Abstract
BackgroundThe sieve analysis for the Step trial found evidence that breakthrough HIV-1 sequences for MRKAd5/HIV-1 Gag/Pol/Nef vaccine recipients were more divergent from the vaccine insert than placebo sequences in regions with predicted epitopes. We linked the viral sequence data with immune response and acute viral load data to explore mechanisms for and consequences of the observed sieve effect.MethodsNinety-one male participants (37 placebo and 54 vaccine recipients) were included; viral sequences were obtained at the time of HIV-1 diagnosis. T-cell responses were measured 4 weeks post-second vaccination and at the first or second week post-diagnosis. Acute viral load was obtained at RNA-positive and antibody-negative visits.FindingsVaccine recipients had a greater magnitude of post-infection CD8+ T cell response than placebo recipients (median 1.68% vs 1.18%; p = 0·04) and greater breadth of post-infection response (median 4.5 vs 2; p = 0·06). Viral sequences for vaccine recipients were marginally more divergent from the insert than placebo sequences in regions of Nef targeted by pre-infection immune responses (p = 0·04; Pol p = 0·13; Gag p = 0·89). Magnitude and breadth of pre-infection responses did not correlate with distance of the viral sequence to the insert (p>0·50). Acute log viral load trended lower in vaccine versus placebo recipients (estimated mean 4·7 vs 5·1) but the difference was not significant (p = 0·27). Neither was acute viral load associated with distance of the viral sequence to the insert (p>0·30).InterpretationDespite evidence of anamnestic responses, the sieve effect was not well explained by available measures of T-cell immunogenicity. Sequence divergence from the vaccine was not significantly associated with acute viral load. While point estimates suggested weak vaccine suppression of viral load, the result was not significant and more viral load data would be needed to detect suppression.
Highlights
The Step trial evaluated the efficacy of the Merck Adenovirus 5 (MRKAd5) Gag/Pol/Nef vaccine to prevent HIV-1 acquisition and reduce viral load
Subsequent studies from the RV144 trial have suggested that reduction in acquisition of HIV-1 is associated with immune responses to envelope, a gene not included in the MRKAd5 vaccine [3]
Pre-infection T-cell responses did not predict divergence of the breakthrough sequences from the vaccine insert, yet there was some evidence of differences between vaccine and placebo breakthrough sequences in regions with observed pre-infection T-cell responses
Summary
The Step trial evaluated the efficacy of the Merck Adenovirus 5 (MRKAd5) Gag/Pol/Nef vaccine to prevent HIV-1 acquisition and reduce viral load. Rolland et al [2] compared breakthrough HIV-1 sequences for male infected vaccine and placebo recipients to the vaccine insert sequence They found greater protein distances to the insert sequence for vaccine recipients than for placebo recipients when restricting the analysis to regions with predicted T-cell epitopes. This sieve effect was specific to the HIV proteins used in the vaccine, and was not found in other proteins. The sieve analysis for the Step trial found evidence that breakthrough HIV-1 sequences for MRKAd5/HIV-1 Gag/Pol/Nef vaccine recipients were more divergent from the vaccine insert than placebo sequences in regions with predicted epitopes. We linked the viral sequence data with immune response and acute viral load data to explore mechanisms for and consequences of the observed sieve effect
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