EClinicalMedicine (Jun 2024)

Bacille Calmette-Guérin vaccination to prevent febrile and respiratory illness in adults (BRACE): secondary outcomes of a randomised controlled phase 3 trialResearch in context

  • Laure F. Pittet,
  • Nicole L. Messina,
  • Ellie McDonald,
  • Francesca Orsini,
  • Simone Barry,
  • Marc Bonten,
  • John Campbell,
  • Julio Croda,
  • Mariana G. Croda,
  • Margareth Dalcolmo,
  • Kaya Gardiner,
  • Amanda Gwee,
  • Bruno Jardim,
  • Marcus V.G. Lacerda,
  • Michaela Lucas,
  • David J. Lynn,
  • Laurens Manning,
  • Kirsten P. Perrett,
  • Jeffrey J. Post,
  • Cristina Prat-Aymerich,
  • Peter C. Richmond,
  • Jorge L. Rocha,
  • Jesus Rodriguez-Baño,
  • Adilia Warris,
  • Nicholas J. Wood,
  • Andrew Davidson,
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  • Nigel Curtis,
  • Andrew Davidson,
  • Kaya Gardiner,
  • Amanda Gwee,
  • Tenaya Jamieson,
  • Nicole Messina,
  • Thilanka Morawakage,
  • Susan Perlen,
  • Kirsten Perrett,
  • Laure Pittet,
  • Amber Sastry,
  • Jia Wei Teo,
  • Francesca Orsini,
  • Katherine Lee,
  • Cecilia Moore,
  • Suzanna Vidmar,
  • Laure Pittet,
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  • Ross Dunn,
  • Peta Edler,
  • Grace Gell,
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  • Ann Krastev,
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  • Ellie McDonald,
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  • Scott Reddiex,
  • Xiaofang Wang,
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  • Kristy Azzopardi,
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  • Anna Czajko,
  • Nadia Mazarakis,
  • Conor McCafferty,
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  • Belinda Ortika,
  • Casey Pell,
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  • Amanda Vlahos,
  • Ashleigh Wee-Hee,
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  • Paulo Henrique Andrade,
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  • Larissa Brasil,
  • Ana Greyce Capella,
  • Ramon Castro,
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  • Renato da Costa Silva,
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  • Rita de Cássia Batista,
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  • Ayla Alcoforado da Silva dos Santos,
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  • Marc Bonten,
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  • David Gutierrez Campos,
  • Jose Manuel Carretero,
  • Angel Dominguez Castellano,
  • Renato Compagnone,
  • Encarnacion Ramirez de Arellano,
  • Almudena de la Serna,
  • Maria Dolores del Toro Lopez,
  • Marie-Alix Clement Espindola,
  • Ana Belen Martin Gutierrez,
  • Alvaro Pascual Hernandez,
  • Virginia Palomo Jiménez,
  • Elisa Moreno,
  • Nicolas Navarrete,
  • Teresa Rodriguez Paño,
  • Jesús Rodríguez-Baño,
  • Enriqueta Tristán,
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  • Erika Castro Amo,
  • Raquel Coya Guerrero,
  • Josune Goikoetxea,
  • Leticia Jorge,
  • Cristina Perez,
  • María Carmen Fariñas Álvarez,
  • Manuel Gutierrez Cuadra,
  • Francisco Arnaiz de las Revillas Almajano,
  • Pilar Bohedo Garcia,
  • Teresa Giménez Poderos,
  • Claudia González Rico,
  • Blanca Sanchez,
  • Olga Valero,
  • Noelia Vega,
  • John Campbell,
  • Anna Barnes,
  • Helen Catterick,
  • Tim Cranston,
  • Phoebe Dawe,
  • Emily Fletcher,
  • Liam Fouracre,
  • Alison Gifford,
  • Neil Gow,
  • John Kirkwood,
  • Christopher Martin,
  • Amy McAnew,
  • Marcus Mitchell,
  • Georgina Newman,
  • Abby O'Connell,
  • Jakob Onysk,
  • Lynne Quinn,
  • Shelley Rhodes,
  • Samuel Stone,
  • Lorrie Symons,
  • Harry Tripp,
  • Darcy Watkins,
  • Bethany Whale,
  • Alex Harding,
  • Gemma Lockhart,
  • Kate Sidaway-Lee,
  • John Campbell,
  • Sam Hilton,
  • Sarah Manton,
  • Daniel Webber-Rookes,
  • Rachel Winder,
  • James Moore,
  • Freya Bateman,
  • Michael Gibbons,
  • Bridget Knight,
  • Julie Moss,
  • Sarah Statton,
  • Josephine Studham,
  • Lydia Hall,
  • Will Moyle,
  • Tamsin Venton

Journal volume & issue
Vol. 72
p. 102616

Abstract

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Summary: 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.

Keywords