A Phase I Double Blind, Placebo-Controlled, Randomized Study of a Multigenic HIV-1 Adenovirus Subtype 35 Vector Vaccine in Healthy Uninfected Adults

BackgroundWe conducted a phase I, randomized, double-blind, placebo-controlled trial to assess the safety and immunogenicity of escalating doses of two recombinant replication defective adenovirus serotype 35 (Ad35) vectors containing gag, reverse transcriptase, integrase and nef (Ad35-GRIN) and env (Ad35-ENV), both derived from HIV-1 subtype A isolates. The trial enrolled 56 healthy HIV-uninfected adults. MethodsAd35-GRIN/ENV (Ad35-GRIN and Ad35-ENV mixed in the same vial in equal proportions) or Ad35-GRIN was administered intramuscularly at 0 and 6 months. Participants were randomized to receive either vaccine or placebo (10/4 per group, respectively) within one of four dosage groups: Ad35-GRIN/ENV 2×109 (A), 2×1010 (B), 2×1011 (C), or Ad35-GRIN 1×1010 (D) viral particles. ResultsNo vaccine-related serious adverse event was reported. Reactogenicity events reported were dose-dependent, mostly mild or moderate, some severe in Group C volunteers, all transient and resolving spontaneously. IFN-γ ELISPOT responses to any vaccine antigen were detected in 50, 56, 70 and 90% after the first vaccination, and in 75, 100, 88 and 86% of Groups A–D vaccine recipients after the second vaccination, respectively. The median spot forming cells (SFC) per 106 PBMC to any antigen was 78–139 across Groups A–C and 158–174 in Group D, after each of the vaccinations with a maximum of 2991 SFC. Four to five HIV proteins were commonly recognized across all the groups and over multiple timepoints. CD4+ and CD8+ T-cell responses were polyfunctional. Env antibodies were detected in all Group A–C vaccinees and Gag antibodies in most vaccinees after the second immunization. Ad35 neutralizing titers remained low after the second vaccination. Conclusion/SignificanceAd35-GRIN/ENV reactogenicity was dose-related. HIV-specific cellular and humoral responses were seen in the majority of volunteers immunized with Ad35-GRIN/ENV or Ad35-GRIN and increased after the second vaccination. T-cell responses were broad and polyfunctional. Trial RegistrationClinicalTrials.gov NCT00851383研究背景：本研究开展一项I期随机双盲安慰剂对照临床试验，以评估两种源自HIV-1 A亚型分离株的重组复制缺陷型35型腺病毒（Ad35）载体的安全性与免疫原性。两种载体分别携带gag、逆转录酶、整合酶及nef基因（Ad35-GRIN）与env基因（Ad35-ENV），并设置递增剂量梯度。本试验共纳入56名健康HIV未感染成年人。 研究方法：将Ad35-GRIN/ENV（Ad35-GRIN与Ad35-ENV按等比例混合于同一西林瓶中）或Ad35-GRIN于第0和6个月肌内注射给药。受试者按1:1比例随机分配至疫苗组或安慰剂组，共分为4个剂量组：Ad35-GRIN/ENV 2×10⁹病毒颗粒组（A组）、2×10¹⁰病毒颗粒组（B组）、2×10¹¹病毒颗粒组（C组），以及Ad35-GRIN 1×10¹⁰病毒颗粒组（D组），每组分别纳入10名与4名受试者。 研究结果：未报告与疫苗相关的严重不良事件。报告的反应原性事件呈剂量依赖性，大多为轻至中度，C组部分受试者出现重度反应原性事件，所有事件均为一过性且可自行缓解。首剂免疫后，A至D组疫苗接种者中分别有50%、56%、70%及90%可检测到针对任一疫苗抗原的IFN-γ酶联免疫斑点试验（ELISPOT）应答；加强免疫后，该比例分别升至75%、100%、88%及86%。两次免疫后，每10⁶个外周血单个核细胞（PBMC）针对任一抗原的斑点形成细胞（SFC）中位数，A至C组为78~139，D组为158~174，最高可达2991 SFC。所有组别在多个时间点均普遍识别4~5种HIV蛋白。CD4+及CD8+ T细胞应答呈现多功能性。加强免疫后，A至C组所有接种者均可检测到Env抗体，多数接种者可检测到Gag抗体。加强免疫后，Ad35中和抗体滴度仍维持在较低水平。 结论与意义：Ad35-GRIN/ENV的反应原性呈剂量相关性。多数接种Ad35-GRIN/ENV或Ad35-GRIN的受试者可产生HIV特异性细胞及体液免疫应答，且加强免疫后应答水平升高。T细胞应答具有广谱性及多功能性。 试验注册：ClinicalTrials.gov NCT00851383