Aaron Diamond AIDS Research Center, New York, New York, United States of America.
PLoS One. 2010 Jan 25;5(1):e8816. doi: 10.1371/journal.pone.0008816.
We conducted a Phase I dose-escalation trial of ADMVA, a Clade-B'/C-based HIV-1 candidate vaccine expressing env, gag, pol, nef, and tat in a modified vaccinia Ankara viral vector. Sequences were derived from a prevalent circulating HIV-1 recombinant form in Yunnan, China, an area of high HIV incidence. The objective was to evaluate the safety and immunogenicity of ADMVA in human volunteers.
METHODOLOGY/PRINCIPAL FINDINGS: ADMVA or placebo was administered intramuscularly at months 0, 1 and 6 to 50 healthy adult volunteers not at high risk for HIV-1. In each dosage group [1x10(7) (low), 5x10(7) (mid), or 2.5x10(8) pfu (high)] volunteers were randomized in a 3:1 ratio to receive ADMVA or placebo in a double-blinded design. Subjects were followed for local and systemic reactogenicity, adverse events including cardiac adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA, immunoflourescent staining, and HIV-1 neutralization. Cellular immunogenicity was assessed by a validated IFNgamma ELISpot assay and intracellular cytokine staining. Anti-vaccinia binding titers were measured by ELISA. ADMVA was generally well-tolerated, with no vaccine-related serious adverse events or cardiac adverse events. Local or systemic reactogenicity events were reported by 77% and 78% of volunteers, respectively. The majority of events were of mild intensity. The IFNgamma ELISpot response rate to any HIV antigen was 0/12 (0%) in the placebo group, 3/12 (25%) in the low dosage group, 6/12 (50%) in the mid dosage group, and 8/13 (62%) in the high dosage group. Responses were often multigenic and occasionally persisted up to one year post vaccination. Antibodies to gp120 were detected in 0/12 (0%), 8/13 (62%), 6/12 (50%) and 10/13 (77%) in the placebo, low, mid, and high dosage groups, respectively. Antibodies persisted up to 12 months after vaccination, with a trend toward agreement with the ability to neutralize HIV-1 SF162 in vitro. Two volunteers mounted antibodies that were able to neutralize clade-matched viruses.
CONCLUSIONS/SIGNIFICANCE: ADMVA was well-tolerated and elicited durable humoral and cellular immune responses.
Clinicaltrials.gov NCT00252148.
我们进行了一项 ADMVA 的 I 期剂量递增试验，ADMVA 是一种基于 Clade-B'/C 的 HIV-1 候选疫苗，在改良安卡拉牛痘病毒载体中表达 env、gag、pol、nef 和 tat。序列源自中国云南流行的 HIV-1 重组形式，该地区 HIV 发病率很高。目的是评估 ADMVA 在人类志愿者中的安全性和免疫原性。
方法/主要发现：ADMVA 或安慰剂在 0、1 和 6 个月时肌肉注射给予 50 名未处于 HIV-1 高风险的健康成年志愿者。在每个剂量组[1x10(7)（低）、5x10(7)（中）或 2.5x10(8) pfu（高）]中，志愿者以 3:1 的比例随机接受 ADMVA 或安慰剂，采用双盲设计。对受试者进行局部和全身反应性、不良事件（包括心脏不良事件）和临床实验室参数的监测。研究随访 18 个月。通过抗 gp120 结合 ELISA、免疫荧光染色和 HIV-1 中和试验评估体液免疫原性。通过经验证的 IFNgamma ELISpot 测定法和细胞内细胞因子染色评估细胞免疫原性。通过 ELISA 测量抗牛痘结合滴度。ADMVA 总体耐受性良好，无疫苗相关严重不良事件或心脏不良事件。分别有 77%和 78%的志愿者报告了局部或全身反应性事件。大多数事件为轻度。在安慰剂组中，对任何 HIV 抗原的 IFNgamma ELISpot 反应率为 0/12（0%），低剂量组为 3/12（25%），中剂量组为 6/12（50%），高剂量组为 8/13（62%）。反应通常是多基因的，偶尔持续到接种后一年。在安慰剂、低剂量、中剂量和高剂量组中，分别有 0/12（0%）、8/13（62%）、6/12（50%）和 10/13（77%）的志愿者检测到针对 gp120 的抗体。抗体持续存在于接种后 12 个月，与体外中和 SF162 型 HIV-1 的能力呈一致趋势。有两名志愿者产生了能够中和匹配谱系的病毒的抗体。
结论/意义：ADMVA 耐受性良好，可引起持久的体液和细胞免疫反应。
Clinicaltrials.gov NCT00252148。
