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

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 V G Lacerda; Michaela Lucas; David J Lynn; Laurens Manning; Helen Marshall; Abby O'Connell; Kirsten P Perrett; Jeffrey J Post; Cristina Prat-Aymerich; Jorge L Rocha; Jesus Rodriguez-Baño; Ushma Wadia; Adilia Warris; Andrew Davidson; Nigel Curtis; the BRACE Trial Consortium Group

doi:10.1016/j.jinf.2024.106245

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

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 V G Lacerda

Michaela Lucas, David J Lynn, Laurens Manning, Helen Marshall, Abby O'Connell, Kirsten P Perrett, Jeffrey J Post, Cristina Prat-Aymerich, Jorge L Rocha, Jesus Rodriguez-Baño, Ushma Wadia, Adilia Warris, Andrew Davidson, Nigel Curtis, the BRACE Trial Consortium Group

Flinders Health and Medical Research Institute

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

52 Downloads (Pure)

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.

Original language	English
Article number	106245
Number of pages	11
Journal	Journal of Infection
Volume	89
Issue number	4
Early online date	8 Aug 2024
DOIs	https://doi.org/10.1016/j.jinf.2024.106245
Publication status	Published - Oct 2024

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

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Messina, N. L., Pittet, L. F., McDonald, E., Moore, C., Barry, S., Bonten, M., Byrne, A., Campbell, J., Croda, J., Croda, M. G., Dalcolmo, M., de Almeida e Val, F. F., de Oliveira, R. D., dos Santos, G., Douglas, M. W., Gardiner, K., Gwee, A., Jardim, B. A., Kollmann, T., ... the BRACE Trial Consortium Group (2024). BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial. Journal of Infection, 89(4), Article 106245. https://doi.org/10.1016/j.jinf.2024.106245

@article{07a33e6a3aeb4c29af752752f3ca21b8,

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

abstract = "Objectives: Bacille Calmette-Gu{\'e}rin (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 na{\"i}ve 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-Gu{\'e}rin (BCG) Vaccine, Breakthrough infection, COVID-19, Immunity, Randomised controlled trial",

author = "Messina, \{Nicole L\} and Pittet, \{Laure F\} and Ellie McDonald and Cecilia Moore and Simone Barry and Marc Bonten and Anthony Byrne and John Campbell and Julio Croda and Croda, \{Mariana G\} and Margareth Dalcolmo and \{de Almeida e Val\}, \{Fernando F\} and \{de Oliveira\}, \{Roberto D\} and \{dos Santos\}, Glauce and Douglas, \{Mark W\} and Kaya Gardiner and Amanda Gwee and Jardim, \{Bruno A\} and Tobias Kollmann and Lacerda, \{Marcus V G\} and Michaela Lucas and Lynn, \{David J\} and Laurens Manning and Helen Marshall and Abby O'Connell and Perrett, \{Kirsten P\} and Post, \{Jeffrey J\} and Cristina Prat-Aymerich and Rocha, \{Jorge L\} and Jesus Rodriguez-Ba{\~n}o and Ushma Wadia and Adilia Warris and Andrew Davidson and Nigel Curtis and \{the BRACE Trial Consortium Group\}",

year = "2024",

month = oct,

doi = "10.1016/j.jinf.2024.106245",

language = "English",

volume = "89",

journal = "Journal of Infection",

issn = "0163-4453",

publisher = "W.B. Saunders Ltd",

number = "4",

}

Messina, NL, Pittet, LF, McDonald, E, Moore, C, Barry, S, Bonten, M, Byrne, A, Campbell, J, Croda, J, Croda, MG, Dalcolmo, M, de Almeida e Val, FF, de Oliveira, RD, dos Santos, G, Douglas, MW, Gardiner, K, Gwee, A, Jardim, BA, Kollmann, T, Lacerda, MVG, Lucas, M, Lynn, DJ, Manning, L, Marshall, H, O'Connell, A, Perrett, KP, Post, JJ, Prat-Aymerich, C, Rocha, JL, Rodriguez-Baño, J, Wadia, U, Warris, A, Davidson, A, Curtis, N & the BRACE Trial Consortium Group 2024, 'BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial', Journal of Infection, vol. 89, no. 4, 106245. https://doi.org/10.1016/j.jinf.2024.106245

TY - JOUR

T1 - BCG vaccination of healthcare workers for protection against COVID-19

T2 - 12-month outcomes from an international randomised controlled trial

AU - Messina, Nicole L

AU - Pittet, Laure F

AU - McDonald, Ellie

AU - Moore, Cecilia

AU - Barry, Simone

AU - Bonten, Marc

AU - Byrne, Anthony

AU - Campbell, John

AU - Croda, Julio

AU - Croda, Mariana G

AU - Dalcolmo, Margareth

AU - de Almeida e Val, Fernando F

AU - de Oliveira, Roberto D

AU - dos Santos, Glauce

AU - Douglas, Mark W

AU - Gardiner, Kaya

AU - Gwee, Amanda

AU - Jardim, Bruno A

AU - Kollmann, Tobias

AU - Lacerda, Marcus V G

AU - Lucas, Michaela

AU - Lynn, David J

AU - Manning, Laurens

AU - Marshall, Helen

AU - O'Connell, Abby

AU - Perrett, Kirsten P

AU - Post, Jeffrey J

AU - Prat-Aymerich, Cristina

AU - Rocha, Jorge L

AU - Rodriguez-Baño, Jesus

AU - Wadia, Ushma

AU - Warris, Adilia

AU - Davidson, Andrew

AU - Curtis, Nigel

AU - the BRACE Trial Consortium Group

PY - 2024/10

Y1 - 2024/10

N2 - 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.

AB - 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.

KW - Bacille Calmette-Guérin (BCG) Vaccine

KW - Breakthrough infection

KW - COVID-19

KW - Immunity

KW - Randomised controlled trial

UR - https://www.scopus.com/pages/publications/85202210560

U2 - 10.1016/j.jinf.2024.106245

DO - 10.1016/j.jinf.2024.106245

M3 - Article

C2 - 39127450

AN - SCOPUS:85202210560

SN - 0163-4453

VL - 89

JO - Journal of Infection

JF - Journal of Infection

IS - 4

M1 - 106245

ER -

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

Abstract

UN SDGs

Keywords

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