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.

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

“…Based on the above observations, it is highly likely that some aspect of immune activation related to the use of Ad5 vectors in the vaccine led to the increased risk of infection. There is evidence that prevaccination anti-Ad5 titers correlated with altered early innate responses to the vaccine (49). Further, there is evidence that Ad5 immunization itself expands memory CD4 + T cells with a mucosal homing phenotype and that such CD4 + T cells are highly susceptible to HIV infection (16,50), which raises the possibility that vaccine-elicited CD4 + T cells provide an increased target population favoring transmission.…”

Systems vaccinology: Probing humanity’s diverse immune systems with vaccines

“…Recent advances have used the tools of systems biology to probe the immune response to vaccination in humans (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). Novel systems biology techniques allow integration of hierarchical levels of information, leading to a deconvolution of the complexity of biological systems (33).…”

Transient IL-10 receptor blockade can enhance CD8+T cell responses to a simian adenovirus-vectored HIV-1 conserved region immunogen

“…S4), though this does not necessarily preclude its upregulation in the tissues. Notably, Zak et al observed a significant increase in IL-10 expression in the peripheral blood mononuclear cells of volunteers immunized with HAdV5 in a Phase 1B clinical trial, 7 suggesting that IL-10R blockade might have a more substantial effect in humans. The use of an immunogen containing an immunodominant murine epitope (peptide H, restricted by murine H-2D d and H-2L d ) may have obscured responses to other epitopes in HIVconsv that are relevant to control of HIV-1.…”

“…We did not assess the duration of antibody binding in vivo, but in a previous study of persistent LCMV infection, administration of aIL-10R antibody every 3 d significantly enhanced responses to a DNA vaccine, suggesting that the half-life may be 3 d or longer. 20 While we elected to transiently block IL-10 signaling due to the short-lived increase in IL-10 expression observed after adenoviral immunization in humans, 7 repeated administrations of aIL-10R could further increase immunogenicity. Once an IL-10-blocking strategy has been optimized, it will be important to test it in a suitable challenge model, such as a humanized mouse or macaque model.…”

“…5 A potential approach to increasing the immunogenicity of adenovirus vectors is to modulate inhibitory signals, such as interleukin-10 (IL-10), that are induced alongside pro-inflammatory cytokines and chemokines as a compensatory anti-inflammatory response. 7 IL-10 inhibits the activation and migration of na€ ıve T cells by downregulating MHC class II and CD86 on antigen-presenting cells 8,9 and inhibiting the production of cytokines and chemokines such as IL-1a, MCP-1, IP-10 and TNFa. 10,11 Antibody blockade of the IL-10R restored proliferation and cytokine production by HIV-1-specific CD4 C and CD8 C T cells in vitro.…”