Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study.
Safety and efficacy of the HVTN 503/Phambili study of a clade-B-based HIV-1 vaccine in South Africa: a double-blind, randomised, placebo-controlled test-of-concept phase 2b study.
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DOI：
10.1016/s1473-3099(11)70098-6
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发表时间：
2011-07
影响因子：
56.3
通讯作者：
Kublin, James G.
中科院分区：
文献类型：
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作者：
Gray, Glenda E.;Allen, Mai;Moodie, Zoe;Churchyard, Gavin;Bekker, Linda-Gail;Nchabeleng, Maphoshane;Mlisana, Koleka;Metch, Barbara;de Bruyn, Guy;Latka, Mary H.;Roux, Surita;Mathebula, Matsontso;Naicker, Nivashnee;Ducar, Constance;Carter, Donald K.;Puren, Adrien;Eaton, Niles;McElrath, M. Julie;Robertson, Michael;Corey, Lawrence;Kublin, James G.
我们报告了MRKad 5 gag/pol/nef HIV-1 B亚型疫苗在南非（SA）的安全性和有效性的初步分析，南非的主要流行分支是C亚型。这项IIb期双盲、随机化概念验证研究在SA的性活跃HIV-1血清阴性受试者中进行。协同主要终点是疫苗诱导的HIV-1感染或病毒载量设定点减少。在改良的意向治疗（MITT）队列中采用按性别分层的双尾显著性检验对这些进行独立评估。通过外周血单个核细胞中的干扰素-γ（IFNγ）ELISPOT评估免疫原性。在Step研究中MRKAd 5 HIV-1疫苗缺乏疗效后，本研究的入组和疫苗接种停止，治疗揭盲并继续随访。本研究在SA国家健康研究数据库（DOH-27-0207-1539）和ClinicalTrials.gov（NCT 00413725）中注册。在计划的3000名参与者中，有801人入组，其中360人（44.9%）为女性，超过一半（55.6%）的Ad 5滴度> 200，近三分之一（29.3%）的男性接受了包皮环切术。62名MITT参与者被诊断为HIV-1，疫苗组34名，安慰剂组28名，感染率分别为4.54和3.70/100人-年。无疫苗有效性（VE）证据;按性别调整的风险比为1.25（95% CI：0.76，2.05）。VE没有不同的Ad 5滴度，性别，年龄，HSV-2状态，或包皮环切术。疫苗接种者的几何平均病毒载量设定值为20，483拷贝/ml（N=33），安慰剂接种者为34，032拷贝/ml（N=28）（p=0.39）。该疫苗诱导了分泌IFNγ的T细胞识别进化枝B（89.2%）和C（77.4%）抗原。MRKAd 5 HIV-1疫苗不能预防HIV-1感染或降低病毒载量设定值，但提前停药可能会影响我们得出结论的能力。SA的高发病率突出表明迫切需要加紧努力开发有效的疫苗。
We report the primary analysis of the safety and efficacy of the MRKad5 gag/pol/nef HIV-1 sub-type B vaccine in South Africa (SA), where the major circulating clade is sub-type C. This phase IIb double-blind, randomized test-of-concept study was conducted in sexually active HIV-1 sero-negative participants in SA. The co-primary endpoints were a vaccine-induced reduction in HIV-1 acquisition or viral-load setpoint. These were assessed independently in the modified intent-to-treat (MITT) cohort with two-tailed significance tests stratified by gender. Immunogenicity was assessed by interferon-gamma (IFNγ) ELISPOT in peripheral blood mononuclear cells. Following the lack of efficacy of the MRKAd5 HIV-1 vaccine in the Step study, enrollment and vaccination in this study was halted, treatment unblinding occurred and follow-up continued. This study is registered with the SA National Health Research Database (DOH-27-0207-1539) and ClinicalTrials.gov (NCT00413725). 801 of a scheduled 3000 participants were enrolled, of whom 360 (44.9%) were women, more than half (55.6%) had Ad5 titres > 200, and almost a third (29.3%) of men were circumcised. 62 MITT participants were diagnosed with HIV-1, 34 in the vaccine arm and 28 in the placebo arm, with infection rates of 4.54 and 3.70 per 100 person-years, respectively. There was no evidence of vaccine efficacy (VE); the hazard ratio adjusted for gender was 1.25 (95% CI: 0.76, 2.05). VE did not differ by Ad5 titre, gender, age, HSV-2 status, or circumcision. The geometric mean viral load setpoint was 20,483 copies/ml (N=33) in vaccinees and 34,032 copies/ml (N=28) in placebo recipients (p=0.39). The vaccine elicited IFNγ-secreting T cells recognizing both clade B (89.2%) and C (77.4%) antigens. The MRKAd5 HIV-1 vaccine did not prevent HIV-1 infection or lower viral-load setpoint however early stopping likely compromised our ability to draw conclusions. The high incidence rates seen in SA highlight the critical need for intensified efforts to develop an efficacious vaccine.