MVA-CMDR，一种多基因、重组改良安卡拉痘苗病毒-HIV-1 候选疫苗的 I 期安全性和免疫原性评价。

BACKGROUND: We conducted a Phase I randomized, dose-escalation, route-comparison trial of MVA-CMDR, a candidate HIV-1 vaccine based on a recombinant modified vaccinia Ankara viral vector expressing HIV-1 genes env/gag/pol. The HIV sequences were derived from circulating recombinant form CRF01_AE, which predominates in Thailand. The objective was to evaluate safety and immunogenicity of MVA-CMDR in human volunteers in the US and Thailand. METHODOLOGY/PRINCIPAL FINDINGS: MVA-CMDR or placebo was administered intra-muscularly (IM; 10(7) or 10(8) pfu) or intradermally (ID; 10(6) or 10(7) pfu) at months 0, 1 and 3, to 48 healthy volunteers at low risk for HIV-1 infection. Twelve volunteers in each dosage group were randomized to receive MVA-CMDR or placebo (10∶2). Volunteers were actively monitored for local and systemic reactogenicity and adverse events post vaccination. Cellular immunogenicity was assessed by a validated IFNγ Elispot assay, an intracellular cytokine staining assay, lymphocyte proliferation and a (51)Cr-release assay. Humoral immunogenicity was assessed by ADCC for gp120 and binding antibody ELISAs for gp120 and p24. MVA-CMDR was safe and well tolerated with no vaccine related serious adverse events. Cell-mediated immune responses were: (i) moderate in magnitude (median IFNγ Elispot of 78 SFC/10(6) PBMC at 10(8) pfu IM), but high in response rate (70% (51)Cr-release positive; 90% Elispot positive; 100% ICS positive, at 10(8) pfu IM); (ii) predominantly HIV Env-specific CD4(+) T cells, with a high proliferative capacity and durable for at least 6 months (100% LPA response rate by the IM route); (iv) dose- and route-dependent with 10(8) pfu IM being the most immunogenic treatment. Binding antibodies against gp120 and p24 were detectable in all vaccination groups with ADCC capacity detectable at the highest dose (40% positive at 10(8) pfu IM). CONCLUSIONS/SIGNIFICANCE: MVA-CMDR delivered both intramuscularly and intradermally was safe, well-tolerated and elicited durable cell-mediated and humoral immune responses. TRIAL REGISTRATION: ClinicalTrials.gov NCT00376090.

背景：我们进行了一项 I 期随机、剂量递增、给药途径比较试验，研究了 MVA-CMDR，这是一种基于表达 HIV-1 基因 env/gag/pol 的重组改良安卡拉痘苗病毒载体的候选 HIV-1 疫苗。HIV 序列源自主要在泰国流行的循环重组形式 CRF01_AE。目的是评估 MVA-CMDR 在 HIV-1 感染低风险的美国和泰国健康志愿者中的安全性和免疫原性。

方法/主要发现：低危 HIV-1 感染的 48 名健康志愿者分别在 0、1 和 3 个月时接受肌肉内（IM；10（7）或 10（8）pfu）或皮内（ID；10（6）或 10（7）pfu）接种 MVA-CMDR 或安慰剂，每组 12 名志愿者随机接受 MVA-CMDR 或安慰剂（10∶2）。接种疫苗后，志愿者会主动监测局部和全身反应原性以及不良事件。细胞免疫原性通过经验证的 IFNγ Elispot 测定、细胞内细胞因子染色测定、淋巴细胞增殖和（51）Cr 释放测定进行评估。体液免疫原性通过 ADCC 对 gp120 和 gp120 和 p24 的结合抗体 ELISA 进行评估。MVA-CMDR 安全且耐受良好，无疫苗相关严重不良事件。细胞介导的免疫反应为：（i）中等强度（10（8）pfu IM 时 IFNγ Elispot 的中位数为 78 SFC/10（6）PBMC），但反应率高（51）Cr 释放阳性率为 70%；Elispot 阳性率为 90%；ICS 阳性率为 100%，10（8）pfu IM）；（ii）主要是 HIV Env 特异性 CD4+T 细胞，具有高增殖能力，至少 6 个月持久（IM 途径 100% LPA 反应率）；（iv）剂量和途径依赖性，10（8）pfu IM 是最具免疫原性的治疗方法。所有接种组均可检测到针对 gp120 和 p24 的结合抗体，在最高剂量下可检测到 ADCC 能力（10（8）pfu IM 时 40%阳性）。

结论/意义：肌肉内和皮内给药的 MVA-CMDR 安全、耐受良好，并引起持久的细胞介导和体液免疫反应。

试验注册：ClinicalTrials.gov NCT00376090。