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Innate and secondary humoral responses are improved by increasing the time between MVA vaccine immunizations.

ABSTRACT: Comprehending the mechanisms behind the impact of vaccine regimens on immunity is critical for improving vaccines. Indeed, the time-interval between immunizations may influence B and T cells, as well as innate responses. We compared two vaccine schedules using cynomolgus macaques immunized with an attenuated vaccinia virus. Two subcutaneous injections 2 weeks apart led to an impaired secondary antibody response and similar innate myeloid responses to both immunizations. In contrast, a delayed boost (2 months) improved the quality of the antibody response and involved more activated/mature innate cells, induced late after the prime and responding to the recall. The magnitude and quality of the secondary antibody response correlated with the abundance of these neutrophils, monocytes, and dendritic cells that were modified phenotypically and enriched prior to revaccination at 2 months, but not 2 weeks. These late phenotypic modifications were associated with an enhanced ex vivo cytokine production (including IL-12/23 and IL-1β) by PBMCs short after the second immunization, linking phenotype and functions. This integrated analysis reveals a deep impact of the timing between immunizations, and highlights the importance of early but also late innate responses involving phenotypical changes, in shaping humoral immunity.

SUBMITTER: Palgen JL

PROVIDER: S-EPMC7081268 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Coadministration of seasonal influenza vaccine and MVA-NP+M1 simultaneously achieves potent humoral and cell-mediated responses.

Project description:Current seasonal influenza vaccines have reduced immunogenicity and are of suboptimal efficacy in older adults. We have previously shown that the novel candidate vaccine MVA-NP+M1 is able to boost memory T cell responses in adults aged 50-85 years. Preclinical studies have demonstrated that viral vectored vaccines can act as adjuvants when coadministered with protein-based vaccines. We have conducted a phase I clinical trial to compare the coadministration of seasonal influenza vaccine and MVA-NP+M1 with seasonal influenza vaccine alone in adults aged 50 years and above. This combination of vaccines was safe and well tolerated. T cell responses to internal influenza proteins were boosted to significantly higher levels in the group receiving MVA-NP+M1 compared with the group receiving seasonal influenza vaccine alone. Rates of seroprotection and seroconversion against the three vaccine strains were similar in both groups; however, there was a significant increase in the geometric mean titer ratio for the H3N2 component of seasonal influenza vaccine in the coadministration group. While some vaccine combinations result in immune interference, the coadministration of MVA-NP+M1 alongside seasonal influenza vaccine is shown here to increase some influenza strain-specific antibody responses and boost memory T cells capable of recognizing a range of influenza A subtypes.

| S-EPMC3978791 | biostudies-literature

Dissecting humoral immune responses to an MVA-vectored MERS-CoV vaccine in humans using a systems serology approach.

Project description:Besides neutralizing antibodies, which are considered an important measure for vaccine immunogenicity, Fc-mediated antibody functions can contribute to antibody-mediated protection. They are strongly influenced by structural antibody properties such as subclass and Fc glycan composition. We here applied a systems serology approach to dissect humoral immune responses induced by MVA-MERS-S, an MVA-vectored vaccine against the Middle East respiratory syndrome coronavirus (MERS-CoV). Building on preceding studies reporting the safety and immunogenicity of MVA-MERS-S, our study highlights the potential of a late boost, administered one year after prime, to enhance both neutralizing and Fc-mediated antibody functionality compared to the primary vaccination series. Distinct characteristics were observed for antibodies specific to the MERS-CoV spike protein S1 and S2 subunits, regarding subclass and glycan compositions as well as Fc functionality. These findings highlight the benefit of a late homologous booster vaccination with MVA-MERS-S and may be of interest for the design of future coronavirus vaccines.

| S-EPMC11325358 | biostudies-literature

Novel MVA Vector Expressing Anti-apoptotic gene, B13R, Delays Apoptosis and Enhances Humoral Responses

Project description:Modified vaccinia virus Ankara (MVA) has been explored as a vaccine vector for use against infectious diseases and cancer. MVA is an immunogenic, attenuated poxvirus capable of eliciting robust cellular and humoral responses in pre-clinical animal models and in patients. However, upon infection with MVA, cells undergo rapid apoptosis leading to faster clearance of recombinant antigens. The fragmentation of the anti-apoptotic gene B13R in MVA could contribute to this effect. Here, we replaced the fragmented B13R with a functional version and observed that MVA-B13R infected HeLa cells and muscle cell lines delayed caspase 3 activation compared to MVA indicating slower progression of apoptosis. For immunogenicity studies, mice were intramuscularly immunized with recombinant MVA or MVA-B13R expressing SIV Gag, Pol and HIV Env (SHIV). We observed higher Env-specific humoral responses from MVA-B13R SHIV compared to MVA SHIV mice. To determine differences in the innate immune response that may have contributed to the augmented humoral response, we performed RNA-Seq analysis on draining lymph node cells after immunization. Gene set enrichment analysis from day 1 after immunization showed that MVA-B13R SHIV immunizations were associated with a negative enrichment for type I and II interferon responses compared to MVA SHIV mice indicating MVA-B13R SHIV induces a delayed anti-viral interferon response that may lead to the enhanced humoral response observed. Taken together, these results demonstrate that restoring B13R functionality in MVA significantly delays MVA-induced apoptosis, augments Env-specific antibody responses, and is associated with reduced interferon-alpha and interferon-gamma responses induced after vaccination.

2018-11-27 | GSE119884 | GEO

Innate gene signature distinguishes humoral versus cytotoxic responses to influenza vaccination.

Project description:BackgroundSystems vaccinology allows cutting-edge analysis of innate biomarkers of vaccine efficacy. We have been exploring novel strategies to shape the adaptive immune response, by targeting innate immune cells through novel immunization routes.MethodsThis randomized phase I/II clinical study (n=60 healthy subjects aged 18-45 years old) used transcriptomic analysis to discover early biomarkers of immune response quality after transcutaneous (t.c.), intradermal (i.d.), and intramuscular (i.m.) administration of a trivalent influenza vaccine (TIV season 2012-2013) (1:1:1 ratio). Safety and immunogenicity (hemagglutinin inhibition (HI), microneutralization (MN) antibodies and CD4, CD8 effector T cells) were measured at baseline Day (D)0 and at D21. Blood transcriptome was analyzed at D0 and D1.ResultsTIV-specific CD8+GranzymeB+(GRZ) T cells appeared in more individuals immunized by the t.c. and i.d. routes, while immunization by the i.d. and i.m. routes prompted high levels of HI antibody titers and MN against A/H1N1 and A/H3N2 influenza viral strains. The early innate gene signature anticipated immunological outcome by discriminating two clusters of individuals with either distinct humoral or CD8 cytotoxic responses. Several pathways explained this dichotomy confirmed by nine genes and serum level of CXCL10 were correlated with either TIV-specific cytotoxic CD8+GRZ+ T-cell or antibody responses. A logistic regression analysis demonstrated that these nine genes and serum levels of CXCL10 (D1/D0) best foreseen TIV-specific CD8+GRZ+ T-cell and antibody responses at D21.ConclusionThis study provides new insight into the impact of immunization routes and innate signature in the quality of adaptive immune responses.

| S-EPMC6486343 | biostudies-literature

Local innate immune responses in the vaccine adjuvant-injected muscle.

Project description:Inducing a high magnitude of antibodies, possibly in combination with T-cell responses that offer epitope breadth over prolonged periods of time is likely a prerequisite for effective vaccines against severe diseases such as HIV-1 infection, malaria and tuberculosis. A much better understanding of the innate immune mechanisms that are critical for inducing desired responses to vaccination would help in the design of novel vaccines. The majority of human vaccines are administered into the muscle. In this brief review, we focus on the initial innate immune events that occur locally at the site of intramuscular vaccine delivery, and how they are influenced by clinically approved vaccine adjuvants. In particular, the effects on cell mobilization, cell activation and vaccine antigen uptake are reviewed. Understanding how distinct adjuvants enhance and tailor vaccine responses would facilitate the selection of the best-suited adjuvant to improve vaccine efficacy to a given pathogen.

| S-EPMC4855268 | biostudies-other

Innate gene signature distinguishes humoral versus cytotoxic responses to influenza vaccination

Project description:Whole blood transcriptomics analysis of healthy individuals, immunized with the trivalent 2012-2013 season flu vaccine via transcutaneous, intramuscular or intradermal route. We define an early gene expression profile, detected at day 1 after immunization, that is associated with the development of either humoral or cytotoxic CD8 T cell responses. We used System Biology approach to analyse vaccine efficacy in order to find innate predictive biomarkers of the quality of adaptive responses for potential clinical use in the future. Moreover, from a methodological point of view this study increases knowledges on how vaccine route(s) can affect resulting immune responses and into mechanisms involved in the induction of humoral and cellular immunity to influenza vaccination.

2019-07-01 | E-MTAB-7741 | biostudies-arrayexpress

Multiple immunizations with adenovirus and MVA vectors improve CD8+ T cell functionality and mucosal homing.

Project description:Recombinant adenovirus vectors and MVA vectors were used in prime boost vaccine regimens to address the impact of repeated immunizations on transgene product-specific CD8(+) T cell frequencies, phenotypes, function, and localization. We show that a regimen with three immunizations incorporating MVA, human adenovirus serotype 5 and chimpanzee-derived adenoviruses serotype 68 or 7 yields high transgene product-specific CD8(+) T cell frequencies in spleen, blood, lymph nodes, and peritoneal lavage. Furthermore, upon triple immunization increased frequencies of transgene-specific T cells were measured at mucosal sites such as mesenteric lymph nodes, intestinal epithelium, and Peyer's patches. Multiple dose vaccine regimens that markedly increase functionally active transgene-specific T cells and target them to the appropriate ports of entry may be important in protection against pathogens such as HIV-1.

| S-EPMC2043483 | biostudies-literature

Innate and Adaptive Humoral Responses Coat Distinct Commensal Bacteria with Immunoglobulin A.

Project description:Immunoglobulin A (IgA) is prominently secreted at mucosal surfaces and coats a fraction of the intestinal microbiota. However, the commensal bacteria bound by IgA are poorly characterized and the type of humoral immunity they elicit remains elusive. We used bacterial flow cytometry coupled with 16S rRNA gene sequencing (IgA-Seq) in murine models of immunodeficiency to identify IgA-bound bacteria and elucidate mechanisms of commensal IgA targeting. We found that residence in the small intestine, rather than bacterial identity, dictated induction of specific IgA. Most commensals elicited strong T-independent (TI) responses that originated from the orphan B1b lineage and from B2 cells, but excluded natural antibacterial B1a specificities. Atypical commensals including segmented filamentous bacteria and Mucispirillum evaded TI responses but elicited T-dependent IgA. These data demonstrate exquisite targeting of distinct commensal bacteria by multiple layers of humoral immunity and reveal a specialized function of the B1b lineage in TI mucosal IgA responses.

| S-EPMC4575282 | biostudies-literature

Simulation Model for Dynamics of Dengue with Innate and Humoral Immune Responses.

Project description:Dengue virus is a mosquito borne Flavivirus and the most prevalent arbovirus in tropical and subtropical regions around the world. The incidence of dengue has increased drastically over the last few years at an alarming rate. The clinical manifestation of dengue ranges from asymptomatic infection to severe dengue. Even though the viral kinetics of dengue infection is lacking, innate immune response and humoral immune response are thought to play a major role in controlling the virus count. Here, we developed a computer simulation mathematical model including both innate and adaptive immune responses to study the within-host dynamics of dengue virus infection. A sensitivity analysis was carried out to identify key parameters that would contribute towards severe dengue. A detailed stability analysis was carried out to identify relevant range of parameters that contributes to different outcomes of the infection. This study provides a qualitative understanding of the biological factors that can explain the viral kinetics during a dengue infection.

| S-EPMC5925133 | biostudies-literature

Proteomic assessment of humoral immune responses in smallpox vaccine recipients.

Project description:The availability of effective smallpox vaccines was a critical element of the successful eradication of smallpox in 1980. Antibody responses play a primary role in protective immunity and neutralizing antibody is an established correlate of protection against smallpox. In this study we used a poxvirus proteome array to assess the antibody response to individual viral proteins in a cohort of 1,037 smallpox vaccine recipients. Several statistically significant differences were observed in the antibody response to immunodominant proteins between men and women, including B5R-a major target of neutralizing antibody in vaccinia immune globulin, and the membrane proteins D8L and A27L, both of which have been used as vaccine antigens providing protection in animal models. We also noted differences across racial/ethnic groups. In this cohort, which consisted of both ACAM2000 and Dryvax recipients, we noted minute differences in the antibody responses to a restricted number of viral proteins, providing additional support for the use of ACAM2000 as a replacement smallpox vaccine. Furthermore, our data indicate that poxvirus proteome microarrays can be valuable for screening and monitoring smallpox vaccine-induced humoral immune responses in large-scale serologic surveillance studies and prove useful in the guidance of developing novel smallpox candidate vaccines.

| S-EPMC8792332 | biostudies-literature

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