Subtype C ALVAC-HIV and bivalent subtype C gp120/MF59 HIV-1 vaccine in low-risk, HIV-uninfected, South African adults: a phase 1/2 trial.
Subtype C ALVAC-HIV and bivalent subtype C gp120/MF59 HIV-1 vaccine in low-risk, HIV-uninfected, South African adults: a phase 1/2 trial.
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DOI：
10.1016/s2352-3018(18)30071-7
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发表时间：
2018-07
期刊：
影响因子：
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通讯作者：
HVTN 100 Protocol Team
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作者：
Bekker LG;Moodie Z;Grunenberg N;Laher F;Tomaras GD;Cohen KW;Allen M;Malahleha M;Mngadi K;Daniels B;Innes C;Bentley C;Frahm N;Morris DE;Morris L;Mkhize NN;Montefiori DC;Sarzotti-Kelsoe M;Grant S;Yu C;Mehra VL;Pensiero MN;Phogat S;DiazGranados CA;Barnett SW;Kanesa-Thasan N;Koutsoukos M;Michael NL;Robb ML;Kublin JG;Gilbert PB;Corey L;Gray GE;McElrath MJ;HVTN 100 Protocol Team
据报道，RV144 试验中测试的 HIV 疫苗具有适度的功效，该疫苗包含金丝雀痘载体 (ALVAC) 和包膜 (env) 糖蛋白 (gp120)。这些疫苗成分经过改造，可表达来自南非流行毒株的 HIV-1 抗原，并改变佐剂以增加免疫原性。此外，还增加了 12 个月的免疫接种以提高耐久性。在 HIV 疫苗试验网络 (HVTN) 100 试验中，我们旨在评估这种新的区域适应方案，以推进功效测试。 HVTN 100 是在南非六个社区研究中心进行的 1/2 期随机对照双盲试验。我们将未感染 HIV 且 HIV 感染风险较低的成年人（18-40 岁）以 5:1 的比例随机分配至疫苗方案（在 0、1、3、6 和 12 个月肌内注射 ALVAC-HIV 载体 [vCP2438]，并在 3、6 和 12 个月肌内注射二价 C 亚型 gp120 和 MF59 佐剂）或安慰剂。随机化是由计算机生成的列表完成的。参与者、研究人员和评估结果的人员都被随机分配。主要结局包括 RV144 中 6 个月（第 6·5 个月）疫苗接种后 2 周与 HIV 风险相关的安全性和免疫反应。我们将 HVTN 100 中符合方案的参与者（即完成前四次疫苗接种并在第 6·5 个月提供样本的参与者）与同时测定的存储的 RV144 样本进行了比较。该试验已在南非国家临床试验注册中心 (DOH-27-0215-4796) 和 ClinicalTrials.gov (NCT02404311) 注册。 2015年2月9日至2015年5月26日期间，共有252名参与者入组，其中210人被分配了疫苗，42人被分配了安慰剂。 222 名参与者参与了符合方案的分析（185 名疫苗和 37 名安慰剂）。 185 名 (100%) 疫苗接种者针对所有三种疫苗匹配的 gp120 抗原产生了 IgG 结合抗体，其滴度显着高于 RV144 的相应疫苗匹配反应（3·6–8·8 倍；所有 p<0·0001）。 HVTN 100 中 CD4+ T 细胞对 ZM96.C env 蛋白的反应为 56·4%（n=102 名应答者），而 RV144 中对 92TH023.AE 的应答为 41·4%（n=79 名应答者）（p=0·0050）。 HVTN 100 中对 1086.C 可变环 1 和 2 (V1V2) env 抗原的 IgG 应答为 70·5%（95% CI 63·5–76·6；n=129 名应答者），低于 RV144 中对 V1V2 的应答（99·0%，95% CI 96·4–99·7；n=199 名应答者）。尽管 HVTN 100 疫苗的 IgG 反应低于 RV144 中报道的反应，但它超过了使用 V1V2 相关保护模型预测的 50% 疫苗功效所需的 63% 阈值。因此，C 亚型 HIV 疫苗方案符合 2b/3 期功效测试的资格，这是疫苗开发的关键下一步。美国国家过敏和传染病研究所 (NIAID) 以及比尔及梅琳达·盖茨基金会。
Modest efficacy was reported for the HIV vaccine tested in the RV144 trial, which comprised a canarypox vector (ALVAC) and envelope (env) glycoprotein (gp120). These vaccine components were adapted to express HIV-1 antigens from strains circulating in South Africa, and the adjuvant was changed to increase immunogenicity. Furthermore, 12-month immunisation was added to improve durability. In the HIV Vaccine Trials Network (HVTN) 100 trial, we aimed to assess this new regionally adapted regimen for advancement to efficacy testing. HVTN 100 is a phase 1/2, randomised controlled, double-blind trial at six community research sites in South Africa. We randomly allocated adults (aged 18–40 years) without HIV infection and at low risk of HIV infection to either the vaccine regimen (intramuscular injection of ALVAC-HIV vector [vCP2438] at 0, 1, 3, 6, and 12 months plus bivalent subtype C gp120 and MF59 adjuvant at 3, 6, and 12 months) or placebo, in a 5:1 ratio. Randomisation was done by computer-generated list. Participants, investigators, and those assessing outcomes were masked to random assignments. Primary outcomes included safety and immune responses associated with correlates of HIV risk in RV144, 2 weeks after vaccination at 6 months (month 6·5). We compared per-protocol participants (ie, those who completed the first four vaccinations and provided samples at month 6·5) from HVTN 100 with stored RV144 samples assayed contemporaneously. This trial is registered with the South African National Clinical Trials Registry (DOH-27-0215-4796) and ClinicalTrials.gov (NCT02404311). Between Feb 9, 2015, and May 26, 2015, 252 participants were enrolled, of whom 210 were assigned vaccine and 42 placebo. 222 participants were included in the per-protocol analysis (185 vaccine and 37 placebo). 185 (100%) vaccine recipients developed IgG binding antibodies to all three vaccine-matched gp120 antigens with significantly higher titres (3·6–8·8 fold; all p<0·0001) than the corresponding vaccine-matched responses of RV144. The CD4+ T-cell response to the ZM96.C env protein in HVTN 100 was 56·4% (n=102 responders), compared with a response of 41·4% (n=79 responders) to 92TH023.AE in RV144 (p=0·0050). The IgG response to the 1086.C variable loops 1 and 2 (V1V2) env antigen in HVTN 100 was 70·5% (95% CI 63·5–76·6; n=129 responders), lower than the response to V1V2 in RV144 (99·0%, 95% CI 96·4–99·7; n=199 responders). Although the IgG response to the HVTN 100 vaccine was lower than that reported in RV144, it exceeded the predicted 63% threshold needed for 50% vaccine efficacy using a V1V2 correlate of protection model. Thus, the subtype C HIV vaccine regimen qualified for phase 2b/3 efficacy testing, a critical next step of vaccine development. US National Institute of Allergy and Infectious Diseases (NIAID), and Bill & Melinda Gates Foundation.