Risk behaviour and time as covariates for efficacy 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

US Military HIV Research Program, Division of Retrovirology, Walter Reed Army Institute of Research, Rockville, MD, USA.
The Lancet Infectious Diseases (Impact Factor: 22.43). 05/2012; 12(7):531-7. DOI: 10.1016/S1473-3099(12)70088-9
Source: PubMed


The Thai phase 3 HIV vaccine trial RV 144 showed modest efficacy of a vaccine against HIV acquisition. Baseline variables of age, sex, marital status, and risk did not modify vaccine efficacy. We did a post-hoc analysis of the trial's data to investigate behavioural risk and efficacy every 6 months after vaccination.
RV 144 was a randomised, multicentre, double-blind, placebo-controlled efficacy 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 modified 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 classified 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 effects after vaccination. Multiple proportional hazards regression models with treatment and time-varying risk covariates were analysed.
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 classified as high or increasing risk at least once during follow-up 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 efficacy was significant (p=0·01), with greater benefit in low-risk individuals. Vaccine efficacy seemed to peak early--cumulative vaccine efficacy 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 affect viral load in either early or late infections.
Future HIV vaccine trials should recognise potential interactions between challenge intensity and risk heterogeneity in both population and treatment effects. The regimen tested in the RV 144 phase 3 trial might benefit from extended immunisation schedules.
US Army Medical Research and Materiel Command and Division of AIDS, National Institute of Allergy and Infectious Disease, National Institutes of Health.

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    • "The Fc region of IgGs would still be able to bind to Fcgbp but they would not demonstrate any benefit to the vaccine recipient. Also, most of the vaccine recipients in the RV144 trial were low-risk heterosexuals and vaccine efficacy decreased with increased risk [27]. Still, the reported 31.2% "
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    ABSTRACT: Years of extensive research have yielded much knowledge in many aspects of HIV-1 infection, treatments, and education. However, without a vaccine, the number of people infected worldwide continues to grow. The partial success of the Thai RV144 vaccine trial provides hope that a method of protection is indeed possible. Understanding the mechanism behind the protection is critical if we hope to achieve our goal of inhibiting new infections of HIV-1. We hypothesize that the Fc of IgG binding protein (Fcgbp) is associated with the protection observed in the RV144 vaccine trial. It has the ability to trap viral-antibody complexes in the mucosa by binding the Fc of IgG to Fcgbp. This property could be used in the form of a microbicide containing antibodies to a variety of HIV-1 epitopes to prevent sexual transmission of HIV-1. The aim of this paper is to stimulate further research into Fcgbp and its role in innate immunity.
    The Open AIDS Journal 09/2014; 8(1):21-4. DOI:10.2174/1874613601408010021
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    • "In another post-hoc analysis, not included in the pre-specified analysis plan, vaccine efficacy appeared to be higher (60%) at 12 months post vaccination, suggesting an early, but nondurable, vaccine effect. The authors pointed out that future HIV vaccine trials should recognize potential interactions between challenge intensity and risk heterogeneity in both population and treatment effects [8]. One can speculate that the RV144 regimen was able to protect because the number of sexual contacts were limited in time and could be countered by a marginally efficacious vaccine, which might or might not hold true with communities at higher risk of sexual transmission and increased number of exposures such as MSM and female sex workers. "
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    ABSTRACT: The RV144 efficacy trial conducted in Thailand provided the first evidence that an HIV vaccine could provide a modest level of protection against HIV acquisition (31.2% at 42 months of follow-up) in populations at low risk for HIV infection. Vaccine efficacy appeared to be higher (60%) at 12 months post vaccination, suggesting an early, but nondurable, vaccine effect. This breakthrough finding led to identification of immune correlates of risk, antibodies directed against the V2 loop, paving the way to new vaccine designs and clinical trials to better characterization of the vaccine-induced adaptive and innate humoral and cell-mediated immune responses in peripheral and mucosal compartments. Whether the RV144 correlates of risk are universal and apply to other populations at higher risk for HIV acquisition and other modes of transmission (rectal, injecting drug users) is unknown and remains to be explored. Future efficacy trials using a similar vaccine concept tested in high-risk heterosexual populations and in men having sex with men are planned.
    Procedia in Vaccinology 01/2013; 7:49–56. DOI:10.1016/j.provac.2013.06.010
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    • "Thus, the outcome of the trial was rather fragile. The apparent vaccine efficacy declined from 60% for the first year to 31% for the 3.5-year post-vaccination period, although with wide confidence intervals because of the small number of infections [5,26,27]. Since Ab titers to gp120 vaccines decline rapidly [3,15], it might be conjectured that the peak responses contribute to the higher efficacy at the earlier times. There is, however, an alternative explanation for the weakening efficacy of a vaccine [27]. "
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    ABSTRACT: Correlates of protection (CoPs) against infection by primate lentiviruses remain undefined. Modest protection against HIV-1 was observed in one human vaccine trial, whereas previous trials and vaccine-challenge experiments in non-human primates have yielded inconsistent but intriguing results. Although high levels of neutralizing antibodies are known to protect macaques from mucosal and intravenous viral challenges, antibody or other adaptive immune responses associated with protection might also be mere markers of innate immunity or susceptibility. Specific strategies for augmenting the design of both human trials and animal experiments could help to identify mechanistic correlates of protection and clarify the influences of confounding factors. Robust protection may, however, require the combined actions of immune responses and other host factors, thereby limiting what inferences can be drawn from statistical associations. Here, we discuss how to analyze immune protection against primate lentiviruses, and how host factors could influence both the elicitation and effectiveness of vaccine-induced responses.
    Retrovirology 10/2012; 9(1):80. DOI:10.1186/1742-4690-9-80 · 4.19 Impact Factor
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