Pelzer Puck T, Stuck Logan, Martinez Leonardo, Richards Alexandra S, Acuña-Villaorduña Carlos, Aronson Naomi E, Bonnet Maryline, Carvalho Anna C, Chan Pei-Chun, Huang Li-Min, Fang Chi-Tai, Churchyard Gavin, Corral-Londoño Helena Del, Datta Manjula, Espinal Marcos A, Fielding Katherine, Fiore-Gartland Andrew J, Garcia-Basteiro Alberto, Hanekom Willem, Hatherill Mark, Hill Phillip C, Huerga Helena, Jones-López Edward C, Kritski Afranio, Mandalakas Anna M, Mangtani Punam, Martins Netto Eduardo, Mayanja Harriet, Mazahir Rufaida, Murray Megan, Rangaka Molebogeng, Scriba Thomas, Singh Jitendra, Singh Sarman, Stein Catherine M, Vekemans Johan, Verhagen Lilly M, Villalba Julian A, Wajja Anne, Watson Basilea, White Richard G, Cobelens Frank G J
Amsterdam University Medical Centres, Amsterdam, Netherlands; KNCV Tuberculosis Foundation, The Hague, Netherlands; London School of Hygiene & Tropical Medicine, London, UK; Department of Global Health and Amsterdam Institute for Global Health and Development, Amsterdam, Netherlands.
Amsterdam University Medical Centres, Amsterdam, Netherlands; Department of Global Health and Amsterdam Institute for Global Health and Development, Amsterdam, Netherlands.
Lancet Microbe. 2025 Feb;6(2):100961. doi: 10.1016/j.lanmic.2024.100961. Epub 2024 Dec 19.
Tuberculosis vaccine trials using disease as the primary endpoint are large, time consuming, and expensive. An earlier immunological measure of the protection against disease would accelerate tuberculosis vaccine development. We aimed to assess whether the effectiveness of the Bacillus Calmette-Guérin (BCG) vaccine for prevention of Mycobacterium tuberculosis infection was consistent with that for prevention of tuberculosis disease.
We conducted an individual participant data (IPD) meta-analysis on experimental and observational longitudinal studies before April 6, 2018, identified through systematic reviews, known to us through expert knowledge in the field, reporting on BCG vaccination status, M tuberculosis infection test (QuantiFERON IFN-γ release assay [IGRA] and tuberculin skin test [TST]), and tuberculosis incidence. Cohort studies were included only for countries with a mandatory neonatal BCG vaccination policy. Exclusion criteria were previous or current tuberculosis disease, HIV infection, tuberculosis preventive treatment usage, and for household contacts, a positive baseline IGRA or TST test and young children aged 0-2 years; for randomised controlled trials, TST results within 2 years after random assignation were excluded. We contacted the investigators of the identified studies to provide IPD. We compared the protective efficacy of the BCG vaccine against M tuberculosis infection with that against tuberculosis disease using mixed-effects, multivariable proportional hazards modelling, by study type, M tuberculosis infection test (IGRA and TST), cutoff for defining test positivity, age, sex, and latitude.
We identified 79 studies eligible for full screening and of these, IPD datasets from 14 studies were included in our analysis: 11 household contact studies (29 147 participants), two adolescent cohort studies (11 368 participants), and one randomised controlled trial (2963 participants). Among 28 188 participants we found no protection by the BCG vaccine against TST conversion regardless of cutoff in any type of study. Among 1491 household contacts, but not among 5644 adolescents, the BCG vaccine protected against QuantiFERON conversion at the primary cutoff of 0·7 IU/mL or more with the adjusted hazard ratio (0·65, 95% CI 0·51-0·82) being consistent with that for protection against disease (0·68, 0·18-2·59). Protection against QuantiFERON conversion at cutoff of 0·35 IU/mL or more (0·64, 0·51-0·81) was similar.
Protection from the BCG vaccination against M tuberculosis infection, measured as QuantiFERON conversion, is inconsistent across different groups. Among groups with recent household exposure, QuantiFERON conversion is consistent with protection against disease and could be evaluated as a proxy for disease in tuberculosis vaccine trials. We found that TST lacks value for prevention in phase 2b proof-of-concept trials.
Bill & Melinda Gates Foundation.
以疾病作为主要终点的结核病疫苗试验规模大、耗时且昂贵。一种针对疾病防护的早期免疫指标将加速结核病疫苗的研发。我们旨在评估卡介苗（BCG）预防结核分枝杆菌感染的有效性是否与预防结核病的有效性一致。
我们对2018年4月6日前通过系统评价确定的、我们通过该领域专家知识知晓的、报告卡介苗接种状况、结核分枝杆菌感染检测（全血γ干扰素释放试验[IGRA]和结核菌素皮肤试验[TST]）以及结核病发病率的实验性和观察性纵向研究进行了个体参与者数据（IPD）荟萃分析。队列研究仅纳入有强制性新生儿卡介苗接种政策的国家。排除标准为既往或当前患有结核病、感染HIV、使用结核病预防性治疗，对于家庭接触者，基线IGRA或TST检测呈阳性以及0 - 2岁幼儿；对于随机对照试验，排除随机分配后2年内的TST结果。我们联系了已识别研究的研究者以获取IPD。我们使用混合效应多变量比例风险模型，按研究类型、结核分枝杆菌感染检测（IGRA和TST）、定义检测阳性的临界值、年龄、性别和纬度，比较了卡介苗预防结核分枝杆菌感染与预防结核病的保护效力。
我们识别出79项符合全面筛查条件的研究，其中14项研究的IPD数据集纳入了我们的分析：11项家庭接触者研究（29147名参与者）、2项青少年队列研究（11368名参与者）和1项随机对照试验（2963名参与者）。在28188名参与者中，我们发现无论在何种类型的研究中，无论临界值如何，卡介苗均未对TST阳转起到保护作用。在1491名家庭接触者中，卡介苗对全血γ干扰素阳转起到了保护作用，但在5644名青少年中未起到保护作用，在主要临界值为0·7 IU/mL及以上时，调整后的风险比为（0·65，95%CI 0·51 - 0·
