Clinical Trial

. 2024 Oct;89(4):106245.

doi: 10.1016/j.jinf.2024.106245. Epub 2024 Aug 8.

BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial

Nicole L Messina¹, Laure F Pittet², Ellie McDonald³, Cecilia Moore⁴, Simone Barry⁵, Marc Bonten⁶, Anthony Byrne⁷, John Campbell⁸, Julio Croda⁹, Mariana G Croda¹⁰, Margareth Dalcolmo¹¹, Fernando F de Almeida E Val¹², Roberto D de Oliveira¹³, Glauce Dos Santos¹¹, Mark W Douglas¹⁴, Kaya Gardiner¹⁵, Amanda Gwee¹⁶, Bruno A Jardim¹⁷, Tobias Kollmann¹⁸, Marcus Vg Lacerda¹⁹, Michaela Lucas²⁰, David J Lynn²¹, Laurens Manning²², Helen Marshall²³, Abby O'Connell²⁴, Kirsten P Perrett²⁵, Jeffrey J Post²⁶, Cristina Prat-Aymerich⁶, Jorge L Rocha²⁷, Jesus Rodriguez-Baño²⁸, Ushma Wadia²⁹, Adilia Warris³⁰, Andrew Davidson³¹, Nigel Curtis³²; BRACE Trial Consortium Group

Affiliations

¹ Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.
² Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia; Immunology, Vaccinology, Rheumatology and Infectious Diseases Unit, Geneva and University Hospitals and Faculty of Medicine, Geneva, Switzerland.
³ Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
⁴ Clinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
⁵ Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia; Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
⁶ Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, the Netherlands; European Clinical Research Alliance on Infectious Diseases, Utrecht, Netherlands.
⁷ St Vincent's Hospitals, Darlinghurst, New South Wales, Australia; Partners In Health, Socios En Salud, Peru; Thoracic Society of Australia & New Zealand (NSW/ACT Branch), Australia.
⁸ Exeter Collaboration for Academic Primary Care, University of Exeter Medical School, Exeter, United Kingdom.
⁹ Fiocruz Mato Grosso do Sul, Fundação Oswaldo Cruz, Campo Grande, Mato Grosso do Sul, Brazil; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA; Universidade Federal de Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.
¹⁰ Universidade Federal de Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.
¹¹ Centro de Referência Professor Hélio Fraga, ENSP/FIOCRUZ (Fundação Oswaldo Cruz), Rio de Janeiro, Brazil.
¹² Tropical Medicine Foundation Dr Heitor Vieira Dourado, Manaus, Brazil.
¹³ State University of Mato Grosso do Sul, Dourados, Brazil; Post Graduate Program in Health Sciences, Federal University of Grande Dourados, Dourados, Brazil.
¹⁴ Storr Liver Centre, The Westmead Institute for Medical Research, The University of Syndey at Westmead Hospital, Westmead, New South Wales, Australia; Centre for Infectious Diseases and Microbiology, Sydney Infectious Diseases Institute, The University of Sydney at Westmead Hospital, Westmead, New South Wales, Australia.
¹⁵ Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Research Operations, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.
¹⁶ Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia; Infectious Diseases, Royal Children's Hospital Melbourne, Parkville, Victoria, Australia; Antimicrobials Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
¹⁷ Institute of Clinical Research Carlos Borborema, Doctor Heitor Vieira Dourado Tropical Medicine Foundation, Manaus, Brazil.
¹⁸ Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Nedlands, Western Australia, Australia.
¹⁹ Institute of Clinical Research Carlos Borborema, Doctor Heitor Vieira Dourado Tropical Medicine Foundation, Manaus, Brazil; Instituto Leônidas & Maria Deane, Oswaldo Cruz Foundation Ministry of Health, Manaus, Brazil; University of Texas Medical Branch, Galveston, TX, USA.
²⁰ Department of Immunology, Pathwest, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia; Department of Immunology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; Department of Immunology, Perth Children's Hospital, Nedlands, Western Australia, Australia; School of Medicine, University of Western Australia, Perth, Western Australia, Australia.
²¹ Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, South Australia, Australia.
²² Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Nedlands, Western Australia, Australia; School of Medicine, University of Western Australia, Perth, Western Australia, Australia; Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Western Australia, Australia.
²³ The University of Adelaide and the Women's and Children's Health Network, Adelaide, SA, Australia.
²⁴ Exeter Clinical Trials Unit, University of Exeter, Exeter, United Kingdom.
²⁵ Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia; Population Allergy Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Allergy and Immunology, Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.
²⁶ Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia; School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia.
²⁷ Helio Fraga Reference Center, Oswaldo Cruz Foundation Ministry of Health, Curicica, Brazil.
²⁸ Division of Infectious Diseases and Microbiology, Department of Medicine, Hospital Universitario Virgen Macarena, University of Seville, Biomedicines Institute of Seville-Consejo Superior de Investigaciones Científicas, Seville, Spain; CIBER de Enfermedades Infecciosas, Instituto de Salud Carloss III, Madrid, Spain.
²⁹ Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Nedlands, Western Australia, Australia; School of Medicine, University of Western Australia, Perth, Western Australia, Australia.
³⁰ Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom; Department of Infectious Diseases, Great Ormond Street Hospital, London, United Kingdom.
³¹ Melbourne Children's Trial Centre, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
³² Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia; Infectious Diseases, Royal Children's Hospital Melbourne, Parkville, Victoria, Australia. Electronic address: nigel.curtis@rch.org.au.

PMID: 39127450
PMCID: PMC11409612
DOI: 10.1016/j.jinf.2024.106245

Clinical Trial

BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial

Nicole L Messina et al. J Infect. 2024 Oct.

. 2024 Oct;89(4):106245.

doi: 10.1016/j.jinf.2024.106245. Epub 2024 Aug 8.

Authors

Affiliations

¹ Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.
² Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia; Immunology, Vaccinology, Rheumatology and Infectious Diseases Unit, Geneva and University Hospitals and Faculty of Medicine, Geneva, Switzerland.
³ Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
⁴ Clinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
⁵ Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia; Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia.
⁶ Julius Center for Health Sciences and Primary Care, University Medical Centre Utrecht, Utrecht University, the Netherlands; European Clinical Research Alliance on Infectious Diseases, Utrecht, Netherlands.
⁷ St Vincent's Hospitals, Darlinghurst, New South Wales, Australia; Partners In Health, Socios En Salud, Peru; Thoracic Society of Australia & New Zealand (NSW/ACT Branch), Australia.
⁸ Exeter Collaboration for Academic Primary Care, University of Exeter Medical School, Exeter, United Kingdom.
⁹ Fiocruz Mato Grosso do Sul, Fundação Oswaldo Cruz, Campo Grande, Mato Grosso do Sul, Brazil; Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA; Universidade Federal de Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.
¹⁰ Universidade Federal de Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.
¹¹ Centro de Referência Professor Hélio Fraga, ENSP/FIOCRUZ (Fundação Oswaldo Cruz), Rio de Janeiro, Brazil.
¹² Tropical Medicine Foundation Dr Heitor Vieira Dourado, Manaus, Brazil.
¹³ State University of Mato Grosso do Sul, Dourados, Brazil; Post Graduate Program in Health Sciences, Federal University of Grande Dourados, Dourados, Brazil.
¹⁴ Storr Liver Centre, The Westmead Institute for Medical Research, The University of Syndey at Westmead Hospital, Westmead, New South Wales, Australia; Centre for Infectious Diseases and Microbiology, Sydney Infectious Diseases Institute, The University of Sydney at Westmead Hospital, Westmead, New South Wales, Australia.
¹⁵ Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Research Operations, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.
¹⁶ Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia; Infectious Diseases, Royal Children's Hospital Melbourne, Parkville, Victoria, Australia; Antimicrobials Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
¹⁷ Institute of Clinical Research Carlos Borborema, Doctor Heitor Vieira Dourado Tropical Medicine Foundation, Manaus, Brazil.
¹⁸ Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Nedlands, Western Australia, Australia.
¹⁹ Institute of Clinical Research Carlos Borborema, Doctor Heitor Vieira Dourado Tropical Medicine Foundation, Manaus, Brazil; Instituto Leônidas & Maria Deane, Oswaldo Cruz Foundation Ministry of Health, Manaus, Brazil; University of Texas Medical Branch, Galveston, TX, USA.
²⁰ Department of Immunology, Pathwest, Queen Elizabeth II Medical Centre, Nedlands, Western Australia, Australia; Department of Immunology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia; Department of Immunology, Perth Children's Hospital, Nedlands, Western Australia, Australia; School of Medicine, University of Western Australia, Perth, Western Australia, Australia.
²¹ Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia; Flinders Health and Medical Research Institute, Flinders University, Bedford Park, South Australia, Australia.
²² Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Nedlands, Western Australia, Australia; School of Medicine, University of Western Australia, Perth, Western Australia, Australia; Department of Infectious Diseases, Fiona Stanley Hospital, Murdoch, Western Australia, Australia.
²³ The University of Adelaide and the Women's and Children's Health Network, Adelaide, SA, Australia.
²⁴ Exeter Clinical Trials Unit, University of Exeter, Exeter, United Kingdom.
²⁵ Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia; Population Allergy Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Allergy and Immunology, Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.
²⁶ Department of Infectious Diseases, Prince of Wales Hospital, Randwick, New South Wales, Australia; School of Clinical Medicine, University of New South Wales, Sydney, New South Wales, Australia.
²⁷ Helio Fraga Reference Center, Oswaldo Cruz Foundation Ministry of Health, Curicica, Brazil.
²⁸ Division of Infectious Diseases and Microbiology, Department of Medicine, Hospital Universitario Virgen Macarena, University of Seville, Biomedicines Institute of Seville-Consejo Superior de Investigaciones Científicas, Seville, Spain; CIBER de Enfermedades Infecciosas, Instituto de Salud Carloss III, Madrid, Spain.
²⁹ Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Nedlands, Western Australia, Australia; School of Medicine, University of Western Australia, Perth, Western Australia, Australia.
³⁰ Medical Research Council Centre for Medical Mycology, University of Exeter, Exeter, United Kingdom; Department of Infectious Diseases, Great Ormond Street Hospital, London, United Kingdom.
³¹ Melbourne Children's Trial Centre, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
³² Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia; Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia; Infectious Diseases, Royal Children's Hospital Melbourne, Parkville, Victoria, Australia. Electronic address: nigel.curtis@rch.org.au.

PMID: 39127450
PMCID: PMC11409612
DOI: 10.1016/j.jinf.2024.106245

Abstract

Objectives: Bacille Calmette-Guérin (BCG) vaccine has immunomodulatory effects that may provide protection against unrelated infectious diseases. We aimed to determine whether BCG vaccination protects adults against COVID-19.

Design: Phase III double-blind randomised controlled trial.

Setting: Healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom during the COVID-19 pandemic.

Participants: 3988 healthcare workers with no prior COVID-19 and no contraindication to BCG.

Intervention: Randomised 1:1 using a web-based procedure to receive a single 0.1 mL intradermal dose of BCG-Denmark (BCG group, n = 1999) or saline (placebo group, n = 1989).

Main outcome measures: Difference in incidence of (i) symptomatic and (ii) severe COVID-19 during the 12 months following randomisation in the modified intention to treat (mITT) population (confirmed SARS-CoV-2 naïve at inclusion).

Results: Of the 3988 participants randomised, 3386 had a negative baseline SARS-CoV-2 test and were included in the mITT population. The 12-month adjusted estimated risk of symptomatic COVID-19 was higher in the BCG group (22.6%; 95% confidence interval [CI] 20.6 to 24.5%) compared with the placebo group (19.6%; 95% CI 17.6 to 21.5%); adjusted difference +3.0% points (95% CI 0.2 to 5.8%; p = 0.04). The 12-month adjusted estimated risk of severe COVID-19 (mainly comprising those reporting being unable to work for ≥3 consecutive days) was 11.0% in the BCG group (95% CI 9.5 to 12.4%) compared with 9.6% in the placebo group (95% CI 8.3 to 11.1%); adjusted difference +1.3% points (95% CI -0.7 to 3.3%, p = 0.2). Breakthrough COVID-19 (post COVID-19 vaccination) and asymptomatic SARS-CoV-2 infections were similar in the two groups. There were 18 hospitalisations due to COVID-19 (11 in BCG group, 7 in placebo group; adjusted hazard ratio 1.56, 95% CI 0.60 to 4.02, p = 0.4) and two deaths due to COVID-19, both in the placebo group.

Conclusions: Compared to placebo, vaccination with BCG-Denmark increased the risk of symptomatic COVID-19 over 12 months among healthcare workers and did not decrease the risk of severe COVID-19 or post-vaccination breakthrough COVID-19.

Trial registration: ClinicalTrials.gov NCT04327206.

Keywords: Bacille Calmette-Guérin (BCG) Vaccine; Breakthrough infection; COVID-19; Immunity; Randomised controlled trial.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The trial is financially supported by the Foundations listed in the Funding section. Authors disclose funding support over the past 36 months: National Health and Medical Research Council (NHMRC) Ideas Grant (NM), NHMRC Investigator Grant (NC), Melbourne Children’s Clinician-Scientist Fellowship Grant (KPP). Outside of the submitted work, JCr has received grants or contracts from Sanofi, MSD & CEPI; payment or honoraria for presentations from Pfizer and participates on Latin American data safety monitoring/advisory boards for mRNA-1273 (Modern/Zodiac), RSV maternal vaccine (Pfizer), Qdenga vaccine (Takeda) and Nirmatrelvir/Ritonavir-Paxlovid (Pfizer). KG is a member of the Royal Children’s Hospital (RCH) Human Research Ethics Committee (the primary ethics committee providing approval for the BRACE trial) and Director of Research Operations at RCH; she abstained from all discussion, voting, approval and review related to the BRACE trial. All other authors declare no conflict of interest.

Figures

**Fig. 1**
Participant CONSORT diagram. Baseline SARS-CoV-2 screening result based on serology or respiratory swab PCR testing (Brazil only) at baseline. PCR, polymerase chain reaction.

**Fig. 2**
COVID-19 by 12 months following randomisation, by treatment arm. Panels A and B present symptomatic COVID‐19 and panels C and D present severe COVID‐19. Panels A and C present Kaplan–Meier curves with 95% confidence intervals in shaded areas (unadjusted analyses in the modified intention‐to‐treat population (mITT)). Panels B and D present forest plots of the between‐group difference in the percentage of participants with symptomatic or severe COVID‐19, with 95% confidence intervals (adjusted for stratification factors used in randomisation; primary, sensitivity, and supplementary analyses). *Population analysed was the subset of the mITT population with scar data available at 12 months, the treatment arms for this analysis are placebo or BCG without a scar evident at 12 months vs BCG with a scar evident at 12 months. COVID-19, coronavirus disease 2019; ITT, intention-to-treat; PCR, polymerase chain reaction; RAT rapid antigen test.

**Fig. 3**
COVID-19 by 12 months following randomisation among subgroups. Forest plots of the between‐group difference in the percentage of participants with symptomatic or severe COVID‐19 with (A) comorbidity and (B) other baseline characteristic sub groups. Data are adjusted for stratification factors used in randomisation and are presented with 95% confidence intervals. *p-value presented is for the interaction between treatment arm and subgroup is presented. BMI, body mass index; COVID-19, coronavirus disease 2019.

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References

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1. Biering-Sorensen S., Aaby P., Lund N., Monteiro I., Jensen K.J., Eriksen H.B., et al. Early BCG-Denmark and neonatal mortality among infants weighing <2500 g: a randomized controlled trial. Clin Infect Dis. 2017;65(7):1183–1190. - PMC - PubMed
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BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial

Affiliations

BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial

Authors

Affiliations

Abstract

Conflict of interest statement

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References

Publication types

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Substances

Associated data

LinkOut - more resources

Full Text Sources

Medical

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