BACKGROUND Results of an earlier analysis of a trial of the M72/AS01E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity. METHODS From August 2014 through November 2015, we enrolled adults 18 to 50 years of age with M. tuberculosis infection (defined by positive results on interferon-γ release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. Participants were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered 1 month apart. The primary objective was to evaluate the efficacy of M72/AS01E to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with human immunodeficiency virus infection). Participants were followed for 3 years after the second dose. Participants with clinical suspicion of tuberculosis provided sputum samples for polymerase-chain-reaction assay, mycobacterial culture, or both. Humoral and cell-mediated immune responses were evaluated until month 36 in a subgroup of 300 participants. Safety was assessed in all participants who received at least one dose of M72/AS01E or placebo. RESULTS A total of 3575 participants underwent randomization, of whom 3573 received at least one dose of M72/AS01E or placebo, and 3330 received both planned doses. Among the 3289 participants in the according-to-protocol efficacy cohort, 13 of the 1626 participants in the M72/AS01E group, as compared with 26 of the 1663 participants in the placebo group, had cases of tuberculosis that met the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years). The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to 71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01E group, the concentrations of M72-specific antibodies and the frequencies of M72-specific CD4+ T cells increased after the first dose and were sustained throughout the follow-up period. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. CONCLUSIONS Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598.).

中文翻译：

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预防结核病的M72 / AS01E疫苗试验的最终分析。

背景技术针对结核分枝杆菌的M72 / AS01E候选疫苗的试验的较早分析结果表明，在受感染的成年人中，该疫苗提供了针对活动性肺结核疾病的54.0％的保护作用，而没有明显的安全隐患。现在，我们报告对有效性，安全性和免疫原性进行3年最终分析的结果。方法从2014年8月至2015年11月，我们在肯尼亚，南非和赞比亚的中心招募了18至50岁患有结核分枝杆菌感染（由干扰素γ释放试验阳性结果定义）的成年人，而没有活动性结核病证据。参与者以1：1的比例随机分配，以接受两个剂量的M72 / AS01E或安慰剂，间隔1个月给药。主要目标是根据第一个病例定义（经细菌学证实与人免疫缺陷病毒感染无关的肺结核）评估M72 / AS01E预防活动性肺结核的功效。第二次给药后随访参与者3年。有结核病临床怀疑的参与者提供了痰样本用于聚合酶链反应测定，分枝杆菌培养或两者。在300名参与者的亚组中，评估了体液和细胞介导的免疫反应，直至第36个月。在接受至少一剂M72 / AS01E或安慰剂的所有参与者中评估安全性。结果共有3575名参与者接受了随机分组，其中3573名参与者接受了至少一剂M72 / AS01E或安慰剂，而3330名参与者接受了这两种计划剂量。在按照协议疗效队列的3289名参与者中，M72 / AS01E组的1626名参与者中有13名，而安慰剂组的1663名参与者中有26名符合第一个病例定义的结核病病例（发病率，每100人年0.3例，而0.6例）。第36个月的疫苗效力为49.7％（90％置信区间[CI]为12.1至71.2； 95％CI为2.1至74.2）。在M72 / AS01E组的参与者中，首次给药后M72特异性抗体的浓度和M72特异性CD4 + T细胞的频率增加，并且在整个随访期间一直持续。两组的严重不良事件，潜在的免疫介导疾病和死亡发生频率相似。结论在感染结核分枝杆菌的成年人中，用M72 / AS01E进行疫苗接种可引发免疫反应，并提供至少3年的预防发展为肺结核疾病的保护。（由葛兰素史克（GlaxoSmithKline）Biologicals and Aeras资助； ClinicalTrials.gov编号，NCT01755598。）。