TY - JOUR
T1 - Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE)
T2 - secondary outcomes of a randomised controlled phase 3 trial
AU - Pittet, Laure
AU - Messina, Nicole
AU - McDonald, Ellie
AU - Orsini, Francesca
AU - Barry, Simone
AU - Bonten, Marc
AU - Campbell, John
AU - Croda, Julio
AU - Croda, Mariana G.
AU - Dalcolmo, Margareth
AU - Gardiner, Kaya
AU - Gwee, Amanda
AU - Jardim, Bruno
AU - Lacerda, Marcus V.G.
AU - Lucas, Michaela
AU - Lynn, David J.
AU - Manning, Laurens
AU - Perrett, Kirsten
AU - Post, Jeffrey J.
AU - Prat-Aymerich, Cristina
AU - Richmond, Peter C.
AU - Rocha, Jorge L.
AU - Rodriguez-Baño, Jesus
AU - Warris, Adilia
AU - Wood, Nicholas J.
AU - Davidson, Andrew
AU - Curtis, Nigel
AU - Jamieson, Tenaya
AU - Messina, Nicole
AU - Morawakage, Thilanka
AU - Perlen, Susan
AU - Perrett, Kirsten
AU - Pittet, Laure
AU - Sastry, Amber
AU - Teo, Jia Wei
AU - Lee, Katherine
AU - Moore, Cecilia
AU - Vidmar, Suzanna
AU - Ali, Rashida
AU - Dunn, Ross
AU - Edler, Peta
AU - Gell, Grace
AU - Goodall, Casey
AU - Hall, Richard
AU - Krastev, Ann
AU - Janssen, Axel
AU - Troeman, Darren
AU - Kluytmans, Jan
AU - Paternotte, Nienke
AU - Meek, Bob
N1 - Publisher Copyright:
© 2024 The Author(s)
PY - 2024/6
Y1 - 2024/6
N2 - Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.
AB - Background: Bacille Calmette-Guérin (BCG) vaccination has off-target (non-specific) effects that are associated with protection against unrelated infections and decreased all-cause mortality in infants. We aimed to determine whether BCG vaccination prevents febrile and respiratory infections in adults. Methods: This randomised controlled phase 3 trial was done in 36 healthcare centres in Australia, Brazil, the Netherlands, Spain, and the United Kingdom. Healthcare workers were randomised to receive BCG-Denmark (single 0.1 ml intradermal injection) or no BCG in a 1:1 ratio using a web-based procedure, stratified by stage, site, age, and presence of co-morbidity. The difference in occurrence of febrile or respiratory illness were measured over 12 months (prespecified secondary outcome) using the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, NCT04327206. Findings: Between March 30, 2020, and April 1, 2021, 6828 healthcare workers were randomised to BCG-Denmark (n = 3417) or control (n = 3411; no intervention or placebo) groups. The 12-month adjusted estimated risk of ≥1 episode of febrile or respiratory illness was 66.8% in the BCG group (95% CI 65.3%–68.2%), compared with 63.4% in the control group (95% CI 61.8%–65.0%), a difference of +3.4 percentage points (95% CI +1.3% to +5.5%; p 0.002). The adjusted estimated risk of a severe episode (defined as being incapacitated for ≥3 consecutive days or hospitalised) was 19.4% in the BCG group (95% CI 18.0%–20.7%), compared with 18.8% in the control group (95% CI 17.4%–20.2%) a difference of +0.6 percentage points (95% CI −1.3% to +2.5%; p 0.6). Both groups had a similar number of episodes of illness, pneumonia, and hospitalisation. There were three deaths, all in the control group. There were no safety concerns following BCG vaccination. Interpretation: In contrast to the beneficial off-target effects reported following neonatal BCG in infants, a small increased risk of symptomatic febrile or respiratory illness was observed in the 12 months following BCG vaccination in adults. There was no evidence of a difference in the risk of severe disease. Funding: Bill & Melinda Gates Foundation, Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the UHG Foundation Pty Ltd, Epworth Healthcare, the National Health and Medical Research Council, the Swiss National Science Foundation and individual donors.
KW - Bacille Calmette-Guérin (BCG) vaccine
KW - Health personnel
KW - Heterologous
KW - Immunity
KW - Placebo
KW - Primary prevention
KW - Randomised controlled trial
UR - http://www.scopus.com/inward/record.url?scp=85192819171&partnerID=8YFLogxK
U2 - 10.1016/j.eclinm.2024.102616
DO - 10.1016/j.eclinm.2024.102616
M3 - Article
AN - SCOPUS:85192819171
SN - 2589-5370
VL - 72
JO - EClinicalMedicine
JF - EClinicalMedicine
M1 - 102616
ER -