Evidence That Blunted CD4 T-Cell Responses Underlie Deficient Protective Antibody Responses to Influenza Vaccines in Repeatedly Vaccinated Human Subjects.
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ABSTRACT:
SUBMITTER: Richards KA
PROVIDER: S-EPMC8494023 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Comparsion of the transcriptomes of naive, resting memory and activated memory CD4+ T lymphocytes. Peripheral blood lymphocytes were collected at baseline and day 13 post-inoculation of a healthy subject administered with vaccinia virus. Cells were isolated by FACs using antibodies against CD4, CD45RO and CD38.
2017-10-01 | GSE60920 | GEO
Project description:BackgroundIn 2009, a novel influenza A/H1N1pdm09 emerged and caused a pandemic. This strain continued to circulate and was therefore included in the seasonal vaccines up to the 2016/2017-season. This provided a unique opportunity to study the long-term antibody responses to H1N1pdm09 in healthcare workers (HCW) with a different vaccination history.MethodsHCW at Haukeland University Hospital, Bergen, Norway were immunized with the AS03-adjuvanted H1N1pdm09 vaccine in 2009 (N=55) and divided into groups according to their vaccination history; one vaccination (N=10), two vaccinations (N=15), three vaccinations (N=5), four vaccinations (N=15) and five vaccinations (N=10). HCW are recommended for influenza vaccination to protect both themselves and their patients, but it is voluntary in Norway. Blood samples were collected pre- and at 21 days, 3, 6, and 12 months after each vaccination, or annually from 2010 HCW without vaccination. ELISA, haemagglutination inhibition (HI) and microneutralization (MN) assays were used to determine the antibody response.ResultsPandemic vaccination induced a significant increase in the H1N1-specific antibodies measured by ELISA, HI and MN. Seasonal vaccination boosted the antibody response, both in HCW with only the current vaccination and those with prior and current vaccination during 2010/11-2013/14. We observed a trend of increased antibody responses in HCW with only the current vaccination in 2013/14. A two- and three-year gap before vaccination in 2013/14 provided a more potent antibody response compared to annually vaccinated HCW.ConclusionsOur long term follow up study elucidates the antibody response in HCW with different vaccination histories. Our findings contribute to our understanding of the impact of repeated vaccination upon antibody responses.
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Project description:BackgroundFurunculosis, a disease caused with gram negative bacteria Aeromonas salmonicida produces heavy losses in aquaculture. Vaccination against furunculosis reduces mortality of Atlantic salmon but fails to eradicate infection. Factors that determine high individual variation of vaccination efficiency remain unknown. We used gene expression analyses to search for the correlates of vaccine protection against furunculosis in Atlantic salmon.ResultsNaïve and vaccinated fish were challenged by co-habitance. Fish with symptoms of furunculosis at the onset of mass mortality (LR - low resistance) and survivors (HR - high resistance) were sampled. Hepatic gene expression was analyzed with microarray (SFA2.0 - immunochip) and real-time qPCR. Comparison of LR and HR indicated changes associated with the protection and results obtained with naïve fish were used to find and filter the vaccine-independent responses. Genes involved in recruitment and migration of immune cells changed expression in both directions with greater magnitude in LR. Induction of the regulators of immune responses was either equal (NFkB) or greater (Jun) in LR. Expression levels of proteasome components and extracellular proteases were higher in LR while protease inhibitors were up-regulated in HR. Differences in chaperones and protein adaptors, scavengers of reactive oxygen species and genes for proteins of iron metabolism suggested cellular and oxidative stress in LR. Reduced levels of free iron and heme can be predicted in LR by gene expression profiles with no protection against pathogen. The level of complement regulation was greater in HR, which showed up-regulation of the components of membrane attack complex and the complement proteins that protect the host against the auto-immune damages. HR fish was also characterized with up-regulation of genes for proteins involved in the protection of extracellular matrix, lipid metabolism and clearance of endogenous and exogenous toxic compounds. A number of genes with marked expression difference between HR and LR can be considered as positive and negative correlates of vaccine protection against furunculosis.ConclusionEfficiency of vaccination against furunculosis depends largely on the ability of host to neutralize the negative impacts of immune responses combined with efficient clearance and prevention of tissue damages.
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Project description:The development of novel human vaccines would be greatly facilitated by the development of in vivo models that permit preclinical analysis of human immune responses. Here, we show that nonobese diabetic severe combined immunodeficiency (NOD/SCID) beta(2) microglobulin(-/-) mice, engrafted with human CD34+ hematopoietic progenitors and further reconstituted with T cells, can mount specific immune responses against influenza virus vaccines. Live attenuated trivalent influenza virus vaccine induces expansion of CD8+ T cells specific to influenza matrix protein (FluM1) and nonstructural protein 1 in blood, spleen, and lungs. On ex vivo exposure to influenza antigens, antigen-specific CD8+ T cells produce IFN-gamma and express cell-surface CD107a. FluM1-specific CD8+ T cells can be also expanded in mice vaccinated with inactivated trivalent influenza virus vaccine. Expansion of antigen-specific CD8+ T cells is dependent on reconstitution of the human myeloid compartment. Thus, this humanized mouse model permits preclinical testing of vaccines designed to induce cellular immunity, including those against influenza virus. Furthermore, this work sets the stage for systematic analysis of the in vivo functions of human DCs. This, in turn, will allow a new approach to the rational design and preclinical testing of vaccines that cannot be tested in human volunteers.
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Project description:Rational immunogen design aims to focus antibody responses to vulnerable sites on primary antigens. Given the size of these antigens, there is, however, potential for eliciting unwanted, off-target responses. Here, we use our electron microscopy polyclonal epitope mapping approach to describe the antibody specificities elicited by immunization of non-human primates with soluble HIV envelope trimers and subsequent repeated viral challenge. An increased diversity of epitopes recognized and the approach angle by which these antibodies bind constitute a hallmark of the humoral response in most protected animals. We also show that fusion peptide-specific antibodies are likely responsible for some neutralization breadth. Moreover, cryoelectron microscopy (cryo-EM) analysis of a fully protected animal reveals a high degree of clonality within a subset of putatively neutralizing antibodies, enabling a detailed molecular description of the antibody paratope. Our results provide important insights into the immune response against a vaccine candidate that entered into clinical trials in 2019.
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Project description:Zoonotic transmission of brucellosis often results from exposure to Brucella-infected livestock, feral animals, or wildlife or frequently via consumption of unpasteurized milk products or raw meat. Since natural infection of humans often occurs by the oral route, mucosal vaccination may offer a means to confer protection for both mucosal and systemic tissues. Significant efforts have focused on developing a live brucellosis vaccine, and deletion of the znuA gene involved in zinc transport has been found to attenuate Brucella abortus. A similar mutation has been adapted for Brucella melitensis and tested to determine whether oral administration of ΔznuA B. melitensis can confer protection against nasal B. melitensis challenge. A single oral vaccination with ΔznuA B. melitensis rapidly cleared from mice within 2 weeks and effectively protected mice upon nasal challenge with wild-type B. melitensis 16M. In 83% of the vaccinated mice, no detectable brucellae were found in their spleens, unlike with phosphate-buffered saline (PBS)-dosed mice, and vaccination also enhanced the clearance of brucellae from the lungs. Moreover, vaccinated gamma interferon-deficient (IFN-γ(-/-)) mice also showed protection in both spleens and lungs, albeit protection that was not as effective as in immunocompetent mice. Although IFN-γ, interleukin 17 (IL-17), and IL-22 were stimulated by these live vaccines, only RB51-mediated protection was codependent upon IL-17 in BALB/c mice. These data suggest that oral immunization with the live, attenuated ΔznuA B. melitensis vaccine provides an attractive strategy to protect against inhalational infection with virulent B. melitensis.
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Project description:Substantial evidence indicates that immunotherapy is a feasible and effective approach for the treatment of numerous types of cancer. Among various immunotherapy options, peptide vaccines to generate antitumor T cells appear as promising candidates, because of their cost effectiveness and ease of implementation. Nevertheless, most peptide vaccines are notorious for being weekly immunogenic and, thus, optimization of the vaccination strategy is essential to achieve therapeutic effectiveness. In addition, effective peptide vaccines must stimulate both CD8 cytotoxic and CD4 helper T lymphocytes. Our group has been successful in designing effective peptide vaccination strategies for inducing CD8 T-cell responses in mouse tumor models. Here, we describe a somewhat similar, but distinct, peptide vaccination strategy capable of generating vast CD4 T-cell responses by combining synthetic peptides with toll-like receptor (TLR) agonists and OX40/CD40 costimulation. This vaccination strategy was efficient in overcoming immune tolerance to a self-tumor-associated antigen and generated significant antitumor effects in a mouse model of malignant melanoma. The optimized peptide vaccine also allowed the expansion of adoptively transferred CD4 T cells without the need for lymphodepletion and IL2 administration, generating effective antimelanoma responses through the enhancement of proliferative and antiapoptotic activities of CD4 T cells. These results have practical implications in the design of more effective T-cell-based immunotherapies. Cancer Immunol Res; 5(1); 72-83. ©2016 AACR.
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Project description:The development of a preventative HIV/AIDS vaccine is challenging due to the diversity of viral genome sequences, especially in the viral envelope (Env???). Since it is not possible to directly match the vaccine strain to the vast number of circulating HIV-1 strains, it is necessary to develop an HIV-1 vaccine that can protect against a heterologous viral challenge. Previous studies from our group demonstrated that a mixture of wild type clade B Env(gp160s) were able to protect against a heterologous clade B challenge more effectively than a consensus clade B Envg(p160) vaccine. In order to broaden the immune response to other clades of HIV, in this study rhesus macaques were vaccinated with a polyvalent mixture of purified HIV-1 trimerized consensus Envg(p140) proteins representing clades A, B, C, and E. The elicited immune responses were compared to a single consensus Env(gp140) representing all isolates in group M (Con M). Both vaccines elicited anti- Env(gp140) IgG antibodies that bound an equal number of HIV-1 Env(gp160) proteins representing clades A, B and C. In addition, both vaccines elicited antibodies that neutralized the HIV-1(SF162) isolate. However, the vaccinated monkeys were not protected against SHIV(SF162p4) challenge. These results indicate that consensus Env(gp160) vaccines, administered as purified Env(gp140) trimers, elicit antibodies that bind to Env(gp160s) from strains representing multiple clades of HIV-1, but these vaccines did not protect against heterologous SHIV challenge.
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Project description:Immunization with vaccinia virus elicits a protective Ab response that is almost completely CD4(+) T cell dependent. A recent study in a rodent model observed a deterministic linkage between Ab and CD4(+) T cell responses to particular vaccinia virus proteins suggesting that CD4(+) T cell help is preferentially provided to B cells with the same protein specificity (Sette et al. 2008. Immunity 28: 847-858). However, a causal linkage between Ab and CD4(+) T cell responses to vaccinia or any other large pathogen in humans has yet to be done. In this study, we measured the Ab and CD4(+) T cell responses against four vaccinia viral proteins (A27L, A33R, B5R, and L1R) known to be strongly targeted by humoral and cellular responses induced by vaccinia virus vaccination in 90 recently vaccinated and 7 long-term vaccinia-immunized human donors. Our data indicate that there is no direct linkage between Ab and CD4(+) T cell responses against each individual protein in both short-term and long-term immunized donors. Together with the observation that the presence of immune responses to these four proteins is linked together within donors, our data suggest that in vaccinia-immunized humans, individual viral proteins are not the primary recognition unit of CD4(+) T cell help for B cells. Therefore, we have for the first time, to our knowledge, shown evidence that CD4(+) T cells provide intermolecular (also known as noncognate or heterotypic) help to generate robust Ab responses against four vaccinia viral proteins in humans.
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Project description:Targeting antigen to surface receptors on dendritic cells (DCs) can improve antibody response against subunit vaccines. We have previously observed that human XCL1-fusion vaccines target murine Xcr1+ DCs without actively inducing endocytosis of the antigen, resulting in enhanced antibody responses in mice. However, the use of foreign chemokines for targeting is undesirable when translating this observation to human or veterinary medicine due to potential cross-reactive responses against the endogenous chemokine. Here we have identified a mutant version of murine Xcl1, labeled Xcl1(Δ1) owing to removal of a conserved valine in position 1 of the mature chemokine, that retains specific binding to Xcr1+ DCs without inducing endocytosis of the receptor. DNA immunization with Xcl1(Δ1) conjugated to influenza hemagglutinin (HA) induced improved antibody responses, with higher end point titers of IgG compared to WT Xcl1-HA. The Xcl1(Δ1) fusion vaccine also resulted in an increased number of HA reactive germinal center B cells with higher avidity toward the antigen, and serum transfer experiments show that Xcl1(Δ1)-HA induced antibody responses provided better protection against influenza infection as compared to WT Xcl1-HA. In summary, our observations indicate that targeting antigen to Xcr1+ DCs in an endocytosis deficient manner enhances antibody responses. This effect was obtained by introducing a single mutation to Xcl1, suggesting our strategy may easily be translated to human or veterinary vaccine settings.
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