BCG Vaccination of Healthcare Workers for Protection Against COVID-19: 12-month Outcomes from an International Randomised Controlled Trial

Overview

Journal J Infect

Specialty Infectious Diseases

Date 2024 Aug 10

PMID 39127450

Authors

Nicole L Messina

Laure F Pittet

Ellie McDonald

Cecilia Moore

Simone Barry

Marc Bonten

Anthony Byrne

John Campbell

Julio Croda

Mariana G Croda

Margareth Dalcolmo

Fernando F de Almeida E Val

Roberto D de Oliveira

Glauce Dos Santos

Mark W Douglas

Kaya Gardiner

Amanda Gwee

Bruno A Jardim

Tobias Kollmann

Marcus Vg Lacerda

Michaela Lucas

David J Lynn

Laurens Manning

Helen Marshall

Abby OConnell

Kirsten P Perrett

Jeffrey J Post

Cristina Prat-Aymerich

Jorge L Rocha

Jesus Rodriguez-Bano

Ushma Wadia

Adilia Warris

Andrew Davidson

Nigel Curtis

Affiliations

Soon will be listed here.

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.

Citing Articles

Effect of Bacille Calmette-Guérin vaccination on immune responses to SARS-CoV-2 and COVID-19 vaccination.

Messina N, Germano S, Chung A, van de Sandt C, Stevens N, Allen L Clin Transl Immunology. 2025; 14(1):e70023.

PMID: 39872402 PMC: 11761716. DOI: 10.1002/cti2.70023.

References

Pittet L, Messina N, Orsini F, Moore C, Abruzzo V, Barry S . Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers. N Engl J Med. 2023; 388(17):1582-1596. PMC: 10497190. DOI: 10.1056/NEJMoa2212616. View

Netea M, Dominguez-Andres J, van de Veerdonk F, van Crevel R, Pulendran B, van der Meer J . Natural resistance against infections: focus on COVID-19. Trends Immunol. 2021; 43(2):106-116. PMC: 8648669. DOI: 10.1016/j.it.2021.12.001. View

Messina N, Sperotto M, Puga M, da Silva P, de Oliveira R, Moore C . Impact of vaccine platform and BCG vaccination on antibody responses to COVID-19 vaccination. Front Immunol. 2023; 14:1172851. PMC: 10352084. DOI: 10.3389/fimmu.2023.1172851. View

Messina N, Germano S, McElroy R, Rudraraju R, Bonnici R, Pittet L . Off-target effects of bacillus Calmette-Guérin vaccination on immune responses to SARS-CoV-2: implications for protection against severe COVID-19. Clin Transl Immunology. 2022; 11(4):e1387. PMC: 9028103. DOI: 10.1002/cti2.1387. View

Faustman D, Lee A, Hostetter E, Aristarkhova A, Ng N, Shpilsky G . Multiple BCG vaccinations for the prevention of COVID-19 and other infectious diseases in type 1 diabetes. Cell Rep Med. 2022; 3(9):100728. PMC: 9376308. DOI: 10.1016/j.xcrm.2022.100728. View

Oran D, Topol E . The Proportion of SARS-CoV-2 Infections That Are Asymptomatic : A Systematic Review. Ann Intern Med. 2021; 174(5):655-662. PMC: 7839426. DOI: 10.7326/M20-6976. View

Villanueva P, Crawford N, Croda M, Collopy S, Jardim B, Jardim T . Safety of BCG vaccination and revaccination in healthcare workers. Hum Vaccin Immunother. 2023; 19(2):2239088. PMC: 10411308. DOI: 10.1080/21645515.2023.2239088. View

Harris P, Taylor R, Thielke R, Payne J, Gonzalez N, Conde J . Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2008; 42(2):377-81. PMC: 2700030. DOI: 10.1016/j.jbi.2008.08.010. View

Higgins J, Soares-Weiser K, Lopez-Lopez J, Kakourou A, Chaplin K, Christensen H . Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review. BMJ. 2016; 355:i5170. PMC: 5063034. DOI: 10.1136/bmj.i5170. View

10.

Netea M, Giamarellos-Bourboulis E, Dominguez-Andres J, Curtis N, van Crevel R, van de Veerdonk F . Trained Immunity: a Tool for Reducing Susceptibility to and the Severity of SARS-CoV-2 Infection. Cell. 2020; 181(5):969-977. PMC: 7196902. DOI: 10.1016/j.cell.2020.04.042. View

11.

Leentjens J, Kox M, Stokman R, Gerretsen J, Diavatopoulos D, van Crevel R . BCG Vaccination Enhances the Immunogenicity of Subsequent Influenza Vaccination in Healthy Volunteers: A Randomized, Placebo-Controlled Pilot Study. J Infect Dis. 2015; 212(12):1930-8. DOI: 10.1093/infdis/jiv332. View

12.

Curtis N, Sparrow A, Ghebreyesus T, Netea M . Considering BCG vaccination to reduce the impact of COVID-19. Lancet. 2020; 395(10236):1545-1546. PMC: 7252177. DOI: 10.1016/S0140-6736(20)31025-4. View

13.

Arts R, Moorlag S, Novakovic B, Li Y, Wang S, Oosting M . BCG Vaccination Protects against Experimental Viral Infection in Humans through the Induction of Cytokines Associated with Trained Immunity. Cell Host Microbe. 2018; 23(1):89-100.e5. DOI: 10.1016/j.chom.2017.12.010. View

14.

Messina N, Zimmermann P, Curtis N . The impact of vaccines on heterologous adaptive immunity. Clin Microbiol Infect. 2019; 25(12):1484-1493. DOI: 10.1016/j.cmi.2019.02.016. View

15.

Hollm-Delgado M, Stuart E, Black R . Acute lower respiratory infection among Bacille Calmette-Guérin (BCG)-vaccinated children. Pediatrics. 2014; 133(1):e73-81. DOI: 10.1542/peds.2013-2218. View

16.

Prentice S, Nassanga B, Webb E, Akello F, Kiwudhu F, Akurut H . BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial. Lancet Infect Dis. 2021; 21(7):993-1003. PMC: 8222005. DOI: 10.1016/S1473-3099(20)30653-8. View

17.

Sah P, Fitzpatrick M, Zimmer C, Abdollahi E, Juden-Kelly L, Moghadas S . Asymptomatic SARS-CoV-2 infection: A systematic review and meta-analysis. Proc Natl Acad Sci U S A. 2021; 118(34). PMC: 8403749. DOI: 10.1073/pnas.2109229118. View

18.

Geckin B, Zoodsma M, Kilic G, Debisarun P, Rakshit S, Adiga V . Differences in Immune Responses in Individuals of Indian and European Origin: Relevance for the COVID-19 Pandemic. Microbiol Spectr. 2023; :e0023123. PMC: 10100912. DOI: 10.1128/spectrum.00231-23. View

19.

Kuhtreiber W, Hostetter E, Wolfe G, Vaishnaw M, Goldstein R, Bulczynski E . Late in the US pandemic, multi-dose BCG vaccines protect against COVID-19 and infectious diseases. iScience. 2024; 27(6):109881. PMC: 11270028. DOI: 10.1016/j.isci.2024.109881. View

20.

Villanueva P, Wadia U, Crawford N, Messina N, Kollmann T, Lucas M . Revaccination with Bacille Calmette-Guérin (BCG) is associated with an increased risk of abscess and lymphadenopathy. NPJ Vaccines. 2022; 7(1):6. PMC: 8760267. DOI: 10.1038/s41541-021-00421-5. View