Risk behaviour and time as covariates for effi cacy of the HIV vaccine regimen ALVAC-HIV (vCP1521) and AIDSVAX B/E: a post-hoc analysis of the Thai phase 3 efficacy trial RV 144

Background The Thai phase 3 HIV vaccine trial RV 144 showed modest effi cacy of a vaccine against HIV acquisition. Baseline variables of age, sex, marital status, and risk did not modify vaccine effi cacy. We did a post-hoc analysis of the trial’s data to investigate behavioural risk and effi cacy every 6 months after vaccination. Methods RV 144 was a randomised, multicentre, double-blind, placebo-controlled effi cacy trial testing the combination of the HIV vaccines ALVAC-HIV (vCP1521) and AIDSVAX B/E to prevent HIV infection or reduce setpoint viral load. Male and female volunteers aged 18–30 years were recruited from the community. In this post-hoc analysis of the modifi ed intention-to-treat population (16 395 participants), HIV risk behaviour was assessed with a self-administered questionnaire at the time of initial vaccination in the trial and every 6 months thereafter for 3 years. We classifi ed participants’ behaviour as low, medium, or high risk. Both the acquisition endpoint and the early viral-load endpoint were examined for interactions with risk status over time and temporal eff ects after vaccination. Multiple proportional hazards regression models with treatment and time-varying risk covariates were analysed. Findings Risk of acquisition of HIV was low in each risk group, but 9187 (58·2%) participants reported higher-risk behaviour at least once during the study. Participants classifi ed as high or increasing risk at least once during followup were compared with those who maintained low-risk or medium-risk behaviour as a time-varying covariate, and the interaction of risk status and acquisition effi cacy was signifi cant (p=0·01), with greater benefi t in low-risk individuals. Vaccine effi cacy seemed to peak early—cumulative vaccine effi cacy was estimated to be 60·5% (95% CI 22–80) through the 12 months after initial vaccination—and declined quickly. Vaccination did not seem to aff ect viral load in either early or late infections. Interpretation Future HIV vaccine trials should recognise potential interactions between challenge intensity and risk heterogeneity in both population and treatment eff ects. The regimen tested in the RV 144 phase 3 trial might benefi t from extended immunisation schedules. Funding US Army Medical Research and Materiel Command and Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health

Antibody to HSV gD peptide induced by vaccination does not protect against HSV-2 infection in HSV-2 seronegative women

<div><p>Background</p><p>In the HIV-1 vaccine trial RV144, ALVAC-HIV prime with an AIDSVAX^® B/E boost reduced HIV-1 acquisition by 31% at 42 months post first vaccination. The bivalent AIDSVAX^® B/E vaccine contains two gp120 envelope glycoproteins, one from the subtype B HIV-1 MN isolate and one from the subtype CRF01_AE A244 isolate. Each envelope glycoprotein harbors a highly conserved 27-amino acid HSV-1 glycoprotein D (gD) tag sequence that shares 93% sequence identity with the HSV-2 gD sequence. We assessed whether vaccine-induced anti-gD antibodies protected females against HSV-2 acquisition in RV144.</p><p>Methods</p><p>Of the women enrolled in RV144, 777 vaccine and 807 placebo recipients were eligible and randomly selected according to their pre-vaccination HSV-1 and HSV-2 serostatus for analysis. Immunoglobulin G (IgG) and IgA responses to gD were determined by a binding antibody multiplex assay and HSV-2 serostatus was determined by Western blot analysis.</p><p>Ninety-three percent and 75% of the vaccine recipients had anti-gD IgG and IgA responses two weeks post last vaccination, respectively. There was no evidence of reduction in HSV-2 infection by vaccination compared to placebo recipients over 78 weeks of follow-up. The annual incidence of HSV-2 infection in individuals who were HSV-2 negative at baseline or HSV-1 positive and HSV-2 indeterminate at baseline were 4.38/100 person-years (py) and 3.28/100 py in the vaccine and placebo groups, respectively. Baseline HSV-1 status did not affect subsequent HSV-2 acquisition. Specifically, the estimated odds ratio of HSV-2 infection by Week 78 for female placebo recipients who were baseline HSV-1 positive (n = 422) vs. negative (n = 1120) was 1.14 [95% confidence interval 0.66 to 1.94, p = 0.64)]. No evidence of reduction in the incidence of HSV-2 infection by vaccination was detected.</p><p>Conclusions</p><p>AIDSVAX^® B/E containing gD did not confer protection from HSV-2 acquisition in HSV-2 seronegative women, despite eliciting anti-gD serum antibodies.</p></div

Comparison of HSV-2 infection rates by week 78 (Vaccine vs. Placebo Female Recipients) (HSV-2 Infection = Positive or Indeterminate at Week 78).

<p>Comparison of HSV-2 infection rates by week 78 (Vaccine vs. Placebo Female Recipients) (HSV-2 Infection = Positive or Indeterminate at Week 78).</p

HSV-2 infection rates by baseline behavioral HIV-1 risk score (Primary Cohort).

<p>HSV-2 infection rates by baseline behavioral HIV-1 risk score (Primary Cohort).</p

IgG and IgA responses and percentage of responders to the gD protein measured at week 26 by binding antibody multiplex array for the n = 85 HIV-1-uninfected female participants in the RV144 case-control study [26] (75 vaccine and 10 placebo recipients).

<p>IgG and IgA responses and percentage of responders to the gD protein measured at week 26 by binding antibody multiplex array for the n = 85 HIV-1-uninfected female participants in the RV144 case-control study [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176428#pone.0176428.ref026" target="_blank">26</a>] (75 vaccine and 10 placebo recipients).</p

CONSORT diagram.

<p>CONSORT diagram.</p

Comparison of the sequence of the gD tag expressed on the AIDSVAX^® B/E gp120 envelope glycoprotein antigens (Global Solutions for Infectious Diseases) with the corresponding published HSV-1 and HSV-2 sequences (retrieved from GenBank on 06/24/15).

<p>The amino acid sequences are shown in weblogos, depicting the different variants at each position as stacked symbols, with the height of each symbol indicating its relative frequency. Asterisks highlight the main differences between HSV-1 and HSV-2. Weblogos were constructed using [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176428#pone.0176428.ref040" target="_blank">40</a>].</p

Distribution of age (≤20, 21–25, ≥26)^* and baseline self-reported behavioral risk score (Percent Low, Medium, High)^** for female RV144 participants with HSV measurements included in the study.

<p>Distribution of age (≤20, 21–25, ≥26)^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176428#t001fn001" target="_blank">*</a>} and baseline self-reported behavioral risk score (Percent Low, Medium, High)^{<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0176428#t001fn002" target="_blank">**</a>} for female RV144 participants with HSV measurements included in the study.</p