Analysis of the HVTN 702 Phase 2b-3 HIV-1 vaccine trial in South Africa assessing RV144 antibody and T cell correlates of HIV-1 acquisition risk


BACKGROUND: Whether the immune correlates of HIV-1 acquisition risk identified in the Thai HIV-1 vaccine efficacy trial of an ALVAC/gp120 pox-protein vaccine regimen (RV144) generalize to other at-risk populations is a critical question. Although the clade C-adapted vaccine regimen was not efficacious in preventing HIV-1 acquisition in South African participants, HVTN 702 (NCT02968849) provides a unique opportunity to answer this important question and to raise hypotheses regarding the observed lack of efficacy.
METHODS: Among 3909 female vaccinees, 60 HIV-1-seropositive cases and 60 matched seronegative controls were sampled. HIV-1-specific CD4+ T-cell and binding antibody (bAb) responses were measured by intracellular cytokine staining and bAb multiplex assays 2 weeks post-fourth and fifth immunizations. Three primary vaccine-matched immunological endpoints that were strong inverse correlates of HIV-1 risk in RV144 were assessed as predictors of HIV-1 acquisition among vaccinees using Cox proportional hazards models: Env-ZM96-specific CD4+ polyfunctionality score based on six markers and total IgG and IgG3 binding antibody responses to A244 and 1086.C V1V2. Secondary endpoints included polyfunctional CD4+ T-cell responses to other Env vaccine inserts, IgG bAbs to gp120 and Env consensus antigens, and IgA bAbs. Interactions among pre-specified primary and secondary endpoints were also assessed using Cox models, with low/medium/high categories defined by tertiles.
RESULTS: Although no significant association was observed between any T-cell or bAb response and HIV-1 acquisition, significant interactions were seen in pre-specified analyses (multiplicity-adjusted p-values <=0.03). Among those with highest tertile IgG A244 V1V2 bAb responses, vaccine-matched CD4+ T-cell endpoints (polyfunctional scores to Env-ZM96 and 1086, triple-functional cells expressing IFN-g, IL2, and CD40L to Env-ZM96) were associated with decreased HIV-1 acquisition risk with estimated hazard ratios=0.40-0.49 per 1-SD increase in the respective CD4+ T-cell endpoint.
CONCLUSIONS: Our study interrogated previously identified correlates of HIV-1 risk and their interplays for an ALVAC/gp120 vaccine in the South African population. We hypothesize that due to low IgG V1V2 bAb responses in HVTN 702 vs. RV144, Env-specific CD4+ T-cell responses were not confirmed as predictors of risk. Higher bAb V1V2 responses in combination with polyfunctional CD4+ T-cell responses may be necessary to reduce HIV-1 acquisition.

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