Abstract
The pox-protein regimen tested in the RV144 trial is the only vaccine strategy demonstrated to prevent HIV-1 infection. Subsequent analyses identified antibody and cellular immune responses as correlates of risk (CoRs) for HIV infection. Early predictors of these CoRs could provide insight into vaccine-induced protection and guide efforts to enhance vaccine efficacy. Using specimens from a phase 1b trial of the RV144 regimen in HIV-1-uninfected South Africans (HVTN 097), we profiled innate responses to the first ALVAC-HIV immunization. PBMC transcriptional responses peaked 1 day post-vaccination. Type I and II interferon signaling pathways were activated, as were innate pathways critical for adaptive immune priming. We then identified two innate immune transcriptional signatures strongly associated with adaptive immune CoR after completion of the 4-dose regimen. Day 1 signatures were positively associated with antibody-dependent cellular cytotoxicity and phagocytosis activity at Month 6.5. Conversely, a signature present on Days 3 and 7 was inversely associated with Env-specific CD4+ T cell responses at Months 6.5 and 12; rapid resolution of this signature was associated with higher Env-specific CD4+ T-cell responses. These are the first-reported early immune biomarkers of vaccine-induced responses associated with HIV-1 acquisition risk in humans and suggest hypotheses to improve HIV-1 vaccine regimens.
Highlights
Recent estimates of the global impact of HIV/AIDS are a reminder that improved methods of prevention are needed to more effectively address this pandemic
For a vaccine with partial efficacy, such as the RV144 HIV vaccine regimen, identifying early innate responses that are linked with adaptive responses— those for which evidence has accumulated that they might be important for protection— could help a more efficacious version be developed
In the HVTN 097 study, the RV144 prime-boost (ALVAC-HIV and AIDSVAX B/E) vaccine regimen was given to South African participants
Summary
Recent estimates of the global impact of HIV/AIDS are a reminder that improved methods of prevention are needed to more effectively address this pandemic. The Env-specific CD4+ T cell polyfunctionality (scored by expression of IFN-γ, TNFα, IL-2, CD40L and IL-4) was shown as an inverse correlate of risk (CoR) for HIV infection [7]. Post hoc analyses at 12 months of study estimated vaccine efficacy at 60.5% (95% CI 22–80), which rapidly declined [8]. This decline mirrored the decays in circulating antiV1V2 antibody [9] and CD4+ T-cell [6] responses, suggesting that vaccine efficacy could be preserved if the magnitude, quality or durability were extended [10]. Vaccine-induced responses were heterogeneous across individuals, suggesting that host factors could account for the variability, and once identified, approaches to increase response rates could be prioritized for future testing
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