BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial)

Laure F Pittet; Nicole L Messina; Kaya Gardiner; Francesca Orsini; Veronica Abruzzo; Samantha Bannister; Marc Bonten; John L Campbell; Julio Croda; Margareth Dalcolmo; Sonja Elia; Susie Germano; Casey Goodall; Amanda Gwee; Tenaya Jamieson; Bruno Jardim; Tobias R Kollmann; Marcus Vinícius Guimarães Lacerda; Katherine J Lee; Donna Legge; Michaela Lucas; David J Lynn; Ellie McDonald; Laurens Manning; Craig F Munns; Kirsten P Perrett; Cristina Prat Aymerich; Peter Richmond; Frank Shann; Eva Sudbury; Paola Villanueva; Nicholas J Wood; Katherine Lieschke; Kanta Subbarao; Andrew Davidson; Nigel Curtis; BRACE trial Consortium Group

doi:10.1136/bmjopen-2021-052101

BCG vaccination to reduce the impact of COVID-19 in healthcare workers: Protocol for a randomised controlled trial (BRACE trial)

BMJ Open. 2021 Oct 28;11(10):e052101. doi: 10.1136/bmjopen-2021-052101.

Authors

Laure F Pittet^{1

2

3}, Nicole L Messina^{1

2}, Kaya Gardiner¹, Francesca Orsini⁴, Veronica Abruzzo¹, Samantha Bannister^{1

2

3}, Marc Bonten⁵, John L Campbell⁶, Julio Croda^{7

8

9}, Margareth Dalcolmo^{10

11}, Sonja Elia^{1

12}, Susie Germano¹, Casey Goodall¹, Amanda Gwee^{1

2

3}, Tenaya Jamieson¹, Bruno Jardim¹³, Tobias R Kollmann¹⁴, Marcus Vinícius Guimarães Lacerda^{13

15}, Katherine J Lee^{2

4}, Donna Legge¹⁶, Michaela Lucas^{17

18

19

20}, David J Lynn^{21

22}, Ellie McDonald¹, Laurens Manning^{14

20

23}, Craig F Munns^{24

25}, Kirsten P Perrett^{2

26

27}, Cristina Prat Aymerich^{5

28}, Peter Richmond^{14

19

20}, Frank Shann³, Eva Sudbury¹, Paola Villanueva^{1

2}, Nicholas J Wood^{25

29

30}, Katherine Lieschke²⁷, Kanta Subbarao³¹, Andrew Davidson²⁷, Nigel Curtis^{32

2

3}; BRACE trial Consortium Group

Collaborators

BRACE trial Consortium Group:
Carolinne Abreu, Veronica Abruzzo, Lynne Addlem, Sophie Agius, Adelita Agripina Barbosa, Ahmed Alamrousi, Ayla Alcoforado Santos, Yasmeen Al-Hindawi, Samyra Almeida Da Silveira, Lais Alves Cruz, Jeremy Anderson, Christina Anthony, Andrea Antonia Pereira, Francisco Arnaiz Almajano, Annabelle Arnold, Beth Arrowsmith, Kristy Azzopardi, Cristina Badia Marti, Twinkle Bahaduri, Samantha Bannister, Sarah Barney, Lydia Barrera, Anabel Barriocanal, Dayanne Barros, Adam Bartlett, Lilian Muranaka, Therese Baulman, Morgan Bealing, Justin Beardsley, Ana Belen Gutierrez, Jason Bell, Vicki Bennett-Wood, Nikki Bergant, Fabiane Bianca Barbosa, Wouter Bijllaardt, Patricia Bimboese, Camila Bitencourt Andrade, Kitty Blauwendraat, Wim Boersma, Pilar Bohedo Garcia, Rhian Bonnici, Marc Bonten, Anne Boon, Anna Bourke, Kirsty Bowes, Larissa Brasil, Clare Brophy, Sandy Buchanan, Jess Bucholc, Alison Burns, Emma Burrell, Natalia Bustos, Bridie Byrne, Anthony Byrne, Esther Calbo, Jorge Calvo Montes, Beatriz Camesella, John Campbell, Atsegiñe Cangas, John Carlin, Maria Carmen Roque, Roberta Carolina Diogo, Estela Carvalho, Irma Casas, Erika Castro, Ramon Castro, Helen Catterick, Rodrigo Cezar Escobar, Joyce Chan, Jo Cheah, Thilakavathi Chengodu, Marianna Ciaverella, Sharon Clark, Marie-Alix Clement Espindola, Annie Cobbledick, Clinton Colaco, Simone Collopy, Patricia Comella, Mary Corbett, Gabriela Correa Castro, Erlane Costa, Raquel Coya, Nigel Crawford, Julio Croda, Alda Cruz, Nigel Curtis, Jac Cushnahan, Anna Czajko, Renato da Silva, Bouchra Daitiri, Margareth Dalcolmo, Karen Dalton, Aiken Dao, Andrew Davidson, Phoebe Dawe, Diane Dawson, Miriam Jesus Costa, Karina De La Cruz, Almudena de Serna, Fabiani de Morais Batista, Adriely de Oliveira, Rocio Del Rey Morillo, Maria Desylva, Helga Dijkstra, Rachel Dixon, Maria Dolores Lopez, Jose Dominguez, Angel Dominguez Castellano, Glauce Dos Santos, Joyce Santos Lencina, Débora Santos Silva, Mark Douglas, Ross Dunn, Andrew Dunn, Jemma Dunnill, Harriet Edmund, Nat Eiffler, Hannah Elborough, Sonja Elia, Olivia Elkington, Michelle England, Wellyngthon Espindola Ayala, Maria Esteve, Nick Evans, Krist Ewe, María Carmen Álvarez, Kieran Fahey, Jill Fairweather, Denise Faustman, Erica Fernandes Silva, Monique Fernandez, Galina Fidler, P M G Filius, Adam Finn, Carolyn Finucane, Stephanie Firth, Emily Fletcher, Catherine Flynn, Lorraine Flynn, Liam Fouracre, Sarah Fowler, Thamires Freitas, Ana Carolina Furtado, Maria Gabriela Oliveira, Anna Gabriela Santos, Leandro Galdino Gonçalves, Laura Galletta, Larissa Gama, Dinusha Gamage, Radhika Ganpat, Mariana Garcia, Carlos García, Mariana Garcia Croda, Kaya Gardiner, Evangeline Gardiner, Grace Gell, Aline Gerhardt Oliveira, Susie Germano, Michael Gibbons, Camille Gibson, Alison Gifford, Teresa Giménez Poderos, Ann Ginsberg, Jet Gisolf, Bojana Gladanac, Penny Glenn, Vanessa Godinho, Mayara Góes Santos, Josune Goikoetxea, Telma Goldenberg, Adriano Gomes, Susana Gonzalez Marcos, Claudia González Rico, Casey Goodall, Victoria Gordon, Frances Greven, Ana Greyce Capella, Christina Guo, David Gutierrez Campos, Manuel Gutierrez Cuadra, Amanda Gwee, Richard Hall, Lydia Hall, Kate Hamilton, Matthew Hannan, Houda Harbech, Alex Harding, Neil Haker, Robert Harrison, Robert Jan Hassing, Thaynara Haynara Rosa, Zaheerah Haywood, Nadine Henare, Paulo Henrique Andrade, Susan Herrmann, Erin Hill, Sam Hilton, Danique Huijbens, Heidi Hutton, Tenaya Jamieson, Axel Janssen, Bruno Jardim, Tyane Jardim, Lance Jarvis, Narelle Jenkins, Jane Jones, Jan Jones, Karen Jones, Leticia Jorge, Maria Jose Vilegas, Sri Joshi, Rosemary Joyce, Joel Junior, Rama Kandasamy, Anushka Karunanayake, Hana Karuppasamy, Tom Keeble, Jennifer Kent, Paul Kloeg, Jan Kluytmans, Bridget Knight, Tobias Kollmann, Tony Korman, Ann Krastev, Nathan La, Marcus Lacerda, Alicia Lacoma, Renier Lagunday, Debbie Lalich, Erin Latkovic, Irene Latorre, Paulo Leandro Junior, Katherine Lee, Donna Legge, Toos Lemmers, Titia Leurink, Katherine Lieschke, Kee Lim, Gemma Lockhart, Cíntia Lopes Bogéa, Karla Lopes Santos, Reyes Lopez Marques, Michaela Lucas, Maria Luciana Freitas, Norine Ma, Sam Macalister, Cristiane Machado, Matheus Machado Ramos, Francesca Machingaifa, Ivan Maia, Bernardo Maia, Richard Malley, Laurens Manning, Sarah Manton, Jose Manuel Carrerero, Ana Maria Barriocanal, Cíntia Maria Alves, Rosa Maria Pereira, Bianca Maria Arruda, Adriana Marins, Christopher Martin, Katya Martinez Almeida, Wayne Mather, Megan Mathers, Fábio Mauricio Gomes, Mariana Mayumi Tadokoro, Nadia Mazarakis, Kelry Mazurega, Sonia McAlister, Amy McAndrews, Ellie McDonald, Fiona McDonald, Rebecca McElroy, Brendan McMullan, Nick McPhate, Lee Mead, Andrea Meehan, Bob Meek, Rosangela Melo, Guillermo Mena, Daniella Mesquita, Nicole Messina, Isabella Mezzetti, Hugo Miguel Vieira, Skye Miller, Kirsten Mitchell, Marcus Mitchell, Jesutofunmi Mojeed, Kitty Molenaar, Gemma Molina, Barbara Molina, Lisa Montgomery, Cecilia Moore, James Moore, Simone Moorlag, Thilanka Morawakage, Julie Moss, Will Moyle, Kim Mulholland, Craig Munns, Elizandra Nascimento, Nicolas Navarrette, Mihai Netea, Juliana Neves, Georgina Newman, Belle Ngien, Jill Nguyen, Khanh Nguyen, Fran Noonan, Wendy Norton, Melissa O'Donnell, Jess O'Bryan, Abby O'Connell, Sasha Odoi, Liz O'Donnell, Roberto Oliveira, Marilena Oliveira, Thais Oliveira, Ingrid Oliveira, Nadia Olivier, Ligia Olivio, Benjamin Ong, Jaslyn Ong, Joanne Ong, Jakob Onysk, Isabelle Ooi, Frances Oppedisano, Francesca Orsini, Belinda Ortika, Orygen Group, Arthur Otsuka, Kristen Overton, Rosie Owens, Rayssa Paes, Pamela Palasanthiran, Virginia Palomo Jiménez, Girlene Pandine, Kimberley Parkin, Alvaro Pascual Hernandez, Nienke Paternotte, David Paterson, Ana Paula Souza, Lisa Pelayo, Casey Pell, Sille Pelser, Handerson Pereira, Gabrielle Pereira, Glady Perez, Cristina Perez, Tomás Perez Porcuna, Susan Perlen, Kirsten Perrett, Amandine Philippart Floy, Sigrid Pitkin, Laure Pittet, R C Pon, Ines Portillo Calderón, Jeffrey Post, Catherine Power, Christiane Prado, Endriaen Prajitno, Cristina Prat-Aymerich, Lieke Preijers, Marco Puga, Evelyn Queiroz, Lynne Quinn, Ashleigh Rak, Leticia Ramires Figueiredo, Encarnacion Ramirez de Arellano, Pedro Ramos, Karla Regina Oliveira, Jack Ren, Stephanie Reynolds, Shelley Rhodes, Claudinalva Ribeiro Santos, Chris Richards, Peter Richmond, Holly Richmond, Ana Rita Souza, Jorge Rocha, Teresa Rodrigues, Laleyska Rodrigues, Bebeto Rodrigues, Iara Rodrigues Fernandes, Jesús Rodríguez-Baño, Nienke Roescher, Sally Rogers, Anke Rol, Jannie Romme, Antoni Rosell, Maria Roser Font, Sonia Sallent, Vanderson Sampaio, Nuria Sanchez, Blanca Sanchez, Daniel Santos, Tilza Santos, Ariandra Sartim, Amber Sastry, Alice Sawka, Nikki Schultz, Clare Seamark, David Seamark, Engelien Septer-Bijleveld, Raquel Serrano, Frank Shann, Ketaki Sharma, Margaret Shave, Lisa Shen, Kate Sidaway-Lee, Adrian Siles Baena, Rafaela Silva, Juliana Silva, Emanuelle Silva, Mariana Simão, Ronita Singh, Marilda Siqueira, Marciléia Soares Chaves, Thijs Sondag, Enoshini Sooriyarachchi, Antonny Sousa, Leena Spry, Sarah Statton, Andrew Steer, Dyenyffer Stéffany Santos, Katrina Sterling, Leah Steve, Luke Stevens, Carolyn Stewart, Lisa Stiglmayer, Lida Stooper, Josephine Studham, Kanta Subbarao, Eva Sudbury, Astrid Suiker, Lorrie Symons, Esther Taks, Niki Tan, Bruna Tayara Meireles, Menno Te Riele, Jaap Ten Oever, Guilherme Teodoro Lima, Rob ter Heine, Jhenyfer Thalyta Angelo, Helen Thomson, Ryan Toh, Alexandre Trindade, Harry Tripp, Enriqueta Tristán, Darren Troeman, Alexandra Truelove, Daniel Tsuha, Marlot Uffing, Fernando Val, Olga Valero, Ester Valls, Chantal van Ven, Leo Van Heuvel, Sigrid van Veen, Marije van Waal, J H van Leusen, Linda van Mook, H van Onzenoort, Marjoleine van Opdorp, Miranda van Rijen, Nicolette van Sluis, Adria Vasconcelos, Noelia Vega, Sunitha Velagapudi, Louise Vennells, Tamsin Venton, Harald Verheij, P M Verhoeven, Caroliny Veron Ramos, Paulo Victor Silva, Sandra Vidal, Patricia Vieira, Matheus Vieira Oliveira, Rosario Vigo Ortega, Paola Villanueva, Raquel Villar, Amanda Vlahos, Ushma Wadia, Kate Wall, Rachael Wallace, Justin Waring, Ruth Warren, Adilia Warris, Emma Watts, Michelle Wearing-Smith, Daniel Webber-Rookes, Jamie Wedderburn, Ashleigh Wee-Hee, Jia Wei Teo, Bethany Whale, Phoebe Williams, Beatrijs Wolters, Nick Wood, Ivy Xie, Angela Younes, Angela Young, Felipe Zampieri Batista, Carmen Zhou, Vivian Zwart

Affiliations

¹ Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
² Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia.
³ Infectious Diseases, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.
⁴ Clinical Epidemiology and Biostatistics Unit, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
⁵ University Medical Center Utrecht, Julius Center for Health Sciences and Primary Care, Utrecht, The Netherlands.
⁶ University of Exeter Medical School, Exeter, UK.
⁷ Oswaldo Cruz Foundation, Campo Grande, Mato Grosso do Sul, Brazil.
⁸ School of Medicine, Federal University of Mato Grosso do Sul, Campo Grande, Mato Grosso do Sul, Brazil.
⁹ Yale School of Public Health, New Haven, Connecticut, USA.
¹⁰ Helio Fraga Reference Center, Oswaldo Cruz Foundation Ministry of Health, Rio de Janeiro, Brazil.
¹¹ Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro, Brazil.
¹² Immunisation Service, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.
¹³ Institute of Clinical Research Carlos Borborema, Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Amazonas, Brazil.
¹⁴ Wesfarmers Centre for Vaccines and Infectious Diseases, Telethon Kids Institute, Perth, Western Australia, Australia.
¹⁵ Instituto Leônidas & Maria Deane, Oswaldo Cruz Foundation, Manaus, Amazonas, Brazil.
¹⁶ Department of Pharmacy, Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.
¹⁷ Department of Immunology, QE2 Medical Centre, PathWest Laboratory Medicine Western Australia, Nedlands, Western Australia, Australia.
¹⁸ Department of Immunology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.
¹⁹ Department of Immunology and General Paediatrics, Perth Children's Hospital, Nedlands, Western Australia, Australia.
²⁰ School of Medicine, The University of Western Australia, Perth, Western Australia, Australia.
²¹ Precision Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.
²² Flinders Health and Medical Research Institute, Flinders University, Bedford Park, South Australia, Australia.
²³ Department of Infectious Diseases, Fiona Stanley Hospital, Bull Creek, Western Australia, Australia.
²⁴ Department of Endocrinology & Diabetes, The Children's Hospital at Westmead, Westmead, New South Wales, Australia.
²⁵ Faculty of Medicine and Health, The University of Sydney, Sydney, New South Wales, Australia.
²⁶ Department of Allergy and Immunology, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.
²⁷ Melbourne Children's Trial Centre, Murdoch Children's Research Institute, Parkville, Victoria, Australia.
²⁸ Institut d'Investigació Germans Trias i Pujol, Departament de Genètica i Microbiologia, CIBER de enfermedades respiratorias (CIBERES), Instituto de Salud Carlos III, Universitat Autònoma de Barcelona, Badalona, Catalunya, Spain.
²⁹ The Sydney Children's Hospitals Network Randwick and Westmead, Sydney, New South Wales, Australia.
³⁰ National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, Sydney, New South Wales, Australia.
³¹ WHO Collaborating Centre for Reference and Research on Influenza and Department of Microbiology and Immunology, University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
³² Infectious Diseases Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia [email protected].

Abstract

Introduction: BCG vaccination modulates immune responses to unrelated pathogens. This off-target effect could reduce the impact of emerging pathogens. As a readily available, inexpensive intervention that has a well-established safety profile, BCG is a good candidate for protecting healthcare workers (HCWs) and other vulnerable groups against COVID-19.

Methods and analysis: This international multicentre phase III randomised controlled trial aims to determine if BCG vaccination reduces the incidence of symptomatic and severe COVID-19 at 6 months (co-primary outcomes) compared with no BCG vaccination. We plan to randomise 10 078 HCWs from Australia, The Netherlands, Spain, the UK and Brazil in a 1:1 ratio to BCG vaccination or no BCG (control group). The participants will be followed for 1 year with questionnaires and collection of blood samples. For any episode of illness, clinical details will be collected daily, and the participant will be tested for SARS-CoV-2 infection. The secondary objectives are to determine if BCG vaccination reduces the rate, incidence, and severity of any febrile or respiratory illness (including SARS-CoV-2), as well as work absenteeism. The safety of BCG vaccination in HCWs will also be evaluated. Immunological analyses will assess changes in the immune system following vaccination, and identify factors associated with susceptibility to or protection against SARS-CoV-2 and other infections.

Ethics and dissemination: Ethical and governance approval will be obtained from participating sites. Results will be published in peer-reviewed open-access journals. The final cleaned and locked database will be deposited in a data sharing repository archiving system.

Trial registration: ClinicalTrials.gov NCT04327206.

Keywords: COVID-19; immunology; infectious diseases; microbiology; virology.

Publication types

Clinical Trial Protocol
Research Support, Non-U.S. Gov't

MeSH terms

BCG Vaccine*
COVID-19*
Health Personnel
Humans
Multicenter Studies as Topic
Randomized Controlled Trials as Topic
SARS-CoV-2
Treatment Outcome
Vaccination

Substances

BCG Vaccine

Associated data

ClinicalTrials.gov/NCT04327206