Effectiveness of the primary Bacillus Calmette-Guérin vaccine against the risk of Mycobacterium tuberculosis infection and tuberculosis disease: a meta-analysis of individual participant data

Puck T Pelzer¹, Logan Stuck², Leonardo Martinez³, Alexandra S Richards⁴, Carlos Acuña-Villaorduña⁵, Naomi E Aronson⁶, Maryline Bonnet⁷, Anna C Carvalho⁸, Pei-Chun Chan⁹, Li-Min Huang¹⁰, Chi-Tai Fang¹¹, Gavin Churchyard¹², Helena Del Corral-Londoño¹³, Manjula Datta¹⁴, Marcos A Espinal¹⁵, Katherine Fielding¹⁶, Andrew J Fiore-Gartland¹⁷, Alberto Garcia-Basteiro¹⁸, Willem Hanekom¹⁹, Mark Hatherill²⁰, Phillip C Hill²¹, Helena Huerga²², Edward C Jones-López²³, Afranio Kritski²⁴, Anna M Mandalakas²⁵, Punam Mangtani¹⁶, Eduardo Martins Netto²⁶, Harriet Mayanja²⁷, Rufaida Mazahir²⁸, Megan Murray²⁹, Molebogeng Rangaka³⁰, Thomas Scriba²⁰, Jitendra Singh³¹, Sarman Singh³², Catherine M Stein³³, Johan Vekemans³⁴, Lilly M Verhagen³⁵, Julian A Villalba³⁶, Anne Wajja²⁷, Basilea Watson³⁷, Richard G White⁴, Frank G J Cobelens²

Affiliations

¹ 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. Electronic address: ppelzer@iavi.org.
² Amsterdam University Medical Centres, Amsterdam, Netherlands; Department of Global Health and Amsterdam Institute for Global Health and Development, Amsterdam, Netherlands.
³ Department of Epidemiology, School of Public Health, Boston University, Boston, MA, USA.
⁴ London School of Hygiene & Tropical Medicine, London, UK.
⁵ Boston University Medical Center, Boston, MA, USA.
⁶ Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁷ TransVIHMI, University of Montpellier, IRD, INSERM, Montpellier, France.
⁸ Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
⁹ Division of Chronic Infectious Disease, Taiwan Centers for Disease Control, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
¹⁰ Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
¹¹ Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
¹² Aurum Institute, Johannesburg, South Africa; School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; Department of Medicine, Vanderbilt University, Nashville, TN, USA.
¹³ Universidad de Antioquia, National School of Public Health, Medellin, Colombia.
¹⁴ A Society for Primary Health Care Intervention, Research and Education, Chennai, India.
¹⁵ National Centre for Research on Maternal and Child Health, Santo Domingo, Dominican Republic.
¹⁶ London School of Hygiene & Tropical Medicine, London, UK; nfectious Disease Epidemiology Department, Epicentre, Paris, France.
¹⁷ Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁸ Barcelona Institute for Global Health, Barcelona, Spain.
¹⁹ Africa Health Research Institute, Durban, South Africa.
²⁰ South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
²¹ Centre for International Health, University of Otago, Dunedin, New Zealand.
²² Field Epidemiology Department, Epicentre, Paris, France.
²³ Division of Infectious Diseases, Department of Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
²⁴ Programa Acadêmico de Tuberculose, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
²⁵ Baylor College of Medicine, Houston, TX, USA; Research Center Borstel, Sülfeld, Germany.
²⁶ Faculdade de Medicina da Bahia, Salvador, Brazil; Hospital Universitário Professor Edgard Santos, Salvador, Brazil; Universidade Federal da Bahia, Salvador, Brazil.
²⁷ Makerere University Infectious Diseases Institute, Kampala, Uganda.
²⁸ Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.
²⁹ Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
³⁰ Institute for Global Health and MRC Clinical Trials Unit, University College London, London, UK.
³¹ Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Madhya Pradesh, India.
³² Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India; All India Institute of Medical Sciences, New Delhi, India; All India Institute of Medical Sciences, Bhopal, India; Aaarupadai Veedu Medical College, Pondicherry, India.
³³ Department of Population and Quantitative Health Sciences, and Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
³⁴ IAVI, New York, NY, USA.
³⁵ Department of Pediatric Infectious Diseases and Immunology, Radboud Community for Infectious Diseases, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands; Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, Netherlands; Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
³⁶ Laboratorio de Tuberculosis, Instituto de Biomedicina, Universidad Central de Venezuela, Caracas, Venezuela; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
³⁷ ICMR-National Institute for Research in Tuberculosis, Chennai, India.

PMID: 39709975
DOI: 10.1016/j.lanmic.2024.100961

Free article

Meta-Analysis

Effectiveness of the primary Bacillus Calmette-Guérin vaccine against the risk of Mycobacterium tuberculosis infection and tuberculosis disease: a meta-analysis of individual participant data

Puck T Pelzer et al. Lancet Microbe. 2025 Feb.

Free article

. 2025 Feb;6(2):100961.

doi: 10.1016/j.lanmic.2024.100961. Epub 2024 Dec 19.

Authors

Affiliations

¹ 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. Electronic address: ppelzer@iavi.org.
² Amsterdam University Medical Centres, Amsterdam, Netherlands; Department of Global Health and Amsterdam Institute for Global Health and Development, Amsterdam, Netherlands.
³ Department of Epidemiology, School of Public Health, Boston University, Boston, MA, USA.
⁴ London School of Hygiene & Tropical Medicine, London, UK.
⁵ Boston University Medical Center, Boston, MA, USA.
⁶ Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
⁷ TransVIHMI, University of Montpellier, IRD, INSERM, Montpellier, France.
⁸ Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.
⁹ Division of Chronic Infectious Disease, Taiwan Centers for Disease Control, Taipei, Taiwan; Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
¹⁰ Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
¹¹ Department of Pediatrics, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
¹² Aurum Institute, Johannesburg, South Africa; School of Public Health, University of the Witwatersrand, Johannesburg, South Africa; Department of Medicine, Vanderbilt University, Nashville, TN, USA.
¹³ Universidad de Antioquia, National School of Public Health, Medellin, Colombia.
¹⁴ A Society for Primary Health Care Intervention, Research and Education, Chennai, India.
¹⁵ National Centre for Research on Maternal and Child Health, Santo Domingo, Dominican Republic.
¹⁶ London School of Hygiene & Tropical Medicine, London, UK; nfectious Disease Epidemiology Department, Epicentre, Paris, France.
¹⁷ Fred Hutchinson Cancer Center, Seattle, WA, USA.
¹⁸ Barcelona Institute for Global Health, Barcelona, Spain.
¹⁹ Africa Health Research Institute, Durban, South Africa.
²⁰ South African Tuberculosis Vaccine Initiative, Institute of Infectious Disease and Molecular Medicine, Division of Immunology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
²¹ Centre for International Health, University of Otago, Dunedin, New Zealand.
²² Field Epidemiology Department, Epicentre, Paris, France.
²³ Division of Infectious Diseases, Department of Medicine, Keck School of Medicine of USC, University of Southern California, Los Angeles, CA, USA.
²⁴ Programa Acadêmico de Tuberculose, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
²⁵ Baylor College of Medicine, Houston, TX, USA; Research Center Borstel, Sülfeld, Germany.
²⁶ Faculdade de Medicina da Bahia, Salvador, Brazil; Hospital Universitário Professor Edgard Santos, Salvador, Brazil; Universidade Federal da Bahia, Salvador, Brazil.
²⁷ Makerere University Infectious Diseases Institute, Kampala, Uganda.
²⁸ Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.
²⁹ Department of Global Health and Social Medicine, Harvard Medical School, Boston, MA, USA.
³⁰ Institute for Global Health and MRC Clinical Trials Unit, University College London, London, UK.
³¹ Department of Translational Medicine, All India Institute of Medical Sciences Bhopal, Madhya Pradesh, India.
³² Department of Laboratory Medicine, All India Institute of Medical Sciences, New Delhi, India; All India Institute of Medical Sciences, New Delhi, India; All India Institute of Medical Sciences, Bhopal, India; Aaarupadai Veedu Medical College, Pondicherry, India.
³³ Department of Population and Quantitative Health Sciences, and Division of Infectious Diseases and HIV Medicine, Department of Medicine, Case Western Reserve University, Cleveland, OH, USA.
³⁴ IAVI, New York, NY, USA.
³⁵ Department of Pediatric Infectious Diseases and Immunology, Radboud Community for Infectious Diseases, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, Netherlands; Department of Laboratory Medicine, Laboratory of Medical Immunology, Radboud University Medical Center, Nijmegen, Netherlands; Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
³⁶ Laboratorio de Tuberculosis, Instituto de Biomedicina, Universidad Central de Venezuela, Caracas, Venezuela; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
³⁷ ICMR-National Institute for Research in Tuberculosis, Chennai, India.

PMID: 39709975
DOI: 10.1016/j.lanmic.2024.100961

Abstract

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

Funding: Bill & Melinda Gates Foundation.

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Conflict of interest statement

Declaration of interests PTP is currently employed by IAVI but was employed at the KNCV Tuberculosis Foundation at the time of the research. RGW is funded by the Wellcome Trust (218261/Z/19/Z), National Institutes of Health (1R01AI147321-01, G-202303-69963, and R-202309-71190), The European & Developing Countries Clinical Trials Partnership (EDCTP; RIA208D-2505B), UK Medical Research Council (CCF17-7779 via SET Bloomsbury), Economic and Social Research Council (ES/P008011/1), Bill & Melinda Gates Foundation (INV-004737, INV-035506), and WHO (2020/985800-0). ASR is supported by the UK Foreign, Commonwealth and Development Office (Leaving No-one Behind Transforming Gendered Pathways to Health for Tuberculosis). FGJC has grants from EDCTP (RIA2018D-2509, RIA2018D-2511, and RIA2020I-3305). ACC is a senior investigator from the Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil. NEA is funded by the US Department of Defense (HU 001-17-2-0023, HU001-19-2-0125, and HU 0001-20-2-007) for unrelated BCG research. MB has grants from EDCTP (HORIZON-JU-GH-EDCTP3-2022-01, RIA2017T-2019, and RIA2018CO-2515) the ANRS Emerging Infectious Diseases (ANRS0405s), the Initiative (23SANIC208), and the INSERM. JAV is currently a federal employee with the National Center for Emerging and Zoonotic Infectious Diseases, Division of High Consequence Pathogens and Pathology, at the Centers for Disease Control and Prevention (CDC). All other authors declare no competing interests.

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Effectiveness of the primary Bacillus Calmette-Guérin vaccine against the risk of Mycobacterium tuberculosis infection and tuberculosis disease: a meta-analysis of individual participant data

Affiliations

Effectiveness of the primary Bacillus Calmette-Guérin vaccine against the risk of Mycobacterium tuberculosis infection and tuberculosis disease: a meta-analysis of individual participant data

Authors

Affiliations

Abstract

Conflict of interest statement

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Grants and funding

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