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 Vg 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

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 Vg LacerdaMichaela 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,

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

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
Journal	The 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

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. (2024). BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial. The Journal of Infection, 89(4), Article 106245. https://doi.org/10.1016/j.jinf.2024.106245

@article{14900f8144024ca58fb547f0277dc071,

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 Vg} 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",

note = "Publisher Copyright: {\textcopyright} 2024 The Authors",

year = "2024",

month = oct,

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

language = "English",

volume = "89",

journal = "The Journal of Infection",

issn = "0163-4453",

publisher = "W.B. Saunders Ltd",

number = "4",

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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, MV, 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 2024, 'BCG vaccination of healthcare workers for protection against COVID-19: 12-month outcomes from an international randomised controlled trial', The 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 Vg

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

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 - http://www.scopus.com/inward/record.url?scp=85202210560&partnerID=8YFLogxK

U2 - 10.1016/j.jinf.2024.106245

DO - 10.1016/j.jinf.2024.106245

M3 - Article

C2 - 39127450

SN - 0163-4453

VL - 89

JO - The Journal of Infection

JF - The 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

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Keywords

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