Background

A large, double-blind, randomised, placebo-controlled trial of repeat BCG found 49% efficacy against leprosy but no protection against tuberculosis after 6–9 years’ follow-up in 1995. We report here additional follow-up, which resulted in greatly increased tuberculosis case numbers, and allowed subgroup analysis.

Methods

Nearly 47 000 individuals of all ages living in northern Malawi with a BCG vaccine scar were randomly assigned (1:1) between 1986 and 1989 to receive a second BCG or placebo. The investigators and project staff remained masked to all interventions. Enhanced passive surveillance ensured ascertainment of tuberculosis and leprosy to the end of 2018. Tuberculosis case definitions included rigorous microbiological or histological confirmation. Prespecified subgroup analyses were by tuberculosis type, age at vaccination, time since vaccination, previous tuberculin reactivity, HIV status and Mycobacterium tuberculosis lineage. The original trial is registered with ISRCTN registry, ISRCTN11311670.

Findings

In follow-up until Dec 31, 2018, 824 participants had developed tuberculosis, including 786 with pulmonary disease, of whom 383 (63%) of 607 with known HIV status were HIV positive. There was no effect of a second BCG overall (odds ratio [OR] 0·92; 95% CI 0·80–1·05), or for pulmonary (0·93; 0·81–1·07), or lymph node tuberculosis (0·60; 0·31–1·17). The OR was lower for those with known HIV-negative tuberculosis (0·77; 0·59–1·00), for those vaccinated as children (aged <5 years, 0·74; 0·41–1·35; aged 5–14 years, 0·77; 0·60–0·99), and for cases arising at least 20 years after vaccination (0·79; 0·63–1·01). There were no differences by tuberculin status at vaccination, or lineage. There was no evidence of protection against leprosy beyond 10 years after vaccination (although there have been only nine diagnostically certain cases since 1995).

Interpretation

There was no evidence that repeat BCG vaccination provides appreciable protection against overall tuberculosis in this rural African population with a high prevalence of HIV. Subgroup effects should not be overinterpreted given the multiple analyses done. However, the evidence for modest protection against HIV-negative tuberculosis, and for a delayed benefit in those vaccinated as children, is consistent with other observations in the literature.

Funding

LEPRA, Wellcome Trust, Bill & Melinda Gates Foundation.

中文翻译：

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马拉维的卡介苗重新接种：一项大型、随机、双盲、安慰剂对照试验的 30 年随访

 背景

1995 年，一项大型、双盲、随机、安慰剂对照的重复 BCG 试验发现，经过 6-9 年的随访，对麻风病有 49% 的疗效，但对结核病没有预防作用。我们在此报告了额外的随访，结果大大增加了结核病病例数，并允许进行亚组分析。

 方法

1986 年至 1989 年间，生活在马拉维北部的近 47 000 名有 BCG 疫苗疤痕的各个年龄段的人被随机分配 (1:1) 接受第二次 BCG 或安慰剂。调查人员和项目工作人员对所有干预措施均保持沉默。加强被动监测确保到 2018 年底确定结核病和麻风病。结核病病例定义包括严格的微生物学或组织学确认。预先指定的亚组分析按结核病类型、接种疫苗时的年龄、接种疫苗后的时间、既往结核菌素反应性、HIV 状况和结核分枝杆菌谱系进行。原始试验已在 ISRCTN 注册中心注册，ISRCTN11311670。

 发现

截至 2018 年 12 月 31 日的随访中，824 名参与者患有结核病，其中 786 名患有肺部疾病，其中 607 名已知艾滋病毒感染状况的人中有 383 名（63%）艾滋病毒呈阳性。第二次 BCG 总体（优势比 [OR] 0·92；95% CI 0·80–1·05）、肺部（0·93；0·81–1·07）或淋巴没有影响淋巴结结核（0·60；0·31–1·17）。对于已知 HIV 阴性结核病患者 (0·77; 0·59–1·00) 和儿童时期接种疫苗的患者 (年龄 <5 岁，0·74; 0·41–1·35; 5-14 岁，0·77；0·60–0·99），以及疫苗接种后至少 20 年发生的病例（0·79；0·63–1·01）。疫苗接种时的结核菌素状态或谱系没有差异。没有证据表明接种疫苗后 10 年后可以预防麻风病（尽管自 1995 年以来只有 9 例诊断确定的病例）。

 解释

没有证据表明，在艾滋病毒高发的非洲农村人口中，重复接种卡介苗可以明显预防结核病。鉴于已完成的多项分析，不应过度解释亚组效应。然而，对于艾滋病毒阴性结核病的适度保护以及儿童时期接种疫苗的延迟获益的证据与文献中的其他观察结果一致。

 资金

LEPRA、威康信托基金、比尔及梅琳达·盖茨基金会。