Comprehensive Sieve Analysis of Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial
Open Access
- 3 February 2015
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Computational Biology
- Vol. 11 (2), e1003973
- https://doi.org/10.1371/journal.pcbi.1003973
Abstract
The RV144 clinical trial showed the partial efficacy of a 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 identified two V2 amino acid sites that differed between the vaccine and placebo groups. Here we extended the V1/V2 analysis to the entire HIV-1 genome using an array of methods based on individual sites, k-mers and genes/proteins. We identified 56 amino acid sites or “signatures” and 119 k-mers that differed between the vaccine and placebo groups. Of those, 19 sites and 38 k-mers were located in the regions comprising the RV144 vaccine (Env-gp120, Gag, and Pro). The nine signature sites in Env-gp120 were significantly enriched for known antibody-associated sites (p = 0.0021). In particular, site 317 in the third variable loop (V3) overlapped with a hotspot of antibody recognition, and sites 369 and 424 were linked to CD4 binding site neutralization. The identified signature sites significantly covaried with other sites across the genome (mean = 32.1) more than did non-signature sites (mean = 0.9) (p < 0.0001), suggesting functional and/or structural relevance of the signature sites. Since signature sites were not preferentially restricted to the vaccine immunogens and because most of the associations were insignificant following correction for multiple testing, we predict that few of the genetic differences are strongly linked to the RV144 vaccine-induced immune pressure. In addition to presenting results of the first complete-genome analysis of the breakthrough infections in the RV144 trial, this work describes a set of statistical methods and tools applicable to analysis of breakthrough infection genomes in general vaccine efficacy trials for diverse pathogens. We present an analysis of the genomes of the HIV viruses that infected some participants of the RV144 Thai trial, which was the first study to show efficacy of a vaccine to prevent HIV infection. We analyzed the HIV genomes of infected vaccine recipients and infected placebo recipients, and found differences between them. These differences coincide with previously-studied genetic features that are relevant to the biology of HIV infection, including features involved in immune recognition of the virus. The findings presented here generate testable hypotheses about the mechanism of the partial protection seen in the Thai trial, and may ultimately lead to improved vaccines. The article also presents a toolkit of methods for computational analyses that can be applied to other vaccine efficacy trials.Keywords
This publication has 54 references indexed in Scilit:
- Evolution of an HIV glycan–dependent broadly neutralizing antibody epitope through immune escapeNature Medicine, 2012
- Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2Nature, 2012
- Magnitude and Breadth of the Neutralizing Antibody Response in the RV144 and Vax003 HIV-1 Vaccine Efficacy TrialsThe Journal of Infectious Diseases, 2012
- Immune-Correlates Analysis of an HIV-1 Vaccine Efficacy TrialNew England Journal of Medicine, 2012
- Polyclonal B Cell Responses to Conserved Neutralization Epitopes in a Subset of HIV-1-Infected IndividualsJournal of Virology, 2011
- Estimation of Stratified Mark‐Specific Proportional Hazards Models with Missing MarksScandinavian Journal of Statistics, 2011
- HIV-1 Vaccines and Adaptive Trial DesignsScience Translational Medicine, 2011
- Genetic impact of vaccination on breakthrough HIV-1 sequences from the STEP trialNature Medicine, 2011
- MHC Class II epitope predictive algorithmsImmunology, 2010
- Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in ThailandNew England Journal of Medicine, 2009