Phase 1 Safety and Immunogenicity Evaluation of ADMVA, a Multigenic, Modified Vaccinia Ankara-HIV-1 B'/C Candidate Vaccine

BackgroundWe 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 FindingsADMVA 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 [1×107 (low), 5×107 (mid), or 2.5×108 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 IFNγ 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 IFNγ 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/SignificanceADMVA was well-tolerated and elicited durable humoral and cellular immune responses.
Trial RegistrationClinicaltrials.gov NCT00252148

研究背景
本研究开展了基于B'/C亚型的HIV-1候选疫苗ADMVA的I期剂量爬坡试验，该疫苗以修饰型痘苗安卡拉病毒载体（modified vaccinia Ankara, MVA）表达env、gag、pol、nef及tat基因。疫苗序列源自中国云南（HIV高发区）当前流行的HIV-1重组毒株。本研究旨在评估ADMVA在健康志愿者中的安全性与免疫原性。

研究方法与主要结果
将50名无HIV-1感染高风险的健康成年志愿者按0、1、6月的方案肌内注射ADMVA或安慰剂。各剂量组[1×10^7（低剂量）、5×10^7（中剂量）或2.5×10^8 噬斑形成单位（plaque-forming unit, pfu）（高剂量）]的志愿者均按3:1的比例随机接受ADMVA或安慰剂，采用双盲试验设计。对受试者进行随访，评估局部与全身反应原性、包括心脏不良事件在内的各类不良反应，以及临床实验室检测指标。研究随访周期为18个月。
体液免疫原性通过抗gp120结合酶联免疫吸附试验（enzyme-linked immunosorbent assay, ELISA）、免疫荧光染色以及HIV-1中和试验进行评估。细胞免疫原性则通过经过验证的干扰素γ（interferon-γ, IFNγ）酶联免疫斑点（enzyme-linked immunospot, ELISpot）试验以及细胞内细胞因子染色进行评估。抗痘苗病毒结合抗体滴度通过ELISA进行检测。

ADMVA整体耐受性良好，未出现与疫苗相关的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原性事件，且多数反应程度为轻度。针对任意HIV抗原的IFNγ ELISpot应答率，安慰剂组为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%）。免疫应答常为多基因特异性，且部分应答可持续至接种后1年。
gp120特异性抗体检出率在安慰剂组、低剂量组、中剂量组和高剂量组中分别为0/12（0%）、8/13（62%）、6/12（50%）和10/13（77%）。抗体可持续存在至接种后12个月，且其水平与体外中和HIV-1 SF162毒株的能力呈正相关趋势。有2名志愿者产生了可中和同源亚型毒株的抗体。

研究结论与意义
ADMVA耐受性良好，可诱导持久的体液与细胞免疫应答。

试验注册：ClinicalTrials.gov NCT00252148