Abstract
BackgroundElevated risk of HIV-1 infection among recipients of an adenovirus serotype 5 (Ad5)-vectored HIV-1 vaccine was previously reported in the Step HIV-1 vaccine efficacy trial. We assessed pre-infection cellular immune responses measured at 4 weeks after the second vaccination to determine their roles in HIV-1 infection susceptibility among Step study male participants.MethodsWe examined ex vivo interferon-γ (IFN-γ) secretion from peripheral blood mononuclear cells (PBMC) using an ELISpot assay in 112 HIV-infected and 962 uninfected participants. In addition, we performed flow cytometric assays to examine T-cell activation, and ex vivo IFN-γ and interleukin-2 secretion from CD4+ and CD8+ T cells. We accounted for the sub-sampling design in Cox proportional hazards models to estimate hazard ratios (HRs) of HIV-1 infection per 1-loge increase of the immune responses.FindingsWe found that HIV-specific immune responses were not associated with risk of HIV-1 infection. However, each 1-loge increase of mock responses measured by the ELISpot assay (i.e., IFN-γ secretion in the absence of antigen-specific stimulation) was associated with a 62% increase of HIV-1 infection risk among vaccine recipients (HR = 1.62, 95% CI: (1.28, 2.04), p<0.001). This association remains after accounting for CD4+ or CD8+ T-cell activation. We observed a moderate correlation between ELISpot mock responses and CD4+ T-cells secreting IFN-γ (ρ = 0.33, p = 0.007). In addition, the effect of the Step vaccine on infection risk appeared to vary with ELISpot mock response levels, especially among participants who had pre-existing anti-Ad5 antibodies (interaction p = 0.04).ConclusionsThe proportion of cells, likely CD4+ T-cells, producing IFN-γ without stimulation by exogenous antigen appears to carry information beyond T-cell activation and baseline characteristics that predict risk of HIV-1 infection. These results motivate additional investigation to understand the potential link between IFN-γ secretion and underlying causes of elevated HIV-1 infection risk among vaccine recipients in the Step study.
Highlights
The Step study was a phase 2b randomized double-blind clinical trial of a preventive human immunodeficiency virus type 1 (HIV-1) vaccine in 3000 participants
The proportion of cells, likely CD4+ T-cells, producing IFN-c without stimulation by exogenous antigen appears to carry information beyond T-cell activation and baseline characteristics that predict risk of HIV-1 infection. These results motivate additional investigation to understand the potential link between IFN-c secretion and underlying causes of elevated HIV-1 infection risk among vaccine recipients in the Step study
A dampening effect of Ad-specific CD4+ T-cell responses on ensuing vaccine insert-specific responses was observed in a clinical trial by Frahm et al [5], no quantitative analysis of the association between pre-existing adenovirus serotype 5 (Ad5)-specific cellular immune responses and risk of HIV-1 infection was performed in the Step study due to the limitation of relevant data
Summary
The Step study was a phase 2b randomized double-blind clinical trial of a preventive human immunodeficiency virus type 1 (HIV-1) vaccine in 3000 participants. It aimed to evaluate whether the adenovirus serotype 5 (Ad5)-vectored MRKAd5 HIV-1 gag/ pol/nef vaccine administered at weeks 0, 4 and 26 could reduce either HIV-1 infection rates or plasma viremia after infection. A dampening effect of Ad-specific CD4+ T-cell responses on ensuing vaccine insert-specific responses was observed in a clinical trial by Frahm et al [5], no quantitative analysis of the association between pre-existing Ad5-specific cellular immune responses and risk of HIV-1 infection was performed in the Step study due to the limitation of relevant data. We assessed pre-infection cellular immune responses measured at 4 weeks after the second vaccination to determine their roles in HIV-1 infection susceptibility among Step study male participants
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