Safety and Immunogenicity of the Recombinant BCG Vaccine AERAS-422 in Healthy BCG-naïve Adults: A Randomized, Active-controlled, First-in-human Phase 1 Trial. Homo sapiens

We report a first-in-human trial evaluating safety and immunogenicity of a recombinant BCG, AERAS-422, over-expressing TB antigens Ag85A, Ag85B, and Rv3407 and expressing mutant perfringolysin. Interpretation: The unexpected development of VZV in two of eight healthy adult vaccine recipients resulted in discontinuation of AERAS-422 vaccine development. Immunological and transcriptomal data identified correlations with the development of TB immunity and VZV that require further investigation. Overall design: This was a randomized, double-blind, dose-escalation trial in HIV-negative, healthy adult, BCG-naïve volunteers, negative for prior exposure to Mtb, at one US clinical site. Volunteers were randomized 2:1 at each dose level to receive a single intradermal dose of AERAS-422 (>105–< 10e6 CFU = low dose, ≥106– < 10e7 CFU = high dose) or non-recombinant Tice BCG (1–8 × 10e5 CFU). Randomization used an independently prepared randomly generated sequence of treatment assignments. The primary and secondary outcomes were safety and immunogenicity, respectively, assessed in all participants through 182 days post-vaccination. ClinicalTrials.gov registration number: NCT01340820

本研究报道了一款重组卡介苗（recombinant BCG）AERAS-422的首次人体临床试验结果，该疫苗过表达结核（TB）抗原Ag85A、Ag85B及Rv3407，并表达突变型产气荚膜梭菌溶血素，本试验旨在评估其安全性与免疫原性。

研究解读：8名健康成人疫苗接种者中有2人意外出现水痘带状疱疹病毒（VZV，Varicella-Zoster Virus）感染，导致AERAS-422疫苗的研发工作终止。免疫学与转录组学数据显示，该疫苗与结核免疫应答及VZV感染的发生存在相关性，有待进一步研究验证。

试验总体设计：本试验为单中心、随机双盲剂量爬坡临床试验，在美国一家临床研究中心开展，招募对象为HIV阴性、健康成年、未接种过卡介苗且既往无结核分枝杆菌（Mtb）暴露史的志愿者。在各剂量水平下，受试者按2:1的比例随机分配，分别接受单次皮内注射AERAS-422（>1×10^5~<1×10^6 菌落形成单位（colony-forming unit, CFU）为低剂量组，≥1×10^6~<1×10^7 CFU为高剂量组）或非重组Tice株卡介苗（1~8×10^5 CFU）。随机化采用由独立第三方生成的随机治疗分配序列。主要结局与次要结局分别为安全性与免疫原性，所有受试者均在疫苗接种后182天内完成随访评估。本试验在ClinicalTrials.gov的注册编号为NCT01340820。