Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial

Abstract

Background: Observational data and non-human primate challenge studies suggest that cell-mediated immune responses might provide control of HIV replication. The Step Study directly assessed the efficacy of a cell-mediated immunity vaccine to protect against HIV-1 infection or change in early plasma HIV-1 levels.

Methods: We undertook a double-blind, phase II, test-of-concept study at 34 sites in North America, the Caribbean, South America, and Australia. We randomly assigned 3000 HIV-1-seronegative participants by computer-generated assignments to receive three injections of MRKAd5 HIV-1 gag/pol/nef vaccine (n=1494) or placebo (n=1506). Randomisation was prestratified by sex, adenovirus type 5 (Ad5) antibody titre at baseline, and study site. Primary objective was a reduction in HIV-1 acquisition rates (tested every 6 months) or a decrease in HIV-1 viral-load setpoint (early plasma HIV-1 RNA measured 3 months after HIV-1 diagnosis). Analyses were per protocol and modified intention to treat. The study was stopped early because it unexpectedly met the prespecified futility boundaries at the first interim analysis. This study is registered with ClinicalTrials.gov, number NCT00095576.

Findings: In a prespecified interim analysis in participants with baseline Ad5 antibody titre 200 or less, 24 (3%) of 741 vaccine recipients became HIV-1 infected versus 21 (3%) of 762 placebo recipients (hazard ratio [HR] 1.2 [95% CI 0.6-2.2]). All but one infection occurred in men. The corresponding geometric mean plasma HIV-1 RNA was comparable in infected male vaccine and placebo recipients (4.61 vs 4.41 log(10) copies per mL, one tailed p value for potential benefit 0.66). The vaccine elicited interferon-gamma ELISPOT responses in 75% (267) of the 25% random sample of all vaccine recipients (including both low and high Ad5 antibody titres) on whose specimens this testing was done (n=354). In exploratory analyses of all study volunteers, irrespective of baseline Ad5 antibody titre, the HR of HIV-1 infection between vaccine and placebo recipients was higher in Ad5 seropositive men (HR 2.3 [95% CI 1.2-4.3]) and uncircumcised men (3.8 [1.5-9.3]), but was not increased in Ad5 seronegative (1.0 [0.5-1.9]) or circumcised (1.0 [0.6-1.7]) men.

Interpretation: This cell-mediated immunity vaccine did not prevent HIV-1 infection or reduce early viral level. Mechanisms for insufficient efficacy of the vaccine and the increased HIV-1 infection rates in subgroups of vaccine recipients are being explored.

Figure 1

Trial profile. Discontinued includes study participants who were unwilling or unable to continue follow-up in the trial at the time the dataset was frozen. All participants who received at least one dose of vaccine or placebo were included in the safety analysis; efficacy analysis was limited to the modified intent-to-treat subgroup who were also HIV negative at baseline. The immunogenicity analysis was performed on a 25% random sample of the entire cohort.

Figure 2

Kaplan Meier plots of HIV infection for male vaccine and placebo groups by A) baseline Ad5 ≤18; B) baseline Ad5 >18 and ≤200; C)baseline Ad5 >200 and ≤1000; and D) baseline Ad5 >1000. Each hazard ratio (HR) is from a univariate Cox regression model.

Figure 3

Early plasma viral load (VL) at ~ 3 months after detection of infection in male study participants by A) baseline Ad5 ≤ 18; B) baseline Ad5 >18; and C) all participants. The bar in each panel denotes the geometric mean titers of the plasma VL.

Figure 4

HIV incidence during 6-month time intervals for male vaccine and placebo groups by A) baseline Ad5 titer ≤18; B) baseline Ad5 >18; C) overall; D) circumcised; and E) uncircumcised. Each 2-tailed p-value (p) is from a univariate Cox regression model.