Higher T-Cell Responses Induced by DNA/rAd5 HIV-1 Preventive Vaccine Are Associated With Lower HIV-1 Infection Risk in an Efficacy Trial

Abstract

Background: It is important to identify vaccine-induced immune responses that predict the preventative efficacy of a human immunodeficiency virus (HIV)-1 vaccine. We assessed T-cell response markers as correlates of risk in the HIV Vaccine Trials Network (HVTN) 505 HIV-1 vaccine efficacy trial.

Methods: 2504 participants were randomized to DNA/rAd5 vaccine or placebo, administered at weeks 0, 4, 8, and 24. Peripheral blood mononuclear cells were obtained at week 26 from all 25 primary endpoint vaccine cases and 125 matched vaccine controls, and stimulated with vaccine-insert-matched peptides. Primary variables were total HIV-1-specific CD4+ T-cell magnitude and Env-specific CD4+ polyfunctionality. Four secondary variables were also assessed. Immune responses were evaluated as predictors of HIV-1 infection among vaccinees using Cox proportional hazards models. Machine learning analyses identified immune response combinations best predicting HIV-1 infection.

Results: We observed an unexpectedly strong inverse correlation between Env-specific CD8+ immune response magnitude and HIV-1 infection risk (hazard ratio [HR] = 0.18 per SD increment; P = .04) and between Env-specific CD8+ polyfunctionality and infection risk (HR = 0.34 per SD increment; P < .01).

Conclusions: Further research is needed to determine if these immune responses are predictors of vaccine efficacy or markers of natural resistance to HIV-1 infection.

Keywords: HIV-1 vaccine; HVTN 505 vaccine efficacy trial; T-cell immunogenicity; T-cell polyfunctionality; correlates of risk; intracellular cytokine staining; machine learning analyses; vaccine-induced immune response..

Figure 1.

Selection of participants for the case-control study. Participants were eligible for case-control sampling if they were primary endpoint cases (HIV-1–uninfected after week 28); had week-26 samples available, and were RNA-negative at week 26; or if they completed the month-24 visit HIV-1–uninfected and before study unblinding (22 April 2013), received all study injections within the allowable visit windows (per-protocol), had sufficient sample quantities available at all immunogenicity time points, and had BMI and race values in strata with 1 or more cases. All eligible HIV-1 cases were sampled. Controls were frequency-matched to cases on treatment group (vaccine vs placebo), BMI, and race/ethnicity (white, black, or Hispanic); 5 controls were sampled per case for the vaccine group and 1 control per case was sampled for the placebo group.

Figure 2.

Heatmap of Env-specific marker-specific T-cell response probabilities (CD4⁺ on top, CD8⁺ on bottom). The columns correspond to the different marker combinations with detectable Env-specific responses (26 subsets for CD4⁺ and 19 for CD8⁺). The marker combinations are shaded by the markers they express (white, “off”; shaded, “on”), and ordered by degree of functionality, from 1 function on the left to 5 functions on the right. The average posterior probability of expressing each marker combination is shown, for vaccine versus placebo and case versus control groups. Marker combinations with average posterior probabilities less than 0.005 have been removed from the heatmap. The average posterior probability is shaded from white (zero) to dark (1).

Figure 3.

Distribution of primary and secondary immune response variables. Boxplots show the primary and secondary immune response variable distributions by HIV-1 infection status and treatment group: total CD4⁺/CD8⁺ T-cell magnitude (top) and Env-specific CD4⁺/CD8⁺ T-cell polyfunctionality score (bottom).

Figure 4.

HIV-1 infection incidence by treatment group and vaccine recipient immune response subgroup. Plots show the cumulative incidence of HIV-1 infection among placebo recipients and among vaccine recipients by primary and secondary binary immune response variables: Env-specific CD4⁺/CD8⁺ T-cell polyfunctionality score (PFN; top) and Total CD4⁺/CD8⁺ T-cell magnitude (Mag; bottom). A high (low) response is defined as by a response above (below) the median response for vaccine recipients.