Effect of rAd5-Vector HIV-1 Preventive Vaccines on HIV-1 Acquisition: A Participant-Level Meta-Analysis of Randomized Trials

BackgroundThree phase 2b, double-blind, placebo-controlled, randomized efficacy trials have tested recombinant Adenovirus serotype-5 (rAd5)-vector preventive HIV-1 vaccines: MRKAd5 HIV-1 gag/pol/nef in Step and Phambili, and DNA/rAd5 HIV-1 env/gag/pol in HVTN505. Due to efficacy futility observed at the first interim analysis in Step and HVTN505, participants of all three studies were unblinded to their vaccination assignments during the study but continued follow–up. Rigorous meta-analysis can provide crucial information to advise the future utility of rAd5-vector vaccines.MethodsWe included participant-level data from all three efficacy trials, and three Phase 1–2 trials evaluating the HVTN505 vaccine regimen. We predefined two co-primary analysis cohorts for assessing the vaccine effect on HIV-1 acquisition. The modified-intention-to-treat (MITT) cohort included all randomly assigned participants HIV-1 uninfected at study entry, who received at least the first vaccine/placebo, and the Ad5 cohort included MITT participants who received at least one dose of rAd5-HIV vaccine or rAd5-placebo. Multivariable Cox regression models were used to estimate hazard ratios (HRs) of HIV-1 infection (vaccine vs. placebo) and evaluate HR variation across vaccine regimens, time since vaccination, and subgroups using interaction tests.FindingsResults are similar for the MITT and Ad5 cohorts; we summarize MITT cohort results. Pooled across the efficacy trials, over all follow-up time 403 (n = 224 vaccine; n = 179 placebo) of 6266 MITT participants acquired HIV-1, with a non-significantly higher incidence in vaccine recipients (HR 1.21, 95% CI 0.99–1.48, P = 0.06). The HRs significantly differed by vaccine regimen (interaction P = 0.03; MRKAd5 HR 1.41, 95% CI 1.11–1.78, P = 0.005 vs. DNA/rAd5 HR 0.88, 95% CI 0.61–1.26, P = 0.48). Results were similar when including the Phase 1–2 trials. Exploratory analyses based on the efficacy trials supported that the MRKAd5 vaccine-increased risk was concentrated in Ad5-positive or uncircumcised men early in follow-up, and in Ad5-negative or circumcised men later. Overall, MRKAd5 vaccine-increased risk was evident across subgroups except in circumcised Ad5-negative men (HR 0.97, 95% CI 0.58−1.63, P = 0.91); there was little evidence that the DNA/rAd5 vaccine, that was tested in this subgroup, increased risk (HR 0.88, 95% CI 0.61–1.26, P = 0.48). When restricting the analysis of Step and Phambili to follow-up time before unblinding, 114 (n = 65 vaccine; n = 49 placebo) of 3770 MITT participants acquired HIV-1, with a non-significantly higher incidence in MRKAd5 vaccine recipients (HR 1.30, 95% CI 0.89–1.14, P = 0.18).Interpretation and SignificanceThe data support increased risk of HIV-1 infection by MRKAd5 over all follow-up time, but do not support increased risk of HIV-1 infection by DNA/rAd5. This study provides a rationale for including monitoring plans enabling detection of increased susceptibility to infection in HIV-1 at-risk populations.背景 三项2b期、双盲、安慰剂对照、随机疗效试验对重组5型腺病毒（recombinant Adenovirus serotype-5, rAd5）载体预防性HIV-1疫苗进行了测试：Step和Phambili研究使用MRKAd5 HIV-1 gag/pol/nef疫苗，HVTN505研究使用DNA/rAd5 HIV-1 env/gag/pol疫苗。由于在Step和HVTN505研究的首次中期分析中观察到疗效无效，三项研究的所有受试者在研究期间均被揭盲知晓自身的疫苗接种分组，但仍继续接受随访。严谨的荟萃分析可为rAd5载体疫苗的未来应用提供关键参考信息。 方法 本研究纳入全部三项疗效试验的受试者水平数据，以及三项评估HVTN505疫苗方案的1-2期试验数据。我们预先设定了两个共同主要分析队列，以评估疫苗对HIV-1感染的作用：改良意向治疗（modified-intention-to-treat, MITT）队列纳入所有在研究入组时未感染HIV-1、且至少接种第一剂疫苗/安慰剂的随机分配受试者；Ad5队列则纳入MITT队列中至少接受过一剂rAd5-HIV疫苗或rAd5安慰剂的受试者。本研究采用多变量Cox回归模型估算HIV-1感染的风险比（hazard ratios, HRs，疫苗组vs安慰剂组），并通过交互检验评估不同疫苗方案、疫苗接种后时间以及各亚组间的HR差异。 结果 MITT队列与Ad5队列的结果相似，本研究将以MITT队列结果进行总结。在所有疗效试验的合并分析中，6266名MITT队列受试者在全部随访期间共有403人感染HIV-1（疫苗组224人，安慰剂组179人），疫苗接种者的感染发生率非显著性升高（HR=1.21，95%置信区间[CI] 0.99–1.48，P=0.06）。不同疫苗方案的HR存在显著性差异（交互检验P=0.03；MRKAd5组HR=1.41，95%CI 1.11–1.78，P=0.005；DNA/rAd5组HR=0.88，95%CI 0.61–1.26，P=0.48）。纳入1-2期试验后结果相似。基于疗效试验的探索性分析显示，MRKAd5疫苗带来的感染风险升高主要集中在随访早期的Ad5血清阳性或未行包皮环切术的男性，以及随访后期的Ad5血清阴性或行包皮环切术的男性。总体而言，除Ad5血清阴性且行包皮环切术的男性亚组（HR=0.97，95%CI 0.58−1.63，P=0.91）外，MRKAd5疫苗的感染风险升高在各亚组中均显著；而在该亚组中测试的DNA/rAd5疫苗几乎未显示出感染风险升高的证据（HR=0.88，95%CI 0.61–1.26，P=0.48）。当将Step和Phambili研究的分析限定在揭盲前的随访时段时，3770名MITT队列受试者中有114人感染HIV-1（疫苗组65人，安慰剂组49人），MRKAd5疫苗接种者的感染发生率仍非显著性升高（HR=1.30，95%CI 0.89–1.14，P=0.18）。 解释与意义 本研究数据显示，在全部随访时段内，MRKAd5疫苗会升高HIV-1感染风险，但未发现DNA/rAd5疫苗会升高HIV-1感染风险。本研究为制定监测计划提供了理论依据，以实现对HIV-1感染高危人群易感性升高的检测。