HIV-1 vaccine-induced immunity in the test-of-concept Step Study: a case–cohort analysis

Abstract

Background In the Step Study, the MRKAd5 HIV-1 gag/pol/nef vaccine did not lower post-infection plasma viremia, and HIV-1 incidence was higher in vaccine-treated than placebo-treated males with pre-existing adenovirus serotype 5 (Ad5) immunity. We evaluated vaccine-induced immunity and its potential contributions to infection risk. Methods To assess immunogenicity, HIV-specific T-cells were characterized ex vivo using validated IFN-γ ELISpot and intracellular cytokine staining (ICS) assays, employing a case-cohort design. To determine effects of vaccine and pre-existing Ad5 immunity on infection risk, flow cytometric studies measured Ad5-specific T-cells and circulating activated (Ki67+/Bcl- 2lo) CD4+ T-cells expressing CCR5. Findings IFN-γ-secreting HIV-specific T-cells (range, 163–686/106 PBMC) were detected ex vivo by ELISpot in 77% (258/354) of vaccinees; the majority recognized 2–3 HIV proteins. HIV- specific CD4+ T-cells were identified by ICS in 41%; ~85% expressed IL-2, and two-thirds of these co-expressed IFN-γ and/or TNF-α. HIV-specific CD8+ T-cells (range, 0.4–1.0%) were observed in 73%, expressing predominantly either IFN-γ alone or with TNF-α. No major differences were found in vaccine-induced HIV-specific immunity, including response rate, magnitude, and cytokine profile comparing vaccinated male cases (pre-infection) with non-cases. Interestingly, Ad5-specific T-cells were lower in cases than non-cases in several subgroup analyses. The percent circulating Ki67+Bcl-2lo/CCR5+ CD4+ T-cells did not differ between cases and non-cases. Interpretation Consistent with previous trials, the MrkAd5/HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T-cells. Comparative analyses did not reveal differences in HIV-specific immunologic responses between cases and non-cases that explain the lack of vaccine efficacy and potential infection enhancement. If T-cell immunity is critical in vaccine-induced HIV protection, our findings suggest that future candidate vaccines must elicit responses that either exceed in magnitude or differ in breadth and/or function from those observed in this trial. Funding National Institute of Allergy and Infectious Diseases, U.S. National Institute of Health; Merck Research Laboratories