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

Abstract

Background The Thai phase III HIV vaccine trial's modest efficacy (VE 31.2% 95% CI 1.1, 51.2) represents the first demonstration that a vaccine can protect against HIV acquisition. Baseline variables of age, gender, marital status, and risk did not modify vaccine efficacy (VE). Here we explore behavioral risk and efficacy at 6 monthly intervals following vaccination. Methods Behavioral risk was assessed with a self-administered questionnaire every 6 months during trial participation. Both the acquisition endpoint and the early viral load endpoint are examined for interactions with risk status over time and temporal effects following vaccination. Finding Risk for HIV acquisition is low in each risk group, but the majority of participants reported higher-risk behavior at least once during the study (N= 9187, 58%). In post-hoc analyses, comparing those participants categorized as high or rising risk at least once during study follow-up versus those who maintained low or medium risk behavior as a time-varying covariate, the interaction of risk status and acquisition efficacy is significant (P = 0.010) with greater benefit in the lower risk individuals. VE appears to peak early with an estimate of cumulative VE = 60% through 12 months after initial vaccination (95% CI 22 –80%), and declines quickly. Vaccination did not appear to affect viral load in either early or late infections. Interpretation Future HIV vaccine trials must recognize potential interactions between challenge intensity and risk heterogeneity in the population and treatment effects. The regimen tested in the Thai phase III trial may benefit from extended immunization schedules.

Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development

“…This finding is shown in Fig. 2A, where data from Yates et al (26) and Robb et al (30) are replotted in a single graph. Protection reached levels as high as ∼60% early but declined to undetectable levels by 18 mo.…”

“…In A, the decay of vaccine efficacy (black line), anti-V1/V2 seropositivity (red line), and anti-gp120 (blue line) are depicted. The protection data are from a study by Robb et al (30), and the seropositivity data are from a study by Yates et al (26). In B, the same data are plotted on a time scale more representative of durable antibody responses elicited by the licensed vaccines in Table 2.…”

“…The green line represents data for the persistence of anti-HPV antibody titers modeled by a modified power law in a study by David et al (60). The data in A and B were plotted from tables in the study by Yates et al (26) or digitized from the original publications (23,30,60) using the commercially available software DigitizeIt (www. digitizeit.de).…”

“…By contrast, modest efficacy of 31.2% was observed in the RV144 trial, where volunteers were immunized four times (at weeks 0, 4, 12, and 24), followed by evaluation every 6 mo over a 3-y period (21). It is important to note that vaccine efficacy was as high as 59.9% within the first year, waning to background over the course of the study (30). This finding leads to the striking possibility that if regular boosting could keep protection at the peak, the RV144 vaccine combination would be potentially licensable.…”

“…Protection correlated with antibodies against the V1/V2 region of gp120 (25), particularly those antibodies of the IgG3 subclass that mediate potent antibody-dependent cellular cytotoxicity (ADCC) (26), in addition to other aspects of anti-gp120 humoral immunity (25)(26)(27)(28)(29). Importantly, efficacy in the RV144 trial was temporally dependent, peaking at ∼59.9% early in the study and waning to background by the end of the 3-y postvaccination follow-up, thus producing an overall efficacy of 31.2% (30). Why did efficacy decline in this study?…”