Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial.
Efficacy assessment of a cell-mediated immunity HIV-1 vaccine (the Step Study): a double-blind, randomised, placebo-controlled, test-of-concept trial.
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DOI：
10.1016/s0140-6736(08)61591-3
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发表时间：
2008-11-29
期刊：
影响因子：
168.9
通讯作者：
Robertson, Michael N.
中科院分区：
文献类型：
--
作者：
Buchbinder, Susan P.;Mehrotra, Devon V.;Duerr, Ann;Fitzgerald, Daniel W.;Mogg, Robin;Li, David;Gilbert, Peter B.;Lama, Javier R.;Marmor, Michael;del Rio, Carlos;McElrath, M. Juliana;Casimiro, Danilo R.;Gottesdiener, Keith M.;Chodakewitz, Jeffrey A.;Corey, Lawrence;Robertson, Michael N.
观察数据和非人灵长类动物攻击研究表明，细胞介导的免疫（CMI）反应可能提供控制艾滋病毒复制。Step研究是第一次直接评估CMI疫苗预防HIV感染或改变人类早期血浆HIV水平的有效性。HIV血清阴性受试者（3000例）随机（1：1）接受3次MRKAd 5 HIV-1 gag/pol/nef疫苗或安慰剂注射。按性别、基线5型腺病毒（Ad 5）滴度和研究中心对随机化进行预分层。参与者每6个月进行一次HIV感染检测; HIV诊断后约3个月测量早期血浆HIV RNA。该疫苗在75%的接种者中引起IFN-γ ELISPOT应答。在一项预先规定的中期分析中，基线Ad 5 ≤200的参与者中，741名疫苗接种者中有24名感染了HIV，而762名安慰剂接种者中有21名感染了HIV。除1例感染外，所有感染均发生在男性中。感染疫苗和安慰剂接受者的早期血浆HIV RNA几何平均值相当。在探索性多变量分析中，在Ad 5血清阳性男性（每年分别为5.1%和2.2%）和未行包皮环切术男性（每年分别为5.2%和1.4%）中，疫苗接种者的HIV发病率高于安慰剂接种者。在Ad 5血清阴性男性和包皮环切男性中，接种疫苗者与安慰剂接受者的HIV发病率相似。该CMI疫苗不能预防HIV感染或降低早期病毒水平。目前正在探讨疫苗未能起到保护作用和接种者亚群中艾滋病毒感染率增加的机制。额外的随访将确定接种者亚组中HIV发病率是否持续升高。
Observational data and non-human primate challenge studies suggest that cell-mediated immune (CMI) responses may provide control of HIV replication. The Step Study is the first direct assessment of the efficacy of a CMI vaccine to protect against HIV infection or alter early plasma HIV levels in humans. HIV-seronegative participants (3000) were randomized (1:1) to receive 3 injections of MRKAd5 HIV-1 gag/pol/nef vaccine or placebo. Randomization was pre-stratified by gender, baseline adenovirus type 5 (Ad5) titer, and study site. Participants were tested ~every 6 months for HIV acquisition; early plasma HIV RNA was measured ~3 months post-HIV diagnosis. The vaccine elicited IFN-γ ELISPOT responses in 75% of vaccinees. In a pre-specified interim analysis among participants with baseline Ad5 ≤200, 24 of 741 vaccinees became HIV infected, versus 21 of 762 placebo recipients. All but one infection occurred in men. The early geometric mean plasma HIV RNA was comparable in infected vaccine and placebo recipients. In exploratory multivariate analyses, HIV incidence was higher in vaccinees versus placebo recipients among Ad5 seropositive men (5.1% versus 2.2% per year, respectively) and uncircumcised men (5.2% versus 1.4% per year, respectively). HIV incidence was similar in vaccinees versus placebo recipients among Ad5 seronegative men and circumcised men. This CMI vaccine did not prevent HIV infection or lower early viral level. Mechanisms for failure of the vaccine to protect and for the increased HIV infection rates in subgroups of vaccinees are being explored. Additional follow-up will determine if elevated HIV incidence in vaccinee subgroups persists.