OA08.04
Background: The RV144 clinical trial showed the partial efficacy of a prime-boost pox-protein vaccine regimen with an estimated vaccine efficacy (VE) of 31% for protecting low-risk Thai volunteers against acquisition of HIV-1. The impact of vaccine-induced immune responses can be investigated through sieve analysis of HIV-1 breakthrough infections (infected vaccine and placebo recipients).
A V1/V2-targeted comparison of the genomes of HIV-1 breakthrough viruses from vaccine and placebo recipients identified two V2 amino acid loci that differed between the vaccine and placebo groups, corroborating the finding that V2-specific antibodies in vaccine recipients were associated with a reduced risk of HIV-1 infection.
Methods: Here we extended the V1/V2 sieve analysis to the entire HIV-1 genome using an array of sieve analysis methods based on individual sites, k-mers and genes/proteins.
Results: Across the HIV-1 proteome, we identified 56 amino acid sites or “signatures” and 119 k-mers that differed between the vaccine and placebo groups; among these, 19 signature sites and 38 k-mers were located in Env-gp120, Gag, and Pro that constituted the RV144 vaccine. The nine signature sites in Env-gp120 were significantly more likely to be known antibody-associated sites than non-signature sites (p=0.0021). In particular, one signature in V3 (317) overlapped with a hotspot of antibody recognition, and sites 369 and 424 are linked to CD4 binding site neutralization.
Conclusions: Since signature sites were not preferentially restricted to the vaccine immunogens and because most of the statistical significance did not withstand multiplicity adjustment, we predict that few of the 56 genetic signatures found across the HIV-1 proteome are strongly linked to the RV144 vaccine-induced immune pressure. The collection of statistical methods and tools we employed constitutes an analysis platform applicable to sieve analysis of breakthrough infection genomes in general vaccine efficacy trials for diverse pathogens.
