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

ABSTRACT: 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

ORGANISM(S): Homo sapiens

PROVIDER: GSE22768 | GEO | 2012/11/20

SECONDARY ACCESSION(S): PRJNA129109

REPOSITORIES: GEO

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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 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

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

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

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

Project description: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.

2012-11-20 | GSE22822 | GEO

Pre-existing cross-reactive antibody responses do not significantly impact inactivated COVID-19 vaccine-induced neutralization

Project description:Recent exposure to seasonal coronaviruses (sCoVs) may stimulate cross-reactive antibody responses against SARS-CoV-2. Previous studies have shown divergent results regarding protective or damaging immunity induced by prior exposure to sCoVs. It is still unknown whether pre-existing humoral immunity may play a role in the vaccine-induced neutralization and antibody responses. In this study, we collected 36 paired sera in healthy volunteers before and after immunization with inactivated SARS-CoV-2 vaccines, and analyzed the distribution and intensity of pre-existing antibody responses at the epitope level before vaccine immunization, as well as the relationship between pre-existing sCoVs immunity and vaccine-induced neutralization.

2021-10-13 | E-MTAB-11084 | biostudies-arrayexpress

Pre-existing cross-reactive antibody responses do not significantly impact inactivated COVID-19 vaccine-induced neutralization

2021-10-29 | E-MTAB-11117 | biostudies-arrayexpress

Direct probing of germinal center responses reveals immunological features and bottlenecks for nAb responses to an engineered HIV trimer

Project description:Generation of Tier 2 HIV neutralizing antibody (nAb) responses by immunization remains a challenging problem, and the immunological barriers to induction of such responses by Env immunogens remain unclear. We explored these barriers by combining a suite of innovative techniques, including longitudinal lymph node fine needle aspirates, germinal center (GC) B cell lineage tracking, and a new method for detecting and quantifying GC T follicular helper (GC Tfh) cells, in non-human primates immunized with a native-like HIV-1 Env trimer protein (BG505 SOSIP.v5.2). A majority of immunized animals (9/12) developed Tier 2 neutralizing antibodies (nAb). Tier 2 nAb development best correlated with GC B cell magnitude in response to later booster immunizations and the quality of the Tfh help. Notably, these immunological factors distinguished between qualitatively successful and unsuccessful vaccine Ab responses, as they correlated with nAb development but did not correlate with simple Env Ab binding titers. Therefore, direct probing of germinal centers in future vaccine trials is key, as this suite of technically robust approaches provides quantitation of the proximal immune correlates of neutralizing antibody development and could allow redesign of optimal multi-stage vaccination schedules.

2016-12-31 | GSE89148 | GEO

A Vaccine (Ad5.F35-hGCC-PADRE) for the Treatment of Gastrointestinal Adenocarcinoma

Project description:This phase IIA trial investigates the side effects of Ad5.F35-hGCC-PADRE vaccine and to see how well it works in treating patients with gastrointestinal adenocarcinoma. Ad5.F35-hGCC-PADRE vaccine may help to train the patient’s own immune system to identify and kill tumor cells and prevent it from coming back.

| 2317938 | ecrin-mdr-crc

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

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