemagglutinin Stalk Domain

PubMed Central

Steel, John; Lowen, Anice C.; Wang, Taia T.; Yondola, Mark; Gao, Qinshan; Haye, Kester; García-Sastre, Adolfo; Palese, Peter

2010-01-01

ABSTRACT Although highly effective in the general population when well matched to circulating influenza virus strains, current influenza vaccines are limited in their utility due to the narrow breadth of protection they provide. The strain specificity of vaccines presently in use mirrors the exquisite specificity of the neutralizing antibodies that they induce, that is, antibodies which bind to the highly variable globular head domain of hemagglutinin (HA). Herein, we describe the construction of a novel immunogen comprising the conserved influenza HA stalk domain and lacking the globular head. Vaccination of mice with this headless HA construct elicited immune sera with broader reactivity than those obtained from mice immunized with a full-length HA. Furthermore, the headless HA vaccine provided full protection against death and partial protection against disease following lethal viral challenge. Our results suggest that the response induced by headless HA vaccines is sufficiently potent to warrant their further development toward a universal influenza virus vaccine. PMID:20689752

The Impact of the Newly Licensed Dengue Vaccine in Endemic Countries

PubMed Central

Stollenwerk, Nico; Halstead, Scott B.

2016-01-01

Background With approximately 3 billion people at risk of acquiring the infection, dengue fever is now considered the most important mosquito-borne viral disease in the world, with 390 million dengue infections occurring every year, of which 96 million manifest symptoms with any level of disease severity. Treatment of uncomplicated dengue cases is only supportive and severe dengue cases require hospital intensive care. A vaccine now licensed in several countries and developed by Sanofi Pasteur (CYD-TDV, named Dengvaxia), was able to protect, in the first 25 months of the two Phase III, 66% of a subset of 9–16 year old participants. However, a significantly lower efficacy (including negative vaccine efficacy) was noted for children younger than 9 years of age. Methodology/Principal Findings Analysis of year 3 results of phase III trials of Dengvaxia suggest high rates of protection of vaccinated partial dengue immunes but high rates of hospitalizations during breakthrough dengue infections of persons who were vaccinated when seronegative, with vaccine appearing to induce enhancing antibodies (ADE). An age structured model was developed based on Sanofi’s recommendation to vaccinate persons age 945 years in dengue endemic countries. The model was used to explore the clinical burden of two vaccination strategies: 1) Vaccinate 4 or 20% of individuals, ages 9–45 years, seropositives and seronegatives, and 2) vaccinate 4 or 20% of individuals, ages 9–45 years, who are dengue immune only. Conclusions/Significance Our results show that vaccinating dengue monotypic immune individuals prevents dengue hospitalizations, but at the same time dengue infections of vaccine-sensitized persons increases hospitalizations. When the vaccine is given only to partial immune individuals, after immunological screening of the population, disease burden decreases considerably. PMID:28002420

The Impact of the Newly Licensed Dengue Vaccine in Endemic Countries.

PubMed

Aguiar, Maíra; Stollenwerk, Nico; Halstead, Scott B

2016-12-01

With approximately 3 billion people at risk of acquiring the infection, dengue fever is now considered the most important mosquito-borne viral disease in the world, with 390 million dengue infections occurring every year, of which 96 million manifest symptoms with any level of disease severity. Treatment of uncomplicated dengue cases is only supportive and severe dengue cases require hospital intensive care. A vaccine now licensed in several countries and developed by Sanofi Pasteur (CYD-TDV, named Dengvaxia), was able to protect, in the first 25 months of the two Phase III, 66% of a subset of 9-16 year old participants. However, a significantly lower efficacy (including negative vaccine efficacy) was noted for children younger than 9 years of age. Analysis of year 3 results of phase III trials of Dengvaxia suggest high rates of protection of vaccinated partial dengue immunes but high rates of hospitalizations during breakthrough dengue infections of persons who were vaccinated when seronegative, with vaccine appearing to induce enhancing antibodies (ADE). An age structured model was developed based on Sanofi's recommendation to vaccinate persons age 945 years in dengue endemic countries. The model was used to explore the clinical burden of two vaccination strategies: 1) Vaccinate 4 or 20% of individuals, ages 9-45 years, seropositives and seronegatives, and 2) vaccinate 4 or 20% of individuals, ages 9-45 years, who are dengue immune only. Our results show that vaccinating dengue monotypic immune individuals prevents dengue hospitalizations, but at the same time dengue infections of vaccine-sensitized persons increases hospitalizations. When the vaccine is given only to partial immune individuals, after immunological screening of the population, disease burden decreases considerably.

Ebola Virus Glycoprotein Induces an Innate Immune Response In vivo via TLR4

PubMed Central

Lai, Chih-Yun; Strange, Daniel P.; Wong, Teri Ann S.; Lehrer, Axel T.; Verma, Saguna

2017-01-01

Ebola virus (EBOV), a member of the Filoviridae family, causes the most severe form of viral hemorrhagic fever. Although no FDA licensed vaccine or treatment against Ebola virus disease (EVD) is currently available, Ebola virus glycoprotein (GP) is the major antigen used in all candidate Ebola vaccines. Recent reports of protection as quickly as within 6 days of administration of the rVSV-based vaccine expressing EBOV GP before robust humoral responses were generated suggests that the innate immune responses elicited early after vaccination may contribute to the protection. However, the innate immune responses induced by EBOV GP in the absence of viral vectors or adjuvants have not been fully characterized in vivo. Our recent studies demonstrated that immunization with highly purified recombinant GP in the absence of adjuvants induced a robust IgG response and partial protection against EBOV infection suggesting that GP alone can induce protective immunity. In this study we investigated the early immune response to purified EBOV GP alone in vitro and in vivo. We show that GP was efficiently internalized by antigen presenting cells and subsequently induced production of key inflammatory cytokines. In vivo, immunization of mice with EBOV GP triggered the production of key Th1 and Th2 innate immune cytokines and chemokines, which directly governed the recruitment of CD11b+ macrophages and CD11c+ dendritic cells to the draining lymph nodes (DLNs). Pre-treatment of mice with a TLR4 antagonist inhibited GP-induced cytokine production and recruitment of immune cells to the DLN. EBOV GP also upregulated the expression of costimulatory molecules in bone marrow derived macrophages suggesting its ability to enhance APC stimulatory capacity, which is critical for the induction of effective antigen-specific adaptive immunity. Collectively, these results provide the first in vivo evidence that early innate immune responses to EBOV GP are mediated via the TLR4 pathway and are able to modulate the innate-adaptive interface. These mechanistic insights into the adjuvant-like property of EBOV GP may help to develop a better understanding of how optimal prophylactic efficacy of EBOV vaccines can be achieved as well as further explore the potential post-exposure use of vaccines to prevent filoviral disease. PMID:28861075

Inflammatory Effects of the Plant Protection Product Stifenia (FEN560) on Vertebrates.

PubMed

Teyssier, Lény; Colussi, Julie; Delemasure, Stéphanie; Chluba, Johanna; Wendehenne, David; Lamotte, Olivier; Connat, Jean-Louis

2017-01-01

Plant defense stimulators (PDSs) rely on the activation of plant innate immunity in order to protect crops against various pests. These molecules are thought to be a safer alternative to classical plant protection products. Given that innate immune systems share common features in plants and vertebrates, PDS can potentially cross-react with innate immunity of non-target organisms. To test this hypothesis, we studied effects of the commercial PDS Stifenia (FEN560), which is composed of crushed fenugreek seeds. We tested various concentrations of Stifenia (0.03-1 mg mL -1 ) on human peripheral blood mononuclear cells and checked, 20 h later, cell metabolic activity (MA) using XTT assay, cell death by flow cytometry analysis, and IL-1β inflammatory cytokine released in the culture medium using ELISA. Stifenia induced a general decrease of the cell MA, which was concomitant with a dose-dependent release of IL-1β. Our results highlight the activation of human immune cells. The inflammatory effect of Stifenia was partially inhibited by pan-caspase inhibitor. Accordingly, Stifenia induced the release of p20 caspase-1 fragment into the culture medium suggesting the involvement of the NLRP3 inflammasome. Furthermore, we observed that Stifenia can induce cell death. We also tested the effect of Stifenia on Zebrafish larvae. After 24 h of exposure, Stifenia induced a dose-dependent IL-1β and TNFα gene expression. The human-cell-based approach developed in this work revealed a high sensitivity concerning inflammatory properties of a plant protection product. These tests could be routinely used to screen the potential adverse effects of this type of compounds. Finally, our results suggest a potential danger of using extensively certain PDS for crop protection.

Enhanced protective immunity of the chimeric vector-based vaccine rAdV-SFV-E2 against classical swine fever in pigs by a Salmonella bacterial ghost adjuvant.

PubMed

Xia, Shui-Li; Lei, Jian-Lin; Du, Mingliang; Wang, Yimin; Cong, Xin; Xiang, Guang-Tao; Li, Lian-Feng; Yu, Shenye; Du, Enqi; Liu, Siguo; Sun, Yuan; Qiu, Hua-Ji

2016-06-14

Classical swine fever (CSF) is a highly contagious swine disease caused by classical swine fever virus (CSFV). Previously, we demonstrated that rAdV-SFV-E2, an adenovirus-delivered, Semliki Forest virus replicon-vectored marker vaccine against CSF, is able to protect pigs against lethal CSFV challenge. From an economical point of view, it will be beneficial to reduce the minimum effective dose of the vaccine. This study was designed to test the adjuvant effects of Salmonella enteritidis-derived bacterial ghosts (BG) to enhance the protective immunity of rAdV-SFV-E2 in pigs. Groups of 5-week-old pigs (n = 4) were immunized intramuscularly twice with 10(5) median tissue culture infective doses (TCID50) rAdV-SFV-E2 combined with 10(10) colony forming units (CFU) BG, 10(6) or 10(5) TCID50 rAdV-SFV-E2 alone or 10(10) CFU BG alone at an interval of 3 weeks, and challenged with the highly virulent CSFV Shimen strain at 1 week post-booster immunization. The results show that the pigs inoculated with 10(5) TCID50 rAdV-SFV-E2 plus BG or 10(6) TCID50 rAdV-SFV-E2 alone were completely protected from lethal CSFV challenge, in contrast with the pigs vaccinated with 10(5) TCID50 rAdV-SFV-E2 or BG alone, which displayed partial or no protection following virulent challenge. The data indicate that BG are a promising adjuvant to enhance the efficacy of rAdV-SFV-E2 and possibly other vaccines.

Inflammatory Effects of the Plant Protection Product Stifenia (FEN560) on Vertebrates

PubMed Central

Teyssier, Lény; Colussi, Julie; Delemasure, Stéphanie; Chluba, Johanna; Wendehenne, David; Lamotte, Olivier; Connat, Jean-Louis

2017-01-01

Plant defense stimulators (PDSs) rely on the activation of plant innate immunity in order to protect crops against various pests. These molecules are thought to be a safer alternative to classical plant protection products. Given that innate immune systems share common features in plants and vertebrates, PDS can potentially cross-react with innate immunity of non-target organisms. To test this hypothesis, we studied effects of the commercial PDS Stifenia (FEN560), which is composed of crushed fenugreek seeds. We tested various concentrations of Stifenia (0.03–1 mg mL−1) on human peripheral blood mononuclear cells and checked, 20 h later, cell metabolic activity (MA) using XTT assay, cell death by flow cytometry analysis, and IL-1β inflammatory cytokine released in the culture medium using ELISA. Stifenia induced a general decrease of the cell MA, which was concomitant with a dose-dependent release of IL-1β. Our results highlight the activation of human immune cells. The inflammatory effect of Stifenia was partially inhibited by pan-caspase inhibitor. Accordingly, Stifenia induced the release of p20 caspase-1 fragment into the culture medium suggesting the involvement of the NLRP3 inflammasome. Furthermore, we observed that Stifenia can induce cell death. We also tested the effect of Stifenia on Zebrafish larvae. After 24 h of exposure, Stifenia induced a dose-dependent IL-1β and TNFα gene expression. The human-cell-based approach developed in this work revealed a high sensitivity concerning inflammatory properties of a plant protection product. These tests could be routinely used to screen the potential adverse effects of this type of compounds. Finally, our results suggest a potential danger of using extensively certain PDS for crop protection. PMID:28484691

Development of Safe and Effective RSV Vaccine by Modified CD4 Epitope in G Protein Core Fragment (Gcf)

PubMed Central

Park, Sung-Moo; Choi, Youngjoo; Jang, Ji Eun; Jung, Dae Im; Kim, Jae-Ouk; Chang, Jun; Yun, Cheol-Heui; Song, Man Ki

2014-01-01

Respiratory syncytial virus (RSV) is a major cause of respiratory tract infection in infants and young children worldwide, but currently no safe and effective vaccine is available. The RSV G glycoprotein (RSVG), a major attachment protein, is an important target for the induction of protective immune responses during RSV infection. However, it has been thought that a CD4+ T cell epitope (a.a. 183–195) within RSVG is associated with pathogenic pulmonary eosinophilia. To develop safe and effective RSV vaccine using RSV G protein core fragment (Gcf), several Gcf variants resulting from modification to CD4+ T cell epitope were constructed. Mice were immunized with each variant Gcf, and the levels of RSV-specific serum IgG were measured. At day 4 post-challenge with RSV subtype A or B, lung viral titers and pulmonary eosinophilia were determined and changes in body weight were monitored. With wild type Gcf derived from RSV A2 (wtAGcf), although RSV A subtype-specific immune responses were induced, vaccine-enhanced disease characterized by excessive pulmonary eosinophil recruitment and body weight loss were evident, whereas wtGcf from RSV B1 (wtBGcf) induced RSV B subtype-specific immune responses without the signs of vaccine-enhanced disease. Mice immunized with Th-mGcf, a fusion protein consisting CD4+ T cell epitope from RSV F (F51–66) conjugated to mGcf that contains alanine substitutions at a.a. position 185 and 188, showed higher levels of RSV-specific IgG response than mice immunized with mGcf. Both wtAGcf and Th-mGcf provided complete protection against RSV A2 and partial protection against RSV B. Importantly, mice immunized with Th-mGcf did not develop vaccine-enhanced disease following RSV challenge. Immunization of Th-mGcf provided protection against RSV infection without the symptom of vaccine-enhanced disease. Our study provides a novel strategy to develop a safe and effective mucosal RSV vaccine by manipulating the CD4+ T cell epitope within RSV G protein. PMID:24736750

DNA Vaccine Encoding the Chimeric Form of Schistosoma mansoni Sm-TSP2 and Sm29 Confers Partial Protection against Challenge Infection

PubMed Central

Gonçalves de Assis, Natan Raimundo; Batistoni de Morais, Suellen; Figueiredo, Bárbara Castro Pimentel; Ricci, Natasha Delaqua; de Almeida, Leonardo Augusto; da Silva Pinheiro, Carina; Martins, Vicente de Paulo; Oliveira, Sergio Costa

2015-01-01

Schistosomiasis is an important parasitic disease worldwide that affects more than 207 million people in 76 countries and causes approximately 250,000 deaths per year. The best long-term strategy to control schistosomiasis is through immunization combined with drug treatment. Due to the ability of DNA vaccines to generate humoral and cellular immune responses, such vaccines are considered a promising approach against schistosomiasis. Sm29 and tetraspanin-2 (Sm-TSP2) are two proteins that are located in the S. mansoni tegument of adult worms and schistosomula and induce high levels of protection through recombinant protein immunization. In this study, we transfected BHK-21 cells with plasmids encoding Sm29, Sm-TSP2 or a chimera containing both genes. Using RT-PCR analysis and western blot, we confirmed that the DNA vaccine constructs were transcribed and translated, respectively, in BHK-21 cells. After immunization of mice, we evaluated the reduction in worm burden. We observed worm burden reductions of 17-22%, 22%, 31-32% and 24-32% in animals immunized with the pUMVC3/Sm29, pUMVC3/SmTSP-2, pUMVC3/Chimera and pUMVC3/Sm29 + pUMVC3/SmTSP-2 plasmids, respectively. We evaluated the humoral response elicited by DNA vaccines, and animals immunized with pUMVC3/Sm29 and pUMVC3/Sm29 + pUMVC3/SmTSP-2 showed higher titers of anti-Sm29 antibodies. The cytokine profile produced by the spleen cells of immunized mice was then evaluated. We observed higher production of Th1 cytokines, such as TNF-α and IFN-γ, in vaccinated mice and no significant production of IL-4 and IL-5. The DNA vaccines tested in this study showed the ability to generate a protective immune response against schistosomiasis, probably through the production of Th1 cytokines. However, future strategies aiming to optimize the protective response induced by a chimeric DNA construct need to be developed. PMID:25942636

Immunization with the hybrid protein vaccine, consisting of Leishmania major cysteine proteinases Type I (CPB) and Type II (CPA), partially protects against leishmaniasis.

PubMed

Zadeh-Vakili, Azita; Taheri, Tahere; Taslimi, Yasaman; Doustdari, Fatemeh; Salmanian, Ali-Hatef; Rafati, Sima

2004-05-07

Cysteine proteinases (CPs) are enzymes that belong to the papain superfamily, which are found in a number of organisms from prokaryotes to mammals. On the parasitic protozoan Leishmania, extensive studies have shown that CPs are involved in parasite survival, replication and the onset of disease, and have, therefore, been considered as attractive drugs and/or vaccine targets for the control of leishmaniasis. We have previously shown that cysteine proteinases, Type I (CPB) and Type II (CPA), in Leishmania major (L. major), delivered as recombinant proteins or in plasmid DNA, induce partial protection against infection with the parasite in BALB/c mice. We had shown that the level of protection was greater if a cocktail of cpa and cpb containing DNA constructs was used. Therefore, to reduce the costs associated with the production of these vaccine candidates, a construct was developed, whereby the cpa and cpb genes were fused together to give rise to a single hybrid protein. The genes were fused in tandem where the C-terminal extension (CTE), encoding region of CPB, was located at the 3' of the fused genes, and ultimately expressed in the bacterial expression construct pET-23a. The expression of the CPA/B hybrid protein (60 kDa) was verified using rabbit anti-CPA and anti-CPB antibodies by SDS-PAGE and immunoblotting. The protective potential of the CPA/B hybrid protein against the infection with Leishmania was then assessed in BALB/c mice. The animals were vaccinated with CPA/B, challenged with live L. major promastigotes, and the degree of protection was examined by measuring footpad lesion sizes. It was found that there was a delay in the expansion of lesions size compared to control groups. Furthermore, an immunological analysis of antibody isotypes, before and after infection, showed high levels of IgG2a compared to IgG1 (more than five-fold) in the CPA/B hybrid protein vaccinated group. In addition, a predominant Th1 immune response characterized by in vitro IFN-gamma production was observed, along with little, if any, IL-5 production. This finding indicates that the hybrid CPA/B is able to elicit a protective immune response against L. major in the mice model. In addition, 54% of individuals tested, who had recovered from cutaneous leishmaniasis, produced more than 50 pg/ml IFN-gamma, in response to the CPA/B hybrid protein in an in vitro assay, demonstrating the importance of cysteine proteinases as targets of immune response in humans.

Cryptosporidium Priming Is More Effective than Vaccine for Protection against Cryptosporidiosis in a Murine Protein Malnutrition Model

PubMed Central

Bartelt, Luther A.; Bolick, David T.; Kolling, Glynis L.; Zaenker, Edna I.; Lara, Ana M.; Noronha, Francisco Jose; Cowardin, Carrie A.; Moore, John H.; Turner, Jerrold R.; Warren, Cirle A.; Buck, Gregory A.; Guerrant, Richard L.

2016-01-01

Cryptosporidium is a major cause of severe diarrhea, especially in malnourished children. Using a murine model of C. parvum oocyst challenge that recapitulates clinical features of severe cryptosporidiosis during malnutrition, we interrogated the effect of protein malnutrition (PM) on primary and secondary responses to C. parvum challenge, and tested the differential ability of mucosal priming strategies to overcome the PM-induced susceptibility. We determined that while PM fundamentally alters systemic and mucosal primary immune responses to Cryptosporidium, priming with C. parvum (106 oocysts) provides robust protective immunity against re-challenge despite ongoing PM. C. parvum priming restores mucosal Th1-type effectors (CD3+CD8+CD103+ T-cells) and cytokines (IFNγ, and IL12p40) that otherwise decrease with ongoing PM. Vaccination strategies with Cryptosporidium antigens expressed in the S. Typhi vector 908htr, however, do not enhance Th1-type responses to C. parvum challenge during PM, even though vaccination strongly boosts immunity in challenged fully nourished hosts. Remote non-specific exposures to the attenuated S. Typhi vector alone or the TLR9 agonist CpG ODN-1668 can partially attenuate C. parvum severity during PM, but neither as effectively as viable C. parvum priming. We conclude that although PM interferes with basal and vaccine-boosted immune responses to C. parvum, sustained reductions in disease severity are possible through mucosal activators of host defenses, and specifically C. parvum priming can elicit impressively robust Th1-type protective immunity despite ongoing protein malnutrition. These findings add insight into potential correlates of Cryptosporidium immunity and future vaccine strategies in malnourished children. PMID:27467505

Vaccination with a DNA vaccine encoding Toxoplasma gondii ROP54 induces protective immunity against toxoplasmosis in mice.

PubMed

Yang, Wen-Bin; Zhou, Dong-Hui; Zou, Yang; Chen, Kai; Liu, Qing; Wang, Jin-Lei; Zhu, Xing-Quan; Zhao, Guang-Hui

2017-12-01

Toxoplasma gondii is an obligatory intracellular protozoan, which infects most of the warm-blooded animals, causing serious public health problems and enormous economic losses worldwide. The rhoptry effector protein 54 (ROP54) has been indicated as a virulence factor that promotes Toxoplasma infection by modulating GBP2 loading onto parasite-containing vacuoles, which can modulate some aspects of the host immune response. In order to evaluate the immuno-protective value of ROP54, we constructed a eukaryotic recombinant plasmid expressing T. gondii ROP54 and intramuscularly immunized Kunming mice with this recombinant plasmid against acute and chronic toxoplasmosis. All mice immunized with pVAX-ROP54 elicited a high level of specific antibody responses, a significant increase of lymphocyte proliferation, and a significant level of Th1-type cytokines (IFN-γ, IL-2 and IL-12p70), in addition to an increased production of Th2-type cytokines (IL-4 and IL-10). These results demonstrated that pVAX-ROP54 induced significant cellular and humoral (Th1/Th2) immune responses, which extended the survival time (13.0±1.15days for pVAX-ROP54 vs 6.7±0.48days for pVAX I, 6.8±0.42days for PBS and 6.5±0.53 for blank control) and significantly reduced cyst burden (35.9% for pVAX-ROP54, 1% for pVAX I and 2% for PBS, compared with blank control) of immunized mice. These results indicate that the recombinant ROP54 plasmid can provide partial protection and might be a potential vaccine candidate against acute and chronic toxoplasmosis. Copyright © 2017 Elsevier B.V. All rights reserved.

Gut Immune Maturation Depends on Colonization with a Host-Specific Microbiota

PubMed Central

Chung, Hachung; Pamp, Sünje J.; Hill, Jonathan A.; Surana, Neeraj K.; Edelman, Sanna M.; Troy, Erin B.; Reading, Nicola C.; Villablanca, Eduardo J.; Wang, Sen; Mora, Jorge R.; Umesaki, Yoshinori; Mathis, Diane; Benoist, Christophe; Relman, David A.; Kasper, Dennis L.

2012-01-01

SUMMARY Gut microbial induction of host immune maturation exemplifies host-microbe mutualism. We colonized germ-free (GF) mice with mouse microbiota (MMb) or human microbiota (HMb) to determine whether small intestinal immune maturation depends on a coevolved host-specific microbiota. Gut bacterial numbers and phylum abundance were similar in MMb and HMb mice, but bacterial species differed, especially the Firmicutes. HMb mouse intestines had low levels of CD4+ and CD8+ T cells, few proliferating T cells, few dendritic cells, and low antimicrobial peptide expression–all characteristics of GF mice. Rat microbiota also failed to fully expand intestinal T cell numbers in mice. Colonizing GF or HMb mice with mouse-segmented filamentous bacteria (SFB) partially restored T cell numbers, suggesting that SFB and other MMb organisms are required for full immune maturation in mice. Importantly, MMb conferred better protection against Salmonella infection than HMb. A host-specific microbiota appears to be critical for a healthy immune system. PMID:22726443

Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice.

PubMed

Shattuck, Wendy M C; Dyer, Megan C; Desrosiers, Joe; Fast, Loren D; Terry, Frances E; Martin, William D; Moise, Leonard; De Groot, Anne S; Mather, Thomas N

2014-01-01

Ticks are notorious vectors of disease for humans, and many species of ticks transmit multiple pathogens, sometimes in the same tick bite. Accordingly, a broad-spectrum vaccine that targets vector ticks and pathogen transmission at the tick/host interface, rather than multiple vaccines against every possible tickborne pathogen, could become an important tool for resolving an emerging public health crisis. The concept for such a tick protective vaccine comes from observations of an acquired tick resistance (ATR) that can develop in non-natural hosts of ticks following sensitization to tick salivary components. Mice are commonly used as models to study immune responses to human pathogens but normal mice are natural hosts for many species of ticks and fail to develop ATR. We evaluated HLA DR3 transgenic (tg) "humanized" mice as a potential model of ATR and assessed the possibility of using this animal model for tick protective vaccine discovery studies. Serial tick infestations with pathogen-free Ixodes scapularis ticks were used to tick-bite sensitize HLA DR3 tg mice. Sensitization resulted in a cytokine skew favoring a Th2 bias as well as partial (57%) protection to infection with Lyme disease spirochetes (Borrelia burgdorferi) following infected tick challenge when compared to tick naïve counterparts. I. scapularis salivary gland homogenate (SGH) and a group of immunoinformatic-predicted T cell epitopes identified from the I. scapularis salivary transcriptome were used separately to vaccinate HLA DR3 tg mice, and these mice also were assessed for both pathogen protection and epitope recognition. Reduced pathogen transmission along with a Th2 skew resulted from SGH vaccination, while no significant protection and a possible T regulatory bias was seen in epitope-vaccinated mice. This study provides the first proof-of-concept for using HLA DR tg "humanized" mice for studying the potential tick protective effects of immunoinformatic- or otherwise-derived tick salivary components as tickborne disease vaccines.

Towards vaccine against toxoplasmosis: evaluation of the immunogenic and protective activity of recombinant ROP5 and ROP18 Toxoplasma gondii proteins.

PubMed

Grzybowski, Marcin M; Dziadek, Bożena; Gatkowska, Justyna M; Dzitko, Katarzyna; Długońska, Henryka

2015-12-01

Toxoplasmosis is one of the most common parasitic infections worldwide. An effective vaccine against human and animal toxoplasmosis is still needed to control this parasitosis. The polymorphic rhoptry proteins, ROP5 and ROP18, secreted by Toxoplasma gondii during the invasion of the host cell have been recently considered as promising vaccine antigens, as they appear to be the major determinants of T. gondii virulence in mice. The goal of this study was to evaluate their immunogenic and immunoprotective activity after their administration (separately or both recombinant proteins together) with the poly I:C as an adjuvant. Immunization of BALB/c and C3H/HeOuJ mice generated both cellular and humoral specific immune responses with some predominance of IgG1 antibodies. The spleen cells derived from vaccinated animals reacted to the parasite's native antigens. Furthermore, the immunization led to a partial protection against acute and chronic toxoplasmosis. These findings confirm the previous assumptions about ROP5 and ROP18 antigens as valuable components of a subunit vaccine against toxoplasmosis.

Immunization with antigenic extracts of Leishmania associated with Montanide ISA 763 adjuvant induces partial protection in BALB/c mice against Leishmania (Leishmania) amazonensis infection.

PubMed

Cargnelutti, Diego Esteban; Salomón, María Cristina; Celedon, Verónica; García Bustos, María Fernanda; Morea, Gastón; Cuello-Carrión, Fernando Darío; Scodeller, Eduardo Alberto

2016-02-01

A proper adjuvant has a relevant role in vaccine formulations to generate an effective immune response. In this study, total Leishmania antigen (TLA) formulated with Montanide ISA 763 or R848 as adjuvants were evaluated as a first generation Leishmania vaccine in a murine model. Immunization protocols were tested in BALB/c mice with a subcutaneous prime/boost regimen with an interval of 3 weeks. Mice immunized with unadjuvanted TLA and phosphate-buffered saline (PBS) served as control groups. On Day 21 and Day 36 of the protocol, we evaluated the humoral immune response induced by each formulation. Fifteen days after the boost, the immunized mice were challenged with 1 × 10(5) promastigotes of Leishmania (Leishmania) amazonensis in the right footpad (RFP). The progress of the infection was followed for 10 weeks; at the end of this period, histopathological studies were performed in the RFP. Vaccines formulated with Montanide ISA 763 generated an increase in the production of immunoglobulin G (IgG; p < 0.05) compared with the control group. There were no statistically significant differences in IgG1 production between the study groups. However, immunization with TLA-Montanide ISA 763 resulted in an increase in IgG2a compared to the unadjuvanted control (p < 0.001). Also noteworthy was the fact that a significant reduction in swelling and histopathological damage of the RFP was recorded with the Montanide ISA 763 formulation. We conclude that the immunization of BALB/c mice with a vaccine formulated with TLA and Montanide ISA 763 generated a protective immune response against L. (L.) amazonensis, characterized by an intense production of IgG2a. Copyright © 2014. Published by Elsevier B.V.

DNA vaccine encoding Haemonchus contortus actin induces partial protection in goats.

PubMed

Yan, Ruofeng; Wang, Jingjing; Xu, Lixin; Song, Xiaokai; Li, Xiangrui

2014-10-01

Actin is a globular multi-functional protein that forms microfilaments, and participates in many important cellular processes. Previous study found that Haemonchus contortus actin could be recognized by the serum of goats infected with the homology parasite. This indicated that H. contortus actin could be a potential candidate for vaccine. In this study, DNA vaccine encoding H. contortus actin was tested for protection against experimental H. contortus infections in goats. Fifteen goats were allocated into three trial groups. The animals of Actin group were vaccinated with the DNA vaccine on day 0 and 14, and challenged with 5000 infective H. contortus third stage larval (L3) on day 28. An unvaccinated positive control group was challenged with L3 at the same time. An unvaccinated negative control group was not challenged with L3. The results showed that DNA vaccine were transcribed at local injection sites and expressed in vivo post immunizations respectively. For goats in Actin vaccinated group, higher levels of serum IgG, serum IgA and mucosal IgA were produced, the percentages of CD4(+) T lymphocytes, CD8(+) T lymphocytes and B lymphocytes and the concentrations of TGF-β were increased significantly (P<0.05). Following L3 challenge, the mean eggs per gram feces (EPG) and worm burdens of Actin group were reduced by 34.4% and 33.1%, respectively. This study suggest that recombinant H. contortus Actin DNA vaccine induced partial immune response and has protective potential against goat haemonchosis.

A Novel Vaccine Delivery Model of the Apicomplexan Eimeria tenella Expressing Eimeria maxima Antigen Protects Chickens against Infection of the Two Parasites

PubMed Central

Tang, Xinming; Liu, Xianyong; Yin, Guangwen; Suo, Jingxia; Tao, Geru; Zhang, Sixin; Suo, Xun

2018-01-01

Vaccine delivery is critical in antigen discovery and vaccine efficacy and safety. The diversity of infectious diseases in humans and livestock has required the development of varied delivery vehicles to target different pathogens. In livestock animals, previous strategies for the development of coccidiosis vaccines have encountered several hurdles, limiting the development of multiple species vaccine formulations. Here, we describe a novel vaccine delivery system using transgenic Eimeria tenella expressing immunodominant antigens of Eimeria maxima. In this delivery system, the immune mapped protein 1 of E. maxima (EmIMP1) was delivered by the closely related species of E. tenella to the host immune system during the whole endogenous life cycle. The overexpression of the exogenous antigen did not interfere with the reproduction and immunogenicity of transgenic Eimeria. After immunization with the transgenic parasite, we detected EmIMP1’s and E. maxima oocyst antigens’ specific humoral and cellular immune responses. In particular, we observed partial protection of chickens immunized with transgenic E. tenella against subsequent E. maxima infections. Our results demonstrate that the transgenic Eimeria parasite is an ideal coccidia antigen delivery vehicle and represents a new type of coccidiosis vaccines. In addition, this model could potentially be used in the development of malaria live sporozoite vaccines, in which antigens from different strains can be expressed in the vaccine strain. PMID:29375584

A Novel Vaccine Delivery Model of the Apicomplexan Eimeria tenella Expressing Eimeria maxima Antigen Protects Chickens against Infection of the Two Parasites.

PubMed

Tang, Xinming; Liu, Xianyong; Yin, Guangwen; Suo, Jingxia; Tao, Geru; Zhang, Sixin; Suo, Xun

2017-01-01

Vaccine delivery is critical in antigen discovery and vaccine efficacy and safety. The diversity of infectious diseases in humans and livestock has required the development of varied delivery vehicles to target different pathogens. In livestock animals, previous strategies for the development of coccidiosis vaccines have encountered several hurdles, limiting the development of multiple species vaccine formulations. Here, we describe a novel vaccine delivery system using transgenic Eimeria tenella expressing immunodominant antigens of Eimeria maxima . In this delivery system, the immune mapped protein 1 of E. maxima (EmIMP1) was delivered by the closely related species of E. tenella to the host immune system during the whole endogenous life cycle. The overexpression of the exogenous antigen did not interfere with the reproduction and immunogenicity of transgenic Eimeria . After immunization with the transgenic parasite, we detected EmIMP1's and E. maxima oocyst antigens' specific humoral and cellular immune responses. In particular, we observed partial protection of chickens immunized with transgenic E. tenella against subsequent E. maxima infections. Our results demonstrate that the transgenic Eimeria parasite is an ideal coccidia antigen delivery vehicle and represents a new type of coccidiosis vaccines. In addition, this model could potentially be used in the development of malaria live sporozoite vaccines, in which antigens from different strains can be expressed in the vaccine strain.

Evaluation of immune response and protective effect of four vaccines against the tick-borne encephalitis virus.

PubMed

Morozova, O V; Bakhvalova, V N; Potapova, O F; Grishechkin, A E; Isaeva, E I; Aldarov, K V; Klinov, D V; Vorovich, M F

2014-05-23

Among three main subtypes of the tick-borne encephalitis virus (TBEV), the Siberian subtype is currently dominant in a majority of the endemic regions of Russia. However, inactivated vaccines are based on TBEV strains of the heterologous Far Eastern or the European subtypes isolated 40-77 years ago. To analyze the efficacy of the available vaccines against currently prevailing TBEV isolates of the Siberian subtype, mice were immunized subcutaneously three times (one group per each vaccine). The expression of seven cytokine genes was determined using RT-PCR. Sera were studied using homologous and heterologous ELISA, hemagglutination inhibition (HI) and neutralization tests with TBEV strains of the Far Eastern, Siberian and European subtypes. Cross-protective efficacy of the vaccines was evaluated with the TBEV strain 2689 of Siberian subtype isolated from an ixodid tick from the Novosibirsk, South-Western Siberia, Russia in 2010. The cytokine gene expression profile indicates a predominantly Th2 response due to exogenous antigen presentation. Titers for homologous combinations of vaccine strain and strain in ELISA, HI and neutralization tests exceeded those for heterologous antigen-antibody pairs. Despite antibody detection by means of ELISA, HI and neutralization tests, the mouse protection afforded by the vaccines differed significantly. Complete protection of mice challenged with 100 LD50 virus of the Siberian subtype was induced by the vaccine "Encevir" ("Microgen", Tomsk, Russia). The minimal immunization doze (MID50) of "Encevir" protecting 50% of the mice was less than 0.0016 ml. Partial protective effect of vaccines produced in Moscow, Russia and Austria revealed MID50 within recommended intervals (0.001-0.017 ml). However, the MID50 for the vaccine "Encepur" (Novartis, Germany) 0.04 ml exceeded acceptable limits with total loss of mice immunized with vaccine diluted 32, 100 and 320 fold. These results suggest regular evaluation of TBEV vaccines in regions where heterologous virus subtypes prevail. Copyright © 2014 Elsevier Ltd. All rights reserved.

[Anti-infective defence strategies and methods of escape from entomologic pathogens under immunologic control of insects].

PubMed

Jarosz, J

1996-01-01

Insect immunity comprises a complex of several distinct systems, both haemocytic and humoral in nature, that cooperate together in a more or less coordinated way to provide protection of the body cavity from invading microorganisms. Insects can respond to infections by a selective synthesis of haemolymph immune proteins that are responsible for antibacterial immunity. Antibacterial activity of insect blood is attributable to innate compounds such as lysozome, and to induced polypeptides or small basic proteins absent in non-immunized insects. The cecropins and attacins in Lepidoptera, and diptericins in Diptera are the inducible antibacterial immune proteins well defined biochemically. Bacterial pathogens and some parasites of insects, preferably entomogenous rhabditid nematodes, have developed the mechanism by which they may counteract insect immunity. This phenomenon is realized either by escaping immune reactions or by degrading antimicrobial factors of haemolymph in an active process. Passive resistance of parasites to insect immunity is a result of a strong evolutionary pressure on parasites to develop mechanisms to escape insect immune reactions or to minimize their effectiveness through changes in the parasite itself. Active resistance to the insect non-self response system involves a partial or total destruction of immune proteins by extracellular proteinases released during parasitism.

Anti-CD25 monoclonal antibody enhances the protective efficacy of Schistosoma japonicum GST vaccine via inhibition of CD4+CD25+Foxp3+ regulatory T cells.

PubMed

Tang, Chun-Lian; Yang, Jin; Cheng, Liang-Yu; Cheng, Lan-Fang; Liu, Zhi-Ming

2017-10-01

The effect of anti-CD25 monoclonal antibody (anti-CD25 mAb) on the protection efficacy of Schistosoma japonicum 26 kDa GST (glutathione-S-transferase) vaccine was evaluated. Mice were immunized with GST before infection with S. japonicum cercariae and then injected with anti-CD25 mAb. The worm reduction rate was promoted from 24.18% in mice with GST immunization to 47.09% in mice with GST plus anti-CD25 mAb. Compared with the control group, the percentages of splenic CD4 + CD25 + Foxp3 + regulatory T cells (Tregs) were significantly lower after administration of anti-CD25 mAb; meanwhile, elevated levels of IFN-γ and IL-2 were secreted by splenocytes. These results indicate that the poor protective efficacy of the GST vaccine against S. japonicum results from the presence of CD4 + CD25 + Foxp3 + Tregs, while anti-CD25 mAb can partially block CD4 + CD25 + Foxp3 + Tregs and thus enhance the protective efficacy of the GST vaccine.

Immunogenicity and efficacy following sequential parenterally-administered doses of Salmonella Enteritidis COPS:FliC glycoconjugates in infant and adult mice.

PubMed

Baliban, Scott M; Curtis, Brittany; Toema, Deanna; Tennant, Sharon M; Levine, Myron M; Pasetti, Marcela F; Simon, Raphael

2018-05-23

In sub-Saharan Africa, invasive nontyphoidal Salmonella (iNTS) infections with serovars S. Enteritidis, S. Typhimurium and I 4,[5],12:i:- are widespread in children < 5 years old. Development of an efficacious vaccine would provide an important public health tool to prevent iNTS disease in this population. Glycoconjugates of S. Enteritidis core and O-polysaccharide (COPS) coupled to the homologous serovar phase 1 flagellin protein (FliC) were previously shown to be immunogenic and protected adult mice against death following challenge with a virulent Malian S. Enteritidis blood isolate. This study extends these observations to immunization of mice in early life and also assesses protection with partial and full regimens. Anti-COPS and anti-FliC serum IgG titers were assessed in infant and adult mice after immunization with 1, 2 or 3 doses of S. Enteritidis COPS:FliC alone or co-formulated with aluminum hydroxide or monophosphoryl lipid A (MPL) adjuvants. S. Enteritidis COPS:FliC was immunogenic in both age groups, although the immune responses were quantitatively lower in infants. Kinetics of antibody production were similar for the native and adjuvanted formulations after three doses; conjugates formulated with MPL elicited significantly increased anti-COPS IgG titers in adult but not infant mice. Nevertheless, robust protection against S. Enteritidis challenge was seen for all three formulations when three doses were given either during infancy or as adults. We further found that significant protection could be achieved with two COPS:FliC doses, despite elicitation of modest serum anti-COPS IgG antibody titers. These findings guide potential immunization strategies that may be translated to develop a human pediatric iNTS vaccine for sub-Saharan Africa.

Bolstering Components of the Immune Response Compromised by Prior Exposure to Adenovirus: Guided Formulation Development for a Nasal Ebola Vaccine

PubMed Central

2014-01-01

The severity and longevity of the current Ebola outbreak highlight the need for a fast-acting yet long-lasting vaccine for at-risk populations (medical personnel and rural villagers) where repeated prime-boost regimens are not feasible. While recombinant adenovirus (rAd)-based vaccines have conferred full protection against multiple strains of Ebola after a single immunization, their efficacy is impaired by pre-existing immunity (PEI) to adenovirus. To address this important issue, a panel of formulations was evaluated by an in vitro assay for their ability to protect rAd from neutralization. An amphiphilic polymer (F16, FW ∼39,000) significantly improved transgene expression in the presence of anti-Ad neutralizing antibodies (NAB) at concentrations of 5 times the 50% neutralizing dose (ND50). In vivo performance of rAd in F16 was compared with unformulated virus, virus modified with poly(ethylene) glycol (PEG), and virus incorporated into poly(lactic-co-glycolic) acid (PLGA) polymeric beads. Histochemical analysis of lung tissue revealed that F16 promoted strong levels of transgene expression in naive mice and those that were exposed to adenovirus in the nasal cavity 28 days prior to immunization. Multiparameter flow cytometry revealed that F16 induced significantly more polyfunctional antigen-specific CD8+ T cells simultaneously producing IFN-γ, IL-2, and TNF-α than other test formulations. These effects were not compromised by PEI. Data from formulations that provided partial protection from challenge consistently identified specific immunological requirements necessary for protection. This approach may be useful for development of formulations for other vaccine platforms that also employ ubiquitous pathogens as carriers like the influenza virus. PMID:25549696

CP7_E2alf oral vaccination confers partial protection against early classical swine fever virus challenge and interferes with pathogeny-related cytokine responses

PubMed Central

2013-01-01

The conventional C-strain vaccine induces early protection against classical swine fever (CSF), but infected animals cannot be distinguished from vaccinated animals. The CP7_E2alf marker vaccine, a pestivirus chimera, could be a suitable substitute for C-strain vaccine to control CSF outbreaks. In this study, single oral applications of CP7_E2alf and C-strain vaccines were compared for their efficacy to induce protection against a CSF virus (CSFV) challenge with the moderately virulent Bas-Rhin isolate, in pigs as early as two days post-immunization. This work emphasizes the powerful potential of CP7_E2alf vaccine administered orally by a rapid onset of partial protection similar to that induced by the C-strain vaccine. Furthermore, our results revealed that both vaccinations attenuated the effects induced by CSFV on production of the pig major acute phase protein (PigMAP), IFN-α, IL-12, IL-10, and TGF-β1 cytokines. By this interference, several cytokines that may play a role in the pathogeny induced by moderately virulent CSFV strains were revealed. New hypotheses concerning the role of each of these cytokines in CSFV pathogeny are discussed. Our results also show that oral vaccination with either vaccine (CP7_E2alf or C-strain) enhanced CSFV–specific IgG2 production, compared to infection alone. Interestingly, despite the similar antibody profiles displayed by both vaccines post-challenge, the production of CSFV-specific IgG1 and neutralizing antibodies without challenge was lower with CP7_E2alf vaccination than with C-strain vaccination, suggesting a slight difference in the balance of adaptive immune responses between these vaccines. PMID:23398967

Hypothesis: the regulation of the partial pressure of oxygen by the serotonergic nervous system in hypoxia.

PubMed

Devereux, Diana; Ikomi-Kumm, Julie

2013-03-01

The regulation of the partial pressure of oxygen by the serotonergic nervous system in hypoxia is a hypothesis, which proposes an inherent operative system in homo sapiens that allows central nervous system and endocrine-mediated vascular system adaption to variables in partial pressure of oxygen, pH and body composition, while maintaining sufficient oxygen saturation for the immune system and ensuring protection of major organs in hypoxic and suboptimal conditions. While acknowledging the importance of the Henderson-Hasselbalch equation in the regulation of acid base balance, the hypothesis seeks to define the specific neuroendocrine/vascular mechanisms at work in regulating acid base balance in hypoxia and infection. The SIA (serotonin-immune-adrenergic) system is proposed as a working model, which allows central nervous system and endocrine-mediated macro- and micro vascular 'fine tuning'. The neurotransmitter serotonin serves as a 'hypoxic sensor' in concert with other operators to orchestrate homeostatic balance in normal and pathological states. The SIA system finely regulates oxygen, fuel and metabolic buffering systems at local sites to ensure optimum conditions for the immune response. The SIA system is fragile and its operation may be affected by infection, stress, diet, environmental toxins and lack of exercise. The hypothesis provides new insight in the area of neuro-gastroenterology, and emphasizes the importance of diet and nutrition as a complement in the treatment of infection, as well as the normalization of intestinal flora following antibiotic therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.

Vaccination with Recombinant Microneme Proteins Confers Protection against Experimental Toxoplasmosis in Mice.

PubMed

Pinzan, Camila Figueiredo; Sardinha-Silva, Aline; Almeida, Fausto; Lai, Livia; Lopes, Carla Duque; Lourenço, Elaine Vicente; Panunto-Castelo, Ademilson; Matthews, Stephen; Roque-Barreira, Maria Cristina

2015-01-01

Toxoplasmosis, a zoonotic disease caused by Toxoplasma gondii, is an important public health problem and veterinary concern. Although there is no vaccine for human toxoplasmosis, many attempts have been made to develop one. Promising vaccine candidates utilize proteins, or their genes, from microneme organelle of T. gondii that are involved in the initial stages of host cell invasion by the parasite. In the present study, we used different recombinant microneme proteins (TgMIC1, TgMIC4, or TgMIC6) or combinations of these proteins (TgMIC1-4 and TgMIC1-4-6) to evaluate the immune response and protection against experimental toxoplasmosis in C57BL/6 mice. Vaccination with recombinant TgMIC1, TgMIC4, or TgMIC6 alone conferred partial protection, as demonstrated by reduced brain cyst burden and mortality rates after challenge. Immunization with TgMIC1-4 or TgMIC1-4-6 vaccines provided the most effective protection, since 70% and 80% of mice, respectively, survived to the acute phase of infection. In addition, these vaccinated mice, in comparison to non-vaccinated ones, showed reduced parasite burden by 59% and 68%, respectively. The protective effect was related to the cellular and humoral immune responses induced by vaccination and included the release of Th1 cytokines IFN-γ and IL-12, antigen-stimulated spleen cell proliferation, and production of antigen-specific serum antibodies. Our results demonstrate that microneme proteins are potential vaccines against T. gondii, since their inoculation prevents or decreases the deleterious effects of the infection.

Protective effect of a polyvalent influenza DNA vaccine in pigs.

PubMed

Karlsson, Ingrid; Borggren, Marie; Rosenstierne, Maiken Worsøe; Trebbien, Ramona; Williams, James A; Vidal, Enric; Vergara-Alert, Júlia; Foz, David Solanes; Darji, Ayub; Sisteré-Oró, Marta; Segalés, Joaquim; Nielsen, Jens; Fomsgaard, Anders

2018-01-01

Influenza A virus in swine herds represents a major problem for the swine industry and poses a constant threat for the emergence of novel pandemic viruses and the development of more effective influenza vaccines for pigs is desired. By optimizing the vector backbone and using a needle-free delivery method, we have recently demonstrated a polyvalent influenza DNA vaccine that induces a broad immune response, including both humoral and cellular immunity. To investigate the protection of our polyvalent influenza DNA vaccine approach in a pig challenge study. By intradermal needle-free delivery to the skin, we immunized pigs with two different doses (500μg and 800μg) of an influenza DNA vaccine based on six genes of pandemic origin, including internally expressed matrix and nucleoprotein and externally expressed hemagglutinin and neuraminidase as previously demonstrated. Two weeks following immunization, the pigs were challenged with the 2009 pandemic H1N1 virus. When challenged with 2009 pandemic H1N1, 0/5 vaccinated pigs (800μg DNA) became infected whereas 5/5 unvaccinated control pigs were infected. The pigs vaccinated with the low dose (500μg DNA) were only partially protected. The DNA vaccine elicited binding-, hemagglutination inhibitory (HI) - as well as cross-reactive neutralizing antibody activity and neuraminidase inhibiting antibodies in the immunized pigs, in a dose-dependent manner. The present data, together with the previously demonstrated immunogenicity of our influenza DNA vaccine, indicate that naked DNA vaccine technology provides a strong approach for the development of improved pig vaccines, applying realistic low doses of DNA and a convenient delivery method for mass vaccination. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Immune protection of microneme 7 (EmMIC7) against Eimeria maxima challenge in chickens.

PubMed

Huang, Jingwei; Zhang, Zhenchao; Li, Menghui; Song, Xiaokai; Yan, Ruofeng; Xu, Lixin; Li, Xiangrui

2015-10-01

In the present study, the immune protective effects of recombinant microneme protein 7 of Eimeria maxima (rEmMIC7) and a DNA vaccine encoding this antigen (pVAX1-EmMIC7) on experimental challenge were evaluated. Two-week-old chickens were randomly divided into five groups. Experimental groups of chickens were immunized with 100 μg DNA vaccine pVAX1-MIC7 or 200 μg rEmMIC7, while control groups of chickens were injected with pVAX1 plasmid or sterile phosphate buffered saline (PBS). The results showed that the anti-EmMIC7 antibody titres in chickens of both rEmMIC7 and pVAX1-MIC7 groups were significantly higher as compared to PBS and pVAX1 control (P < .05). The splenocytes from both vaccinated groups of chickens displayed significantly greater proliferation response compared with the controls (P < .05). Serum from chickens immunized with pVAX1-MIC7 and rEmMIC7 displayed significantly high levels of interleukin-2, interferon-γ, IL-10, IL-17, tumour growth factor-β and IL-4 (P < .05) compared to those of negative controls. The challenge experiment results showed that both the recombinant antigen and the DNA vaccine could obviously alleviate jejunum lesions, body weight loss and enhance oocyst decrease ratio. The anti-coccidial index (ACI) of the pVAX1-MIC7 group was 167.84, higher than that of the recombinant MIC7 protein group, 167.10. Our data suggested that immunization with EmMIC7 was effective in imparting partial protection against E. maxima challenge in chickens and it could be an effective antigen candidate for the development of new vaccines against E. maxima.

Concerted Activity of IgG1 Antibodies and IL-4/IL-25-Dependent Effector Cells Trap Helminth Larvae in the Tissues following Vaccination with Defined Secreted Antigens, Providing Sterile Immunity to Challenge Infection

PubMed Central

Hewitson, James P.; Filbey, Kara J.; Esser-von Bieren, Julia; Camberis, Mali; Schwartz, Christian; Murray, Janice; Reynolds, Lisa A.; Blair, Natalie; Robertson, Elaine; Harcus, Yvonne; Boon, Louis; Huang, Stanley Ching-Cheng; Yang, Lihua; Tu, Yizheng; Miller, Mark J.; Voehringer, David; Le Gros, Graham; Harris, Nicola; Maizels, Rick M.

2015-01-01

Over 25% of the world's population are infected with helminth parasites, the majority of which colonise the gastrointestinal tract. However, no vaccine is yet available for human use, and mechanisms of protective immunity remain unclear. In the mouse model of Heligmosomoides polygyrus infection, vaccination with excretory-secretory (HES) antigens from adult parasites elicits sterilising immunity. Notably, three purified HES antigens (VAL-1, -2 and -3) are sufficient for effective vaccination. Protection is fully dependent upon specific IgG1 antibodies, but passive transfer confers only partial immunity to infection, indicating that cellular components are also required. Moreover, immune mice show greater cellular infiltration associated with trapping of larvae in the gut wall prior to their maturation. Intra-vital imaging of infected intestinal tissue revealed a four-fold increase in extravasation by LysM+GFP+ myeloid cells in vaccinated mice, and the massing of these cells around immature larvae. Mice deficient in FcRγ chain or C3 complement component remain fully immune, suggesting that in the presence of antibodies that directly neutralise parasite molecules, the myeloid compartment may attack larvae more quickly and effectively. Immunity to challenge infection was compromised in IL-4Rα- and IL-25-deficient mice, despite levels of specific antibody comparable to immune wild-type controls, while deficiencies in basophils, eosinophils or mast cells or CCR2-dependent inflammatory monocytes did not diminish immunity. Finally, we identify a suite of previously uncharacterised heat-labile vaccine antigens with homologs in human and veterinary parasites that together promote full immunity. Taken together, these data indicate that vaccine-induced immunity to intestinal helminths involves IgG1 antibodies directed against secreted proteins acting in concert with IL-25-dependent Type 2 myeloid effector populations. PMID:25816012

A Plasmodium vivax Plasmid DNA- and Adenovirus-Vectored Malaria Vaccine Encoding Blood-Stage Antigens AMA1 and MSP142 in a Prime/Boost Heterologous Immunization Regimen Partially Protects Aotus Monkeys against Blood-Stage Challenge.

PubMed

Obaldia, Nicanor; Stockelman, Michael G; Otero, William; Cockrill, Jennifer A; Ganeshan, Harini; Abot, Esteban N; Zhang, Jianfeng; Limbach, Keith; Charoenvit, Yupin; Doolan, Denise L; Tang, De-Chu C; Richie, Thomas L

2017-04-01

Malaria is caused by parasites of the genus Plasmodium , which are transmitted to humans by the bites of Anopheles mosquitoes. After the elimination of Plasmodium falciparum , it is predicted that Plasmodium vivax will remain an important cause of morbidity and mortality outside Africa, stressing the importance of developing a vaccine against P. vivax malaria. In this study, we assessed the immunogenicity and protective efficacy of two P. vivax antigens, apical membrane antigen 1 (AMA1) and the 42-kDa C-terminal fragment of merozoite surface protein 1 (MSP1 42 ) in a plasmid recombinant DNA prime/adenoviral (Ad) vector boost regimen in Aotus monkeys. Groups of 4 to 5 monkeys were immunized with plasmid DNA alone, Ad alone, prime/boost regimens with each antigen, prime/boost regimens with both antigens, and empty vector controls and then subjected to blood-stage challenge. The heterologous immunization regimen with the antigen pair was more protective than either antigen alone or both antigens delivered with a single vaccine platform, on the basis of their ability to induce the longest prepatent period and the longest time to the peak level of parasitemia, the lowest peak and mean levels of parasitemia, the smallest area under the parasitemia curve, and the highest self-cure rate. Overall, prechallenge MSP1 42 antibody titers strongly correlated with a decreased parasite burden. Nevertheless, a significant proportion of immunized animals developed anemia. In conclusion, the P. vivax plasmid DNA/Ad serotype 5 vaccine encoding blood-stage parasite antigens AMA1 and MSP1 42 in a heterologous prime/boost immunization regimen provided significant protection against blood-stage challenge in Aotus monkeys, indicating the suitability of these antigens and this regimen for further development. Copyright © 2017 American Society for Microbiology.

Recombinant Avian Paramyxovirus Serotypes 2, 6, and 10 as Vaccine Vectors for Highly Pathogenic Avian Influenza in Chickens with Antibodies Against Newcastle Disease Virus.

PubMed

Tsunekuni, Ryota; Hikono, Hirokazu; Tanikawa, Taichiro; Kurata, Riho; Nakaya, Takaaki; Saito, Takehiko

2017-09-01

Recombinant Newcastle disease virus (rNDV) expressing the hemagglutinin of highly pathogenic avian influenza virus (HPAIV HA) induces protective immunity against HPAIV in chickens. However, the efficacy of rNDV vectors is hampered when chickens are pre-immune to NDV, and most commercial chickens are routinely vaccinated against NDV. We recently showed that avian paramyxovirus serotypes 2, 6, and 10 (APMV-2, APMV-6, and APMV-10), which belong to the same genus as NDV, have low cross-reactivity with anti-NDV antisera. Here, we used reverse genetics to generate recombinant APMV-2, APMV-6, and APMV-10 (rAPMV-2/HA, rAPMV-6/HA, and rAPMV-10/HA) that expressed an HA protein derived of subtype H5N1 HPAIV, A/chicken/Yamaguchi/7/2004. Chickens pre-immunized against NDV (age, 7 wk) were vaccinated with rAPMV/HAs; 14 days after vaccination, chickens were challenged with a lethal dose of HPAIV. Immunization of chickens pre-immunized against NDV with rAPMV-2/HA, rAPMV-6/HA, or rAPMV-10/HA protected 50%, 50%, and 25%, respectively, in groups of chickens given an rAPMV/HA with 106 median embryo infectious dose (EID 50 ) or 50%, 50%, and 90%, respectively, in those with 10 7 EID 50 ; in contrast, rNDV/HA protected none of the chicken vaccinated with 10 6 EID 50 and induced only partial protection even with 10 7 EID 50. Therefore, the presence of anti-NDV antibodies did not hamper the efficacy of rAPMV-2/HA, rAPMV-6/HA, or rAPMV-10/HA. These results suggest that rAPMV-2, rAPMV-6, and rAPMV-10 are potential vaccine vectors, especially for commercial chickens, which are routinely vaccinated against NDV.

Glycogen synthase kinase 3β promotes liver innate immune activation by restraining AMP-activated protein kinase activation.

PubMed

Zhou, Haoming; Wang, Han; Ni, Ming; Yue, Shi; Xia, Yongxiang; Busuttil, Ronald W; Kupiec-Weglinski, Jerzy W; Lu, Ling; Wang, Xuehao; Zhai, Yuan

2018-07-01

Glycogen synthase kinase 3β (Gsk3β [Gsk3b]) is a ubiquitously expressed kinase with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and ischaemia and reperfusion injuries (IRIs) have been well documented, the underlying mechanisms remain ambiguous, in part because of the lack of cell-specific tools in vivo. We created a myeloid-specific Gsk3b knockout (KO) strain to study the function of Gsk3β in macrophages in a murine liver partial warm ischaemia model. Compared with controls, myeloid Gsk3b KO mice were protected from IRI, with diminished proinflammatory but enhanced anti-inflammatory immune responses in livers. In bone marrow-derived macrophages, Gsk3β deficiency resulted in an early reduction of Tnf gene transcription but sustained increase of Il10 gene transcription on Toll-like receptor 4 stimulation in vitro. These effects were associated with enhanced AMP-activated protein kinase (AMPK) activation, which led to an accelerated and higher level of induction of the novel innate immune negative regulator small heterodimer partner (SHP [Nr0b2]). The regulatory function of Gsk3β on AMPK activation and SHP induction was confirmed in wild-type bone marrow-derived macrophages with a Gsk3 inhibitor. Furthermore, we found that this immune regulatory mechanism was independent of Gsk3β Ser9 phosphorylation and the phosphoinositide 3-kinase-Akt signalling pathway. In vivo, myeloid Gsk3β deficiency facilitated SHP upregulation by ischaemia-reperfusion in liver macrophages. Treatment of Gsk3b KO mice with either AMPK inhibitor or SHP small interfering RNA before the onset of liver ischaemia restored liver proinflammatory immune activation and IRI in these otherwise protected hosts. Additionally, pharmacological activation of AMPK protected wild-type mice from liver IRI, with reduced proinflammatory immune activation. Inhibition of the AMPK-SHP pathway by liver ischaemia was demonstrated in tumour resection patients. Gsk3β promotes innate proinflammatory immune activation by restraining AMPK activation. Glycogen synthase kinase 3β promotes macrophage inflammatory activation by inhibiting the immune regulatory signalling of AMP-activated protein kinase and the induction of small heterodimer partner. Therefore, therapeutic targeting of glycogen synthase kinase 3β enhances innate immune regulation and protects liver from ischaemia and reperfusion injury. Copyright © 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Attenuated Phenotype and Immunogenic Characteristics of a Mutated Herpes Simplex Virus 1 Strain in the Rhesus Macaque.

PubMed

Fan, Shengtao; Xu, Xingli; Liao, Yun; Wang, Yongrong; Wang, Jianbin; Feng, Min; Wang, Lichun; Zhang, Ying; He, Zhanlong; Yang, Fengmei; Fraser, Nigel W; Li, Qihan

2018-05-02

Herpes simplex virus type 1(HSV-1) presents a conundrum to public health worldwide because of its specific pathogenicity and clinical features. Some experimental vaccines, such as the recombinant viral glycoproteins, exhibit the viral immunogenicity of a host-specific immune response, but none of these has achieved a valid epidemiological protective efficacy in the human population. In the present study, we constructed an attenuated HSV-1 strain M3 through the partial deletion of UL7, UL41 , and the latency-associated transcript ( LAT ) using the CRISPR/Cas9 system. The mutant strain exhibited lowered infectivity and virulence in macaques. Neutralization testing and ELISpot detection of the specific T-cell responses confirmed the specific immunity induced by M3 immunization and this immunity defended against the challenges of the wild-type strain and restricted the entry of the wild-type strain into the trigeminal ganglion. These results in rhesus macaques demonstrated the potential of the attenuated vaccine for the prevention of HSV-1 in humans.

Understanding the impact of Hib conjugate vaccine on transmission, immunity and disease in the United Kingdom

PubMed Central

McVERNON, J.; RAMSAY, M. E.; McLEAN, A. R.

2008-01-01

SUMMARY A rise in invasive Haemophilus influenzae type b (Hib) infections occurred 8 years after vaccine introduction in the United Kingdom. Aspects of Hib vaccine delivery unique to the United Kingdom have been implicated. The authors developed a fully age-structured deterministic susceptible–infected–resistant–susceptible mathematical model, expressed as a set of partial differential equations, to better understand the causes of declining vaccine effectiveness. We also investigated the consequences of the vaccine's impact on reducing Hib transmission for maintenance of immunity. Our findings emphasized the importance of maintaining high post-immunization antibody titres among age groups at greatest risk of invasive infections. In keeping with UK population-based estimates, low direct efficacy of immunological memory against disease was found, cautioning against over-reliance on evidence of priming alone as a correlate of population protection. The contribution of herd immunity to disease control was reinforced. Possible intervention strategies will be explored in subsequent work. PMID:17678559

Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model.

PubMed

Zhang, Baihao; Chikuma, Shunsuke; Hori, Shohei; Fagarasan, Sidonia; Honjo, Tasuku

2016-07-26

PD-1 (programmed-death 1), an immune-inhibitory receptor required for immune self-tolerance whose deficiency causes autoimmunity with variable severity and tissue specificity depending on other genetic factors, is expressed on activated T cells, including the transcription factor FoxP3(+) Treg cells known to play critical roles in maintaining immune tolerance. However, whether PD-1 expression by the Treg cells is required for their immune regulatory function, especially in autoimmune settings, is still unclear. We found that mice with partial FoxP3 insufficiency developed early-onset lympho-proliferation and lethal autoimmune pancreatitis only when PD-1 is absent. The autoimmune phenotype was rescued by the transfer of FoxP3-sufficient T cells, regardless of whether they were derived from WT or PD-1-deficient mice, indicating that Treg cells dominantly protect against development of spontaneous autoimmunity without intrinsic expression of PD-1. The absence of PD-1 combined with partial FoxP3 insufficiency, however, led to generation of ex-FoxP3 T cells with proinflammatory properties and expansion of effector/memory T cells that contributed to the autoimmune destruction of target tissues. Altogether, the results suggest that PD-1 and FoxP3 work collaboratively in maintaining immune tolerance mostly through nonoverlapping pathways. Thus, PD-1 is modulating the activation threshold and maintaining the balance between regulatory and effector T cells, whereas FoxP3 is sufficient for dominant regulation through maintaining the integrity of the Treg function. We suggest that genetic or environmental factors that even moderately affect the expression of both PD-1 and FoxP3 can cause life-threatening autoimmune diseases by disrupting the T-cell homeostasis.

Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model

PubMed Central

Zhang, Baihao; Chikuma, Shunsuke; Hori, Shohei; Fagarasan, Sidonia; Honjo, Tasuku

2016-01-01

PD-1 (programmed-death 1), an immune-inhibitory receptor required for immune self-tolerance whose deficiency causes autoimmunity with variable severity and tissue specificity depending on other genetic factors, is expressed on activated T cells, including the transcription factor FoxP3+ Treg cells known to play critical roles in maintaining immune tolerance. However, whether PD-1 expression by the Treg cells is required for their immune regulatory function, especially in autoimmune settings, is still unclear. We found that mice with partial FoxP3 insufficiency developed early-onset lympho-proliferation and lethal autoimmune pancreatitis only when PD-1 is absent. The autoimmune phenotype was rescued by the transfer of FoxP3-sufficient T cells, regardless of whether they were derived from WT or PD-1–deficient mice, indicating that Treg cells dominantly protect against development of spontaneous autoimmunity without intrinsic expression of PD-1. The absence of PD-1 combined with partial FoxP3 insufficiency, however, led to generation of ex-FoxP3 T cells with proinflammatory properties and expansion of effector/memory T cells that contributed to the autoimmune destruction of target tissues. Altogether, the results suggest that PD-1 and FoxP3 work collaboratively in maintaining immune tolerance mostly through nonoverlapping pathways. Thus, PD-1 is modulating the activation threshold and maintaining the balance between regulatory and effector T cells, whereas FoxP3 is sufficient for dominant regulation through maintaining the integrity of the Treg function. We suggest that genetic or environmental factors that even moderately affect the expression of both PD-1 and FoxP3 can cause life-threatening autoimmune diseases by disrupting the T-cell homeostasis. PMID:27410049

A polyvalent Clade B virus-like particle HIV vaccine combined with partially protective oral preexposure prophylaxis prevents simian-human immunodeficiency virus Infection in macaques and primes for virus-amplified immunity.

PubMed

Ross, Ted M; Pereira, Lara E; Luckay, Amara; McNicholl, Janet M; García-Lerma, J Gerardo; Heneine, Walid; Eugene, Hermancia S; Pierce-Paul, Brooke R; Zhang, Jining; Hendry, R Michael; Smith, James M

2014-11-01

Vaccination and preexposure prophylaxis (PrEP) with antiretrovirals have shown only partial protection from HIV-1 infection in human trials. Oral Truvada (emtricitabine/tenofovir disoproxil fumarate) is FDA approved as PrEP but partial adherence reduces efficacy. If combined as biomedical preventions (CBP), an HIV vaccine could protect when PrEP adherence is low and PrEP could prevent vaccine breakthroughs. The efficacy of combining oral PrEP with an HIV vaccine has not been evaluated in humans. We determined the efficacy of combining a DNA/virus-like particle (VLP) vaccine with partially effective intermittent PrEP in Indian rhesus macaques (RM). Eight RM received intramuscular inoculations of five DNA plasmids encoding four HIV-1 Clade B primary isolate Envs and SIVmac239 Gag (at weeks 0 and 4), followed by intramuscular and intranasal inoculations of homologous Gag VLPs and four Env VLPs (at weeks 12, 16, and 53). At week 61, we initiated weekly rectal exposures with heterologous SHIV162p3 (10 TCID50) along with oral Truvada (TDF, 22 mg/kg; FTC 20 mg/kg) dosing 2 h before and 22 h after each exposure. This PrEP regimen previously demonstrated 50% efficacy. Five controls (no vaccine, no PrEP) received weekly SHIV162p3. All controls were infected after a median of four exposures; the mean peak plasma viral load (VL) was 3.9×10(7) vRNA copies/ml. CBP protected seven of eight (87.5%) RM. The one infected CBP RM had a reduced peak VL of 8.8×10(5) copies/ml. SHIV exposures during PrEP amplified Gag and Env antibody titers in protected RM. These results suggest that combining oral PrEP with HIV vaccines could enhance protection against HIV-1 infection.

Transcriptional Modulation of the Immune Response by Peroxisome Proliferator-Activated Receptor-α Agonists in Autoimmune Disease1

PubMed Central

Gocke, Anne R.; Hussain, Rehana Z.; Yang, Yuhong; Peng, Haiyan; Weiner, Jeffrey; Ben, Li-Hong; Drew, Paul D.; Stuve, Olaf; Lovett-Racke, Amy E.; Racke, Michael K.

2010-01-01

Peroxisome proliferator-activated receptor-α (PPARα) agonists have been shown to have a therapeutic benefit in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). In this study, we investigated the mechanism by which the PPARα agonist gemfibrozil induces immune deviation and protects mice from EAE. We demonstrated that treatment with gemfibrozil increases expression of the Th2 transcription factor GATA-3 and decreases expression of the Th1 transcription factor T-bet in vitro and directly ex vivo. These changes correlated with an increase in nuclear PPARα expression. Moreover, the protective effects of PPARα agonists in EAE were shown to be partially dependent on IL-4 and to occur in a receptor-dependent manner. PPARα was demonstrated, for the first time, to regulate the IL-4 and IL-5 genes and to bind the IL-4 promoter in the presence of steroid receptor coactivator-1, indicating that PPARα can directly transactivate the IL-4 gene. Finally, therapeutic administration of PPARα agonists ameliorated clinically established EAE, suggesting that PPARα agonists may provide a treatment option for immune-mediated inflammatory diseases. PMID:19299749

Immunologic and Virologic Mechanisms for Partial Protection from Intravenous Challenge by an Integration-Defective SIV Vaccine †

PubMed Central

Wang, Chu; Jiang, Chunlai; Gao, Nan; Zhang, Kaikai; Liu, Donglai; Wang, Wei; Cong, Zhe; Qin, Chuan; Ganusov, Vitaly V.; Ferrari, Guido; LaBranche, Celia; Montefiori, David C.; Kong, Wei; Yu, Xianghui; Gao, Feng

2017-01-01

The suppression of viral loads and identification of selection signatures in non-human primates after challenge are indicators for effective human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) vaccines. To mimic the protective immunity elicited by attenuated SIV vaccines, we developed an integration-defective SIV (idSIV) vaccine by inactivating integrase, mutating sequence motifs critical for integration, and inserting the cytomegalovirus (CMV) promoter for more efficient expression in the SIVmac239 genome. Chinese rhesus macaques were immunized with idSIV DNA and idSIV particles, and the cellular and humoral immune responses were measured. After the intravenous SIVmac239 challenge, viral loads were monitored and selection signatures in viral genomes from vaccinated monkeys were identified by single genome sequencing. T cell responses, heterologous neutralization against tier-1 viruses, and antibody-dependent cellular cytotoxicity (ADCC) were detected in idSIV-vaccinated macaques post immunization. After challenge, the median peak viral load in the vaccine group was significantly lower than that in the control group. However, this initial viral control did not last as viral set-points were similar between vaccinated and control animals. Selection signatures were identified in Nef, Gag, and Env proteins in vaccinated and control macaques, but these signatures were different, suggesting selection pressure on viruses from vaccine-induced immunity in the vaccinated animals. Our results showed that the idSIV vaccine exerted some pressure on the virus population early during the infection but future modifications are needed in order to induce more potent immune responses. PMID:28574482

Impact of waning acquired immunity and asymptomatic infections on case-control studies for enteric pathogens.

PubMed

Havelaar, Arie H; Swart, Arno

2016-12-01

Case-control studies of outbreaks and of sporadic cases of infectious diseases may provide a biased estimate of the infection rate ratio, due to selecting controls that are not at risk of disease. We use a dynamic mathematical model to explore biases introduced in results drawn from case-control studies of enteric pathogens by waning and boosting of immunity, and by asymptomatic infections, using Campylobacter jejuni as an example. Individuals in the population are either susceptible (at risk of infection and disease), fully protected (not at risk of either) or partially protected (at risk of infection but not of disease). The force of infection is a function of the exposure frequency and the exposure dose. We show that the observed disease odds ratios are indeed strongly biased towards the null, i.e. much lower than the infection rate ratio, and furthermore even not proportional to it. The bias could theoretically be controlled by sampling controls only from the reservoir of susceptible individuals. The population at risk is in a dynamic equilibrium, and cannot be identified as those who are not and have never experienced disease. Individual-level samples to measure protective immunity would be required, complicating the design, cost and execution of case-control studies. Copyright © 2016 The Author(s). Published by Elsevier B.V. All rights reserved.

Malaria vaccines and human immune responses.

PubMed

Long, Carole A; Zavala, Fidel

2016-08-01

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

Immune mechanisms induced by an HSV-1 mutant strain: Discrepancy analysis of the immune system gene profile in comparison with a wild-type strain.

PubMed

Zhang, Xiaolong; Jiang, Quanlong; Xu, Xingli; Wang, Yongrong; Liu, Lei; Lian, Yaru; Li, Hao; Wang, Lichun; Zhang, Ying; Jiang, Guorun; Zeng, Jieyuan; Zhang, Han; Han, Jing-Dong Jackie; Li, Qihan

2018-04-25

Herpes simplex virus is a prevalent pathogen of humans of various age groups. The fact that no prophylactic or therapeutic vaccine is currently available suggests a significant need to further investigate the immune mechanisms induced by the virus and various vaccine candidates. We previously generated an HSV-1 mutant strain, M3, with partial deletions in ul7, ul41 and LAT that produced an attenuated phenotype in mice. In the present study, we performed a comparative analysis to characterize the immune responses induced by M3 versus wild-type HSV-1 in a mouse model. Infection with wild-type HSV-1 triggered an inflammatory-dominated response and adaptive immunity suppression and was accompanied by severe pathological damage. In contrast, infection with M3 induced a systematic immune response involving full activation of both innate and adaptive immunity and was accompanied by no obvious pathological changes. Furthermore, the immune response induced by M3 protected mice from lethal challenge with wild-type strains of HSV-1 and restrained virus proliferation and impaired latency. These data are useful for further HSV-1 vaccine development using a mutant strain construction strategy. Copyright © 2018 Elsevier Ltd. All rights reserved.

Intrahepatic T cell receptor β immune repertoire is essential for liver regeneration.

PubMed

Liang, Qing; Liu, Zeyuan; Zhu, Chao; Wang, Bin; Liu, Xiaoke; Yang, Yanan; Lv, Xue; Mu, Haiyu; Wang, Kejia

2018-04-27

T lymphocytes synergize with the cellular immune system to promote hepatocyte regeneration. The T cell receptor (TCR) immune repertoire is closely associated with the host immune response and regenerative proliferation. High-throughput sequencing of TCR provides deep insight into monitoring the immune microenvironment. Here, we aimed to determine the role of the TCRβ immune repertoire in liver regeneration. We investigated the hepatic regeneration in TCRβ chain-deficient (Tcrb -/- ) mice by two-thirds partial hepatectomy (PHx) method. Our results demonstrated that Tcrb -/- mice revealed a reduced capacity for liver regeneration, which was characterized by impaired hepatocyte proliferation and enhanced hepatocyte apoptosis. Dysregulation of inflammatory signalling activation and inflammatory factors was observed in regenerated Tcrb -/- livers. Simultaneously, significantly altered immunocyte levels and aberrant cytokine levels were observed during hepatic regeneration. In addition, we first determined the profile of the TCRβ immune repertoire during liver regeneration, indicating that PHx resulted in remarkably lower TCRβ diversity in intrahepatic T lymphocytes. Taken together, our data suggest that TCRβ deficiency gives a rise to aberrant intrahepatic immune microenvironment that impairs liver regeneration, and the TCRβ reconstitution is required for hepatic immunocyte recruitment and activation during liver regeneration. This article is protected by copyright. All rights reserved. © 2018 by the American Association for the Study of Liver Diseases.

Protective Immunity and Safety of a Genetically Modified Influenza Virus Vaccine

PubMed Central

Garcia, Cristiana Couto; Filho, Bruno Galvão; Gonçalves, Ana Paula de Faria; Lima, Braulio Henrique Freire; Lopes, Gabriel Augusto Oliveira; Rachid, Milene Alvarenga; Peixoto, Andiara Cristina Cardoso; de Oliveira, Danilo Bretas; Ataíde, Marco Antônio; Zirke, Carla Aparecida; Cotrim, Tatiane Marques; Costa, Érica Azevedo; Almeida, Gabriel Magno de Freitas; Russo, Remo Castro; Gazzinelli, Ricardo Tostes; Machado, Alexandre de Magalhães Vieira

2014-01-01

Recombinant influenza viruses are promising viral platforms to be used as antigen delivery vectors. To this aim, one of the most promising approaches consists of generating recombinant viruses harboring partially truncated neuraminidase (NA) segments. To date, all studies have pointed to safety and usefulness of this viral platform. However, some aspects of the inflammatory and immune responses triggered by those recombinant viruses and their safety to immunocompromised hosts remained to be elucidated. In the present study, we generated a recombinant influenza virus harboring a truncated NA segment (vNA-Δ) and evaluated the innate and inflammatory responses and the safety of this recombinant virus in wild type or knock-out (KO) mice with impaired innate (Myd88 -/-) or acquired (RAG -/-) immune responses. Infection using truncated neuraminidase influenza virus was harmless regarding lung and systemic inflammatory response in wild type mice and was highly attenuated in KO mice. We also demonstrated that vNA-Δ infection does not induce unbalanced cytokine production that strongly contributes to lung damage in infected mice. In addition, the recombinant influenza virus was able to trigger both local and systemic virus-specific humoral and CD8+ T cellular immune responses which protected immunized mice against the challenge with a lethal dose of homologous A/PR8/34 influenza virus. Taken together, our findings suggest and reinforce the safety of using NA deleted influenza viruses as antigen delivery vectors against human or veterinary pathogens. PMID:24927156

Progranulin Protects Hippocampal Neurogenesis via Suppression of Neuroinflammatory Responses Under Acute Immune Stress.

PubMed

Ma, Yanbo; Matsuwaki, Takashi; Yamanouchi, Keitaro; Nishihara, Masugi

2017-07-01

Immune stress is well known to suppress adult neurogenesis in the hippocampus. We have demonstrated that progranulin (PGRN) has a mitogenic effect on neurogenesis under several experimental conditions. We have also shown that PGRN suppresses excessive neuroinflammatory responses after traumatic brain injury. However, the role of PGRN in modulating neurogenesis under acute immune stress is yet to be elucidated. In the present study, we evaluated the involvement of PGRN in neurogenesis and inflammatory responses in the hippocampus using a lipopolysaccharide (LPS)-induced immune stress model. Treatment of mice with LPS significantly increased the expression of PGRN in activated microglia and decreased neurogenesis in the dentate gyrus of the hippocampus. PGRN deficiency increased CD68-immunoreactive area and exacerbated suppression of neurogenesis following LPS treatment. The expression levels of lysosomal genes including lysozyme M, macrophage expressed gene 1, and cathepsin Z were higher in PGRN-deficient than in wild-type mice, while PGRN deficiency decreased mammalian target of rapamycin (mTOR) mRNA levels, suggesting that PGRN suppresses excessive lysosomal biogenesis by promoting mTOR signaling. LPS treatment also increased the expression of proinflammatory genes such as interleukin (IL)-1β, tumor necrosis factor-α, and microsomal prostaglandin E synthase-1 (mPGES-1) in the hippocampus, and PGRN deficiency further enhanced gene expression of IL-6 and mPGES-1. These results suggest that PGRN plays a protecting role in hippocampal neurogenesis at least partially by attenuating neuroinflammatory responses during LPS-induced acute immune stress.

An adenovirus-vectored nasal vaccine confers rapid and sustained protection against anthrax in a single-dose regimen.

PubMed

Zhang, Jianfeng; Jex, Edward; Feng, Tsungwei; Sivko, Gloria S; Baillie, Leslie W; Goldman, Stanley; Van Kampen, Kent R; Tang, De-chu C

2013-01-01

Bacillus anthracis is the causative agent of anthrax, and its spores have been developed into lethal bioweapons. To mitigate an onslaught from airborne anthrax spores that are maliciously disseminated, it is of paramount importance to develop a rapid-response anthrax vaccine that can be mass administered by nonmedical personnel during a crisis. We report here that intranasal instillation of a nonreplicating adenovirus vector encoding B. anthracis protective antigen could confer rapid and sustained protection against inhalation anthrax in mice in a single-dose regimen in the presence of preexisting adenovirus immunity. The potency of the vaccine was greatly enhanced when codons of the antigen gene were optimized to match the tRNA pool found in human cells. In addition, an adenovirus vector encoding lethal factor can confer partial protection against inhalation anthrax and might be coadministered with a protective antigen-based vaccine.

An Adenovirus-Vectored Nasal Vaccine Confers Rapid and Sustained Protection against Anthrax in a Single-Dose Regimen

PubMed Central

Jex, Edward; Feng, Tsungwei; Sivko, Gloria S.; Baillie, Leslie W.; Goldman, Stanley; Van Kampen, Kent R.; Tang, De-chu C.

2013-01-01

Bacillus anthracis is the causative agent of anthrax, and its spores have been developed into lethal bioweapons. To mitigate an onslaught from airborne anthrax spores that are maliciously disseminated, it is of paramount importance to develop a rapid-response anthrax vaccine that can be mass administered by nonmedical personnel during a crisis. We report here that intranasal instillation of a nonreplicating adenovirus vector encoding B. anthracis protective antigen could confer rapid and sustained protection against inhalation anthrax in mice in a single-dose regimen in the presence of preexisting adenovirus immunity. The potency of the vaccine was greatly enhanced when codons of the antigen gene were optimized to match the tRNA pool found in human cells. In addition, an adenovirus vector encoding lethal factor can confer partial protection against inhalation anthrax and might be coadministered with a protective antigen-based vaccine. PMID:23100479

Formalin-Inactivated Coxiella burnetii Phase I Vaccine-Induced Protection Depends on B Cells To Produce Protective IgM and IgG

PubMed Central

Peng, Ying; Schoenlaub, Laura; Elliott, Alexandra; Mitchell, William; Zhang, Yan

2013-01-01

To further understand the mechanisms of formalin-inactivated Coxiella burnetii phase I (PI) vaccine (PIV)-induced protection, we examined if B cell, T cell, CD4+ T cell, or CD8+ T cell deficiency in mice significantly affects the ability of PIV to confer protection against a C. burnetii infection. Interestingly, compared to wild-type (WT) mice, PIV conferred comparable levels of protection in CD4+ T cell- or CD8+ T cell-deficient mice and partial protection in T cell-deficient mice but did not provide measurable protection in B cell-deficient mice. These results suggest that PIV-induced protection depends on B cells. In addition, anti-PI-specific IgM was the major detectable antibody (Ab) in immune sera from PIV-vaccinated CD4+ T cell-deficient mice, and passive transfer of immune sera from PIV-vaccinated CD4+ T cell-deficient mice conferred significant protection. These results suggest that T cell-independent anti-PI-specific IgM may contribute to PIV-induced protection. Our results also suggested that PIV-induced protection may not depend on complement activation and Fc receptor-mediated effector functions. Furthermore, our results demonstrated that both IgM and IgG from PIV-vaccinated WT mouse sera were able to inhibit C. burnetii infection in vivo, but only IgM from PIV-vaccinated CD4+ T cell-deficient mouse sera inhibited C. burnetii infection. Collectively, these findings suggest that PIV-induced protection depends on B cells to produce protective IgM and IgG and that T cell-independent anti-PI-specific IgM may play a critical role in PIV-induced protection against C. burnetii infection. PMID:23545296

Potential Efficacy of Citicoline as Adjunct Therapy in Treatment of Cerebral Malaria

PubMed Central

El-Assaad, Fatima; Combes, Valery; Grau, Georges Emile Raymond

2014-01-01

Cerebral malaria (CM) is characterized by a dysregulated immune response that results in endothelial membrane destabilization and increased microparticle (MP) production. Citicoline (CTC) is a membrane stabilizer used for the treatment of neurological disorders. We evaluated the efficacy of CTC as adjunct therapy to aid recovery from experimental CM. We show that CTC reduces MP production in vitro; in combination with artesunate in vivo, confers partial protection against CM; and prolongs survival. PMID:24165175

Added Value of Avian Influenza (H5) Day-Old Chick Vaccination for Disease Control in Egypt.

PubMed

Peyre, Marisa; Choisy, Marc; Sobhy, Heba; Kilany, Walid H; Gély, Marie; Tripodi, Astrid; Dauphin, Gwenaëlle; Saad, Mona; Roger, François; Lubroth, Juan; Jobre, Yilma

2016-05-01

The immunity profile against H5N1 highly pathogenic avian influenza (HPAI) in the commercial poultry value chain network in Egypt was modeled with the use of different vaccination scenarios. The model estimated the vaccination coverage, the protective seroconversion level, and the duration of immunity for each node of the network and vaccination scenario. Partial budget analysis was used to compare the benefit-cost of the different vaccination scenarios. The model predicted that targeting day-old chick avian influenza (AI) vaccination in industrial and large hatcheries would increase immunity levels in the overall poultry population in Egypt and especially in small commercial poultry farms (from <30% to >60%). This strategy was shown to be more efficient than the current strategy of using inactivated vaccines. Improving HPAI control in the commercial poultry sector in Egypt would have a positive impact to improve disease control.

Yersinia pestis with regulated delayed attenuation as a vaccine candidate to induce protective immunity against plague.

PubMed

Sun, Wei; Roland, Kenneth L; Kuang, Xiaoying; Branger, Christine G; Curtiss, Roy

2010-03-01

Two mutant strains of Yersinia pestis KIM5+, a Deltacrp mutant and a mutant with arabinose-dependent regulated delayed-shutoff crp expression (araC P(BAD) crp), were constructed, characterized in vitro, and evaluated for virulence, immunogenicity, and protective efficacy in mice. Both strains were highly attenuated by the subcutaneous (s.c.) route. The 50% lethal doses (LD(50)s) of the Deltacrp and araC P(BAD) crp mutants were approximately 1,000,000-fold and 10,000-fold higher than those of Y. pestis KIM5+, respectively, indicating that both strains were highly attenuated. Mice vaccinated s.c. with 3.8 x 10(7) CFU of the Deltacrp mutant developed high anti-Y. pestis and anti-LcrV serum IgG titers, both with a strong Th2 bias, and induced protective immunity against subcutaneous challenge with virulent Y. pestis (80% survival) but no protection against pulmonary challenge. Mice vaccinated with 3.0 x 10(4) CFU of the araC P(BAD) crp mutant also developed high anti-Y. pestis and anti-LcrV serum IgG titers but with a more balanced Th1/Th2 response. This strain induced complete protection against s.c. challenge and partial protection (70% survival) against pulmonary challenge. Our results demonstrate that arabinose-dependent regulated crp expression is an effective strategy to attenuate Y. pestis while retaining strong immunogenicity, leading to protection against the pneumonic and bubonic forms of plague.

Which is more effective for suppressing an infectious disease: imperfect vaccination or defense against contagion?

NASA Astrophysics Data System (ADS)

Kuga, Kazuki; Tanimoto, Jun

2018-02-01

We consider two imperfect ways to protect against an infectious disease such as influenza, namely vaccination giving only partial immunity and a defense against contagion such as wearing a mask. We build up a new analytic framework considering those two cases instead of perfect vaccination, conventionally assumed as a premise, with the assumption of an infinite and well-mixed population. Our framework also considers three different strategy-updating rules based on evolutionary game theory: conventional pairwise comparison with one randomly selected agent, another concept of pairwise comparison referring to a social average, and direct alternative selection not depending on the usual copying concept. We successfully obtain a phase diagram in which vaccination coverage at equilibrium can be compared when assuming the model of either imperfect vaccination or a defense against contagion. The obtained phase diagram reveals that a defense against contagion is marginally inferior to an imperfect vaccination as long as the same coefficient value is used. Highlights - We build a new analytical framework for a vaccination game combined with the susceptible-infected-recovered (SIR) model. - Our model can evaluate imperfect provisions such as vaccination giving only partial immunity and a defense against contagion. - We obtain a phase diagram with which to compare the quantitative effects of partial vaccination and a defense against contagion.

Plague in Guinea Pigs and Its Prevention by Subunit Vaccines

PubMed Central

Quenee, Lauriane E.; Ciletti, Nancy; Berube, Bryan; Krausz, Thomas; Elli, Derek; Hermanas, Timothy; Schneewind, Olaf

2011-01-01

Human pneumonic plague is a devastating and transmissible disease for which a Food and Drug Administration–approved vaccine is not available. Suitable animal models may be adopted as a surrogate for human plague to fulfill regulatory requirements for vaccine efficacy testing. To develop an alternative to pneumonic plague in nonhuman primates, we explored guinea pigs as a model system. On intranasal instillation of a fully virulent strain, Yersinia pestis CO92, guinea pigs developed lethal lung infections with hemorrhagic necrosis, massive bacterial replication in the respiratory system, and blood-borne dissemination to other organ systems. Expression of the Y. pestis F1 capsule was not required for the development of pulmonary infection; however, the capsule seemed to be important for the establishment of bubonic plague. The mean lethal dose (MLD) for pneumonic plague in guinea pigs was estimated to be 1000 colony-forming units. Immunization of guinea pigs with the recombinant forms of LcrV, a protein that resides at the tip of Yersinia type III secretion needles, or F1 capsule generated robust humoral immune responses. Whereas LcrV immunization resulted in partial protection against pneumonic plague challenge with 250 MLD Y. pestis CO92, immunization with recombinant F1 did not. rV10, a vaccine variant lacking LcrV residues 271-300, elicited protection against pneumonic plague, which seemed to be based on conformational antibodies directed against LcrV. PMID:21406168

Factors Affecting Formation of Incomplete Vi Antibody in Mice

PubMed Central

Gaines, Sidney; Currie, Julius A.; Tully, Joseph G.

1965-01-01

Gaines, Sidney (Walter Reed Army Institute of Research, Washington, D.C.), Julius A. Currie, and Joseph G. Tully. Factors affecting formation of incomplete Vi antibody in mice. J. Bacteriol. 90:635–642. 1965.—Single immunizing doses of purified Vi antigen elicited complete and incomplete Vi antibodies in BALB/c mice, but only incomplete antibody in Cinnamon mice. Three of six other mouse strains tested responded like BALB/c mice; the remaining three, like Cinnamon mice. Varying the quantity of antigen injected or the route of administration failed to stimulate the production of detectable complete Vi antibody in Cinnamon mice. Such antibody was evoked in these animals by multiple injections of Vi antigen or by inoculating them with Vi-containing bacilli or Vi-coated erythrocytes. The early protection afforded by serum from Vi-immunized BALB/c mice coincided with the appearance of incomplete Vi antibody, 1 day prior to the advent of complete antibody. Persistence of incomplete as well as complete antibody in the serum of immunized mice was demonstrated for at least 56 days after injection of 10 μg of Vi antigen. Incomplete Vi antibody was shown to have blocking ability, in vitro bactericidal activity, and the capability of protecting mice against intracerebral as well as intraperitoneal challenge with virulent typhoid bacilli. Production of incomplete and complete Vi antibodies was adversely affected by immunization with partially depolymerized Vi antigens. PMID:16562060

Cell-wall preparation containing poly-γ-D-glutamate covalently linked to peptidoglycan, a straightforward extractable molecule, protects mice against experimental anthrax infection.

PubMed

Candela, Thomas; Dumetz, Fabien; Tosi-Couture, Evelyne; Mock, Michèle; Goossens, Pierre L; Fouet, Agnès

2012-12-17

Bacillus anthracis is the causative agent of anthrax that is characterized by septicemia and toxemia. Many vaccine strategies were described to counteract anthrax infection. In contrast with veterinary live vaccines, currently human vaccines are acellular with the protective antigen, a toxin component, as the main constituent. However, in animal models this vaccine is less efficient than the live vaccine. In this study, we analyzed the protection afforded by a single extractable surface element. The poly-γ-D-glutamate capsule is covalently linked to the peptidoglycan. A preparation of peptidoglycan-linked poly-γ-D-glutamate (GluPG) was tested for its immunogenicity and its protective effect. GluPG injection, in mice, elicited the production of specific antibodies directed against poly-glutamate and partially protected the animals against lethal challenges with a non-toxinogenic strain. When combined to protective antigen, GluPG immunization conferred full protection against cutaneous anthrax induced with a fully virulent strain. Copyright © 2012 Elsevier Ltd. All rights reserved.

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

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.

Effects of Postchallenge Administration of ST-246 on Dissemination of IHD-J-Luc Vaccinia Virus in Normal Mice and in Immune-Deficient Mice Reconstituted with T Cells

PubMed Central

Shotwell, Elisabeth; Scott, John; Cruz, Stephanie; King, Lisa R.; Manischewitz, Jody; Diaz, Claudia G.; Jordan, Robert A.; Grosenbach, Douglas W.; Golding, Hana

2013-01-01

Whole-body bioimaging was used to study dissemination of vaccinia virus (VACV) in normal and in immune deficient (nu−/nu−) mice protected from lethality by postchallenge administration of ST-246. Total fluxes were recorded in the liver, spleen, lungs, and nasal cavities of live mice after intranasal infection with a recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve were calculated for individual mice to assess viral loads. Treatment for 2 to 5 days of normal BALB/c mice with ST-246 at 100 mg/kg starting 24 h postchallenge conferred 100% protection and reduced viral loads in four organs compared to control mice. Mice also survived after 5 days of treatment with ST-246 at 30 mg/kg, and yet the viral loads and poxes were higher in these mice compared to 100-mg/kg treatment group. Nude mice were not protected by ST-246 alone or by 10 million adoptively transferred T cells. In contrast, nude mice that received T cells and 7-day treatment with ST-246 survived infection and exhibited reduced viral loads compared to nonreconstituted and ST-246-treated mice after ST-246 was stopped. Similar protection of nude mice was achieved using adoptively transferred 1.0 and 0.1 million, but not 0.01 million, purified T cells or CD4+ or CD8+ T cells in conjunction with ST-246 treatment. These data suggest that ST-246 protects immunocompetent mice from lethality and reduces viral dissemination in internal organs and poxvirus lesions. Furthermore, immune-deficient animals with partial T cell reconstitution can control virus replication after a course of ST-246 and survive lethal vaccinia virus challenge. PMID:23468500

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

PubMed

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

2014-08-01

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

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 stimulation with the corresponding antigens in vitro. Immunization with both ACT-F and ACT-T could confer partial to complete protection and trigger strong Th1/Th2 mixed humoral and cellular immune responses in the mouse host. This suggested that recombinant α-actinin subunit antigens may be promising vaccine candidates against trichomoniasis.

Intermittent Fasting Confers Protection in CNS Autoimmunity by Altering the Gut Microbiota.

PubMed

Cignarella, Francesca; Cantoni, Claudia; Ghezzi, Laura; Salter, Amber; Dorsett, Yair; Chen, Lei; Phillips, Daniel; Weinstock, George M; Fontana, Luigi; Cross, Anne H; Zhou, Yanjiao; Piccio, Laura

2018-06-05

Multiple sclerosis (MS) is more common in western countries with diet being a potential contributing factor. Here we show that intermittent fasting (IF) ameliorated clinical course and pathology of the MS model, experimental autoimmune encephalomyelitis (EAE). IF led to increased gut bacteria richness, enrichment of the Lactobacillaceae, Bacteroidaceae, and Prevotellaceae families and enhanced antioxidative microbial metabolic pathways. IF altered T cells in the gut with a reduction of IL-17 producing T cells and an increase in regulatory T cells. Fecal microbiome transplantation from mice on IF ameliorated EAE in immunized recipient mice on a normal diet, suggesting that IF effects are at least partially mediated by the gut flora. In a pilot clinical trial in MS patients, intermittent energy restriction altered blood adipokines and the gut flora resembling protective changes observed in mice. In conclusion, IF has potent immunomodulatory effects that are at least partially mediated by the gut microbiome. Copyright © 2018 Elsevier Inc. All rights reserved.

A novel live attenuated anthrax spore vaccine based on an acapsular Bacillus anthracis Sterne strain with mutations in the htrA, lef and cya genes.

PubMed

Chitlaru, Theodor; Israeli, Ma'ayan; Rotem, Shahar; Elia, Uri; Bar-Haim, Erez; Ehrlich, Sharon; Cohen, Ofer; Shafferman, Avigdor

2017-10-20

We recently reported the development of a novel, next-generation, live attenuated anthrax spore vaccine based on disruption of the htrA (High Temperature Requirement A) gene in the Bacillus anthracis Sterne veterinary vaccine strain. This vaccine exhibited a highly significant decrease in virulence in murine, guinea pig and rabbit animal models yet preserved the protective value of the parental Sterne strain. Here, we report the evaluation of additional mutations in the lef and cya genes, encoding for the toxin components lethal factor (LF) and edema factor (EF), to further attenuate the SterneΔhtrA strain and improve its compatibility for human use. Accordingly, we constructed seven B. anthracis Sterne-derived strains exhibiting different combinations of mutations in the htrA, cya and lef genes. The various strains were indistinguishable in growth in vitro and in their ability to synthesise the protective antigen (PA, necessary for the elicitation of protection). In the sensitive murine model, we observed a gradual increase (ΔhtrA<ΔhtrAΔcya<ΔhtrAΔlef<ΔhtrAΔlefΔcya) in attenuation - up to 10 8 -fold relative to the parental Sterne vaccine strain. Most importantly, all various SterneΔhtrA derivative strains did not differ in their ability to elicit protective immunity in guinea pigs. Immunisation of guinea pigs with a single dose (10 9 spores) or double doses (>10 7 spores) of the most attenuated triple mutant strain SterneΔhtrAlef MUT Δcya induced a robust immune response, providing complete protection against a subsequent respiratory lethal challenge. Partial protection was observed in animals vaccinated with a double dose of as few as 10 5 spores. Furthermore, protective immune status was maintained in all vaccinated guinea pigs and rabbits for at least 40 and 30weeks, respectively. Copyright © 2017 Elsevier Ltd. All rights reserved.

DNA Vaccination of the American Crow (Corvus brachyrhynchos) Provides Partial Protection Against Lethal Challenge with West Nile Virus

DTIC Science & Technology

2007-01-01

mortality but did not provide sterile immunity. RESUMEN. La vacunación del cuervo Americano (Corvus brachyrhynchos) con vacuna de ADN proporciona...casi 100% fatal en el cuervo Americano (Corvus brachyrhynchos). Evaluamos cuatro formulaciones de vacunas en cuervos Americanos, incluyendo una vacuna de...ADN, una vacuna de ADN con adyuvante, ambas aplicadas por la vı́a intramuscular, una vacuna de ADN microencapsulada aplicada por la vı́a oral, y una

Parental concern about vaccine safety in Canadian children partially immunized at age 2: a multivariable model including system level factors.

PubMed

MacDonald, Shannon E; Schopflocher, Donald P; Vaudry, Wendy

2014-01-01

Children who begin but do not fully complete the recommended series of childhood vaccines by 2 y of age are a much larger group than those who receive no vaccines. While parents who refuse all vaccines typically express concern about vaccine safety, it is critical to determine what influences parents of 'partially' immunized children. This case-control study examined whether parental concern about vaccine safety was responsible for partial immunization, and whether other personal or system-level factors played an important role. A random sample of parents of partially and completely immunized 2 y old children were selected from a Canadian regional immunization registry and completed a postal survey assessing various personal and system-level factors. Unadjusted odds ratios (OR) and adjusted ORs (aOR) were calculated with logistic regression. While vaccine safety concern was associated with partial immunization (OR 7.338, 95% CI 4.138-13.012), other variables were more strongly associated and reduced the strength of the relationship between concern and partial immunization in multivariable analysis (aOR 2.829, 95% CI 1.151-6.957). Other important factors included perceived disease susceptibility and severity (aOR 4.629, 95% CI 2.017-10.625), residential mobility (aOR 3.908, 95% CI 2.075-7.358), daycare use (aOR 0.310, 95% CI 0.144-0.671), number of needles administered at each visit (aOR 7.734, 95% CI 2.598-23.025) and access to a regular physician (aOR 0.219, 95% CI 0.057-0.846). While concern about vaccine safety may be addressed through educational strategies, this study suggests that additional program and policy-level strategies may positively impact immunization uptake.

Cutting Edge: Protection by Antiviral Memory CD8 T Cells Requires Rapidly Produced Antigen in Large Amounts.

PubMed

Remakus, Sanda; Ma, Xueying; Tang, Lingjuan; Xu, Ren-Huan; Knudson, Cory; Melo-Silva, Carolina R; Rubio, Daniel; Kuo, Yin-Ming; Andrews, Andrew; Sigal, Luis J

2018-05-15

Numerous attempts to produce antiviral vaccines by harnessing memory CD8 T cells have failed. A barrier to progress is that we do not know what makes an Ag a viable target of protective CD8 T cell memory. We found that in mice susceptible to lethal mousepox (the mouse homolog of human smallpox), a dendritic cell vaccine that induced memory CD8 T cells fully protected mice when the infecting virus produced Ag in large quantities and with rapid kinetics. Protection did not occur when the Ag was produced in low amounts, even with rapid kinetics, and protection was only partial when the Ag was produced in large quantities but with slow kinetics. Hence, the amount and timing of Ag expression appear to be key determinants of memory CD8 T cell antiviral protective immunity. These findings may have important implications for vaccine design. Copyright © 2018 by The American Association of Immunologists, Inc.

Vaccines and immunization strategies for dengue prevention

PubMed Central

Liu, Yang; Liu, Jianying; Cheng, Gong

2016-01-01

Dengue is currently the most significant arboviral disease afflicting tropical and sub-tropical countries worldwide. Dengue vaccines, such as the multivalent attenuated, chimeric, DNA and inactivated vaccines, have been developed to prevent dengue infection in humans, and they function predominantly by stimulating immune responses against the dengue virus (DENV) envelope (E) and nonstructural-1 proteins (NS1). Of these vaccines, a live attenuated chimeric tetravalent DENV vaccine developed by Sanofi Pasteur has been licensed in several countries. However, this vaccine renders only partial protection against the DENV2 infection and is associated with an unexplained increased incidence of hospitalization for severe dengue disease among children younger than nine years old. In addition to the virus-based vaccines, several mosquito-based dengue immunization strategies have been developed to interrupt the vector competence and effectively reduce the number of infected mosquito vectors, thus controlling the transmission of DENV in nature. Here we summarize the recent progress in the development of dengue vaccines and novel immunization strategies and propose some prospective vaccine strategies for disease prevention in the future. PMID:27436365

Glutamine antagonist-mediated immune suppression decreases pathology but delays virus clearance in mice during nonfatal alphavirus encephalomyelitis.

PubMed

Baxter, Victoria K; Glowinski, Rebecca; Braxton, Alicia M; Potter, Michelle C; Slusher, Barbara S; Griffin, Diane E

2017-08-01

Infection of weanling C57BL/6 mice with the TE strain of Sindbis virus (SINV) causes nonfatal encephalomyelitis associated with hippocampal-based memory impairment that is partially prevented by treatment with 6-diazo-5-oxo-l-norleucine (DON), a glutamine antagonist (Potter et al., J Neurovirol 21:159, 2015). To determine the mechanism(s) of protection, lymph node and central nervous system (CNS) tissues from SINV-infected mice treated daily for 1 week with low (0.3mg/kg) or high (0.6mg/kg) dose DON were examined. DON treatment suppressed lymphocyte proliferation in cervical lymph nodes resulting in reduced CNS immune cell infiltration, inflammation, and cell death compared to untreated SINV-infected mice. Production of SINV-specific antibody and interferon-gamma were also impaired by DON treatment with a delay in virus clearance. Cessation of treatment allowed activation of the antiviral immune response and viral clearance, but revived CNS pathology, demonstrating the ability of the immune response to mediate both CNS damage and virus clearance. Copyright © 2017 Elsevier Inc. All rights reserved.

GlyCAM1 negatively regulates monocyte entry into the optic nerve head and contributes to radiation-based protection in glaucoma.

PubMed

Williams, Pete A; Braine, Catherine E; Foxworth, Nicole E; Cochran, Kelly E; John, Simon W M

2017-04-26

We previously reported a profound long-term neuroprotection subsequent to a single radiation-therapy in the DBA/2J mouse model of glaucoma. This neuroprotection prevents entry of monocyte-like immune cells into the optic nerve head during glaucoma. Gene expression studies in radiation-treated mice implicated Glycam1 in this protection. Glycam1 encodes a proteoglycan ligand for L-selectin and is an excellent candidate to modulate immune cell entry into the eye. Here, we experimentally test the hypothesis that radiation-induced over-expression of Glycam1 is a key component of the neuroprotection. We generated a null allele of Glycam1 on a DBA/2J background. Gene and protein expression of Glycam1, monocyte entry into the optic nerve head, retinal ganglion cell death, and axon loss in the optic nerve were assessed. Radiation therapy potently inhibits monocyte entry into the optic nerve head and prevents retinal ganglion cell death and axon loss. DBA/2J mice carrying a null allele of Glycam1 show increased monocyte entry and increased retinal ganglion cell death and axon loss following radiation therapy, but the majority of optic nerves were still protected by radiation therapy. Although GlyCAM1 is an L-selectin ligand, its roles in immunity are not yet fully defined. The current study demonstrates a partial role for GlyCAM1 in radiation-mediated protection. Furthermore, our results clearly show that GlyCAM1 levels modulate immune cell entry from the vasculature into neural tissues. As Glycam1 deficiency has a more profound effect on cell entry than on neurodegeneration, further experiments are needed to precisely define the role of monocyte entry in DBA/2J glaucoma. Nevertheless, GlyCAM1's function as a negative regulator of extravasation may lead to novel therapeutic strategies for an array of common conditions involving inflammation.

A recombinant anchorless respiratory syncytial virus (RSV) fusion (F) protein/monophosphoryl lipid A (MPL) vaccine protects against RSV-induced replication and lung pathology.

PubMed

Blanco, Jorge C G; Boukhvalova, Marina S; Pletneva, Lioubov M; Shirey, Kari Ann; Vogel, Stefanie N

2014-03-14

We previously demonstrated that the severe cytokine storm and pathology associated with RSV infection following intramuscular vaccination of cotton rats with FI-RSV Lot 100 could be completely abolished by formulating the vaccine with the mild TLR4 agonist and adjuvant, monophosphoryl lipid A (MPL). Despite this significant improvement, the vaccine failed to blunt viral replication in the lungs. Since MPL is a weak TLR4 agonist, we hypothesized that its adjuvant activity was mediated by modulating the innate immune response of respiratory tract resident macrophages. Therefore, we developed a new vaccine preparation with purified, baculovirus expressed, partially purified, anchorless RSV F protein formulated with synthetic MPL that was administered to cotton rats intranasally, followed by an intradermal boost. This novel formulation and heterologous "prime/boost" route of administration resulted in decreased viral titers compared to that seen in animals vaccinated with F protein alone. Furthermore, animals vaccinated by this route showed no evidence of enhanced lung pathology upon RSV infection. This indicates that MPL acts as an immune modulator that protects the host from vaccine-enhanced pathology, and reduces RSV replication in the lower respiratory tract when administered by a heterologous prime/boost immunization regimen. Copyright © 2013 Elsevier Ltd. All rights reserved.

Influence of health providers on pediatrics' immunization rate.

PubMed

Al-lela, Omer Q B; Baidi Bahari, Mohd; Al-abbassi, Mustafa G; Salih, Muhannad R M; Basher, Amena Y

2012-12-01

To identify the immunization providers' characteristics associated with immunization rate in children younger than 2 years. A cohort and a cluster sampling design were implemented; 528 children between 18 and 70 months of age were sampled in five public health clinics in Mosul-Iraq. Providers' characterizations were obtained. Immunization rate for the children was assessed. Risk factors for partial immunization were explored using both bivariate analyses and multi-level logistic regression models. Less than half of the children had one or more than one missed dose, considered as partial immunization cases. The study found significant association of immunization rate with provider's type. Two factors were found that strongly impacted on immunization rate in the presence of other factors: birthplace and immunization providers' type.

C-terminal domain deletion enhances the protective activity of cpa/cpb loaded solid lipid nanoparticles against Leishmania major in BALB/c mice.

PubMed

Doroud, Delaram; Zahedifard, Farnaz; Vatanara, Alireza; Taslimi, Yasaman; Vahabpour, Rouholah; Torkashvand, Fatemeh; Vaziri, Behrooz; Rouholamini Najafabadi, Abdolhossein; Rafati, Sima

2011-07-01

We have demonstrated that vaccination with pDNA encoding cysteine proteinase Type II (CPA) and Type I (CPB) with its unusual C-terminal extension (CTE) can partially protect BALB/c mice against cutaneous leishmanial infection. Unfortunately, this protection is insufficient to completely control infection without booster injection. Furthermore, in developing vaccines for leishmaniasis, it is necessary to consider a proper adjuvant and/or delivery system to promote an antigen specific immune response. Solid lipid nanoparticles have found their way in drug delivery system development against intracellular infections and cancer, but not Leishmania DNA vaccination. Therefore, undefined effect of cationic solid lipid nanoparticles (cSLN) as an adjuvant in enhancing the immune response toward leishmanial antigens led us to refocus our vaccine development projects. Three pDNAs encoding L. major cysteine proteinase type I and II (with or without CTE) were formulated by cSLN. BALB/c mice were immunized twice by 3-week interval, with cSLN-pcDNA-cpa/b, pcDNA-cpa/b, cSLN-pcDNA-cpa/b(-CTE), pcDNA-cpa/b(-CTE), cSLN, cSLN-pcDNA and PBS. Mice vaccinated with cSLN-pcDNA-cpa/b(-CTE) showed significantly higher levels of parasite inhibition related to protection with specific Th1 immune response development, compared to other groups. Parasite inhibition was determined by different techniques currently available in exploration vacciation efficacy, i.e., flowcytometry on footpad and lymph node, footpad caliper based measurements and imaging as well as lymph node microtitration assay. Among these techniques, lymph node flowcytometry was found to be the most rapid, sensitive and easily reproducible method for discrimination between the efficacy of vaccination strategies. This report demonstrates cSLN's ability to boost immune response magnitude of cpa/cpb(-CTE) cocktail vaccination against leishmaniasis so that the average parasite inhibition percent could be increased significantly. Hence, cSLNs can be considered as suitable adjuvant and/or delivery systems for designing third generation cocktail vaccines.

Evaluation of TcpF-A2-CTB Chimera and Evidence of Additive Protective Efficacy of Immunizing with TcpF and CTB in the Suckling Mouse Model of Cholera

PubMed Central

Price, Gregory A.; Holmes, Randall K.

2012-01-01

The secreted colonization factor, TcpF, which is produced by Vibrio cholerae 01 and 0139, has generated interest as a potential protective antigen in the development of a subunit vaccine against cholera. This study evaluated immunogenicity/protective efficacy of a TcpF holotoxin-like chimera (TcpF-A2-CTB) following intraperitoneal immunization compared to TcpF alone, a TcpF+CTB mixture, or CTB alone. Immunization with the TcpF-A2-CTB chimera elicited significantly greater amounts of anti-TcpF IgG than immunization with the other antigens (P<0.05). Protective efficacy was measured using 6-day-old pups reared from immunized dams and orogastrically challenged with a lethal dose of El Tor V. cholerae 01 Inaba strain N16961. Protection from death, and weight loss analysis at 24 and 48 hours post-infection demonstrated that immunization with TcpF alone was poorly protective. However, immunization with TcpF+CTB was highly protective and showed a trend toward greater protection than immunization with CTB alone (82% vs 64% survival). Immunization with the TcpF-A2-CTB chimera demonstrated less protection (50% survival) than immunization with the TcpF+CTB mixture. The TcpF-A2-CTB chimera used for this study contained the heterologous classical CTB variant whereas the El Tor CTB variant (expressed by the challenge strain) was used in the other immunization groups. For all immunization groups that received CTB, quantitative ELISA data demonstrated that the amounts of serum IgG directed against the homologous immunizing CTB antigen was statistically greater than the amount to the heterologous CTB antigen (P≤0.003). This finding provides a likely explanation for the poorer protection observed following immunization with the TcpF-A2-CTB chimera and the relatively high level of protection seen after immunization with homologous CTB alone. Though immunization with TcpF alone provided no protection, the additive protective effect when TcpF was combined with CTB demonstrates its possible value as a component of a multivalent subunit vaccine against Vibrio cholerae 01 and 0139. PMID:22879984

Coadministration of the Three Antigenic Leishmania infantum Poly (A) Binding Proteins as a DNA Vaccine Induces Protection against Leishmania major Infection in BALB/c Mice

PubMed Central

Corvo, Laura; Garde, Esther; Ramírez, Laura; Iniesta, Virginia; Bonay, Pedro; Gómez-Nieto, Carlos; González, Víctor M.; Martín, M. Elena; Alonso, Carlos; Coelho, Eduardo A. F.; Barral, Aldina; Barral-Netto, Manoel

2015-01-01

Background Highly conserved intracellular proteins from Leishmania have been described as antigens in natural and experimental infected mammals. The present study aimed to evaluate the antigenicity and prophylactic properties of the Leishmania infantum Poly (A) binding proteins (LiPABPs). Methodology/Principal Findings Three different members of the LiPABP family have been described. Recombinant tools based on these proteins were constructed: recombinant proteins and DNA vaccines. The three recombinant proteins were employed for coating ELISA plates. Sera from human and canine patients of visceral leishmaniasis and human patients of mucosal leishmaniasis recognized the three LiPABPs. In addition, the protective efficacy of a DNA vaccine based on the combination of the three Leishmania PABPs has been tested in a model of progressive murine leishmaniasis: BALB/c mice infected with Leishmania major. The induction of a Th1-like response against the LiPABP family by genetic vaccination was able to down-regulate the IL-10 predominant responses elicited by parasite LiPABPs after infection in this murine model. This modulation resulted in a partial protection against L. major infection. LiPABP vaccinated mice showed a reduction on the pathology that was accompanied by a decrease in parasite burdens, in antibody titers against Leishmania antigens and in the IL-4 and IL-10 parasite-specific mediated responses in comparison to control mice groups immunized with saline or with the non-recombinant plasmid. Conclusion/Significance The results presented here demonstrate for the first time the prophylactic properties of a new family of Leishmania antigenic intracellular proteins, the LiPABPs. The redirection of the immune response elicited against the LiPABP family (from IL-10 towards IFN-γ mediated responses) by genetic vaccination was able to induce a partial protection against the development of the disease in a highly susceptible murine model of leishmaniasis. PMID:25955652

Plague in Guinea pigs and its prevention by subunit vaccines.

PubMed

Quenee, Lauriane E; Ciletti, Nancy; Berube, Bryan; Krausz, Thomas; Elli, Derek; Hermanas, Timothy; Schneewind, Olaf

2011-04-01

Human pneumonic plague is a devastating and transmissible disease for which a Food and Drug Administration-approved vaccine is not available. Suitable animal models may be adopted as a surrogate for human plague to fulfill regulatory requirements for vaccine efficacy testing. To develop an alternative to pneumonic plague in nonhuman primates, we explored guinea pigs as a model system. On intranasal instillation of a fully virulent strain, Yersinia pestis CO92, guinea pigs developed lethal lung infections with hemorrhagic necrosis, massive bacterial replication in the respiratory system, and blood-borne dissemination to other organ systems. Expression of the Y. pestis F1 capsule was not required for the development of pulmonary infection; however, the capsule seemed to be important for the establishment of bubonic plague. The mean lethal dose (MLD) for pneumonic plague in guinea pigs was estimated to be 1000 colony-forming units. Immunization of guinea pigs with the recombinant forms of LcrV, a protein that resides at the tip of Yersinia type III secretion needles, or F1 capsule generated robust humoral immune responses. Whereas LcrV immunization resulted in partial protection against pneumonic plague challenge with 250 MLD Y. pestis CO92, immunization with recombinant F1 did not. rV10, a vaccine variant lacking LcrV residues 271-300, elicited protection against pneumonic plague, which seemed to be based on conformational antibodies directed against LcrV. Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

A novel recombinant Leishmania donovani p45, a partial coding region of methionine aminopeptidase, generates protective immunity by inducing a Th1 stimulatory response against experimental visceral leishmaniasis.

PubMed

Gupta, Reema; Kushawaha, Pramod K; Tripathi, Chandra Dev Pati; Sundar, Shyam; Dube, Anuradha

2012-05-01

The development of a vaccine against visceral leishmaniasis (VL) conferring long-lasting immunity remains a challenge. Identification and proteomic characterization of parasite proteins led to the detection of p45, a member of the methionine aminopeptidase family. To our knowledge the present study is the first known report that describes the molecular and immunological characterization of p45. Recombinant Leishmania donovani p45 (rLdp45) induced cellular responses in cured hamsters and generated Th1-type cytokines from peripheral blood mononuclear cells of cured/endemic VL patients. Immunization with rLdp45 exerted considerable prophylactic efficacy (∼85%) supported by an increase in mRNA expression of iNOS, IFN-γ, TNF-α and IL-12 and decrease in TGF-β and IL-4, indicating its potential as a vaccine candidate against VL. Copyright © 2012. Published by Elsevier Ltd.

Production of Escherichia coli heat labile toxin (LT) B subunit in soybean seed and analysis of its immunogenicity as an oral vaccine.

PubMed

Moravec, Tomas; Schmidt, Monica A; Herman, Eliot M; Woodford-Thomas, Terry

2007-02-19

The B subunit of the heat labile toxin of enterotoxigenic Escherichia coli (LTB) was used as a model immunogen for production in soybean seed. LTB expression was directed to the endoplasmic reticulum (ER) of seed storage parenchyma cells for sequestration in de novo synthesized inert protein accretions derived from the ER. Pentameric LTB accumulated to 2.4% of the total seed protein at maturity and was stable in desiccated seed. LTB-soybean extracts administered orally to mice induced both systemic IgG and IgA, and mucosal IgA antibody responses, and was particularly efficacious when used in a parenteral prime-oral gavage boost immunization strategy. Sera from immunized mice blocked ligand binding in vitro and immunized mice exhibited partial protection against LT challenge. Moreover, soybean-expressed LTB stimulated the antibody response against a co-administered antigen by 500-fold. These results demonstrate the utility of soybean as an efficient production platform for vaccines that can be used for oral delivery.

Reversible synthesis of colanic acid and O-antigen polysaccharides in Salmonella Typhimurium enhances induction of cross-immune responses and provides protection against heterologous Salmonella challenge.

PubMed

Li, Pei; Liu, Qing; Huang, Chun; Zhao, Xinxin; Roland, Kenneth L; Kong, Qingke

2017-05-15

Colanic Acid (CA) and lipopolysaccharide (LPS) are two major mannose-containing extracellular polysaccharides of Salmonella. Their presence on the bacterial surface can mask conserved protective outer membrane proteins (OMPs) from the host immune system. The mannose moiety in these molecules is derived from GDP-mannose, which is synthesized in several steps. The first two steps require the action of phosphomannose isomerase, encoded by pmi (manA), followed by phosphomannomutase, encoded by manB. There are two copies of manB present in the Salmonella chromosome, one located in the cps gene cluster (cpsG) responsible for CA synthesis, and the other in the rfb gene cluster (rfbK) involved in LPS O-antigen synthesis. In this study, it was demonstrated that the products of cpsG and rfbK are isozymes. To evaluate the impact of these genes on O-antigen synthesis, virulence and immunogenicity, single mutations (Δpmi, ΔrfbK or ΔcpsG) and a double mutation (ΔrfbK ΔcpsG) were introduced into both wild-type Salmonella enterica and an attenuated Δcya Δcrp vaccine strain. The Δpmi, ΔrfbK and ΔcpsG ΔrfbK mutants were defective in LPS synthesis and attenuated for virulence. In orally inoculated mice, strain S122 (Δcrp Δcya ΔcpsG ΔrfbK) and its parent S738 (Δcrp Δcya) were both avirulent and colonized internal tissues. Strain S122 elicited higher levels of anti-S. Typhimurium OMP serum IgG than its parent strain. Mice immunized with S122 were completely protected against challenge with wild-type virulent S. Typhimurium and partially protected against challenge with either wild-type virulent S. Choleraesuis or S. Enteritidis. These data indicate that deletions in rfbK and cpsG are useful mutations for inclusion in future attenuated Salmonella vaccine strains to induce cross-protective immunity. Copyright © 2017 Elsevier Ltd. All rights reserved.

Protection against rat vaginal candidiasis by adoptive transfer of vaginal B lymphocytes.

PubMed

De Bernardis, Flavia; Santoni, Giorgio; Boccanera, Maria; Lucciarini, Roberta; Arancia, Silvia; Sandini, Silvia; Amantini, Consuelo; Cassone, Antonio

2010-06-01

Vulvovaginal candidiasis is a mucosal infection affecting many women, but the immune mechanisms operating against Candida albicans at the mucosal level remain unknown. A rat model was employed to further characterize the contribution of B and T cells to anti-Candida vaginal protection. Particularly, the protective role of vaginal B cells was studied by means of adoptive transfer of vaginal CD3(-) CD5(+) IgM(+) cells from Candida-immunized rats to naïve animals. This passive transfer of B cells resulted into a number of vaginal C. albicans CFU approximately 50% lower than their controls. Sorted CD3(-) CD5(+) IgM(+) vaginal B lymphocytes from Candida-infected rats proliferated in response to stimulation with an immunodominant mannoprotein (MP) antigen of the fungus. Importantly, anti-MP antibodies and antibody-secreting B cells were detected in the supernatant and cell cultures, respectively, of vaginal B lymphocytes from infected rats incubated in vitro with vaginal T cells and stimulated with MP. No such specific antibodies were found when using vaginal B cells from uninfected rats. Furthermore, inflammatory and anti-inflammatory cytokines, such as interleukin-2 (IL-2), IL-6 and IL-10, were found in the supernatant of vaginal B cells from infected rats. These data are evidence of a partial anti-Candida protective role of CD3(-) CD5(+) IgM(+) vaginal B lymphocytes in our experimental model.

A Design Method for Topologically Insulating Metamaterials

NASA Astrophysics Data System (ADS)

Matlack, Kathryn; Serra-Garcia, Marc; Palermo, Antonio; Huber, Sebastian; Daraio, Chiara

Topological insulators are a unique class of electronic materials that exhibit protected edge states that are insulating in the bulk, and immune to back-scattering and defects. Discrete models, such as mass-spring systems, provide a means to translate these properties, based on the quantum hall spin effect, to the mechanical domain. This talk will present how to engineer a 2D mechanical metamaterial that supports topologically-protected and defect-immune edge states, directly from the mass-spring model of a topological insulator. The design method uses combinatorial searches plus gradient-based optimizations to determine the configuration of the metamaterials building blocks that leads to the global behavior specified by the target mass-spring model. We use metamaterials with weakly coupled unit cells to isolate the dynamics within our frequency range of interest and to enable a systematic design process. This approach can generally be applied to implement behaviors of a discrete model directly in mechanical, acoustic, or photonic metamaterials within the weak-coupling regime. This work was partially supported by the ETH Postdoctoral Fellowship, and by the Swiss National Science Foundation.

The neutralizing antibody response to the vaccinia virus A28 protein is specifically enhanced by its association with the H2 protein

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

Shinoda, Kaori; Wyatt, Linda S.; Moss, Bernard, E-mail: bmoss@niaid.nih.go

2010-09-15

The vaccinia virus (VACV) entry-fusion complex (EFC) is composed of at least nine membrane proteins. Immunization of mice with individual EFC genes induced corresponding protein-binding antibody but failed to protect against VACV intranasal challenge and only DNA encoding A28 elicited low neutralizing antibody. Because the A28 and H2 proteins interact, we determined the effect of immunizing with both genes simultaneously. This procedure greatly enhanced the amount of antibody that bound intact virions, neutralized infectivity, and provided partial protection against respiratory challenge. Neither injection of A28 and H2 plasmids at different sites or mixing A28 and H2 sera enhanced neutralizing antibody.more » The neutralizing antibody could be completely removed by binding to the A28 protein alone and the epitope was located in the C-terminal segment. These data suggest that the interaction of H2 with A28 stabilizes the immunogenic form of A28, mimicking an exposed region of the entry-fusion complex on infectious virions.« less

Observations on cattle schistosomiasis in the Sudan, a study in comparative medicine. III. Field testing of an irradiated Schistosoma bovis vaccine

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

Majid, A.A.; Bushera, H.O.; Saad, A.M.

1980-05-29

Previous work has shown that cattle can acquire a strong resistance to Schistosoma bovis infection following repeated natural exposure. Partial resistance to a laboratory challenge with S. bovis has also been demonstrated in calves after immunization with an irradiated schistosomular or cercarial vaccine. The aim of the present study was to see whether this type of caccine could protect calves under the very different conditions of natural exposure to S. bovis in the field. Thirty 6- to 9-month-old calves were each immunized with 10,000 irradiated S. bovis schistosomula by intramuscular injection and 8 weeks later were released into an enzooticmore » area along with 30 unvaccinated animals. The calves were followed up for 10 months, during which period protection was evidenced by a lower mortality rate, a slower rate of acquisition of infection, and lower fecal egg counts in the vaccinated calves. Necropsy of the survivors showed 60 to 70% reductions in worm and tissue egg counts of the vaccinated calves as compared to those not vaccinated.« less

Protective Efficacy of the Conserved NP, PB1, and M1 Proteins as Immunogens in DNA- and Vaccinia Virus-Based Universal Influenza A Virus Vaccines in Mice

PubMed Central

Wang, Wenling; Li, Renqing; Deng, Yao; Lu, Ning; Chen, Hong; Meng, Xin; Wang, Wen; Wang, Xiuping; Yan, Kexia; Qi, Xiangrong; Zhang, Xiangmin; Xin, Wei; Lu, Zhenhua; Li, Xueren; Bian, Tao; Gao, Yingying; Tan, Wenjie

2015-01-01

The conventional hemagglutinin (HA)- and neuraminidase (NA)-based influenza vaccines need to be updated most years and are ineffective if the glycoprotein HA of the vaccine strains is a mismatch with that of the epidemic strain. Universal vaccines targeting conserved viral components might provide cross-protection and thus complement and improve conventional vaccines. In this study, we generated DNA plasmids and recombinant vaccinia viruses expressing the conserved proteins nucleoprotein (NP), polymerase basic 1 (PB1), and matrix 1 (M1) from influenza virus strain A/Beijing/30/95 (H3N2). BALB/c mice were immunized intramuscularly with a single vaccine based on NP, PB1, or M1 alone or a combination vaccine based on all three antigens and were then challenged with lethal doses of the heterologous influenza virus strain A/PR/8/34 (H1N1). Vaccines based on NP, PB1, and M1 provided complete or partial protection against challenge with 1.7 50% lethal dose (LD50) of PR8 in mice. Of the three antigens, NP-based vaccines induced protection against 5 LD50 and 10 LD50 and thus exhibited the greatest protective effect. Universal influenza vaccines based on the combination of NP, PB1, and M1 induced a strong immune response and thus might be an alternative approach to addressing future influenza virus pandemics. PMID:25834017

Protective Efficacy of the Conserved NP, PB1, and M1 Proteins as Immunogens in DNA- and Vaccinia Virus-Based Universal Influenza A Virus Vaccines in Mice.

PubMed

Wang, Wenling; Li, Renqing; Deng, Yao; Lu, Ning; Chen, Hong; Meng, Xin; Wang, Wen; Wang, Xiuping; Yan, Kexia; Qi, Xiangrong; Zhang, Xiangmin; Xin, Wei; Lu, Zhenhua; Li, Xueren; Bian, Tao; Gao, Yingying; Tan, Wenjie; Ruan, Li

2015-06-01

The conventional hemagglutinin (HA)- and neuraminidase (NA)-based influenza vaccines need to be updated most years and are ineffective if the glycoprotein HA of the vaccine strains is a mismatch with that of the epidemic strain. Universal vaccines targeting conserved viral components might provide cross-protection and thus complement and improve conventional vaccines. In this study, we generated DNA plasmids and recombinant vaccinia viruses expressing the conserved proteins nucleoprotein (NP), polymerase basic 1 (PB1), and matrix 1 (M1) from influenza virus strain A/Beijing/30/95 (H3N2). BALB/c mice were immunized intramuscularly with a single vaccine based on NP, PB1, or M1 alone or a combination vaccine based on all three antigens and were then challenged with lethal doses of the heterologous influenza virus strain A/PR/8/34 (H1N1). Vaccines based on NP, PB1, and M1 provided complete or partial protection against challenge with 1.7 50% lethal dose (LD50) of PR8 in mice. Of the three antigens, NP-based vaccines induced protection against 5 LD50 and 10 LD50 and thus exhibited the greatest protective effect. Universal influenza vaccines based on the combination of NP, PB1, and M1 induced a strong immune response and thus might be an alternative approach to addressing future influenza virus pandemics. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Recombinant Salmonella Expressing Burkholderia mallei LPS O Antigen Provides Protection in a Murine Model of Melioidosis and Glanders

PubMed Central

Moustafa, Dina A.; Scarff, Jennifer M.; Garcia, Preston P.; Cassidy, Sara K. B.; DiGiandomenico, Antonio; Waag, David M.; Inzana, Thomas J.; Goldberg, Joanna B.

2015-01-01

Burkholderia pseudomallei and Burkholderia mallei are the etiologic agents of melioidosis and glanders, respectively. These bacteria are highly infectious via the respiratory route and can cause severe and often fatal diseases in humans and animals. Both species are considered potential agents of biological warfare; they are classified as category B priority pathogens. Currently there are no human or veterinary vaccines available against these pathogens. Consequently efforts are directed towards the development of an efficacious and safe vaccine. Lipopolysaccharide (LPS) is an immunodominant antigen and potent stimulator of host immune responses. B. mallei express LPS that is structurally similar to that expressed by B. pseudomallei, suggesting the possibility of constructing a single protective vaccine against melioidosis and glanders. Previous studies of others have shown that antibodies against B. mallei or B. pseudomallei LPS partially protect mice against subsequent lethal virulent Burkholderia challenge. In this study, we evaluated the protective efficacy of recombinant Salmonella enterica serovar Typhimurium SL3261 expressing B. mallei O antigen against lethal intranasal infection with Burkholderia thailandensis, a surrogate for biothreat Burkholderia spp. in a murine model that mimics melioidosis and glanders. All vaccine-immunized mice developed a specific antibody response to B. mallei and B. pseudomallei O antigen and to B. thailandensis and were significantly protected against challenge with a lethal dose of B. thailandensis. These results suggest that live-attenuated SL3261 expressing B. mallei O antigen is a promising platform for developing a safe and effective vaccine. PMID:26148026

Recombinant Salmonella Expressing Burkholderia mallei LPS O Antigen Provides Protection in a Murine Model of Melioidosis and Glanders.

PubMed

Moustafa, Dina A; Scarff, Jennifer M; Garcia, Preston P; Cassidy, Sara K B; DiGiandomenico, Antonio; Waag, David M; Inzana, Thomas J; Goldberg, Joanna B

2015-01-01

Burkholderia pseudomallei and Burkholderia mallei are the etiologic agents of melioidosis and glanders, respectively. These bacteria are highly infectious via the respiratory route and can cause severe and often fatal diseases in humans and animals. Both species are considered potential agents of biological warfare; they are classified as category B priority pathogens. Currently there are no human or veterinary vaccines available against these pathogens. Consequently efforts are directed towards the development of an efficacious and safe vaccine. Lipopolysaccharide (LPS) is an immunodominant antigen and potent stimulator of host immune responses. B. mallei express LPS that is structurally similar to that expressed by B. pseudomallei, suggesting the possibility of constructing a single protective vaccine against melioidosis and glanders. Previous studies of others have shown that antibodies against B. mallei or B. pseudomallei LPS partially protect mice against subsequent lethal virulent Burkholderia challenge. In this study, we evaluated the protective efficacy of recombinant Salmonella enterica serovar Typhimurium SL3261 expressing B. mallei O antigen against lethal intranasal infection with Burkholderia thailandensis, a surrogate for biothreat Burkholderia spp. in a murine model that mimics melioidosis and glanders. All vaccine-immunized mice developed a specific antibody response to B. mallei and B. pseudomallei O antigen and to B. thailandensis and were significantly protected against challenge with a lethal dose of B. thailandensis. These results suggest that live-attenuated SL3261 expressing B. mallei O antigen is a promising platform for developing a safe and effective vaccine.

Analysis of Vaginal Cell Populations during Experimental Vaginal Candidiasis

PubMed Central

Fidel, Paul L.; Luo, Wei; Steele, Chad; Chabain, Joseph; Baker, Marc; Wormley, Floyd

1999-01-01

Studies with an estrogen-dependent murine model of vaginal candidiasis suggest that local cell-mediated immunity (CMI) is more important than systemic CMI for protection against vaginitis. The present study, however, showed that, compared to uninfected mice, little to no change in the percentage or types of vaginal T cells occurred during a primary vaginal infection or during a secondary vaginal infection where partial protection was observed. Furthermore, depletion of polymorphonuclear leukocytes (PMN) had no effect on infection in the presence or absence of pseudoestrus. These results indicate a lack of demonstrable effects by systemic CMI or PMN against vaginitis and suggest that if local T cells are important, they are functioning without showing significant increases in numbers within the vaginal mucosa during infection. PMID:10338532

Dectin-1 Positive Dendritic Cells Expand after Infection with Leishmania major Parasites and Represent Promising Targets for Vaccine Development

PubMed Central

Zimara, Nicole; Chanyalew, Menberework; Aseffa, Abraham; van Zandbergen, Ger; Lepenies, Bernd; Schmid, Maximilian; Weiss, Richard; Rascle, Anne; Wege, Anja Kathrin; Jantsch, Jonathan; Schatz, Valentin; Brown, Gordon D.; Ritter, Uwe

2018-01-01

Resistant mouse strains mount a protective T cell-mediated immune response upon infection with Leishmania (L.) parasites. Healing correlates with a T helper (Th) cell-type 1 response characterized by a pronounced IFN-γ production, while susceptibility is associated with an IL-4-dependent Th2-type response. It has been shown that dermal dendritic cells are crucial for inducing protective Th1-mediated immunity. Additionally, there is growing evidence that C-type lectin receptor (CLR)-mediated signaling is involved in directing adaptive immunity against pathogens. However, little is known about the function of the CLR Dectin-1 in modulating Th1- or Th2-type immune responses by DC subsets in leishmaniasis. We characterized the expression of Dectin-1 on CD11c+ DCs in peripheral blood, at the site of infection, and skin-draining lymph nodes of L. major-infected C57BL/6 and BALB/c mice and in peripheral blood of patients suffering from cutaneous leishmaniasis (CL). Both mouse strains responded with an expansion of Dectin-1+ DCs within the analyzed tissues. In accordance with the experimental model, Dectin-1+ DCs expanded as well in the peripheral blood of CL patients. To study the role of Dectin-1+ DCs in adaptive immunity against L. major, we analyzed the T cell stimulating potential of bone marrow-derived dendritic cells (BMDCs) in the presence of the Dectin-1 agonist Curdlan. These experiments revealed that Curdlan induces the maturation of BMDCs and the expansion of Leishmania-specific CD4+ T cells. Based on these findings, we evaluated the impact of Curdlan/Dectin-1 interactions in experimental leishmaniasis and were able to demonstrate that the presence of Curdlan at the site of infection modulates the course of disease in BALB/c mice: wild-type BALB/c mice treated intradermally with Curdlan developed a protective immune response against L. major whereas Dectin-1−/− BALB/c mice still developed the fatal course of disease after Curdlan treatment. Furthermore, the vaccination of BALB/c mice with a combination of soluble L. major antigens and Curdlan was able to provide a partial protection from severe leishmaniasis. These findings indicate that the ligation of Dectin-1 on DCs acts as an important checkpoint in adaptive immunity against L. major and should therefore be considered in future whole-organism vaccination strategies. PMID:29535708

Factors that deregulate the protective immune response in tuberculosis.

PubMed

Hernandez-Pando, Rogelio; Orozco, Hector; Aguilar, Diana

2009-01-01

Tuberculosis (TB) is a chronic infectious disease which essentially affects the lungs and produces profound abnormalities on the immune system. Although most people infected by the tubercle bacillus (90%) do not develop the disease during their lifetime, when there are alterations in the immune system, such as co-infection with HIV, malnutrition, or diabetes, the risk of developing active disease increases considerably. Interestingly, during the course of active disease, even in the absence of immunosuppressive conditions, there is a profound and prolonged suppression of Mycobacterium tuberculosis-specific protective immune responses. Several immune factors can contribute to downregulate the protective immunity, permitting disease progression. In general, many of these factors are potent anti-inflammatory molecules that are probably overproduced with the intention to protect against tissue damage, but the consequence of this response is a decline in protective immunity facilitating bacilli growth and disease progression. Here the most significant participants in protective immunity are reviewed, in particular the factors that deregulate protective immunity in TB. Their manipulation as novel forms of immunotherapy are also briefly commented.

Differential protective effects of immune lymphoid cells against transplanted line Ib leukemia and immune polioencephalomyelitis. [X radiation, mice

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

Duffey, P.S.; Lukasewycz, O.A.; Olson, D.S.

1978-12-01

The capacity of immune cells obtained from the major lymphoid compartments to protect C58 mice from transplanted line Ib leukemia, and from an age-dependent autoimmune CNS disease (immune polioencephalomyelitis = IPE) elicited by immunizing old C58 mice with inactivated Ib cells was quantified. Cells used for comparative adoptive protection tests were harvested from the major lymphoid compartments 14 to 15 days after young C58 mice were immunized with inactivated Ib cell preparations. Regression curves were plotted from survival data and the log/sub 10/PD/sub 50/ values were determined. Immune spleen (ISC) and peritoneal cells (IPEC) were significantly more protective against transplantedmore » Ib cells than immune lymph node (ILNC), thymic (ITC), and marrow cells (IMC). In contrast, IPEC and IMC were not protective against IPE and ITC were only marginally protective. ILNC afforded significant protection to transplantable leukemia but were only marginally protective to IPE. When ISC were treated with anti-thy 1.2 serum and complement, protection against transplanted leukemia and IPE was reduced > 99%. When donors of immune lymphoid cells were treated with 12.5 mg of cortisone acetate daily for 2 days before lymphoid cells were harvested, protection against transplanted Ib cells by ISC was reduced by approximately 90% whereas protection against IPE was totally eliminated. Considered together, these results indicate that the protective mechanisms to transplantable leukemia and IPE differ significantly in the same indicator mouse strain.« less

Mathematical modeling of diphtheria transmission in Thailand.

PubMed

Sornbundit, Kan; Triampo, Wannapong; Modchang, Charin

2017-08-01

In this work, a mathematical model for describing diphtheria transmission in Thailand is proposed. Based on the course of diphtheria infection, the population is divided into 8 epidemiological classes, namely, susceptible, symptomatic infectious, asymptomatic infectious, carrier with full natural-acquired immunity, carrier with partial natural-acquired immunity, individual with full vaccine-induced immunity, and individual with partial vaccine-induced immunity. Parameter values in the model were either directly obtained from the literature, estimated from available data, or estimated by means of sensitivity analysis. Numerical solutions show that our model can correctly describe the decreasing trend of diphtheria cases in Thailand during the years 1977-2014. Furthermore, despite Thailand having high DTP vaccine coverage, our model predicts that there will be diphtheria outbreaks after the year 2014 due to waning immunity. Our model also suggests that providing booster doses to some susceptible individuals and those with partial immunity every 10 years is a potential way to inhibit future diphtheria outbreaks. Copyright © 2017 Elsevier Ltd. All rights reserved.

Understanding the transmission dynamics of respiratory syncytial virus using multiple time series and nested models.

PubMed

White, L J; Mandl, J N; Gomes, M G M; Bodley-Tickell, A T; Cane, P A; Perez-Brena, P; Aguilar, J C; Siqueira, M M; Portes, S A; Straliotto, S M; Waris, M; Nokes, D J; Medley, G F

2007-09-01

The nature and role of re-infection and partial immunity are likely to be important determinants of the transmission dynamics of human respiratory syncytial virus (hRSV). We propose a single model structure that captures four possible host responses to infection and subsequent reinfection: partial susceptibility, altered infection duration, reduced infectiousness and temporary immunity (which might be partial). The magnitude of these responses is determined by four homotopy parameters, and by setting some of these parameters to extreme values we generate a set of eight nested, deterministic transmission models. In order to investigate hRSV transmission dynamics, we applied these models to incidence data from eight international locations. Seasonality is included as cyclic variation in transmission. Parameters associated with the natural history of the infection were assumed to be independent of geographic location, while others, such as those associated with seasonality, were assumed location specific. Models incorporating either of the two extreme assumptions for immunity (none or solid and lifelong) were unable to reproduce the observed dynamics. Model fits with either waning or partial immunity to disease or both were visually comparable. The best fitting structure was a lifelong partial immunity to both disease and infection. Observed patterns were reproduced by stochastic simulations using the parameter values estimated from the deterministic models.

The herpes zoster subunit vaccine.

PubMed

Cunningham, Anthony L

2016-01-01

Herpes zoster (HZ) causes severe pain and rash in older people and may be complicated by prolonged pain (postherpetic neuralgia; PHN). HZ results from reactivation of latent varicella-zoster virus (VZV) infection, often associated with age related or other causes of decreased T cell immunity. A concentrated live attenuated vaccine boosts this immunity and provides partial protection against HZ, but this decreases with age and declines over 5-8 years. The new HZ subunit (HZ/su or Shingrix) vaccine combines a key surface VZV glycoprotein (E) with T cell boosting adjuvant (AS01B). It is highly efficacious in protection (97%) against HZ in immunocompetent subjects, with no decline in advancing age and protection maintained for >3 years. Phase I-II trials showed safety and similar immunogenicity in severely immunocompromised patients. Local injection site pain and swelling can be severe in a minority (9.5%) but is transient (2 days). The HZ/su vaccine appears very promising in immunocompetent patients in the ZoE-50 controlled trial. The unblinding of the current ZoE-50 trial and publication of results from the accompanying ZoE-70 trial will reveal more about its mechanism of action and its efficacy against PHN, particularly in subjects >70 years. Phase III trial results in immunocompromised patients are eagerly awaited.

Effective and lesion-free cutaneous influenza vaccination

PubMed Central

Wang, Ji; Li, Bo; Wu, Mei X.

2015-01-01

The current study details efficient lesion-free cutaneous vaccination via vaccine delivery into an array of micropores in the skin, instead of bolus injection at a single site. Such delivery effectively segregated vaccine-induced inflammation, resulting in rapid resolution of the inflammation, provided that distances between any two micropores were sufficient. When the inoculation site was treated by FDA-approved nonablative fractional laser (NAFL) before insertion of a PR8 model influenza vaccine-packaged, biodegradable microneedle array (MNs), mice displayed vigorous antigen-uptake, eliciting strong Th1-biased immunity. These animals were completely protected from homologous viral challenges, and fully or partially protected from heterologous H1N1 and H3N2 viral challenges, whereas mice receiving MNs alone suffered from severe illnesses or died of similar viral challenges. NAFL-mediated adjuvanicity was ascribed primarily to dsDNA and other “danger” signals released from laser-damaged skin cells. Thus, mice deficient in dsDNA-sensing pathway, but not Toll like receptor (TLR) or inflammasome pathways, showed poor responses to NAFL. Importantly, with this novel approach both mice and swine exhibited strong protective immunity without incurring any appreciable skin irritation, in sharp contrast to the overt skin irritation caused by intradermal injections. The effective lesion-free cutaneous vaccination merits further clinical studies. PMID:25848020

Immunity to Intracellular Salmonella Depends on Surface-associated Antigens

PubMed Central

Claudi, Beatrice; Mazé, Alain; Schemmer, Anne K.; Kirchhoff, Dennis; Schmidt, Alexander; Burton, Neil; Bumann, Dirk

2012-01-01

Invasive Salmonella infection is an important health problem that is worsening because of rising antimicrobial resistance and changing Salmonella serovar spectrum. Novel vaccines with broad serovar coverage are needed, but suitable protective antigens remain largely unknown. Here, we tested 37 broadly conserved Salmonella antigens in a mouse typhoid fever model, and identified antigen candidates that conferred partial protection against lethal disease. Antigen properties such as high in vivo abundance or immunodominance in convalescent individuals were not required for protectivity, but all promising antigen candidates were associated with the Salmonella surface. Surprisingly, this was not due to superior immunogenicity of surface antigens compared to internal antigens as had been suggested by previous studies and novel findings for CD4 T cell responses to model antigens. Confocal microscopy of infected tissues revealed that many live Salmonella resided alone in infected host macrophages with no damaged Salmonella releasing internal antigens in their vicinity. In the absence of accessible internal antigens, detection of these infected cells might require CD4 T cell recognition of Salmonella surface-associated antigens that could be processed and presented even from intact Salmonella. In conclusion, our findings might pave the way for development of an efficacious Salmonella vaccine with broad serovar coverage, and suggest a similar crucial role of surface antigens for immunity to both extracellular and intracellular pathogens. PMID:23093937

DNA vaccination with a plasmid encoding LACK-TSA fusion against Leishmania major infection in BALB/c mice.

PubMed

Maspi, N; Ghaffarifar, F; Sharifi, Z; Dalimi, A; Khademi, S Z

2017-12-01

Vaccination would be the most important strategy for the prevention and elimination of leishmaniasis. The aim of the present study was to compare the immune responses induced following DNA vaccination with LACK (Leishmania analogue of the receptor kinase C), TSA (Thiol-specific-antioxidant) genes alone or LACK-TSA fusion against cutaneous leishmaniasis (CL). Cellular and humoral immune responses were evaluated before and after challenge with Leishmania major (L. major). In addition, the mean lesion size was also measured from 3th week post-infection. All immunized mice showed a partial immunity characterized by higher interferon (IFN)-γ and Immunoglobulin G (IgG2a) levels compared to control groups (p<0.05). IFN-γ/ Interleukin (IL)-4 and IgG2a/IgG1 ratios demonstrated the highest IFN-γ and IgG2a levels in the group receiving LACK-TSA fusion. Mean lesion sizes reduced significantly in all immunized mice compared with control groups at 7th week post-infection (p<0.05). In addition, there was a significant reduction in mean lesion size of LACK-TSA and TSA groups than LACK group after challenge (p<0.05). In the present study, DNA immunization promoted Th1 immune response and confirmed the previous observations on immunogenicity of LACK and TSA antigens against CL. Furthermore, this study demonstrated that a bivalent vaccine can induce stronger immune responses and protection against infectious challenge with L. major.

Sublingual immunization with the phosphate-binding-protein (PstS) reduces oral colonization by Streptococcus mutans.

PubMed

Ferreira, E L; Batista, M T; Cavalcante, R C M; Pegos, V R; Passos, H M; Silva, D A; Balan, A; Ferreira, L C S; Ferreira, R C C

2016-10-01

Bacterial ATP-binding cassette (ABC) transporters play a crucial role in the physiology and pathogenicity of different bacterial species. Components of ABC transporters have also been tested as target antigens for the development of vaccines against different bacterial species, such as those belonging to the Streptococcus genus. Streptococcus mutans is the etiological agent of dental caries, and previous studies have demonstrated that deletion of the gene encoding PstS, the substrate-binding component of the phosphate uptake system (Pst), reduced the adherence of the bacteria to abiotic surfaces. In the current study, we generated a recombinant form of the S. mutans PstS protein (rPstS) with preserved structural features, and we evaluated the induction of antibody responses in mice after sublingual mucosal immunization with a formulation containing the recombinant protein and an adjuvant derived from the heat-labile toxin from enterotoxigenic Escherichia coli strains. Mice immunized with rPstS exhibited systemic and secreted antibody responses, measured by the number of immunoglobulin A-secreting cells in draining lymph nodes. Serum antibodies raised in mice immunized with rPstS interfered with the adhesion of bacteria to the oral cavity of naive mice challenged with S. mutans. Similarly, mice actively immunized with rPstS were partially protected from oral colonization after challenge with the S. mutans NG8 strain. Therefore, our results indicate that S. mutans PstS is a potential target antigen capable of inducing specific and protective antibody responses after sublingual administration. Overall, these observations raise interesting perspectives for the development of vaccines to prevent dental caries. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Anti-bacterial immunity to Listeria monocytogenes in allogeneic bone marrow chimera in mice

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

Onoe, K.; Good, R.A.; Yamamoto, K.

1986-06-01

Protection and delayed-type hypersensitivity (DTH) to the facultative intracellular bacterium Listeria monocytogenes (L.m.) were studied in allogeneic and syngeneic bone marrow chimeras. Lethally irradiated AKR (H-2k) mice were successfully reconstituted with marrow cells from C57BL/10 (B10) (H-2b), B10 H-2-recombinant strains or syngeneic mice. Irradiated AKR mice reconstituted with marrow cells from H-2-compatible B10.BR mice, (BR----AKR), as well as syngeneic marrow cells, (AKR----AKR), showed a normal level of responsiveness to the challenge stimulation with the listeria antigens when DTH was evaluated by footpad reactions. These mice also showed vigorous activities in acquired resistance to the L.m. By contrast, chimeric mice thatmore » had total or partial histoincompatibility at the H-2 determinants between donor and recipient, (B10----AKR), (B10.AQR----AKR), (B10.A(4R)----AKR), or (B10.A(5R)----AKR), were almost completely unresponsive in DTH and antibacterial immunity. However, when (B10----AKR) H-2-incompatible chimeras had been immunized with killed L.m. before challenge with live L.m., these mice manifested considerable DTH and resistance to L.m. These observations suggest that compatibility at the entire MHC between donor and recipient is required for bone marrow chimeras to be able to manifest DTH and protection against L.m. after a short-term immunization schedule. However, this requirement is overcome by a preceding or more prolonged period of immunization with L.m. antigens. These antigens, together with marrow-derived antigen-presenting cells, can then stimulate and expand cell populations that are restricted to the MHC (H-2) products of the donor type.« less

The temperature-sensitive mutants of Toxoplasma gondii and ocular toxoplasmosis.

PubMed

Lu, Fangli; Huang, Shiguang; Kasper, Lloyd H

2009-01-22

The risk of blindness caused by ocular toxoplasmosis supports efforts to improve our understanding for control of this disease. In this study, the involvement of CD8(+), CD4(+), B cell, and IL-10 gene in the immune response of primary ocular infection with the temperature-sensitive mutant (ts-4) of the RH Toxoplasma gondii strain, and in the protective immunity of ocular ts-4 vaccination and challenge with RH strain was investigated in murine models utilizing inbred C57BL/6 mice-deficient in CD4(+), CD8(+), B cells (microMT), or IL-10 gene. Compared to naive mice, all WT and mutant mice had different degree of ocular pathological changes after ts-4 ocular infection, in which both CD8 KO and IL-10 KO mice showed the most severe ocular lesions. Immunized by ts-4 intracameral (i.c.) inoculation, all mutant mice had partially decreased vaccine-induced resistance associated with increased ocular parasite burdens after RH strain challenge. A significant increase of the percentages of B cells and CD8(+) T cells in the draining lymph nodes were observed in WT and IL-10 KO mice after either infection or challenge. The levels of specific anti-toxoplasma IgG in both eye fluid and serum from all the mice were significantly increased after ts-4 i.c. immunization, except microMT mice. These results suggest that the avirulent ts-4 of T. gondii inoculated intracamerally can induce both ocular pathology and ocular protective immunity; CD4(+), CD8(+), B cell, and IL-10 gene are all necessary to the vaccine-induced resistance to ocular challenge by virulent RH strain, in which CD8(+) T cells are the most important component.

Pre-clinical evaluation of a replication-competent recombinant adenovirus serotype 4 vaccine expressing influenza H5 hemagglutinin.

PubMed

Alexander, Jeff; Ward, Simone; Mendy, Jason; Manayani, Darly J; Farness, Peggy; Avanzini, Jenny B; Guenther, Ben; Garduno, Fermin; Jow, Lily; Snarsky, Victoria; Ishioka, Glenn; Dong, Xin; Vang, Lo; Newman, Mark J; Mayall, Tim

2012-01-01

Influenza virus remains a significant health and social concern in part because of newly emerging strains, such as avian H5N1 virus. We have developed a prototype H5N1 vaccine using a recombinant, replication-competent Adenovirus serotype 4 (Ad4) vector, derived from the U.S. military Ad4 vaccine strain, to express the hemagglutinin (HA) gene from A/Vietnam/1194/2004 influenza virus (Ad4-H5-Vtn). Our hypothesis is that a mucosally-delivered replicating Ad4-H5-Vtn recombinant vector will be safe and induce protective immunity against H5N1 influenza virus infection and disease pathogenesis. The Ad4-H5-Vtn vaccine was designed with a partial deletion of the E3 region of Ad4 to accommodate the influenza HA gene. Replication and growth kinetics of the vaccine virus in multiple human cell lines indicated that the vaccine virus is attenuated relative to the wild type virus. Expression of the HA transgene in infected cells was documented by flow cytometry, western blot analysis and induction of HA-specific antibody and cellular immune responses in mice. Of particular note, mice immunized intranasally with the Ad4-H5-Vtn vaccine were protected against lethal H5N1 reassortant viral challenge even in the presence of pre-existing immunity to the Ad4 wild type virus. Several non-clinical attributes of this vaccine including safety, induction of HA-specific humoral and cellular immunity, and efficacy were demonstrated using an animal model to support Phase 1 clinical trial evaluation of this new vaccine.

Eimeria maxima microneme protein 2 delivered as DNA vaccine and recombinant protein induces immunity against experimental homogenous challenge.

PubMed

Huang, Jingwei; Zhang, Zhenchao; Li, Menghui; Song, Xiaokai; Yan, Ruofeng; Xu, Lixin; Li, Xiangrui

2015-10-01

E. maxima is one of the seven species of Eimeria that infects chicken. Until now, only a few antigenic genes of E. maxima have been reported. In the present study, the immune protective effects against E. maxima challenge of recombinant protein and DNA vaccine encoding EmMIC2 were evaluated. Two-week-old chickens were randomly divided into five groups. The experimental group of chickens was immunized with 100 μg DNA vaccine pVAX1-MIC2 or 200 μg rEmMIC2 protein while the control group of chickens was injected with pVAX1 plasmid or sterile PBS. The results showed that the anti-EmMIC2 antibody titers of both rEmMIC2 protein and pVAX1-MIC2 groups were significantly higher as compared to PBS and pVAX1 control (P<0.05). The splenocytes from both vaccinated groups of chickens displayed significantly greater proliferation compared with the controls (P<0.05). Serum from chickens immunized with pVAX1-MIC2 and rEmMIC2 protein displayed significantly high levels of IL-2, IFN-γ, IL-10, IL-17, TGF-β and IL-4 (P<0.05) compared to those of negative controls. The challenge experiment results showed that both the recombinant protein and the DNA vaccine could obviously alleviate jejunum lesions, body weight loss, increase oocyst, decrease ratio and provide ACIs of more than 165. All the above results suggested that immunization with EmMIC2 was effective in imparting partial protection against E. maxima challenge and it could be an effective antigen candidate for the development of new vaccines against E. maxima. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Systems analysis of protective immune responses to RTS,S malaria vaccination in humans

PubMed Central

Kazmin, Dmitri; Nakaya, Helder I.; Lee, Eva K.; Johnson, Matthew J.; van der Most, Robbert; van den Berg, Robert A.; Ballou, W. Ripley; Jongert, Erik; Wille-Reece, Ulrike; Ockenhouse, Christian; Aderem, Alan; Zak, Daniel E.; Sadoff, Jerald; Hendriks, Jenny; Wrammert, Jens; Ahmed, Rafi; Pulendran, Bali

2017-01-01

RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in ∼50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4+ T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination. PMID:28193898

Maternal Immunization with Chimpanzee Adenovirus Expressing RSV Fusion Protein Protects Against Neonatal RSV Pulmonary Infection

PubMed Central

Sharma, Anurag; Wendland, Rebecca; Sung, Biin; Wu, Wendy; Grunwald, Thomas; Worgall, Stefan

2014-01-01

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease with high morbidity and mortality in young infants and children. Despite numerous efforts, a licensed vaccine against RSV remains elusive. Since young infants form the primary target group of RSV disease, maternal immunization to boost the protection in neonates is an attractive strategy. In this study we tested the efficacy of maternal immunization with a chimpanzee adenovirus expressing codon-optimized RSV fusion protein (AdC7-Fsyn) to protect infants against RSV infection. Single intranasal immunization of mice by AdC7-Fsyn induced robust anti-RSV systemic and mucosal immunity that protected against RSV without causing vaccine-enhanced RSV disease. RSV humoral immunity was transferred to pups born to immunized mothers that provided protection against RSV. Immunization with AdC7-Fsyn was effective even in the presence of Ad5 preimmunity. The maternally derived immunity was durable with the half-life of 14.63 days that reduced the viral replication up to 15 weeks of age. Notably, the passively immunized mice could be actively re-immunized with AdC7-Fsyn to boost and extend the protection. This substantiates maternal immunization with an AdC7-based vaccine expressing RSV F as feasible approach to protect against RSV early in life. PMID:25171847

Yersinia outer proteins (YOPS) E, K and N are antigenic but non-protective compared to V antigen, in a murine model of bubonic plague.

PubMed

Leary, S E; Griffin, K F; Galyov, E E; Hewer, J; Williamson, E D; Holmström, A; Forsberg, A; Titball, R W

1999-03-01

The pathogenic Yersiniae produce a range of virulence proteins, encoded by a 70 kb plasmid, which are essential for infection, and also form part of a contact-dependent virulence mechanism. One of these proteins, V antigen, has been shown to confer a high level of protection against parenteral infection with Y. pestis in murine models, and is considered to be a protective antigen. In this study, the protective efficacy of V antigen has been compared in the same model with that of other proteins (YopE, YopK and YopN), which are part of the contact-dependent virulence mechanism. Mice immunised with two intraperitoneal doses of V antigen or each of the Yops, administered with either Alhydrogel or interleukin-12, produced high antigen-specific serum IgG titres. As shown in previous studies, V+Alhydrogel was fully protective, and 5/5 mice survived a subcutaneous challenge with 90 or 9x10(3) LD50's of Y. pestis GB. In addition, these preliminary studies also showed that V+IL-12 was partially protective: 4/5 or 3/5 mice survived a challenge with 90 or 9x10(3) LD50's, respectively. In contrast, none of the mice immunised with the Yops survived the challenges, and there was no significant delay in the mean time to death compared to mice receiving a control protein. These results show that using two different vaccine regimens, Yops E, K and N, failed to elicit protective immune responses in a murine model of plague, whereas under the same conditions, V antigen was fully or partially protective. Copyright 1999 Academic Press.

Cross-protective efficacy of Leishmania infantum LiHyD protein against tegumentary leishmaniasis caused by Leishmania major and Leishmania braziliensis species.

PubMed

Lage, Daniela Pagliara; Martins, Vívian Tamietti; Duarte, Mariana Costa; Costa, Lourena Emanuele; Tavares, Grasiele de Sousa Vieira; Ramos, Fernanda Fonseca; Chávez-Fumagalli, Miguel Angel; Menezes-Souza, Daniel; Roatt, Bruno Mendes; Tavares, Carlos Alberto Pereira; Coelho, Eduardo Antonio Ferraz

2016-06-01

Vaccination can be considered the most cost-effective strategy to control neglected diseases, but nowadays there is not an effective vaccine available against leishmaniasis. In the present study, a vaccine based on the combination of the Leishmania-specific hypothetical protein (LiHyD) with saponin was tested in BALB/c mice against infection caused by Leishmania major and Leishmania braziliensis species. This antigen was firstly identified in Leishmania infantum and showed to be protective against infection of BALB/c mice using this parasite species. The immunogenicity of rLiHyD/saponin vaccine was evaluated, and the results showed that immunized mice produced high levels of IFN-γ, IL-12 and GM-CSF after in vitro stimulation with rLiHyD, as well as by using L. major or L. braziliensis protein extracts. After challenge, vaccinated animals showed significant reductions in the infected footpad swellings, as well as in the parasite burden in the infection site, liver, spleen, and infected paws draining lymph nodes, when compared to those that were inoculated with the vaccine diluent (saline) or immunized with saponin. The immunization of rLiHyD without adjuvant was not protective against both challenges. The partial protection obtained by the rLiHyD/saponin vaccine was associated with a parasite-specific IL-12-dependent IFN-γ secretion, which was produced mainly by CD4(+) T cells. In these animals, a decrease in the parasite-mediated IL-4 and IL-10 responses, associated with the presence of high levels of LiHyD- and parasite-specific IgG2a isotype antibodies, were also observed. The present study showed that a hypothetical protein that was firstly identified in L. infantum, when combined to a Th1 adjuvant, was able to confer a cross-protection against highly infective stationary-phase promastigotes of two Leishmania species causing tegumentary leishmaniasis. Copyright © 2016 Elsevier B.V. All rights reserved.

The Lectin Complement Pathway Is Involved in Protection Against Enteroaggregative Escherichia coli Infection.

PubMed

Adler Sørensen, Camilla; Rosbjerg, Anne; Hebbelstrup Jensen, Betina; Krogfelt, Karen Angeliki; Garred, Peter

2018-01-01

Enteroaggregative Escherichia coli (EAEC) causes acute and persistent diarrhea worldwide. Still, the involvement of host factors in EAEC infections is unresolved. Binding of recognition molecules from the lectin pathway of complement to EAEC strains have been observed, but the importance is not known. Our aim was to uncover the involvement of these molecules in innate complement dependent immune protection toward EAEC. Binding of mannose-binding lectin, ficolin-1, -2, and -3 to four prototypic EAEC strains, and ficolin-2 binding to 56 clinical EAEC isolates were screened by a consumption-based ELISA method. Flow cytometry was used to determine deposition of C4b, C3b, and the bactericidal C5b-9 membrane attack complex (MAC) on the bacteria in combination with different complement inhibitors. In addition, the direct serum bactericidal effect was assessed. Screening of the prototypic EAEC strains revealed that ficolin-2 was the major binder among the lectin pathway recognition molecules. However, among the clinical EAEC isolates only a restricted number ( n  = 5) of the isolates bound ficolin-2. Using the ficolin-2 binding isolate C322-17 as a model, we found that incubation with normal human serum led to deposition of C4b, C3b, and to MAC formation. No inhibition of complement deposition was observed when a C1q inhibitor was added, while partial inhibition was observed when ficolin-2 or factor D inhibitors were used separately. Combining the inhibitors against ficolin-2 and factor D led to virtually complete inhibition of complement deposition and protection against direct bacterial killing. These results demonstrate that ficolin-2 may play an important role in innate immune protection against EAEC when an appropriate ligand is exposed, but many EAEC strains evade lectin pathway recognition and may, therefore, circumvent this strategy of innate host immune protection.

Intramuscular Adeno-Associated Virus-Mediated Expression of Monoclonal Antibodies Provides 100% Protection Against Ebola Virus Infection in Mice.

PubMed

van Lieshout, Laura P; Soule, Geoff; Sorensen, Debra; Frost, Kathy L; He, Shihua; Tierney, Kevin; Safronetz, David; Booth, Stephanie A; Kobinger, Gary P; Qiu, Xiangguo; Wootton, Sarah K

2018-03-05

The 2013-2016 West Africa outbreak demonstrated the epidemic potential of Ebola virus and highlighted the need for counter strategies. Monoclonal antibody (mAb)-based therapies hold promise as treatment options for Ebola virus infections. However, production of clinical-grade mAbs is labor intensive, and immunity is short lived. Conversely, adeno-associated virus (AAV)-mediated mAb gene transfer provides the host with a genetic blueprint to manufacture mAbs in vivo, leading to steady release of antibody over many months. Here we demonstrate that AAV-mediated expression of nonneutralizing mAb 5D2 or 7C9 confers 100% protection against mouse-adapted Ebola virus infection, while neutralizing mAb 2G4 was 83% protective. A 2-component cocktail, AAV-2G4/AAV-5D2, provided complete protection when administered 7 days prior to challenge and was partially protective with a 3-day lead time. Finally, AAV-mAb therapies provided sustained protection from challenge 5 months following AAV administration. AAV-mAb may be a viable alternative strategy for vaccination against emerging infectious diseases.

Fractional Third and Fourth Dose of RTS,S/AS01 Malaria Candidate Vaccine: A Phase 2a Controlled Human Malaria Parasite Infection and Immunogenicity Study.

PubMed

Regules, Jason A; Cicatelli, Susan B; Bennett, Jason W; Paolino, Kristopher M; Twomey, Patrick S; Moon, James E; Kathcart, April K; Hauns, Kevin D; Komisar, Jack L; Qabar, Aziz N; Davidson, Silas A; Dutta, Sheetij; Griffith, Matthew E; Magee, Charles D; Wojnarski, Mariusz; Livezey, Jeffrey R; Kress, Adrian T; Waterman, Paige E; Jongert, Erik; Wille-Reece, Ulrike; Volkmuth, Wayne; Emerling, Daniel; Robinson, William H; Lievens, Marc; Morelle, Danielle; Lee, Cynthia K; Yassin-Rajkumar, Bebi; Weltzin, Richard; Cohen, Joe; Paris, Robert M; Waters, Norman C; Birkett, Ashley J; Kaslow, David C; Ballou, W Ripley; Ockenhouse, Christian F; Vekemans, Johan

2016-09-01

Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses. In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months. A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge. A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria. NCT01857869. Published by Oxford University Press on behalf of the Infectious Diseases Society of America, 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Influence of Route of Administration on Immediate and Extended Protection in Rats Immunized with Escherichia coli Heat-Labile Enterotoxin

PubMed Central

Klipstein, Frederick A.; Engert, Richard F.

1980-01-01

The effect of route of administration, dosage, and number of boosts employed during immunization with the polymyxin-release form of Escherichia coli heat-labile (LT) enterotoxin on the degree and duration of protection afforded was evaluated in rats which were challenged by the ligated loop technique. Increasing the boosting dosage by fivefold from 50 to 250 μg resulted in a marked increase in protection against challenge with toxin in rats immunized either just by the parenteral route (i.p./i.p.) or by a parenteral prime, followed by peroral boosts (i.p./p.o.) in rats pretreated with cimetidine to ablate gastric secretions; such was not the case, however, even with a 50-fold increase in dosage in rats immunized just by the peroral route (p.o./p.o.). Four weekly peroral boosts were required to achieve the strongest degree of protection. Increasing the boosting dosage also increased the degree of protection against challenge with viable LT+/ST− and LT+/ST+ strains (ST indicates heat-stable enterotoxin) in rats immunized by the i.p./p.o., but not by the i.p./i.p., route; no protection was evident against an LT−/ST+ strain. Protection was lost within 3 weeks after immunization in rats immunized by the i.p./i.p. route. In contrast, protection was extended over the 3-month observation period in those immunized by the i.p./p.o. route; the degree of protection was enhanced in rats which received an additional boost at 2 months. These observations establish the fact that immunization with LT is similar to that with cholera toxin in that arousal of the local immune intestinal response by means of peroral immunization provides maximal extended protection. PMID:6987180

Dietary docosahexaenoic acid alleviates autistic-like behaviors resulting from maternal immune activation in mice.

PubMed

Weiser, Michael J; Mucha, Brittany; Denheyer, Heather; Atkinson, Devon; Schanz, Norman; Vassiliou, Evros; Benno, Robert H

2016-03-01

The prevalence of autism spectrum disorders over the last several decades has risen at an alarming rate. Factors such as broadened clinical definitions and increased parental age only partially account for this precipitous increase, suggesting that recent changes in environmental factors may also be responsible. One such factor could be the dramatic decrease in consumption of anti-inflammatory dietary omega-3 (n-3) polyunsaturated fatty acids (PUFAs) relative to the amount of pro-inflammatory omega-6 (n-6) PUFAs and saturated fats in the Western diet. Docosahexaenoic acid (DHA) is the principle n-3 PUFA found in neural tissue and is important for optimal brain development, especially during late gestation when DHA rapidly and preferentially accumulates in the brain. In this study, we tested whether supplementation of a low n-3 PUFA diet with DHA throughout development could improve measures related to autism in a mouse model of maternal immune activation. We found that dietary DHA protected offspring from the deleterious effects of gestational exposure to the viral mimetic polyriboinosinic-polyribocytidilic acid on behavioral measures of autism and subsequent adulthood immune system reactivity. These data suggest that elevated dietary levels of DHA, especially during pregnancy and nursing, may help protect normal neurodevelopment from the potentially adverse consequences of environmental insults like maternal infection. Copyright © 2015 Elsevier Ltd. All rights reserved.

A novel chimeric Newcastle disease virus vectored vaccine against highly pathogenic avian influenza virus.

PubMed

Kim, Shin-Hee; Paldurai, Anandan; Samal, Siba K

2017-03-01

Avian influenza (AI) is an economically-important disease of poultry worldwide. The use of vaccines to control AI has increased because of frequent outbreaks of the disease in endemic countries. Newcastle disease virus (NDV) vectored vaccine has shown to be effective in protecting chickens against a highly pathogenic avian influenza virus (HPAIV) infection. However, preexisting antibodies to NDV vector might affect protective efficacy of the vaccine in the field. As an alternative strategy, we evaluated vaccine efficacy of a chimeric NDV vectored vaccine in which the ectodomains of F and HN proteins were replaced by those of avian paramyxovirus serotype-2. The chimeric NDV vector stably expressed the HA protein in vivo, did not cross-react with NDV, was attenuated to be used as a safe vaccine, and provided a partial protection of 1-day-old immunized chickens against HPAIV subtype H5N1challenge, indicating its potential use for early protection of chickens. Copyright © 2017 Elsevier Inc. All rights reserved.

Dicer-2-Dependent Generation of Viral DNA from Defective Genomes of RNA Viruses Modulates Antiviral Immunity in Insects.

PubMed

Poirier, Enzo Z; Goic, Bertsy; Tomé-Poderti, Lorena; Frangeul, Lionel; Boussier, Jérémy; Gausson, Valérie; Blanc, Hervé; Vallet, Thomas; Loyd, Hyelee; Levi, Laura I; Lanciano, Sophie; Baron, Chloé; Merkling, Sarah H; Lambrechts, Louis; Mirouze, Marie; Carpenter, Susan; Vignuzzi, Marco; Saleh, Maria-Carla

2018-03-14

The RNAi pathway confers antiviral immunity in insects. Virus-specific siRNA responses are amplified via the reverse transcription of viral RNA to viral DNA (vDNA). The nature, biogenesis, and regulation of vDNA are unclear. We find that vDNA produced during RNA virus infection of Drosophila and mosquitoes is present in both linear and circular forms. Circular vDNA (cvDNA) is sufficient to produce siRNAs that confer partially protective immunity when challenged with a cognate virus. cvDNAs bear homology to defective viral genomes (DVGs), and DVGs serve as templates for vDNA and cvDNA synthesis. Accordingly, DVGs promote the amplification of vDNA-mediated antiviral RNAi responses in infected Drosophila. Furthermore, vDNA synthesis is regulated by the DExD/H helicase domain of Dicer-2 in a mechanism distinct from its role in siRNA generation. We suggest that, analogous to mammalian RIG-I-like receptors, Dicer-2 functions like a pattern recognition receptor for DVGs to modulate antiviral immunity in insects. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Effect of a cocoa-enriched diet on immune response and anaphylaxis in a food allergy model in Brown Norway rats.

PubMed

Abril-Gil, Mar; Pérez-Cano, Francisco J; Franch, Àngels; Castell, Margarida

2016-01-01

Previous studies have demonstrated that cocoa intake decreased Th2 immune-related antibodies in rats. In consequence, we aimed to study in depth this cocoa action, particularly assessing its effect on a rat model of food allergy (FA) and also on an anaphylactic response. The involvement of the intestinal immune system was analyzed to allow the action mechanisms to be investigated. The role of cocoa flavonoids in the antiallergic properties of cocoa was also established. Brown Norway rats were fed either a reference diet or diets containing conventional cocoa (CC) or nonfermented cocoa (NFC). FA to ovalbumin (OVA) was induced and, later, an anaphylactic response was provoked. As expected, the synthesis of anti-OVA IgE and other Th2-related antibodies was inhibited by CC diet. In addition, the release of mast cell protease II after anaphylaxis was partially prevented by CC, although other variables were not modified. The CC diet also attenuated the increase of some Th2-related cytokines released from mesenteric lymph node and spleen cells, and modulated the intestinal gene expression of molecules involved in allergic response. These results demonstrated the local and systemic influence of CC diet. The effects of the NFC diet were weaker than those of CC, suggesting that cocoa components other than flavonoids play a role in cocoa's action. In conclusion, by acting on intestinal and systemic immune functions, a cocoa-enriched diet in rats exhibited a protective effect against FA and partially against anaphylaxis, making this a food of high interest to the fields of health and immunonutrition. Copyright © 2015 Elsevier Inc. All rights reserved.

Comparison of immune responses to different foot-and-mouth disease genetically engineered vaccines in guinea pigs.

PubMed

Yao, Qingxia; Qian, Ping; Huang, Qinfeng; Cao, Yi; Chen, Huanchun

2008-01-01

The P12A3C gene from FMDV (serotype O) encoding the capsid precursor protein, and the highly immunogenic gene FHG, which encodes multiple epitopes of FMDV capsid proteins, were inserted into eukaryotic expression vectors to compare different candidate genetically engineered vaccines for foot-and-mouth disease (FMD). A modified live pseudorabies virus (MLPRV) was also used to deliver P12A3C. Guinea pigs were inoculated intramuscularly with the candidate vaccines to compare the ability to elicit immunity of the DNA vector and a live viral vector. An indirect enzyme-linked immunosorbent assay (iELISA), virus-neutralization test and lymphoproliferation assay were used to detect antibody and cellular responses. The group immunized with P12A3C delivered by MLPRV produced significantly greater antibody and cellular responses indicating that MLPRV has a greater ability to mediate exogenous gene delivery than the plasmid DNA vector. Comparison of the immune responses induced by P12A3C and FHG, which were both mediated by DNA plasmids, showed that FHG and P12A3C elicited similar cellular responses, while P12A3C induced higher antibody levels, suggesting that P12A3C is a more powerful immunogen than FHG. In challenge experiments, guinea pigs vaccinated with P12A3C delivered by MLPRV were protected fully from FMDV challenge, whereas guinea pigs vaccinated with P12A3C or FHG delivered by DNA plasmid were only protected partially. This study provides a basis for future construction of a genetically engineered vaccine for FMDV.

Transcutaneous immunization with cross-reacting material CRM(197) of diphtheria toxin boosts functional antibody levels in mice primed parenterally with adsorbed diphtheria toxoid vaccine.

PubMed

Stickings, Paul; Peyre, Marisa; Coombes, Laura; Muller, Sylviane; Rappuoli, Rino; Del Giudice, Giuseppe; Partidos, Charalambos D; Sesardic, Dorothea

2008-04-01

Transcutaneous immunization (TCI) capitalizes on the accessibility and immunocompetence of the skin, elicits protective immunity, simplifies vaccine delivery, and may be particularly advantageous when frequent boosting is required. In this study we examined the potential of TCI to boost preexisting immune responses to diphtheria in mice. The cross-reacting material (CRM(197)) of diphtheria toxin was used as the boosting antigen and was administered alone or together with either one of two commonly used mucosal adjuvants, cholera toxin (CT) and a partially detoxified mutant of heat-labile enterotoxin of Escherichia coli (LTR72). We report that TCI with CRM(197) significantly boosted preexisting immune responses elicited after parenteral priming with aluminum hydroxide-adsorbed diphtheria toxoid (DTxd) vaccine. In the presence of LTR72 as an adjuvant, toxin-neutralizing antibody titers were significantly higher than those elicited by CRM(197) alone and were comparable to the functional antibody levels induced after parenteral booster immunization with the adsorbed DTxd vaccine. Time course study showed that high levels of toxin-neutralizing antibodies persisted for at least 14 weeks after the transcutaneous boost. In addition, TCI resulted in a vigorous antigen-specific proliferative response in all groups of mice boosted with the CRM(197) protein. These findings highlight the promising prospect of using booster administrations of CRM(197) via the transcutaneous route to establish good herd immunity against diphtheria.

Immunity to sporozoite-induced malaria infection in mice. I. The effect of immunization of T and B cell-deficient mice. [X Radiation

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

Chen, D.H.; Tigelaar, R.E.; Weinbaum, F.I.

1977-04-01

The cellular basis of immunity to sporozoites was investigated by examining the effect of immunization of T and B cell-deficient C57BL/6N x BALB/c AnN F/sub 1/ (BLCF/sub 1/) mice compared to immunocompetent controls. Immunization of T cell-deficient (ATX-BM-ATS) BLCF/sub 1/ mice with x-irradiated sporozoites did not result in the generation of protective immunity. The same immunization protocols protected all immunocompetent controls. In contrast, B cell-deficient (..mu..-suppressed) BLCF/sub 1/ mice were protected by immunization in the majority of cases. The absence of detectable serum circumsporozoite precipitins or sporozoite neutralizing activity in the ..mu..-suppressed mice that resisted a sporozoite challenge suggests amore » minor role for these humoral factors in protection. These data demonstrate a preeminent role for T cells in the induction of protective immunity in BLCF/sub 1/ mice against a P. berghei sporozoite infection.« less

Diverse manifestations of tumorigenicity and immunogenicity displayed by the poorly immunogenic B16-BL6 melanoma transduced with cytokine genes.

PubMed

Arca, M J; Krauss, J C; Strome, S E; Cameron, M J; Chang, A E

1996-05-01

We evaluated the in vivo response to the poorly immunogenic B16-BL6 (BL6) murine melanoma genetically altered to secrete interleukin-2 (IL-2), IL-4, interferon gamma (IFN gamma) and granulocyte/macrophage-colony-stimulating factor (GM-CSF). Three parameters were evaluated: (1) tumorigenicity, (2) vaccination of naive animals, and (3) assessment of antitumor reactivity of T cells derived from tumor-draining lymph nodes (TDLN). Secretion of IL-2 abrogated the tumorigenicity of BL6, while IFN gamma and IL-4 partially reduced tumorigenicity, and GM-CSF had no effect. Protective immunity to wild-type tumor challenge could not be achieved by vaccination with irradiated cytokine-secreting tumors, although IL-2 and IL-4 secretion appeared to retard the growth of the challenge inoculum significantly. An alternative method to evaluate the immunogenicity of the cytokine-secreting tumors was to measure the ability of T cells obtained from TDLN to mediate regression of wild-type tumor in adoptive immunotherapy. Neither IL-2 nor IFN gamma secretion resulted in the induction of immune T cells. By contrast, GM-CSF and IL-4 secretion were found to induce immune T cells in the TDLN with GM-CSF being superior to IL-4. The combined secretion of GM-CSF and IL-4 did not lead to enhanced induction of immune T cells. GM-CSF secretion was found to upregulate B7-1 expression in TDLN, consistent with an increase in the population of antigen-presenting cells. These studies demonstrated that reduced tumorigenicity by cytokine secretion did not correlate with increased immunogenicity. With the cytokines examined, there was limited capability of developing protective immunity against the BL6 tumor. Nevertheless, GM-CSF and IL-4 secretion significantly enhanced T cell immune reactivity to the poorly immunogenic BL6 tumor.

Induction of Protective Immunity against Toxoplasmosis in BALB/c Mice Vaccinated with Toxoplasma gondii Rhoptry-1

PubMed Central

Sonaimuthu, Parthasarathy; Ching, Xiao T.; Fong, Mun Y.; Kalyanasundaram, Ramaswamy; Lau, Yee L.

2016-01-01

Toxoplasma gondii is the causative agent for toxoplasmosis. The rhoptry protein 1 (ROP1) is secreted by rhoptry, an apical secretory organelle of the parasite. ROP1 plays an important role in host cell invasion. In this study, the efficacy of ROP1 as a vaccine candidate against toxoplasmosis was evaluated through intramuscular or subcutaneous injection of BALB/c mice followed by immunological characterization (humoral- and cellular-mediated) and lethal challenge against virulent T. gondii RH strain in BALB/c mice. Briefly, a recombinant DNA plasmid (pVAX1-GFP-ROP1) was expressed in CHO cells while expression of recombinant ROP1 protein (rROP1) was carried out in Escherichia coli expression system. Immunization study involved injection of the recombinant pVAX1-ROP1 and purified rROP1 into different group of mice. Empty vector and PBS served as two different types of negative controls. Results obtained demonstrated that ROP1 is an immunogenic antigen that induced humoral immune response whereby detection of a protein band with expected size of 43 kDa was observed against vaccinated mice sera through western blot analysis. ROP1 antigen was shown to elicit cellular-mediated immunity as well whereby stimulated splenocytes with total lysate antigen (TLA) and rROP1 from pVAX1-ROP1 and rROP1-immunized mice, respectively, readily proliferated and secreted large amount of IFN-γ (712 ± 28.1 pg/ml and 1457 ± 31.19 pg/ml, respectively) and relatively low IL-4 level (94 ± 14.5 pg/ml and 186 ± 14.17 pg/ml, respectively). These phenomena suggested that Th1-favored immunity was being induced. Vaccination with ROP1 antigen was able to provide partial protection in the vaccinated mice against lethal challenge with virulent RH strain of tachyzoites. These findings proposed that the ROP1 antigen is a potential candidate for the development of vaccine against toxoplasmosis. PMID:27303390

Friends and foes of tuberculosis: modulation of protective immunity.

PubMed

Brighenti, Susanna; Joosten, Simone A

2018-05-27

Protective immunity in tuberculosis (TB) is subject of debate in the TB research community, as this is key to fully understand TB pathogenesis and to develop new promising tools for TB diagnosis and prognosis as well as a more efficient TB vaccine. IFN-γ producing CD4 + T cells are key in TB control, but may not be sufficient to provide protection. Additional subsets have been identified that contribute to protection such as multifunctional and cytolytic T cell subsets, including classical and non-classical T cells as well as novel innate immune cell subsets resulting from trained immunity. However, to define protective immune responses against TB, the complexity of balancing TB immunity also has to be considered. In this review, insights in effector cell immunity and how this is modulated by regulatory cells, associated comorbidities and the host microbiome is discussed. We systematically map how different suppressive immune cell subsets may affect effector cell responses at the local site of infection. We also dissect how common co-morbidities such as HIV, helminthes and diabetes may bias protective TB immunity towards pathogenic and regulatory responses. Finally, also the composition and diversity of the microbiome in the lung and gut could affect host TB immunity. Understanding these various aspects of the immunological balance in the human host is fundamental to prevent TB infection and disease. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Establishing a small animal model for evaluating protective immunity against mumps virus.

PubMed

Pickar, Adrian; Xu, Pei; Elson, Andrew; Zengel, James; Sauder, Christian; Rubin, Steve; He, Biao

2017-01-01

Although mumps vaccines have been used for several decades, protective immune correlates have not been defined. Recently, mumps outbreaks have occurred in vaccinated populations. To better understand the causes of the outbreaks and to develop means to control outbreaks in mumps vaccine immunized populations, defining protective immune correlates will be critical. Unfortunately, no small animal model for assessing mumps immunity exists. In this study, we evaluated use of type I interferon (IFN) alpha/beta receptor knockout mice (IFN-α/βR-/-) for such a model. We found these mice to be susceptible to mumps virus administered intranasally and intracranially. Passive transfer of purified IgG from immunized mice protected naïve mice from mumps virus infection, confirming the role of antibody in protection and demonstrating the potential for this model to evaluate mumps immunity.

Pertussis Maternal Immunization: Narrowing the Knowledge Gaps on the Duration of Transferred Protective Immunity and on Vaccination Frequency

PubMed Central

Gaillard, María Emilia; Bottero, Daniela; Zurita, María Eugenia; Carriquiriborde, Francisco; Martin Aispuro, Pablo; Bartel, Erika; Sabater-Martínez, David; Bravo, María Sol; Castuma, Celina; Hozbor, Daniela Flavia

2017-01-01

Maternal safety through pertussis vaccination and subsequent maternal–fetal-antibody transfer are well documented, but information on infant protection from pertussis by such antibodies and by subsequent vaccinations is scarce. Since mice are used extensively for maternal-vaccination studies, we adopted that model to narrow those gaps in our understanding of maternal pertussis immunization. Accordingly, we vaccinated female mice with commercial acellular pertussis (aP) vaccine and measured offspring protection against Bordetella pertussis challenge and specific-antibody levels with or without revaccination. Maternal immunization protected the offspring against pertussis, with that immune protection transferred to the offspring lasting for several weeks, as evidenced by a reduction (4–5 logs, p < 0.001) in the colony-forming-units recovered from the lungs of 16-week-old offspring. Moreover, maternal-vaccination-acquired immunity from the first pregnancy still conferred protection to offspring up to the fourth pregnancy. Under the conditions of our experimental protocol, protection to offspring from the aP-induced immunity is transferred both transplacentally and through breastfeeding. Adoptive-transfer experiments demonstrated that transferred antibodies were more responsible for the protection detected in offspring than transferred whole spleen cells. In contrast to reported findings, the protection transferred was not lost after the vaccination of infant mice with the same or other vaccine preparations, and conversely, the immunity transferred from mothers did not interfere with the protection conferred by infant vaccination with the same or different vaccines. These results indicated that aP-vaccine immunization of pregnant female mice conferred protective immunity that is transferred both transplacentally and via offspring breastfeeding without compromising the protection boostered by subsequent infant vaccination. These results—though admittedly not necessarily immediately extrapolatable to humans—nevertheless enabled us to test hypotheses under controlled conditions through detailed sampling and data collection. These findings will hopefully refine hypotheses that can then be validated in subsequent human studies. PMID:28932228

Vaccine-induced, simian immunodeficiency virus-specific CD8+ T cells reduce virus replication but do not protect from simian immunodeficiency virus disease progression.

PubMed

Engram, Jessica C; Dunham, Richard M; Makedonas, George; Vanderford, Thomas H; Sumpter, Beth; Klatt, Nichole R; Ratcliffe, Sarah J; Garg, Seema; Paiardini, Mirko; McQuoid, Monica; Altman, John D; Staprans, Silvija I; Betts, Michael R; Garber, David A; Feinberg, Mark B; Silvestri, Guido

2009-07-01

Our limited understanding of the interaction between primate lentiviruses and the host immune system complicates the design of an effective HIV/AIDS vaccine. To identify immunological correlates of protection from SIV disease progression, we immunized two groups of five rhesus macaques (RMs) with either modified vaccinia Ankara (MVA) or MVADeltaudg vectors that expressed SIVmac239 Gag and Tat. Both vectors raised a SIV-specific CD8(+) T cell response, with a magnitude that was greater in mucosal tissues than in peripheral blood. After challenge with SIVmac239, all vaccinated RMs showed mucosal and systemic CD8(+) T cell recall responses that appeared faster and were of greater magnitude than those in five unvaccinated control animals. All vaccinated RMs showed a approximately 1-log lower peak and early set-point SIV viral load than the unvaccinated animals, and then, by 8 wk postchallenge, exhibited levels of viremia similar to the controls. We observed a significant direct correlation between the magnitude of postchallenge SIV-specific CD8(+) T cell responses and SIV viral load. However, vaccinated RMs showed no protection from either systemic or mucosal CD4(+) T cell depletion and no improved survival. The observation that vaccine-induced, SIV-specific CD8(+) T cells that partially control SIVmac239 virus replication fail to protect from immunological or clinical progression of SIV infection underscores both the complexity of AIDS pathogenesis and the challenges of properly assessing the efficacy of candidate AIDS vaccines.

Tumor-targeted IL-2 amplifies T cell-mediated immune response induced by gene therapy with single-chain IL-12

PubMed Central

Lode, Holger N.; Xiang, Rong; Duncan, Steven R.; Theofilopoulos, Argyrios N.; Gillies, Stephen D.; Reisfeld, Ralph A.

1999-01-01

Induction, maintenance, and amplification of tumor-protective immunity after cytokine gene therapy is essential for the clinical success of immunotherapeutic approaches. We investigated whether this could be achieved by single-chain IL-12 (scIL-12) gene therapy followed by tumor-targeted IL-2 using a fusion protein containing a tumor-specific recombinant anti-ganglioside GD2 antibody and IL-2 (ch14.18-IL-2) in a poorly immunogenic murine neuroblastoma model. Herein, we demonstrate the absence of liver and bone marrow metastases after a lethal challenge with NXS2 wild-type cells only in mice (five of six animals) vaccinated with scIL-12-producing NXS2 cells and given a booster injection of low-dose ch14.18-IL-2 fusion protein. This tumor-protective immunity was effective 3 months after initial vaccination, in contrast to control animals treated with a nonspecific fusion protein or an equivalent mixture of antibody and IL-2. Only vaccinated mice receiving the tumor-specific ch14.18-IL-2 fusion protein revealed a reactivation of CD8+ T cells and subsequent MHC class I-restricted tumor target cell lysis in vitro. The sequential increase in the usage of TCR chains Vβ11 and -13 in mouse CD8+ T cells after vaccination and amplification with ch14.18-IL-2 suggests that the initial polyclonal CD8+ T cell response is effectively boosted by targeted IL-2. In conclusion, we demonstrate that a successful boost of a partially protective memory T cell immune response that is induced by scIL-12 gene therapy could be generated by tumor-specific targeting of IL-2 with a ch14.18-IL-2 fusion protein. This approach could increase success rates of clinical cancer vaccine trials. PMID:10411920

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.

Immunogenicity and protective efficacy of an elastase-dependent live attenuated swine influenza virus vaccine administered intranasally in pigs.

PubMed

Masic, Aleksandar; Lu, Xinya; Li, Junwei; Mutwiri, George K; Babiuk, Lorne A; Brown, Earl G; Zhou, Yan

2010-10-08

Influenza A virus is an important respiratory pathogen of swine that causes significant morbidity and economic impact on the swine industry. Vaccination is the first choice for prevention and control of influenza infections. Live attenuated influenza vaccines (LAIV) are approved for use in humans and horses and their application provides broad protective immunity, however no LAIV against swine influenza virus (SIV) exists in the market. Previously we reported that an elastase-dependent mutant SIV A/Sw/Sk-R345V (R345V) derived from A/Sw/Saskatchewan/18789/02 (H1N1) (SIV/Sk02) is highly attenuated in pigs. Two intratracheal administrations of R345V induced strong cell-mediated and humoral immune responses and provided a high degree of protection to antigenically different SIV infection in pigs. Here we evaluated the immunogenicity and the protective efficacy of R345V against SIV infection by intranasal administration, the more practical route for vaccination of pigs in the field. Our data showed that intranasally administered R345V live vaccine is capable of inducing strong antigen-specific IFN-γ response from local tracheo-bronchial lymphocytes and antibody responses in serum and respiratory mucosa after two applications. Intranasal vaccination of R345V provided pigs with complete protection not only from parental wild type virus infection, but also from homologous antigenic variant A/Sw/Indiana/1726/88 (H1N1) infection. Moreover, intranasal administration of R345V conferred partial protection from heterologous subtypic H3N2 SIV infection in pigs. Thus, R345V elastase-dependent mutant SIV can serve as a live vaccine against antigenically different swine influenza viruses in pigs. Copyright © 2010 Elsevier Ltd. All rights reserved.

TpUB05, a Homologue of the Immunodominant Plasmodium falciparum Protein UB05, Is a Marker of Protective Immune Responses in Cattle Experimentally Vaccinated against East Coast Fever

PubMed Central

Dinga, Jerome Nyhalah; Wamalwa, Mark; Njimoh, Dieudonné Lemuh; Njahira, Moses N.; Djikeng, Appolinaire; Skilton, Rob; Titanji, Vincent Pryde Kehdingha; Pellé, Roger

2015-01-01

Introduction East Coast fever, a devastating disease of cattle, can be controlled partially by vaccination with live T. parva sporozoites. The antigens responsible for conferring immunity are not fully characterized. Recently it was shown that the P. falciparum immunodominant protein UB05 is highly conserved in T. parva, the causative agent of East Coast fever. The aim of the present investigation was to determine the role of the homologue TpUB05 in protective immunity to East Coast fever. Methods The cloning, sequencing and expression of TpUB05 were done according to standard protocols. Bioinformatics analysis of TpUB05 gene was carried out using algorithms found in the public domain. Polyclonal antiserum against recombinant TpUB05 were raised in rabbits and used for further analysis by Western blotting, ELISA, immunolocalization and in vitro infection neutralization assay. The ability of recombinant TpUB05 (r-TpUB05) to stimulate bovine PBMCs ex-vivo to produce IFN-γ or to proliferate was tested using ELISpot and [3H]-thymidine incorporation assays, respectively. Results All the 20 cattle immunised by the infection and treatment method (ITM) developed significantly higher levels of TpUB05 specific antibodies (p<0.0001) compared to the non-vaccinated ones. Similarly, r-TpUB05 highly stimulated bovine PMBCs from 8/12 (67%) of ITM-immunized cattle tested to produce IFN-γ and proliferate (p< 0.029) as compared to the 04 naїve cattle included as controls. Polyclonal TpUB05 antiserum raised against r-TpUB05 also marginally inhibited infection (p < 0.046) of bovine PBMCs by T. parva sporozoites. In further experiments RT-PCR showed that the TpUB05 gene is expressed by the parasite. This was confirmed by immunolocalization studies which revealed TpUB05 expression by schizonts and piroplasms. Bioinformatics analysis also revealed that this antigen possesses two transmembrane domains, a N-glycosylation site and several O-glycosylation sites. Conclusion It was concluded that TpUB05 is a potential marker of protective immunity in ECF worth investigating further. PMID:26053064

TpUB05, a Homologue of the Immunodominant Plasmodium falciparum Protein UB05, Is a Marker of Protective Immune Responses in Cattle Experimentally Vaccinated against East Coast Fever.

PubMed

Dinga, Jerome Nyhalah; Wamalwa, Mark; Njimoh, Dieudonné Lemuh; Njahira, Moses N; Djikeng, Appolinaire; Skilton, Rob; Titanji, Vincent Pryde Kehdingha; Pellé, Roger

2015-01-01

East Coast fever, a devastating disease of cattle, can be controlled partially by vaccination with live T. parva sporozoites. The antigens responsible for conferring immunity are not fully characterized. Recently it was shown that the P. falciparum immunodominant protein UB05 is highly conserved in T. parva, the causative agent of East Coast fever. The aim of the present investigation was to determine the role of the homologue TpUB05 in protective immunity to East Coast fever. The cloning, sequencing and expression of TpUB05 were done according to standard protocols. Bioinformatics analysis of TpUB05 gene was carried out using algorithms found in the public domain. Polyclonal antiserum against recombinant TpUB05 were raised in rabbits and used for further analysis by Western blotting, ELISA, immunolocalization and in vitro infection neutralization assay. The ability of recombinant TpUB05 (r-TpUB05) to stimulate bovine PBMCs ex-vivo to produce IFN-γ or to proliferate was tested using ELISpot and [3H]-thymidine incorporation assays, respectively. All the 20 cattle immunised by the infection and treatment method (ITM) developed significantly higher levels of TpUB05 specific antibodies (p<0.0001) compared to the non-vaccinated ones. Similarly, r-TpUB05 highly stimulated bovine PMBCs from 8/12 (67%) of ITM-immunized cattle tested to produce IFN-γ and proliferate (p< 0.029) as compared to the 04 naїve cattle included as controls. Polyclonal TpUB05 antiserum raised against r-TpUB05 also marginally inhibited infection (p < 0.046) of bovine PBMCs by T. parva sporozoites. In further experiments RT-PCR showed that the TpUB05 gene is expressed by the parasite. This was confirmed by immunolocalization studies which revealed TpUB05 expression by schizonts and piroplasms. Bioinformatics analysis also revealed that this antigen possesses two transmembrane domains, a N-glycosylation site and several O-glycosylation sites. It was concluded that TpUB05 is a potential marker of protective immunity in ECF worth investigating further.

Optimal vaccination and bednet maintenance for the control of malaria in a region with naturally acquired immunity.

PubMed

Prosper, Olivia; Ruktanonchai, Nick; Martcheva, Maia

2014-07-21

Following over two decades of research, the malaria vaccine candidate RTS,S has reached the final stages of vaccine trials, demonstrating an efficacy of roughly 50% in young children. Regions with high malaria prevalence tend to have high levels of naturally acquired immunity (NAI) to severe malaria; NAI is caused by repeated exposure to infectious bites and results in large asymptomatic populations. To address concerns about how these vaccines will perform in regions with existing NAI, we developed a simple malaria model incorporating vaccination and NAI. Typically, if the basic reproduction number (R0) for malaria is greater than unity, the disease will persist; otherwise, the disease will become extinct. However, analysis of this model revealed that NAI, compounded by a subpopulation with only partial protection to malaria, may render vaccination efforts ineffective and potentially detrimental to malaria control, by increasing R0 and increasing the likelihood of malaria persistence even when R0<1. The likelihood of this scenario increases when non-immune infected individuals are treated disproportionately compared with partially immune individuals - a plausible scenario since partially immune individuals are more likely to be asymptomatically infected. Consequently, we argue that active case-detection of asymptomatic infections is a critical component of an effective malaria control program. We then investigated optimal vaccination and bednet control programs under two endemic settings with varying levels of naturally acquired immunity: a typical setting under which prevalence decays when R0<1, and a setting in which subthreshold endemic equilibria exist. A qualitative comparison of the optimal control results under the first setting revealed that the optimal policy differs depending on whether the goal is to reduce total morbidity, or to reduce clinical infections. Furthermore, this comparison dictates that control programs should place less effort in vaccination as the level of NAI in a population, and as disease prevalence, increases. In the second setting, we demonstrated that the optimal policy is able to confer long-term benefits with a 10-year control program by pushing the system into a new state where the disease-free equilibrium becomes the attracting equilibrium. While this result suggests that one can theoretically achieve long-term benefits with a short-term strategy, we illustrate that in this second setting, a small environmental change, or the introduction of new cases via immigration, places the population at high risk for a malaria epidemic. Copyright © 2014 Elsevier Ltd. All rights reserved.

Persistent infection with ebola virus under conditions of partial immunity.

PubMed

Gupta, Manisha; Mahanty, Siddhartha; Greer, Patricia; Towner, Jonathan S; Shieh, Wun-Ju; Zaki, Sherif R; Ahmed, Rafi; Rollin, Pierre E

2004-01-01

Ebola hemorrhagic fever in humans is associated with high mortality; however, some infected hosts clear the virus and recover. The mechanisms by which this occurs and the correlates of protective immunity are not well defined. Using a mouse model, we determined the role of the immune system in clearance of and protection against Ebola virus. All CD8 T-cell-deficient mice succumbed to subcutaneous infection and had high viral antigen titers in tissues, whereas mice deficient in B cells or CD4 T cells cleared infection and survived, suggesting that CD8 T cells, independent of CD4 T cells and antibodies, are critical to protection against subcutaneous Ebola virus infection. B-cell-deficient mice that survived the primary subcutaneous infection (vaccinated mice) transiently depleted or not depleted of CD4 T cells also survived lethal intraperitoneal rechallenge for >/==" BORDER="0">25 days. However, all vaccinated B-cell-deficient mice depleted of CD8 T cells had high viral antigen titers in tissues following intraperitoneal rechallenge and died within 6 days, suggesting that memory CD8 T cells by themselves can protect mice from early death. Surprisingly, vaccinated B-cell-deficient mice, after initially clearing the infection, were found to have viral antigens in tissues later (day 120 to 150 post-intraperitoneal infection). Furthermore, following intraperitoneal rechallenge, vaccinated B-cell-deficient mice that were transiently depleted of CD4 T cells had high levels of viral antigen in tissues earlier (days 50 to 70) than vaccinated undepleted mice. This demonstrates that under certain immunodeficiency conditions, Ebola virus can persist and that loss of primed CD4 T cells accelerates the course of persistent infections. These data show that CD8 T cells play an important role in protection against acute disease, while both CD4 T cells and antibodies are required for long-term protection, and they provide evidence of persistent infection by Ebola virus suggesting that under certain conditions of immunodeficiency a host can harbor virus for prolonged periods, potentially acting as a reservoir.

Phytomonas serpens: immunological similarities with the human trypanosomatid pathogens.

PubMed

Santos, André L S; d'Avila-Levy, Claudia M; Elias, Camila G R; Vermelho, Alane B; Branquinha, Marta H

2007-07-01

The present review provides an overview of recent discoveries concerning the immunological similarities between Phytomonas serpens, a tomato parasite, and human trypanosomatid pathogens, with special emphasis on peptidases. Leishmania spp. and Trypanosoma cruzi express peptidases that are well-known virulence factors, named leishmanolysin and cruzipain. P. serpens synthesizes two distinct classes of proteolytic enzymes, metallo- and cysteine-type peptidases, that share common epitopes with leishmanolysin and cruzipain, respectively. The leishmanolysin-like and cruzipain-like molecules from P. serpens participate in several biological processes including cellular growth and adhesion to the salivary glands of Oncopeltus fasciatus, a phytophagous insect experimental model. Since previous reports demonstrated that immunization of mice with P. serpens induced a partial protective immune response against T. cruzi, this plant trypanosomatid may be a suitable candidate for vaccine studies. Moreover, comparative approaches in the Trypanosomatidae family may be useful to understand kinetoplastid biology, biochemistry and evolution.

Use of the nonavalent HPV vaccine in individuals previously fully or partially vaccinated with bivalent or quadrivalent HPV vaccines.

PubMed

Van Damme, Pierre; Bonanni, Paolo; Bosch, F Xavier; Joura, Elmar; Kjaer, Susanne Krüger; Meijer, Chris J L M; Petry, Karl-Ulrich; Soubeyrand, Benoit; Verstraeten, Thomas; Stanley, Margaret

2016-02-03

With the availability of the nonavalent human papillomavirus (HPV) vaccine, vaccinees, parents and healthcare providers need guidance on how to complete an immunization course started with the bi- or quadrivalent vaccine and whether to revaccinate individuals who have completed a full immunization course with the bi- or quadrivalent vaccine. To answer these questions three parameters should be considered: age at the start of vaccination (9 to 14 years of age versus 15 years and older, the cut-off for 2 or 3 doses schedule), the number of doses already received and the time interval between doses. Based on a number of scenarios, we propose that the 9-valent vaccine can be used to complete an incomplete vaccination regimen or might be added to a previous completed schedule to extend protection. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

HIV and HLA Class I: an evolving relationship

PubMed Central

Goulder, Philip J.R.; Walker, Bruce D

2014-01-01

Successful vaccine development for infectious diseases has largely been achieved in settings where natural immunity to the pathogen results in clearance in at least some individuals. HIV presents an additional challenge in that natural clearance of infection does not occur, and the correlates of immune protection are still uncertain. However, partial control of viremia and markedly different outcomes of disease are observed in HIV infected persons. Here we examine the antiviral mechanisms implicated by one variable that has been consistently associated with extremes of outcome, namely HLA class I alleles, and in particular HLA-B, and examine the mechanisms by which this modulation is likely to occur, and the impact of these interactions on evolution of the virus and the host. Studies to date provide evidence for both HLA-dependent and epitope-dependent influences on viral control and viral evolution, and have important implications for the continued quest for an effective HIV vaccine. PMID:22999948

Community Immunity: How Vaccines Protect Us All

MedlinePlus

... Issues Subscribe October 2011 Print this issue Community Immunity How Vaccines Protect Us All Send us your ... This type of protection is known as “community immunity” or “herd immunity.” When enough of the community ...

'My child did not like using sun protection': practices and perceptions of child sun protection among rural black African mothers.

PubMed

Kunene, Zamantimande; Albers, Patricia N; Lucas, Robyn M; Banwell, Cathy; Mathee, Angela; Wright, Caradee Y

2017-08-25

Photodamage is partially mitigated by darker skin pigmentation, but immune suppression, photoaging and cataracts occur among individuals with all skin types. To assess practices and acceptability to Black African mothers of sun protection equipment for their children living in a rural area, participants were recruited at the time of their child's 18-month vaccinations. Mothers completed a baseline questionnaire on usual sun behaviours and sun protection practices. They were then provided with sun protection equipment and advice. A follow-up questionnaire was administered two weeks later. Mothers reported that during the week prior to the baseline questionnaire, children spent on average less than 1 hour of time outdoors (most often spent in the shade). Most mothers (97%) liked the sun protection equipment. However, many (78 of 86) reported that their child did not like any of the sun protection equipment and two-thirds stated that the sun protection equipment was not easy to use. Among Black Africans in rural northern South Africa, we found a mismatch between parental preferences and child acceptance for using sun protection when outdoors. A better understanding of the health risks of incidental excess sun exposure and potential benefits of sun protection is required among Black Africans.

[Advances in molecular mechanisms of adaptive immunity mediated by type I-E CRISPR/Cas system--A review].

PubMed

Sun, Dongchang; Qiu, Juanping

2016-01-04

To better adapt to the environment, prokaryocyte can take up exogenous genes (from bacteriophages, plasmids or genomes of other species) through horizontal gene transfer. Accompanied by the acquisition of exogenous genes, prokaryocyte is challenged by the invasion of 'selfish genes'. Therefore, to protect against the risk of gene transfer, prokaryocyte needs to establish mechanisms for selectively taking up or degrading exogenous DNA. In recent years, researchers discovered an adaptive immunity, which is mediated by the small RNA guided DNA degradation, prevents the invasion of exogenous genes in prokaryocyte. During the immune process, partial DNA fragments are firstly integrated.to the clustered regularly interspaced short palindromic repeats (CRISPR) located within the genome DNA, and then the mature CRISPR RNA transcript and the CRISPR associated proteins (Cas) form a complex CRISPR/Cas for degrading exogenous DNA. In this review, we will first briefly describe the CRISPR/Cas systems and then mainly focus on the recent advances of the function mechanism and the regulation mechanism of the type I-E CRISPR/Cas system in Escherichia coli.

Current thinking on genital herpes.

PubMed

Hofstetter, Annika M; Rosenthal, Susan L; Stanberry, Lawrence R

2014-02-01

Genital herpes has a high global prevalence and burden of disease. This manuscript highlights recent advances in our understanding of genital herpes simplex virus (HSV) infections. Studies demonstrate a changing epidemiological landscape with an increasing proportion of genital herpes cases associated with HSV type 1. There is also growing evidence that the majority of infected individuals exhibit frequent, brief shedding episodes that are most often asymptomatic, which likely contribute to high HSV transmission rates. Given this finding as well as readily available serological assays, some have proposed that routine HSV screening be performed; however, this remains controversial and is not currently recommended. Host immune responses, particularly local CD4 and CD8 T cell activity, are crucial for HSV control and clearance following initial infection, during latency and after reactivation. Prior HSV immunity may also afford partial protection against HSV reinfection and disease. Although HSV vaccine trials have been disappointing to date and existing antiviral medications are limited, novel prophylactic and therapeutic modalities are currently in development. Although much remains unknown about genital herpes, improved knowledge of HSV epidemiology, pathogenesis and host immunity may help guide new strategies for disease prevention and control.

Development of TV003/TV005, a single dose, highly immunogenic live attenuated dengue vaccine; what makes this vaccine different from the Sanofi-Pasteur CYD™ vaccine?

PubMed

Whitehead, Stephen S

2016-01-01

Dengue is caused by four serotype-distinct dengue viruses (DENVs), and developing a multivalent vaccine against dengue has not been straightforward since partial immunity to DENV may predispose to more severe disease upon subsequent DENV infection. The vaccine that is furthest along in development is CYD™, a live attenuated tetravalent vaccine (LATV) produced by Sanofi Pasteur. Although the multi-dose vaccine demonstrated protection against severe dengue, its overall efficacy was limited by DENV serotype, serostatus at vaccination, region and age. The National Institute of Allergy and Infectious Diseases has developed the LATV dengue vaccines TV003/TV005. A single dose of either TV003 or TV005 induced seroconversion to four DENV serotypes in 74-92% (TV003) and 90% (TV005) of flavivirus seronegative adults and elicited near-sterilizing immunity to a second dose of vaccine administered 6-12 months later. The important differences in the structure, infectivity and immune responses to TV003/TV005 are compared with CYD™.

Importance of exercise immunology in health promotion.

PubMed

Neto, J C Rosa; Lira, F S; de Mello, M T; Santos, Ronaldo Vagner T

2011-11-01

Chronic physical exercise with adequate intensity and volume associated with sufficient recovery promotes adaptations in several physiological systems. While intense and exhaustive exercise is considered an important immunosuppressor agent and increases the incidence of upper respiratory tract infections (URTI), moderate regular exercise has been associated with significant disease protection and is a complementary treatment of many chronic diseases. The effects of chronic exercise occur because physical training can induce several physiological, biochemical and psychological adaptations. More recently, the effect of acute exercise and training on the immunological system has been discussed, and many studies suggest the importance of the immune system in prevention and partial recovery in pathophysiological situations. Currently, there are two important hypotheses that may explain the effects of exercise and training on the immune system. These hypotheses including (1) the effect of exercise upon hormones and cytokines (2) because exercise can modulate glutamine concentration. In this review, we discuss the hypothesis that exercise may modulate immune functions and the importance of exercise immunology in respect to chronic illnesses, chronic heart failure, malnutrition and inflammation.

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.

Reevaluating leishmanin skin test as a marker for immunity against cutaneous leishmaniasis.

PubMed

Momeni Boroujeni, Amir; Aminjavaheri, Malih; Moshtaghian, Bahador; Momeni, Arash; Momeni, Ali Z

2013-07-01

The leishmanin skin test (LST) has been used for clinical diagnosis of leishmaniasis and epidemiological studies of the disease. Thus far, evidence has suggested that LST conversion indicates a degree of protection against leishmaniasis. In this study, we have put this assumption to test. A total of 273 participants with positive LST living in a hyperendemic area for leishmaniasis were followed for three years for any occurrence of cutaneous leishmaniasis. Twenty-two of the 273 participants contracted leishmaniasis during the 3-year follow-up. These new cases included participants who had a previous history of active disease, those who had a history of leishmanization, or those who were suspected of having a history of subclinical infection. In this study, the incidence of leishmaniasis in individuals with positive LST was close to the general incidence of the disease in the same hyperendemic area. These results suggest that although LST conversion may be a marker for partial immunity towards leishmaniasis, it may not, however, indicate complete protection against the disease, and consequently there is a need for revision of current vaccine development approaches which are based on rendering vaccinated individuals LST positive. © 2013 The International Society of Dermatology.

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.

Effectiveness analyses may underestimate protection of infants after group C meningococcal immunization.

PubMed

Vu, David M; Kelly, Dominic; Heath, Paul T; McCarthy, Noel D; Pollard, Andrew J; Granoff, Dan M

2006-07-15

Group C meningococcal conjugate-vaccine effectiveness in the United Kingdom declines from ~90% in the first year to 0% between 1 and 4 years after immunization in infants immunized at 2, 3, and 4 months of age and to 61% in toddlers given a single dose. Confidence intervals are wide, and the extent of protection is uncertain. Serum samples were obtained from children 3-5 years of age who were participants in a preschool booster-vaccine trial. Serum bactericidal activity was measured with human complement. Group C anticapsular antibody concentrations were measured by a radioantigen binding assay. Passive protection was analyzed in an infant rat bacteremia model. Serum samples from UK children who had been immunized 2-3 years earlier as infants or toddlers had higher levels of radioantigen binding, bactericidal activity, and passive protection than did historical control serum samples from unimmunized children (P<.05). A higher proportion of children immunized as infants had serum bactericidal activity titers > or =1 : 4 (considered to be protective) than those immunized as toddlers (61% vs. 24%; P<.01), but there were no significant differences in the proportion of serum samples conferring passive protection (50% and 41%, respectively; P=.4). We found no evidence of lower immunity in children immunized as infants than as toddlers. On the basis of serum bactericidal activity and/or passive protection, 40%-50% of both age groups are protected at 2-3 years after immunization, which was significantly greater than in unimmunized historical controls (<5%).

Gold nanoparticle–M2e conjugate coformulated with CpG induces protective immunity against influenza A virus

PubMed Central

Tao, Wenqian; Ziemer, Katherine S; Gill, Harvinder S

2014-01-01

Aim: This study aimed to develop a novel influenza A vaccine by conjugating the highly conserved extracellular region of the matrix 2 protein (M2e) of influenza A virus to gold nanoparticles (AuNPs) and to test the vaccine in a mouse influenza challenge model. Materials & methods: Citrate-reduced AuNPs (diameter: 12 nm) were synthesized, and characterized by transmission electron microscopy and dynamic light scattering. M2e was conjugated to AuNPs through thiol–gold interactions to form M2e–AuNP conjugates. Particle stability was confirmed by UV–visible spectra, and M2e conjugation was further characterized by x-ray photoelectron spectroscopy. Mice were immunized with M2e–AuNPs with or without CpG (cytosine-guanine rich oligonucleotide) as an adjuvant with appropriate control groups. Sera was collected and M2e-specific immunoglobulin (IgG) was measured, and immunized mice were challenged with PR8-H1N1 influenza virus. Results: M2e-capped AuNPs could be lyophilized and stably resuspended in water. Intranasal vaccination of mice with M2e–AuNP conjugates induced M2e-specific IgG serum antibodies, which significantly increased upon addition of soluble CpG as adjuvant. Upon challenge with lethal PR8, mice vaccinated with M2e-AuNP conjugates were only partially protected, while mice that received soluble CpG as adjuvant in addition to M2e–AuNP were fully protected. Conclusion: Overall, this study demonstrates the potential of using the M2e–AuNP conjugates with CpG as an adjuvant as a platform for developing an influenza A vaccine. PMID:23829488

The Molecular Characterization and Immunity Identification of Rhoptry protein 22 (ROP22) of Toxoplasma gondii as a DNA Vaccine Candidate Against Toxoplasmosis.

PubMed

Zhang, Zhenchao; Li, Yuhua; Xie, Qing; Li, Pengju; Nan, Xiaoxu; Kong, Lingmin; Zeng, Dapeng; Ding, Zhifang; Wang, Shuai

2018-06-02

Toxoplasma gondii (T. gondii) rhoptry proteins (TgROPs) have been considered main targets and indicator molecules for immune diagnosis and prophylaxis since they initially present during the process of invasion. In this study, the effect of intramuscularly injecting the genetic vaccine pVAX-ROP22 was evaluated, made by inserting the TgROP22 sequence into the eukaryotic expression vector of pVAX I, into BALB/c mice. The levels of IgG, IgG1 and IgG2a in pVAX-ROP22 vaccinated animals were integrally increased. It was uncovered by cytokine profile analyses that the levels of IFN-γ and IL-2 were significantly increased, while no significant changes were detected in IL-4 and IL-10 levels. Additionally, we found that immunization with pVAX-ROP22 significantly prolonged the survival time (13.80 ± 1.75 days) of mice after challenge infection with the virulent T. gondii RH strain, in comparison to those of control animals (died within 10 days). Moreover, the number of brain cysts (1406 ± 277) in the animals subjected to pVAX-TgROP22 vaccination decreased remarkably (P < 0.05) compared to the blank control mice (2333 ± 473), and the size of brain cysts in pVAX-TgROP22 group was significantly smaller than the groups of blank, PBS and pVAXI. These results suggested that TgROP22 as DNA vaccine could trigger strong humoral and cellular responses and induce partial protection against toxoplasmosis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Expression, purification, immunogenicity, and protective efficacy of a recombinant Tc24 antigen as a vaccine against Trypanosoma cruzi infection in mice.

PubMed

Martinez-Campos, Viridiana; Martinez-Vega, Pedro; Ramirez-Sierra, Maria Jesus; Rosado-Vallado, Miguel; Seid, Christopher A; Hudspeth, Elissa M; Wei, Junfei; Liu, Zhuyun; Kwityn, Cliff; Hammond, Molly; Ortega-López, Jaime; Zhan, Bin; Hotez, Peter J; Bottazzi, Maria Elena; Dumonteil, Eric

2015-08-26

The Tc24 calcium binding protein from the flagellar pocket of Trypanosoma cruzi is under evaluation as a candidate vaccine antigen against Chagas disease. Previously, a DNA vaccine encoding Tc24 was shown to be an effective vaccine (both as a preventive and therapeutic intervention) in mice and dogs, as evidenced by reductions in T. cruzi parasitemia and cardiac amastigotes, as well as reduced cardiac inflammation and increased host survival. Here we developed a suitable platform for the large scale production of recombinant Tc24 (rTc24) and show that when rTc24 is combined with a monophosphoryl-lipid A (MPLA) adjuvant, the formulated vaccine induces a Th1-biased immune response in mice, comprised of elevated IgG2a antibody levels and interferon-gamma levels from splenocytes, compared to controls. These immune responses also resulted in statistically significant decreased T. cruzi parasitemia and cardiac amastigotes, as well as increased survival following T. cruzi challenge infections, compared to controls. Partial protective efficacy was shown regardless of whether the antigen was expressed in Escherichia coli or in yeast (Pichia pastoris). While mouse vaccinations will require further modifications in order to optimize protective efficacy, such studies provide a basis for further evaluations of vaccines comprised of rTc24, together with alternative adjuvants and additional recombinant antigens. Copyright © 2015. Published by Elsevier Ltd.

Immunogenicity of allogeneic mesenchymal stem cells

PubMed Central

Schu, Sabine; Nosov, Mikhail; O'Flynn, Lisa; Shaw, Georgina; Treacy, Oliver; Barry, Frank; Murphy, Mary; O'Brien, Timothy; Ritter, Thomas

2012-01-01

Mesenchymal stem cells (MSCs) inhibit proliferation of allogeneic T cells and express low levels of major histocompatibility complex class I (MHCI), MHCII and vascular adhesion molecule-1 (VCAM-1). We investigated whether their immunosuppressive properties and low immunophenotype protect allogeneic rat MSCs against cytotoxic lysis in vitro and result in a reduced immune response in vivo. Rat MSCs were partially protected against alloantigen-specific cytotoxic T cells in vitro. However, after treatment with IFN-γ and IL-1β, MSCs upregulated MHCI, MHCII and VCAM-1, and cytotoxic lysis was significantly increased. In vivo, allogeneic T cells but not allogeneic MSCs induced upregulation of the activation markers CD25 and CD71 as well as downregulation of CD62L on CD4+ T cells from recipient rats. However, intravenous injection of allo-MSCs in rats led to the formation of alloantibodies with the capacity to facilitate complement-mediated lysis, although IgM levels were markedly decreased compared with animals that received T cells. The allo-MSC induced immune response was sufficient to lead to significantly reduced survival of subsequently injected allo-MSCs. Interestingly, no increased immunogenicity of IFN-γ stimulated allo-MSCs was observed in vivo. Both the loss of protection against cytotoxic lysis under inflammatory conditions and the induction of complement-activating antibodies will likely impact the utility of allogeneic MSCs for therapeutic applications. PMID:22151542

Recombinant domains III of Tick-Borne Encephalitis Virus envelope protein in combination with dextran and CpGs induce immune response and partial protectiveness against TBE virus infection in mice.

PubMed

Ershova, Anna S; Gra, Olga A; Lyaschuk, Alexander M; Grunina, Tatyana M; Tkachuk, Artem P; Bartov, Mikhail S; Savina, Darya M; Sergienko, Olga V; Galushkina, Zoya M; Gudov, Vladimir P; Kozlovskaya, Liubov I; Kholodilov, Ivan S; Gmyl, Larissa V; Karganova, Galina G; Lunin, Vladimir G; Karyagina, Anna S; Gintsburg, Alexander L

2016-10-07

E protein of tick-borne encephalitis virus (TBEV) and other flaviviruses is located on the surface of the viral particle. Domain III of this protein seems to be a promising component of subunit vaccines for prophylaxis of TBE and kits for diagnostics of TBEV. Three variants of recombinant TBEV E protein domain III of European, Siberian and Far Eastern subtypes fused with dextran-binding domain of Leuconostoc citreum KM20 were expressed in E. coli and purified. The native structure of domain III was confirmed by ELISA antibody kit and sera of patients with tick-borne encephalitis. Immunogenic and protective properties of the preparation comprising these recombinant proteins immobilized on a dextran carrier with CpG oligonucleotides as an adjuvant were investigated on the mice model. All 3 variants of recombinant proteins immobilized on dextran demonstrate specific interaction with antibodies from the sera of TBE patients. Thus, constructed recombinant proteins seem to be promising for TBE diagnostics. The formulation comprising the 3 variants of recombinant antigens immobilized on dextran and CpG oligonucleotides, induces the production of neutralizing antibodies against TBEV of different subtypes and demonstrates partial protectivity against TBEV infection. Studied proteins interact with the sera of TBE patients, and, in combination with dextran and CPGs, demonstrate immunogenicity and limited protectivity on mice compared with reference "Tick-E-Vac" vaccine.

Balancing Immune Protection and Immune Pathology by CD8+ T-Cell Responses to Influenza Infection

PubMed Central

Duan, Susu; Thomas, Paul G.

2016-01-01

Influenza A virus (IAV) is a significant human pathogen causing annual epidemics and periodic pandemics. CD8+ cytotoxic T lymphocyte (CTL)-mediated immunity contributes to the clearance of virus-infected cells, and CTL immunity targeting the conserved internal proteins of IAVs is a key protection mechanism when neutralizing antibodies are absent during heterosubtypic IAV infection. However, CTL infiltration into the airways, its cytotoxicity, and the effects of produced proinflammatory cytokines can cause severe lung tissue injury, thereby contributing to immunopathology. Studies have discovered complicated and exquisite stimulatory and inhibitory mechanisms that regulate CTL magnitude and effector activities during IAV infection. Here, we review the state of knowledge on the roles of IAV-specific CTLs in immune protection and immunopathology during IAV infection in animal models, highlighting the key findings of various requirements and constraints regulating the balance of immune protection and pathology involved in CTL immunity. We also discuss the evidence of cross-reactive CTL immunity as a positive correlate of cross-subtype protection during secondary IAV infection in both animal and human studies. We argue that the effects of CTL immunity on protection and immunopathology depend on multiple layers of host and viral factors, including complex host mechanisms to regulate CTL magnitude and effector activity, the pathogenic nature of the IAV, the innate response milieu, and the host historical immune context of influenza infection. Future efforts are needed to further understand these key host and viral factors, especially to differentiate those that constrain optimally effective CTL antiviral immunity from those necessary to restrain CTL-mediated non-specific immunopathology in the various contexts of IAV infection, in order to develop better vaccination and therapeutic strategies for modifying protective CTL immunity. PMID:26904022

Expression of interleukin-6 by a recombinant rabies virus enhances its immunogenicity as a potential vaccine.

PubMed

Luo, Jun; Zhang, Boyue; Wu, Yuting; Tian, Qin; Zhao, Jing; Lyu, Ziyu; Zhang, Qiong; Mei, Mingzhu; Luo, Yongwen; Guo, Xiaofeng

2017-02-07

Several studies have confirmed that interleukin-6 (IL6) mediates multiple biological effects that enhance immune responses when used as an adjuvant. In the present study, recombinant rabies virus (RABV) expressing canine IL6 (rHEP-CaIL6) was rescued and its pathogenicity and immunogenicity were investigated in mice. We demonstrated that mice received a single intramuscular immunization with rHEP-CaIL6 showed an earlier increase and higher maximum titres of virus-neutralizing antibody (VNA) as well as anti-RABV antibodies compared with mice immunized with the parent strain. Moreover, survival rates of mice immunized with rHEP-CaIL6 were higher compared with mice immunized with parent HEP-Flury according to the challenge assay. Flow cytometry further confirmed that immunization with rHEP-CaIL6 induced the strong recruitment of mature B cells and CD8 + T cells to lymph nodes, which may partially explain the high levels of VNA and enhanced cellular immunity. Quantitative real-time PCR indicated that rHEP-CaIL6 induced stronger inflammatory and immune responses in the central nervous system, which might have allowed virus clearance in the early infection phase. Furthermore, mice infected intranasally with rHEP-CaIL6 developed no clinical symptoms while mice infected with HEP-Flury showed piloerection. In summary, these data indicate that rHEP-CaIL6 induces a strong, protective immune response with a good safety profile. Therefore, a recombinant RABV strain expressing canine IL6 may aid the development of an effective, safe attenuated rabies vaccine. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cocoa Diet and Antibody Immune Response in Preclinical Studies

PubMed Central

Camps-Bossacoma, Mariona; Massot-Cladera, Malen; Abril-Gil, Mar; Franch, Angels; Pérez-Cano, Francisco J.; Castell, Margarida

2017-01-01

The ability of cocoa to interact with the immune system in vitro and in vivo has been described. In the latter context, a cocoa-enriched diet in healthy rats was able to modify the immune system’s functionality. This fact could be observed in the composition and functionality of lymphoid tissues, such as the thymus, spleen, and lymph nodes. Consequently, immune effector mechanisms, such as antibody synthesis, were modified. A cocoa-enriched diet in young rats was able to attenuate the serum levels of immunoglobulin (Ig) G, IgM, and IgA and also the intestinal IgM and IgA secretion. Moreover, in immunized rats, the intake of cocoa decreased specific IgG1, IgG2a, IgG2c, and IgM concentrations in serum. This immune-regulator potential was then tested in disease models in which antibodies play a pathogenic role. A cocoa-enriched diet was able to partially prevent the synthesis of autoantibodies in a model of autoimmune arthritis in rats and was also able to protect against IgE and T helper 2-related antibody synthesis in two rat models of allergy. Likewise, a cocoa-enriched diet prevented an oral sensitization process in young rats. In this review, we will focus on the influence of cocoa on the acquired branch of the immune function. Therefore, we will focus on how a cocoa diet influences lymphocyte function both in the systemic and intestinal immune system. Likewise, its potential role in preventing some antibody-induced immune diseases is also included. Although further studies must characterize the particular cocoa components responsible for such effects and nutritional studies in humans need to be carried out, cocoa has potential as a nutraceutical agent in some hypersensitivity status. PMID:28702458

Cocoa Diet and Antibody Immune Response in Preclinical Studies.

PubMed

Camps-Bossacoma, Mariona; Massot-Cladera, Malen; Abril-Gil, Mar; Franch, Angels; Pérez-Cano, Francisco J; Castell, Margarida

2017-01-01

The ability of cocoa to interact with the immune system in vitro and in vivo has been described. In the latter context, a cocoa-enriched diet in healthy rats was able to modify the immune system's functionality. This fact could be observed in the composition and functionality of lymphoid tissues, such as the thymus, spleen, and lymph nodes. Consequently, immune effector mechanisms, such as antibody synthesis, were modified. A cocoa-enriched diet in young rats was able to attenuate the serum levels of immunoglobulin (Ig) G, IgM, and IgA and also the intestinal IgM and IgA secretion. Moreover, in immunized rats, the intake of cocoa decreased specific IgG1, IgG2a, IgG2c, and IgM concentrations in serum. This immune-regulator potential was then tested in disease models in which antibodies play a pathogenic role. A cocoa-enriched diet was able to partially prevent the synthesis of autoantibodies in a model of autoimmune arthritis in rats and was also able to protect against IgE and T helper 2-related antibody synthesis in two rat models of allergy. Likewise, a cocoa-enriched diet prevented an oral sensitization process in young rats. In this review, we will focus on the influence of cocoa on the acquired branch of the immune function. Therefore, we will focus on how a cocoa diet influences lymphocyte function both in the systemic and intestinal immune system. Likewise, its potential role in preventing some antibody-induced immune diseases is also included. Although further studies must characterize the particular cocoa components responsible for such effects and nutritional studies in humans need to be carried out, cocoa has potential as a nutraceutical agent in some hypersensitivity status.

Protective Effect of Active Immunization with Purified Escherichia coli Heat-Labile Enterotoxin in Rats

PubMed Central

Klipstein, Frederick A.; Engert, Richard F.

1979-01-01

The protective effect of active immunization by different routes with a purified preparation of the polymyxin-release form of Escherichia coli heat-labile toxin was evaluated in rats. Immunized animals were challenged by placing toxin into ligated ileal loops at dosages which produced either 50% or the maximum secretory response in unimmunized rats. Immunization exclusively by the parenteral route yielded significant protection. Rats were also protected when parenteral priming was followed by boosting given either directly into the duodenum or perorally 2 h after intragastric cimetidine, but not when the peroral boosts were given with bicarbonate. Immunization administered entirely by the peroral route with cimetidine yielded protection but only when the immunizing dosage was fivefold greater than that found effective in the parenteral-peroral approach. Rats immunized exclusively by the parenteral route and those boosted perorally with cimetidine were also tested, and found to be protected, against challenge with viable organisms of strains that produce either heat-labile toxin alone or both heat-labile and heat-stable toxin, but they were not protected against a strain which produces just heat-stable toxin. Geometric mean serum antibody titers were increased by 16-fold or more over control values in those groups of rats in which protection was achieved, with the exception of those immunized exclusively by the peroral route. These observations demonstrate that (i) active immunization with purified E. coli heat-labile toxin results in significant protection against both this toxin as well as viable organisms which produce it, but not against viable strains which produce heat-stable toxin only, and (ii) concomitant ablation of gastric secretion by the use of cimetidine renders the peroral route of immunization effective. They suggest that prophylactic immunization against diarrheal disease caused by heat-labile toxin-producing strains of E. coli may be feasible in humans. PMID:378831

Vaccination Programs for Endemic Infections: Modelling Real versus Apparent Impacts of Vaccine and Infection Characteristics

NASA Astrophysics Data System (ADS)

Ragonnet, Romain; Trauer, James M.; Denholm, Justin T.; Geard, Nicholas L.; Hellard, Margaret; McBryde, Emma S.

2015-10-01

Vaccine effect, as measured in clinical trials, may not accurately reflect population-level impact. Furthermore, little is known about how sensitive apparent or real vaccine impacts are to factors such as the risk of re-infection or the mechanism of protection. We present a dynamic compartmental model to simulate vaccination for endemic infections. Several measures of effectiveness are calculated to compare the real and apparent impact of vaccination, and assess the effect of a range of infection and vaccine characteristics on these measures. Although broadly correlated, measures of real and apparent vaccine effectiveness can differ widely. Vaccine impact is markedly underestimated when primary infection provides partial natural immunity, when coverage is high and when post-vaccination infectiousness is reduced. Despite equivalent efficacy, ‘all or nothing’ vaccines are more effective than ‘leaky’ vaccines, particularly in settings with high risk of re-infection and transmissibility. Latent periods result in greater real impacts when risk of re-infection is high, but this effect diminishes if partial natural immunity is assumed. Assessments of population-level vaccine effects against endemic infections from clinical trials may be significantly biased, and vaccine and infection characteristics should be considered when modelling outcomes of vaccination programs, as their impact may be dramatic.

Vaccination Programs for Endemic Infections: Modelling Real versus Apparent Impacts of Vaccine and Infection Characteristics

PubMed Central

Ragonnet, Romain; Trauer, James M.; Denholm, Justin T.; Geard, Nicholas L.; Hellard, Margaret; McBryde, Emma S.

2015-01-01

Vaccine effect, as measured in clinical trials, may not accurately reflect population-level impact. Furthermore, little is known about how sensitive apparent or real vaccine impacts are to factors such as the risk of re-infection or the mechanism of protection. We present a dynamic compartmental model to simulate vaccination for endemic infections. Several measures of effectiveness are calculated to compare the real and apparent impact of vaccination, and assess the effect of a range of infection and vaccine characteristics on these measures. Although broadly correlated, measures of real and apparent vaccine effectiveness can differ widely. Vaccine impact is markedly underestimated when primary infection provides partial natural immunity, when coverage is high and when post-vaccination infectiousness is reduced. Despite equivalent efficacy, ‘all or nothing’ vaccines are more effective than ‘leaky’ vaccines, particularly in settings with high risk of re-infection and transmissibility. Latent periods result in greater real impacts when risk of re-infection is high, but this effect diminishes if partial natural immunity is assumed. Assessments of population-level vaccine effects against endemic infections from clinical trials may be significantly biased, and vaccine and infection characteristics should be considered when modelling outcomes of vaccination programs, as their impact may be dramatic. PMID:26482413

HIV neuropathogenesis: a tight rope walk of innate immunity.

PubMed

Yao, Honghong; Bethel-Brown, Crystal; Li, Cicy Zidong; Buch, Shilpa J

2010-12-01

During the course of HIV-1 disease, virus neuroinvasion occurs as an early event, within weeks following infection. Intriguingly, subsequent central nervous system (CNS) complications manifest only decades after the initial virus exposure. Although CNS is commonly regarded as an immune-privileged site, emerging evidence indicates that innate immunity elicited by the CNS glial cells is a critical determinant for the establishment of protective immunity. Sustained expression of these protective immune responses, however, can be a double-edged sword. As protective immune mediators, cytokines have the ability to function in networks and co-operate with other host/viral mediators to tip the balance from a protective to toxic state in the CNS. Herein, we present an overview of some of the essential elements of the cerebral innate immunity in HIV neuropathogenesis including the key immune cell types of the CNS with their respective soluble immune mediators: (1) cooperative interaction of IFN-γ with the host/virus factor (platelet-derived host factor (PDGF)/viral Tat) in the induction of neurotoxic chemokine CXCL10 by macrophages, (2) response of astrocytes to viral infection, and (3) protective role of PDGF and MCP-1 in neuronal survival against HIV Tat toxicity. These components of the cerebral innate immunity do not act separately from each other but form a functional immunity network. The ultimate outcome of HIV infection in the CNS will thus be dependent on the regulation of the net balance of cell-specific protective versus detrimental responses.

Ly49H signaling through DAP10 is essential for optimal natural killer cell responses to mouse cytomegalovirus infection

PubMed Central

Orr, Mark T.; Sun, Joseph C.; Hesslein, David G.T.; Arase, Hisashi; Phillips, Joseph H.; Takai, Toshiyuki

2009-01-01

The activating natural killer (NK) cell receptor Ly49H recognizes the mouse cytomegalovirus (MCMV) m157 glycoprotein expressed on the surface of infected cells and is required for protection against MCMV. Although Ly49H has previously been shown to signal via DAP12, we now show that Ly49H must also associate with and signal via DAP10 for optimal function. In the absence of DAP12, DAP10 enables Ly49H-mediated killing of m157-bearing target cells, proliferation in response to MCMV infection, and partial protection against MCMV. DAP10-deficient Ly49H+ NK cells, expressing only Ly49H–DAP12 receptor complexes, are partially impaired in their ability to proliferate during MCMV infection, display diminished ERK1/2 activation, produce less IFN-γ upon Ly49H engagement, and demonstrate reduced control of MCMV infection. Deletion of both DAP10 and DAP12 completely abrogates Ly49H surface expression and control of MCMV infection. Thus, optimal NK cell–mediated immunity to MCMV depends on Ly49H signaling through both DAP10 and DAP12. PMID:19332875

A comb-like branched β-D-glucan produced by a Cordyceps sinensis fungus and its protective effect against cyclophosphamide-induced immunosuppression in mice.

PubMed

Hu, Ting; Jiang, Chenbo; Huang, Qilin; Sun, Fengyuan

2016-05-20

An exopolysaccharide (EPS) was fractionated from fermentation media of a Cordyceps sinensis fungus (Cs-HK1) by ethanol precipitation at 2/5 volume ratio of ethanol/media. Its structural characteristics were elucidated by FT-IR, GC, GC-MS, 1D and 2D NMR combined with periodate oxidation, Smith degradation, partial acid hydrolysis, and methylation analysis. Furthermore, the immunomodulatory activity of EPS was evaluated by the model of cyclophosphamide-induced immunosuppression. The results from monosaccharide composition and partial acid hydrolysis indicated that EPS almost consisted of glucose excluding a trace amount of mannose. GC-MS and NMR analysis further confirmed EPS had a linear backbone of (1→3)-β-D-glucopyranosyl residues with a single (1→6)-β-D-glucopyranosyl side-branching unit for every three β-D-glucopyranosyl residues, showing a comb-like β-D-glucan with short and intensive branches, which was responsible for high viscosity. Moreover, EPS could significantly enhance immune organs and stimulate the release of major cytokines TNF-α and INF-γ, suggesting that EPS exhibited protective effect in immunocompromised mice. Copyright © 2016 Elsevier Ltd. All rights reserved.

Applying Convergent Immunity to Innovative Vaccines Targeting Staphylococcus aureus

PubMed Central

Yeaman, Michael R.; Filler, Scott G.; Schmidt, Clint S.; Ibrahim, Ashraf S.; Edwards, John E.; Hennessey, John P.

2014-01-01

Recent perspectives forecast a new paradigm for future “third generation” vaccines based on commonalities found in diverse pathogens or convergent immune defenses to such pathogens. For Staphylococcus aureus, recurring infections and a limited success of vaccines containing S. aureus antigens imply that native antigens induce immune responses insufficient for optimal efficacy. These perspectives exemplify the need to apply novel vaccine strategies to high-priority pathogens. One such approach can be termed convergent immunity, where antigens from non-target organisms that contain epitope homologs found in the target organism are applied in vaccines. This approach aims to evoke atypical immune defenses via synergistic processes that (1) afford protective efficacy; (2) target an epitope from one organism that contributes to protective immunity against another; (3) cross-protect against multiple pathogens occupying a common anatomic or immunological niche; and/or (4) overcome immune subversion or avoidance strategies of target pathogens. Thus, convergent immunity has a potential to promote protective efficacy not usually elicited by native antigens from a target pathogen. Variations of this concept have been mainstays in the history of viral and bacterial vaccine development. A more far-reaching example is the pre-clinical evidence that specific fungal antigens can induce cross-kingdom protection against bacterial pathogens. This trans-kingdom protection has been demonstrated in pre-clinical studies of the recombinant Candida albicans agglutinin-like sequence 3 protein (rAls3) where it was shown that a vaccine containing rAls3 provides homologous protection against C. albicans, heterologous protection against several other Candida species, and convergent protection against several strains of S. aureus. Convergent immunity reflects an intriguing new approach to designing and developing vaccine antigens and is considered here in the context of vaccines to target S. aureus. PMID:25309545

Systemic immunity influences hearing preservation in cochlear implantation.

PubMed

Souter, Melanie; Eastwood, Hayden; Marovic, Paul; Kel, Gordana; Wongprasartsuk, Sarin; Ryan, Allen F; O'Leary, Stephen John

2012-06-01

To determine whether a systemic immune response influences hearing thresholds and tissue response after cochlear implantation of hearing guinea pigs. Guinea pigs were inoculated with sterile antigen (Keyhole limpet hemocyanin) 3 weeks before cochlear implantation. Pure-tone auditory brainstem response thresholds were performed before implantation and 1 and 4 weeks later. Dexamethasone phosphate 20% was adsorbed onto a hyaluronic acid carboxymethylcellulose sponge and was applied to the round window for 30 minutes before electrode insertion. Normal saline was used for controls. Cochlear histology was performed at 4 weeks after implantation to assess the tissue response to implantation. To control for the effect of keyhole limpet hemocyanin priming, a group of unprimed animals underwent cochlear implantation with a saline-soaked pledget applied to the round window. Keyhole limpet hemocyanin priming had no significant detrimental effect on thresholds without implantation. Thresholds were elevated after implantation across all frequencies tested (2-32 kHz) in primed animals but only at higher frequencies (4-32 kHz) in unprimed controls. In primed animals, dexamethasone treatment significantly reduced threshold shifts at 2 and 8 kHz. Keyhole limpet hemocyanin led to the more frequent observation of lymphocytes in the tissue response to the implant. Systemic immune activation at the time of cochlear implantation broadened the range of frequencies experiencing elevated thresholds after implantation. Local dexamethasone provides partial protection against this hearing loss, but the degree and extent of protection are less compared to previous studies with unprimed animals.

Immunization with Streptococcal Heme Binding Protein (Shp) Protects Mice Against Group A Streptococcus Infection.

PubMed

Zhang, Xiaolan; Song, Yingli; Li, Yuanmeng; Cai, Minghui; Meng, Yuan; Zhu, Hui

2017-01-01

Streptococcal heme binding protein (Shp) is a surface protein of the heme acquisition system that is an essential iron nutrient in Group A Streptococcus (GAS). Here, we tested whether Shp immunization protects mice from subcutaneous infection. Mice were immunized subcutaneously with recombinant Shp and then challenged with GAS. The protective effects against GAS challenge were evaluated two weeks after the last immunization. Immunization with Shp elicited a robust IgG response, resulting in high anti-Shp IgG titers in the serum. Immunized mice had a higher survival rate and smaller skin lesions than adjuvant control mice. Furthermore, immunized mice had lower GAS numbers at the skin lesions and in the liver, spleen and lung. Histological analysis with Gram staining showed that GAS invaded the surrounding area of the inoculation sites in the skin in control mice, but not in immunized mice. Thus, Shp immunization enhances GAS clearance and reduces GAS skin invasion and systemic dissemination. These findings indicate that Shp is a protective antigen.

Protective Efficacy of Plasmodium vivax Radiation-Attenuated Sporozoites in Colombian Volunteers: A Randomized Controlled Trial

PubMed Central

Arévalo-Herrera, Myriam; Vásquez-Jiménez, Juan M.; Lopez-Perez, Mary; Vallejo, Andrés F.; Amado-Garavito, Andrés B.; Céspedes, Nora; Castellanos, Angélica; Molina, Karen; Trejos, Johanna; Oñate, José; Epstein, Judith E.; Richie, Thomas L.; Herrera, Sócrates

2016-01-01

Background Immunizing human volunteers by mosquito bite with radiation-attenuated Plasmodium falciparum sporozoites (RAS) results in high-level protection against infection. Only two volunteers have been similarly immunized with P. vivax (Pv) RAS, and both were protected. A phase 2 controlled clinical trial was conducted to assess the safety and protective efficacy of PvRAS immunization. Methodology/Principal Findings A randomized, single-blinded trial was conducted. Duffy positive (Fy+; Pv susceptible) individuals were enrolled: 14 received bites from irradiated (150 ± 10 cGy) Pv-infected Anopheles mosquitoes (RAS) and 7 from non-irradiated non-infected mosquitoes (Ctl). An additional group of seven Fy- (Pv refractory) volunteers was immunized with bites from non-irradiated Pv-infected mosquitoes. A total of seven immunizations were carried out at mean intervals of nine weeks. Eight weeks after last immunization, a controlled human malaria infection (CHMI) with non-irradiated Pv-infected mosquitoes was performed. Nineteen volunteers completed seven immunizations (12 RAS, 2 Ctl, and 5 Fy-) and received a CHMI. Five of 12 (42%) RAS volunteers were protected (receiving a median of 434 infective bites) compared with 0/2 Ctl. None of the Fy- volunteers developed infection by the seventh immunization or after CHMI. All non-protected volunteers developed symptoms 8–13 days after CHMI with a mean pre-patent period of 12.8 days. No serious adverse events related to the immunizations were observed. Specific IgG1 anti-PvCS response was associated with protection. Conclusion Immunization with PvRAS was safe, immunogenic, and induced sterile immunity in 42% of the Fy+ volunteers. Moreover, Fy- volunteers were refractory to Pv malaria. Trial registration Identifier: NCT01082341. PMID:27760143

Protective Efficacy of Plasmodium vivax Radiation-Attenuated Sporozoites in Colombian Volunteers: A Randomized Controlled Trial.

PubMed

Arévalo-Herrera, Myriam; Vásquez-Jiménez, Juan M; Lopez-Perez, Mary; Vallejo, Andrés F; Amado-Garavito, Andrés B; Céspedes, Nora; Castellanos, Angélica; Molina, Karen; Trejos, Johanna; Oñate, José; Epstein, Judith E; Richie, Thomas L; Herrera, Sócrates

2016-10-01

Immunizing human volunteers by mosquito bite with radiation-attenuated Plasmodium falciparum sporozoites (RAS) results in high-level protection against infection. Only two volunteers have been similarly immunized with P. vivax (Pv) RAS, and both were protected. A phase 2 controlled clinical trial was conducted to assess the safety and protective efficacy of PvRAS immunization. A randomized, single-blinded trial was conducted. Duffy positive (Fy+; Pv susceptible) individuals were enrolled: 14 received bites from irradiated (150 ± 10 cGy) Pv-infected Anopheles mosquitoes (RAS) and 7 from non-irradiated non-infected mosquitoes (Ctl). An additional group of seven Fy- (Pv refractory) volunteers was immunized with bites from non-irradiated Pv-infected mosquitoes. A total of seven immunizations were carried out at mean intervals of nine weeks. Eight weeks after last immunization, a controlled human malaria infection (CHMI) with non-irradiated Pv-infected mosquitoes was performed. Nineteen volunteers completed seven immunizations (12 RAS, 2 Ctl, and 5 Fy-) and received a CHMI. Five of 12 (42%) RAS volunteers were protected (receiving a median of 434 infective bites) compared with 0/2 Ctl. None of the Fy- volunteers developed infection by the seventh immunization or after CHMI. All non-protected volunteers developed symptoms 8-13 days after CHMI with a mean pre-patent period of 12.8 days. No serious adverse events related to the immunizations were observed. Specific IgG1 anti-PvCS response was associated with protection. Immunization with PvRAS was safe, immunogenic, and induced sterile immunity in 42% of the Fy+ volunteers. Moreover, Fy- volunteers were refractory to Pv malaria. Identifier: NCT01082341.

Complex Immune Correlates of Protection in HIV-1 Vaccine Efficacy Trials

PubMed Central

Tomaras, Georgia D.; Plotkin, Stanley A.

2016-01-01

Summary Development of an efficacious HIV-1 vaccine is a major priority for improving human health worldwide. Vaccine mediated protection against human pathogens can be achieved through elicitation of protective innate, humoral, and cellular responses. Identification of specific immune responses responsible for pathogen protection enables vaccine development and provides insights into host defenses against pathogens and the immunological mechanisms that most effectively fight infection. Defining immunological correlates of transmission risk in preclinical and clinical HIV-1 vaccine trials has moved the HIV-1 vaccine development field forward and directed new candidate vaccine development. Immune correlate studies are providing novel hypotheses about immunological mechanisms that may be responsible for preventing HIV-1 acquisition. Recent results from HIV-1 immune correlates work has demonstrated that there are multiple types of immune responses that together, comprise an immune correlate—thus implicating polyfunctional immune control of HIV-1 transmission. An in depth understanding of these complex immunological mechanisms of protection against HIV-1 will accelerate the development of an efficacious HIV-1 vaccine. PMID:28133811

Rodent malaria: BCG-induced protection and immunosuppression. [Mice, gamma radiation, Plasmodium berghei

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

Smrkovski, L.L.; Strickland, G.T.

1978-10-01

One dose of 10/sup 7/ viable units of Mycobacterium bovis, strain BCG, protected a significant number of Swiss mice from a primary challenge with 10/sup 4/ thoracic sporozoites of Plasmodium berghei. Immunization with irradiated sporozoites induced greater protection than that observed in BCG-treated animals. Mice treated with BCG and surviving a primary sporozoite challenge were not protected from rechallenge, whereas mice immunized with irradiated sporozoites and surviving initial challenge of sporozoites were solidly immune to further challenge. Immunizing mice with BCG and irradiated sporozoites simulataneously resulted in a synergistic effect of increased protection against a primary challenge of sporozoites onlymore » if the two immunogens were administered on the same day and if the mice were challenged 1 to 3 days later. Mice given BCG and irradiated sporozoites and surviving a primary challenge of sporozoites were unable to survive rechallenge. BCG given to mice previously immunized with irradiated sporozoites suppressed their protective immunity against sporozoite challenge.« less

Relative Contribution of Th1 and Th17 Cells in Adaptive Immunity to Bordetella pertussis: Towards the Rational Design of an Improved Acellular Pertussis Vaccine

PubMed Central

Ross, Pádraig J.; Allen, Aideen C.; Walsh, Kevin; Misiak, Alicja; Lavelle, Ed C.; McLoughlin, Rachel M.; Mills, Kingston H. G.

2013-01-01

Whooping cough caused by Bordetella pertussis is a re-emerging infectious disease despite the introduction of safer acellular pertussis vaccines (Pa). One explanation for this is that Pa are less protective than the more reactogenic whole cell pertussis vaccines (Pw) that they replaced. Although Pa induce potent antibody responses, and protection has been found to be associated with high concentrations of circulating IgG against vaccine antigens, it has not been firmly established that host protection induced with this vaccine is mediated solely by humoral immunity. The aim of this study was to examine the relative contribution of Th1 and Th17 cells in host immunity to infection with B. pertussis and in immunity induced by immunization with Pw and Pa and to use this information to help rationally design a more effective Pa. Our findings demonstrate that Th1 and Th17 both function in protective immunity induced by infection with B. pertussis or immunization with Pw. In contrast, a current licensed Pa, administered with alum as the adjuvant, induced Th2 and Th17 cells, but weak Th1 responses. We found that IL-1 signalling played a central role in protective immunity induced with alum-adsorbed Pa and this was associated with the induction of Th17 cells. Pa generated strong antibody and Th2 responses, but was fully protective in IL-4-defective mice, suggesting that Th2 cells were dispensable. In contrast, Pa failed to confer protective immunity in IL-17A-defective mice. Bacterial clearance mediated by Pa-induced Th17 cells was associated with cell recruitment to the lungs after challenge. Finally, protective immunity induced by an experimental Pa could be enhanced by substituting alum with a TLR agonist that induces Th1 cells. Our findings demonstrate that alum promotes protective immunity through IL-1β-induced IL-17A production, but also reveal that optimum protection against B. pertussis requires induction of Th1, but not Th2 cells. PMID:23592988

Immunogenicity and efficacy of a bivalent DNA vaccine containing LeIF and TSA genes against murine cutaneous leishmaniasis.

PubMed

Maspi, Nahid; Ghaffarifar, Fatemeh; Sharifi, Zohreh; Dalimi, Abdolhossein; Dayer, Mohammad Saaid

2017-03-01

There is no effective vaccine for the prevention and elimination of leishmaniasis. For this reason, we assessed the protective effects of DNA vaccines containing LeIF, TSA genes alone, or LeIF-TSA fusion against cutaneous leishmaniasis pEGFP-N1 plasmid (empty vector) and phosphate buffer saline (PBS) were used as control groups. Therefore, cellular and humoral immune responses were evaluated before and after the challenge with Leishmania major. Lesion diameter was also measured 3-12 weeks after challenge. All immunized mice with plasmid DNA encoding Leishmania antigens induced the partial immunity characterized by increased IFN-γ and IgG2a levels compared with control groups (p < 0.001). Furthermore, the immunized mice showed significant reduction in mean lesion sizes compared with mice in empty vector and PBS groups (p < 0.05). The reduction in lesion diameter was 29.3%, 34.1%, and 46.2% less in groups vaccinated with LeIF, TSA, and LeIF-TSA, respectively, than in PBS group at 12th week post infection. IFN/IL-4 and IgG2a/IgG1 ratios indicated that group receiving LeIF-TSA fusion had the highest IFN-γ and IgG2a levels. In this study, DNA immunization promoted Th1 immune response characterized by higher IFN-γ and IgG2a levels and also reduction in lesion size. These results showed that a bivalent vaccine containing two distinct antigens may induce more potent immune responses against leishmaniasis. © 2017 APMIS. Published by John Wiley & Sons Ltd.

Intranasal boosting with an adenovirus-vectored vaccine markedly enhances protection by parenteral Mycobacterium bovis BCG immunization against pulmonary tuberculosis.

PubMed

Santosuosso, Michael; McCormick, Sarah; Zhang, Xizhong; Zganiacz, Anna; Xing, Zhou

2006-08-01

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. We examined a heterologous prime-boost regimen utilizing BCG as a prime vaccine and our recently described adenoviral vector expressing Ag85A (AdAg85A) as a boost vaccine. Since we recently demonstrated that a single intranasal but not intramuscular immunization with AdAg85A was able to induce potent protection from pulmonary Mycobacterium tuberculosis challenge in a mouse model, we compared the protective effects of parenteral and mucosal booster immunizations following subcutaneous BCG priming. Protection by BCG prime immunization was not effectively boosted by subcutaneous BCG or intramuscular AdAg85A. In contrast, protection by BCG priming was remarkably boosted by intranasal AdAg85A. Such enhanced protection by intranasal AdAg85A was correlated to the numbers of gamma interferon-positive CD4 and CD8 T cells residing in the airway lumen of the lung. Our study demonstrates that intranasal administration of AdAg85A represents an effective way to boost immune protection by parenteral BCG vaccination.

Interacting epidemics on overlay networks

NASA Astrophysics Data System (ADS)

Funk, Sebastian; Jansen, Vincent A. A.

2010-03-01

The interaction between multiple pathogens spreading on networks connecting a given set of nodes presents an ongoing theoretical challenge. Here, we aim to understand such interactions by studying bond percolation of two different processes on overlay networks of arbitrary joint degree distribution. We find that an outbreak of a first pathogen providing immunity to another one spreading subsequently on a second network connecting the same set of nodes does so most effectively if the degrees on the two networks are positively correlated. In that case, the protection is stronger the more heterogeneous the degree distributions of the two networks are. If, on the other hand, the degrees are uncorrelated or negatively correlated, increasing heterogeneity reduces the potential of the first process to prevent the second one from reaching epidemic proportions. We generalize these results to cases where the edges of the two networks overlap to arbitrary amount, or where the immunity granted is only partial. If both processes grant immunity to each other, we find a wide range of possible situations of coexistence or mutual exclusion, depending on the joint degree distribution of the underlying networks and the amount of immunity granted mutually. These results generalize the concept of a coexistence threshold and illustrate the impact of large-scale network structure on the interaction between multiple spreading agents.

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

Location and Dynamics of the Immunodominant CD8 T Cell Response to SIVΔnef Immunization and SIVmac251 Vaginal Challenge

PubMed Central

Sasikala-Appukuttan, Arun K.; Kim, Hyeon O.; Kinzel, Nikilyn J.; Hong, Jung Joo; Smith, Anthony J.; Wagstaff, Reece; Reilly, Cavan; Piatak, Michael; Lifson, Jeffrey D.; Reeves, R. Keith; Johnson, R. Paul; Haase, Ashley T.; Skinner, Pamela J.

2013-01-01

Live-attenuated SIV vaccines (LAVs) have been the most effective to date in preventing or partially controlling infection by wild-type SIV in non-human primate models of HIV-1 transmission to women acting by mechanisms of protection that are not well understood. To gain insights into mechanisms of protection by LAVs that could aid development of effective vaccines to prevent HIV-1 transmission to women, we used in situ tetramer staining to determine whether increased densities or changes in the local distribution of SIV-specific CD8 T cells correlated with the maturation of SIVΔnef vaccine-induced protection prior to and after intra-vaginal challenge with wild-type SIVmac251. We evaluated the immunodominant Mamu-A1*001:01/Gag (CM9) and Mamu-A1*001:01/Tat (SL8) epitope response in genital and lymphoid tissues, and found that tetramer+ cells were present at all time points examined. In the cervical vaginal tissues, most tetramer+ cells were distributed diffusely throughout the lamina propria or co-localized with other CD8 T cells within lymphoid aggregates. The distribution and densities of the tetramer+ cells at the portal of entry did not correlate with the maturation of protection or change after challenge. Given these findings, we discuss the possibility that changes in other aspects of the immune system, including the quality of the resident population of virus-specific effector CD8 T cells could contribute to maturation of protection, as well as the potential for vaccine strategies that further increase the size and quality of this effector population to prevent HIV-1 transmission. PMID:24349100

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.

Strain-Specific Protective Effect of the Immunity Induced by Live Malarial Sporozoites under Chloroquine Cover

PubMed Central

Wijayalath, Wathsala; Cheesman, Sandra; Tanabe, Kazuyuki; Handunnetti, Shiroma; Carter, Richard; Pathirana, Sisira

2012-01-01

The efficacy of a whole-sporozoite malaria vaccine would partly be determined by the strain-specificity of the protective responses against malarial sporozoites and liver-stage parasites. Evidence from previous reports were inconsistent, where some studies have shown that the protective immunity induced by irradiated or live sporozoites in rodents or humans were cross-protective and in others strain-specific. In the present work, we have studied the strain-specificity of live sporozoite-induced immunity using two genetically and immunologically different strains of Plasmodium cynomolgi, Pc746 and PcCeylon, in toque monkeys. Two groups of monkeys were immunized against live sporozoites of either the Pc746 (n = 5), or the PcCeylon (n = 4) strain, by the bites of 2–4 sporozoite-infected Anopheles tessellates mosquitoes per monkey under concurrent treatments with chloroquine and primaquine to abrogate detectable blood infections. Subsequently, a group of non-immunized monkeys (n = 4), and the two groups of immunized monkeys were challenged with a mixture of sporozoites of the two strains by the bites of 2–5 infective mosquitoes from each strain per monkey. In order to determine the strain-specificity of the protective immunity, the proportions of parasites of the two strains in the challenge infections were quantified using an allele quantification assay, Pyrosequencing™, based on a single nucleotide polymorphism (SNP) in the parasites’ circumsporozoite protein gene. The Pyrosequencing™ data showed that a significant reduction of parasites of the immunizing strain in each group of strain-specifically immunized monkeys had occurred, indicating a stronger killing effect on parasites of the immunizing strain. Thus, the protective immunity developed following a single, live sporozoite/chloroquine immunization, acted specifically against the immunizing strain and was, therefore, strain-specific. As our experiment does not allow us to determine the parasite stage at which the strain-specific protective immunity is directed, it is possible that the target of this immunity could be either the pre-erythrocytic stage, or the blood-stage, or both. PMID:23029282

Accumulation of 24 nucleotide transgene-derived siRNAs is associated with crinivirus immunity in transgenic plants.

PubMed

Qiao, Wenjie; Zarzyńska-Nowak, Aleksandra; Nerva, Luca; Kuo, Yen-Wen; Falk, Bryce W

2018-04-28

RNA silencing is a conserved antiviral defense mechanism that has been used to develop robust resistance against plant virus infections. Previous efforts have been made to develop RNA silencing-mediated resistance to criniviruses, yet none have given immunity. In this study, transgenic Nicotiana benthamiana plants harboring a hairpin construct of the Lettuce infectious yellows virus (LIYV) RdRp sequence exhibited immunity to systemic LIYV infection. Deep-sequencing analysis was performed to characterize virus-derived siRNAs (vsiRNAs) generated upon systemic LIYV infection in non-transgenic N. benthamiana plants as well as transgene-derived siRNAs (t-siRNAs) derived from the immune transgenic plants before and after LIYV inoculation. Interestingly, a similar sequence distribution pattern was obtained with t-siRNAs and vsiRNAs mapped to the transgene region in both immune and susceptible plants except a significant increase of t-siRNAs of 24 nt in length, which was consistent with small RNA northern blot results that showed the abundance of t-siRNAs of 21-, 22-, and 24- nt in length. The accumulated 24-nt sequences haven't yet been reported in transgenic plants partially resistant to criniviruses, thus may indicate their correlation with crinivirus immunity. To further test this hypothesis, we developed transgenic melon (Cucumis melo) plants immune to systemic infection of another crinivirus, Cucurbit yellow stunting disorder virus (CYSDV). As predicted, the accumulation of 24-nt t-siRNAs was detected in transgenic melon plants by northern blot. Together with our findings and previous studies on crinivirus resistance, we propose that the accumulation of 24 nt t-siRNAs is associated with crinivirus immunity in transgenic plants. This article is protected by copyright. All rights reserved. © 2018 BSPP and John Wiley & Sons Ltd.

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

PubMed Central

Jensen, Kara; dela Pena-Ponce, Myra Grace; Piatak, Michael; Shoemaker, Rebecca; Oswald, Kelli; Jacobs, William R.; Fennelly, Glenn; Lucero, Carissa; Mollan, Katie R.; Hudgens, Michael G.; Amedee, Angela; Kozlowski, Pamela A.; Estes, Jacob D.; Lifson, Jeffrey D.; Van Rompay, Koen K. A.; Larsen, Michelle

2016-01-01

ABSTRACT Our goal is to develop a pediatric combination vaccine to protect the vulnerable infant population against human immunodeficiency virus type 1 (HIV-1) and tuberculosis (TB) infections. The vaccine consists of an auxotroph Mycobacterium tuberculosis strain that coexpresses HIV antigens. Utilizing an infant rhesus macaque model, we have previously shown that this attenuated M. tuberculosis (AMtb)-simian immunodeficiency virus (SIV) vaccine is immunogenic, and although the vaccine did not prevent oral SIV infection, a subset of vaccinated animals was able to partially control virus replication. However, unexpectedly, vaccinated infants required fewer SIV exposures to become infected compared to naive controls. Considering that the current TB vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), can induce potent innate immune responses and confer pathogen-unspecific trained immunity, we hypothesized that an imbalance between enhanced myeloid cell function and immune activation might have influenced the outcome of oral SIV challenge in AMtb-SIV-vaccinated infants. To address this question, we used archived samples from unchallenged animals from our previous AMtb-SIV vaccine studies and vaccinated additional infant macaques with BCG or AMtb only. Our results show that vaccinated infants, regardless of vaccine strain or regimen, had enhanced myeloid cell responses. However, CD4+ T cells were concurrently activated, and the persistence of these activated target cells in oral and/or gastrointestinal tissues may have facilitated oral SIV infection. Immune activation was more pronounced in BCG-vaccinated infant macaques than in AMtb-vaccinated infant macaques, indicating a role for vaccine attenuation. These findings underline the importance of understanding the interplay of vaccine-induced immunity and immune activation and its effect on HIV acquisition risk and outcome in infants. PMID:27655885

Targeting the permeability barrier and peptidoglycan recycling pathways to disarm Pseudomonas aeruginosa against the innate immune system

PubMed Central

Moya, Bartolomé; Munar-Bestard, Marta; Zamorano, Laura; Cabot, Gabriel; Blázquez, Jesús; Ayala, Juan A.; Oliver, Antonio

2017-01-01

Antimicrobial resistance is a continuously increasing threat that severely compromises our antibiotic arsenal and causes thousands of deaths due to hospital-acquired infections by pathogens such as Pseudomonas aeruginosa, situation further aggravated by the limited development of new antibiotics. Thus, alternative strategies such as those targeting bacterial resistance mechanisms, virulence or potentiating the activity of our immune system resources are urgently needed. We have recently shown that mutations simultaneously causing the peptidoglycan recycling blockage and the β-lactamase AmpC overexpression impair the virulence of P.aeruginosa. These findings suggested that peptidoglycan metabolism might be a good target not only for fighting antibiotic resistance, but also for the attenuation of virulence and/or potentiation of our innate immune weapons. Here we analyzed the activity of the innate immune elements peptidoglycan recognition proteins (PGRPs) and lysozyme against P. aeruginosa. We show that while lysozyme and PGRPs have a very modest basal effect over P. aeruginosa, their bactericidal activity is dramatically increased in the presence of subinhibitory concentrations of the permeabilizing agent colistin. We also show that the P. aeruginosa lysozyme inhibitors seem to play a very residual protective role even in permeabilizing conditions. In contrast, we demonstrate that, once the permeability barrier is overpassed, the activity of lysozyme and PGRPs is dramatically enhanced when inhibiting key peptidoglycan recycling components (such as the 3 AmpDs, AmpG or NagZ), indicating a decisive protective role for cell-wall recycling and that direct peptidoglycan-binding supports, at least partially, the activity of these enzymes. Finally, we show that recycling blockade when occurring simultaneously with AmpC overexpression determines a further decrease in the resistance against PGRP2 and lysozyme, linked to quantitative changes in the cell-wall. Thus, our results help to delineate new strategies against P. aeruginosa infections, simultaneously targeting β–lactam resistance, cell-wall metabolism and virulence, ultimately enhancing the activity of our innate immune weapons. PMID:28742861

48 CFR 1852.228-80 - Insurance-Immunity From Tort Liability.

Code of Federal Regulations, 2012 CFR

2012-10-01

..., Insurance—Liability to Third Persons, and the associated NFS clause 1852.228-81, Insurance—Partial Immunity... clause at NFS 1852.228-82 Insurance—Total Immunity From Tort Liability, will be included in the contract...

48 CFR 1852.228-80 - Insurance-Immunity From Tort Liability.

Code of Federal Regulations, 2013 CFR

2013-10-01

..., Insurance—Liability to Third Persons, and the associated NFS clause 1852.228-81, Insurance—Partial Immunity... clause at NFS 1852.228-82 Insurance—Total Immunity From Tort Liability, will be included in the contract...

48 CFR 1852.228-80 - Insurance-Immunity From Tort Liability.

Code of Federal Regulations, 2014 CFR

2014-10-01

..., Insurance—Liability to Third Persons, and the associated NFS clause 1852.228-81, Insurance—Partial Immunity... clause at NFS 1852.228-82 Insurance—Total Immunity From Tort Liability, will be included in the contract...

48 CFR 1852.228-80 - Insurance-Immunity From Tort Liability.

Code of Federal Regulations, 2011 CFR

2011-10-01

..., Insurance—Liability to Third Persons, and the associated NFS clause 1852.228-81, Insurance—Partial Immunity... clause at NFS 1852.228-82 Insurance—Total Immunity From Tort Liability, will be included in the contract...

48 CFR 1852.228-80 - Insurance-Immunity From Tort Liability.

Code of Federal Regulations, 2010 CFR

2010-10-01

..., Insurance—Liability to Third Persons, and the associated NFS clause 1852.228-81, Insurance—Partial Immunity... clause at NFS 1852.228-82 Insurance—Total Immunity From Tort Liability, will be included in the contract...

Yersinia pestis caf1 variants and the limits of plague vaccine protection.

PubMed

Quenee, Lauriane E; Cornelius, Claire A; Ciletti, Nancy A; Elli, Derek; Schneewind, Olaf

2008-05-01

Yersinia pestis, the highly virulent agent of plague, is a biological weapon. Strategies that prevent plague have been sought for centuries, and immunization with live, attenuated (nonpigmented) strains or subunit vaccines with F1 (Caf1) antigen is considered effective. We show here that immunization with live, attenuated strains generates plague-protective immunity and humoral immune responses against F1 pilus antigen and LcrV. Y. pestis variants lacking caf1 (F1 pili) are not only fully virulent in animal models of bubonic and pneumonic plague but also break through immune responses generated with live, attenuated strains or F1 subunit vaccines. In contrast, immunization with purified LcrV, a protein at the tip of type III needles, generates protective immunity against the wild-type and the fully virulent caf1 mutant strain, in agreement with the notion that LcrV can elicit vaccine protection against both types of virulent plague strains.

Prevalence and socio-demographic factors associated with non-protective immunity against tetanus among high school adolescents girls in Nigeria

PubMed Central

2014-01-01

Background The low uptake of tetanus vaccine and its resultant high burden of tetanus in Nigeria suggest the need to improve routine and booster vaccination in children and adolescents. However, epidemiological evidence for vaccination in the adolescent age group needed for effective strategy and policy formulation is lacking. This study was carried out to determine the prevalence of protective immunity against tetanus and to identify risk factors for non-protective immunity among schooling adolescents. Methods Using a three-stage sampling technique, 851 female adolescents were randomly selected from secondary schools in Ibadan, Nigeria. A pre-tested questionnaire was used to obtain data on demographic and socio-economic characteristics and history of tetanus vaccination. An immuno-chromatographic rapid test kit, “Tetanos Quick Stick” was used to test specific anti-tetanus antibody protective level in venous blood samples. Descriptive statistics, Chi-square and logistic regression analyses were done with level of significance set at p = 0.05. Results Mean age of participants was 14.3 ± 1.9 years. Seroprevalence of protective immunity against tetanus was 38.1% and it significantly decreased with increasing age. More adolescents in public (65.4%) than private (44.7%) schools had non-protective level of immunity. A significantly increasing trend in the risk of non-protective immunity was observed with decreasing level of mothers’ education. Also, the Odds of non-protective level of immunity was significantly higher in public than private schools (OR = 2.14; 95% CI =1.39, 3.20) but lower among adolescents who had history of recent tetanus toxoid injection than those who did not (OR = 0.11 95% CI = 0.09, 0.22). However, no significant association was found between protective immunity against tetanus and parents’ marital status as well as family size. Conclusion Protective immunity against tetanus among female adolescents was poor, more so in public schools and those who had not received vaccination a year prior to the study. Policy-makers need to consider the inclusion of immunization against tetanus in the school health programme. PMID:24636576

Human Milk and Allergic Diseases: An Unsolved Puzzle

PubMed Central

Peroni, Diego G.; Boix-Amorós, Alba; Hsu, Peter S.; Van’t Land, Belinda; Skevaki, Chrysanthi; Collado, Maria Carmen; Garssen, Johan; Geddes, Donna T.; Nanan, Ralph; Slupsky, Carolyn; Wegienka, Ganesa; Kozyrskyj, Anita L.; Warner, John O.

2017-01-01

There is conflicting evidence on the protective role of breastfeeding in relation to the development of allergic sensitisation and allergic disease. Studies vary in methodology and definition of outcomes, which lead to considerable heterogeneity. Human milk composition varies both within and between individuals, which may partially explain conflicting data. It is known that human milk composition is very complex and contains variable levels of immune active molecules, oligosaccharides, metabolites, vitamins and other nutrients and microbial content. Existing evidence suggests that modulation of human breast milk composition has potential for preventing allergic diseases in early life. In this review, we discuss associations between breastfeeding/human milk composition and allergy development. PMID:28817095

Human Milk and Allergic Diseases: An Unsolved Puzzle.

PubMed

Munblit, Daniel; Peroni, Diego G; Boix-Amorós, Alba; Hsu, Peter S; Van't Land, Belinda; Gay, Melvin C L; Kolotilina, Anastasia; Skevaki, Chrysanthi; Boyle, Robert J; Collado, Maria Carmen; Garssen, Johan; Geddes, Donna T; Nanan, Ralph; Slupsky, Carolyn; Wegienka, Ganesa; Kozyrskyj, Anita L; Warner, John O

2017-08-17

There is conflicting evidence on the protective role of breastfeeding in relation to the development of allergic sensitisation and allergic disease. Studies vary in methodology and definition of outcomes, which lead to considerable heterogeneity. Human milk composition varies both within and between individuals, which may partially explain conflicting data. It is known that human milk composition is very complex and contains variable levels of immune active molecules, oligosaccharides, metabolites, vitamins and other nutrients and microbial content. Existing evidence suggests that modulation of human breast milk composition has potential for preventing allergic diseases in early life. In this review, we discuss associations between breastfeeding/human milk composition and allergy development.

Single-dose live-attenuated Nipah virus vaccines confer complete protection by eliciting antibodies directed against surface glycoproteins

PubMed Central

DeBuysscher, Blair L.; Scott, Dana; Marzi, Andrea; Prescott, Joseph; Feldmann, Heinz

2016-01-01

Background Nipah virus (NiV), a zoonotic pathogen causing severe respiratory illness and encephalitis in humans, emerged in Malaysia in 1998 with subsequent outbreaks on an almost annual basis since 2001 in parts of the Indian subcontinent. The high case fatality rate, human-to-human transmission, wide-ranging reservoir distribution and lack of licensed intervention options are making NiV a serious regional and potential global public health problem. The objective of this study was to develop a fast-acting, single-dose NiV vaccine that could be implemented in a ring vaccination approach during outbreaks. Methods In this study we have designed new live-attenuated vaccine vectors based on recombinant vesicular stomatitis viruses (rVSV) expressing NiV glycoproteins (G or F) or nucleoprotein (N) and evaluated their protective efficacy in Syrian hamsters, an established NiV animal disease model. We further characterized the humoral immune response to vaccination in hamsters using ELISA and neutralization assays and performed serum transfer studies. Results Vaccination of Syrian hamsters with a single dose of the rVSV vaccine vectors resulted in strong humoral immune responses with neutralizing activities found only in those animals vaccinated with rVSV expressing NiV G or F proteins. Vaccinated animals with neutralizing antibody responses were completely protected from lethal NiV disease, whereas animals vaccinated with rVSV expressing NiV N showed only partial protection. Protection of NiV G or F vaccinated animals was conferred by antibodies, most likely the neutralizing fraction, as demonstrated by serum transfer studies. Protection of N-vaccinated hamsters was not antibody-dependent indicating a role of adaptive cellular responses for protection. Conclusions The rVSV vectors expressing Nipah virus G or F are prime candidates for new ‘emergency vaccines’ to be utilized for NiV outbreak management. PMID:24631094

Single-dose live-attenuated Nipah virus vaccines confer complete protection by eliciting antibodies directed against surface glycoproteins.

PubMed

DeBuysscher, Blair L; Scott, Dana; Marzi, Andrea; Prescott, Joseph; Feldmann, Heinz

2014-05-07

Nipah virus (NiV), a zoonotic pathogen causing severe respiratory illness and encephalitis in humans, emerged in Malaysia in 1998 with subsequent outbreaks on an almost annual basis since 2001 in parts of the Indian subcontinent. The high case fatality rate, human-to-human transmission, wide-ranging reservoir distribution and lack of licensed intervention options are making NiV a serious regional and potential global public health problem. The objective of this study was to develop a fast-acting, single-dose NiV vaccine that could be implemented in a ring vaccination approach during outbreaks. In this study we have designed new live-attenuated vaccine vectors based on recombinant vesicular stomatitis viruses (rVSV) expressing NiV glycoproteins (G or F) or nucleoprotein (N) and evaluated their protective efficacy in Syrian hamsters, an established NiV animal disease model. We further characterized the humoral immune response to vaccination in hamsters using ELISA and neutralization assays and performed serum transfer studies. Vaccination of Syrian hamsters with a single dose of the rVSV vaccine vectors resulted in strong humoral immune responses with neutralizing activities found only in those animals vaccinated with rVSV expressing NiV G or F proteins. Vaccinated animals with neutralizing antibody responses were completely protected from lethal NiV disease, whereas animals vaccinated with rVSV expressing NiV N showed only partial protection. Protection of NiV G or F vaccinated animals was conferred by antibodies, most likely the neutralizing fraction, as demonstrated by serum transfer studies. Protection of N-vaccinated hamsters was not antibody-dependent indicating a role of adaptive cellular responses for protection. The rVSV vectors expressing Nipah virus G or F are prime candidates for new 'emergency vaccines' to be utilized for NiV outbreak management. Published by Elsevier Ltd.

Impact of partial sleep deprivation on immune markers.

PubMed

Wilder-Smith, A; Mustafa, F B; Earnest, A; Gen, L; Macary, P A

2013-10-01

Sleep quality is considered to be an important predictor of immunity. Lack of sleep therefore may reduce immunity, thereby increasing the susceptibility to respiratory pathogens. A previous study showed that reduced sleep duration was associated with an increased likelihood of the common cold. It is important to understand the role of sleep in altering immune responses to understand how sleep deprivation leads to an increased susceptibility to the common cold or other respiratory infections. We sought to examine the impact of partial sleep deprivation on various immune markers. Fifty-two healthy volunteers were partially sleep deprived for one night. We took blood samples before the sleep deprivation, immediately after, and 4 and 7 days after sleep deprivation. We measured various immune markers and used a generalized estimating equation (GEE) to examine the differences in the repeated measures. CD4, CD8, CD14, and CD16 all showed significant time-dependent changes, but CD3 did not. The most striking time-dependent change was observed for the mitogen proliferation assay and for HLA-DR. There was a significant decrease in the mitogen proliferation values and HLA-DR immediately after the sleep deprivation experiment, which started to rise again on day 4 and normalized by day 7. The transiently impaired mitogen proliferation, the decreased HLA-DR, the upregulated CD14, and the variations in CD4 and CD8 that we observed in temporal relationship with partial sleep deprivation could be one possible explanation for the increased susceptibility to respiratory infections reported after reduced sleep duration. Copyright © 2013 Elsevier B.V. All rights reserved.

Protective immunity against Trypanosoma cruzi provided by oral immunization with Phytomonas serpens: role of nitric oxide.

PubMed

Pinge-Filho, P; Peron, J P S; de Moura, T R; Menolli, R A; Graça, V K; Estevão, D; Tadokoro, C E; Jankevicius, J V; Rizzo, L V

2005-01-31

We have previously demonstrated that Phytomonas serpens, a tomato parasite, shares antigens with Trypanosoma cruzi, the protozoa that causes Chagas' disease. These antigens are recognized by human sera and induce protective immunity in Balb/c mice. In the present study, inducible nitric oxide synthase (iNOS) knockout (KO) mice and C57BL/6 mice treated with the nitric oxide inhibitor, aminoguanidine (AG, 50 mg kg(-1)) infected with T. cruzi, were used to demonstrate the role of nitric oxide (NO) to host protection against T. cruzi infection achieved by oral immunization with live P. serpens. A reduction in parasitaemia and an increase in survival were observed in C57BL/6 infected mice and previously immunized with P. serpens, when compared to non-immunized mice. iNOS (KO) mice immunized and C57BL/6 immunized and treated with AG presented parasitaemia and mortality rates comparable to those of infected and non-immunized mice. By itself, immunization with P. serpens did not induce inflammation in the myocardium, but C57BL/6 mice so immunized showed fewer amastigotes nests in the heart following an acute T. cruzi infection than those in non-immunized mice. These results suggest that protective immunity against T. cruzi infection induced by immunization with P. serpens is dependent upon enhanced NO production during the acute phase of T. cruzi infection.

Insect immunity shows specificity in protection upon secondary pathogen exposure.

PubMed

Sadd, Ben M; Schmid-Hempel, Paul

2006-06-20

Immunological memory in vertebrates, conferring lasting specific protection after an initial pathogen exposure, has implications for a broad spectrum of evolutionary, epidemiological, and medical phenomena . However, the existence of specificity in protection upon secondary pathogen exposure in invertebrates remains controversial . To separate this functional phenomenon from a particular mechanism, we refer to it as specific immune priming. We investigate the presence of specific immune priming in workers of the social insect Bombus terrestris. Using three bacterial pathogens, we test whether a prior homologous pathogen exposure gives a benefit in terms of long-term protection against a later challenge, over and above a heterologous combination. With a reciprocally designed initial and second-exposure protocol (i.e., all combinations of bacteria were tested), we demonstrate, even several weeks after the clearance of a first exposure, increased protection and narrow specificity upon secondary exposure. This demonstrates that the invertebrate immune system is functionally capable of unexpectedly specific and durable induced protection. Ultimately, despite general broad differences between vertebrates and invertebrates, the ability of both immune systems to show specificity in protection suggests that their immune defenses have found comparable solutions to similar selective pressures over evolutionary time.

Intramuscular delivery of adenovirus serotype 5 vector expressing humanized protective antigen induces rapid protection against anthrax that may bypass intranasally originated preexisting adenovirus immunity.

PubMed

Wu, Shipo; Zhang, Zhe; Yu, Rui; Zhang, Jun; Liu, Ying; Song, Xiaohong; Yi, Shaoqiong; Liu, Ju; Chen, Jianqin; Yin, Ying; Xu, Junjie; Hou, Lihua; Chen, Wei

2014-02-01

Developing an effective anthrax vaccine that can induce a rapid and sustained immune response is a priority for the prevention of bioterrorism-associated anthrax infection. Here, we developed a recombinant replication-deficient adenovirus serotype 5-based vaccine expressing the humanized protective antigen (Ad5-PAopt). A single intramuscular injection of Ad5-PAopt resulted in rapid and robust humoral and cellular immune responses in Fisher 344 rats. Animals intramuscularly inoculated with a single dose of 10⁸ infectious units of Ad5-PAopt achieved 100% protection from challenge with 10 times the 50% lethal dose (LD₅₀) of anthrax lethal toxin 7 days after vaccination. Although preexisting intranasally induced immunity to Ad5 slightly weakened the humoral and cellular immune responses to Ad5-PAopt via intramuscular inoculation, 100% protection was achieved 15 days after vaccination in Fisher 344 rats. The protective efficacy conferred by intramuscular vaccination in the presence of preexisting intranasally induced immunity was significantly better than that of intranasal delivery of Ad5-PAopt and intramuscular injection with recombinant PA and aluminum adjuvant without preexisting immunity. As natural Ad5 infection often occurs via the mucosal route, the work here largely illuminates that intramuscular inoculation with Ad5-PAopt can overcome the negative effects of immunity induced by prior adenovirus infection and represents an efficient approach for protecting against emerging anthrax.

Intramuscular Delivery of Adenovirus Serotype 5 Vector Expressing Humanized Protective Antigen Induces Rapid Protection against Anthrax That May Bypass Intranasally Originated Preexisting Adenovirus Immunity

PubMed Central

Wu, Shipo; Zhang, Zhe; Yu, Rui; Zhang, Jun; Liu, Ying; Song, Xiaohong; Yi, Shaoqiong; Liu, Ju; Chen, Jianqin; Yin, Ying; Xu, Junjie

2014-01-01

Developing an effective anthrax vaccine that can induce a rapid and sustained immune response is a priority for the prevention of bioterrorism-associated anthrax infection. Here, we developed a recombinant replication-deficient adenovirus serotype 5-based vaccine expressing the humanized protective antigen (Ad5-PAopt). A single intramuscular injection of Ad5-PAopt resulted in rapid and robust humoral and cellular immune responses in Fisher 344 rats. Animals intramuscularly inoculated with a single dose of 108 infectious units of Ad5-PAopt achieved 100% protection from challenge with 10 times the 50% lethal dose (LD50) of anthrax lethal toxin 7 days after vaccination. Although preexisting intranasally induced immunity to Ad5 slightly weakened the humoral and cellular immune responses to Ad5-PAopt via intramuscular inoculation, 100% protection was achieved 15 days after vaccination in Fisher 344 rats. The protective efficacy conferred by intramuscular vaccination in the presence of preexisting intranasally induced immunity was significantly better than that of intranasal delivery of Ad5-PAopt and intramuscular injection with recombinant PA and aluminum adjuvant without preexisting immunity. As natural Ad5 infection often occurs via the mucosal route, the work here largely illuminates that intramuscular inoculation with Ad5-PAopt can overcome the negative effects of immunity induced by prior adenovirus infection and represents an efficient approach for protecting against emerging anthrax. PMID:24307239

Partial protection of SIV-infected rhesus monkeys against superinfection with a heterologous SIV isolate

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

Korber, Bette

2009-01-01

Although there is increasing evidence that individuals already infected with human immunodeficiency virus type 1 (HIV-1) can be infected with a heterologous strain of the virus, the extent of protection against superinfection conferred by the first infection and the biologic consequences of superinfection are not well understood. We explored these questions in the simian immunodeficiency virus (SIV)/rhesus monkey model of HIV-1/AIDS. We infected cohorts of rhesus monkeys with either SIVmac251 or SIVsmE660 and then exposed animals to the reciprocal virus through intrarectal inoculations. Employing a quantitative real-time PCR assay, we determined the replication kinetics of the two strains of virusmore » for 20 weeks. We found that primary infection with a replication-competent virus did not protect against acquisition of infection by a heterologous virus but did confer relative control of the superinfecting virus. In animals that became superinfected, there was a reduction in peak replication and rapid control of the second virus. The relative susceptibility to superinfection was not correlated with CD4(+) T-cell count, CD4(+) memory T-cell subsets, cytokine production by virus-specific CD8(+) or CD4(+) cells, or neutralizing antibodies at the time of exposure to the second virus. Although there were transient increases in viral loads of the primary virus and a modest decline in CD4(+) T-cell counts after superinfection, there was no evidence of disease acceleration. These findings indicate that an immunodeficiency virus infection confers partial protection against a second immunodeficiency virus infection, but this protection may be mediated by mechanisms other than classical adaptive immune responses.« less

Yeast-expressed recombinant As16 protects mice against Ascaris suum infection through induction of a Th2-skewed immune response

PubMed Central

Liu, Zhuyun; Keegan, Brian; Gazzinelli-Guimarães, Ana Clara; Fujiwara, Ricardo T.; Briggs, Neima; Jones, Kathryn M.; Strych, Ulrich; Beaumier, Coreen M.; Bottazzi, Maria Elena; Zhan, Bin

2017-01-01

Background Ascariasis remains the most common helminth infection in humans. As an alternative or complementary approach to global deworming, a pan-anthelminthic vaccine is under development targeting Ascaris, hookworm, and Trichuris infections. As16 and As14 have previously been described as two genetically related proteins from Ascaris suum that induced protective immunity in mice when formulated with cholera toxin B subunit (CTB) as an adjuvant, but the exact protective mechanism was not well understood. Methodology/Principal findings As16 and As14 were highly expressed as soluble recombinant proteins (rAs16 and rAs14) in Pichia pastoris. The yeast-expressed rAs16 was highly recognized by immune sera from mice infected with A. suum eggs and elicited 99.6% protection against A. suum re-infection. Mice immunized with rAs16 formulated with ISA720 displayed significant larva reduction (36.7%) and stunted larval development against A. suum eggs challenge. The protective immunity was associated with a predominant Th2-type response characterized by high titers of serological IgG1 (IgG1/IgG2a > 2000) and high levels of IL-4 and IL-5 produced by restimulated splenocytes. A similar level of protection was observed in mice immunized with rAs16 formulated with alum (Alhydrogel), known to induce mainly a Th2-type immune response, whereas mice immunized with rAs16 formulated with MPLA or AddaVax, both known to induce a Th1-type biased response, were not significantly protected against A. suum infection. The rAs14 protein was not recognized by A. suum infected mouse sera and mice immunized with rAs14 formulated with ISA720 did not show significant protection against challenge infection, possibly due to the protein’s inaccessibility to the host immune system or a Th1-type response was induced which would counter a protective Th2-type response. Conclusions/Significance Yeast-expressed rAs16 formulated with ISA720 or alum induced significant protection in mice against A. suum egg challenge that associates with a Th2-skewed immune response, suggesting that rAS16 could be a feasible vaccine candidate against ascariasis. PMID:28708895

Superior Efficacy of a Human Immunodeficiency Virus Vaccine Combined with Antiretroviral Prevention in Simian-Human Immunodeficiency Virus-Challenged Nonhuman Primates.

PubMed

Le Grand, Roger; Dereuddre-Bosquet, Nathalie; Dispinseri, Stefania; Gosse, Leslie; Desjardins, Delphine; Shen, Xiaoying; Tolazzi, Monica; Ochsenbauer, Christina; Saidi, Hela; Tomaras, Georgia; Prague, Mélanie; Barnett, Susan W; Thiebaut, Rodolphe; Cope, Alethea; Scarlatti, Gabriella; Shattock, Robin J

2016-06-01

Although vaccines and antiretroviral (ARV) prevention have demonstrated partial success against human immunodeficiency virus (HIV) infection in clinical trials, their combined introduction could provide more potent protection. Furthermore, combination approaches could ameliorate the potential increased risk of infection following vaccination in the absence of protective immunity. We used a nonhuman primate model to determine potential interactions of combining a partially effective ARV microbicide with an envelope-based vaccine. The vaccine alone provided no protection from infection following 12 consecutive low-dose intravaginal challenges with simian-HIV strain SF162P3, with more animals infected compared to naive controls. The microbicide alone provided a 68% reduction in the risk of infection relative to that of the vaccine group and a 45% reduction relative to that of naive controls. The vaccine-microbicide combination provided an 88% reduction in the per-exposure risk of infection relative to the vaccine alone and a 79% reduction relative to that of the controls. Protected animals in the vaccine-microbicide group were challenged a further 12 times in the absence of microbicide and demonstrated a 98% reduction in the risk of infection. A total risk reduction of 91% was observed in this group over 24 exposures (P = 0.004). These important findings suggest that combined implementation of new biomedical prevention strategies may provide significant gains in HIV prevention. There is a pressing need to maximize the impact of new biomedical prevention tools in the face of the 2 million HIV infections that occur each year. Combined implementation of complementary biomedical approaches could create additive or synergistic effects that drive improved reduction of HIV incidence. Therefore, we assessed a combination of an untested vaccine with an ARV-based microbicide in a nonhuman primate vaginal challenge model. The vaccine alone provided no protection (and may have increased susceptibility to a simian-HIV vaginal challenge), while the microbicide reduced the infection risk compared to that of vaccinated and naive animals. Importantly, the combined interventions provided the greatest level of protection, which was sustained following withdrawal of the microbicide. The data suggest that provision of ARV prophylaxis during vaccination reduces the potential for unexpected increased risks of infection following immunization and augments vaccine efficacy. These findings are important for the potential adoption of ARV prophylaxis as the baseline intervention for future HIV/AIDS vaccines. Copyright © 2016 Le Grand et al.

Superior Efficacy of a Human Immunodeficiency Virus Vaccine Combined with Antiretroviral Prevention in Simian-Human Immunodeficiency Virus-Challenged Nonhuman Primates

PubMed Central

Le Grand, Roger; Dereuddre-Bosquet, Nathalie; Dispinseri, Stefania; Gosse, Leslie; Desjardins, Delphine; Shen, Xiaoying; Tolazzi, Monica; Ochsenbauer, Christina; Saidi, Hela; Tomaras, Georgia; Prague, Mélanie; Barnett, Susan W.; Thiebaut, Rodolphe; Scarlatti, Gabriella

2016-01-01

ABSTRACT Although vaccines and antiretroviral (ARV) prevention have demonstrated partial success against human immunodeficiency virus (HIV) infection in clinical trials, their combined introduction could provide more potent protection. Furthermore, combination approaches could ameliorate the potential increased risk of infection following vaccination in the absence of protective immunity. We used a nonhuman primate model to determine potential interactions of combining a partially effective ARV microbicide with an envelope-based vaccine. The vaccine alone provided no protection from infection following 12 consecutive low-dose intravaginal challenges with simian-HIV strain SF162P3, with more animals infected compared to naive controls. The microbicide alone provided a 68% reduction in the risk of infection relative to that of the vaccine group and a 45% reduction relative to that of naive controls. The vaccine-microbicide combination provided an 88% reduction in the per-exposure risk of infection relative to the vaccine alone and a 79% reduction relative to that of the controls. Protected animals in the vaccine-microbicide group were challenged a further 12 times in the absence of microbicide and demonstrated a 98% reduction in the risk of infection. A total risk reduction of 91% was observed in this group over 24 exposures (P = 0.004). These important findings suggest that combined implementation of new biomedical prevention strategies may provide significant gains in HIV prevention. IMPORTANCE There is a pressing need to maximize the impact of new biomedical prevention tools in the face of the 2 million HIV infections that occur each year. Combined implementation of complementary biomedical approaches could create additive or synergistic effects that drive improved reduction of HIV incidence. Therefore, we assessed a combination of an untested vaccine with an ARV-based microbicide in a nonhuman primate vaginal challenge model. The vaccine alone provided no protection (and may have increased susceptibility to a simian-HIV vaginal challenge), while the microbicide reduced the infection risk compared to that of vaccinated and naive animals. Importantly, the combined interventions provided the greatest level of protection, which was sustained following withdrawal of the microbicide. The data suggest that provision of ARV prophylaxis during vaccination reduces the potential for unexpected increased risks of infection following immunization and augments vaccine efficacy. These findings are important for the potential adoption of ARV prophylaxis as the baseline intervention for future HIV/AIDS vaccines. PMID:27009957

Comparative In Vitro and In Vivo Studies of Porcine Rotavirus G9P[13] and Human Rotavirus Wa G1P[8

PubMed Central

Shao, Lulu; Fischer, David D.; Kandasamy, Sukumar; Rauf, Abdul; Langel, Stephanie N.; Wentworth, David E.; Stucker, Karla M.; Halpin, Rebecca A.; Lam, Ham Ching; Marthaler, Douglas

2015-01-01

ABSTRACT The changing epidemiology of group A rotavirus (RV) strains in humans and swine, including emerging G9 strains, poses new challenges to current vaccines. In this study, we comparatively assessed the pathogenesis of porcine RV (PRV) G9P[13] and evaluated the short-term cross-protection between this strain and human RV (HRV) Wa G1P[8] in gnotobiotic pigs. Complete genome sequencing demonstrated that PRV G9P[13] possessed a human-like G9 VP7 genotype but shared higher overall nucleotide identity with historic PRV strains. PRV G9P[13] induced longer rectal virus shedding and RV RNAemia in pigs than HRV Wa G1P[8] and generated complete short-term cross-protection in pigs challenged with HRV or PRV, whereas HRV Wa G1P[8] induced only partial protection against PRV challenge. Moreover, PRV G9P[13] replicated more extensively in porcine monocyte-derived dendritic cells (MoDCs) than did HRV Wa G1P[8]. Cross-protection was likely not dependent on serum virus-neutralizing (VN) antibodies, as the heterologous VN antibody titers in the sera of G9P[13]-inoculated pigs were low. Thus, our results suggest that heterologous protection by the current monovalent G1P[8] HRV vaccine against emerging G9 strains should be evaluated in clinical and experimental studies to prevent further dissemination of G9 strains. Differences in the pathogenesis of these two strains may be partially attributable to their variable abilities to replicate and persist in porcine immune cells, including dendritic cells (DCs). Additional studies are needed to evaluate the emerging G9 strains as potential vaccine candidates and to test the susceptibility of various immune cells to infection by G9 and other common HRV/PRV genotypes. IMPORTANCE The changing epidemiology of porcine and human group A rotaviruses (RVs), including emerging G9 strains, may compromise the efficacy of current vaccines. An understanding of the pathogenesis and genetic, immunological, and biological features of the new emerging RV strains will contribute to the development of new surveillance and prevention tools. Additionally, studies of cross-protection between the newly identified emerging G9 porcine RV strains and a human G1 RV vaccine strain in a susceptible host (swine) will allow evaluation of G9 strains as potential novel vaccine candidates to be included in porcine or human vaccines. PMID:26468523

LEE-encoded regulator (Ler) mutants elicit serotype-specific protection, but not cross protection, against attaching and effacing E. coli strains.

PubMed

Zhu, C; Feng, S; Yang, Z; Davis, K; Rios, H; Kaper, J B; Boedeker, E C

2007-02-26

We previously showed that single dose orogastric immunization with an attenuated regulatory Lee-encoded regulator (ler) mutant of the rabbit enteropathogenic Escherichia coli (REPEC) strain E22 (O103:H2) protected rabbits from fatal infection with the highly virulent parent strain. In the current study we assessed the degree of homologous (serotype-specific) and heterologous (cross-serotype) protection induced by immunization with REPEC ler mutant strains of differing serotypes, or with a prototype strain RDEC-1 (O15:H-) which expresses a full array of ler up-regulated proteins. We constructed an additional ler mutant using RDEC-1 thus, permitting immunization with a ler mutant of either serotype, O15 or O103, followed by challenge with a virulent REPEC strain of the same or different serotypes. Consistent with our previous data, the current study demonstrated that rabbits immunized with a RDEC-1 ler mutant were protected from challenge with virulent RDEC-H19A (RDEC-1 transduced with Shiga toxin-producing phage H19A) of the same serotype. Rabbits immunized with RDEC-1 or E22 derivative ler mutants demonstrated significant increase in serum antibody titers to the respective whole bacterial cells expressing O antigen but not to the LEE-encoded proteins. However, immunization with the ler mutants of either E22 or RDEC-1 failed to protect rabbits from infections with virulent organisms belonging to different serotypes. In contrast, rabbits immunized with the prototype RDEC-1 were cross protected against challenge with the heterologous E22 strain as shown by normal weight gain, and the absence of clinical signs of disease or characteristic attaching and effacing (A/E) lesions. Immunization with RDEC-1 induced significantly elevated serum IgG titers to LEE-encoded proteins. We thus, demonstrated homologous protection induced by the REPEC ler mutants and heterologous protection by RDEC-1. The observed correlation between elevated immune responses to the LEE-encoded proteins and the protection against challenge with heterologous virulent REPEC strain suggests that serotype-non-specific cross protection requires the expression of, and induction of antibody to, LEE-encoded virulence factors.

Virus-Like Particle Vaccine Protects against 2009 H1N1 Pandemic Influenza Virus in Mice

PubMed Central

Quan, Fu-Shi; Vunnava, Aswani; Compans, Richard W.; Kang, Sang-Moo

2010-01-01

Background The 2009 influenza pandemic and shortages in vaccine supplies worldwide underscore the need for new approaches to develop more effective vaccines. Methodology/Principal Findings We generated influenza virus-like particles (VLPs) containing proteins derived from the A/California/04/2009 virus, and tested their efficacy as a vaccine in mice. A single intramuscular vaccination with VLPs provided complete protection against lethal challenge with the A/California/04/2009 virus and partial protection against A/PR/8/1934 virus, an antigenically distant human isolate. VLP vaccination induced predominant IgG2a antibody responses, high hemagglutination inhibition (HAI) titers, and recall IgG and IgA antibody responses. HAI titers after VLP vaccination were equivalent to those observed after live virus infection. VLP immune sera also showed HAI responses against diverse geographic pandemic isolates. Notably, a low dose of VLPs could provide protection against lethal infection. Conclusion/Significance This study demonstrates that VLP vaccination provides highly effective protection against the 2009 pandemic influenza virus. The results indicate that VLPs can be developed into an effective vaccine, which can be rapidly produced and avoid the need to isolate high growth reassortants for egg-based production. PMID:20161790

DNA vaccines: protective immunizations by parenteral, mucosal, and gene-gun inoculations.

PubMed Central

Fynan, E F; Webster, R G; Fuller, D H; Haynes, J R; Santoro, J C; Robinson, H L

1993-01-01

Plasmid DNAs expressing influenza virus hemagglutinin glycoproteins have been tested for their ability to raise protective immunity against lethal influenza challenges of the same subtype. In trials using two inoculations of from 50 to 300 micrograms of purified DNA in saline, 67-95% of test mice and 25-63% of test chickens have been protected against a lethal influenza challenge. Parenteral routes of inoculation that achieved good protection included intramuscular and intravenous injections. Successful mucosal routes of vaccination included DNA drops administered to the nares or trachea. By far the most efficient DNA immunizations were achieved by using a gene gun to deliver DNA-coated gold beads to the epidermis. In mice, 95% protection was achieved by two immunizations with beads loaded with as little as 0.4 micrograms of DNA. The breadth of routes supporting successful DNA immunizations, coupled with the very small amounts of DNA required for gene-gun immunizations, highlight the potential of this remarkably simple technique for the development of subunit vaccines. Images Fig. 1 PMID:8265577

Expression library immunization can confer protection against lethal challenge with African swine fever virus.

PubMed

Lacasta, Anna; Ballester, María; Monteagudo, Paula L; Rodríguez, Javier M; Salas, María L; Accensi, Francesc; Pina-Pedrero, Sonia; Bensaid, Albert; Argilaguet, Jordi; López-Soria, Sergio; Hutet, Evelyne; Le Potier, Marie Frédérique; Rodríguez, Fernando

2014-11-01

African swine fever is one of the most devastating pig diseases, against which there is no vaccine available. Recent work from our laboratory has demonstrated the protective potential of DNA vaccines encoding three African swine fever viral antigens (p54, p30, and the hemagglutinin extracellular domain) fused to ubiquitin. Partial protection was afforded in the absence of detectable antibodies prior to virus challenge, and survival correlated with the presence of a large number of hemagglutinin-specific CD8(+) T cells in blood. Aiming to demonstrate the presence of additional CD8(+) T-cell determinants with protective potential, an expression library containing more than 4,000 individual plasmid clones was constructed, each one randomly containing a Sau3AI restriction fragment of the viral genome (p54, p30, and hemagglutinin open reading frames [ORFs] excluded) fused to ubiquitin. Immunization of farm pigs with the expression library yielded 60% protection against lethal challenge with the virulent E75 strain. These results were further confirmed by using specific-pathogen-free pigs after challenging them with 10(4) hemadsorbing units (HAU) of the cell culture-adapted strain E75CV1. On this occasion, 50% of the vaccinated pigs survived the lethal challenge, and 2 out of the 8 immunized pigs showed no viremia or viral excretion at any time postinfection. In all cases, protection was afforded in the absence of detectable specific antibodies prior to challenge and correlated with the detection of specific T-cell responses at the time of sacrifice. In summary, our results clearly demonstrate the presence of additional protective determinants within the African swine fever virus (ASFV) genome and open up the possibility for their future identification. African swine fever is a highly contagious disease of domestic and wild pigs that is endemic in many sub-Saharan countries, where it causes important economic losses and is currently in continuous expansion across Europe. Unfortunately, there is no treatment nor an available vaccine. Early attempts using attenuated vaccines demonstrated their potential to protect pigs against experimental infection. However, their use in the field remains controversial due to safety issues. Although inactive and subunit vaccines did not confer solid protection against experimental ASFV infection, our DNA vaccination results have generated new expectations, confirming the key role of T-cell responses in protection and the existence of multiple ASFV antigens with protective potential, more of which are currently being identified. Thus, the future might bring complex and safe formulations containing more than a single viral determinant to obtain broadly protective vaccines. We believe that obtaining the optimal vaccine formulation it is just a matter of time, investment, and willingness. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Protective Immunity and Reduced Renal Colonization Induced by Vaccines Containing Recombinant Leptospira interrogans Outer Membrane Proteins and Flagellin Adjuvant

PubMed Central

Monaris, D.; Sbrogio-Almeida, M. E.; Dib, C. C.; Canhamero, T. A.; Souza, G. O.; Vasconcellos, S. A.; Ferreira, L. C. S.

2015-01-01

Leptospirosis is a global zoonotic disease caused by different Leptospira species, such as Leptospira interrogans, that colonize the renal tubules of wild and domestic animals. Thus far, attempts to develop effective leptospirosis vaccines, both for humans and animals, have failed to induce immune responses capable of conferring protection and simultaneously preventing renal colonization. In this study, we evaluated the protective immunity induced by subunit vaccines containing seven different recombinant Leptospira interrogans outer membrane proteins, including the carboxy-terminal portion of the immunoglobulinlike protein A (LigAC) and six novel antigens, combined with aluminum hydroxide (alum) or Salmonella flagellin (FliC) as adjuvants. Hamsters vaccinated with the different formulations elicited high antigen-specific antibody titers. Immunization with LigAC, either with alum or flagellin, conferred protective immunity but did not prevent renal colonization. Similarly, animals immunized with LigAC or LigAC coadministered with six leptospiral proteins with alum adjuvant conferred protection but did not reduce renal colonization. In contrast, immunizing animals with the pool of seven antigens in combination with flagellin conferred protection and significantly reduced renal colonization by the pathogen. The present study emphasizes the relevance of antigen composition and added adjuvant in the efficacy of antileptospirosis subunit vaccines and shows the complex relationship between immune responses and renal colonization by the pathogen. PMID:26108285

Mechanisms of Cross-protection by Influenza Virus M2-based Vaccines.

PubMed

Lee, Yu-Na; Kim, Min-Chul; Lee, Young-Tae; Kim, Yu-Jin; Kang, Sang-Moo

2015-10-01

Current influenza virus vaccines are based on strain-specific surface glycoprotein hemagglutinin (HA) antigens and effective only when the predicted vaccine strains and circulating viruses are well-matched. The current strategy of influenza vaccination does not prevent the pandemic outbreaks and protection efficacy is reduced or ineffective if mutant strains emerge. It is of high priority to develop effective vaccines and vaccination strategies conferring a broad range of cross protection. The extracellular domain of M2 (M2e) is highly conserved among human influenza A viruses and has been utilized to develop new vaccines inducing cross protection against different subtypes of influenza A virus. However, immune mechanisms of cross protection by M2e-based vaccines still remain to be fully elucidated. Here, we review immune correlates and mechanisms conferring cross protection by M2e-based vaccines. Molecular and cellular immune components that are known to be involved in M2 immune-mediated protection include antibodies, B cells, T cells, alveolar macrophages, Fc receptors, complements, and natural killer cells. Better understanding of protective mechanisms by immune responses induced by M2e vaccination will help facilitate development of broadly cross protective vaccines against influenza A virus.

Supplementation of H1N1pdm09 split vaccine with heterologous tandem repeat M2e5x virus-like particles confers improved cross-protection in ferrets.

PubMed

Music, Nedzad; Reber, Adrian J; Kim, Min-Chul; York, Ian A; Kang, Sang-Moo

2016-01-20

Current influenza vaccines induce strain-specific immunity to the highly variable hemagglutinin (HA) protein. It is therefore a high priority to develop vaccines that induce broadly cross-protective immunity to different strains of influenza. Since influenza A M2 proteins are highly conserved among different strains, five tandem repeats of the extracellular peptide of M2 in a membrane-anchored form on virus-like particles (VLPs) have been suggested to be a promising candidate for universal influenza vaccine. In this study, ferrets were intramuscularly immunized with 2009 H1N1 split HA vaccine ("Split") alone, influenza split vaccine supplemented with M2e5x VLP ("Split+M2e5x"), M2e5x VLP alone ("M2e5x"), or mock immunized. Vaccine efficacy was measured serologically and by protection against a serologically distinct viral challenge. Ferrets immunized with Split+M2e5x induced HA strain specific and conserved M2e immunity. Supplementation of M2e5x VLP to split vaccination significantly increased the immunogenicity of split vaccine compared to split alone. The Split+M2e5x ferret group showed evidence of cross-reactive protection, including faster recovery from weight loss, and reduced inflammation, as inferred from changes in peripheral leukocyte subsets, compared to mock-immunized animals. In addition, ferrets immunized with Split+M2e5x shed lower viral nasal-wash titers than the other groups. Ferrets immunized with M2e5x alone also show some protective effects, while those immunized with split vaccine alone induced no protective effects compared to mock-immunized ferrets. These studies suggest that supplementation of split vaccine with M2e5x-VLP may provide broader and improved cross-protection than split vaccine alone. Published by Elsevier Ltd.

Supplementation of H1N1pdm09 split vaccine with heterologous tandem repeat M2e5x virus-like particles confers improved cross-protection in ferrets

PubMed Central

Music, Nedzad; Reber, Adrian J.; Kim, Min-Chul; York, Ian A.; Kang, Sang-Moo

2015-01-01

Current influenza vaccines induce strain-specific immunity to the highly variable hemagglutinin (HA) protein. It is therefore a high priority to develop vaccines that induce broadly cross-protective immunity to different strains of influenza. Since influenza A M2 proteins are highly conserved among different strains, five tandem repeats of the extracellular peptide of M2 in a membrane-anchored form on virus-like particles (VLPs) have been suggested to be a promising candidate for universal influenza vaccine. In this study, ferrets were intramuscularly immunized with 2009 H1N1 split HA vaccine (“Split”) alone, influenza split vaccine supplemented with M2e5x VLP (“Split+M2e5x”), M2e5x VLP alone (“M2e5x”), or mock immunized. Vaccine efficacy was measured serologically and by protection against a serologically distinct viral challenge. Ferrets immunized with Split+M2e5x induced HA strain specific and conserved M2e immunity. Supplementation of M2e5x VLP to split vaccination significantly increased the immunogenicity of split vaccine compared to split alone. The Split+M2e5x ferret group showed evidence of cross-reactive protection, including faster recovery from weight loss, and reduced inflammation, as inferred from changes in peripheral leukocyte subsets, compared to mock-immunized animals. In addition, ferrets immunized with Split+M2e5x shed lower viral nasal-wash titers than the other groups. Ferrets immunized with M2e5x alone also show some protective effects, while those immunized with split vaccine alone induced no protective effects compared to mock-immunized ferrets. These studies suggest that supplementation of split vaccine with M2e5x-VLP may provide broader and improved cross-protection than split vaccine alone. PMID:26709639

Correlates of Vaccine-Induced Protection against Mycobacterium tuberculosis Revealed in Comparative Analyses of Lymphocyte Populations

PubMed Central

Kurtz, Sherry L.

2015-01-01

A critical hindrance to the development of a novel vaccine against Mycobacterium tuberculosis is a lack of understanding of protective correlates of immunity and of host factors involved in a successful adaptive immune response. Studies from our group and others have used a mouse-based in vitro model system to assess correlates of protection. Here, using this coculture system and a panel of whole-cell vaccines with varied efficacy, we developed a comprehensive approach to understand correlates of protection. We compared the gene and protein expression profiles of vaccine-generated immune peripheral blood lymphocytes (PBLs) to the profiles found in immune splenocytes. PBLs not only represent a clinically relevant cell population, but comparing the expression in these populations gave insight into compartmentally specific mechanisms of protection. Additionally, we performed a direct comparison of host responses induced when immune cells were cocultured with either the vaccine strain Mycobacterium bovis BCG or virulent M. tuberculosis. These comparisons revealed host-specific and bacterium-specific factors involved in protection against virulent M. tuberculosis. Most significantly, we identified a set of 13 core molecules induced in the most protective vaccines under all of the conditions tested. Further validation of this panel of mediators as a predictor of vaccine efficacy will facilitate vaccine development, and determining how each promotes adaptive immunity will advance our understanding of antimycobacterial immune responses. PMID:26269537

Protective Microbiota: From Localized to Long-Reaching Co-Immunity

PubMed Central

Chiu, Lynn; Bazin, Thomas; Truchetet, Marie-Elise; Schaeverbeke, Thierry; Delhaes, Laurence; Pradeu, Thomas

2017-01-01

Resident microbiota do not just shape host immunity, they can also contribute to host protection against pathogens and infectious diseases. Previous reviews of the protective roles of the microbiota have focused exclusively on colonization resistance localized within a microenvironment. This review shows that the protection against pathogens also involves the mitigation of pathogenic impact without eliminating the pathogens (i.e., “disease tolerance”) and the containment of microorganisms to prevent pathogenic spread. Protective microorganisms can have an impact beyond their niche, interfering with the entry, establishment, growth, and spread of pathogenic microorganisms. More fundamentally, we propose a series of conceptual clarifications in support of the idea of a “co-immunity,” where an organism is protected by both its own immune system and components of its microbiota. PMID:29270167

Characterization of leptospiral proteins that afford partial protection in hamsters against lethal challenge with Leptospira interrogans.

PubMed

Atzingen, Marina V; Gonçales, Amane P; de Morais, Zenaide M; Araújo, Eduardo R; De Brito, Thales; Vasconcellos, Silvio A; Nascimento, Ana L T O

2010-09-01

Leptospirosis is a worldwide zoonosis caused by pathogenic Leptospira. The whole-genome sequence of Leptospira interrogans serovar Copenhageni together with bioinformatic tools allow us to search for novel antigen candidates suitable for improved vaccines against leptospirosis. This study focused on three genes encoding conserved hypothetical proteins predicted to be exported to the outer membrane. The genes were amplified by PCR from six predominant pathogenic serovars in Brazil. The genes were cloned and expressed in Escherichia coli strain BL21-SI using the expression vector pDEST17. The recombinant proteins tagged with N-terminal 6xHis were purified by metal-charged chromatography. The proteins were recognized by antibodies present in sera from hamsters that were experimentally infected. Immunization of hamsters followed by challenge with a lethal dose of a virulent strain of Leptospira showed that the recombinant protein rLIC12730 afforded statistically significant protection to animals (44 %), followed by rLIC10494 (40 %) and rLIC12922 (30 %). Immunization with these proteins produced an increase in antibody titres during subsequent boosters, suggesting the involvement of a T-helper 2 response. Although more studies are needed, these data suggest that rLIC12730 and rLIC10494 are promising candidates for a multivalent vaccine for the prevention of leptospirosis.

Innate and adaptive immunity at Mucosal Surfaces of the Female Reproductive Tract: Stratification and Integration of Immune Protection against the Transmission of Sexually Transmitted Infections

PubMed Central

Hickey, DK; Patel, MV; Fahey, JV; Wira, CR

2011-01-01

This review examines the multiple levels of pre-existing immunity in the upper and lower female reproductive tract. In addition, we highlight the need for further research of innate and adaptive immune protection of mucosal surfaces in the female reproductive tract. Innate mechanisms include the mucus lining, a tight epithelial barrier and the secretion of antimicrobial peptides and cytokines by epithelial and innate immune cells. Stimulation of the innate immune system also serves to bridge the adaptive arm resulting in the generation of pathogen-specific humoral and cell-mediated immunity. Less understood are the multiple components that act in a coordinated way to provide a network of ongoing protection. Innate and adaptive immunity in the human female reproductive tract are influenced by the stage of menstrual cycle and are directly regulated by the sex steroid hormones, progesterone and estradiol. Furthermore, the effect of hormones on immunity is mediated both directly on immune and epithelial cells and indirectly by stimulating growth factor secretion from stromal cells. The goal of this review is to focus on the diverse aspects of the innate and adaptive immune systems that contribute to a unique network of protection throughout the female reproductive tract. PMID:21353708

Plant immunity triggered by engineered in vivo release of oligogalacturonides, damage-associated molecular patterns.

PubMed

Benedetti, Manuel; Pontiggia, Daniela; Raggi, Sara; Cheng, Zhenyu; Scaloni, Flavio; Ferrari, Simone; Ausubel, Frederick M; Cervone, Felice; De Lorenzo, Giulia

2015-04-28

Oligogalacturonides (OGs) are fragments of pectin that activate plant innate immunity by functioning as damage-associated molecular patterns (DAMPs). We set out to test the hypothesis that OGs are generated in planta by partial inhibition of pathogen-encoded polygalacturonases (PGs). A gene encoding a fungal PG was fused with a gene encoding a plant polygalacturonase-inhibiting protein (PGIP) and expressed in transgenic Arabidopsis plants. We show that expression of the PGIP-PG chimera results in the in vivo production of OGs that can be detected by mass spectrometric analysis. Transgenic plants expressing the chimera under control of a pathogen-inducible promoter are more resistant to the phytopathogens Botrytis cinerea, Pectobacterium carotovorum, and Pseudomonas syringae. These data provide strong evidence for the hypothesis that OGs released in vivo act as a DAMP signal to trigger plant immunity and suggest that controlled release of these molecules upon infection may be a valuable tool to protect plants against infectious diseases. On the other hand, elevated levels of expression of the chimera cause the accumulation of salicylic acid, reduced growth, and eventually lead to plant death, consistent with the current notion that trade-off occurs between growth and defense.

Plant immunity triggered by engineered in vivo release of oligogalacturonides, damage-associated molecular patterns

PubMed Central

Benedetti, Manuel; Pontiggia, Daniela; Raggi, Sara; Cheng, Zhenyu; Scaloni, Flavio; Ferrari, Simone; Ausubel, Frederick M.; Cervone, Felice; De Lorenzo, Giulia

2015-01-01

Oligogalacturonides (OGs) are fragments of pectin that activate plant innate immunity by functioning as damage-associated molecular patterns (DAMPs). We set out to test the hypothesis that OGs are generated in planta by partial inhibition of pathogen-encoded polygalacturonases (PGs). A gene encoding a fungal PG was fused with a gene encoding a plant polygalacturonase-inhibiting protein (PGIP) and expressed in transgenic Arabidopsis plants. We show that expression of the PGIP–PG chimera results in the in vivo production of OGs that can be detected by mass spectrometric analysis. Transgenic plants expressing the chimera under control of a pathogen-inducible promoter are more resistant to the phytopathogens Botrytis cinerea, Pectobacterium carotovorum, and Pseudomonas syringae. These data provide strong evidence for the hypothesis that OGs released in vivo act as a DAMP signal to trigger plant immunity and suggest that controlled release of these molecules upon infection may be a valuable tool to protect plants against infectious diseases. On the other hand, elevated levels of expression of the chimera cause the accumulation of salicylic acid, reduced growth, and eventually lead to plant death, consistent with the current notion that trade-off occurs between growth and defense. PMID:25870275

Discovering naturally processed antigenic determinants that confer protective T cell immunity

PubMed Central

Gilchuk, Pavlo; Spencer, Charles T.; Conant, Stephanie B.; Hill, Timothy; Gray, Jennifer J.; Niu, Xinnan; Zheng, Mu; Erickson, John J.; Boyd, Kelli L.; McAfee, K. Jill; Oseroff, Carla; Hadrup, Sine R.; Bennink, Jack R.; Hildebrand, William; Edwards, Kathryn M.; Crowe, James E.; Williams, John V.; Buus, Søren; Sette, Alessandro; Schumacher, Ton N.M.; Link, Andrew J.; Joyce, Sebastian

2013-01-01

CD8+ T cells (TCD8) confer protective immunity against many infectious diseases, suggesting that microbial TCD8 determinants are promising vaccine targets. Nevertheless, current T cell antigen identification approaches do not discern which epitopes drive protective immunity during active infection — information that is critical for the rational design of TCD8-targeted vaccines. We employed a proteomics-based approach for large-scale discovery of naturally processed determinants derived from a complex pathogen, vaccinia virus (VACV), that are presented by the most frequent representatives of four major HLA class I supertypes. Immunologic characterization revealed that many previously unidentified VACV determinants were recognized by smallpox-vaccinated human peripheral blood cells in a variegated manner. Many such determinants were recognized by HLA class I–transgenic mouse immune TCD8 too and elicited protective TCD8 immunity against lethal intranasal VACV infection. Notably, efficient processing and stable presentation of immune determinants as well as the availability of naive TCD8 precursors were sufficient to drive a multifunctional, protective TCD8 response. Our approach uses fundamental insights into T cell epitope processing and presentation to define targets of protective TCD8 immunity within human pathogens that have complex proteomes, suggesting that this approach has general applicability in vaccine sciences. PMID:23543059

Discovering naturally processed antigenic determinants that confer protective T cell immunity.

PubMed

Gilchuk, Pavlo; Spencer, Charles T; Conant, Stephanie B; Hill, Timothy; Gray, Jennifer J; Niu, Xinnan; Zheng, Mu; Erickson, John J; Boyd, Kelli L; McAfee, K Jill; Oseroff, Carla; Hadrup, Sine R; Bennink, Jack R; Hildebrand, William; Edwards, Kathryn M; Crowe, James E; Williams, John V; Buus, Søren; Sette, Alessandro; Schumacher, Ton N M; Link, Andrew J; Joyce, Sebastian

2013-05-01

CD8+ T cells (TCD8) confer protective immunity against many infectious diseases, suggesting that microbial TCD8 determinants are promising vaccine targets. Nevertheless, current T cell antigen identification approaches do not discern which epitopes drive protective immunity during active infection - information that is critical for the rational design of TCD8-targeted vaccines. We employed a proteomics-based approach for large-scale discovery of naturally processed determinants derived from a complex pathogen, vaccinia virus (VACV), that are presented by the most frequent representatives of four major HLA class I supertypes. Immunologic characterization revealed that many previously unidentified VACV determinants were recognized by smallpox-vaccinated human peripheral blood cells in a variegated manner. Many such determinants were recognized by HLA class I-transgenic mouse immune TCD8 too and elicited protective TCD8 immunity against lethal intranasal VACV infection. Notably, efficient processing and stable presentation of immune determinants as well as the availability of naive TCD8 precursors were sufficient to drive a multifunctional, protective TCD8 response. Our approach uses fundamental insights into T cell epitope processing and presentation to define targets of protective TCD8 immunity within human pathogens that have complex proteomes, suggesting that this approach has general applicability in vaccine sciences.

Immune-system-dependent anti-tumor activity of a plant-derived polyphenol rich fraction in a melanoma mouse model

PubMed Central

Gomez-Cadena, A; Urueña, C; Prieto, K; Martinez-Usatorre, A; Donda, A; Barreto, A; Romero, P; Fiorentino, S

2016-01-01

Recent findings suggest that part of the anti-tumor effects of several chemotherapeutic agents require an intact immune system. This is in part due to the induction of immunogenic cell death. We have identified a gallotannin-rich fraction, obtained from Caesalpinia spinosa (P2Et) as an anti-tumor agent in both breast carcinoma and melanoma. Here, we report that P2Et treatment results in activation of caspase 3 and 9, mobilization of cytochrome c and externalization of annexin V in tumor cells, thus suggesting the induction of apoptosis. This was preceded by the onset of autophagy and the expression of immunogenic cell death markers. We further demonstrate that P2Et-treated tumor cells are highly immunogenic in vaccinated mice and induce immune system activation, clearly shown by the generation of interferon gamma (IFN-γ) producing tyrosine-related protein 2 antigen-specific CD8+ T cells. Moreover, the tumor protective effects of P2Et treatment were abolished in immunodeficient mice, and partially lost after CD4 and CD8 depletion, indicating that P2Et's anti-tumor activity is highly dependent on immune system and at least in part of T cells. Altogether, these results support the hypothesis that the gallotannin-rich fraction P2Et's anti-tumor effects are mediated to a great extent by the endogenous immune response following to the exposure to immunogenic dying tumor cells. PMID:27253407

[Study on the immunization status and its influencing factors among workers from the polio network laboratories in China].

PubMed

Guo, Y S; Wang, J Q; Xu, C; Liu, Y N; He, X H; Wei, Q

2017-06-10

Objective: To Investigate the immune status and influencing factors of provincial polio network laboratory (PNL) workers in China so as to provide evidence for the development of related strategies to protect personnel working at the PNLs. Methods: All the practitioners from the PNLs at the provincial centers for disease control, were selected as objects for this study, from October to December, 2016, under a questionnaire survey. Information on status of immunity and influencing factors was collected, with SAS software, trend chi-square used for statistics analysis. Results: A total of 77 workers were involved in this survey, with 60 (78 % ) of them completed the polio-based immune program but the rest 17 (22 % ) remained records unclear. 66 people (about 86 % ) remembered clearly that they had received vaccination when engaging in the polio-lab work, but the rest 11 (14 % ) with only partial vaccination records. We also noticed that the Influencing factors realted to vaccination status were: age ( χ (2)=2.48, P <0.05), title ( χ (2)=2.51, P <0.05), years of employment ( P <0.000 1), education ( χ (2)=0.74, P =0.46) and gender ( χ (2)=0.46, P =0.50). Conclusion: Immune status of the Chinese provincial PNL practitioners appeared fairly good as 86 % of all the workers had received polio-related vaccination, with 41 % of them completed a 3-time inoculation program, when started working in this field.

Social immunity and the superorganism: Behavioral defenses protecting honey bee colonies from pathogens and parasites

USDA-ARS?s Scientific Manuscript database

Honey bees (Apis mellifera) have a number of traits that effectively reduce the spread of pathogens and parasites throughout the colony. These mechanisms of social immunity are often analogous to the individual immune system. As such social immune defences function to protect the colony or superorga...

Mice are actively immunized after passive monoclonal antibody prophylaxis and ricin toxin challenge. (Reannouncement with new availability information)

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

Lemley, P.V.; Wright, D.C.

1992-12-31

Mice passively immunized by a protective, anti-ricin A-chain monoclonal antibody, then challenged intravenously with ricin, were protected from a subsequent ricin challenge, and were actively immunized. Two significant advantages accrued from this experiment: the monoclonal antibody neutralized the toxicity of the ricin immunogen, and active immunization was achieved with very low antigen load (approx. 0.5 micrograms/mouse). We ruled out the possibility that residual monoclonal antibody provided the protection by using three independent criteria. There was significant (four orders of magnitude) enhancement of the immune response in the presence of the monoclonal antibody; control immunizations of mice with ricin A-chain, ricinmore » B-chain or either chain with the monoclonal antibody did not induce active immunity; and the active immunization could not be replicated when protective goat polyclonal antibody was substituted for the monoclonal antibody. Because high titers were achieved rapidly without any adjuvant, we are currently investigating haptenized ricin to determine if anti-hapten monoclonal antibodies can be produced by this refined procedure.« less

Human symbionts inject and neutralize antibacterial toxins to persist in the gut.

PubMed

Wexler, Aaron G; Bao, Yiqiao; Whitney, John C; Bobay, Louis-Marie; Xavier, Joao B; Schofield, Whitman B; Barry, Natasha A; Russell, Alistair B; Tran, Bao Q; Goo, Young Ah; Goodlett, David R; Ochman, Howard; Mougous, Joseph D; Goodman, Andrew L

2016-03-29

The human gut microbiome is a dynamic and densely populated microbial community that can provide important benefits to its host. Cooperation and competition for nutrients among its constituents only partially explain community composition and interpersonal variation. Notably, certain human-associated Bacteroidetes--one of two major phyla in the gut--also encode machinery for contact-dependent interbacterial antagonism, but its impact within gut microbial communities remains unknown. Here we report that prominent human gut symbionts persist in the gut through continuous attack on their immediate neighbors. Our analysis of just one of the hundreds of species in these communities reveals 12 candidate antibacterial effector loci that can exist in 32 combinations. Through the use of secretome studies, in vitro bacterial interaction assays and multiple mouse models, we uncover strain-specific effector/immunity repertoires that can predict interbacterial interactions in vitro and in vivo, and find that some of these strains avoid contact-dependent killing by accumulating immunity genes to effectors that they do not encode. Effector transmission rates in live animals can exceed 1 billion events per minute per gram of colonic contents, and multiphylum communities of human gut commensals can partially protect sensitive strains from these attacks. Together, these results suggest that gut microbes can determine their interactions through direct contact. An understanding of the strategies human gut symbionts have evolved to target other members of this community may provide new approaches for microbiome manipulation.

Human Milk: Bioactive Proteins/Peptides and Functional Properties.

PubMed

Lönnerdal, Bo

2016-06-23

Breastfeeding has been associated with many benefits, both in the short and in the long term. Infants being breastfed generally have less illness and have better cognitive development at 1 year of age than formula-fed infants. Later in life, they have a lower risk of obesity, diabetes and cardiovascular disease. Several components in breast milk may be responsible for these different outcomes, but bioactive proteins/peptides likely play a major role. Some proteins in breast milk are comparatively resistant towards digestion and may therefore exert their functions in the gastrointestinal tract in intact form or as larger fragments. Other milk proteins may be partially digested in the upper small intestine and the resulting peptides may exert functions in the lower small intestine. Lactoferrin, lysozyme and secretory IgA have been found intact in the stool of breastfed infants and are therefore examples of proteins that are resistant against proteolytic degradation in the gut. Together, these proteins serve protective roles against infection and support immune function in the immature infant. α-lactalbumin, β-casein, κ-casein and osteopontin are examples of proteins that are partially digested in the upper small intestine, and the resulting peptides influence functions in the gut. Such functions include stimulation of immune function, mineral and trace element absorption and defense against infection. © 2016 Nestec Ltd., Vevey/S. Karger AG, Basel.

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

PubMed

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

2013-10-01

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

Molecular Signatures of Immunity and Immunogenicity in Infection and Vaccination

PubMed Central

Haks, Mariëlle C.; Bottazzi, Barbara; Cecchinato, Valentina; De Gregorio, Corinne; Del Giudice, Giuseppe; Kaufmann, Stefan H. E.; Lanzavecchia, Antonio; Lewis, David J. M.; Maertzdorf, Jeroen; Mantovani, Alberto; Sallusto, Federica; Sironi, Marina; Uguccioni, Mariagrazia; Ottenhoff, Tom H. M.

2017-01-01

Vaccinology aims to understand what factors drive vaccine-induced immunity and protection. For many vaccines, however, the mechanisms underlying immunity and protection remain incompletely characterized at best, and except for neutralizing antibodies induced by viral vaccines, few correlates of protection exist. Recent omics and systems biology big data platforms have yielded valuable insights in these areas, particularly for viral vaccines, but in the case of more complex vaccines against bacterial infectious diseases, understanding is fragmented and limited. To fill this gap, the EC supported ADITEC project (http://www.aditecproject.eu/; http://stm.sciencemag.org/content/4/128/128cm4.full) featured a work package on “Molecular signatures of immunity and immunogenicity,” aimed to identify key molecular mechanisms of innate and adaptive immunity during effector and memory stages of immune responses following vaccination. Specifically, technologies were developed to assess the human immune response to vaccination and infection at the level of the transcriptomic and proteomic response, T-cell and B-cell memory formation, cellular trafficking, and key molecular pathways of innate immunity, with emphasis on underlying mechanisms of protective immunity. This work intersected with other efforts in the ADITEC project. This review summarizes the main achievements of the work package. PMID:29204145

The Immunomodulatory Role of Adjuvants in Vaccines Formulated with the Recombinant Antigens Ov-103 and Ov-RAL-2 against Onchocerca volvulus in Mice.

PubMed

Hess, Jessica A; Zhan, Bin; Torigian, April R; Patton, John B; Petrovsky, Nikolai; Zhan, Tingting; Bottazzi, Maria Elena; Hotez, Peter J; Klei, Thomas R; Lustigman, Sara; Abraham, David

2016-07-01

In some regions in Africa, elimination of onchocerciasis may be possible with mass drug administration, although there is concern based on several factors that onchocerciasis cannot be eliminated solely through this approach. A vaccine against Onchocerca volvulus would provide a critical tool for the ultimate elimination of this infection. Previous studies have demonstrated that immunization of mice with Ov-103 and Ov-RAL-2, when formulated with alum, induced protective immunity. It was hypothesized that the levels of protective immunity induced with the two recombinant antigens formulated with alum would be improved by formulation with other adjuvants known to enhance different types of antigen-specific immune responses. Immunizing mice with Ov-103 and Ov-RAL-2 in conjunction with alum, Advax 2 and MF59 induced significant levels of larval killing and host protection. The immune response was biased towards Th2 with all three of the adjuvants, with IgG1 the dominant antibody. Improved larval killing and host protection was observed in mice immunized with co-administered Ov-103 and Ov-RAL-2 in conjunction with each of the three adjuvants as compared to single immunizations. Antigen-specific antibody titers were significantly increased in mice immunized concurrently with the two antigens. Based on chemokine levels, it appears that neutrophils and eosinophils participate in the protective immune response induced by Ov-103, and macrophages and neutrophils participate in immunity induced by Ov-RAL-2. The mechanism of protective immunity induced by Ov-103 and Ov-RAL-2, with the adjuvants alum, Advax 2 and MF59, appears to be multifactorial with roles for cytokines, chemokines, antibody and specific effector cells. The vaccines developed in this study have the potential of reducing the morbidity associated with onchocerciasis in humans.

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

PubMed

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

2013-12-01

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

Partial reconstitution of the CD4+-T-cell compartment in CD4 gene knockout mice restores responses to tuberculosis DNA vaccines.

PubMed

D'Souza, Sushila; Romano, Marta; Korf, Johanna; Wang, Xiao-Ming; Adnet, Pierre-Yves; Huygen, Kris

2006-05-01

Reactivation tuberculosis (TB) is a serious problem in immunocompromised individuals, especially those with human immunodeficiency virus (HIV) coinfection. The adaptive immune response mediated by CD4+ and CD8+ T cells is known to confer protection against TB. Hence, vaccines against TB are designed to activate these two components of the immune system. Anti-TB DNA vaccines encoding the immunodominant proteins Ag85A, Ag85B, and PstS-3 from Mycobacterium tuberculosis are ineffective in mice lacking CD4+ T cells (CD4-/- mice). In this study, we demonstrate that reconstitution of the T-cell compartment in CD4-/- mice restores vaccine-specific antibody and gamma interferon (IFN-gamma) responses to these DNA vaccines. The magnitude of the immune responses correlated with the extent of reconstitution of the CD4+-T-cell compartment. Reconstituted mice vaccinated with DNA encoding PstS-3, known to encode a dominant D(b)-restricted CD8+-T-cell epitope, displayed CD8+-T-cell responses not observed in CD4-/- mice. M. tuberculosis challenge in reconstituted mice led to the extravasation of IFN-gamma-producing CD4+ and CD8+ T cells into lungs, the primary site of bacterial replication. Importantly, a reconstitution of 12 to 15% of the CD4+-T-cell compartment resulted in Ag85B plasmid DNA-mediated protection against a challenge M. tuberculosis infection. Our findings provide evidence that anti-TB DNA vaccines could be effective in immunodeficient individuals after CD4+-T-lymphocyte reconstitution, as may occur following antiretroviral therapy in HIV+ patients.

26 CFR 301.7507-8 - Procedure during immunity.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 26 Internal Revenue 18 2014-04-01 2014-04-01 false Procedure during immunity. 301.7507-8 Section... States § 301.7507-8 Procedure during immunity. (a) Statements to be filed. As long as complete or partial immunity is claimed, a bank within section 7507(b) shall file with each income tax return a statement as...

26 CFR 301.7507-8 - Procedure during immunity.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 26 Internal Revenue 18 2011-04-01 2011-04-01 false Procedure during immunity. 301.7507-8 Section... States § 301.7507-8 Procedure during immunity. (a) Statements to be filed. As long as complete or partial immunity is claimed, a bank within section 7507(b) shall file with each income tax return a statement as...

26 CFR 301.7507-8 - Procedure during immunity.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 26 Internal Revenue 18 2012-04-01 2012-04-01 false Procedure during immunity. 301.7507-8 Section... States § 301.7507-8 Procedure during immunity. (a) Statements to be filed. As long as complete or partial immunity is claimed, a bank within section 7507(b) shall file with each income tax return a statement as...

26 CFR 301.7507-8 - Procedure during immunity.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 26 Internal Revenue 18 2010-04-01 2010-04-01 false Procedure during immunity. 301.7507-8 Section... States § 301.7507-8 Procedure during immunity. (a) Statements to be filed. As long as complete or partial immunity is claimed, a bank within section 7507(b) shall file with each income tax return a statement as...

26 CFR 301.7507-8 - Procedure during immunity.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 26 Internal Revenue 18 2013-04-01 2013-04-01 false Procedure during immunity. 301.7507-8 Section... States § 301.7507-8 Procedure during immunity. (a) Statements to be filed. As long as complete or partial immunity is claimed, a bank within section 7507(b) shall file with each income tax return a statement as...

Genetic immunization based on the ubiquitin-fusion degradation pathway against Trypanosoma cruzi

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

Chou, Bin; Department of Parasitology, Graduate School of Medical Science, Kyushu University, Fukuoka 812-8582; Hiromatsu, Kenji, E-mail: khiromatsu@fukuoka-u.ac.jp

2010-02-12

Cytotoxic CD8{sup +} T cells are particularly important to the development of protective immunity against the intracellular protozoan parasite, Trypanosoma cruzi, the etiological agent of Chagas disease. We have developed a new effective strategy of genetic immunization by activating CD8{sup +} T cells through the ubiquitin-fusion degradation (UFD) pathway. We constructed expression plasmids encoding the amastigote surface protein-2 (ASP-2) of T. cruzi. To induce the UFD pathway, a chimeric gene encoding ubiquitin fused to ASP-2 (pUB-ASP-2) was constructed. Mice immunized with pUB-ASP-2 presented lower parasitemia and longer survival period, compared with mice immunized with pASP-2 alone. Depletion of CD8{sup +}more » T cells abolished protection against T. cruzi in mice immunized with pUB-ASP-2 while depletion of CD4{sup +} T cells did not influence the effective immunity. Mice deficient in LMP2 or LMP7, subunits of immunoproteasomes, were not able to develop protective immunity induced. These results suggest that ubiquitin-fused antigens expressed in antigen-presenting cells were effectively degraded via the UFD pathway, and subsequently activated CD8{sup +} T cells. Consequently, immunization with pUB-ASP-2 was able to induce potent protective immunity against infection of T. cruzi.« less

Protective effect of intranasal immunization with Neospora caninum membrane antigens against murine neosporosis established through the gastrointestinal tract

PubMed Central

Ferreirinha, Pedro; Dias, Joana; Correia, Alexandra; Pérez-Cabezas, Begoña; Santos, Carlos; Teixeira, Luzia; Ribeiro, Adília; Rocha, António; Vilanova, Manuel

2014-01-01

Neospora caninum is an Apicomplexa parasite that in the last two decades was acknowledged as the main pathogenic agent responsible for economic losses in the cattle industry. In the present study, the effectiveness of intranasal immunization with N. caninum membrane antigens plus CpG adjuvant was assessed in a murine model of intragastrically established neosporosis. Immunized mice presented a lower parasitic burden in the brain on infection with 5 × 107 tachyzoites, showing that significant protection was achieved by this immunization strategy. Intestinal IgA antibodies raised by immunization markedly agglutinated live N. caninum tachyzoites whereas previous opsonization with IgG antibodies purified from immunized mice sera reduced parasite survival within macrophage cells. Although an IgG1 : IgG2a ratio < 1 was detected in the immunized mice before and after infection, indicative of a predominant T helper type 1 immune response, no increased production of interferon-γ was detected in the spleen or mesenteric lymph nodes of the immunized mice. Altogether, these results show that mucosal immunization with N. caninum membrane proteins plus CpG adjuvant protect against intragastrically established neosporosis and indicate that parasite-specific mucosal and circulating antibodies have a protective role against this parasitic infection. PMID:24128071

Measles Vaccination of Nonhuman Primates Provides Partial Protection against Infection with Canine Distemper Virus

PubMed Central

de Vries, Rory D.; Ludlow, Martin; Verburgh, R. Joyce; van Amerongen, Geert; Yüksel, Selma; Nguyen, D. Tien; McQuaid, Stephen; Osterhaus, Albert D. M. E.; Duprex, W. Paul

2014-01-01

ABSTRACT Measles virus (MV) is being considered for global eradication, which would likely reduce compliance with MV vaccination. As a result, children will grow up without MV-specific immunity, creating a potential niche for closely related animal morbilliviruses such as canine distemper virus (CDV). Natural CDV infection causing clinical signs has never been reported in humans, but recent outbreaks in captive macaques have shown that CDV can cause disease in primates. We studied the virulence and tropism of recombinant CDV expressing enhanced green fluorescent protein in naive and measles-vaccinated cynomolgus macaques. In naive animals CDV caused viremia and fever and predominantly infected CD150+ lymphocytes and dendritic cells. Virus was reisolated from the upper and lower respiratory tracts, but infection of epithelial or neuronal cells was not detectable at the time points examined, and the infections were self-limiting. This demonstrates that CDV readily infects nonhuman primates but suggests that additional mutations are necessary to achieve full virulence in nonnatural hosts. Partial protection against CDV was observed in measles-vaccinated macaques, as demonstrated by accelerated control of virus replication and limited shedding from the upper respiratory tract. While neither CDV infection nor MV vaccination induced detectable cross-reactive neutralizing antibodies, MV-specific neutralizing antibody levels of MV-vaccinated macaques were boosted by CDV challenge infection, suggesting that cross-reactive VN epitopes exist. Rapid increases in white blood cell counts in MV-vaccinated macaques following CDV challenge suggested that cross-reactive cellular immune responses were also present. This study demonstrates that zoonotic morbillivirus infections can be controlled by measles vaccination. IMPORTANCE Throughout history viral zoonoses have had a substantial impact on human health. Given the drive toward global eradication of measles, it is essential to understand the zoonotic potential of animal morbilliviruses. Morbilliviruses are thought to have evolved from a common ancestral virus that jumped species and adapted to new hosts. Recently, canine distemper virus (CDV), a morbillivirus normally restricted to carnivores, caused disease outbreaks in nonhuman primates. Here, we report that experimental CDV infection of monkeys resulted in fever and leukopenia. The virus replicated to high levels in lymphocytes but did not spread to epithelial cells or the central nervous system. Importantly, like measles virus in macaques, the infections were self-limiting. In measles-vaccinated macaques CDV was cleared more rapidly, resulting in limited virus shedding from the upper respiratory tract. These studies demonstrate that although CDV can readily infect primates, measles immunity is protective, and CDV infection is self-limiting. PMID:24501402

Measles vaccination of nonhuman primates provides partial protection against infection with canine distemper virus.

PubMed

de Vries, Rory D; Ludlow, Martin; Verburgh, R Joyce; van Amerongen, Geert; Yüksel, Selma; Nguyen, D Tien; McQuaid, Stephen; Osterhaus, Albert D M E; Duprex, W Paul; de Swart, Rik L

2014-04-01

Measles virus (MV) is being considered for global eradication, which would likely reduce compliance with MV vaccination. As a result, children will grow up without MV-specific immunity, creating a potential niche for closely related animal morbilliviruses such as canine distemper virus (CDV). Natural CDV infection causing clinical signs has never been reported in humans, but recent outbreaks in captive macaques have shown that CDV can cause disease in primates. We studied the virulence and tropism of recombinant CDV expressing enhanced green fluorescent protein in naive and measles-vaccinated cynomolgus macaques. In naive animals CDV caused viremia and fever and predominantly infected CD150(+) lymphocytes and dendritic cells. Virus was reisolated from the upper and lower respiratory tracts, but infection of epithelial or neuronal cells was not detectable at the time points examined, and the infections were self-limiting. This demonstrates that CDV readily infects nonhuman primates but suggests that additional mutations are necessary to achieve full virulence in nonnatural hosts. Partial protection against CDV was observed in measles-vaccinated macaques, as demonstrated by accelerated control of virus replication and limited shedding from the upper respiratory tract. While neither CDV infection nor MV vaccination induced detectable cross-reactive neutralizing antibodies, MV-specific neutralizing antibody levels of MV-vaccinated macaques were boosted by CDV challenge infection, suggesting that cross-reactive VN epitopes exist. Rapid increases in white blood cell counts in MV-vaccinated macaques following CDV challenge suggested that cross-reactive cellular immune responses were also present. This study demonstrates that zoonotic morbillivirus infections can be controlled by measles vaccination. Throughout history viral zoonoses have had a substantial impact on human health. Given the drive toward global eradication of measles, it is essential to understand the zoonotic potential of animal morbilliviruses. Morbilliviruses are thought to have evolved from a common ancestral virus that jumped species and adapted to new hosts. Recently, canine distemper virus (CDV), a morbillivirus normally restricted to carnivores, caused disease outbreaks in nonhuman primates. Here, we report that experimental CDV infection of monkeys resulted in fever and leukopenia. The virus replicated to high levels in lymphocytes but did not spread to epithelial cells or the central nervous system. Importantly, like measles virus in macaques, the infections were self-limiting. In measles-vaccinated macaques CDV was cleared more rapidly, resulting in limited virus shedding from the upper respiratory tract. These studies demonstrate that although CDV can readily infect primates, measles immunity is protective, and CDV infection is self-limiting.

Correlative Gene Expression to Protective Seroconversion in Rift Valley Fever Vaccinates.

PubMed

Laughlin, Richard C; Drake, Kenneth L; Morrill, John C; Adams, L Garry

2016-01-01

Rift Valley fever Virus (RVFV), a negative-stranded RNA virus, is the etiological agent of the vector-borne zoonotic disease, Rift Valley fever (RVF). In both humans and livestock, protective immunity can be achieved through vaccination. Earlier and more recent vaccine trials in cattle and sheep demonstrated a strong neutralizing antibody and total IgG response induced by the RVF vaccine, authentic recombinant MP-12 (arMP-12). From previous work, protective immunity in sheep and cattle vaccinates normally occurs from 7 to 21 days after inoculation with arMP-12. While the serology and protective response induced by arMP-12 has been studied, little attention has been paid to the underlying molecular and genetic events occurring prior to the serologic immune response. To address this, we isolated RNA from whole blood of vaccinated calves over a time course of 21 days before and after vaccination with arMP-12. The time course RNAs were sequenced by RNASeq and bioinformatically analyzed. Our results revealed time-dependent activation or repression of numerous gene ontologies and pathways related to the vaccine induced immune response and its regulation. Additional bioinformatic analyses identified a correlative relationship between specific host immune response genes and protective immunity prior to the detection of protective serum neutralizing antibody responses. These results contribute an important proof of concept for identifying molecular and genetic components underlying the immune response to RVF vaccination and protection prior to serologic detection.

Group 2 ILCs: A way of enhancing immune protection against human helminths?

PubMed

Nausch, N; Mutapi, F

2018-02-01

Group 2 innate lymphoid cells (ILC2s) play crucial roles in type 2 immune responses associated with allergic and autoimmune diseases, viral and helminth infections and tissue homoeostasis. Experimental models show that in helminth infections ILC2s provide an early source of type 2 cytokines and therefore are essential for the induction of potentially protective type 2 responses. Much of our knowledge of ILC2s in helminth infections has come from experimental mouse models with very few studies analysing ILC2s in natural human infections. In attempts to harness knowledge from paradigms of the development of protective immunity in human helminth infections for vaccine development, the role of ILC2 cells could be pivotal. So far, potential vaccines against human helminth infections have failed to provide effective protection when evaluated in human studies. In addition to appropriate antigen selection, it is apparent that more detailed knowledge on mechanisms of induction and maintenance of protective immune responses is required. Therefore, there is need to understand how ILC2 cells induce type 2 responses and subsequently support the development of a protective immune response in the context of immunizations. Within this review, we summarize the current knowledge of the biology of ILC2s, discuss the importance of ILC2s in human helminth infections and explore how ILC2 responses could be boosted to efficiently induce protective immunity. © 2017 The Authors. Parasite Immunology Published by John Wiley & Sons Ltd.

Beyond empiricism: informing vaccine development through innate immunity research.

PubMed

Levitz, Stuart M; Golenbock, Douglas T

2012-03-16

Although a great public heath success, vaccines provide suboptimal protection in some patient populations and are not available to protect against many infectious diseases. Insights from innate immunity research have led to a better understanding of how existing vaccines work and have informed vaccine development. New adjuvants and delivery systems are being designed based upon their capacity to stimulate innate immune sensors and target antigens to dendritic cells, the cells responsible for initiating adaptive immune responses. Incorporating these adjuvants and delivery systems in vaccines can beneficially alter the quantitative and qualitative nature of the adaptive immune response, resulting in enhanced protection. Copyright © 2012 Elsevier Inc. All rights reserved.

Beyond empiricism: Informing vaccine development through innate immunity research

PubMed Central

Levitz, Stuart M.; Golenbock, Douglas T.

2012-01-01

Summary While a great public heath success, vaccines provide suboptimal protection in some patient populations and are not available to protect against many infectious diseases. Insights from innate immunity research have led to a better understanding of how existing vaccines work and informed vaccine development. New adjuvants and delivery systems are being designed based upon their capacity to stimulate innate immune sensors and target antigens to dendritic cells, the cells responsible for initiating adaptive immune responses. Incorporating these adjuvants and delivery systems in vaccines can beneficially alter the quantitative and qualitative nature of the adaptive immune response resulting in enhanced protection. PMID:22424235

Prolonged protection against Intranasal challenge with influenza virus following systemic immunization or combinations of mucosal and systemic immunizations with a heat-labile toxin mutant.

PubMed

Zhou, Fengmin; Goodsell, Amanda; Uematsu, Yasushi; Vajdy, Michael

2009-04-01

Seasonal influenza virus infections cause considerable morbidity and mortality in the world, and there is a serious threat of a pandemic influenza with the potential to cause millions of deaths. Therefore, practical influenza vaccines and vaccination strategies that can confer protection against intranasal infection with influenza viruses are needed. In this study, we demonstrate that using LTK63, a nontoxic mutant of the heat-labile toxin from Escherichia coli, as an adjuvant for both mucosal and systemic immunizations, systemic (intramuscular) immunization or combinations of mucosal (intranasal) and intramuscular immunizations protected mice against intranasal challenge with a lethal dose of live influenza virus at 3.5 months after the second immunization.

Vaccination with plasmid DNA encoding TSA/LmSTI1 leishmanial fusion proteins confers protection against Leishmania major infection in susceptible BALB/c mice.

PubMed

Campos-Neto, A; Webb, J R; Greeson, K; Coler, R N; Skeiky, Y A W; Reed, S G

2002-06-01

We have recently shown that a cocktail containing two leishmanial recombinant antigens (LmSTI1 and TSA) and interleukin-12 (IL-12) as an adjuvant induces solid protection in both a murine and a nonhuman primate model of cutaneous leishmaniasis. However, because IL-12 is difficult to prepare, is expensive, and does not have the stability required for a vaccine product, we have investigated the possibility of using DNA as an alternative means of inducing protective immunity. Here, we present evidence that the antigens TSA and LmSTI1 delivered in a plasmid DNA format either as single genes or in a tandem digene construct induce equally solid protection against Leishmania major infection in susceptible BALB/c mice. Immunization of mice with either TSA DNA or LmSTI1 DNA induced specific CD4(+)-T-cell responses of the Th1 phenotype without a requirement for specific adjuvant. CD8 responses, as measured by cytotoxic-T-lymphocyte activity, were generated after immunization with TSA DNA but not LmSTI1 DNA. Interestingly, vaccination of mice with TSA DNA consistently induced protection to a much greater extent than LmSTI1 DNA, thus supporting the notion that CD8 responses might be an important accessory arm of the immune response for acquired resistance against leishmaniasis. Moreover, the protection induced by DNA immunization was specific for infection with Leishmania, i.e., the immunization had no effect on the course of infection of the mice challenged with an unrelated intracellular pathogen such as Mycobacterium tuberculosis. Conversely, immunization of BALB/c mice with a plasmid DNA that is protective against challenge with M. tuberculosis had no effect on the course of infection of these mice with L. major. Together, these results indicate that the protection observed with the leishmanial DNA is mediated by acquired specific immune response rather than by the activation of nonspecific innate immune mechanisms. In addition, a plasmid DNA containing a fusion construct of the two genes was also tested. Similarly to the plasmids encoding individual proteins, the fusion construct induced both specific immune responses to the individual antigens and protection against challenge with L. major. These results confirm previous observations about the possibility of DNA immunization against leishmaniasis and lend support to the idea of using a single polygenic plasmid DNA construct to achieve polyspecific immune responses to several distinct parasite antigens.

Differential Requirements for T Cells in Viruslike Particle- and Rotavirus-Induced Protective Immunity▿

PubMed Central

Blutt, Sarah E.; Warfield, Kelly L.; Estes, Mary K.; Conner, Margaret E.

2008-01-01

Correlates of protection from rotavirus infection are controversial. We compared the roles of B and T lymphocytes in protective immunity induced either by intranasally administered nonreplicating viruslike particles or inactivated virus or by orally administered murine rotavirus. We found that protection induced by nonreplicating vaccines requires CD4+ T cells and CD40/CD40L. In contrast, T cells were not required for short-term protective immunity induced by infection, but both T-cell-dependent and -independent mechanisms contributed to long-term maintenance of protection. Our findings indicate that more than one marker of protective immunity exists and that these markers depend on the vaccine that is administered. PMID:18184712

Streptococcus pneumoniae fructose-1,6-bisphosphate aldolase, a protein vaccine candidate, elicits Th1/Th2/Th17-type cytokine responses in mice.

PubMed

Elhaik Goldman, Shirin; Dotan, Shahar; Talias, Amir; Lilo, Amit; Azriel, Shalhevet; Malka, Itay; Portnoi, Maxim; Ohayon, Ariel; Kafka, Daniel; Ellis, Ronald; Elkabets, Moshe; Porgador, Angel; Levin, Ditza; Azhari, Rosa; Swiatlo, Edwin; Ling, Eduard; Feldman, Galia; Tal, Michael; Dagan, Ron; Mizrachi Nebenzahl, Yaffa

2016-04-01

Streptococcus pneumoniae (S. pneumoniae) is a major pathogen worldwide. The currently available polysaccharide-based vaccines significantly reduce morbidity and mortality. However, the inherent disadvantages of the currently available polysaccharide-based vaccines have motivated the search for other bacterial immunogens capable of eliciting a protective immune response against S. pneumoniae. Fructose-1,6-bisphosphate aldolase (FBA) is a glycolytic enzyme, which was found to localize to the bacterial surface, where it functions as an adhesin. Previously, immunizing mice with recombinant FBA (rFBA) in the presence of alum elicited a protective immune response against a lethal challenge with S. pneumoniae. Thus, the aim of the present study was to determine the cytokine responses that are indicative of protective immunity following immunization with rFBA. The protective effects against pneumococcal challenge in mice immunized with rFBA with complete Freund's adjuvant (CFA) in the initial immunization and with incomplete Freund's adjuvant (IFA) in booster immunizations surpassed the protective effects observed following immunization with either rFBA + alum or pVACfba. CD4+ T-cells obtained from the rFBA/CFA/IFA/IFA-immunized mice co-cultured with rFBA-pulsed antigen-presenting cells (APCs), exhibited a significantly greater proliferative ability than CD4+ T-cells obtained from the adjuvant-immunized mice co-cultured with rFBA‑pulsed APCs. The levels of the Th1-type cytokines, interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF)-α and IL-12, the Th2-type cytokines, IL-4, IL-5 and IL-10, and the Th17-type cytokine, IL-17A, significantly increased within 72 h of the initiation of co-culture with CD4+ T-cells obtained from the rFBA‑immunized mice, in comparison with the co-cultures with CD4+ T-cells obtained from the adjuvant-immunized mice. Immunizing mice with rFBA resulted in an IgG1/IgG2 ratio of 41, indicating a Th2 response with substantial Th1 involvement. In addition, rabbit and mouse anti-rFBA antisera significantly protected the mice against a lethal S. pneumoniae challenge in comparison with preimmune sera. Our results emphasize the mixed involvement of the Th1, Th2 and Th17 arms of the immune system in response to immunization with pneumococcal rFBA, a potential vaccine candidate.

Revisiting immunosurveillance and immunostimulation: Implications for cancer immunotherapy

PubMed Central

Ichim, Christine V

2005-01-01

Experimental and clinical experience demonstrates that the resolution of a pathogenic challenge depends not only on the presence or absence of an immune reaction, but also on the initiation of the proper type of immune reaction. The initiation of a non-protective type of immune reaction will not only result in a lack of protection, but may also exacerbate the underlying condition. For example, in cancer, constituents of the immune system have been shown to augment tumor proliferation, angiogenesis, and metastases. This review discusses the duality of the role of the immune system in cancer, from the theories of immunosurveillance and immunostimulation to current studies, which illustrate that the immune system has both a protective role and a tumor-promoting role in neoplasia. The potential of using chemotherapy to inhibit a tumor-promoting immune reaction is also discussed. PMID:15698481

Induction of Broad-Spectrum Protective Immunity against Disparate Cryptococcus Serotypes

PubMed Central

Van Dyke, Marley C. Caballero; Chaturvedi, Ashok K.; Hardison, Sarah E.; Leopold Wager, Chrissy M.; Castro-Lopez, Natalia; Hole, Camaron R.; Wozniak, Karen L.; Wormley, Floyd L.

2017-01-01

Cryptococcosis is a fungal disease caused by multiple Cryptococcus serotypes; particularly C. neoformans (serotypes A and D) and C. gattii (serotypes B and C). To date, there is no clinically available vaccine to prevent cryptococcosis. Mice given an experimental pulmonary vaccination with a C. neoformans serotype A strain engineered to produce interferon-γ, denoted H99γ, are protected against a subsequent otherwise lethal experimental infection with C. neoformans serotype A. Thus, we determined the efficacy of immunization with C. neoformans strain H99γ to elicit broad-spectrum protection in BALB/c mice against multiple disparate Cryptococcus serotypes. We observed significantly increased survival rates and significantly decreased pulmonary fungal burden in H99γ immunized mice challenged with Cryptococcus serotypes A, B, or D compared to heat-killed H99γ (HKH99γ) immunized mice. Results indicated that prolonged protection against Cryptococcus serotypes B or D in H99γ immunized mice was CD4+ T cell dependent and associated with the induction of predominantly Th1-type cytokine responses. Interestingly, immunization with H99γ did not elicit greater protection against challenge with the Cryptococcus serotype C tested either due to low overall virulence of this strain or enhanced capacity of this strain to evade host immunity. Altogether, these studies provide “proof-of-concept” for the development of a cryptococcal vaccine that provides cross-protection against multiple disparate serotypes of Cryptococcus. PMID:29163469

From folklore to fact: the rhetorical history of breastfeeding and immunity, 1950-1997.

PubMed

Koerber, Amy

2006-01-01

This article examines the recent construction of human milk's immune-protective qualities as scientific fact, demonstrating that long-standing controversies about human milk's immune-protective effects have not been resolved by a particular scientific discovery. Rather, experts' consensus on how to respond to this uncertainty has been transformed, and this transformation has had as much to do with a change in the metaphor that governs interpretation of evidence about immune protection as it has with discovering new evidence about either human milk or the antibodies in it.

[Mucosal immunity with emphasis on urinary tract immunity and diabetes].

PubMed

Krejsek, J; Kudlová, M; Kolácková, M; Novosad, J

2008-05-01

Protective immune response in urinary tract is frequently impaired in patients with diabetes. Immunity in this mucosal compartment displays unique characteristics; e.g. absence of physiological microflora and lack of mucus. Pathogens are identified by the PRR receptors expressed on both epithelial and immune cells. Inflammatory response characterised by the acumulation ofgranulocytes is followed. Both protective and harm characteristics of inflammatory response are inseparable linked and delineated by gene polymorphisms in PRR receptors.

Evaluation of immunogenicity and protective efficacy of orally delivered Shigella type III secretion system proteins IpaB and IpaD

PubMed Central

Heine, Shannon J.; Diaz-McNair, Jovita; Martinez-Becerra, Francisco J.; Choudhari, Shyamal P.; Clements, John D.; Picking, Wendy L.; Pasetti, Marcela F.

2013-01-01

Shigella spp. are food- and water-borne pathogens that cause shigellosis, a severe diarrheal and dysenteric disease that is associated with a high morbidity and mortality in resource-poor countries. No licensed vaccine is available to prevent shigellosis. We have recently demonstrated that Shigella invasion plasmid antigens (Ipas), IpaB and IpaD, which are components of the bacterial type III secretion system (TTSS), can prevent infection in a mouse model of intranasal immunization and lethal pulmonary challenge. Because they are conserved across Shigella spp. and highly immunogenic, these proteins are excellent candidates for a cross-protective vaccine. Ideally, such a vaccine could be administered to humans orally to induce mucosal and systemic immunity. In this study, we investigated the immunogenicity and protective efficacy of Shigella IpaB and IpaD administered orally with a double mutant of the Escherichia coli heat labile toxin (dmLT) as a mucosal adjuvant. We characterized the immune responses induced by oral vs. intranasal immunization and the protective efficacy using a mouse pulmonary infection model. Serum IgG and fecal IgA against IpaB were induced after oral immunization. These responses, however, were lower than those obtained after intranasal immunization despite a 100-fold dosage increase. The level of protection induced by oral immunization with IpaB and IpaD was 40%, while intranasal immunization resulted in 90% protective efficacy. IpaB- and IpaD-specific IgA antibody-secreting cells in the lungs and spleen and T-cell-derived IL-2, IL-5, IL-17 and IL-10 were associated with protection. These results demonstrate the immunogenicity of orally administered IpaB and IpaD and support further studies in humans. PMID:23644075

Functional Transplant of a Dengue Virus Serotype 3 (DENV3)-Specific Human Monoclonal Antibody Epitope into DENV1.

PubMed

Messer, William B; Yount, Boyd L; Royal, Scott R; de Alwis, Ruklanthi; Widman, Douglas G; Smith, Scott A; Crowe, James E; Pfaff, Jennifer M; Kahle, Kristen M; Doranz, Benjamin J; Ibarra, Kristie D; Harris, Eva; de Silva, Aravinda M; Baric, Ralph S

2016-05-15

The four dengue virus (DENV) serotypes, DENV1 through 4, are endemic throughout tropical and subtropical regions of the world. While first infection confers long-term protective immunity against viruses of the infecting serotype, a second infection with virus of a different serotype carries a greater risk of severe dengue disease, including dengue hemorrhagic fever and dengue shock syndrome. Recent studies demonstrate that humans exposed to DENV infections develop neutralizing antibodies that bind to quaternary epitopes formed by the viral envelope (E) protein dimers or higher-order assemblies required for the formation of the icosahedral viral envelope. Here we show that the quaternary epitope target of the human DENV3-specific neutralizing monoclonal antibody (MAb) 5J7 can be partially transplanted into a DENV1 strain by changing the core residues of the epitope contained within a single monomeric E molecule. MAb 5J7 neutralized the recombinant DENV1/3 strain in cell culture and was protective in a mouse model of infection with the DENV1/3 strain. However, the 5J7 epitope was only partially recreated by transplantation of the core residues because MAb 5J7 bound and neutralized wild-type (WT) DENV3 better than the DENV1/3 recombinant. Our studies demonstrate that it is possible to transplant a large number of discontinuous residues between DENV serotypes and partially recreate a complex antibody epitope, while retaining virus viability. Further refinement of this approach may lead to new tools for measuring epitope-specific antibody responses and new vaccine platforms. Dengue virus is the most important mosquito-borne pathogen of humans worldwide, with approximately one-half the world's population living in regions where dengue is endemic. Dengue immunity following infection is robust and thought to be conferred by antibodies raised against the infecting virus. However, the specific viral components that these antibodies recognize and how they neutralize the virus have been incompletely described. Here we map a region on dengue virus serotype 3 recognized by the human neutralizing antibody 5J7 and then test the functional significance of this region by transplanting it into a serotype 1 virus. Our studies demonstrate a region on dengue virus necessary for 5J7 binding and neutralization. Our work also demonstrates the technical feasibility of engineering dengue viruses to display targets of protective antibodies. This technology can be used to develop new dengue vaccines and diagnostic assays. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Prophylactic immunization against experimental leishmaniasis. III. Protection against fatal Leishmania tropica infection induced by irradiated promastigotes involves Lyt-1/sup +/2/sup -/ T cells that do not mediate cutaneous DTH

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

Liew, F.Y.; Howard, J.G.; Hale, C.

1984-01-01

Protective immunity against fatal L. tropica infection in genetically vulnerable BALB/c mice can be induced by prophylactic immunization with irradiated promastigotes even when heat-killed. Such immunity is adoptively transferable transiently into intact or durably into sub-lethally irradiated (200 or 550 rad) syngeneic recipients by splenic T but not B cells. The effector T cells are of the Lyt-1/sup +/2/sup -/ phenotype, devoid of demonstrable cytotoxic activity. The immune splenic T cell population expresses specific helper activity for antibody synthesis. A causal role for helper T cells in this capacity, however, seems unlikely, because it was shown that antibody does notmore » determine the protective immunity against L. tropica. The immunized donors show no detectable cutaneous DTH or its early memory recall in response to live or killed promastigotes or a soluble L. tropica antigen preparation. Spleen, lymph node, and peritoneal exudate cells from protectively immunized donors similarly fail to transfer DTH locally or systemically. These cells also lack demonstrable suppressive activity against the expression or induction of DTH to L. tropica. Thus, protection against L. tropica induced by prophylactic i.v. immunization with irradiated promastigotes appears to be conferred by Lyt-1/sup +/2/sup -/ T cells that are distinguishable from T cells mediating either both DTH and T help, or cytotoxicity.« less

Dissecting polyclonal vaccine-induced humoral immunity against HIV using Systems Serology

PubMed Central

Chung, Amy W.; Kumar, Manu P.; Arnold, Kelly B.; Yu, Wen Han; Schoen, Matthew K.; Dunphy, Laura J.; Suscovich, Todd J.; Frahm, Nicole; Linde, Caitlyn; Mahan, Alison E.; Hoffner, Michelle; Streeck, Hendrik; Ackerman, Margaret E.; McElrath, M. Juliana; Schuitemaker, Hanneke; Pau, Maria G.; Baden, Lindsey R.; Kim, Jerome H.; Michael, Nelson L.; Barouch, Dan H.; Lauffenburger, Douglas A.; Alter, Galit

2017-01-01

While antibody titers and neutralization are considered the gold standard for the selection of successful vaccines, these parameters are often inadequate predictors of protective immunity. As antibodies mediate an array of extra-neutralizing Fc-functions, when neutralization fails to predict protection, investigating Fc-mediated activity may help identify immunological correlates and mechanism(s) of humoral protection. Here, we used an integrative approach termed Systems Serology to analyze relationships among humoral responses elicited in four HIV vaccine-trials. Each vaccine regimen induced a unique humoral “Fc-fingerprint”. Moreover, analysis of case:control data from the first moderately protective HIV vaccine trial, RV144, pointed to mechanistic insights into immune complex composition that may underlie protective immunity to HIV. Thus, multi-dimensional relational comparisons of vaccine humoral fingerprints offer a unique approach for the evaluation and design of novel vaccines against pathogens for which correlates of protection remain elusive. PMID:26544943

Identification of immune signatures predictive of clinical protection from malaria.

PubMed

Valletta, John Joseph; Recker, Mario

2017-10-01

Antibodies are thought to play an essential role in naturally acquired immunity to malaria. Prospective cohort studies have frequently shown how continuous exposure to the malaria parasite Plasmodium falciparum cause an accumulation of specific responses against various antigens that correlate with a decreased risk of clinical malaria episodes. However, small effect sizes and the often polymorphic nature of immunogenic parasite proteins make the robust identification of the true targets of protective immunity ambiguous. Furthermore, the degree of individual-level protection conferred by elevated responses to these antigens has not yet been explored. Here we applied a machine learning approach to identify immune signatures predictive of individual-level protection against clinical disease. We find that commonly assumed immune correlates are poor predictors of clinical protection in children. On the other hand, antibody profiles predictive of an individual's malaria protective status can be found in data comprising responses to a large set of diverse parasite proteins. We show that this pattern emerges only after years of continuous exposure to the malaria parasite, whereas susceptibility to clinical episodes in young hosts (< 10 years) cannot be ascertained by measured antibody responses alone.

Sterile Immunity to Malaria after DNA Prime/Adenovirus Boost Immunization Is Associated with Effector Memory CD8+T Cells Targeting AMA1 Class I Epitopes

PubMed Central

Sedegah, Martha; Hollingdale, Michael R.; Farooq, Fouzia; Ganeshan, Harini; Belmonte, Maria; Kim, Yohan; Peters, Bjoern; Sette, Alessandro; Huang, Jun; McGrath, Shannon; Abot, Esteban; Limbach, Keith; Shi, Meng; Soisson, Lorraine; Diggs, Carter; Chuang, Ilin; Tamminga, Cindy; Epstein, Judith E.; Villasante, Eileen; Richie, Thomas L.

2014-01-01

Background Fifteen volunteers were immunized with three doses of plasmid DNA encoding P. falciparum circumsporozoite protein (CSP) and apical membrane antigen-1 (AMA1) and boosted with human adenovirus-5 (Ad) expressing the same antigens (DNA/Ad). Four volunteers (27%) demonstrated sterile immunity to controlled human malaria infection and, overall, protection was statistically significantly associated with ELISpot and CD8+ T cell IFN-γ activities to AMA1 but not CSP. DNA priming was required for protection, as 18 additional subjects immunized with Ad alone (AdCA) did not develop sterile protection. Methodology/Principal Findings We sought to identify correlates of protection, recognizing that DNA-priming may induce different responses than AdCA alone. Among protected volunteers, two and three had higher ELISpot and CD8+ T cell IFN-γ responses to CSP and AMA1, respectively, than non-protected volunteers. Unexpectedly, non-protected volunteers in the AdCA trial showed ELISpot and CD8+ T cell IFN-γ responses to AMA1 equal to or higher than the protected volunteers. T cell functionality assessed by intracellular cytokine staining for IFN-γ, TNF-α and IL-2 likewise did not distinguish protected from non-protected volunteers across both trials. However, three of the four protected volunteers showed higher effector to central memory CD8+ T cell ratios to AMA1, and one of these to CSP, than non-protected volunteers for both antigens. These responses were focused on discrete regions of CSP and AMA1. Class I epitopes restricted by A*03 or B*58 supertypes within these regions of AMA1 strongly recalled responses in three of four protected volunteers. We hypothesize that vaccine-induced effector memory CD8+ T cells recognizing a single class I epitope can confer sterile immunity to P. falciparum in humans. Conclusions/Significance We suggest that better understanding of which epitopes within malaria antigens can confer sterile immunity and design of vaccine approaches that elicit responses to these epitopes will increase the potency of next generation gene-based vaccines. PMID:25211344

Stabilization of Influenza Vaccine Enhances Protection by Microneedle Delivery in the Mouse Skin

PubMed Central

Yoo, Dae-Goon; Compans, Richard W.; Prausnitz, Mark R.; Kang, Sang-Moo

2009-01-01

Background Simple and effective vaccine administration is particularly important for annually recommended influenza vaccination. We hypothesized that vaccine delivery to the skin using a patch containing vaccine-coated microneedles could be an attractive approach to improve influenza vaccination compliance and efficacy. Methodology/Principal Findings Solid microneedle arrays coated with inactivated influenza vaccine were prepared for simple vaccine delivery to the skin. However, the stability of the influenza vaccine, as measured by hemagglutination activity, was found to be significantly damaged during microneedle coating. The addition of trehalose to the microneedle coating formulation retained hemagglutination activity, indicating stabilization of the coated influenza vaccine. For both intramuscular and microneedle skin immunization, delivery of un-stabilized vaccine yielded weaker protective immune responses including viral neutralizing antibodies, protective efficacies, and recall immune responses to influenza virus. Immunization using un-stabilized vaccine also shifted the pattern of antibody isotypes compared to the stabilized vaccine. Importantly, a single microneedle-based vaccination using stabilized influenza vaccine was found to be superior to intramuscular immunization in controlling virus replication as well as in inducing rapid recall immune responses post challenge. Conclusions/Significance The functional integrity of hemagglutinin is associated with inducing improved protective immunity against influenza. Simple microneedle influenza vaccination in the skin produced superior protection compared to conventional intramuscular immunization. This approach is likely to be applicable to other vaccines too. PMID:19779615

The Bulgarian vaccine Crimean-Congo haemorrhagic fever virus strain.

PubMed

Papa, Anna; Papadimitriou, Evangelia; Christova, Iva

2011-03-01

The Crimean-Congo haemorrhagic fever virus (CCHFV) is a 3-segmented RNA virus, which causes disease with a high fatality rate in humans. An inactivated suckling mouse brain-derived vaccine is used in Bulgaria for protection against CCHF. Strain V42/81 is currently used for the vaccine preparation. As the M-RNA segment plays a major role in the immune response, the full-length M segment sequence of the V42/81 strain was characterized. A great genetic diversity was observed among CCHFV strains. In order to gain an insight into the topology of the strain in the CCHFV phylogenetic trees, the full-length S and partial L segments were additionally sequenced and analyzed.

Does homologous reinfection drive multiple-wave influenza outbreaks? Accounting for immunodynamics in epidemiological models.

PubMed

Camacho, A; Cazelles, B

2013-12-01

Epidemiological models of influenza transmission usually assume that recovered individuals instantly develop a fully protective immunity against the infecting strain. However, recent studies have highlighted host heterogeneity in the development of this immune response, characterized by delay and even absence of protection, that could lead to homologous reinfection (HR). Here, we investigate how these immunological mechanisms at the individual level shape the epidemiological dynamics at the population level. In particular, because HR was observed during the successive waves of past pandemics, we assess its role in driving multiple-wave influenza outbreaks. We develop a novel mechanistic model accounting for host heterogeneity in the immune response. Immunological parameters are inferred by fitting our dynamical model to a two-wave influenza epidemic that occurred on the remote island of Tristan da Cunha (TdC) in 1971, and during which HR occurred in 92 of 284 islanders. We then explore the dynamics predicted by our model for various population settings. We find that our model can explain HR over both short (e.g. week) and long (e.g. month) time-scales, as reported during past pandemics. In particular, our results reveal that the HR wave on TdC was a natural consequence of the exceptional contact configuration and high susceptibility of this small and isolated community. By contrast, in larger, less mixed and partially protected populations, HR alone cannot generate multiple-wave outbreaks. However, in the latter case, we find that a significant proportion of infected hosts would remain unprotected at the end of the pandemic season and should therefore benefit from vaccination. Crucially, we show that failing to account for these unprotected individuals can lead to large underestimation of the magnitude of the first post-pandemic season. These results are relevant in the context of the 2009 A/H1N1 influenza post-pandemic era. Copyright © 2013 The Authors. Published by Elsevier B.V. All rights reserved.

A bivalent dendrimeric peptide bearing a T-cell epitope from foot-and-mouth disease virus protein 3A improves humoral response against classical swine fever virus.

PubMed

Bohórquez, José Alejandro; Defaus, Sira; Muñoz-González, Sara; Perez-Simó, Marta; Rosell, Rosa; Fraile, Lorenzo; Sobrino, Francisco; Andreu, David; Ganges, Llilianne

2017-06-15

Three dendrimeric peptides were synthesized in order to evaluate their immunogenicity and their potential protection against classical swine fever virus (CSFV) in domestic pigs. Construct 1, an optimized version of a previously used dendrimer, had four copies of a B-cell epitope derived from CSFV E2 glycoprotein connected to an also CSFV-derived T-cell epitope through maleimide instead of thioether linkages. Construct 2 was similarly built but included only two copies of the B-cell epitope, and in also bivalent construct 3 the CSFV T-cell epitope was replaced by a previously described one from the 3A protein of foot-and-mouth disease virus (FMDV). Animals were inoculated twice with a 21-day interval and challenged 15days after the second immunization. Clinical signs were recorded daily and ELISA tests were performed to detect antibodies against specific peptide and E2. The neutralising antibody response was assessed 13days after challenge. Despite the change to maleimide connectivity, only partial protection against CSFV was again observed. The best clinical protection was observed in group 3. Animals inoculated with constructs 2 and 3 showed higher anti-peptide humoral response, suggesting that two copies of the B-cell epitope are sufficient or even better than four copies for swine immune recognition. In addition, for construct 3 higher neutralizing antibody titres against CSFV were detected. Our results support the immunogenicity of the CSFV B-cell epitope and the cooperative role of the FMDV 3A T-cell epitope in inducing a neutralising response against CSFV in domestic pigs. This is also the first time that the FMDV T-cell epitope shows effectivity in improving swine immune response against a different virus. Our findings highlight the relevance of dendrimeric peptides as a powerful tool for epitope characterization and antiviral strategies development. Copyright © 2017 Elsevier B.V. All rights reserved.

Active Immunizations with Peptide-DC Vaccines and Passive Transfer with Antibodies Protect Neutropenic Mice against Disseminated Candidiasis

PubMed Central

Xin, Hong

2015-01-01

We previously report that peptide-pulsed dendritic cell (DC) vaccination, which targeting two peptides (Fba and Met6) expressed on the cell surface of Candida albicans, can induce high degree of protection against disseminated candidiasis in immunocompetent mice. Passive transfer of immune sera from the peptide immunized mice or peptide-related monoclonal antibodies demonstrated that protection was medicated by peptide-specific antibodies. In this study the efficacy of active and passive immunization against disseminated candidiasis was tested in mice with cyclophosphamide-induced neutropenia. Peptide-DC vaccines were given to mice prior to induction of neutropenia. We show active immunization with either Fba or Met6 peptide-DC vaccine significantly improved the survival and reduced the fungal burden of disseminated candidiasis in those immunocompromised mice. Importantly, we show that administration of two protective monoclonal antibodies also protect neutropenic mice against the disease, implying possibility of developing a successful passive immunotherapy strategy to treat the disease and protect against disseminated candidiasis. The results of this study are crucial as they address the fundamental questions as to whether the synthetic peptide vaccine induced immunity protects the host during a neutropenic episode. We anticipate that this peptide-vaccine study will serve as the foundation of future investigations into new peptide vaccines comprised of cell surface peptides from other medically important Candida species, as well as other fungi. PMID:26620842

Evaluation of the protective immunogencity of the N, P, M, NV and G proteins of infectious hematopoietic necrosis virus in rainbow trout Oncorhynchus mykiss using DNA vaccines

USGS Publications Warehouse

Corbeil, S.; LaPatra, S.E.; Anderson, E.D.; Jones, J.; Vincent, B.; Hsu, Ya Li; Kurath, G.

1999-01-01

The protective immunogenicity of the nucleoprotein (N), phosphoprotein (P), matrix protein (M), non-virion protein (NV) and glycoprotein (G) of the rhabdovirus infectious hematopoietic necrosis virus (IHNV) was assessed in rainbow trout using DNA vaccine technology. DNA vaccines were produced by amplifying and cloning the viral genes in the plasmid pCDNA 3.1. The protective immunity elicited by each vaccine was evaluated through survival of immunized fry after challenge with live virus. Neutralizing antibody titers were also determined in vaccinated rainbow troutOncorhynchus mykiss fry (mean weight 2 g) and 150 g sockeye salmon Oncorhynchus nerka. The serum from the 150 g fish was also used in passive immunization studies with naïve fry. Our results showed that neither the internal structural proteins (N, P and M) nor the NV protein of IHNV induced protective immunity in fry or neutralizing antibodies in fry and 150 g fish when expressed by a DNA vaccine construct. The G protein, however, did confer significant protection in fry up to 80 d post-immunization and induced protective neutralizing antibodies. We are currently investigating the role of different arms of the fish immune system that contribute to the high level of protection against IHNV seen in vaccinated fish.

A Burkholderia pseudomallei Outer Membrane Vesicle Vaccine Provides Cross Protection against Inhalational Glanders in Mice and Non-Human Primates.

PubMed

Baker, Sarah M; Davitt, Christopher J H; Motyka, Natalya; Kikendall, Nicole L; Russell-Lodrigue, Kasi; Roy, Chad J; Morici, Lisa A

2017-12-09

Burkholderia mallei is a Gram-negative, non-motile, facultative intracellular bacillus and the causative agent of glanders, a highly contagious zoonotic disease. B. mallei is naturally resistant to multiple antibiotics and there is concern for its potential use as a bioweapon, making the development of a vaccine against B. mallei of critical importance. We have previously demonstrated that immunization with multivalent outer membrane vesicles (OMV) derived from B. pseudomallei provide significant protection against pneumonic melioidosis. Given that many virulence determinants are highly conserved between the two species, we sought to determine if the B. pseudomallei OMV vaccine could cross-protect against B. mallei . We immunized C57Bl/6 mice and rhesus macaques with B. pseudomallei OMVs and subsequently challenged animals with aerosolized B. mallei . Immunization with B. pseudomallei OMVs significantly protected mice against B. mallei and the protection observed was comparable to that achieved with a live attenuated vaccine. OMV immunization induced the production of B.mallei- specific serum IgG and a mixed Th1/Th17 CD4 and CD8 T cell response in mice. Additionally, immunization of rhesus macaques with B. pseudomallei OMVs provided protection against glanders and induced B.mallei -specific serum IgG in non-human primates. These results demonstrate the ability of the multivalent OMV vaccine platform to elicit cross-protection against closely-related intracellular pathogens and to induce robust humoral and cellular immune responses against shared protective antigens.

A Burkholderia pseudomallei Outer Membrane Vesicle Vaccine Provides Cross Protection against Inhalational Glanders in Mice and Non-Human Primates

PubMed Central

Davitt, Christopher J. H.; Motyka, Natalya; Kikendall, Nicole L.; Roy, Chad J.

2017-01-01

Burkholderia mallei is a Gram-negative, non-motile, facultative intracellular bacillus and the causative agent of glanders, a highly contagious zoonotic disease. B. mallei is naturally resistant to multiple antibiotics and there is concern for its potential use as a bioweapon, making the development of a vaccine against B. mallei of critical importance. We have previously demonstrated that immunization with multivalent outer membrane vesicles (OMV) derived from B. pseudomallei provide significant protection against pneumonic melioidosis. Given that many virulence determinants are highly conserved between the two species, we sought to determine if the B. pseudomallei OMV vaccine could cross-protect against B. mallei. We immunized C57Bl/6 mice and rhesus macaques with B. pseudomallei OMVs and subsequently challenged animals with aerosolized B. mallei. Immunization with B. pseudomallei OMVs significantly protected mice against B. mallei and the protection observed was comparable to that achieved with a live attenuated vaccine. OMV immunization induced the production of B.mallei-specific serum IgG and a mixed Th1/Th17 CD4 and CD8 T cell response in mice. Additionally, immunization of rhesus macaques with B. pseudomallei OMVs provided protection against glanders and induced B.mallei-specific serum IgG in non-human primates. These results demonstrate the ability of the multivalent OMV vaccine platform to elicit cross-protection against closely-related intracellular pathogens and to induce robust humoral and cellular immune responses against shared protective antigens. PMID:29232837

Plant Immunity Inducer Development and Application.

PubMed

Dewen, Qiu; Yijie, Dong; Yi, Zhang; Shupeng, Li; Fachao, Shi

2017-05-01

Plant immunity inducers represent a new and rapidly developing field in plant-protection research. In this paper, we discuss recent research on plant immunity inducers and their development and applications in China. Plant immunity inducers include plant immunity-inducing proteins, chitosan oligosaccharides, and microbial inducers. These compounds and microorganisms can trigger defense responses and confer disease resistance in plants. We also describe the mechanisms of plant immunity inducers and how they promote plant health. Furthermore, we summarize the current situation in plant immunity inducer development in China and the global marketplace. Finally, we also deeply analyze the development trends and application prospects of plant immunity inducers in environmental protection and food safety.

How might infant and paediatric immune responses influence malaria vaccine efficacy?

PubMed

Moormann, A M

2009-09-01

Naturally acquired immunity to malaria requires repeat infections yet does not engender sterile immunity or long-lasting protective immunologic memory. This renders infants and young children the most susceptible to malaria-induced morbidity and mortality, and the ultimate target for a malaria vaccine. The prevailing paradigm is that infants initially garner protection due to transplacentally transferred anti-malarial antibodies and other intrinsic factors such as foetal haemoglobin. As these wane infants have an insufficient immune repertoire to prevent genetically diverse Plasmodium infections and an inability to control malaria-induced immunopathology. This Review discusses humoral, cell-mediated and innate immune responses to malaria and how each contributes to protection - focusing on how deficiencies in infant and paediatric immune responses might influence malaria vaccine efficacy in this population. In addition, burgeoning evidence suggests a role for inhibitory receptors that limit immunopathology and guide the development of long-lived immunity. Precisely how age or malaria infections influence the function of these regulators is unknown. Therefore the possibility that infants may not have the immune-dexterity to balance effective parasite clearance with timely immune-regulation leading to protective immunologic memory is considered. And thus, malaria vaccines tested in adults and older children may not be predictive for trials conducted in infants.

Use of the mice passive protection test to evaluate the humoral response in goats vaccinated with Sterne 34F2 live spore vaccine.

PubMed

Phaswana, P H; Ndumnego, O C; Koehler, S M; Beyer, W; Crafford, J E; van Heerden, H

2017-09-07

The Sterne live spore vaccine (34F2) is the most widely used veterinary vaccine against anthrax in animals. Antibody responses to several antigens of Bacillus anthracis have been described with a large focus on those against protective antigen (PA). The focus of this study was to evaluate the protective humoral immune response induced by the live spore anthrax vaccine in goats. Boer goats vaccinated twice (week 0 and week 12) with the Sterne live spore vaccine and naive goats were used to monitor the anti-PA and toxin neutralizing antibodies at week 4 and week 17 (after the second vaccine dose) post vaccination. A/J mice were passively immunized with different dilutions of sera from immune and naive goats and then challenged with spores of B. anthracis strain 34F2 to determine the protective capacity of the goat sera. The goat anti-PA ELISA titres indicated significant sero-conversion at week 17 after the second doses of vaccine (p = 0.009). Mice receiving undiluted sera from goats given two doses of vaccine (twice immunized) showed the highest protection (86%) with only 20% of mice receiving 1:1000 diluted sera surviving lethal challenge. The in vitro toxin neutralization assay (TNA) titres correlated to protection of passively immunized A/J mice against lethal infection with the vaccine strain Sterne 34F2 spores using immune goat sera up to a 1:10 dilution (r s  ≥ 0.522, p = 0.046). This study suggests that the passive mouse protection model could be potentially used to evaluate the protective immune response in livestock animals vaccinated with the current live vaccine and new vaccines.

Innate control of adaptive immunity: Beyond the three-signal paradigm

PubMed Central

Jain, Aakanksha; Pasare, Chandrashekhar

2017-01-01

Activation of cells in the adaptive immune system is a highly orchestrated process dictated by multiples cues from the innate immune system. Although the fundamental principles of innate control of adaptive immunity are well established, it is not fully understood how innate cells integrate qualitative pathogenic information in order to generate tailored protective adaptive immune responses. In this review, we discuss complexities involved in the innate control of adaptive immunity that extend beyond T cell receptor engagement, co-stimulation and priming cytokine production but are critical for generation of protective T cell immunity. PMID:28483987

Synergy between the classical and alternative pathways of complement is essential for conferring effective protection against the pandemic influenza A(H1N1) 2009 virus infection

PubMed Central

Rattan, Ajitanuj; Pawar, Shailesh D.; Nawadkar, Renuka; Kulkarni, Neeraja

2017-01-01

The pandemic influenza A(H1N1) 2009 virus caused significant morbidity and mortality worldwide thus necessitating the need to understand the host factors that influence its control. Previously, the complement system has been shown to provide protection during the seasonal influenza virus infection, however, the role of individual complement pathways is not yet clear. Here, we have dissected the role of intact complement as well as of its individual activation pathways during the pandemic influenza virus infection using mouse strains deficient in various complement components. We show that the virus infection in C3-/- mice results in increased viral load and 100% mortality, which can be reversed by adoptive transfer of naïve wild-type (WT) splenocytes, purified splenic B cells, or passive transfer of immune sera from WT, but not C3-/- mice. Blocking of C3a and/or C5a receptor signaling in WT mice using receptor antagonists and use of C3aR-/- and C5aR-/- mice showed significant mortality after blocking/ablation of C3aR, with little or no effect after blocking/ablation of C5aR. Intriguingly, deficiency of C4 and FB in mice resulted in only partial mortality (24%-32%) suggesting a necessary cross-talk between the classical/lectin and alternative pathways for providing effective protection. In vitro virus neutralization experiments performed to probe the cross-talk between the various pathways indicated that activation of the classical and alternative pathways in concert, owing to coating of viral surface by antibodies, is needed for its efficient neutralization. Examination of the virus-specific complement-binding antibodies in virus positive subjects showed that their levels vary among individuals. Together these results indicate that cooperation between the classical and alternative pathways not only result in efficient direct neutralization of the pandemic influenza virus, but also lead to the optimum generation of C3a, which when sensed by the immune cells along with the antigen culminates in generation of effective protective immune responses. PMID:28301559

Pulmonary immunization of chickens using non-adjuvanted spray-freeze dried whole inactivated virus vaccine completely protects against highly pathogenic H5N1 avian influenza virus.

PubMed

Peeters, Ben; Tonnis, Wouter F; Murugappan, Senthil; Rottier, Peter; Koch, Guus; Frijlink, Henderik W; Huckriede, Anke; Hinrichs, Wouter L J

2014-11-12

Highly pathogenic avian influenza (HPAI) H5N1 virus is a major threat to public health as well as to the global poultry industry. Most fatal human infections are caused by contact with infected poultry. Therefore, preventing the virus from entering the poultry population is a priority. This is, however, problematic in emergency situations, e.g. during outbreaks in poultry, as there are currently no mass application methods to effectively vaccinate large numbers of birds within a short period of time. To evaluate the suitability of needle-free pulmonary immunization for mass vaccination of poultry against HPAI H5N1, we performed a proof-of-concept study in which we investigated whether non-adjuvanted spray-freeze-dried (SFD) whole inactivated virus (WIV) can be used as a dry powder aerosol vaccine to immunize chickens. Our results show that chickens that received SFD-WIV vaccine as aerosolized powder directly at the syrinx (the site of the tracheal bifurcation), mounted a protective antibody response after two vaccinations and survived a lethal challenge with HPAI H5N1. Furthermore, both the number of animals that shed challenge virus, as well as the level of virus shedding, were significantly reduced. Based on antibody levels and reduction of virus shedding, pulmonary vaccination with non-adjuvanted vaccine was at least as efficient as intratracheal vaccination using live virus. Animals that received aerosolized SFD-WIV vaccine by temporary passive inhalation showed partial protection (22% survival) and a delay in time-to-death, thereby demonstrating the feasibility of the method, but indicating that the efficiency of vaccination by passive inhalation needs further improvement. Altogether our results provide a proof-of-concept that pulmonary vaccination using an SFD-WIV powder vaccine is able to protect chickens from lethal HPAI challenge. If the efficacy of pulmonary vaccination by passive inhalation can be improved, this method might be suitable for mass application. Copyright © 2014 Elsevier Ltd. All rights reserved.

Vaccination with Brucella abortus rough mutant RB51 protects BALB/c mice against virulent strains of Brucella abortus, Brucella melitensis, and Brucella ovis.

PubMed Central

Jiménez de Bagüés, M P; Elzer, P H; Jones, S M; Blasco, J M; Enright, F M; Schurig, G G; Winter, A J

1994-01-01

Vaccination of BALB/c mice with live Brucella abortus RB51, a stable rough mutant, produced protection against challenge with virulent strains of Brucella abortus, Brucella melitensis, and Brucella ovis. Passive-transfer experiments indicated that vaccinated mice were protected against B. abortus 2308 through cell-mediated immunity, against B. ovis PA through humoral immunity, and against B. melitensis 16M through both forms of immunity. Live bacteria were required for the induction of protective cell-mediated immunity; vaccination with whole killed cells of strain RB51 failed to protect mice against B. abortus 2308 despite development of good delayed-type hypersensitivity reactions. Protective antibodies against the heterologous species were generated in vaccinated mice primarily through anamnestic responses following challenge infections. Growth of the antigenically unrelated bacterium Listeria monocytogenes in the spleens of vaccinated mice indicated that nonspecific killing by residual activated macrophages contributed minimally to protection. These results encourage the continued investigation of strain RB51 as an alternative vaccine against heterologous Brucella species. However, its usefulness against B. ovis would be limited if, as suggested here, epitopes critical for protective cell-mediated immunity are not shared between B. abortus and B. ovis. Images PMID:7927779

Streptococcal Immunity Is Constrained by Lack of Immunological Memory following a Single Episode of Pyoderma

PubMed Central

Pandey, Manisha; Ozberk, Victoria; Calcutt, Ainslie; Langshaw, Emma; Powell, Jessica; Rivera-Hernandez, Tania; Philips, Zachary; Batzloff, Michael R.; Good, Michael F.

2016-01-01

The immunobiology underlying the slow acquisition of skin immunity to group A streptococci (GAS), is not understood, but attributed to specific virulence factors impeding innate immunity and significant antigenic diversity of the type-specific M-protein, hindering acquired immunity. We used a number of epidemiologically distinct GAS strains to model the development of acquired immunity. We show that infection leads to antibody responses to the serotype-specific determinants on the M-protein and profound protective immunity; however, memory B cells do not develop and immunity is rapidly lost. Furthermore, antibodies do not develop to a conserved M-protein epitope that is able to induce immunity following vaccination. However, if re-infected with the same strain within three weeks, enduring immunity and memory B-cells (MBCs) to type-specific epitopes do develop. Such MBCs can adoptively transfer protection to naïve recipients. Thus, highly protective M-protein-specific MBCs may never develop following a single episode of pyoderma, contributing to the slow acquisition of immunity and to streptococcal endemicity in at-risk populations. PMID:28027314

T lymphocyte-mediated protection against Pseudomonas aeruginosa infection in granulocytopenic mice.

PubMed Central

Powderly, W G; Pier, G B; Markham, R B

1986-01-01

BALB/c mice immunized with Pseudomonas aeruginosa immunotype 1 polysaccharide develop protective T cell immunity to bacterial challenge. In vitro, T cells from immunized mice kill P. aeruginosa by production of a bactericidal lymphokine. The present study demonstrates that adoptive transfer of T cells from immunized BALB/c mice to granulocytopenic mice resulted in 97% survival on challenge with P. aeruginosa, compared with 17% survival with adoptive transfer of T cells from nonimmune BALB/c mice. This protection is specifically elicited by reexposure to the original immunizing antigen; adoptive recipients cannot withstand challenge with immunotype 3 P. aeruginosa. However, the adoptive recipients do survive simultaneous infection with both P. aeruginosa immunotypes 1 and 3. Adoptive transfer of T cells from the congenic CB.20 mice, which are unable to kill P. aeruginosa in vitro, provides only 20% protection to granulocytopenic mice. These studies indicate that transfer of specific immune T lymphocytes can significantly enhance the resistance to P. aeruginosa infection in granulocytopenic mice. PMID:2426306

Live-Attenuated Lentivirus Immunization Modulates Innate Immunity and Inflammation while Protecting Rhesus Macaques from Vaginal Simian Immunodeficiency Virus Challenge

PubMed Central

Genescà, Meritxell; Ma, Zhong-Min; Wang, Yichuan; Assaf, Basel; Qureshi, Huma; Fritts, Linda; Huang, Ying; McChesney, Michael B.

2012-01-01

Immunization with attenuated lentiviruses is the only reliable method of protecting rhesus macaques (RM) from vaginal challenge with pathogenic simian immunodeficiency virus (SIV). CD8+ lymphocyte depletion prior to SIVmac239 vaginal challenge demonstrated that a modest, Gag-specific CD8+ T cell response induced by immunization with simian-human immunodeficiency virus 89.6 (SHIV89.6) protects RM. Although CD8+ T cells are required for protection, there is no anamnestic expansion of SIV-specific CD8+ T cells in any tissues except the vagina after challenge. Further, SHIV immunization increased the number of viral target cells in the vagina and cervix, suggesting that the ratio of target cells to antiviral CD8+ T cells was not a determinant of protection. We hypothesized that persistent replication of the attenuated vaccine virus modulates inflammatory responses and limits T cell activation and expansion by inducing immunoregulatory T cell populations. We found that attenuated SHIV infection decreased the number of circulating plasmacytoid dendritic cells, suppressed T cell activation, decreased mRNA levels of proinflammatory mediators, and increased mRNA levels of immunoregulatory molecules. Three days after SIV vaginal challenge, SHIV-immunized RM had significantly more T regulatory cells in the vagina than the unimmunized RM. By day 14 postchallenge, immune activation and inflammation were characteristic of unimmunized RM but were minimal in SHIV-immunized RM. Thus, a modest vaccine-induced CD8+ T cell response in the context of immunoregulatory suppression of T cell activation may protect against vaginal HIV transmission. PMID:22696662

Neutrophils Are Central to Antibody-Mediated Protection against Genital Chlamydia.

PubMed

Naglak, Elizabeth K; Morrison, Sandra G; Morrison, Richard P

2017-10-01

Determining the effector populations involved in humoral protection against genital chlamydia infection is crucial to development of an effective chlamydial vaccine. Antibody has been implicated in protection studies in multiple animal models, and we previously showed that the passive transfer of immune serum alone does not confer immunity in the mouse. Using the Chlamydia muridarum model of genital infection, we demonstrate a protective role for both Chlamydia -specific immunoglobulin G (IgG) and polymorphonuclear neutrophils and show the importance of an antibody/effector cell interaction in mediating humoral immunity. While neutrophils were found to contribute significantly to antibody-mediated protection in vivo , natural killer (NK) cells were dispensable for protective immunity. Furthermore, gamma interferon (IFN-γ)-stimulated primary peritoneal neutrophils (PPNs) killed chlamydiae in vitro in an antibody-dependent manner. The results from this study support the view that an IFN-γ-activated effector cell population cooperates with antibody to protect against genital chlamydia and establish neutrophils as a key effector cell in this response. Copyright © 2017 Naglak et al.

Influence of temperature on the efficacy of homologous and heterologous DNA vaccines against viral hemorrhagic septicemia in Pacific Herring

USGS Publications Warehouse

Hart, Lucas; Lorenzen, Niels; Einer-Jensen, Katja; Purcell, Maureen; Hershberger, Paul

2017-01-01

Homologous and heterologous (genogroup Ia) DNA vaccines against viral hemorrhagic septicemia virus (genogroup IVa) conferred partial protection in Pacific Herring Clupea pallasii. Early protection at 2 weeks postvaccination (PV) was low and occurred only at an elevated temperature (12.6°C, 189 degree days), where the relative percent survival following viral exposure was similar for the two vaccines (IVa and Ia) and higher than that of negative controls at the same temperature. Late protection at 10 weeks PV was induced by both vaccines but was higher with the homologous vaccine at both 9.0°C and 12.6°C. Virus neutralization titers were detected among 55% of all vaccinated fish at 10 weeks PV. The results suggest that the immune response profile triggered by DNA vaccination of herring was similar to that reported for Rainbow Trout Oncorhynchus mykiss by Lorenzen and LaPatra in 2005, who found interferon responses in the early days PV and the transition to adaptive response later. However, the protective effect was far less prominent in herring, possibly reflecting different physiologies or adaptations of the two fish species.

Recombinant Newcastle disease virus expressing the infectious bronchitis virus S1 gene protects chickens against Newcastle disease virus and infectious bronchitis virus challenge.

PubMed

Zhao, Ran; Sun, Junfeng; Qi, Tianming; Zhao, Wen; Han, Zongxi; Yang, Xiaopu; Liu, Shengwang

2017-04-25

The recombinant LaSota strain expressing a chimeric IBV S1 gene (rLaSota-S1) was constructed with the S1 gene of the LX4 type IBV ck/CH/LDL/091022. The expression of the S1 protein was detected by an indirect immunofluorescence assay and Western blotting. The rLaSota-S1 strain was slightly attenuated, and its growth dynamics were similar to that of the parental LaSota strain. Vaccination of specific pathogen-free chickens with the rLaSota-S1 strain induced NDV hemagglutination inhibition antibodies, and it protected chickens from challenge with virulent NDV. In addition, vaccination with the rLaSota-S1 strain induced IBV-specific IgG antibodies and cellular immunity; however, a single vaccination provided partial protection with reduced virus shedding. Better protection efficiency was observed after a booster vaccination, which resulted in higher antibody titers, significantly fewer disease symptoms, and reduced virus replication and shedding. Our results suggest that the rLaSota-S1 strain is a bivalent vaccine candidate against both NDV and IBV. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evaluation of adaptive immune responses and heterologous protection induced by inactivated bluetongue virus vaccines.

PubMed

Breard, Emmanuel; Belbis, Guillaume; Viarouge, Cyril; Nomikou, Kyriaki; Haegeman, Andy; De Clercq, Kris; Hudelet, Pascal; Hamers, Claude; Moreau, Francis; Lilin, Thomas; Durand, Benoit; Mertens, Peter; Vitour, Damien; Sailleau, Corinne; Zientara, Stéphan

2015-01-15

Eradication of bluetongue virus is possible, as has been shown in several European countries. New serotypes have emerged, however, for which there are no specific commercial vaccines. This study addressed whether heterologous vaccines would help protect against 2 serotypes. Thirty-seven sheep were randomly allocated to 7 groups of 5 or 6 animals. Four groups were vaccinated with commercial vaccines against BTV strains 2, 4, and 9. A fifth positive control group was given a vaccine against BTV-8. The other 2 groups were unvaccinated controls. Sheep were then challenged by subcutaneous injection of either BTV-16 (2 groups) or BTV-8 (5 groups). Taken together, 24/25 sheep from the 4 experimental groups developed detectable antibodies against the vaccinated viruses. Furthermore, sheep that received heterologous vaccines showed significantly reduced viraemia and clinical scores for BTV-16 when compared to unvaccinated controls. Reductions in clinical signs and viraemia among heterologously vaccinated sheep were not as common after challenge with BTV-8. This study shows that heterologous protection can occur, but that it is difficult to predict if partial or complete protection will be achieved following inactivated-BTV vaccination. Copyright © 2014 Elsevier Ltd. All rights reserved.

CD4+ T-Cell- and Gamma Interferon-Dependent Protection against Murine Malaria by Immunization with Linear Synthetic Peptides from a Plasmodium yoelii 17-Kilodalton Hepatocyte Erythrocyte Protein

PubMed Central

Charoenvit, Yupin; Majam, Victoria Fallarme; Corradin, Giampietro; Sacci, John B.; Wang, Ruobing; Doolan, Denise L.; Jones, Trevor R.; Abot, Esteban; Patarroyo, Manuel E.; Guzman, Fanny; Hoffman, Stephen L.

1999-01-01

Most work on protective immunity against the pre-erythrocytic stages of malaria has focused on induction of antibodies that prevent sporozoite invasion of hepatocytes, and CD8+ T-cell responses that eliminate infected hepatocytes. We recently reported that immunization of A/J mice with an 18-amino-acid synthetic linear peptide from Plasmodium yoelii sporozoite surface protein 2 (SSP2) in TiterMax adjuvant induces sterile protection that is dependent on CD4+ T cells and gamma interferon (IFN-γ). We now report that immunization of inbred A/J mice and outbred CD1 mice with each of two linear synthetic peptides from the 17-kDa P. yoelii hepatocyte erythrocyte protein (HEP17) in the same adjuvant also induces protection against sporozoite challenge that is dependent on CD4+ T cells and IFN-γ. The SSP2 peptide and the two HEP17 peptides are recognized by B cells as well as T cells, and the protection induced by these peptides appears to be directed against the infected hepatocytes. In contrast to the peptide-induced protection, immunization of eight different strains of mice with radiation-attenuated sporozoites induces protection that is absolutely dependent on CD8+ T cells. Data represented here demonstrate that CD4+ T-cell-dependent protection can be induced by immunization with linear synthetic peptides. These studies therefore provide the foundation for an approach to pre-erythrocytic-stage malaria vaccine development, based on the induction of protective CD4+ T-cell responses, which will complement efforts to induce protective antibody and CD8+ T-cell responses. PMID:10531206

Inactivated Recombinant Rabies Viruses Displaying Canine Distemper Virus Glycoproteins Induce Protective Immunity against Both Pathogens

PubMed Central

da Fontoura Budaszewski, Renata; Hudacek, Andrew; Sawatsky, Bevan; Krämer, Beate; Yin, Xiangping

2017-01-01

ABSTRACT The development of multivalent vaccines is an attractive methodology for the simultaneous prevention of several infectious diseases in vulnerable populations. Both canine distemper virus (CDV) and rabies virus (RABV) cause lethal disease in wild and domestic carnivores. While RABV vaccines are inactivated, the live-attenuated CDV vaccines retain residual virulence for highly susceptible wildlife species. In this study, we developed recombinant bivalent vaccine candidates based on recombinant vaccine strain rabies virus particles, which concurrently display the protective CDV and RABV glycoprotein antigens. The recombinant viruses replicated to near-wild-type titers, and the heterologous glycoproteins were efficiently expressed and incorporated in the viral particles. Immunization of ferrets with beta-propiolactone-inactivated recombinant virus particles elicited protective RABV antibody titers, and animals immunized with a combination of CDV attachment protein- and fusion protein-expressing recombinant viruses were protected from lethal CDV challenge. However, animals that were immunized with only a RABV expressing the attachment protein of CDV vaccine strain Onderstepoort succumbed to infection with a more recent wild-type strain, indicating that immune responses to the more conserved fusion protein contribute to protection against heterologous CDV strains. IMPORTANCE Rabies virus and canine distemper virus (CDV) cause high mortality rates and death in many carnivores. While rabies vaccines are inactivated and thus have an excellent safety profile and high stability, live-attenuated CDV vaccines can retain residual virulence in highly susceptible species. Here we generated recombinant inactivated rabies viruses that carry one of the CDV glycoproteins on their surface. Ferrets immunized twice with a mix of recombinant rabies viruses carrying the CDV fusion and attachment glycoproteins were protected from lethal CDV challenge, whereas all animals that received recombinant rabies viruses carrying only the CDV attachment protein according to the same immunization scheme died. Irrespective of the CDV antigens used, all animals developed protective titers against rabies virus, illustrating that a bivalent rabies virus-based vaccine against CDV induces protective immune responses against both pathogens. PMID:28148801

Immunogenicity and protective efficacy of heparan sulphate binding proteins of Entamoeba histolytica in a guinea pig model of intestinal amoebiasis.

PubMed

Kaur, Upninder; Khurana, Sumeeta; Saikia, Uma Nahar; Dubey, M L

2013-11-01

Entamoeba histolytica infection is associated with considerable morbidity and mortality in the form of intestinal and extraintestinal amoebiasis. No vaccine is yet available for amoebiasis. Heparan Sulphate Binding Proteins (HSBPs) from E. histolytica were evaluated for immunogenicity and protective efficacy in a Guinea pig model. Animals were immunized subcutaneously with 30μg of HSBP by three weekly inoculations. The immunogenicity of HSBP was determined by antibody response (IgG, IgM and IgA), splenocyte proliferation assay and in vitro direct amoebicidal assay with splenic lymphocytes and monocytes from vaccinated and control animals. The efficacy of the vaccine was evaluated by challenge infection to vaccinated and control animals by intra-caecal inoculation of E. histolytica trophozoites and comparing gross and histopathological findings in caeca of these animals. HSBP was found to induce specific anti-amoebic response as seen by specific antibody production and direct amoebicidal activity of splenocytes. The vaccine also showed partial protection against challenge infection in vaccinated animals as shown by mild/absent lesions and histopathological findings. Copyright © 2013 Elsevier Inc. All rights reserved.

Chimpanzee adenovirus vaccine generates acute and durable protective immunity against ebolavirus challenge.

PubMed

Stanley, Daphne A; Honko, Anna N; Asiedu, Clement; Trefry, John C; Lau-Kilby, Annie W; Johnson, Joshua C; Hensley, Lisa; Ammendola, Virginia; Abbate, Adele; Grazioli, Fabiana; Foulds, Kathryn E; Cheng, Cheng; Wang, Lingshu; Donaldson, Mitzi M; Colloca, Stefano; Folgori, Antonella; Roederer, Mario; Nabel, Gary J; Mascola, John; Nicosia, Alfredo; Cortese, Riccardo; Koup, Richard A; Sullivan, Nancy J

2014-10-01

Ebolavirus disease causes high mortality, and the current outbreak has spread unabated through West Africa. Human adenovirus type 5 vectors (rAd5) encoding ebolavirus glycoprotein (GP) generate protective immunity against acute lethal Zaire ebolavirus (EBOV) challenge in macaques, but fail to protect animals immune to Ad5, suggesting natural Ad5 exposure may limit vaccine efficacy in humans. Here we show that a chimpanzee-derived replication-defective adenovirus (ChAd) vaccine also rapidly induced uniform protection against acute lethal EBOV challenge in macaques. Because protection waned over several months, we boosted ChAd3 with modified vaccinia Ankara (MVA) and generated, for the first time, durable protection against lethal EBOV challenge.

45 CFR 61.16 - Immunity.

Code of Federal Regulations, 2010 CFR

2010-10-01

... 45 Public Welfare 1 2010-10-01 2010-10-01 false Immunity. 61.16 Section 61.16 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION HEALTHCARE INTEGRITY AND PROTECTION DATA BANK... Information by the Healthcare Integrity and Protection Data Bank § 61.16 Immunity. Individuals, entities or...

45 CFR 61.16 - Immunity.

Code of Federal Regulations, 2012 CFR

2012-10-01

... 45 Public Welfare 1 2012-10-01 2012-10-01 false Immunity. 61.16 Section 61.16 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION HEALTHCARE INTEGRITY AND PROTECTION DATA BANK... Information by the Healthcare Integrity and Protection Data Bank § 61.16 Immunity. Individuals, entities or...

45 CFR 61.16 - Immunity.

Code of Federal Regulations, 2011 CFR

2011-10-01

... 45 Public Welfare 1 2011-10-01 2011-10-01 false Immunity. 61.16 Section 61.16 Public Welfare DEPARTMENT OF HEALTH AND HUMAN SERVICES GENERAL ADMINISTRATION HEALTHCARE INTEGRITY AND PROTECTION DATA BANK... Information by the Healthcare Integrity and Protection Data Bank § 61.16 Immunity. Individuals, entities or...

Protection of Broiler Chicks Housed with Immunized Cohorts Against Infection with Eimeria maxima and E. acervulina.

PubMed

Fetterer, Raymond H; Barfield, Ruth C; Jenkins, Mark C

2015-03-01

The use of live oocyst vaccines is becoming increasingly important in the control of avian coccidiosis in broilers. Knowledge of the mechanisms employed when chicks uptake oocysts and become immune is important for optimizing delivery of live vaccines. The current study tests the hypothesis that chicks not initially immunized may ingest oocysts by contact with litter containing oocysts shed by immunized cohorts. In Experiment 1, day-old broiler chicks were housed in pens containing clean litter. In Trial 1, 100% of chicks in some pens were immunized with 2.5 X 10(3) Eimeria acervulina oocysts while in other pens only 75% of chicks were immunized and remaining cohorts within the pens were not immunized. Other pens contained chicks that served as nonimmunized nonchallenged controls or nonimmunized challenged controls (NIC). On day 21, birds were given a homologous challenge of 6 X 10(5) oocysts. A second identical trial was conducted, except birds were immunized with 500 Eimeria maxima oocysts and were challenged with 3 X 10(3) E. maxima oocysts. In Experiment 2, 100% of chicks in some pens were immunized with 500 E. acervulina oocysts while in other pens either 75% or 50% of the birds were immunized. On day 14, birds were challenged with 1 X 10(6) oocysts. Trial 2 was identical to Trial 1 except that birds were immunized with 100 E. maxima oocysts and challenged with 1 X 10(6) oocysts. For all experiments weight gain, feed conversion ratio (FCR), plasma carotenoids, and litter oocyst counts were measured. In Experiment 1, the level of protection in groups containing 25% nonimmunized cohorts, as measured by weight gain, carotenoid level, FCR, and oocyst litter counts, was identical to groups containing 100% immunized chicks. In Experiment 2, pens where 50% or 75% of birds were immunized with either E. maxima or E. acervulina were not well protected from decreases in weight gain and plasma carotenoids nor from increases in litter oocyst counts following a challenge infection administered on day 14 relative to NIC. In addition, pens of birds where 100% of chicks were immunized were not well protected compared to NIC, and resistance to coccidiosis infection in immunized chicks was less than resistance in chicks challenged at 21 days. These results in total suggest that, when birds are challenged after 21 days, cohorts are protected from detrimental effects of challenge infection. However, when challenge infection is given at 14 days, cohorts are not well protected. The results support a conclusion that protection to coccidiosis is conveyed to cohorts by contact with oocysts shed into the litter by immunized chicks, but this resistance may take 14 days to develop.

Influenza Virus-Like Particles Containing M2 Induce Broadly Cross Protective Immunity

PubMed Central

Song, Jae-Min; Wang, Bao-Zhong; Park, Kyoung-Mi; Van Rooijen, Nico; Quan, Fu-Shi; Kim, Min-Chul; Jin, Hyun-Tak; Pekosz, Andrew; Compans, Richard W.; Kang, Sang-Moo

2011-01-01

Background Current influenza vaccines based on the hemagglutinin protein are strain specific and do not provide good protection against drifted viruses or emergence of new pandemic strains. An influenza vaccine that can confer cross-protection against antigenically different influenza A strains is highly desirable for improving public health. Methodology/Principal Findings To develop a cross protective vaccine, we generated influenza virus-like particles containing the highly conserved M2 protein in a membrane-anchored form (M2 VLPs), and investigated their immunogenicity and breadth of cross protection. Immunization of mice with M2 VLPs induced anti-M2 antibodies binding to virions of various strains, M2 specific T cell responses, and conferred long-lasting cross protection against heterologous and heterosubtypic influenza viruses. M2 immune sera were found to play an important role in providing cross protection against heterosubtypic virus and an antigenically distinct 2009 pandemic H1N1 virus, and depletion of dendritic and macrophage cells abolished this cross protection, providing new insight into cross-protective immune mechanisms. Conclusions/Significance These results suggest that presenting M2 on VLPs in a membrane-anchored form is a promising approach for developing broadly cross protective influenza vaccines. PMID:21267073

Estimation of the Population Susceptibility Against Measles in Slovakia.

PubMed

Zibolenová, Jana; Chladná, Zuzana; Švihrová, Viera; Baška, Tibor; Waczulíková, Iveta; Hudečková, Henrieta

2017-03-01

In Slovakia, thanks to a highly effective vaccination programme, no domestic cases of measles have been reported since 1999. However, there are several outbreaks of measles currently hitting some countries in Europe. Difficulties in reaching the goal of measles elimination make it necessary to monitor the status of the population susceptibility to prevent similar outbreaks in the future. We hypothesize that immunity wanes overtime, which can substantially impact the population susceptibility. This work introduces a model that estimates a proportion of individuals susceptible to measles in the Slovak population in 2015. Our analysis is based on an age-cohort model that incorporates waning immunity, vaccination schedule and changes in demographic structure. The inputs of the model are data on the vaccination coverage, last seroprevalence survey in 2002 and age structure of the population. In a short-term horizon, waning immunity does not affect the estimated proportion of the susceptible population. However, in a long-term horizon, the antibody titers can fall below the level of protection, which would result in a substantial transfer of initially immune individuals to the compartment of the susceptible ones. Incorporating of waning immunity in the cohort model has indicated that the most susceptible cohorts are not-vaccinated youngest children and cohorts born between 1969 and 1986. Applying the model to the current situation shows that people aged 30-45 years and unvaccinated infants represent the most susceptible groups. Model partially replaces missing seroprevalence survey, but, because the parameters of model and phenomenon of waning immunity are not exactly known, we suggest reintroducing the regular national serosurveys in order to empirically determine the level of susceptibility for measles in Slovakia. Copyright© by the National Institute of Public Health, Prague 2017

Systems integration of innate and adaptive immunity.

PubMed

Zak, Daniel E; Aderem, Alan

2015-09-29

The pathogens causing AIDS, malaria, and tuberculosis have proven too complex to be overcome by classical approaches to vaccination. The complexities of human immunology and pathogen-induced modulation of the immune system mandate new approaches to vaccine discovery and design. A new field, systems vaccinology, weds holistic analysis of innate and adaptive immunity within a quantitative framework to enable rational design of new vaccines that elicit tailored protective immune responses. A key step in the approach is to discover relationships between the earliest innate inflammatory responses to vaccination and the subsequent vaccine-induced adaptive immune responses and efficacy. Analysis of these responses in clinical studies is complicated by the inaccessibility of relevant tissue compartments (such as the lymph node), necessitating reliance upon peripheral blood responses as surrogates. Blood transcriptomes, although indirect to vaccine mechanisms, have proven very informative in systems vaccinology studies. The approach is most powerful when innate and adaptive immune responses are integrated with vaccine efficacy, which is possible for malaria with the advent of a robust human challenge model. This is more difficult for AIDS and tuberculosis, given that human challenge models are lacking and efficacy observed in clinical trials has been low or highly variable. This challenge can be met by appropriate clinical trial design for partially efficacious vaccines and by analysis of natural infection cohorts. Ultimately, systems vaccinology is an iterative approach in which mechanistic hypotheses-derived from analysis of clinical studies-are evaluated in model systems, and then used to guide the development of new vaccine strategies. In this review, we will illustrate the above facets of the systems vaccinology approach with case studies. Copyright © 2015. Published by Elsevier Ltd.

Immunization with LJM11 salivary protein protects against infection with Leishmania braziliensis in the presence of Lutzomyia longipalpis saliva.

PubMed

Cunha, Jurema M; Abbehusen, Melissa; Suarez, Martha; Valenzuela, Jesus; Teixeira, Clarissa R; Brodskyn, Cláudia I

2018-01-01

Leishmania is transmitted in the presence of sand fly saliva. Protective immunity generated by saliva has encouraged identification of a vector salivary-based vaccine. Previous studies have shown that immunization with LJM11, a salivary protein from Lutzomyia longipalpis, is able to induce a Th1 immune response and protect mice against bites of Leishmania major-infected Lutzomyia longipalpis. Here, we further investigate if immunization with LJM11 recombinant protein is able to confer cross-protection against infection with Leishmania braziliensis associated with salivary gland sonicate (SGS) from Lutzomyia intermedia or Lu. longipalpis. Mice immunized with LJM11 protein exhibited an increased production of anti-LJM11 IgG, IgG1 and IgG2a and a DTH response characterized by an inflammatory infiltrate with the presence of CD4 + IFN-γ + T cells. LJM11-immunized mice were intradermally infected in the ear with L. braziliensis in the presence of Lu. longipalpis or Lu. intermedia SGS. A significant reduction of parasite numbers in the ear and lymph node in the group challenged with L. braziliensis plus Lu. longipalpis SGS was observed, but not when the challenge was performed with L. braziliensis plus Lu. intermedia SGS. A higher specific production of IFN-γ and absence of IL-10 by lymph node cells were only observed in LJM11 immunized mice after infection. After two weeks, a similar frequency of CD4 + IFN-γ + T cells was detected in LJM11 and BSA groups challenged with L. braziliensis plus Lu. longipalpis SGS, suggesting that early events possibly triggered by immunization are essential for protection against Leishmania infection. Our findings support the specificity of saliva-mediated immune responses and reinforce the importance of identifying cross-protective salivary antigens. Copyright © 2017 Elsevier B.V. All rights reserved.

Does a monovalent inactivated human rotavirus vaccine induce heterotypic immunity?

PubMed Central

Jiang, Baoming; Wang, Yuhuan; Glass, Roger I.

2013-01-01

There is substantial evidence for broad cross-reactive immunity and heterotypic protection among human rotavirus strains in children with natural infection or with monovalent Rotarix vaccination. In this commentary, we addressed this same topic by testing sera of guinea pigs and gnotobiotic piglets that were intramuscularly immunized with an inactivated human rotavirus vaccine and also demonstrated a broad cross-protective immunity among human rotavirus strains. Our findings from a single human strain in animal studies bode well for a low cost and efficacious inactivated vaccine to protect children against rotavirus disease throughout the world. PMID:23744507

Immobilization antibodies of tiger puffer Takifugu rubripes induced by i.p. injection against monogenean Heterobothrium okamotoi oncomiracidia do not prevent the infection.

PubMed

Umeda, N; Hatanaka, A; Hirazawa, N

2007-06-01

We examined whether infection by the monogenean Heterobothrium okamotoi induces production of specific antibodies against oncomiracidia and their cilia, larvae on the gills, and adults on the branchial cavity wall of tiger puffer Takifugu rubripes. We also investigated whether specific antibody production participates in acquired protection against H. okamotoi. Sera from persistently infected fish immobilized H. okamotoi oncomiracidia 89 days after exposure and antibody levels (measured by enzyme-linked immunosorbent assays) in the sera against oncomiracidia and their cilia increased compared with sera from control (naïve) fish. Antibody levels in these sera against the larvae and adult stages did not increase. The number of H. okamotoi on persistently infected fish was significantly lower than for control fish (P<0.05) when persistently infected fish and control fish were exposed to oncomiracidia in the same tank. Thus tiger puffer produced specific antibodies against oncomiracidia and their cilia, and acquired partial protection against H. okamotoi. Intraperitoneal injection of proteins of sonicated oncomiracidia or their cilia with an adjuvant also produced oncomiracidium agglutination antibodies in sera from tiger puffer; the antibody levels in these sera against oncomiracidia and their cilia increased compared with sera from control fish (injection of BSA with an adjuvant) at 14, 44, and 75 days after the booster immunization. However, in a parasite challenge at 54-58 days after the booster immunization, the infection levels of fish immunized with parasites of sonicated oncomiracidia or their cilia were the same as the control fish. Western blot showed that sera from persistently infected fish and fish immunized with sonicated oncomiracidia or their cilia recognized similar antigenic bands, suggesting that tiger puffer tends to react against these antigens compared with other antigens. These results indicated that specific antibodies against these cilia and oncomiracidia induced by i.p. injection do not prevent H. okamotoi infection.

Immunoprotection of Mice against Schistosomiasis Mansoni Using Solubilized Membrane Antigens

PubMed Central

Sulbarán, Guidenn; Noya, Oscar; Brito, Beatríz; Ballén, Diana E.; Cesari, Italo M.

2013-01-01

Background Schistosomiasis continues to be one of the most prevalent parasitic diseases in the world. Despite the existence of a highly effective antischistosome drug, the disease is spreading into new areas, and national control programs do not arrive to complete their tasks particularly in low endemic areas. The availability of a vaccine could represent an additional component to chemotherapy. Experimental vaccination studies are however necessary to identify parasite molecules that would serve as vaccine candidates. In the present work, C57BL/6 female mice were subcutaneously immunized with an n-butanol extract of the adult worm particulate membranous fraction (AWBE) and its protective effect against a S. mansoni challenge infection was evaluated. Methodology and Findings Water-saturated n-butanol release into the aqueous phase a set of membrane-associated (glyco)proteins that are variably recognized by antibodies in schistosome-infected patients; among the previously identified AWBE antigens there is Alkaline Phosphatase (SmAP) which has been associated with resistance to the infection in mice. As compared to control, a significantly lower number of perfuse parasites was obtained in the immunized/challenged mouse group (P<0.05, t test); and consequently, a lower number of eggs and granulomas (with reduced sizes), overall decreasing pathology. Immunized mice produced high levels of sera anti-AWBE IgG recognizing antigens of ∼190-, 130-, 98-, 47-, 28-23, 14-, and 9-kDa. The ∼130-kDa band (the AP dimer) exhibited in situ SmAP activity after addition of AP substrate and the activity was not apparently inhibited by host antibodies. A preliminary proteomic analysis of the 25-, 27-, and 28-kDa bands in the immunodominant 28–23 kDa region suggested that they are composed of actin. Conclusions Immunization with AWBE induced the production of specific antibodies to various adult worm membrane molecules (including AP) and a partial (43%) protection against a challenging S. mansoni infection by mechanism(s) that still has to be elucidated. PMID:23818994

Nasal and skin delivery of IC31(®)-adjuvanted recombinant HSV-2 gD protein confers protection against genital herpes.

PubMed

Wizel, Benjamin; Persson, Josefine; Thörn, Karolina; Nagy, Eszter; Harandi, Ali M

2012-06-19

Genital herpes caused by herpes simplex virus type 2 (HSV-2) remains the leading cause of genital ulcers worldwide. Given the disappointing results of the recent genital herpes vaccine trials in humans, development of novel vaccine strategies capable of eliciting protective mucosal and systemic immune responses to HSV-2 is urgently required. Here we tested the ability of the adjuvant IC31(®) in combination with HSV-2 glycoprotein D (gD) used through intranasal (i.n.), intradermal (i.d.), or subcutaneous (s.c.) immunization routes for induction of protective immunity against genital herpes infection in C57BL/6 mice. Immunization with gD plus IC31(®) through all three routes of immunization developed elevated gD-specific serum antibody responses with HSV-2 neutralizing activity. Whereas the skin routes promoted the induction of a mixed IgG2c/IgG1 isotype profile, the i.n. route only elicited IgG1 antibodies. All immunization routes were able to induce gD-specific IgG antibody responses in the vaginas of mice immunized with IC31(®)-adjuvanted gD. Although specific lymphoproliferative responses were observed in splenocytes from mice of most groups vaccinated with IC31(®)-adjuvanted gD, only i.d. immunization resulted in a significant splenic IFN-γ response. Further, immunization with gD plus IC31(®) conferred 80-100% protection against an otherwise lethal vaginal HSV-2 challenge with amelioration of viral replication and disease severity in the vagina. These results warrant further exploration of IC31(®) for induction of protective immunity against genital herpes and other sexually transmitted infections. Copyright © 2012 Elsevier Ltd. All rights reserved.

Immune protection duration and efficacy stability of DNA vaccine encoding Eimeria tenella TA4 and chicken IL-2 against coccidiosis.

PubMed

Song, Xiaokai; Zhao, Xiaofang; Xu, Lixin; Yan, Ruofeng; Li, Xiangrui

2017-04-01

In our previous study, an effective DNA vaccine encoding Eimeria tenella TA4 and chicken IL-2 was constructed. In the present study, the immunization dose of the DNA vaccine pVAX1.0-TA4-IL-2 was further optimized. With the optimized dose, the dynamics of antibodies induced by the DNA vaccine was determined using indirect ELISA. To evaluate the immune protection duration of the DNA vaccine, two-week-old chickens were intramuscularly immunized twice and the induced efficacy was evaluated by challenging with E. tenella at 5, 9, 13, 17 and 21weeks post the last immunization (PLI) separately. To evaluate the efficacy stability of the DNA vaccine, two-week-old chickens were immunized with 3 batches of the DNA vaccine, and the induced efficacy was evaluated by challenging with E. tenella. The results showed that the optimal dose was 25μg. The induced antibody level persisted until 10weeks PPI. For the challenge time of 5 and 9weeks PLI, the immunization resulted in ACIs of 182.28 and 162.23 beyond 160, showing effective protection. However, for the challenge time of 13, 17 and 21weeks PLI, the immunization resulted in ACIs below 160 which means poor protection. Therefore, the immune protection duration of the DNA vaccination was at least 9weeks PLI. DNA immunization with three batches DNA vaccine resulted in ACIs of 187.52, 191.57 and 185.22, which demonstrated that efficacies of the three batches DNA vaccine were effective and stable. Overall, our results indicate that DNA vaccine pVAX1.0-TA4-IL-2 has the potential to be developed as effective vaccine against coccidiosis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Induction of protective immunity against toxoplasmosis in mice by immunization with Toxoplasma gondii RNA.

PubMed

Dimier-Poisson, Isabelle; Aline, Fleur; Bout, Daniel; Mévélec, Marie-Noëlle

2006-03-06

Toxoplasma gondii enters the mucosal surfaces of the host, and so immunity at these sites is of major interest. Due to the compartmentalization of the immune response, systemic immunization does not induce high levels of immunity at mucosal surfaces. Intranasal immunization has been shown to be very effective in inducing both systemic and mucosal immune responses. Immunization with mRNA can induce both humoral and cell-mediated immune responses, both of which are important in conferring immunity to T. gondii. The efficacy of RNA vaccination by the nasal route with T. gondii RNA was evaluated. We assessed the percentage of cumulative survival after an oral challenge with a lethal dose of T. gondii cysts (40 cysts), and the number of brain cysts following a challenge with a sublethal dose of T. gondii 76 K cysts (15 cysts). Vaccinated mice were found to be significantly better protected than non-immunized mice after a challenge with a lethal dose of cysts; and a challenge with a sublethal dose also resulted in fewer brain cysts than in non-immunized mice. Sera and intestinal secretions of immunized mice recognized T. gondii antigens, suggesting that a specific humoral immune response may occur. Moreover, a specific lymphoproliferative response observed in cervical lymph nodes may confer protection. These preliminary findings suggest that RNA vaccination by a mucosal route could be feasible.

Governmental Immunity for Public Education: A Shield of Legal Protection.

ERIC Educational Resources Information Center

Aitken, Joan E.

The American tradition of sovereign immunity and the Eleventh Amendment of the United States Constitution have provided certain legal protection to government personnel, including leaders of public elementary, secondary, and post-secondary institutions, but the concept of governmental immunity may be difficult to understand as it applies to…

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.

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

Autovaccination confers protection against Devriesea agamarum associated septicemia but not dermatitis in bearded dragons (Pogona vitticeps).

PubMed

Hellebuyck, Tom; Van Steendam, Katleen; Deforce, Dieter; Blooi, Mark; Van Nieuwerburgh, Filip; Bullaert, Evelien; Ducatelle, Richard; Haesebrouck, Freddy; Pasmans, Frank; Martel, An

2014-01-01

Devrieseasis caused by Devriesea agamarum is a highly prevalent disease in captive desert lizards, resulting in severe dermatitis and in some cases mass mortality. In this study, we assessed the contribution of autovaccination to devrieseasis control by evaluating the capacity of 5 different formalin-inactivated D. agamarum vaccines to induce a humoral immune response in bearded dragons (Pogona vitticeps). Each vaccine contained one of the following adjuvants: CpG, incomplete Freund's, Ribi, aluminium hydroxide, or curdlan. Lizards were administrated one of the vaccines through subcutaneous injection and booster vaccination was given 3 weeks after primo-vaccination. An indirect ELISA was developed and used to monitor lizard serological responses. Localized adverse effects following subcutaneous immunization were observed in all but the Ribi adjuvanted vaccine group. Following homologous experimental challenge, the incomplete Freund's as well as the Ribi vaccine were observed to confer protection in bearded dragons against the development of D. agamarum associated septicemia but not against dermatitis. Subsequently, two-dimensional gelelectrophoresis followed by immunoblotting and mass spectrometry was conducted with serum obtained from 3 lizards that showed seroconversion after immunisation with the Ribi vaccine. Fructose-bisphosphate aldolase and aldo-keto reductase of D. agamarum reacted with serum from the latter lizards. Based on the demonstrated seroconversion and partial protection against D. agamarum associated disease following the use of formalin-inactivated vaccines as well as the identification of target antigens in Ribi vaccinated bearded dragons, this study provides promising information towards the development of a vaccination strategy to control devrieseasis in captive lizard collections.

Autovaccination Confers Protection against Devriesea agamarum Associated Septicemia but Not Dermatitis in Bearded Dragons (Pogona vitticeps)

PubMed Central

Deforce, Dieter; Blooi, Mark; Van Nieuwerburgh, Filip; Bullaert, Evelien; Ducatelle, Richard; Haesebrouck, Freddy

2014-01-01

Devrieseasis caused by Devriesea agamarum is a highly prevalent disease in captive desert lizards, resulting in severe dermatitis and in some cases mass mortality. In this study, we assessed the contribution of autovaccination to devrieseasis control by evaluating the capacity of 5 different formalin-inactivated D. agamarum vaccines to induce a humoral immune response in bearded dragons (Pogona vitticeps). Each vaccine contained one of the following adjuvants: CpG, incomplete Freund's, Ribi, aluminium hydroxide, or curdlan. Lizards were administrated one of the vaccines through subcutaneous injection and booster vaccination was given 3 weeks after primo-vaccination. An indirect ELISA was developed and used to monitor lizard serological responses. Localized adverse effects following subcutaneous immunization were observed in all but the Ribi adjuvanted vaccine group. Following homologous experimental challenge, the incomplete Freund's as well as the Ribi vaccine were observed to confer protection in bearded dragons against the development of D. agamarum associated septicemia but not against dermatitis. Subsequently, two-dimensional gelelectrophoresis followed by immunoblotting and mass spectrometry was conducted with serum obtained from 3 lizards that showed seroconversion after immunisation with the Ribi vaccine. Fructose-bisphosphate aldolase and aldo-keto reductase of D. agamarum reacted with serum from the latter lizards. Based on the demonstrated seroconversion and partial protection against D. agamarum associated disease following the use of formalin-inactivated vaccines as well as the identification of target antigens in Ribi vaccinated bearded dragons, this study provides promising information towards the development of a vaccination strategy to control devrieseasis in captive lizard collections. PMID:25479609

Surfactant Protein D Facilitates Cryptococcus neoformans Infection

PubMed Central

Geunes-Boyer, Scarlett; Beers, Michael F.; Heitman, Joseph; Wright, Jo Rae

2012-01-01

Concurrent with the global escalation of the AIDS pandemic, cryptococcal infections are increasing and are of significant medical importance. Furthermore, Cryptococcus neoformans has become a primary human pathogen, causing infection in seemingly healthy individuals. Although numerous studies have elucidated the virulence properties of C. neoformans, less is understood regarding lung host immune factors during early stages of fungal infection. Based on our previous studies documenting that pulmonary surfactant protein D (SP-D) protects C. neoformans cells against macrophage-mediated defense mechanisms in vitro (S. Geunes-Boyer et al., Infect. Immun. 77:2783–2794, 2009), we postulated that SP-D would facilitate fungal infection in vivo. To test this hypothesis, we examined the role of SP-D in response to C. neoformans using SP-D−/− mice. Here, we demonstrate that mice lacking SP-D were partially protected during C. neoformans infection; they displayed a longer mean time to death and decreased fungal burden at several time points postinfection than wild-type mice. This effect was reversed by the administration of exogenous SP-D. Furthermore, we show that SP-D bound to the surface of the yeast cells and protected the pathogenic microbes against macrophage-mediated defense mechanisms and hydrogen peroxide (H2O2)-induced oxidative stress in vitro and in vivo. These findings indicate that C. neoformans is capable of coopting host SP-D to increase host susceptibility to the yeast. This study establishes a new paradigm for the role played by SP-D during host responses to C. neoformans and consequently imparts insight into potential future preventive and/or treatment strategies for cryptococcosis. PMID:22547543

Effectiveness of rotavirus pentavalent vaccine under a universal immunization programme in Israel, 2011-2015: a case-control study.

PubMed

Muhsen, K; Anis, E; Rubinstein, U; Kassem, E; Goren, S; Shulman, L M; Ephros, M; Cohen, D

2018-01-01

The use of rotavirus pentavalent vaccine (RotaTeq ® ) as a sole vaccine within rotavirus universal immunization programmes remains limited. We examined the effectiveness of RotaTeq in preventing rotavirus gastroenteritis (RVGE) hospitalization in Israel, after the introduction of universal immunization against the disease. A test-negative case-control study included age-eligible children for universal RotaTeq immunization (aged 2-59 months, born in 2011-2015). Cases (n = 98) were patients who tested positive for rotavirus by immunochromatography; those who tested negative (n = 628) comprised the control group. Information on rotavirus immunization history was obtained through linkage with a national immunization registry. Vaccination status was compared between cases and controls, adjusted odds ratios (aORs) were obtained from logistic regression models, and vaccine effectiveness calculated as (1 - aOR)*100. Immunization with RotaTeq was less frequent in RVGE cases (73.5%) than in controls (90.1%), p < 0.001; this association persisted after controlling for potential confounders. Effectiveness of the complete vaccine series was estimated at 77% (95% confidence interval (CI): 49-90) in children aged 6-59 months, and 86% (95% CI: 65-94) in children aged 6-23 months; whereas for the incomplete series, the respective estimates were 72% (95% CI: 28-89) and 75% (95% CI: 30-91). Vaccine effectiveness was estimated at 79% (95% CI: 45-92) against G1P[8]-associated RVGE hospitalizations and 69% (95% CI: 11-89) against other genotype-RVGE hospitalizations. High effectiveness of RotaTeq as the sole rotavirus vaccine in a universal immunization programme was demonstrated in a high-income country. Although partial vaccination conferred protection, completing the vaccine series is warranted to maximize the benefit. Copyright © 2017 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

T Cell-Mediated Immunity towards Yellow Fever Virus and Useful Animal Models

PubMed Central

Watson, Alan M.; Klimstra, William B.

2017-01-01

The 17D line of yellow fever virus vaccines is among the most effective vaccines ever created. The humoral and cellular immunity elicited by 17D has been well characterized in humans. Neutralizing antibodies have long been known to provide protection against challenge with a wild-type virus. However, a well characterized T cell immune response that is robust, long-lived and polyfunctional is also elicited by 17D. It remains unclear whether this arm of immunity is protective following challenge with a wild-type virus. Here we introduce the 17D line of yellow fever virus vaccines, describe the current state of knowledge regarding the immunity directed towards the vaccines in humans and conclude with a discussion of animal models that are useful for evaluating T cell-mediated immune protection to yellow fever virus. PMID:28398253

T Cell-Mediated Immunity towards Yellow Fever Virus and Useful Animal Models.

PubMed

Watson, Alan M; Klimstra, William B

2017-04-11

The 17D line of yellow fever virus vaccines is among the most effective vaccines ever created. The humoral and cellular immunity elicited by 17D has been well characterized in humans. Neutralizing antibodies have long been known to provide protection against challenge with a wild-type virus. However, a well characterized T cell immune response that is robust, long-lived and polyfunctional is also elicited by 17D. It remains unclear whether this arm of immunity is protective following challenge with a wild-type virus. Here we introduce the 17D line of yellow fever virus vaccines, describe the current state of knowledge regarding the immunity directed towards the vaccines in humans and conclude with a discussion of animal models that are useful for evaluating T cell-mediated immune protection to yellow fever virus.

Cellular and Humoral Immunity Protect against Vaginal Zika Virus Infection in Mice.

PubMed

Scott, Jason M; Lebratti, Tania J; Richner, Justin M; Jiang, Xiaoping; Fernandez, Estefania; Zhao, Haiyan; Fremont, Daved H; Diamond, Michael S; Shin, Haina

2018-01-17

Zika virus (ZIKV), which can cause devastating disease in fetuses of infected pregnant women, can be transmitted by mosquito inoculation and sexual routes. Little is known about immune protection against sexually transmitted ZIKV. In this study, we show that previous infection through intravaginal or subcutaneous routes with a contemporary Brazilian strain of ZIKV can protect against subsequent intravaginal challenge with a homologous strain. Both routes of inoculation induced high titers of ZIKV-specific and neutralizing antibody in serum and the vaginal lumen. Virus-specific T cells were recruited to and retained in the female reproductive tract after intravaginal and subcutaneous ZIKV infection. Studies in mice with genetic or acquired deficiencies in B and/or T cells demonstrated that both lymphocyte populations redundantly protect against intravaginal challenge in ZIKV-immune animals. Passive transfer of ZIKV immune IgG or T cells significantly limited intravaginal infection of naïve mice, although antibody more effectively prevented dissemination throughout the reproductive tract. Collectively, our experiments begin to establish the immune correlates of protection against intravaginal ZIKV infection, which should inform vaccination strategies in non-pregnant and pregnant women. IMPORTANCE The recent ZIKV epidemic resulted in devastating outcomes in fetuses and may affect reproductive health. Unlike other flaviviruses, ZIKV can be spread by sexual contact as well as a mosquito vector. While previous studies have identified correlates of protection for mosquito-mediated infection, few have focused on immunity against sexual transmission. As exposure to ZIKV via mosquito bite has likely occurred to many living in endemic areas, our study addresses whether this route of infection can protect against subsequent sexual exposure. We demonstrate that subcutaneous ZIKV infection can protect against subsequent vaginal infection by generating both local antiviral T cell and antibody responses. Our research begins to define the immune correlates of protection for ZIKV infection in the vagina and provides a foundation for testing ZIKV vaccines against sexual transmission. Copyright © 2018 American Society for Microbiology.

Differing rates of antibody acquisition to merozoite antigens in malaria: implications for immunity and surveillance.

PubMed

McCallum, Fiona J; Persson, Kristina E M; Fowkes, Freya J I; Reiling, Linda; Mugyenyi, Cleopatra K; Richards, Jack S; Simpson, Julie A; Williams, Thomas N; Gilson, Paul R; Hodder, Anthony N; Sanders, Paul R; Anders, Robin F; Narum, David L; Chitnis, Chetan; Crabb, Brendan S; Marsh, Kevin; Beeson, James G

2017-04-01

Antibodies play a key role in acquired human immunity to Plasmodium falciparum (Pf) malaria and target merozoites to reduce or prevent blood-stage replication and the development of disease. Merozoites present a complex array of antigens to the immune system, and currently, there is only a partial understanding of the targets of protective antibodies and how responses to different antigens are acquired and boosted. We hypothesized that there would be differences in the rate of acquisition of antibodies to different antigens and how well they are boosted by infection, which impacts the acquisition of immunity. We examined responses to a range of merozoite antigens in 2 different cohorts of children and adults with different age structures and levels of malaria exposure. Overall, antibodies were associated with age, exposure, and active infection, and the repertoire of responses increased with age and active infection. However, rates of antibody acquisition varied between antigens and different regions within an antigen following exposure to malaria, supporting our hypothesis. Antigen-specific responses could be broadly classified into early response types in which antibodies were acquired early in childhood exposure and late response types that appear to require substantially more exposure for the development of substantial levels. We identified antigen-specific responses that were effectively boosted after recent infection, whereas other responses were not. These findings advance our understanding of the acquisition of human immunity to malaria and are relevant to the development of malaria vaccines targeting merozoite antigens and the selection of antigens for use in malaria surveillance. © Society for Leukocyte Biology.

A Sequential Phase 2b Trial Design for Evaluating Vaccine Efficacy and Immune Correlates for Multiple HIV Vaccine Regimens

PubMed Central

Gilbert, Peter B.; Grove, Douglas; Gabriel, Erin; Huang, Ying; Gray, Glenda; Hammer, Scott M.; Buchbinder, Susan P.; Kublin, James; Corey, Lawrence; Self, Steven G.

2012-01-01

Five preventative HIV vaccine efficacy trials have been conducted over the last 12 years, all of which evaluated vaccine efficacy (VE) to prevent HIV infection for a single vaccine regimen versus placebo. Now that one of these trials has supported partial VE of a prime-boost vaccine regimen, there is interest in conducting efficacy trials that simultaneously evaluate multiple prime-boost vaccine regimens against a shared placebo group in the same geographic region, for accelerating the pace of vaccine development. This article proposes such a design, which has main objectives (1) to evaluate VE of each regimen versus placebo against HIV exposures occurring near the time of the immunizations; (2) to evaluate durability of VE for each vaccine regimen showing reliable evidence for positive VE; (3) to expeditiously evaluate the immune correlates of protection if any vaccine regimen shows reliable evidence for positive VE; and (4) to compare VE among the vaccine regimens. The design uses sequential monitoring for the events of vaccine harm, non-efficacy, and high efficacy, selected to weed out poor vaccines as rapidly as possible while guarding against prematurely weeding out a vaccine that does not confer efficacy until most of the immunizations are received. The evaluation of the design shows that testing multiple vaccine regimens is important for providing a well-powered assessment of the correlation of vaccine-induced immune responses with HIV infection, and is critically important for providing a reasonably powered assessment of the value of identified correlates as surrogate endpoints for HIV infection. PMID:23181167

Current topics in HIV pathogenesis, part 2: Inflammation drives a Warburg-like effect on the metabolism of HIV-infected subjects.

PubMed

Aounallah, Mouna; Dagenais-Lussier, Xavier; El-Far, Mohamed; Mehraj, Vikram; Jenabian, Mohammad-Ali; Routy, Jean-Pierre; van Grevenynghe, Julien

2016-04-01

HIV-1 infection leads to a depletion of CD4 T-cells associated with a persistent immune inflammation and changes in cellular metabolism. Most effort of managing HIV infection with combination of antiretroviral therapies (ART) has been focused on CD4 T-cell recovery, while control of persistent immune inflammation and metabolism were relatively underappreciated in the past. Recent discoveries on the interplay between innate immunity, inflammation (especially the inflammasome) and metabolic changes in the context of cancer and autoimmunity provide an emerging field for chronic viral infections including HIV-1. In a previous review, we described the deregulated metabolism contributing to immune dysfunctions such as alteration of memory T-cell responses, mucosal protection, and dendritic cell-related antigen presentation. Here, we summarize the latest knowledge on the detrimental influence of long-lasting inflammation and inflammasome activation induced by HIV-1, gut dysbiosis, and bacterial translocation, on metabolism during the course of viral infection. We also report on the inability of ART to fully counteract inflammation, resulting in partial metabolic improvement and leading to an insufficient decrease in the risk of non-AIDS events. Further advances in our understanding of the relationship between inflammation, altered metabolism, and long-term ART is warranted. Additionally, there is a critical need for developing new strategies to regulate the pro-inflammatory signals to enhance cellular metabolism and immune functions in order to improve the quality of life of individuals living with HIV-1. Crown Copyright © 2016. Published by Elsevier Ltd. All rights reserved.

Murine Polyomavirus Virus-Like Particles Carrying Full-Length Human PSA Protect BALB/c Mice from Outgrowth of a PSA Expressing Tumor

PubMed Central

Eriksson, Mathilda; Andreasson, Kalle; Weidmann, Joachim; Lundberg, Kajsa; Tegerstedt, Karin

2011-01-01

Virus-like particles (VLPs) consist of capsid proteins from viruses and have been shown to be usable as carriers of protein and peptide antigens for immune therapy. In this study, we have produced and assayed murine polyomavirus (MPyV) VLPs carrying the entire human Prostate Specific Antigen (PSA) (PSA-MPyVLPs) for their potential use for immune therapy in a mouse model system. BALB/c mice immunized with PSA-MPyVLPs were only marginally protected against outgrowth of a PSA-expressing tumor. To improve protection, PSA-MPyVLPs were co-injected with adjuvant CpG, either alone or loaded onto murine dendritic cells (DCs). Immunization with PSA-MPyVLPs loaded onto DCs in the presence of CpG was shown to efficiently protect mice from tumor outgrowth. In addition, cellular and humoral immune responses after immunization were examined. PSA-specific CD4+ and CD8+ cells were demonstrated, but no PSA-specific IgG antibodies. Vaccination with DCs loaded with PSA-MPyVLPs induced an eight-fold lower titre of anti-VLP antibodies than vaccination with PSA-MPyVLPs alone. In conclusion, immunization of BALB/c mice with PSA-MPyVLPs, loaded onto DCs and co-injected with CpG, induces an efficient PSA-specific tumor protective immune response, including both CD4+ and CD8+ cells with a low induction of anti-VLP antibodies. PMID:21858228

[IMMUNE SYSTEM INTERNSHIP WITH SYMBIOTIC MICROORGANISMS IN GNOTOBIOTIC ANIMAL'S INTESTINUM ILEUM].

PubMed

Kochlamasashvili, B; Gogiashvili, L; Jandieri, K

2017-11-01

Structures, responsible for acceptive (comensaling relation) and protective (pathogenic defense) immunity, were studied and compared in small intestine - to ileum mucosa. Data shown, that main application of the both domains of immune system is to support the correlation between body and foreign microbes, but they response is different. Most significant differences are as follows: in acceptive reactions presented only in aseptic animals - gnotobionts, inflammatory changes absent, so immune reaction complex develops into physiological condition. Symbiotic reactions release in mucosa epithelial cells, also in cells, responsible for adaptive and congenital immune reactivity. Thus, acceptive immune reactions contribute symbiotic biocenosis versus elimination; which is function of protective immunity.

Controversies in chicken-pox immunization.

PubMed

Bhave, Swati Y

2003-06-01

Chicken-pox is one more newer vaccine in our armamentarium against infectious diseases. Due to its extremely contagious nature, varicella is experienced by almost every child or young adult in the world. Each year from 1990 to 1994, prior to availability of varicella vaccine, about 4 million cases of varicella occurred in the United States. Of these cases approximately 10,000 required hospitalization and 100 died. Although varicella is not commonly perceived as an important public health problem, the socioeconomic consequences in industrialized countries of a disease that affects practically every child and causes the carrier absence from work should not be underestimated. The varicella vaccines available in the market are safe and effective. A recent cost-benefit analysis in USA showed that routine chicken-pox vaccination is likely to save five times the investment. Even when only direct costs were considered, benefits almost balanced the costs. At present similar studies from developing countries are not available. The public health impact of varicella and zoster may be increasing in regions with high endemic rates of HIV infection. Varicella vaccine may be used either at an individual level to protect susceptible adolescents and adults, or at a population level, to cover all children as part of a national immunization programme. Vaccination of adolescents and adults will protect at-risk individuals, but will not have a significant impact on the epidemiology of the disease on a population basis. On the other hand, extensive use as a routine vaccine in children will have a significant impact on the epidemiology of the disease. If sustained high coverage can be achieved, the disease may virtually disappear. If only partial coverage can be obtained, the epidemiology may shift, leading to an increase in the number of cases in older children and adults. Hence, routine childhood varicella immunization programmes should emphasize high, sustained coverage. At present, this vaccine will have a lower priority in the National Immunization Schedule that does not have MMR and typhoid, which have a greater socioeconomic impact. Hence, at the present time WHO does not recommend the inclusion of varicella vaccination into the routine immunization programmes of developing countries.

Active immunizations with peptide-DC vaccines and passive transfer with antibodies protect neutropenic mice against disseminated candidiasis.

PubMed

Xin, Hong

2016-01-04

We previously report that peptide-pulsed dendritic cell (DC) vaccination, which targeting two peptides (Fba and Met6) expressed on the cell surface of Candida albicans, can induce high degree of protection against disseminated candidiasis in immunocompetent mice. Passive transfer of immune sera from the peptide immunized mice or peptide-related monoclonal antibodies demonstrated that protection was medicated by peptide-specific antibodies. In this study the efficacy of active and passive immunization against disseminated candidiasis was tested in mice with cyclophosphamide-induced neutropenia. Peptide-DC vaccines were given to mice prior to induction of neutropenia. We show active immunization with either Fba or Met6 peptide-DC vaccine significantly improved the survival and reduced the fungal burden of disseminated candidiasis in those immunocompromised mice. Importantly, we show that administration of two protective monoclonal antibodies also protect neutropenic mice against the disease, implying possibility of developing a successful passive immunotherapy strategy to treat the disease and protect against disseminated candidiasis. The results of this study are crucial as they address the fundamental questions as to whether the synthetic peptide vaccine induced immunity protects the host during a neutropenic episode. We anticipate that this peptide-vaccine study will serve as the foundation of future investigations into new peptide vaccines comprised of cell surface peptides from other medically important Candida species, as well as other fungi. Copyright © 2015 Elsevier Ltd. All rights reserved.

CXCR6 is a marker for protective antigen-specific cells in the lungs after intranasal immunization against Mycobacterium tuberculosis.

PubMed

Lee, Lian Ni; Ronan, Edward O; de Lara, Catherine; Franken, Kees L M C; Ottenhoff, Tom H M; Tchilian, Elma Z; Beverley, Peter C L

2011-08-01

Convincing correlates of protective immunity against tuberculosis have been elusive. In BALB/c mice, intranasal immunization with a replication-deficient recombinant adenovirus expressing Mycobacterium tuberculosis antigen 85A (adenovirus-85A) induces protective lower respiratory tract immunity against pulmonary challenge with Mycobacterium tuberculosis, while intradermal immunization with adenovirus-85A does not. Here we report that intranasal immunization with adenovirus-85A induces expression of the chemokine receptor CXCR6 on lung CD8 T lymphocytes, which is maintained for at least 3 months. CXCR6-positive antigen-specific T cell numbers are increased among bronchoalveolar lavage-recoverable cells. Similarly, intranasal immunization with recombinant antigen 85A with adjuvant induces CXCR6 expression on lung CD4 cells in BALB/c and C57BL/6 mice, while a synthetic ESAT6(1-20) peptide with adjuvant induces CXCR6 expression in C57BL/6 mice. Parenteral immunization fails to do so. Upregulation of CXCR6 is accompanied by a transient elevation of serum CXCL16 after intranasal immunization, and lung cells cultured ex vivo from mice immunized intranasally show increased production of CXCL16. Administration of CXCL16 and cognate antigen intranasally to mice previously immunized parenterally increases the number of antigen-specific T lymphocytes in the bronchoalveolar lavage-recoverable population, which mediates inhibition of the early growth of Mycobacterium tuberculosis after challenge. We conclude that expression of CXCR6 on lung T lymphocytes is a correlate of local protective immunity against Mycobacterium tuberculosis after intranasal immunization and that CXCR6 and CXCL16 play an important role in the localization of T cells within lung tissue and the bronchoalveolar lavage-recoverable compartment.

CXCR6 Is a Marker for Protective Antigen-Specific Cells in the Lungs after Intranasal Immunization against Mycobacterium tuberculosis▿

PubMed Central

Lee, Lian Ni; Ronan, Edward O.; de Lara, Catherine; Franken, Kees L. M. C.; Ottenhoff, Tom H. M.; Tchilian, Elma Z.; Beverley, Peter C. L.

2011-01-01

Convincing correlates of protective immunity against tuberculosis have been elusive. In BALB/c mice, intranasal immunization with a replication-deficient recombinant adenovirus expressing Mycobacterium tuberculosis antigen 85A (adenovirus-85A) induces protective lower respiratory tract immunity against pulmonary challenge with Mycobacterium tuberculosis, while intradermal immunization with adenovirus-85A does not. Here we report that intranasal immunization with adenovirus-85A induces expression of the chemokine receptor CXCR6 on lung CD8 T lymphocytes, which is maintained for at least 3 months. CXCR6-positive antigen-specific T cell numbers are increased among bronchoalveolar lavage-recoverable cells. Similarly, intranasal immunization with recombinant antigen 85A with adjuvant induces CXCR6 expression on lung CD4 cells in BALB/c and C57BL/6 mice, while a synthetic ESAT61–20 peptide with adjuvant induces CXCR6 expression in C57BL/6 mice. Parenteral immunization fails to do so. Upregulation of CXCR6 is accompanied by a transient elevation of serum CXCL16 after intranasal immunization, and lung cells cultured ex vivo from mice immunized intranasally show increased production of CXCL16. Administration of CXCL16 and cognate antigen intranasally to mice previously immunized parenterally increases the number of antigen-specific T lymphocytes in the bronchoalveolar lavage-recoverable population, which mediates inhibition of the early growth of Mycobacterium tuberculosis after challenge. We conclude that expression of CXCR6 on lung T lymphocytes is a correlate of local protective immunity against Mycobacterium tuberculosis after intranasal immunization and that CXCR6 and CXCL16 play an important role in the localization of T cells within lung tissue and the bronchoalveolar lavage-recoverable compartment. PMID:21628524

Mucosal immunization: a review of strategies and challenges.

PubMed

Patel, Hinal; Yewale, Chetan; Rathi, Mohan N; Misra, Ambikanandan

2014-01-01

The vast majority of pathogens enter the human body via the mucosal surfaces of the gastrointestinal, respiratory, and urogenital tracts, where they initiate mucosal infections that lead to systemic infections. Despite strong evidence that a good mucosal immune response can effectively prevent systemic infection too, only a few mucosal vaccines are available due to their low efficiency. Most current immunization techniques involve systemic injection, but they are ineffective to induce immunization at a mucosal site. It is a great challenge to target a mucosal compartment that can induce protective immunity at mucosal sites as well as systemic sites. A better understanding of cellular and molecular factors involved in the regulation of mucosal immunity will aid in the design of safer mucosal vaccines that elicit the desired protective immunity against infectious diseases such as HIV. The development of mucosal vaccines, whether for prevention of infectious diseases or for immunotherapy, requires antigen delivery and adjuvant systems that can effectively present vaccine or immunotherapeutic antigens to the mucosal sites. In this review, we examine the mechanism of mucosal protection, induction of mucosal immune response, types of vaccines, current status of marketed vaccines, and novel strategies for protection against infections and for treatment of inflammatory disorders. Additionally, we offer perspectives on future challenges and research directions.

Biochemical and immunological mechanisms by which sickle cell trait protects against malaria.

PubMed

Gong, Lauren; Parikh, Sunil; Rosenthal, Philip J; Greenhouse, Bryan

2013-09-11

Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria.

Biochemical and immunological mechanisms by which sickle cell trait protects against malaria

PubMed Central

2013-01-01

Sickle cell trait (HbAS) is the best-characterized genetic polymorphism known to protect against falciparum malaria. Although the protective effect of HbAS against malaria is well known, the mechanism(s) of protection remain unclear. A number of biochemical and immune-mediated mechanisms have been proposed, and it is likely that multiple complex mechanisms are responsible for the observed protection. Increased evidence for an immune component of protection as well as novel mechanisms, such as enhanced tolerance to disease mediated by HO-1 and reduced parasitic growth due to translocation of host micro-RNA into the parasite, have recently been described. A better understanding of relevant mechanisms will provide valuable insight into the host-parasite relationship, including the role of the host immune system in protection against malaria. PMID:24025776

Mycobacterium smegmatis proteoliposome induce protection in a murine progressive pulmonary tuberculosis model.

PubMed

Tirado, Yanely; Puig, Alina; Alvarez, Nadine; Borrero, Reinier; Aguilar, Alicia; Camacho, Frank; Reyes, Fatima; Fernandez, Sonsire; Perez, Jose Luis; Acevedo, Reynaldo; Mata Espinoza, Dulce; Payan, Jorge Alberto Barrios; Garcia, Maria de Los A; Kadir, Ramlah; Sarmiento, María E; Hernandez-Pando, Rogelio; Norazmi, Mohd-Nor; Acosta, Armando

2016-12-01

Tuberculosis (TB) remains an important cause of mortality and morbidity. The TB vaccine, BCG, is not fully protective against the adult form of the disease and is unable to prevent its transmission although it is still useful against severe childhood TB. Hence, the search for new vaccines is of great interest. In a previous study, we have shown that proteoliposomes obtained from Mycobacterium smegmatis (PLMs) induced cross reactive humoral and cellular response against Mycobacterium tuberculosis (Mtb) antigens. With the objective to evaluate the protective capability of PLMs, a murine model of progressive pulmonary TB was used. Animals immunized with PLMs with and without alum (PLMs/PLMsAL respectively) showed protection compared to non-immunized animals. Mice immunized with PLMsAL induced similar protection as that of BCG. Animals immunized with BCG, PLMs and PLMsAL showed a significant decrease in tissue damage (percentage of pneumonic area/lung) compared to non-immunized animals, with a more prominent effect in BCG vaccinated mice. The protective effect of the administration of PLMs in mice supports its future evaluation as experimental vaccine candidate against Mtb. Copyright © 2016 Elsevier Ltd. All rights reserved.

Identification of immune signatures predictive of clinical protection from malaria

PubMed Central

2017-01-01

Antibodies are thought to play an essential role in naturally acquired immunity to malaria. Prospective cohort studies have frequently shown how continuous exposure to the malaria parasite Plasmodium falciparum cause an accumulation of specific responses against various antigens that correlate with a decreased risk of clinical malaria episodes. However, small effect sizes and the often polymorphic nature of immunogenic parasite proteins make the robust identification of the true targets of protective immunity ambiguous. Furthermore, the degree of individual-level protection conferred by elevated responses to these antigens has not yet been explored. Here we applied a machine learning approach to identify immune signatures predictive of individual-level protection against clinical disease. We find that commonly assumed immune correlates are poor predictors of clinical protection in children. On the other hand, antibody profiles predictive of an individual’s malaria protective status can be found in data comprising responses to a large set of diverse parasite proteins. We show that this pattern emerges only after years of continuous exposure to the malaria parasite, whereas susceptibility to clinical episodes in young hosts (< 10 years) cannot be ascertained by measured antibody responses alone. PMID:29065113

Co-administration of plasmid expressing IL-12 with 14-kDa Schistosoma mansoni fatty acid-binding protein cDNA alters immune response profiles and fails to enhance protection induced by Sm14 DNA vaccine alone.

PubMed

Fonseca, Cristina T; Pacífico, Lucila G G; Barsante, Michele M; Rassi, Tatiana; Cassali, Geovanni D; Oliveira, Sérgio C

2006-08-01

Schistosomiasis is an endemic disease that affects 200 million people worldwide. DNA-based vaccine is a promising strategy to induce protective immunity against schistosomiasis, since both humoral and cellular immune responses are involved in parasite elimination. In this study, we evaluated the ability of Sm14 cDNA alone or in association with a plasmid expressing murine interleukin (IL)-12 to induce protection against challenge infection. Mice were immunized with four doses of the DNA vaccine and the levels of protection were determined by worm burden recovery after challenge infection. Specific antibody production to rSm14 was determined by ELISA, and cytokine production was measured in splenocyte culture supernatants stimulated with rSm14 and in bronchoalveolar lavage of vaccinated mice after challenge infection. DNA immunization with pCI/Sm14 alone induced 40.5% of worm reduction. However, the use of pCI/IL-12 as adjuvant to pCI/Sm14 immunization failed to enhance protection against challenge infection. Protection induced by pCI/Sm14 immunization correlates with specific IgG antibody production against Sm14, Th1 type of immune response with high levels of interferon (IFN)-gamma and low levels of IL-4 in splenocyte culture supernatants and in bronchoalveolar lavage after challenge infection. IL-12 co-administration with pCI/Sm14 induced a significant production of nitric oxide in splenocyte culture supernatants and also lymphocyte suppression, with reduced percentage of T cells producing IFN-gamma and tumor necrosis factor-alpha.

Medical Versus Nonmedical Immunization Exemptions for Child Care and School Attendance.

PubMed

2016-09-01

Routine childhood immunizations against infectious diseases are an integral part of our public health infrastructure. They provide direct protection to the immunized individual and indirect protection to children and adults unable to be immunized via the effect of community immunity. All 50 states, the District of Columbia, and Puerto Rico have regulations requiring proof of immunization for child care and school attendance as a public health strategy to protect children in these settings and to secondarily serve as a mechanism to promote timely immunization of children by their caregivers. Although all states and the District of Columbia have mechanisms to exempt school attendees from specific immunization requirements for medical reasons, the majority also have a heterogeneous collection of regulations and laws that allow nonmedical exemptions from childhood immunizations otherwise required for child care and school attendance. The American Academy of Pediatrics (AAP) supports regulations and laws requiring certification of immunization to attend child care and school as a sound means of providing a safe environment for attendees and employees of these settings. The AAP also supports medically indicated exemptions to specific immunizations as determined for each individual child. The AAP views nonmedical exemptions to school-required immunizations as inappropriate for individual, public health, and ethical reasons and advocates for their elimination. Copyright © 2016 by the American Academy of Pediatrics.

Endothelial cells in the eyes of an immunologist.

PubMed

Young, M Rita

2012-10-01

Endothelial cell activation in the process of tumor angiogenesis and in various aspects of vascular biology has been extensively studied. However, endothelial cells also function in other capacities, including in immune regulation. Compared to the more traditional immune regulatory populations (Th1, Th2, Treg, etc.), endothelial cells have received far less credit as being immune regulators. Their regulatory capacity is multifaceted. They are critical in both limiting and facilitating the trafficking of various immune cell populations, including T cells and dendritic cells, out of the vasculature and into tissue. They also can be induced to stimulate immune reactivity or to be immune inhibitory. In each of these parameters (trafficking, immune stimulation and immune inhibition), their role can be physiological, whereby they have an active role in maintaining health. Alternatively, their role can be pathological, whereby they contribute to disease. In theory, endothelial cells are in an ideal location to recruit cells that can mediate immune reactivity to tumor tissue. Furthermore, they can activate the immune cells as they transmigrate across the endothelium into the tumor. However, what is seen is the absence of these protective effects of endothelial cells and, instead, the endothelial cells succumb to the defense mechanisms of the tumor, resulting in their acquisition of a tumor-protective role. To understand the immune regulatory potential of endothelial cells in protecting the host versus the tumor, it is useful to better understand the other circumstances in which endothelial cells modulate immune reactivities. Which of the multitude of immune regulatory roles that endothelial cells can take on seems to rely on the type of stimulus that they are encountering. It also depends on the extent to which they can be manipulated by potential dangers to succumb and contribute toward attack on the host. This review will explore the physiological and pathological roles of endothelial cells as they regulate immune trafficking, immune stimulation and immune inhibition in a variety of conditions and will then apply this information to their role in the tumor environment. Strategies to harness the immune regulatory potential of endothelial cells are starting to emerge in the non-tumor setting. Results from such efforts are expected to be applicable to being able to skew endothelial cells from having a tumor-protective role to a host-protective role.

Clostridium perfringens beta toxin DNA prime-protein boost elicits enhanced protective immune response in mice.

PubMed

Solanki, Amit Kumar; Bhatia, Bharati; Kaushik, Himani; Deshmukh, Sachin K; Dixit, Aparna; Garg, Lalit C

2017-07-01

Clostridium perfringens beta toxin (CPB) is the primary pathogenic factor responsible for necrotic enteritis in sheep, cattle and humans. Owing to rapid progression of the disease, vaccination is the only possible recourse to avoid high mortality in animal farms and huge economic losses. The present study reports evaluation of a cpb gene-based DNA vaccine encoding the beta toxin of C. perfringens with homologous as well as heterologous booster strategy. Immunization strategy employing heterologous booster with heat-inactivated rCPB mounted stronger immune response when compared to that generated by homologous booster. Antibody isotyping and cytokine ELISA demonstrated the immune response to be Th1-biased mixed immune response. While moderate protection of immunized BALB/c and C57BL/6 mice against rCPB challenge was observed with homologous booster strategy, heterologous booster strategy led to complete protection. Thus, beta toxin-based DNA vaccine using the heterologous prime-boosting strategy was able to generate better immune response and conferred greater degree of protection against high of dose rCPB challenge than homologous booster regimen, making it an effective vaccination approach against C. perfringens beta toxin.

Host Immune Response to Histophilus somni.

PubMed

Corbeil, Lynette B

2016-01-01

Histophilus somni is known to cause several overlapping syndromes or to be found in genital or upper respiratory carrier states in ruminants. Vaccines have been used for decades, yet efficacy is controversial and mechanisms of protective immunity are not well understood. Since H. somni survives phagocytosis, it has sometimes been considered to be a facultative intercellular parasite, implying that cell-mediated immunity would be critical in protection. However, H. somni not only inhibits phagocyte function, but also is cytotoxic for macrophages. Therefore, it does not live for long periods in healthy phagocytes. Protection of calves against H. somni pneumonia by passive immunization is also evidence that H. somni is more like an extracellular pathogen than an intracellular pathogen. Several studies showed that bovine IgG2 antibodies are more protective than IgG1 antibodies. Even the IgG2 allotypes tend to vary in protection. Of course, antigenic specificity also determines protection. So far, there is most evidence for protection by a 40 K outer membrane protein and by Immunoglobulin binding protein A fibrils. Serology and immunohistochemistry have both been used for immunodiagnosis. Many evasive mechanisms by H. somni have been defined, including decreased phagocyte function, antibodies bound by shed antigens, decreased immune stimulation, and antigenic variation. Interaction of H. somni with other bovine respiratory disease organisms is another layer of pathogenesis. Studies of bovine respiratory syncytial virus (BRSV) and H. somni in calfhood pneumonia revealed an increase in IgE antibodies to H. somni, which were associated with more severe disease of longer duration than with either agent alone. Innate immune mechanisms at the epithelial cell level are also affected by dual infection by BRSV and H. somni as compared to either pathogen alone. Although much more work needs to be done, the complex mechanisms of H. somni immunity are becoming clearer.

Immunization of Mice with Formalin-Inactivated Spores from Avirulent Bacillus cereus Strains Provides Significant Protection from Challenge with Bacillus anthracis Ames

PubMed Central

Vergis, James M.; Cote, Christopher K.; Bozue, Joel; Alem, Farhang; Ventura, Christy L.; Welkos, Susan L.

2013-01-01

Bacillus anthracis spores are the infectious form of the organism for humans and animals. However, the approved human vaccine in the United States is derived from a vegetative culture filtrate of a toxigenic, nonencapsulated B. anthracis strain that primarily contains protective antigen (PA). Immunization of mice with purified spore proteins and formalin-inactivated spores (FIS) from a nonencapsulated, nontoxigenic B. anthracis strain confers protection against B. anthracis challenge when PA is also administered. To investigate the capacity of the spore particle to act as a vaccine without PA, we immunized mice subcutaneously with FIS from nontoxigenic, nonencapsulated B. cereus strain G9241 pBCXO1−/pBC210− (dcG9241), dcG9241 ΔbclA, or 569-UM20 or with exosporium isolated from dcG9241. FIS vaccination provided significant protection of mice from intraperitoneal or intranasal challenge with spores of the virulent B. anthracis Ames or Ames ΔbclA strain. Immunization with dcG9241 ΔbclA FIS, which are devoid of the immunodominant spore protein BclA, provided greater protection from challenge with either Ames strain than did immunization with FIS from BclA-producing strains. In addition, we used prechallenge immune antisera to probe a panel of recombinant B. anthracis Sterne spore proteins to identify novel immunogenic vaccine candidates. The antisera were variably reactive with BclA and with 10 other proteins, four of which were previously tested as vaccine candidates. Overall our data show that immunization with FIS from nontoxigenic, nonencapsulated B. cereus strains provides moderate to high levels of protection of mice from B. anthracis Ames challenge and that neither PA nor BclA is required for this protection. PMID:23114705

The sickle-cell trait modifies the intensity and specificity of the immune response against P. falciparum malaria and leads to acquired protective immunity.

PubMed

Bayoumi, R A

1987-03-01

It is proposed that the in vivo mechanism of protection against falciparum malaria in individuals of the Hb AS genotype is not due solely to the adverse influence of Hb AS erythrocytes on the intraerythrocytic growth and development of P. falciparum. Instead, the simple physiological effect of Hb S on parasite growth appears to trigger an in vivo process of enhancement of the intensity and/or specificity of the host immune response, leading to acquired protective immunity, in a process simulating vaccination. Testing the hypothesis may lead to the identification of plasmodial antigens that induce protective responses in the human host and distinguish them from non-protective, immunosuppressive or decoy antigens that promote parasite survival. This may ultimately help in the selection of candidate antigens for a malaria blood-stage vaccine.

Protective immunity against nervous necrosis virus in convict grouper Epinephelus septemfasciatus following vaccination with virus-like particles produced in yeast Saccharomyces cerevisiae.

PubMed

Wi, Ga Ram; Hwang, Jee Youn; Kwon, Mun-Gyeong; Kim, Hyoung Jin; Kang, Hyun Ah; Kim, Hong-Jin

2015-05-15

Infection with nervous necrosis virus (NNV) causes viral nervous necrosis, which inflicts serious economic losses in marine fish cultivation. Virus-like particles (VLPs) are protein complexes consisting of recombinant virus capsid proteins, whose shapes are similar to native virions. VLPs are considered a novel vaccine platform because they are not infectious and have the ability to induce neutralizing antibodies efficiently. However, there have been few studies of protective immune responses employing virus challenge following immunization with NNV VLPs, and this is important for evaluating the utility of the vaccine. In the present study, we produced red-spotted grouper (Epinephelus akaara) NNV (RGNNV) VLPs in Saccharomyces cerevisiae and investigated protective immune responses in convict grouper (Epinephelus septemfasciatus) following intraperitoneal injection and oral immunization with the RGNNV VLPs. The parenterally administered VLPs elicited neutralizing antibody with high efficacy, and provided the fish with full protection against RGNNV challenge: 100% of the immunized fish survived compared with only 37% of the control fish receiving phosphate-buffered saline. RGNNV VLPs administered orally provoked neutralizing antibody systemically and conferred protective immunity against virus challenge: however only 57% of the fish survived. Our results demonstrate that RGNNV VLP produced in yeast has great potential as vaccine in fish. Copyright © 2015 Elsevier B.V. All rights reserved.

Parasite genetics and the immune host: recombination between antigenic types of Eimeria maxima as an entrée to the identification of protective antigens.

PubMed

Blake, Damer P; Hesketh, Patricia; Archer, Andrew; Carroll, Fionnadh; Smith, Adrian L; Shirley, Martin W

2004-11-01

The genomes of protozoan parasites encode thousands of gene products and identification of the subset that stimulates a protective immune response is a daunting task. Most screens for vaccine candidates identify molecules by capacity to induce immune responses rather than protection. This paper describes the core findings of a strategy developed with the coccidial parasite Eimeria maxima to rationally identify loci within its genome that encode immunoprotective antigens. Our strategy uses a novel combination of parasite genetics, DNA fingerprinting, drug-resistance and strain-specific immunity and centres on two strains of E. maxima that each induce a lethal strain-specific protective immune response in the host and show a differential response to anti-Eimeria chemotherapy. Through classical mating studies with these strains we have demonstrated that loci encoding molecules stimulating strain-specific protective immunity or resistance to the anti-coccidial drug robenidine segregate independently. Furthermore, passage of populations of recombinant parasites in the face of killing in the immune host was accompanied by the elimination of some polymorphic DNA markers defining the parent strain used to immunise the host. Consideration of the numbers of parasites recombinant for the two traits implicates very few antigen-encoding loci. Our data provide a potential strategy to identify putative antigen-encoding loci in other parasites.

Vaccine profile of herpes zoster (HZ/su) subunit vaccine.

PubMed

Cunningham, Anthony L; Heineman, Thomas

2017-07-01

Herpes zoster (HZ) causes an often severe and painful rash in older people and may be complicated by prolonged pain (postherpetic neuralgia; PHN) and by dissemination in immune-compromised patients. HZ results from reactivation of latent varicella-zoster virus (VZV) infection, often associated with age-related or other causes of decreased T cell immunity. A live attenuated vaccine boosts this immunity and provides partial protection against HZ, but this decreases with age and declines over 8 years. Areas covered: A new HZ subunit (HZ/su) vaccine combines a key surface VZV glycoprotein (E) with a T cell-boosting adjuvant system (AS01 B ) and is administered by two intramuscular injections two months apart. Expert commentary: HZ/su showed excellent efficacy of ~90% in immunocompetent adults ≥50 and ≥70 years of age, respectively, in the ZOE-50 and ZOE-70 phase III controlled trials. Efficacy was unaffected by advancing age and persisted for >3 years. Approximately 9.5% of subjects had severe, but transient (1-2 days) injection site pain, swelling or redness. Compliance with both vaccine doses was high (95%). The vaccine will have a major impact on HZ management. Phase I-II trials showed safety and immunogenicity in severely immunocompromised patients. Phase III trial results are expected soon.

Therapeutics of Ebola hemorrhagic fever: whole-genome transcriptional analysis of successful disease mitigation.

PubMed

Yen, Judy Y; Garamszegi, Sara; Geisbert, Joan B; Rubins, Kathleen H; Geisbert, Thomas W; Honko, Anna; Xia, Yu; Connor, John H; Hensley, Lisa E

2011-11-01

The mechanisms of Ebola (EBOV) pathogenesis are only partially understood, but the dysregulation of normal host immune responses (including destruction of lymphocytes, increases in circulating cytokine levels, and development of coagulation abnormalities) is thought to play a major role. Accumulating evidence suggests that much of the observed pathology is not the direct result of virus-induced structural damage but rather is due to the release of soluble immune mediators from EBOV-infected cells. It is therefore essential to understand how the candidate therapeutic may be interrupting the disease process and/or targeting the infectious agent. To identify genetic signatures that are correlates of protection, we used a DNA microarray-based approach to compare the host genome-wide responses of EBOV-infected nonhuman primates (NHPs) responding to candidate therapeutics. We observed that, although the overall circulating immune response was similar in the presence and absence of coagulation inhibitors, surviving NHPs clustered together. Noticeable differences in coagulation-associated genes appeared to correlate with survival, which revealed a subset of distinctly differentially expressed genes, including chemokine ligand 8 (CCL8/MCP-2), that may provide possible targets for early-stage diagnostics or future therapeutics. These analyses will assist us in understanding the pathogenic mechanisms of EBOV infection and in identifying improved therapeutic strategies.

Effectiveness of one dose of mumps vaccine against clinically diagnosed mumps in Guangzhou, China, 2006–2012

PubMed Central

Fu, Chuanxi; Xu, Jianxiong; Cai, Yuanjun; He, Qing; Zhang, Chunhuan; Chen, Jian; Dong, Zhiqiang; Hu, Wensui; Wang, Hui; Zhu, Wei; Wang, Ming

2013-01-01

Although mumps-containing vaccines were introduced in China in 1990s, mumps continues to be a public health concern due to the lack of decline in reported mumps cases. To assess the mumps vaccine effectiveness (VE) in Guangzhou, China, we performed a 1:1 matched case-control study. Among children in Guangzhou aged 8 mo to 12 y during 2006 to 2012, we matched one healthy child to each child with clinically diagnosed mumps. Cases with clinically diagnosed mumps were identified from surveillance sites system and healthy controls were randomly sampled from the Children’s Expanded Programmed Immunization Administrative Computerized System in Guangzhou. Conditional logistic regression was used to calculate VE. We analyzed the vaccination information for 1983 mumps case subjects and 1983 matched controls and found that the overall VE for 1 dose of mumps vaccine, irrespective of the manufacture, was 53.6% (95% confidence interval [CI], 41.0–63.5%) to children aged 8 mo to 12 y. This post-marketing mumps VE study found that immunization with one dose of the mumps vaccine confers partial protection against mumps disease. Evaluation of the VE for the current mumps vaccines, introduction of a second dose of mumps vaccine, and assessment of modifications to childhood immunization schedules is essential. PMID:23955378

Effectiveness of one dose of mumps vaccine against clinically diagnosed mumps in Guangzhou, China, 2006-2012.

PubMed

Fu, Chuanxi; Xu, Jianxiong; Cai, Yuanjun; He, Qing; Zhang, Chunhuan; Chen, Jian; Dong, Zhiqiang; Hu, Wensui; Wang, Hui; Zhu, Wei; Wang, Ming

2013-12-01

Although mumps-containing vaccines were introduced in China in 1990s, mumps continues to be a public health concern due to the lack of decline in reported mumps cases. To assess the mumps vaccine effectiveness (VE) in Guangzhou, China, we performed a 1:1 matched case-control study. Among children in Guangzhou aged 8 mo to 12 y during 2006 to 2012, we matched one healthy child to each child with clinically diagnosed mumps. Cases with clinically diagnosed mumps were identified from surveillance sites system and healthy controls were randomly sampled from the Children's Expanded Programmed Immunization Administrative Computerized System in Guangzhou. Conditional logistic regression was used to calculate VE. We analyzed the vaccination information for 1983 mumps case subjects and 1983 matched controls and found that the overall VE for 1 dose of mumps vaccine, irrespective of the manufacture, was 53.6% (95% confidence interval [CI], 41.0-63.5%) to children aged 8 mo to 12 y. This post-marketing mumps VE study found that immunization with one dose of the mumps vaccine confers partial protection against mumps disease. Evaluation of the VE for the current mumps vaccines, introduction of a second dose of mumps vaccine, and assessment of modifications to childhood immunization schedules is essential.

The Protective Effects of Extra Virgin Olive Oil on Immune-mediated Inflammatory Responses.

PubMed

Casas, Rosa; Estruch, Ramon; Sacanella, Emilio

2018-01-01

The increasing interest in the Mediterranean diet (MeDiet) hinges on the relevant role it plays in inflammatory diseases. Several clinical, epidemiological and experimental evidences suggest that consumption of the MeDiet reduces the incidence of certain pathologies related to oxidative stress, chronic inflammation and immune system diseases such as cancer, atherosclerosis and cardiovascular disease (CVD). These reductions can be partially attributed to extra virgin olive oil (EVOO) consumption which has been described as a key bioactive food because of its high nutritional quality and its particular composition of fatty acids, vitamins and polyphenols. Indeed, the beneficial effects of EVOO have been linked to its fatty acid composition, which is very rich in monounsaturated fatty acids (MUFA), and has moderate saturated and polyunsaturated fatty acids (PUFA). The current knowledge available on the beneficial effects of EVOO and its phenolic compounds, specifically its biological properties and antioxidant capacity against immune-mediated inflammatory responses (atherosclerosis, rheumatoid arthritis, diabetes, obesity, cancer, inflammatory bowel disease or neurodegenerative disease, among others) in addition to its potential clinical applications. The increasing body of studies carried out provides compelling evidence that olive polyphenols are potential candidates to combat chronic inflammatory states. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Increasing transcriptome response of serpins during the ontogenetic stages in the salmon louse Caligus rogercresseyi (Copepoda: Caligidae).

PubMed

Maldonado-Aguayo, W; Gallardo-Escárate, C

2014-06-01

Serine protease inhibitors, or serpins, target serine proteases, and are important regulators of intra- and extracellular proteolysis. For parasite survival, parasite-derived protease inhibitors have been suggested to play essential roles in evading the host's immune system and protecting against exogenous host proteases. The aim of this work was to identify serpins via high throughput transcriptome sequencing and elucidate their potential functions during the lifecycle of the salmon louse Caligus rogercresseyi. Eleven putative, partial serpin sequences in the C. rogercresseyi transcriptome were identified and denoted as Cr-serpins 1 to 11. Comparative analysis of the deduced serpin-like amino acid sequences revealed a highly conserved reactive center loop region. Interestingly, P1 residues suggest putative functions involved with the trypsin/subtilisin, elastase, or subtilisin inhibitors, which evidenced increasing gene expression profiles from the copepodid to adult stage in C. rogercresseyi. Concerning this, Cr-serpin 10 was mainly expressed in the copepodid stage, while Cr-serpins 3, 4, 5, and 11 were mostly expressed in chalimus and adult stages. These results suggest that serpins could be involved in evading the immune response of the host fish. The identification of these serpins furthers the understanding of the immune system in this important ectoparasite species. Copyright © 2014 Elsevier B.V. All rights reserved.

Generation of an antibody that recognizes Plasmodium chabaudi cysteine protease (chabaupain-1) in both sexual and asexual parasite life cycle and evaluation of chabaupain-1 vaccine potential.

PubMed

Armada, Ana; Gazarini, Marcos L; Gonçalves, Lídia M; Antunes, Sandra; Custódio, Ana; Rodrigues, Armanda; Almeida, António J; Silveira, Henrique; Rosário, Virgílio do; Santos-Gomes, Gabriela; Domingos, Ana

2013-09-01

Malaria cysteine proteases have been shown to be immunogenic and are being exploited as serodiagnostic markers, drug and vaccine targets. Several Plasmodium spp. cysteine proteases have been described and the best characterized of these are the falcipains, a family of papain-family enzymes. Falcipain-2 and falcipain-3 act in concert with other proteases to hydrolyze host erythrocyte hemoglobin in the parasite food vacuole. Falcipain-1 has less similarity to the other falcipains and its physiological role in parasite asexual blood stage still remains uncertain. Immunolocalization studies using an antibody developed against the Plasmodium chabaudi recombinant chabaupain-1, the falcipain-1 ortholog, were performed confirming its cellular localization in both erythrocyte and mosquito ookinete stage. Immunostaining of chabaupain-1 preferentially in apical portion of parasite ookinete suggests that this protease may be related with parasite egression from mosquito midgut. Immune responses to chabaupain-1 were evaluated using two different adjuvants, chitosan nanoparticles and hydroxide aluminum. Mice immunized with the recombinant protein alone or in association with nanoparticles were challenged with P. chabaudi showing that immunization with the recombinant protein confers partial protection to blood stage infection in BALB/c animal model. Copyright © 2013 Elsevier Inc. All rights reserved.

Skin-resident CD4+ T cells protect against Leishmania major by recruiting and activating inflammatory monocytes

PubMed Central

Glennie, Nelson D.; Volk, Susan W.

2017-01-01

Tissue-resident memory T cells are required for establishing protective immunity against a variety of different pathogens, although the mechanisms mediating protection by CD4+ resident memory T cells are still being defined. In this study we addressed this issue with a population of protective skin-resident, IFNγ-producing CD4+ memory T cells generated following Leishmania major infection. We previously found that resident memory T cells recruit circulating effector T cells to enhance immunity. Here we show that resident memory CD4+ T cells mediate the delayed-hypersensitivity response observed in immune mice and provide protection without circulating T cells. This protection occurs rapidly after challenge, and requires the recruitment and activation of inflammatory monocytes, which limit parasites by production of both reactive oxygen species and nitric oxide. Overall, these data highlight a novel role for tissue-resident memory cells in recruiting and activating inflammatory monocytes, and underscore the central role that skin-resident T cells play in immunity to cutaneous leishmaniasis. PMID:28419151

Antibody responses to prime-boost vaccination with an HIV-1 gp145 envelope protein and chimpanzee adenovirus vectors expressing HIV-1 gp140.

PubMed

Emmer, Kristel L; Wieczorek, Lindsay; Tuyishime, Steven; Molnar, Sebastian; Polonis, Victoria R; Ertl, Hildegund C J

2016-10-23

Over 2 million individuals are infected with HIV type 1 (HIV-1) each year, yet an effective vaccine remains elusive. The most successful HIV-1 vaccine to date demonstrated 31% efficacy. Immune correlate analyses associated HIV-1 envelope (Env)-specific antibodies with protection, thus providing a path toward a more effective vaccine. We sought to test the antibody response from novel prime-boost vaccination with a chimpanzee-derived adenovirus (AdC) vector expressing a subtype C Env glycoprotein (gp)140 combined with either a serologically distinct AdC vector expressing gp140 of a different subtype C isolate or an alum-adjuvanted, partially trimeric gp145 from yet another subtype C isolate. Three different prime-boost regimens were tested in mice: AdC prime-protein boost, protein prime-AdC boost, and AdC prime-AdC boost. Each regimen was tested at two different doses of AdC vector in a total of six experimental groups. Sera were collected at various time points and evaluated by ELISA for Env-specific antibody binding, isotype, and avidity. Antibody functionality was assessed by pseudovirus neutralization assay. Priming with AdC followed by a protein boost or sequential immunizations with two AdC vectors induced HIV-1 Env-specific binding antibodies, including those to the variable region 2, whereas priming with protein followed by an AdC boost was relatively ineffective. Antibodies that cross-neutralized tier 1 HIV-1 from different subtypes were elicited with vaccine regimens that included immunizations with protein. Our study warrants further investigation of AdC vector and gp145 protein prime-boost vaccines and their ability to protect against acquisition in animal challenge studies.

Leptin attenuates lipopolysaccharide-induced apoptosis of thymocytes partially via down-regulation of cPLA2 and p38 MAPK activation.

PubMed

Liang, Chen; Liao, Jie; Deng, Zihui; Song, Cuihong; Zhang, Jinying; Zabeau, Lennart; Tavernier, Jan; Zhang, Kai; Xue, Hui; Yan, Guangtao

2013-03-01

Leptin, a 16-kDa protein that is mainly secreted by adipocytes, plays a protective role in many cell types. It has been shown that leptin acts in the central and peripheral immune system to protect thymocytes. Cytosolic phospholipase A(2) (cPLA(2)) is an enzyme that can specifically initiate the release of arachidonic acid (AA) to produce eicosanoids, which regulate inflammation and immune responses. Our previous work has shown that leptin is important to prevent apoptosis of thymocytes. However, the role of cPLA(2) is still unclear, and the precise mechanism also remains to be elucidated. In this work, we demonstrated that leptin inhibited the LPS-induced toxicity and apoptosis of thymocytes. Western blot and RT-PCR showed that leptin led to a reduction of cPLA(2) activity and mRNA level, as well as caspase-3 cleavage. Moreover, we found that leptin could decrease the activation of p38 MAPK. Accordingly, we pre-treated apoptotic thymocytes with the p38 MAPK inhibitor, SB203580 and observed an effect similar to the leptin alone treated group. SB203580 also suppressed expression of cPLA(2) and cleavage of caspase-3. Based on these results, we suggest that leptin could attenuate LPS-induced apoptotic injury in mouse thymocyte cells, mainly through the p38/cPLA(2) signalling pathway. The study of the regulatory role of leptin in LPS-induced thymocyte apoptosis can help to explain the role of leptin in the immune system and may provide a novel treatment option in cases of severe trauma, infection, shock, organ failure and autoimmune disease caused by thymic atrophy. Copyright © 2013. Published by Elsevier B.V.

Molecular characterization of the recombinant protein RmLTI-BmCG-LTB: Protective immunity against Rhipicephalus (Boophilus) microplus

PubMed Central

2018-01-01

The bovine tick Rhipicephalus (Boophilus) microplus is found in several tropical and subtropical regions of the world. This parasite transmits pathogens that cause disease, such as babesiosis (Babesia bovis and B. bigemina) and anaplasmosis (Anaplasma marginale). Tick infestations cause enormous livestock losses, and controlling tick infestations and the transmission of tick-borne diseases remains a challenge for the livestock industry. Because the currently available commercial vaccines offer only partial protection against R. (B.) microplus, there is a need for more efficient vaccines. Several recombinant antigens have been evaluated using different immunization strategies, and they show great promise. This work describes the construction and immunological characterization of a multi-antigen chimera composed of two R. (B.) microplus antigens (RmLTI and BmCG) and one Escherichia coli antigen (B subunit, LTB). The immunogenic regions of each antigen were selected and combined to encode a single polypeptide. The gene was cloned and expressed in E. coli. For all of the experiments, two groups (treated and control) of four Angus heifers (3–6 months old) were used. The inoculation was performed via intramuscular injection with 200 μg of purified recombinant chimeric protein and adjuvated. The chimeric protein was recognized by specific antibodies against each subunit and by sera from cattle inoculated with the chimera. Immunization of RmLTI-BmCG-LTB cattle reduced the number of adult female ticks by 6.29% and vaccination of cattle with the chimeric antigen provided 55.6% efficacy against R. (B.) microplus infestation. The results of this study indicate that the novel chimeric protein is a potential candidate for the future development of a more effective vaccine against R. (B.) microplus. PMID:29415034

Molecular characterization of the recombinant protein RmLTI-BmCG-LTB: Protective immunity against Rhipicephalus (Boophilus) microplus.

PubMed

Csordas, Bárbara Guimarães; Cunha, Rodrigo Casquero; Garcia, Marcos Valério; da Silva, Sérgio Silva; Leite, Fábio Leivas; Andreotti, Renato

2018-01-01

The bovine tick Rhipicephalus (Boophilus) microplus is found in several tropical and subtropical regions of the world. This parasite transmits pathogens that cause disease, such as babesiosis (Babesia bovis and B. bigemina) and anaplasmosis (Anaplasma marginale). Tick infestations cause enormous livestock losses, and controlling tick infestations and the transmission of tick-borne diseases remains a challenge for the livestock industry. Because the currently available commercial vaccines offer only partial protection against R. (B.) microplus, there is a need for more efficient vaccines. Several recombinant antigens have been evaluated using different immunization strategies, and they show great promise. This work describes the construction and immunological characterization of a multi-antigen chimera composed of two R. (B.) microplus antigens (RmLTI and BmCG) and one Escherichia coli antigen (B subunit, LTB). The immunogenic regions of each antigen were selected and combined to encode a single polypeptide. The gene was cloned and expressed in E. coli. For all of the experiments, two groups (treated and control) of four Angus heifers (3-6 months old) were used. The inoculation was performed via intramuscular injection with 200 μg of purified recombinant chimeric protein and adjuvated. The chimeric protein was recognized by specific antibodies against each subunit and by sera from cattle inoculated with the chimera. Immunization of RmLTI-BmCG-LTB cattle reduced the number of adult female ticks by 6.29% and vaccination of cattle with the chimeric antigen provided 55.6% efficacy against R. (B.) microplus infestation. The results of this study indicate that the novel chimeric protein is a potential candidate for the future development of a more effective vaccine against R. (B.) microplus.

Antibodies to the A27 protein of vaccinia virus neutralize and protect against infection but represent a minor component of Dryvax vaccine--induced immunity.

PubMed

He, Yong; Manischewitz, Jody; Meseda, Clement A; Merchlinsky, Michael; Vassell, Russell A; Sirota, Lev; Berkower, Ira; Golding, Hana; Weiss, Carol D

2007-10-01

The smallpox vaccine Dryvax, which consists of replication-competent vaccinia virus, elicits antibodies that play a major role in protection. Several vaccinia proteins generate neutralizing antibodies, but their importance for protection is unknown. We investigated the potency of antibodies to the A27 protein of the mature virion in neutralization and protection experiments and the contributions of A27 antibodies to Dryvax-induced immunity. Using a recombinant A27 protein (rA27), we confirmed that A27 contains neutralizing determinants and that vaccinia immune globulin (VIG) derived from Dryvax recipients contains reactivity to A27. However, VIG neutralization was not significantly reduced when A27 antibodies were removed, and antibodies elicited by an rA27 enhanced the protection conferred by VIG in passive transfer experiments. These findings demonstrate that A27 antibodies do not represent the major fraction of neutralizing activity in VIG and suggest that immunity may be augmented by vaccines and immune globulins that include strong antibody responses to A27.

Immunization against leishmaniasis by PLGA nanospheres loaded with an experimental autoclaved Leishmania major (ALM) and Quillaja saponins.

PubMed

Tafaghodi, M; Eskandari, M; Kharazizadeh, M; Khamesipour, A; Jaafari, M R

2010-12-01

Immune responses against the Leishmania antigens are not sufficient to protect against a leishmania challenge. Therefore these antigens need to be potentiated by various adjuvants and delivery systems. In this study, Poly (d,l-lactide-co-glycolide (PLGA) nanospheres as antigen delivery system and Quillaja saponins (QS) as immunoadjuvant have been used to enhance the immune response against autoclaved Leishmania major (ALM). PLGA nanospheres were prepared by a double-emulsion (W/O/W) technique. Particulate characteristics were studied by scanning electron microscopy and particle size analysis. Mean diameter for nanospheres loaded with ALM+QS was 294 ± 106 nm. BALB/c mice were immunized three times in 3-weeks intervals using ALM plus QS loaded nanospheres [(ALM+QS)PLGA], ALM encapsulated with PLGA nanospheres [(ALM)PLGA], (ALM)PLGA + QS, ALM + QS, ALM alone or PBS. The intensity of infection induced by L. major challenge was assessed by measuring size of footpad swelling. The strongest protection, showed by significantly (P < 0.05) smaller footpad, were observed in mice immunized with (ALM)PLGA. The (ALM+QS)PLGA group showed the least protection and highest swelling, while the (ALM)PLGA+QS, ALM+QS and ALM showed an intermediate protection with no significant difference. The mice immunized with ALM and ALM+QS showed the highest IgG2a/IgG1 ratio (P < 0.01), followed by (ALM)PLGA+QS. The highest IFN-γ and lowest IL-4 production was seen in (ALM)PLGA+QS, ALM+QS groups. The highest parasite burden was observed in (ALM)PLGA+QS and (ALM+QS)PLGA groups. It is concluded that PLGA nanospheres as a vaccine delivery system could increase the protective immune responses, but QS adjuvant has a reverse effect on protective immune responses and the least protective responses were seen in the presence of this adjuvant.

Klebsiella pneumoniae type 3 fimbria-mediated immunity to infection in the murine model of respiratory disease.

PubMed

Lavender, Heather; Jagnow, Jennifer J; Clegg, Steven

2005-06-01

Type 3 fimbriae are expressed by most strains of Klebsiella pneumoniae and facilitate adherence to the basement membrane of human respiratory tissues. The ability of these appendages to stimulate a protective immune response in vivo has not been investigated. A murine model of acute pneumonia was used to determine whether the production of type 3 fimbria-specific antibodies correlated with protection against infection by K. pneumoniae. Purified fimbriae from several strains were used to immunize mice prior to challenge with a virulent strain. The immunized mice produced high titers of specific antibody and this was associated with protection against challenge with a low dose of bacteria that was lethal in unimmunized animals. However, challenge with a high number of bacteria resulted in no protection against infection.

Cellular Self-Defense: How Cell-Autonomous Immunity Protects Against Pathogens

PubMed Central

Randow, Felix; MacMicking, John D.; James, Leo C.

2013-01-01

Our prevailing view of vertebrate host defense is strongly shaped by the notion of a specialized set of immune cells as sole guardians of antimicrobial resistance. Yet this view greatly underestimates a capacity for most cell lineages—the majority of which fall outside the traditional province of the immune system—to defend themselves against infection. This ancient and ubiquitous form of host protection is termed cell-autonomous immunity and operates across all three domains of life. Here, we discuss the organizing principles that govern cellular self-defense and how intracellular compartmentalization has shaped its activities to provide effective protection against a wide variety of microbial pathogens. PMID:23661752

Cellular self-defense: how cell-autonomous immunity protects against pathogens.

PubMed

Randow, Felix; MacMicking, John D; James, Leo C

2013-05-10

Our prevailing view of vertebrate host defense is strongly shaped by the notion of a specialized set of immune cells as sole guardians of antimicrobial resistance. Yet this view greatly underestimates a capacity for most cell lineages-the majority of which fall outside the traditional province of the immune system-to defend themselves against infection. This ancient and ubiquitous form of host protection is termed cell-autonomous immunity and operates across all three domains of life. Here, we discuss the organizing principles that govern cellular self-defense and how intracellular compartmentalization has shaped its activities to provide effective protection against a wide variety of microbial pathogens.

Role of pro-inflammatory cytokine IL-17 in Leishmania pathogenesis and in protective immunity by Leishmania vaccines.

PubMed

Banerjee, Antara; Bhattacharya, Parna; Joshi, Amritanshu B; Ismail, Nevien; Dey, Ranadhir; Nakhasi, Hira L

2016-11-01

The clinical outcome of Leishmania pathogenesis ranges from active skin lesions to fatal visceral dissemination and severely impaired T cell immunity. It is well established that a strong Th1 immune response is protective against cutaneous forms of the disease, however a mixed Th1/Th2 response is most commonly observed against visceral infections as evident from previous studies. Aside from Th1/Th2 cytokines, the pro-inflammatory IL-17 cytokine family plays an important role in the clearance of intracellular pathogens. In Leishmania induced skin lesions, IL-17 produced by Th17 cells is shown to exacerbate the disease, suggesting a role in pathogenesis. However, a protective role for IL-17 is indicated by the expansion of IL-17 producing cells in vaccine-induced immunity. In human visceral leishmaniasis (VL) it has been demonstrated that IL-17 and IL-22 are associated with protection against re-exposure to Leishmania, which further suggests the involvement of IL-17 in vaccine induced protective immunity. Although there is no vaccine against any form of leishmaniasis, the development of genetically modified live attenuated parasites as vaccine candidates prove to be promising, as they successfully induce a robust protective immune response in various animal models. However, the role of IL-17 producing cells and Th17 cells in response to these vaccine candidates remains unexplored. In this article, we review the role of IL-17 in Leishmania pathogenesis and the potential impact on vaccine induced immunity, with a special focus on live attenuated Leishmania parasites. Published by Elsevier Inc.

Experimental Vaccine Induces Th1-driven Immune Responses and Resistance to Neisseria gonorrhoeae Infection in a Murine Model

PubMed Central

Liu, Yingru; Hammer, Laura A.; Liu, Wensheng; Hobbs, Marcia M.; Zielke, Ryszard A.; Sikora, Aleksandra E.; Jerse, Ann E.; Egilmez, Nejat K.; Russell, Michael W.

2017-01-01

Female mice were immunized intravaginally with gonococcal outer membrane vesicles (OMV) plus microencapsulated IL-12, and challenged using an established model of genital infection with Neisseria gonorrhoeae. Whereas sham-immunized and control animals cleared the infection in 10–13 days, those immunized with OMV plus IL-12 cleared infection with homologous gonococcal strains in 6–9 days. Significant protection was also seen after challenge with antigenically distinct strains of N. gonorrhoeae, and protective anamnestic immunity persisted for at least 6 months after immunization. Serum and vaginal IgG and IgA antibodies were generated against antigens expressed by homologous and heterologous strains. Iliac lymph node CD4+ T cells secreted IFNγ, but not IL-4, in response to immunization, and produced IL-17 in response to challenge regardless of immunization. Antigens recognized by immunized mouse serum included several shared between gonococcal strains, including two identified by immunoproteomics approaches as EF-Tu and PotF3. Experiments with immunodeficient mice showed that protective immunity depended upon IFNγ and B cells, presumably to generate antibodies. The results demonstrated that immunity to gonococcal infection can be induced by immunization with a non-living gonococcal antigen, and suggest that efforts to develop a human vaccine should focus on strategies to generate Th1-driven immune responses in the genital tract. PMID:28272393

A retrospective analysis of the Alzheimer's disease vaccine progress - The critical need for new development strategies.

PubMed

Marciani, Dante J

2016-06-01

The promising results obtained with aducanumab and solanezumab against Alzheimer's disease (AD) strengthen the vaccine approach to prevent AD, despite of the many clinical setbacks. It has been problematic to use conjugated peptides with Th1/Th2 adjuvants to induce immune responses against conformational epitopes formed by Aβ oligomers, which is critical to induce protective antibodies. Hence, vaccination should mimic natural immunity by using whole or if possible conjugated antigens, but biasing the response to Th2 with anti-inflammatory adjuvants. Also, selection of the carrier and cross-linking agents is important to prevent suppression of the immune response against the antigen. That certain compounds having phosphorylcholine or fucose induce a sole Th2 immunity would allow antigens with T-cell epitopes without inflammatory autoimmune reactions to be used. Another immunization method is DNA vaccines combined with antigenic ones, which favors the clonal selection and expansion of high affinity antibodies needed for immune protection, but this also requires Th2 immunity. Since AD transgenic mouse models have limited value for immunogen selection as shown by the clinical studies, screening may require the use of validated antibodies and biophysical methods to identify the antigens that would be most likely recognized by the human immune system and thus capable to stimulate a protective antibody response. To induce an anti-Alzheimer's disease protective immunity and prevent possible damage triggered by antigens having B-cell epitopes-only, whole antigens might be used; while inducing Th2 immunity with sole anti-inflammatory fucose-based adjuvants. This approach would avert a damaging systemic inflammatory immunity and the suppression of immunoresponse against the antigen because of carrier and cross-linkers; immune requirements that extend to DNA vaccines. © 2016 International Society for Neurochemistry.

Immunization against chlamydial genital infection in guinea pigs with UV-inactivated and viable chlamydiae administered by different routes

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

Rank, R.G.; Batteiger, B.E.; Soderberg, L.S.

1990-08-01

Female guinea pigs were immunized with viable or UV light-inactivated chlamydiae, belonging to the species Chlamydia psittaci, by intravenous, subcutaneous, oral, or ocular routes. All animals were then inoculated vaginally with viable chlamydiae to determine the extent of protection against challenge infection induced by the various regimens. The course of genital infection was significantly reduced in intensity in all groups of animals except the unimmunized controls and those animals immunized orally with inactivated antigen. Guinea pigs immunized with viable antigen were more likely to develop resistance to challenge infection and, in general, had a significantly greater degree of protection thanmore » animals immunized with inactivated antigen. No one route seemed superior in producing a protective response. Animals in all groups demonstrating protection developed serum and secretion immunoglobulin G antibody responses to chlamydiae. Lymphocyte proliferative reactions to chlamydial antigen were variable among groups. Immunoblot analysis of serum and secretions indicated a wide range of antibody specificities, but most protected animals produced antibodies to the major outer membrane protein, lipopolysaccharide, and the 61-kilodalton protein. No definitive associations could be made between the increased ability of immunization with viable organisms to produce resistance to challenge infection and a particular immune parameter. These data indicate that viable chlamydiae given by various routes are able to induce a strong immune response which can provide resistance against reinfection in some cases or at least reduce the degree of infection to a greater degree than inactivated antigen. However, complete resistance to genital tract infection may be difficult to obtain and alternate immunizations strategies may have to be developed.« less

Analysis of immune responses in genital tracts of mice immunised with purified ribosomal fractions of Neisseria gonorrhoeae.

PubMed Central

Kita, E; Kashiba, S

1984-01-01

Immunisation of ddY mice with the purified ribosomal fraction of Neisseria gonorrhoeae was found to protect against intravaginal challenge with homologous organisms. This protection correlated with the presence of bactericidal antibody to purified ribosomal fraction in serum as well as in vaginal secretions. Analysis of the vaginal fluids from control mice and those immunised with purified ribosomal fraction showed that the enhanced elimination of gonococci in immune mice might be because of an early response of leucocytes generated by the reaction mediated by antibody and complement. Absorption studies showed that there was at least one major protective antigen in purified ribosomal fraction, other than cell surface substances such as lipopolysaccharide, outer membrane proteins, and pili. Bactericidal assays mediated by antibody and complement showed that matched samples of serum and vaginal fluid from immune mice had comparable gonococcidal activity, which was augmented by the effect of progesterone. Although delayed hypersensitivity was produced in immune mice that were resistant to N gonorrhoeae, the exact role of cellular immunity could not be clarified in this study. These results suggest that antibody to purified ribosomal fraction plays a major part in protection against gonococcal infection in the genital tract, and that such protection may entail both cellular immunity and hormonal changes. PMID:6430462

Inactivated Influenza Vaccine That Provides Rapid, Innate-Immune-System-Mediated Protection and Subsequent Long-Term Adaptive Immunity.

PubMed

Chua, Brendon Y; Wong, Chinn Yi; Mifsud, Edin J; Edenborough, Kathryn M; Sekiya, Toshiki; Tan, Amabel C L; Mercuri, Francesca; Rockman, Steve; Chen, Weisan; Turner, Stephen J; Doherty, Peter C; Kelso, Anne; Brown, Lorena E; Jackson, David C

2015-10-27

The continual threat to global health posed by influenza has led to increased efforts to improve the effectiveness of influenza vaccines for use in epidemics and pandemics. We show in this study that formulation of a low dose of inactivated detergent-split influenza vaccine with a Toll-like receptor 2 (TLR2) agonist-based lipopeptide adjuvant (R4Pam2Cys) provides (i) immediate, antigen-independent immunity mediated by the innate immune system and (ii) significant enhancement of antigen-dependent immunity which exhibits an increased breadth of effector function. Intranasal administration of mice with vaccine formulated with R4Pam2Cys but not vaccine alone provides protection against both homologous and serologically distinct (heterologous) viral strains within a day of administration. Vaccination in the presence of R4Pam2Cys subsequently also induces high levels of systemic IgM, IgG1, and IgG2b antibodies and pulmonary IgA antibodies that inhibit hemagglutination (HA) and neuraminidase (NA) activities of homologous but not heterologous virus. Improved primary virus nucleoprotein (NP)-specific CD8(+) T cell responses are also induced by the use of R4Pam2Cys and are associated with robust recall responses to provide heterologous protection. These protective effects are demonstrated in wild-type and antibody-deficient animals but not in those depleted of CD8(+) T cells. Using a contact-dependent virus transmission model, we also found that heterologous virus transmission from vaccinated mice to naive mice is significantly reduced. These results demonstrate the potential of adding a TLR2 agonist to an existing seasonal influenza vaccine to improve its utility by inducing immediate short-term nonspecific antiviral protection and also antigen-specific responses to provide homologous and heterologous immunity. The innate and adaptive immune systems differ in mechanisms, specificities, and times at which they take effect. The innate immune system responds within hours of exposure to infectious agents, while adaptive immunity takes several days to become effective. Here we show, by using a simple lipopeptide-based TLR2 agonist, that an influenza detergent-split vaccine can be made to simultaneously stimulate and amplify both systems to provide immediate antiviral protection while giving the adaptive immune system time to implement long-term immunity. Both types of immunity induced by this approach protect against vaccine-matched as well as unrelated virus strains and potentially even against strains yet to be encountered. Conferring dual functionality to influenza vaccines is beneficial for improving community protection, particularly during periods between the onset of an outbreak and the time when a vaccine becomes available or in scenarios in which mass vaccination with a strain to which the population is immunologically naive is imperative. Copyright © 2015 Chua et al.

Enhancing the Immune Response to Recombinant Plague Antigens

DTIC Science & Technology

2007-05-01

protection against rotavirus infection of mice stimulated by intranasal immunization with chimeric VP4 or VP6 protein. J Virol 1999;73(9):7574–81. [13] Choi...AH, Basu M, McNeal MM, Flint J, VanCott JL, Clements JD, et al. Functional mapping of protective domains and epitopes in the rotavirus VP6 protein. J...McNeal MM, Rae MN, Bean JA, Ward RL. Antibody-dependent and -independent protection following intranasal immunization of mice with rotavirus particles. J

Use of a Vaccinia Construct Expressing the Circumsporozoite Protein in the Analysis of Protective Immunity to Plasmodium yoelii

DTIC Science & Technology

1988-01-01

William R. Majarian, 2 ,5 Frank A. Robey, 3 Walter Weiss, 1 and Stephen L. Hoffman 1 lInfectious Diseases Department, Naval Medical Research Institute...autoradiography. Recombinant viruses which were positive in this assay were subject to 3 rounds of plaque purification. Finally, plaque purified virus was...mechanisms in the protective immunity elicited by inmunization with irradiated sporozoites (3,7,8,9). In an attempt to induce a protective cellular immune

[Evaluation of the protection efficiency of secretory antibodies in experimental Yersinia infection in guinea-pigs immunized with polyvalent vaccine against this infection].

PubMed

Pogorel'skiĭ, I P; Drobkov, V I

2009-01-01

The paper presents the results of experiments to elucidate the protection efficiency of secretory antibodies via parenteral and oral inoculation with pathogenic Yersinia in guinea pigs immunized with a polyvalent yersiniasis vaccine designed on the basis of the pseudotuberculosis microbial strain that synthesizes the F1 antigen of a plague microbe. Immunization of guinea pigs with the polyvalent yersiniasis vaccine protects experimental animals against pseudotuberculosis, intestinal yersiniasis, and plague infections.

The T cell STAT signaling network is reprogrammed within hours of bacteremia via secondary signals1

PubMed Central

Hotson, Andrew N.; Hardy, Jonathan W.; Hale, Matthew B.; Contag, Christopher H.; Nolan, Garry P.

2014-01-01

The delicate balance between protective immunity and inflammatory disease is challenged during sepsis, a pathologic state characterized by aspects of both a hyper-active immune response and immunosuppression. The events driven by systemic infection by bacterial pathogens on the T cell signaling network that likely control these responses have not been illustrated in great detail. We characterized how intracellular signaling within the immune compartment is reprogrammed at the single cell level when the host is challenged with a high levels of pathogen. To accomplish this, we applied flow cytometry to measure the phosphorylation potential of key signal transduction proteins during acute bacterial challenge. We modeled the onset of sepsis by intravenous administration of avirulent strains of Listeria and E. coli to mice. Within six hours of bacterial challenge, T cells were globally restricted in their ability to respond to specific cytokine stimulations as determined by assessing the extent of STAT protein phosphorylation. Mechanisms by which this negative feedback response occurred included SOCS1 and SOCS3 gene up regulation and IL-6 induced endocystosis of the IL-6 receptor. In addition, macrophages were partially tolerized in their ability to respond to TLR agonists. Thus, in contrast to the view that there is a wholesale immune activation during sepsis, one immediate host response to blood borne bacteria was induction of a refractory period during which leukocyte activation by specific stimulations was attenuated. PMID:19494279

Intranasal immunization with protective antigen of Bacillus anthracis induces a long-term immunological memory response.

PubMed

Woo, Sun-Je; Kang, Seok-Seong; Park, Sung-Moo; Yang, Jae Seung; Song, Man Ki; Yun, Cheol-Heui; Han, Seung Hyun

2015-10-01

Although intranasal vaccination has been shown to be effective for the protection against inhalational anthrax, establishment of long-term immunity has yet to be achieved. Here, we investigated whether intranasal immunization with recombinant protective antigen (rPA) of Bacillus anthracis induces immunological memory responses in the mucosal and systemic compartments. Intranasal immunization with rPA plus cholera toxin (CT) sustained PA-specific antibody responses for 6 months in lung, nasal washes, and vaginal washes as well as serum. A significant induction of PA-specific memory B cells was observed in spleen, cervical lymph nodes (CLNs) and lung after booster immunization. Furthermore, intranasal immunization with rPA plus CT remarkably generated effector memory CD4(+) T cells in the lung. PA-specific CD4(+) T cells preferentially increased the expression of Th1- and Th17-type cytokines in lung, but not in spleen or CLNs. Collectively, the intranasal immunization with rPA plus CT promoted immunologic memory responses in the mucosal and systemic compartments, providing long-term immunity. Copyright © 2015 Elsevier Ltd. All rights reserved.

Immunization of ducks for type C botulism.

PubMed

Martinez, R; Wobeser, G

1999-10-01

A single subcutaneous immunization with a vaccine used for protecting ranch mink (Mustela vison) against type C botulism reduced morbidity and mortality in mallard (Anas platyrhynchos) and northern pintail (Anas acuta) ducks challenged with approximately 4.5 x 10(4) and 2.25 x 10(4) mouse lethal doses (MLD50), respectively, of botulinum toxin at 10 and 15 days post-immunization (pi). There was no significant protection at 5 days pi. Protection persisted in mallards for 90 days pi. To simulate use of vaccine as a part of treatment of sick birds in the field, mallards were exposed to toxin and, when clinical signs were evident, each bird was treated by intraperitoneal injection of type C botulinum antitoxin and one-half of the birds were immunized. Immunization had no significant effect on recovery from intoxication. At 10 days posttreatment, all birds were challenged with toxin. Clinical signs and mortality were significantly less frequent among immunized birds than among non-immunized birds after the second exposure. Immunization might be useful as part of the treatment regimen in botulism outbreaks.

Protective and pathological immunity during CNS infections

PubMed Central

Klein, Robyn S.; Hunter, Christopher A.

2017-01-01

The concept of immune privilege of the central nervous system (CNS) has dominated the study of inflammatory processes in the brain. However, clinically relevant models have highlighted the innate pathways that limit pathogen invasion of the CNS and that adaptive immunity mediates control of many neural infections. Because protective responses can result in bystander damage there are regulatory mechanisms that balance protective and pathological inflammation but which may also allow microbial persistence. The focus of this review is to consider the host-pathogen interactions that influence neurotropic infections and to highlight advances in understanding of innate and adaptive mechanisms of resistance as key determinants of the outcome of CNS infection. Advances in these areas have broadened our comprehension of how the immune system functions in the brain and can readily overcome immune privilege. PMID:28636958

Seroprevalence of tetanus toxoid antibody and booster vaccination efficacy in Japanese travelers.

PubMed

Mizuno, Yasutaka; Yamamoto, Akihiko; Komiya, Takako; Takeshita, Nozomi; Takahashi, Motohide

2014-01-01

Tetanus can be prevented by vaccination, which is especially important for overseas travelers. However, despite booster vaccination every 10 years being recommended, most Japanese adults do not receive it in the absence of physical injury or overseas travel. We aimed to investigate the level of protective immunity against tetanus among Japanese travelers, which may provide valuable information for formulating booster vaccination recommendations. 113 Japanese travelers given tetanus toxoid were recruited. The collected samples included paired samples prior to and 3-5 weeks after receiving the booster vaccination. Travelers who did not return and those lacking sample collection at the second visit were excluded. Finally, 96 paired blood samples were collected. History of immunization against tetanus, including DPT and DT vaccines, was determined from interviews or immunization records. The pre-vaccination geometric mean titer for the 96 participants was 1.07 IU/mL; 76% had a protective antitoxin level (>0.1 IU/mL), and 50% had a long-term protective antitoxin level (>1.0 IU/mL). Most participants <40 years old had protective immunity without receiving booster vaccination, whereas only 30.8% of those >50 years of age had protective immunity. Among the 23 participants without protective antitoxin levels (<0.1 IU/mL), booster vaccination was efficient in 100% of those <40 years but in only 28.6% of those >50 years of age. Although the tetanus antitoxin level decreases with age, booster vaccination helped to achieve an adequate protective antitoxin levels in Japanese travelers <40 years of age. Furthermore, the individuals who have never been vaccinated against tetanus especially in those >50 years old need to obtain protective immunity against tetanus according to a basic immunization schedule to prevent tetanus in travelers and residents of Japan. Copyright © 2013 Japanese Society of Chemotherapy and the Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Live Attenuated Leishmania donovani Centrin Gene-Deleted Parasites Induce IL-23-Dependent IL-17-Protective Immune Response against Visceral Leishmaniasis in a Murine Model.

PubMed

Banerjee, Antara; Bhattacharya, Parna; Dagur, Pradeep K; Karmakar, Subir; Ismail, Nevien; Joshi, Amritanshu B; Akue, Adovi D; KuKuruga, Mark; McCoy, John Philip; Dey, Ranadhir; Nakhasi, Hira L

2018-01-01

No vaccine exists against visceral leishmaniasis. To develop effective vaccines, we have previously reported protective role of live attenuated centrin gene-deleted Leishmania donovani ( LdCen -/- ) parasites through induction of Th1 type immune response in mice, hamsters, and dogs. In this study, we specifically explored the role of Th17 cells in LdCen -/- -induced host protection in mice. Our results showed that compared with wild-type L. donovani infection, LdCen -/- parasites induce significantly higher expression of Th17 differentiation cytokines in splenic dendritic cells. There was also induction of IL-17 and its promoting cytokines in total splenocytes and in both CD4 and CD8 T cells following immunization with LdCen -/- Upon challenge with wild-type parasites, IL-17 and its differentiating cytokines were significantly higher in LdCen -/- -immunized mice compared with nonimmunized mice that resulted in parasite control. Alongside IL-17 induction, we observed induction of IFN-γ-producing Th1 cells as reported earlier. However, Th17 cells are generated before Th1 cells. Neutralization of either IL-17 or IFN-γ abrogated LdCen -/- -induced host protection further confirming the essential role of Th17 along with Th1 cytokines in host protection. Treatment with recombinant IL-23, which is required for stabilization and maintenance of IL-17, heightened Th17, and Tc17 responses in immunized mice splenocytes. In contrast, Th17 response was absent in immunized IL-23R -/- mice that failed to induce protection upon virulent Leishmania challenge suggesting that IL-23 plays an essential role in IL-17-mediated protection by LdCen -/- parasites. This study unveiled the role of IL-23-dependent IL-17 induction in LdCen -/- parasite-induced immunity and subsequent protection against visceral leishmaniasis.

Persistent Low-Level Replication of SIVΔnef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection.

PubMed

Adnan, Sama; Reeves, R Keith; Gillis, Jacqueline; Wong, Fay E; Yu, Yi; Camp, Jeremy V; Li, Qingsheng; Connole, Michelle; Li, Yuan; Piatak, Michael; Lifson, Jeffrey D; Li, Wenjun; Keele, Brandon F; Kozlowski, Pamela A; Desrosiers, Ronald C; Haase, Ashley T; Johnson, R Paul

2016-12-01

Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.

Inactivated Recombinant Rabies Viruses Displaying Canine Distemper Virus Glycoproteins Induce Protective Immunity against Both Pathogens.

PubMed

da Fontoura Budaszewski, Renata; Hudacek, Andrew; Sawatsky, Bevan; Krämer, Beate; Yin, Xiangping; Schnell, Matthias J; von Messling, Veronika

2017-04-15

The development of multivalent vaccines is an attractive methodology for the simultaneous prevention of several infectious diseases in vulnerable populations. Both canine distemper virus (CDV) and rabies virus (RABV) cause lethal disease in wild and domestic carnivores. While RABV vaccines are inactivated, the live-attenuated CDV vaccines retain residual virulence for highly susceptible wildlife species. In this study, we developed recombinant bivalent vaccine candidates based on recombinant vaccine strain rabies virus particles, which concurrently display the protective CDV and RABV glycoprotein antigens. The recombinant viruses replicated to near-wild-type titers, and the heterologous glycoproteins were efficiently expressed and incorporated in the viral particles. Immunization of ferrets with beta-propiolactone-inactivated recombinant virus particles elicited protective RABV antibody titers, and animals immunized with a combination of CDV attachment protein- and fusion protein-expressing recombinant viruses were protected from lethal CDV challenge. However, animals that were immunized with only a RABV expressing the attachment protein of CDV vaccine strain Onderstepoort succumbed to infection with a more recent wild-type strain, indicating that immune responses to the more conserved fusion protein contribute to protection against heterologous CDV strains. IMPORTANCE Rabies virus and canine distemper virus (CDV) cause high mortality rates and death in many carnivores. While rabies vaccines are inactivated and thus have an excellent safety profile and high stability, live-attenuated CDV vaccines can retain residual virulence in highly susceptible species. Here we generated recombinant inactivated rabies viruses that carry one of the CDV glycoproteins on their surface. Ferrets immunized twice with a mix of recombinant rabies viruses carrying the CDV fusion and attachment glycoproteins were protected from lethal CDV challenge, whereas all animals that received recombinant rabies viruses carrying only the CDV attachment protein according to the same immunization scheme died. Irrespective of the CDV antigens used, all animals developed protective titers against rabies virus, illustrating that a bivalent rabies virus-based vaccine against CDV induces protective immune responses against both pathogens. Copyright © 2017 American Society for Microbiology.

Eimeria maxima recombinant Gam82 gametocyte antigen vaccine protects against coccidiosis and augments humoral and cell-mediated immunity

USDA-ARS?s Scientific Manuscript database

Intestinal infection with Eimeria, the etiologic agent of avian coccidiosis, stimulates protective immunity to subsequent colonization by the homologous parasite, whilst cross-protection against heterologous species is poor. As a first step toward the development of a broad specificity Eimeria vacci...

Schistosoma mansoni: radiation dose and morphologic integrity of schistosomules as factors for an effective cryopreserved live vaccine

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

Lewis, F.A.; Stirewalt, M.; Leef, J.L.

1984-01-01

The effectiveness of a cryopreserved, irradiated schistosomule vaccine against an homologous Schistosoma mansoni cercarial challenge was tested in C57B1/6 mice. Highly significant levels of protection developed consistently when mice were immunized with the vaccine irradiated at 10-20 Krad, i.e., doses below that considered optimal for irradiated cercariae (50 Krad). Cryopreserved schistosomules irradiated at 10 or 20 Krad induced greater levels of protection than did schistosomules irradiated at 2, 5, 30, or 50 Krad. Protective immunity developed as early as 3 weeks post-immunization. When immunizing inocula were injected at various times post-thaw, or when schistosomule subpopulations of normal-appearing, damaged or deadmore » organisms were injected, those populations which had appeared to sustain the least degree of damage were those most capable of stimulating protective immunity. These findings highlight the hazards of extrapolating conditions considered standard for an irradiated cercarial vaccine to one in which cryopreservation, for storage of the schistosomules, is an added stress.« less

Immunization with plasmid DNA encoding the hemagglutinin and the nucleoprotein confers robust protection against a lethal canine distemper virus challenge.

PubMed

Dahl, Lotte; Jensen, Trine Hammer; Gottschalck, Elisabeth; Karlskov-Mortensen, Peter; Jensen, Tove Dannemann; Nielsen, Line; Andersen, Mads Klindt; Buckland, Robin; Wild, T Fabian; Blixenkrone-Møller, Merete

2004-09-09

We have investigated the protective effect of immunization of a highly susceptible natural host of canine distemper virus (CDV) with DNA plasmids encoding the viral nucleoprotein (N) and hemagglutinin (H). The combined intradermal and intramuscular routes of immunization elicited high virus-neutralizing serum antibody titres in mink (Mustela vison). To mimic natural exposure, we also conducted challenge infection by horizontal transmission from infected contact animals. Other groups received a lethal challenge infection by administration to the mucosae of the respiratory tract and into the muscle. One of the mink vaccinated with N plasmid alone developed severe disease after challenge. In contrast, vaccination with the H plasmid together with the N plasmid conferred solid protection against disease and we were unable to detect CDV infection in PBMCs or in different tissues after challenge. Our findings show that DNA immunization by the combined intradermal and intramuscular routes can confer solid protective immunity against naturally transmitted morbillivirus infection and disease.

Patterns of HIV/SIV Prevention and Control by Passive Antibody Immunization.

PubMed

Yamamoto, Hiroyuki; Matano, Tetsuro

2016-01-01

Neutralizing antibody (NAb) responses are promising immune effectors for control of human immunodeficiency virus (HIV) infection. Protective activity and mechanisms of immunodeficiency virus-specific NAbs have been increasingly scrutinized in animals infected with simian immunodeficiency virus (SIV), chimeric simian/human immunodeficiency virus (SHIV) and related viruses. Studies on such models have unraveled a previously underscored protective potential against in vivo immunodeficiency virus replication. Pre-challenge NAb titers feasibly provide sterile protection from SIV/SHIV infection by purging the earliest onset of viral replication and likely modulate innate immune cell responses. Sufficient sub-sterile NAb titers after established infection also confer dose-dependent reduction of viremia, and in certain earlier time frames augment adaptive immune cell responses and even provide rebound-free viral control. Here, we provide an overview of the obtained patterns of SIV/SHIV protection and viral control by various types of NAb passive immunizations and discuss how these notions may be extrapolated to NAb-based clinical control of HIV infection.

rBCG30-Induced Immunity and Cross-Protection against Mycobacterium leprae Challenge Are Enhanced by Boosting with the Mycobacterium tuberculosis 30-Kilodalton Antigen 85B

PubMed Central

Gillis, Thomas P.; Tullius, Michael V.

2014-01-01

Leprosy remains a major global health problem and typically occurs in regions in which tuberculosis is endemic. Vaccines are needed that protect against both infections and do so better than the suboptimal Mycobacterium bovis BCG vaccine. Here, we evaluated rBCG30, a vaccine previously demonstrated to induce protection superior to that of BCG against Mycobacterium tuberculosis and Mycobacterium bovis challenge in animal models, for efficacy against Mycobacterium leprae challenge in a murine model of leprosy. rBCG30 overexpresses the M. tuberculosis 30-kDa major secretory protein antigen 85B, which is 85% homologous with the M. leprae homolog (r30ML). Mice were sham immunized or immunized intradermally with BCG or rBCG30 and challenged 2.5 months later by injection of viable M. leprae into each hind footpad. After 7 months, vaccine efficacy was assessed by enumerating the M. leprae bacteria per footpad. Both BCG and rBCG30 induced significant protection against M. leprae challenge. In the one experiment in which a comparison between BCG and rBCG30 was feasible, rBCG30 induced significantly greater protection than did BCG. Immunization of mice with purified M. tuberculosis or M. leprae antigen 85B also induced protection against M. leprae challenge but less so than BCG or rBCG30. Notably, boosting rBCG30 with M. tuberculosis antigen 85B significantly enhanced r30ML-specific immune responses, substantially more so than boosting BCG, and significantly augmented protection against M. leprae challenge. Thus, rBCG30, a vaccine that induces improved protection against M. tuberculosis, induces cross-protection against M. leprae that is comparable or potentially superior to that induced by BCG, and boosting rBCG30 with antigen 85B further enhances immune responses and protective efficacy. PMID:25001602

rBCG30-induced immunity and cross-protection against Mycobacterium leprae challenge are enhanced by boosting with the Mycobacterium tuberculosis 30-kilodalton antigen 85B.

PubMed

Gillis, Thomas P; Tullius, Michael V; Horwitz, Marcus A

2014-09-01

Leprosy remains a major global health problem and typically occurs in regions in which tuberculosis is endemic. Vaccines are needed that protect against both infections and do so better than the suboptimal Mycobacterium bovis BCG vaccine. Here, we evaluated rBCG30, a vaccine previously demonstrated to induce protection superior to that of BCG against Mycobacterium tuberculosis and Mycobacterium bovis challenge in animal models, for efficacy against Mycobacterium leprae challenge in a murine model of leprosy. rBCG30 overexpresses the M. tuberculosis 30-kDa major secretory protein antigen 85B, which is 85% homologous with the M. leprae homolog (r30ML). Mice were sham immunized or immunized intradermally with BCG or rBCG30 and challenged 2.5 months later by injection of viable M. leprae into each hind footpad. After 7 months, vaccine efficacy was assessed by enumerating the M. leprae bacteria per footpad. Both BCG and rBCG30 induced significant protection against M. leprae challenge. In the one experiment in which a comparison between BCG and rBCG30 was feasible, rBCG30 induced significantly greater protection than did BCG. Immunization of mice with purified M. tuberculosis or M. leprae antigen 85B also induced protection against M. leprae challenge but less so than BCG or rBCG30. Notably, boosting rBCG30 with M. tuberculosis antigen 85B significantly enhanced r30ML-specific immune responses, substantially more so than boosting BCG, and significantly augmented protection against M. leprae challenge. Thus, rBCG30, a vaccine that induces improved protection against M. tuberculosis, induces cross-protection against M. leprae that is comparable or potentially superior to that induced by BCG, and boosting rBCG30 with antigen 85B further enhances immune responses and protective efficacy. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys

PubMed Central

Letvin, Norman L.; Rao, Srinivas S.; Montefiori, David C.; Seaman, Michael S.; Sun, Yue; Lim, So-Yon; Yeh, Wendy W.; Asmal, Mohammed; Gelman, Rebecca S.; Shen, Ling; Whitney, James B.; Seoighe, Cathal; Lacerda, Miguel; Keating, Sheila; Norris, Philip J.; Hudgens, Michael G.; Gilbert, Peter B.; Buzby, Adam P.; Mach, Linh V.; Zhang, Jinrong; Balachandran, Harikrishnan; Shaw, George M.; Schmidt, Stephen D.; Todd, John-Paul; Dodson, Alan; Mascola, John R.; Nabel, Gary J.

2013-01-01

The RV144 vaccine trial in Thailand demonstrated that an HIV vaccine could prevent infection in humans and highlights the importance of understanding protective immunity against HIV. We used a nonhuman primate model to define immune and genetic mechanisms of protection against mucosal infection by the simian immunodeficiency virus (SIV). A plasmid DNA prime/recombinant adenovirus serotype 5 (rAd5) boost vaccine regimen was evaluated for its ability to protect monkeys from infection by SIVmac251 or SIVsmE660 isolates after repeat intrarectal challenges. Although this prime-boost vaccine regimen failed to protect against SIVmac251 infection, 50% of vaccinated monkeys were protected from infection with SIVsmE660. Among SIVsmE660-infected animals, there was an about one-log reduction in peak plasma virus RNA in monkeys expressing the major histocompatibility complex class I allele Mamu-A*01, implicating cytotoxic T lymphocytes in the control of SIV replication once infection is established. Among Mamu-A*01–negative monkeys challenged with SIVsmE660, no CD8+ T cell response or innate immune response was associated with protection against virus acquisition. However, low levels of neutralizing antibodies and an envelope-specific CD4+ T cell response were associated with vaccine protection in these monkeys. Moreover, monkeys that expressed two TRIM5 alleles that restrict SIV replication were more likely to be protected from infection than monkeys that expressed at least one permissive TRIM5 allele. This study begins to elucidate the mechanism of vaccine protection against immunodeficiency viruses and highlights the need to analyze these immune and genetic correlates of protection in future trials of HIV vaccine strategies. PMID:21543722

Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys.

PubMed

Letvin, Norman L; Rao, Srinivas S; Montefiori, David C; Seaman, Michael S; Sun, Yue; Lim, So-Yon; Yeh, Wendy W; Asmal, Mohammed; Gelman, Rebecca S; Shen, Ling; Whitney, James B; Seoighe, Cathal; Lacerda, Miguel; Keating, Sheila; Norris, Philip J; Hudgens, Michael G; Gilbert, Peter B; Buzby, Adam P; Mach, Linh V; Zhang, Jinrong; Balachandran, Harikrishnan; Shaw, George M; Schmidt, Stephen D; Todd, John-Paul; Dodson, Alan; Mascola, John R; Nabel, Gary J

2011-05-04

The RV144 vaccine trial in Thailand demonstrated that an HIV vaccine could prevent infection in humans and highlights the importance of understanding protective immunity against HIV. We used a nonhuman primate model to define immune and genetic mechanisms of protection against mucosal infection by the simian immunodeficiency virus (SIV). A plasmid DNA prime/recombinant adenovirus serotype 5 (rAd5) boost vaccine regimen was evaluated for its ability to protect monkeys from infection by SIVmac251 or SIVsmE660 isolates after repeat intrarectal challenges. Although this prime-boost vaccine regimen failed to protect against SIVmac251 infection, 50% of vaccinated monkeys were protected from infection with SIVsmE660. Among SIVsmE660-infected animals, there was about a one-log reduction in peak plasma virus RNA in monkeys expressing the major histocompatibility complex class I allele Mamu-A*01, implicating cytotoxic T lymphocytes in the control of SIV replication once infection is established. Among Mamu-A*01-negative monkeys challenged with SIVsmE660, no CD8(+) T cell response or innate immune response was associated with protection against virus acquisition. However, low levels of neutralizing antibodies and an envelope-specific CD4(+) T cell response were associated with vaccine protection in these monkeys. Moreover, monkeys that expressed two TRIM5 alleles that restrict SIV replication were more likely to be protected from infection than monkeys that expressed at least one permissive TRIM5 allele. This study begins to elucidate the mechanisms of vaccine protection against immunodeficiency viruses and highlights the need to analyze these immune and genetic correlates of protection in future trials of HIV vaccine strategies.

The early cellular signatures of protective immunity induced by live viral vaccination.

PubMed

Kohler, Siegfried; Bethke, Nicole; Böthe, Matthias; Sommerick, Sophie; Frentsch, Marco; Romagnani, Chiara; Niedrig, Matthias; Thiel, Andreas

2012-09-01

Here, we have used primary vaccination of healthy donors with attenuated live yellow fever virus 17D (YFV-17D) as a model to study the generation of protective immunity. In short intervals after vaccination, we analyzed the induction of YFV-17D specific T- and B-cell immunity, bystander activation, dendritic cell subsets, changes in serum cytokine levels, and YFV-17D-specific antibodies. We show activation of innate immunity and a concomitant decline of numbers of peripheral blood T and B cells. An early peak of antigen-specific T cells at day 2, followed by mobilization of innate immune cells, preceded the development of maximal adaptive immunity against YFV-17D at day 14 after vaccination. Interestingly, potent adaptive immunity as measured by high titers of neutralizing YFV-17D-specific antibodies, correlated with early activation and recruitment of YFV-17D-specific CD4(+) T cells and higher levels of sIL-6R. Thus our data might provide new insights into the interplay of innate and adaptive immunity for the induction of protective immunity. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Estimates of Mumps Seroprevalence May Be Influenced by Antibody Specificity and Serologic Method

PubMed Central

McGrew, Marcia; Williams, Nobia J.; Sowers, Sun B.; Bellini, William J.; Hickman, Carole J.

2014-01-01

Neutralizing antibodies are assumed to be essential for protection against mumps virus infection, but their measurement is labor- and time-intensive. For this reason, enzyme-linked immunosorbent assays (ELISAs) are typically used to measure mumps-specific IgG levels. However, since there is poor correlation between mumps neutralization titers and ELISAs that measure the presence of mumps-specific IgG levels, ELISAs that better correlate with neutralization are needed. To address this issue, we measured mumps antibody levels by plaque reduction neutralization, by a commercial ELISA (whole-virus antigen), and by ELISAs specific for the mumps nucleoprotein and hemagglutinin. The results indicate that differences in the antibody response to the individual mumps proteins could partially explain the lack of correlation among various serologic tests. Furthermore, the data indicate that some seropositive individuals have low levels of neutralizing antibody. If neutralizing antibody is important for protection, this suggests that previous estimates of immunity based on whole-virus ELISAs may be overstated. PMID:24371258

Immunization with the recombinant antigen Ss-IR induces protective immunity to infection with Strongyloides stercoralis in mice.

PubMed

Abraham, David; Hess, Jessica A; Mejia, Rojelio; Nolan, Thomas J; Lok, James B; Lustigman, Sara; Nutman, Thomas B

2011-10-19

Human intestinal infections with the nematode Strongyloides stercoralis remain a significant problem worldwide and a vaccine would be a useful addition to the tools available to prevent and control this infection. The goal of this study was to test single antigens for their efficacy in a vaccine against S. stercoralis larvae in mice. Alum was used as the adjuvant in these studies and antigens selected for analysis were either recognized by protective human IgG (Ss-TMY-1, Ss-EAT-6, and Ss-LEC-5) or were known to be highly immunogenic in humans (Ss-NIE-1 and Ss-IR). Only mice immunized with the Ss-IR antigen demonstrated a significant decrease of approximately 80% in the survival of larval parasites in the challenge infection. Antibodies, recovered from mice with protective immunity to S. stercoralis after immunization with Ss-IR, were used to locate the antigen in the larvae. Confocal microscopy revealed that IgG from mice immunized with Ss-IR bound to the surface of the parasites and observations by electron microscopy indicated that IgG bound to granules in the glandular esophagus. Serum collected from mice immunized with Ss-IR passively transferred immunity to naïve mice. These studies demonstrate that Ss-IR, in combination with alum, induces high levels of protective immunity through an antibody dependent mechanism and may therefore be suitable for further development as a vaccine against human strongyloidiasis. Copyright © 2011 Elsevier Ltd. All rights reserved.

Immunogenicity and protective immunity against bubonic plague and pneumonic plague by immunization of mice with the recombinant V10 antigen, a variant of LcrV.

PubMed

DeBord, Kristin L; Anderson, Deborah M; Marketon, Melanie M; Overheim, Katie A; DePaolo, R William; Ciletti, Nancy A; Jabri, Bana; Schneewind, Olaf

2006-08-01

In contrast to Yersinia pestis LcrV, the recombinant V10 (rV10) variant (lacking residues 271 to 300) does not suppress the release of proinflammatory cytokines by immune cells. Immunization with rV10 generates robust antibody responses that protect mice against bubonic plague and pneumonic plague, suggesting that rV10 may serve as an improved plague vaccine.

Natural Killer Cell Recruitment to the Lung During Influenza A Virus Infection Is Dependent on CXCR3, CCR5, and Virus Exposure Dose

PubMed Central

Carlin, Lindsey E.; Hemann, Emily A.; Zacharias, Zeb R.; Heusel, Jonathan W.; Legge, Kevin L.

2018-01-01

Natural killer (NK) cells are vital components of the antiviral immune response, but their contributions in defense against influenza A virus (IAV) are not well understood. To better understand NK cell responses during IAV infections, we examined the magnitude, kinetics, and contribution of NK cells to immunity and protection during high- and low-dose IAV infections. Herein, we demonstrate an increased accumulation of NK cells in the lung in high-dose vs. low-dose infections. In part, this increase is due to the local proliferation of pulmonary NK cells. However, the majority of NK cell accumulation within the lungs and airways during an IAV infection is due to recruitment that is partially dependent upon CXCR3 and CCR5, respectively. Therefore, altogether, our results demonstrate that NK cells are actively recruited to the lungs and airways during IAV infection and that the magnitude of the recruitment may relate to the inflammatory environment found within the tissues during high- and low-dose IAV infections. PMID:29719539

The RTS,S/AS01 malaria vaccine in children 5 to 17 months of age at first vaccination.

PubMed

Vandoolaeghe, Pascale; Schuerman, Lode

2016-12-01

The RTS,S/AS01 malaria vaccine received a positive scientific opinion from the European Medicines Agency in July 2015. The World Health Organization recommended pilot implementation of the vaccine in children at least 5 months of age according to an initial 3-dose schedule given at least 1 month apart, and a 4th dose 15-18 months post-dose 3. Clinical trials and mathematical modeling demonstrated that the partial protection provided by RTS,S/AS01 against malaria has the potential to provide substantial public health benefit when used in parallel with other malaria interventions, especially in highly endemic regions. The highest impact was seen with 4 vaccine doses in children aged 5 months or older. The vaccine will be evaluated in real-life settings to further assess its impact on mortality, vaccine safety in the context of routine immunization, and programmatic feasibility of delivering a 4-dose vaccination schedule requiring new immunization contacts. If successful, this will pave the way for larger-scale implementation.

Enhanced immune response and protective efficacy of a Treponema pallidum Tp92 DNA vaccine vectored by chitosan nanoparticles and adjuvanted with IL-2.

PubMed

Zhao, Feijun; Wu, Yimou; Zhang, Xiaohong; Yu, Jian; Gu, Weiming; Liu, Shuangquan; Zeng, Tiebing; Zhang, Yuejun; Wang, Shiping

2011-10-01

In this study, the immune-modulatory and protective efficacy of using an interleukin-2 (IL-2) expression plasmid as a genetic adjuvant and chitosan (CS) nanoparticles as vectors to enhance a Tp92 DNA vaccine candidate were investigated in a Treponema pallidum (Tp) rabbit challenge model. CS vectoring of pTp92 or pIL-2 were both demonstrated to augment anti-Tp92 antibody levels induced by pTp92 DNA vaccines. Interestingly, the combination of CS vectored Tp92 and pIL-2 led to the greatest enhancements of anti-Tp92 antibodies and T-cell proliferation (p < 0.05). At week 10 after the first immunization, 15 of the 18 rabbits in each group were challenged with Tp Nichols strain and monitored for skin lesions and ulcer lesions. Ratios of positive skin lesions and ratios of ulcer lesions in groups immunized with pTp92 were significantly lower than those of the empty vector or PBS groups (p < 0.05), demonstrating that pTp92 immunization elicited significant protective efficacy against the Tp Nichols strain challenge. CS vectored and pIL-2 adjuvanted pTp92 immunized animals exhibited the lowest rates of positive skin and ulcer lesions. Male New Zealand white rabbits were randomly assigned to groups (n = 18/group) and immunized intramuscularly with pTp92 based plasmid DNA constructs (100 μg of DNA/rabbit/immunization). Two weeks before Tp challenge (Week 8), three rabbits from each group were used to determine cytokine measurements and fifteen rabbits from each group were used for Tp challenge studies. Intramuscular injection of pTp92 induced strong humoral and cellular immune responses and conferred protection from Tp challenge in rabbits. The use of CS as a pTp92 vector or pIL-2 as an adjuvant achieved a superior level of protective efficacy against Tp challenge, however CS vectored, IL-2 adjuvanted pTp92 immunization conferred the highest level of protective efficacy.

48 CFR 352.228-7 - Insurance-liability to third persons.

Code of Federal Regulations, 2012 CFR

2012-10-01

... represents in its offer that it is partially immune from tort liability as a State agency, the Contracting...) Alternate II (APR 1984). If the successful offeror represents in its offer that it is totally immune from...

48 CFR 352.228-7 - Insurance-liability to third persons.

Code of Federal Regulations, 2011 CFR

2011-10-01

... represents in its offer that it is partially immune from tort liability as a State agency, the Contracting...) Alternate II (APR 1984). If the successful offeror represents in its offer that it is totally immune from...

48 CFR 352.228-7 - Insurance-liability to third persons.

Code of Federal Regulations, 2010 CFR

2010-10-01

... represents in its offer that it is partially immune from tort liability as a State agency, the Contracting...) Alternate II (APR 1984). If the successful offeror represents in its offer that it is totally immune from...

Immune signatures of protective spleen memory CD8 T cells.

PubMed

Brinza, Lilia; Djebali, Sophia; Tomkowiak, Martine; Mafille, Julien; Loiseau, Céline; Jouve, Pierre-Emmanuel; de Bernard, Simon; Buffat, Laurent; Lina, Bruno; Ottmann, Michèle; Rosa-Calatrava, Manuel; Schicklin, Stéphane; Bonnefoy, Nathalie; Lauvau, Grégoire; Grau, Morgan; Wencker, Mélanie; Arpin, Christophe; Walzer, Thierry; Leverrier, Yann; Marvel, Jacqueline

2016-11-24

Memory CD8 T lymphocyte populations are remarkably heterogeneous and differ in their ability to protect the host. In order to identify the whole range of qualities uniquely associated with protective memory cells we compared the gene expression signatures of two qualities of memory CD8 T cells sharing the same antigenic-specificity: protective (Influenza-induced, Flu-TM) and non-protective (peptide-induced, TIM) spleen memory CD8 T cells. Although Flu-TM and TIM express classical phenotypic memory markers and are polyfunctional, only Flu-TM protects against a lethal viral challenge. Protective memory CD8 T cells express a unique set of genes involved in migration and survival that correlate with their unique capacity to rapidly migrate within the infected lung parenchyma in response to influenza infection. We also enlighten a new set of poised genes expressed by protective cells that is strongly enriched in cytokines and chemokines such as Ccl1, Ccl9 and Gm-csf. CCL1 and GM-CSF genes are also poised in human memory CD8 T cells. These immune signatures are also induced by two other pathogens (vaccinia virus and Listeria monocytogenes). The immune signatures associated with immune protection were identified on circulating cells, i.e. those that are easily accessible for immuno-monitoring and could help predict vaccines efficacy.

A new rabies vaccine based on a recombinant ORF virus (parapoxvirus) expressing the rabies virus glycoprotein.

PubMed

Amann, Ralf; Rohde, Jörg; Wulle, Ulrich; Conlee, Douglas; Raue, Rudiger; Martinon, Olivier; Rziha, Hanns-Joachim

2013-02-01

The present study describes the generation of a new Orf virus (ORFV) recombinant, D1701-V-RabG, expressing the rabies virus (RABV) glycoprotein that is correctly presented on the surface of infected cells without the need of replication or production of infectious recombinant virus. One single immunization with recombinant ORFV can stimulate high RABV-specific virus-neutralizing antibody (VNA) titers in mice, cats, and dogs, representing all nonpermissive hosts for the ORFV vector. The protective immune response against severe lethal challenge infection was analyzed in detail in mice using different dosages, numbers, and routes for immunization with the ORFV recombinant. Long-term levels of VNA could be elicited that remained greater than 0.5 IU per ml serum, indicative for the protective status. Single applications of higher doses (10(7) PFU) can be sufficient to confer complete protection against intracranial (i.c.) challenge, whereas booster immunization was needed for protection by the application of lower dosages. Anamnestic immune responses were achieved by each of the seven tested routes of inoculation, including oral application. Finally, in vivo antibody-mediated depletion of CD4-positive and/or CD8-posititve T cell subpopulations during immunization and/or challenge infection attested the importance of CD4 T cells for the induction of protective immunity by D1701-V-RabG. This report demonstrates another example of the potential of the ORFV vector and also indicates the capability of the new recombinant for vaccination of animals.

A New Rabies Vaccine Based on a Recombinant Orf Virus (Parapoxvirus) Expressing the Rabies Virus Glycoprotein

PubMed Central

Amann, Ralf; Rohde, Jörg; Wulle, Ulrich; Conlee, Douglas; Raue, Rudiger; Martinon, Olivier

2013-01-01

The present study describes the generation of a new Orf virus (ORFV) recombinant, D1701-V-RabG, expressing the rabies virus (RABV) glycoprotein that is correctly presented on the surface of infected cells without the need of replication or production of infectious recombinant virus. One single immunization with recombinant ORFV can stimulate high RABV-specific virus-neutralizing antibody (VNA) titers in mice, cats, and dogs, representing all nonpermissive hosts for the ORFV vector. The protective immune response against severe lethal challenge infection was analyzed in detail in mice using different dosages, numbers, and routes for immunization with the ORFV recombinant. Long-term levels of VNA could be elicited that remained greater than 0.5 IU per ml serum, indicative for the protective status. Single applications of higher doses (107 PFU) can be sufficient to confer complete protection against intracranial (i.c.) challenge, whereas booster immunization was needed for protection by the application of lower dosages. Anamnestic immune responses were achieved by each of the seven tested routes of inoculation, including oral application. Finally, in vivo antibody-mediated depletion of CD4-positive and/or CD8-posititve T cell subpopulations during immunization and/or challenge infection attested the importance of CD4 T cells for the induction of protective immunity by D1701-V-RabG. This report demonstrates another example of the potential of the ORFV vector and also indicates the capability of the new recombinant for vaccination of animals. PMID:23175365

Neutralization of Yersinia pestis-mediated macrophage cytotoxicity by anti-LcrV antibodies and its correlation with protective immunity in a mouse model of bubonic plague.

PubMed

Zauberman, Ayelet; Cohen, Sara; Levy, Yinon; Halperin, Gideon; Lazar, Shirley; Velan, Baruch; Shafferman, Avigdor; Flashner, Yehuda; Mamroud, Emanuelle

2008-03-20

Plague is a life-threatening disease caused by Yersinia pestis, for which effective-licensed vaccines and reliable predictors of in vivo immunity are lacking. V antigen (LcrV) is a major Y. pestis virulence factor that mediates translocation of the cytotoxic Yersinia protein effectors (Yops). It is a well-established protective antigen and a part of currently tested plague subunit vaccines. We have developed a highly sensitive in vitro macrophage cytotoxicity neutralization assay which is mediated by anti-LcrV antibodies; and studied the potential use of these neutralizing antibodies as an in vitro correlate of plague immunity in mice. The assay is based on a Y. pestis strain with enhanced cytotoxicity to macrophages in which endogenous yopJ was replaced by the more effectively translocated yopP of Y. enterocolitica O:8. Mice passively immunized with rabbit anti-LcrV IgG or actively immunized with recombinant LcrV were protected against lethal doses of a virulent Y. pestis strain, in a mouse model of bubonic plague. This protection significantly correlated with the in vitro neutralizing activity of the antisera but not with their corresponding ELISA titers. In actively immunized mice, a cutoff value for serum neutralizing activity, above which survival was assured with high degree of confidence, could be established for different vaccination regimes. The impact of overall findings on the potential use of serum neutralizing activity as a correlate of protective immunity is discussed.

Involvement of CD8+ T cell-mediated immune responses in LcrV DNA vaccine induced protection against lethal Yersinia pestis challenge.

PubMed

Wang, Shixia; Goguen, Jon D; Li, Fusheng; Lu, Shan

2011-09-09

Yersinia pestis (Y. pestis) is the causative pathogen of plague, a highly fatal disease for which an effective vaccine, especially against mucosal transmission, is still not available. Like many bacterial infections, antigen-specific antibody responses have been traditionally considered critical, if not solely responsible, for vaccine-induced protection against Y. pestis. Studies in recent years have suggested the importance of T cell immune responses against Y. pestis infection but information is still limited about the details of Y. pestis antigen-specific T cell immune responses. In current report, studies are conducted to identify the presence of CD8+ T cell epitopes in LcrV protein, the leading antigen of plague vaccine development. Furthermore, depletion of CD8+ T cells in LcrV DNA vaccinated Balb/C mice led to reduced protection against lethal intranasal challenge of Y. pestis. These findings establish that an LcrV DNA vaccine is able to elicit CD8+ T cell immune responses against specific epitopes of this key plague antigen and that a CD8+ T cell immune response is involved in LcrV DNA vaccine-elicited protection. Future studies in plague vaccine development will need to examine if the presence of detectable T cell immune responses, in particular CD8+ T-cell immune responses, will enhance the protection against Y. pestis in higher animal species or humans. Copyright © 2010 Elsevier Ltd. All rights reserved.

Reproducing SIVΔnef vaccine correlates of protection: trimeric gp41 antibody concentrated at mucosal front lines

PubMed Central

Voss, James E.; Macauley, Matthew S.; Rogers, Kenneth A.; Villinger, Francois; Duan, Lijie; Shang, Liang; Fink, Elizabeth A.; Andrabi, Raiees; Colantonio, Arnaud D.; Robinson, James E.; Johnson, R. Paul; Burton, Dennis R.; Haase, Ashley T.

2016-01-01

Vaccination with SIVmac239Δnef provides robust protection against subsequent challenge with wild type SIV, but safety issues have precluded designing an HIV-1 vaccine based on a live attenuated virus concept. Safe immunogens and adjuvants that could reproduce identified immune correlates of SIVmac239Δnef protection therefore offer an alternative path for development of an HIV vaccine. Here we describe SIV envelope trimeric gp41 (gp41t) immunogens based on a protective correlate of antibodies to gp41t concentrated on the path of virus entry by the neonatal Fc receptor (FcRn) in cervical vaginal epithelium. We developed a gp41t immunogen-MPLA adjuvant liposomal nanoparticle for intra-muscular immunization and a gp41t-Fc immunogen for intranasal immunization for pilot studies in mice, rabbits, and rhesus macaques. Repeated immunizations to mimic persistent antigen exposure in infection elicited gp41t antibodies in rhesus macaques that were detectable in FcRn+ cervical vaginal epithelium, thus recapitulating one key feature of SIVmac239Δnef vaccinated and protected animals. While this strategy did not reproduce the system of local production of antibody in SIVmac239Δnef-vaccinated animals, passive immunization experiments supported the concept that sufficiently high levels of antibody can be concentrated by the FcRn at mucosal frontlines, thus setting the stage for assessing protection against vaginal challenge by gp41t immunization. PMID:27428745

Oral immunization with hepatitis B surface antigen expressed in transgenic plants

PubMed Central

Kong, Qingxian; Richter, Liz; Yang, Yu Fang; Arntzen, Charles J.; Mason, Hugh S.; Thanavala, Yasmin

2001-01-01

Oral immunogenicity of recombinant hepatitis B surface antigen (HBsAg) derived from yeast (purified product) or in transgenic potatoes (uncooked unprocessed sample) was compared. An oral adjuvant, cholera toxin, was used to increase immune responses. Transgenic plant material containing HBsAg was the superior means of both inducing a primary immune response and priming the mice to respond to a subsequent parenteral injection of HBsAg. Electron microscopy of transgenic plant samples revealed evidence that the HBsAg accumulated intracellularly; we conclude that natural bioencapsulation of the antigen may provide protection from degradation in the digestive tract until plant cell degradation occurs near an immune effector site in the gut. The correlate of protection from hepatitis B virus infection is serum antibody titers induced by vaccination; the protective level in humans is 10 milliunits/ml or greater. Mice fed HBsAg-transgenic potatoes produced HBsAg-specific serum antibodies that exceeded the protective level and, on parenteral boosting, generated a strong long-lasting secondary antibody response. We have also shown the effectiveness of oral delivery by using a parenteral prime-oral boost immunization schedule. The demonstrated success of oral immunization for hepatitis B virus with an “edible vaccine” provides a strategy for contributing a means to achieve global immunization for hepatitis B prevention and eradication. PMID:11553782

Immune Response to Dengue and Zika.

PubMed

Ngono, Annie Elong; Shresta, Sujan

2018-04-26

Flaviviruses such as dengue (DENV), yellow fever (YFV), West Nile (WNV), and Zika (ZIKV) are human pathogens of global significance. In particular, DENV causes the most prevalent mosquito-borne viral diseases in humans, and ZIKV emerged from obscurity into the spotlight in 2016 as the etiologic agent of congenital Zika syndrome. Owing to the recent emergence of ZIKV as a global pandemic threat, the roles of the immune system during ZIKV infections are as yet unclear. In contrast, decades of DENV research implicate a dual role for the immune system in protection against and pathogenesis of DENV infection. As DENV and ZIKV are closely related, knowledge based on DENV studies has been used to prioritize investigation of ZIKV immunity and pathogenesis, and to accelerate ZIKV diagnostic, therapeutic, and vaccine design. This review discusses the following topics related to innate and adaptive immune responses to DENV and ZIKV: the interferon system as the key mechanism of host defense and viral target for immune evasion, antibody-mediated protection versus antibody-dependent enhancement, and T cell-mediated protection versus original T cell antigenic sin. Understanding the mechanisms that regulate the balance between immune-mediated protection and pathogenesis during DENV and ZIKV infections is critical toward development of safe and effective DENV and ZIKV therapeutics and vaccines.

Immunological Signatures after Bordetella pertussis Infection Demonstrate Importance of Pulmonary Innate Immune Cells

PubMed Central

Brummelman, Jolanda; van der Maas, Larissa; Tilstra, Wichard; Pennings, Jeroen L. A.; Han, Wanda G. H.; van Els, Cécile A. C. M.; van Riet, Elly; Kersten, Gideon F. A.; Metz, Bernard

2016-01-01

Effective immunity against Bordetella pertussis is currently under discussion following the stacking evidence of pertussis resurgence in the vaccinated population. Natural immunity is more effective than vaccine-induced immunity indicating that knowledge on infection-induced responses may contribute to improve vaccination strategies. We applied a systems biology approach comprising microarray, flow cytometry and multiplex immunoassays to unravel the molecular and cellular signatures in unprotected mice and protected mice with infection-induced immunity, around a B. pertussis challenge. Pre-existing systemic memory Th1/Th17 cells, memory B-cells, and mucosal IgA specific for Ptx, Vag8, Fim2/3 were detected in the protected mice 56 days after an experimental infection. In addition, pre-existing high activity and reactivation of pulmonary innate cells such as alveolar macrophages, M-cells and goblet cells was detected. The pro-inflammatory responses in the lungs and serum, and neutrophil recruitment in the spleen upon an infectious challenge of unprotected mice were absent in protected mice. Instead, fast pulmonary immune responses in protected mice led to efficient bacterial clearance and harbored potential new gene markers that contribute to immunity against B. pertussis. These responses comprised of innate makers, such as Clca3, Retlna, Glycam1, Gp2, and Umod, next to adaptive markers, such as CCR6+ B-cells, CCR6+ Th17 cells and CXCR6+ T-cells as demonstrated by transcriptome analysis. In conclusion, besides effective Th1/Th17 and mucosal IgA responses, the primary infection-induced immunity benefits from activation of pulmonary resident innate immune cells, achieved by local pathogen-recognition. These molecular signatures of primary infection-induced immunity provided potential markers to improve vaccine-induced immunity against B. pertussis. PMID:27711188

Specific β-Turns Precede PPIIL Structures Binding to Allele-Specific HLA-DRβ1* PBRs in Fully-Protective Malaria Vaccine Components

PubMed Central

Bermudez, Adriana; Alba, Martha P.; Vanegas, Magnolia; Patarroyo, Manuel A.; Patarroyo, Manuel E.

2018-01-01

The 3D structural analysis of 62 peptides derived from highly pathogenic Plasmodium falciparum malaria parasite proteins involved in host cell invasion led to finding a striking association between particular β-turn types located in the N-terminal peripheral flanking residue region (preceding the polyproline II left-handed structures fitting into the HLA-DRβ* allele family) and modified immune protection-inducing protein structure induced long-lasting protective immunity. This is the first time association between two different secondary structures associated with a specific immunological function has been described: full, long-lasting protective immunity. PMID:29682500

Specific β-turns precede PPIIL structures binding to allele-specific HLA-DRβ1* PBRs in fully-protective malaria vaccine components

NASA Astrophysics Data System (ADS)

Bermudez, Adriana; Alba, Martha P.; Vanegas, Magnolia; Patarroyo, Manuel A.; Patarroyo, Manuel E.

2018-04-01

The 3D structural analysis of 62 peptides derived from highly pathogenic Plasmodium falciparum malaria parasite proteins involved in host cell invasion led to finding a striking association between particular β-turn types located in the N-terminal peripheral flanking residue region (preceding the polyproline II left-handed structures fitting into the HLA-DRβ* allele family) and modified immune protection-inducing protein structure induced long-lasting protective immunity. This is the first time association between two different secondary structures associated with a specific immunological function has been described: full, long-lasting protective immunity.

As-CATH1-6, novel cathelicidins with potent antimicrobial and immunomodulatory properties from Alligator sinensis, play pivotal roles in host antimicrobial immune responses.

PubMed

Chen, Yan; Cai, Shasha; Qiao, Xue; Wu, Mali; Guo, Zhilai; Wang, Renping; Kuang, Yi-Qun; Yu, Haining; Wang, Yipeng

2017-08-10

Crocodilians are regarded as possessing a powerful immune system. However, the composition and action of the crocodilian immune system have remained unclear until now. Cathelicidins, the principal family of host defense peptides, play pivotal roles in vertebrate immune defense against microbial invasions. However, cathelicidins from crocodilians have not been extensively studied to date. In the present study, six novel cathelicidins (As-CATH1-6) were identified and characterized from the endangered Chinese alligator ( Alligator sinensis ). As-CATH1-6 exhibit no sequence similarity with any of the known cathelicidins. Structure analysis indicated that As-CATH1-3 adopt a random coil secondary conformation, whereas As-CATH4-6 were predicted to mainly adopt an amphipathic α-helix conformation. Among them, As-CATH4-6 exhibited potent, broad-spectrum and rapid antimicrobial activity by inducing the disruption of cell membrane integrity. They also exhibited strong ability to prevent the formation of bacterial biofilms and eradicate preformed biofilms. Furthermore, As-CATH4-6 exhibited potent anti-inflammatory activity by inhibiting the lipopolysaccharide (LPS)-induced production of nitric oxide (NO) and pro-inflammatory cytokines in mouse peritoneal macrophages. They directly neutralized LPS toxicity and therefore inhibited the binding of LPS to the TLR4 receptor and the subsequent activation of inflammatory response pathways. In a peritonitis mice model, As-CATH2-6 provided effective protection against bacterial infection through enhanced immune cell recruitment. In the host Chinese alligator, As-CATH1-6 are mainly expressed in immune organs and epithelial tissues. Bacterial infection significantly enhances their expression, which implies an important role in host anti-infective response. Taken together, the diversity and multiple functions of As-CATH1-6 partially reveal the powerful immune system of the Chinese alligator. © 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

Perforin and gamma interferon expression are required for CD4+ and CD8+ T-cell-dependent protective immunity against a human parasite, Trypanosoma cruzi, elicited by heterologous plasmid DNA prime-recombinant adenovirus 5 boost vaccination.

PubMed

de Alencar, Bruna C G; Persechini, Pedro M; Haolla, Filipe A; de Oliveira, Gabriel; Silverio, Jaline C; Lannes-Vieira, Joseli; Machado, Alexandre V; Gazzinelli, Ricardo T; Bruna-Romero, Oscar; Rodrigues, Mauricio M

2009-10-01

A heterologous prime-boost strategy using plasmid DNA, followed by replication-defective recombinant adenovirus 5, is being proposed as a powerful way to elicit CD4(+) and CD8(+) T-cell-mediated protective immunity against intracellular pathogens. We confirmed this concept and furthered existing research by providing evidence that the heterologous prime-boost regimen using the gene encoding amastigote surface protein 2 elicited CD4(+) and CD8(+) T-cell-mediated protective immunity (reduction of acute parasitemia and prolonged survival) against experimental infection with Trypanosoma cruzi. Protective immunity correlated with the presence of in vivo antigen-specific cytotoxic activity prior to challenge. Based on this, our second goal was to determine the outcome of infection after heterologous prime-boost immunization of perforin-deficient mice. These mice were highly susceptible to infection. A detailed analysis of the cell-mediated immune responses in immunized perforin-deficient mice showed an impaired gamma interferon (IFN-gamma) secretion by immune spleen cells upon restimulation in vitro with soluble recombinant antigen. In spite of a normal numeric expansion, specific CD8(+) T cells presented several functional defects detected in vivo (cytotoxicity) and in vitro (simultaneous expression of CD107a/IFN-gamma or IFN-gamma/tumor necrosis factor alpha) paralleled by a decreased expression of CD44 and KLRG-1. Our final goal was to determine the importance of IFN-gamma in the presence of highly cytotoxic T cells. Vaccinated IFN-gamma-deficient mice developed highly cytotoxic cells but failed to develop any protective immunity. Our study thus demonstrated a role for perforin and IFN-gamma in a number of T-cell-mediated effector functions and in the antiparasitic immunity generated by a heterologous plasmid DNA prime-adenovirus boost vaccination strategy.

Perforin and Gamma Interferon Expression Are Required for CD4+ and CD8+ T-Cell-Dependent Protective Immunity against a Human Parasite, Trypanosoma cruzi, Elicited by Heterologous Plasmid DNA Prime-Recombinant Adenovirus 5 Boost Vaccination▿

PubMed Central

de Alencar, Bruna C. G.; Persechini, Pedro M.; Haolla, Filipe A.; de Oliveira, Gabriel; Silverio, Jaline C.; Lannes-Vieira, Joseli; Machado, Alexandre V.; Gazzinelli, Ricardo T.; Bruna-Romero, Oscar; Rodrigues, Mauricio M.

2009-01-01

A heterologous prime-boost strategy using plasmid DNA, followed by replication-defective recombinant adenovirus 5, is being proposed as a powerful way to elicit CD4+ and CD8+ T-cell-mediated protective immunity against intracellular pathogens. We confirmed this concept and furthered existing research by providing evidence that the heterologous prime-boost regimen using the gene encoding amastigote surface protein 2 elicited CD4+ and CD8+ T-cell-mediated protective immunity (reduction of acute parasitemia and prolonged survival) against experimental infection with Trypanosoma cruzi. Protective immunity correlated with the presence of in vivo antigen-specific cytotoxic activity prior to challenge. Based on this, our second goal was to determine the outcome of infection after heterologous prime-boost immunization of perforin-deficient mice. These mice were highly susceptible to infection. A detailed analysis of the cell-mediated immune responses in immunized perforin-deficient mice showed an impaired gamma interferon (IFN-γ) secretion by immune spleen cells upon restimulation in vitro with soluble recombinant antigen. In spite of a normal numeric expansion, specific CD8+ T cells presented several functional defects detected in vivo (cytotoxicity) and in vitro (simultaneous expression of CD107a/IFN-γ or IFN-γ/tumor necrosis factor alpha) paralleled by a decreased expression of CD44 and KLRG-1. Our final goal was to determine the importance of IFN-γ in the presence of highly cytotoxic T cells. Vaccinated IFN-γ-deficient mice developed highly cytotoxic cells but failed to develop any protective immunity. Our study thus demonstrated a role for perforin and IFN-γ in a number of T-cell-mediated effector functions and in the antiparasitic immunity generated by a heterologous plasmid DNA prime-adenovirus boost vaccination strategy. PMID:19651871

Cellular and humoral immune responses to a tetanus toxoid booster in perinatally HIV-1-infected children and adolescents receiving highly active antiretroviral therapy (HAART).

PubMed

Ching, Natascha; Deville, Jaime G; Nielsen, Karin A; Ank, Bonnie; Wei, Lian S; Sim, Myung Shin; Wolinsky, Steven M; Bryson, Yvonne J

2007-01-01

Human immunodeficiency virus type 1 (HIV-1) infected children treated with highly active antiretroviral therapy (HAART) may develop a significant reduction of plasma viremia associated with an increase in CD4+ T-cell counts. Functional capacity of this reconstituted immune system in response to recall antigens is important to maintain protective immunity to vaccine-preventable diseases. We therefore determined cellular and humoral immune responses to tetanus toxoid (TT) booster in perinatally HIV-1-infected children and adolescents receiving HAART. Immune responses were prospectively evaluated pre- and post-tetanus booster using lymphocyte proliferation assay (LPA) stimulation index (SI > or = 3.0) and tetanus antibody (TAb > or = 0.15) in 15 patients. The median interval from primary tetanus immunization series was 6 years (range 2-12 years). We compared patients by their virological response to HAART (complete responders, CR, n=7; incomplete responders, ICR, n=8). There were no significant differences in median age 12.6 years (CR: 12.9; ICR: 10.6) or median CD4 T-cell pre-booster (CR: 35%/819; ICR: 26%/429) between groups. Tetanus LPA responses were observed in one patient prior to booster and in seven patients post-booster. In contrast, 38% of patients had protective TAb pre-booster, but 92% developed protective TAb post-booster. All of the CR and 5/6 ICR patients developed protective TAb. HIV-1-infected children and adolescents had modest LPA responses to tetanus following booster, similar to HIV-1-infected adults. However, the majority of patients developed protective TAb levels after booster and maintained the response. Shorter intervals may need to be considered for TT immunization boosters in HIV-1-infected pediatric patients, as only 38% had protective TAb at baseline.

The novel Lyme borreliosis vaccine VLA15 shows broad protection against Borrelia species expressing six different OspA serotypes.

PubMed

Comstedt, Pär; Schüler, Wolfgang; Meinke, Andreas; Lundberg, Urban

2017-01-01

We have previously shown that the Outer surface protein A (OspA) based Lyme borreliosis vaccine VLA15 induces protective immunity in mice. Herein, we report the induction of protective immunity by VLA15 with mouse models using ticks infected with B. burgdorferi (OspA serotype 1), B. afzelii (OspA serotype 2) and B. bavariensis (OspA serotype 4) or with in vitro grown B. garinii (OspA serotype 5 and 6) for challenge. For B. garinii (OspA serotype 3), we have developed a growth inhibition assay using chicken complement and functional antibodies targeting B. garinii (OspA serotype 3) could be demonstrated after immunization with VLA15. Furthermore, following three priming immunizations, a booster dose was administered five months later and the induction of immunological memory could be confirmed. Thus, the antibody titers after the booster dose were increased considerably compared to those after primary immunization. In addition, the half-lives of anti-OspA serotype specific antibodies after administration of the booster immunization were longer than after primary immunization. Taken together, we could show that VLA15 induced protection in mice against challenge with four different clinically relevant Borrelia species (B. burgdorferi, B. afzelii, B. garinii and B. bavariensis) expressing five of the six OspA serotypes included in the vaccine. The protection data is supported by functional assays showing efficacy against spirochetes expressing any of the six OspA serotypes (1 to 6). To our knowledge, this is the first time a Lyme borreliosis vaccine has been able to demonstrate such broad protection in preclinical studies. These new data provide further promise for the clinical development of VLA15 and supports our efforts to provide a new Lyme borreliosis vaccine available for global use.

Outer membrane vesicles of Gallibacterium anatis induce protective immunity in egg-laying hens.

PubMed

Pors, Susanne E; Pedersen, Ida J; Skjerning, Ragnhild Bager; Thøfner, Ida C N; Persson, Gry; Bojesen, Anders M

2016-11-15

Gallibacterium anatis causes infections in the reproductive tract of egg-laying hens and induce increased mortality and decreased egg production. New prophylactic measures are needed in order to improve animal welfare and production efficiency. Bacterial outer membrane vesicles (OMVs) have previously shown promising results in protection against infections and we hypothesized that OMVs could serve as an immunogen to protect egg-laying hens against G. anatis. To investigate the immunogenic potential of G. anatis OMVs, two in vivo studies in egg-laying hens were made. The trials assessedthe degree of protection provided by immunization with G. anatis OMV against challenge and the IgY responses in serum after immunization and challenge, respectively. A total of 64 egg-laying hens were included in the trials. OMVs for immunization were produced and purified from a high-producing G. anatis ΔtolR mutant. Challenge was done with G. anatis 12656-12 and evaluated by scoring lesions and bacterial re-isolation rates from peritoneum. Finally, levels of OMV-specific IgY in sera were assayed by ELISA. Immunization with OMVs decreased the lesions scores significantly, while the bacterial re-isolation remained unchanged. Furthermore, a high OMV-specific IgY response was induced by immunization and subsequent challenge of the hens. The results strongly indicate that immunization with G. anatis OMVs provides significant protection against G. anatis challenge and induces specific antibody responses with high titers of OMV-specific IgY in serum. The results therefore show great promise for OMV based vaccines aiming at providing protecting against G. anatis in egg-laying hens. Copyright © 2016 Elsevier B.V. All rights reserved.

The Contribution of Systemic and Pulmonary Immune Effectors to Vaccine-Induced Protection from H5N1 Influenza Virus Infection

PubMed Central

Lau, Yuk-Fai; Wright, Amber R.

2012-01-01

Live attenuated influenza vaccines (LAIVs) are effective in providing protection against influenza challenge in animal models and in preventing disease in humans. We previously showed that LAIVs elicit a range of immune effectors and that successful induction of pulmonary cellular and humoral immunity in mice requires pulmonary replication of the vaccine virus. An upper respiratory tract immunization (URTI) model was developed in mice to mimic the human situation, in which the vaccine virus does not replicate in the lower respiratory tract, allowing us to assess the protective efficacy of an H5N1 LAIV against highly pathogenic H5N1 virus challenge in the absence of significant pulmonary immunity. Our results show that, after one dose of an H5N1 LAIV, pulmonary influenza-specific lymphocytes are the main contributors to clearance of challenge virus from the lungs and that contributions of influenza-specific enzyme-linked immunosorbent assay (ELISA) antibodies in serum and splenic CD8+ T cells were negligible. Complete protection from H5N1 challenge was achieved after two doses of H5N1 LAIV and was associated with maturation of the antibody response. Although passive transfer of sera from mice that received two doses of vaccine prevented lethality in naive recipients following challenge, the mice showed significant weight loss, with high pulmonary titers of the H5N1 virus. These data highlight the importance of mucosal immunity in mediating optimal protection against H5N1 infection. Understanding the requirements for effective induction and establishment of these protective immune effectors in the respiratory tract paves the way for a more rational and effective vaccine approach in the future. PMID:22379093

Phytol-based novel adjuvants in vaccine formulation: 2. Assessment of efficacy in the induction of protective immune responses to lethal bacterial infections in mice.

PubMed

Lim, So-Yon; Bauermeister, Adam; Kjonaas, Richard A; Ghosh, Swapan K

2006-10-23

Adjuvants are known to significantly enhance vaccine efficacy. However, commercial adjuvants often have limited use because of toxicity in humans. The objective of this study was to determine the comparative effectiveness of a diterpene alcohol, phytol and its hydrogenated derivative PHIS-01, relative to incomplete Freund's adjuvant (IFA), a commonly used adjuvant in augmenting protective immunity in mice against E. coli and S. aureus, and in terms of inflammatory cytokines. Vaccines, consisting of heat-attenuated E. coli or S. aureus and either of the two phytol-based adjuvants or IFA, were tested in female BALB/c mice. The vaccines were administered intraperitoneally at 10-day intervals. The efficacy of the phytol and PHIS-01, as compared to IFA, was assessed by ELISA in terms of anti-bacterial antibody and inflammatory cytokines. We also examined the ability of the vaccines to induce specific protective immunity by challenging mice with different doses of live bacteria. IFA, phytol, and PHIS-01 were equally efficient in evoking anti-E. coli antibody response and in providing protective immunity against live E. coli challenges. In contrast, the antibody response to S. aureus was significant when PHIS-01 was used as the adjuvant. However, in terms of the ability to induce protective immunity, phytol was most effective against S. aureus. Moreover, during challenges with live E. coli and S. aureus immune mice produced much less IL-6, the mediators of fatal septic shock syndromes. Our results show that vaccine formulations containing phytol and PHIS-01 as adjuvants confer a robust and protective immunity against both Gram-negative and Gram-positive bacteria without inducing adverse inflammatory cytokine due to IL-6.

Changes in Fish Assemblages following the Establishment of a Network of No-Take Marine Reserves and Partially-Protected Areas

PubMed Central

Kelaher, Brendan P.; Coleman, Melinda A.; Broad, Allison; Rees, Matthew J.; Jordan, Alan; Davis, Andrew R.

2014-01-01

Networks of no-take marine reserves and partially-protected areas (with limited fishing) are being increasingly promoted as a means of conserving biodiversity. We examined changes in fish assemblages across a network of marine reserves and two different types of partially-protected areas within a marine park over the first 5 years of its establishment. We used Baited Remote Underwater Video (BRUV) to quantify fish communities on rocky reefs at 20–40 m depth between 2008–2011. Each year, we sampled 12 sites in 6 no-take marine reserves and 12 sites in two types of partially-protected areas with contrasting levels of protection (n = 4 BRUV stations per site). Fish abundances were 38% greater across the network of marine reserves compared to the partially-protected areas, although not all individual reserves performed equally. Compliance actions were positively associated with marine reserve responses, while reserve size had no apparent relationship with reserve performance after 5 years. The richness and abundance of fishes did not consistently differ between the two types of partially-protected areas. There was, therefore, no evidence that the more regulated partially-protected areas had additional conservation benefits for reef fish assemblages. Overall, our results demonstrate conservation benefits to fish assemblages from a newly established network of temperate marine reserves. They also show that ecological monitoring can contribute to adaptive management of newly established marine reserve networks, but the extent of this contribution is limited by the rate of change in marine communities in response to protection. PMID:24454934

Association of the host immune response with protection using a live attenuated African swine fever virus model

USDA-ARS?s Scientific Manuscript database

African swine fever virus (ASFV) causes a lethal disease of swine. Infection with attenuated strains protect against challenge but there is limited knowledge of the immune mechanisms generating that protection. ASFV Pret4 produces a fatal disease, while its derivative, lacking virulence-associated g...

Protective and Pathological Immunity during Central Nervous System Infections.

PubMed

Klein, Robyn S; Hunter, Christopher A

2017-06-20

The concept of immune privilege of the central nervous system (CNS) has dominated the study of inflammatory processes in the brain. However, clinically relevant models have highlighted that innate pathways limit pathogen invasion of the CNS and adaptive immunity mediates control of many neural infections. As protective responses can result in bystander damage, there are regulatory mechanisms that balance protective and pathological inflammation, but these mechanisms might also allow microbial persistence. The focus of this review is to consider the host-pathogen interactions that influence neurotropic infections and to highlight advances in our understanding of innate and adaptive mechanisms of resistance as key determinants of the outcome of CNS infection. Advances in these areas have broadened our comprehension of how the immune system functions in the brain and can readily overcome immune privilege. Copyright © 2017. Published by Elsevier Inc.

Emerging concepts on the role of innate immunity in the prevention and control of HIV infection.

PubMed

Ackerman, Margaret E; Dugast, Anne-Sophie; Alter, Galit

2012-01-01

While neutralizing antibodies can provide sterilizing protection from HIV infection via their variable domains, the antibody constant domain provides a functional link between innate and adaptive immunity and offers a means to harness the potent antiviral properties of a wide spectrum of innate immune effector cells. There has been a growing appreciation of the role of these effector mechanisms across fields from cancer immunotherapy to autoimmunity and infectious disease, as well as speculation that this mechanism may be responsible for the protection observed in the RV144 HIV vaccine trial. This review summarizes these extraneutralizing humoral immune activities, progress in defining the importance of these effector mechanisms during progression in HIV infection, and the potential impact that such vaccine-induced immune responses may have on protection from infection.

Evaluation of YadC protein delivered by live attenuated Salmonella as a vaccine against plague.

PubMed

Sun, Wei; Olinzock, Joseph; Wang, Shifeng; Sanapala, Shilpa; Curtiss, Roy

2014-03-01

Yersinia pestis YadB and YadC are two new outer membrane proteins related to its pathogenicity. Here, codon-optimized yadC, yadC810 (aa 32-551), or yadBC antigen genes delivered by live attenuated Salmonella strains are evaluated in mice for induction of protective immune responses against Y. pestis CO92 through subcutaneous or intranasal challenge. Our findings indicate that mice immunized with Salmonella synthesizing YadC, YadC810, or YadBC develop significant serum IgG responses to purified recombinant YadC protein. For subcutaneous challenge (approximately 230 LD50 of Y. pestis CO92), mice immunized with Salmonella synthesizing YadC or YadC810 are afforded 50% protection, but no protection by immunization with the Salmonella strain synthesizing YadBC. None of these antigens provided protection against intranasal challenge (approximately 31 LD50 of Y. pestis CO92). In addition, subcutaneous immunization with purified YadC810 protein emulsified with alum adjuvant does not elicit a protective response against Y. pestis administered by either challenge route. © 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.

Oral or parenteral administration of replication-deficient adenoviruses expressing the measles virus haemagglutinin and fusion proteins: protective immune responses in rodents.

PubMed

Fooks, A R; Jeevarajah, D; Lee, J; Warnes, A; Niewiesk, S; ter Meulen, V; Stephenson, J R; Clegg, J C

1998-05-01

The genes encoding the measles virus (MV) haemagglutinin (H) and fusion (F) proteins were placed under the control of the human cytomegalovirus immediate early promoter in a replication-deficient adenovirus vector. Immunofluorescence and radioimmune precipitation demonstrated the synthesis of each protein and biological activity was confirmed by the detection of haemadsorption and fusion activities in infected cells. Oral as well as parenteral administration of the H-expressing recombinant adenovirus elicited a significant protective response in mice challenged with MV. While the F-expressing adenovirus failed to protect mice, cotton rats immunized with either the H- or F-expressing recombinant showed reduced MV replication in the lungs. Antibodies elicited in mice following immunization with either recombinant had no in vitro neutralizing activity, suggesting a protective mechanism involving a cell-mediated immune response. This study demonstrates the feasibility of using oral administration of adenovirus recombinants to induce protective responses to heterologous proteins.

Immunity to current H5 highly pathogenic avian influenza viruses: From vaccines to adaptive immunity in wild birds

USDA-ARS?s Scientific Manuscript database

Following the 2014-2015 outbreaks of H5N2 and H5N8 highly pathogenic avian influenza (HPAI) in the U.S., studies were performed to assess the immunity required for protection against future outbreaks should they occur. We assessed the ability of vaccines to induce protection of chickens and turkeys...

Peroral Immunization of Rats with Escherichia coli Heat-Labile Enterotoxin Delivered by Microspheres

PubMed Central

Klipstein, Frederick A.; Engert, Richard F.; Sherman, William T.

1983-01-01

The antigenicity of the Escherichia coli heat-labile enterotoxin was not protected against the adverse effect of gastric acidity when the toxin was given together with bicarbonate for peroral immunization to rats, but immunization with the heat-labile enterotoxin encapsulated in pH-dependent microspheres aroused the same strong degree of serum and mucosal antitoxin responses and of protection against challenge as was achieved by peroral immunization after ablation of gastric secretions by pretreatment with cimetidine. PMID:6339378

Toxoplasma gondii Antigen-Pulsed-Dendritic Cell-Derived Exosomes Induce a Protective Immune Response against T. gondii Infection

PubMed Central

Aline, Fleur; Bout, Daniel; Amigorena, Sébastian; Roingeard, Philippe; Dimier-Poisson, Isabelle

2004-01-01

It was previously demonstrated that immunizing mice with spleen dendritic cells (DCs) that had been pulsed ex vivo with Toxoplasma gondii antigens triggers a systemic Th1-biased specific immune response and induces protection against infection. T. gondii can cause severe sequelae in the fetuses of mothers who acquire the infection during pregnancy, as well as life-threatening neuropathy in immunocompromised patients, in particular those with AIDS. Here, we investigate the efficacy of a novel cell-free vaccine composed of DC exosomes, which are secreted antigen-presenting vesicles that express functional major histocompatibility complex class I and II and T-cell-costimulatory molecules. They have already been shown to induce potent antitumor immune responses. We investigated the potential of DC2.4 cell line-derived exosomes to induce protective immunity against toxoplasmosis. Our data show that most adoptively transferred T. gondii-pulsed DC-derived exosomes were transferred to the spleen, elicited a strong systemic Th1-modulated Toxoplasma-specific immune response in vivo, and conferred good protection against infection. These findings support the possibility that DC-derived exosomes can be used for T. gondii immunoprophylaxis and for immunoprophylaxis against many other pathogens. PMID:15213158

Host protective roles of type 2 immunity: Parasite killing and tissue repair, flip sides of the same coin

PubMed Central

Allen, Judith E.; Sutherland, Tara E.

2014-01-01

Metazoan parasites typically induce a type 2 immune response, characterized by T helper 2 (Th2) cells that produce the cytokines IL-4, IL-5 and IL-13 among others. The type 2 response is host protective, reducing the number of parasites either through direct killing in the tissues, or expulsion from the intestine. Type 2 immunity also protects the host against damage mediated by these large extracellular parasites as they migrate through the body. At the center of both the innate and adaptive type 2 immune response, is the IL-4Rα that mediates many of the key effector functions. Here we highlight the striking overlap between the molecules, cells and pathways that mediate both parasite control and tissue repair. We have proposed that adaptive Th2 immunity evolved out of our innate repair pathways to mediate both accelerated repair and parasite control in the face of continual assault from multicellular pathogens. Type 2 cytokines are involved in many aspects of mammalian physiology independent of helminth infection. Therefore understanding the evolutionary relationship between helminth killing and tissue repair should provide new insight into immune mechanisms of tissue protection in the face of physical injury. PMID:25028340