Analysis of the HIV Vaccine Trials Network 702 Phase 2b-3 HIV-1 Vaccine Trial in South Africa Assessing RV144 Antibody and T-Cell Correlates of HIV-1 Acquisition Risk

Abstract

Background: The ALVAC/gp120 + MF59 vaccines in the HIV Vaccine Trials Network (HVTN) 702 efficacy trial did not prevent human immunodeficiency virus-1 (HIV-1) acquisition. Vaccine-matched immunological endpoints that were correlates of HIV-1 acquisition risk in RV144 were measured in HVTN 702 and evaluated as correlates of HIV-1 acquisition.

Methods: Among 1893 HVTN 702 female vaccinees, 60 HIV-1-seropositive cases and 60 matched seronegative noncases were sampled. HIV-specific CD4+ T-cell and binding antibody responses were measured 2 weeks after fourth and fifth immunizations. Cox proportional hazards models assessed prespecified responses as predictors of HIV-1 acquisition.

Results: The HVTN 702 Env-specific CD4+ T-cell response rate was significantly higher than in RV144 (63% vs 40%, P = .03) with significantly lower IgG binding antibody response rate and magnitude to 1086.C V1V2 (67% vs 100%, P < .001; Pmag < .001). Although no significant univariate associations were observed between any T-cell or binding antibody response and HIV-1 acquisition, significant interactions were observed (multiplicity-adjusted P ≤.03). Among vaccinees with high IgG A244 V1V2 binding antibody responses, vaccine-matched CD4+ T-cell endpoints associated with decreased HIV-1 acquisition (estimated hazard ratios = 0.40-0.49 per 1-SD increase in CD4+ T-cell endpoint).

Conclusions: HVTN 702 and RV144 had distinct immunogenicity profiles. However, both identified significant correlations (univariate or interaction) for IgG V1V2 and polyfunctional CD4+ T cells with HIV-1 acquisition. Clinical Trials Registration . NCT02968849.

Keywords: HIV-1 vaccine; HVTN 702; RV144; T-cell immunogenicity; T-cell polyfunctionality; binding antibodies; correlates of risk; intracellular cytokine staining; vaccine efficacy trial; vaccine-induced immune response.

© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Figures

Figure 1.

Characterization of HVTN 702 cellular and humoral immune responses among per-protocol vaccinated noncases and comparison with HVTN 100, HVTN 097, and RV144 per-protocol vaccinated noncases. A, Response rates and magnitudes of CD4+ T cells expressing IFN-γ and/or IL-2 and/or CD40L among HVTN 702 vaccinated noncases, measured by intracellular cytokine staining at months 6.5 and 12.5. B, Month 6.5 and 12.5 IgG binding antibody responses to 1086.C V1V2, HVTN 702. C, Response rates and magnitudes of CD4+ T cells expressing IFN-γ and/or IL-2 among HVTN 702 vaccinated noncases compared to those in HVTN 100, HVTN 097, and RV144 at month 6.5, measured by intracellular cytokine staining. D, Month 6.5 IgG binding antibody responses to 1086.C V1V2 in HVTN 702 compared to HVTN 100 and RV144 (HVTN 097 data not available). Positive response rates and 95% CIs in the top panels and mean magnitudes and 95% CIs in the bottom panels are estimated by targeted maximum likelihood estimation. All Holm-adjusted P values < .05 for HVTN 702 contrasts with earlier trials are displayed. Abbreviations: CI, confidence interval; HVTN, HIV Vaccine Trials Network; IFN-γ, interferon-γ; IgG, immunoglobulin G; IL-2, interleukin 2; MFI, mean fluorescence intensity.

Figure 2.

Distribution of primary immune response variables. Boxplots show the primary immune response variable distributions by HIV-1 acquisition status and treatment group: (A) CD4+ polyfunctionality score to ZM96; (B) IgG binding antibody response to A244 V1V2; and (C) IgG3 binding antibody response to 1086 V1V2. A, Month 6.5 polyfunctionality score categories were, high, ≥0.121; med, 0.067 to <0.121; low, <0.067. Month 12.5 polyfunctionality score categories were high, ≥0.125; med, 0.080 to <0.125; low, <0.080. B, The positive response rates were 88% at month 6.5 and 90.1% at month 12.5. Month 6.5 binding antibody categories were high, ≥1498.83 MFI; med, 421.08 to <1498.83 MFI; low, <421.08 MFI. Month 12.5 binding antibody categories were, high, ≥1603.5 MFI; med, 468.25 to <1603.5 MFI; low, <468.25 MFI. The mid-line of the box denotes the median and the ends of the box denote the 25th and 75th percentiles. The whiskers that extend from the top and bottom of the box extend to the most extreme data points that are no more than 1.5 times the interquartile range or if no value meets this criterion, to the data extremes. Abbreviations: HIV-1, human immunodeficiency virus 1; IgG, immunoglobulin G; Med, medium; MFI, mean fluorescence intensity; Neg, negative; PFS, polyfunctionality score; Pos, positive.

Figure 3.

HIV-1 acquisition incidence by vaccine recipient immune response subgroup. Plots show the cumulative incidence of HIV-1 acquisition among per-protocol vaccine recipients by primary categorical immune response variables at month 6.5 or month 12.5: (A) CD4+ T-cell polyfunctionality score to ZM96; (B) IgG binding antibody response to A244 V1V2; and (C) IgG3 binding antibody response to 1086 V1V2. A, Month 6.5 polyfunctionality score categories were high, ≥0.121; med, 0.067 to <0.121; low, <0.067. Month 12.5 polyfunctionality score categories were high, ≥0.125; med, 0.080 to <0.125; low, <0.080. B, The positive response rates were 88% at month 6.5 and 90.1% at month 12.5. Month 6.5 binding antibody categories were high, ≥1498.83 MFI; med, 421.08 to <1498.83 MFI; low, <421.08 MFI. Month 12.5 binding antibody categories were high, ≥1603.5 MFI; med, 468.25 to <1603.5 MFI; low, <468.25 MFI. Abbreviations: HIV-1, human immunodeficiency virus 1; IgG, immunoglobulin G; PFS, polyfunctionality score.