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Merck Ad5/HIV induces broad innate immune activation that predicts CD8+ T-cell responses but is attenuated by preexisting Ad5 immunity.

ABSTRACT: To better understand how innate immune responses to vaccination can lead to lasting protective immunity, we used a systems approach to define immune signatures in humans over 1 wk following MRKAd5/HIV vaccination that predicted subsequent HIV-specific T-cell responses. Within 24 h, striking increases in peripheral blood mononuclear cell gene expression associated with inflammation, IFN response, and myeloid cell trafficking occurred, and lymphocyte-specific transcripts decreased. These alterations were corroborated by marked serum inflammatory cytokine elevations and egress of circulating lymphocytes. Responses of vaccinees with preexisting adenovirus serotype 5 (Ad5) neutralizing antibodies were strongly attenuated, suggesting that enhanced HIV acquisition in Ad5-seropositive subgroups in the Step Study may relate to the lack of appropriate innate activation rather than to increased systemic immune activation. Importantly, patterns of chemoattractant cytokine responses at 24 h and alterations in 209 peripheral blood mononuclear cell transcripts at 72 h were predictive of subsequent induction and magnitude of HIV-specific CD8(+) T-cell responses. This systems approach provides a framework to compare innate responses induced by vectors, as shown here by contrasting the more rapid, robust response to MRKAd5/HIV with that to yellow fever vaccine. When applied iteratively, the findings may permit selection of HIV vaccine candidates eliciting innate immune response profiles more likely to drive HIV protective immunity. This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE22822 | GEO | 2012/11/20

SECONDARY ACCESSION(S): PRJNA127865

REPOSITORIES: GEO

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Merck Ad5/HIV induces broad innate immune activation that predicts CD8+ T-cell responses but is attenuated by preexisting Ad5 immunity.

Project description:This SuperSeries is composed of the following subset Series: GSE22768: Systems analysis of the Merck Ad5/HIV vaccine reveals robust induction of a core innate immune gene network: in vivo analysis GSE22769: Systems analysis of the Merck Ad5/HIV vaccine reveals robust induction of a core innate immune gene network: in vitro analysis To better understand how innate immune responses to vaccination can lead to lasting protective immunity, we used a systems approach to define immune signatures in humans over 1 wk following MRKAd5/HIV vaccination that predicted subsequent HIV-specific T-cell responses. Within 24 h, striking increases in peripheral blood mononuclear cell gene expression associated with inflammation, IFN response, and myeloid cell trafficking occurred, and lymphocyte-specific transcripts decreased. These alterations were corroborated by marked serum inflammatory cytokine elevations and egress of circulating lymphocytes. Responses of vaccinees with preexisting adenovirus serotype 5 (Ad5) neutralizing antibodies were strongly attenuated, suggesting that enhanced HIV acquisition in Ad5-seropositive subgroups in the Step Study may relate to the lack of appropriate innate activation rather than to increased systemic immune activation. Importantly, patterns of chemoattractant cytokine responses at 24 h and alterations in 209 peripheral blood mononuclear cell transcripts at 72 h were predictive of subsequent induction and magnitude of HIV-specific CD8(+) T-cell responses. This systems approach provides a framework to compare innate responses induced by vectors, as shown here by contrasting the more rapid, robust response to MRKAd5/HIV with that to yellow fever vaccine. When applied iteratively, the findings may permit selection of HIV vaccine candidates eliciting innate immune response profiles more likely to drive HIV protective immunity. Refer to individual Series

2012-11-20 | E-GEOD-22822 | biostudies-arrayexpress

Systems analysis of the Merck Ad5/HIV vaccine reveals robust induction of a core innate immune gene network: in vivo analysis

Project description:Here we applied a systems approach to define human innate immune signatures following MRKAd5/HIV immunization and to analyze the effects of pre-existing Ad5 immunity. We defined the global early immune response to MRKAd5/HIV by profiling the PBMC transcriptomes from seven Ad5Neg individuals pre- and post-vaccination in vivo. Since the Step Study results suggested a deleterious effect of pre-existing Ad5 nAb on vaccine immunogenicity, we examined the vaccine-induced transcriptional responses from two Ad5Med and one Ad5Low individual 50 total samples were analyzed. This includes 5 time points post vaccination with MRKAd5/HIV for 10 independent human subjects. The time points were 0hr, 6hrs, 24hrs, 72hrs, and 168hrs. Seven of the subjects did not have pre-existing neutralizing antibodies to the vaccine vector (Ad5Neg). One subject had low level pre-existing neutralizing antibodies to the vaccine vector (Ad5Low). Two subjects had moderate level pre-existing neutralizing antibodies to the vaccine vector (Ad5Low).

2012-11-20 | E-GEOD-22768 | biostudies-arrayexpress

Systems analysis of the Merck Ad5/HIV vaccine reveals robust induction of a core innate immune gene network: in vivo analysis

2012-11-20 | GSE22768 | GEO

Systems analysis of the Merck Ad5/HIV vaccine reveals robust induction of a core innate immune gene network: in vitro analysis

Project description:Here we applied a systems approach to define human innate immune signatures following MRKAd5/HIV immunization and to analyze the effects of pre-existing Ad5 immunity. To determine whether vaccine-induced changes could be ascribed to cell-intrinsic responses rather than cell population fluxes, fresh PBMC from independent Ad5Neg donors were stimulated in vitro with MRKAd5 vector lacking HIV-1 transgenes (MRKAd5). 22 total samples were analyzed. 14 of these are from in vivo vaccination of seven Ad5 seronegative subjects at two time points (0hr and 24hrs). 8 of these are from 24hr in vitro stimulation of PBMCs from four independent Ad5 seronegative donors with MRKAd5 empty vector or GTS buffer (Mock) at 20,000 viral particles per cell.

2012-11-20 | E-GEOD-22769 | biostudies-arrayexpress

Systems analysis of the Merck Ad5/HIV vaccine reveals robust induction of a core innate immune gene network: in vitro analysis

Project description:Here we applied a systems approach to define human innate immune signatures following MRKAd5/HIV immunization and to analyze the effects of pre-existing Ad5 immunity. To determine whether vaccine-induced changes could be ascribed to cell-intrinsic responses rather than cell population fluxes, fresh PBMC from independent Ad5Neg donors were stimulated in vitro with MRKAd5 vector lacking HIV-1 transgenes (MRKAd5).

2012-11-20 | GSE22769 | GEO

Adenovirus Serotype 5 Vectors Trigger IL-27-Dependent Inhibitory CD4+ T Cell Responses

Project description:Viral vectors are attractive vaccine platforms that elicit robust innate and adaptive immune responses; however, viral vector vaccine candidates vary greatly in their ability to induce protective immunity. Ad5 vectors elicit robust CD8+ T cell responses but typically characterized by an exhausted phenotype. The mechanisms by which Ad5 vectors induce dysfunctional CD8+ T cells have not been fully elucidated. Here we demonstrate that Ad5 vectors, but not Ad26 vectors, elicit exhausted antigen-specific IL-10+PD1+ CD4+ T cells with a dysfunctional transcriptional profile, and these cells effectively suppress CD8+ T cells responses in vivo. Induction of inhibitory CD4+ T cells by Ad5 vectors was associated with increased IL-27 expression, and IL-27 blockade improved CD4+ T cell polyfunctionality. Together our data highlight a novel role for IL-27 in regulating responses to viral vector vaccines. Splenic CD45.2+ OT-II TCR-Tg CD4 T cells from CD45.1+ B6 mice immunized with Ad5-OVA or Ad26-OVA were purified by FACS on day 10 post-immunization

2016-06-01 | E-GEOD-73118 | biostudies-arrayexpress

Molecular signatures of aging and flu vaccine response in Healthy and HIV infected individuals

Project description:Individuals living with chronic HIV experience similar immune impairments as HIV-negative elderly however they manifest symptoms (e.g. suboptimal responses to vaccination) at a younger age. Mechanisms underlying premature immune-senescence are unclear. In this study, we aimed to identify molecular signatures of aging and vaccine response in HIV infected (HIV) individuals as compared to age-matched healthy-control participants (HC). Using RNA-sequencing, we evaluated transcriptomic profiles in peripheral blood mononuclear cells in study participants before and 1-week after influenza vaccination. Despite that fewer differentially expressed genes between young (<40yrs) and old (>59yrs) were observed in HIV, metabolic and innate immune activation pathways were associated with increasing age in both HIV and HC. Age was also associated with pathways involved with T cell immune activation in HC, and with Interferon signaling pathways in HIV. Predictive and correlative models of vaccine response using gene expression were different in HC and HIV. In this study, molecular signatures were defined for aging and vaccine response in HC and HIV. We observed signs of precocious immune aging at the transcriptional level in HIV and described a transcriptional perturbation associated with innate immunity and glucose metabolism induced by aging in both HC and HIV in resting conditions.

2022-01-19 | GSE178670 | GEO

Modified Vaccinia virus Ankara vector induces specific cellular and humoral responses in the female reproductive tract, the main HIV portal of entry

Project description:The female reproductive tract is one of the major mucosal invasion site of HIV-1. This site has been neglected in previous HIV-1 vaccine studies. Immune responses in the female reproductive tract after systemic vaccination remain to be characterized. Using a modified vaccinia virus Ankara (MVA) as a vaccine model, we characterized specific immune responses in all compartments of the female reproductive tract (FRT) of non-human primates after systemic vaccination. Memory T cells were preferentially found in the lower tract (vagina and cervix), whereas antigen-presenting cells and innate lymphoid cells were mainly located in the upper tract (uterus and fallopian tubes). This compartmentalisation of immune cells in the FRT was supported by transcriptomic analyses and correlation network. Polyfunctional MVA-specific CD8+ T cells were detected in the blood, lymph nodes, vagina, cervix, uterus and fallopian tubes. Anti-MVA IgG and IgA were detected in cervicovaginal fluid after a second vaccine dose. Systemic vaccination with an MVA vector thus elicits cellular and antibody responses in the female reproductive tract.

2017-06-09 | E-MTAB-5663 | biostudies-arrayexpress

Adenovirus Serotype 5 Vectors Trigger IL-27-Dependent Inhibitory CD4+ T Cell Responses

2016-06-01 | GSE73118 | GEO

Vaccine inoculation route modulates early immunity and consequently antigen-specific immune response

Project description:Vaccination is one of the most efficient public healthcare measures to fight infectious diseases. Nevertheless, the immune mechanisms induced in vivo by vaccination are still unclear. The route of administration, an important vaccination parameter, can substantially modify the quality of the response. How the route of administration affects the generation and profile of immune responses is of major interest. Here, we aimed to extensively characterize the profiles of the innate and adaptive response to vaccination induced after intradermal, subcutaneous, or intramuscular administration with a modified vaccinia virus Ankara model vaccine in non-human primates. The adaptive response following subcutaneous immunization was clearly different from that following intradermal or intramuscular immunization. The subcutaneous route induced a higher level of neutralizing antibodies than the intradermal and intramuscular vaccination routes. In contrast, polyfunctional CD8+ T-cell responses were preferentially induced after intradermal or intramuscular injection. We observed the same dichotomy when analyzing the early molecular and cellular immune events, highlighting the recruitment of cell populations, such as CD8+ T lymphocytes and myeloid-derived suppressive cells, and the activation of key immunomodulatory gene pathways. These results demonstrate that the quality of the vaccine response induced by an attenuated vaccine is shaped by early and subtle modifications of the innate immune response. In this immunization context, the route of administration must be tailored to the desired type of protective immune response. This will be achieved through systems vaccinology and mathematical modeling, which will be critical for predicting the efficacy of the vaccination route for personalized medicine.

2021-05-17 | E-MTAB-10309 | biostudies-arrayexpress

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