A world-leading international trial into the immune boosting benefits of a tuberculosis vaccine has found it does not protect healthcare workers against COVID-19.

The BRACE trial, led by the Murdoch Children’s Research Institute with collaborators including the University of Exeter, tested whether the BCG vaccine could protect healthcare workers against SARS-CoV-2. The trial found the vaccine did not reduce the risk of developing COVID-19 among those on the pandemic frontline.

BCG was originally developed to prevent tuberculosis and is still given to more than 130 million babies worldwide each year for that purpose.

The BRACE trial was built on previous research, which showed BCG also boosted ‘front-line’ immunity in infants and protected against respiratory infections in adolescents and adults. It was hoped the vaccine could be repurposed to buy crucial time in a pandemic like COVID-19 until disease-specific vaccines were developed and tested.  

The research, published in the New England Journal of Medicine and based on the second stage of the BRACE randomised controlled trial, involved 3,988 of the almost 7,000 healthcare workers who signed up across 36 sites in Australia, the Netherlands, UK, Spain and Brazil. University of Exeter in the UK, UMC Utrecht in the Netherlands, and the Oswaldo Cruz Foundation in Brazil helped to oversee the international arms of the trial. In the UK, the trial was delivered in collaboration with the Exeter Clinical Trials Unit.

The risk of symptomatic COVID-19 was 14.7 per cent in the BCG group and 12.3 per cent in the placebo group during the first six months after joining the trial. The research could not determine whether the vaccine reduced hospitalisations or death due to the low numbers of participants with severe COVID-19. 

Murdoch Children’s and the University of Melbourne Professor Nigel Curtis, Chief Principal Investigator of BRACE, said symptomatic COVID-19 being observed slightly more frequently in the BCG group might be explained by stronger immune responses induced by the vaccine.

“When we analysed the immune cells from our healthcare workers, we saw that the BCG vaccine induces a more robust immune response to COVID-19,” he said

“Symptoms reflect the immune system working hard to fight the virus. A stronger response could be beneficial in killing the virus more rapidly and protecting against progression to more severe disease. There was some evidence of this in trial participants over the age of 60, where COVID-19 symptoms were shorter in the BCG-vaccinated group.”

The trial also found amongst those who had COVID-19, the BCG group was less likely to be confined to a bed for three days compared to the placebo group.

Professor Curtis said because COVID-19 vaccines were developed and rolled out at lightning speed and healthcare workers prioritised, less participants developed severe disease. The low case numbers meant the team was unable to investigate whether BCG protected against hospitalisation and death from COVID-19, he said.

A Murdoch Children’s led study, published in Clinical & Translational Immunology earlier this year using blood samples from BRACE participants, showed that the BCG vaccine did provide a protective immune response against the SARS-CoV-2 virus.

University of Exeter Professor John Campbell, who led the UK arm of BRACE, said the trial represented an important opportunity to test the potential for BCG to protect against COVID-19.

“The findings raise important questions about how BCG can modify the course of a range of viral illnesses and allows us to develop a fuller understanding of whether the vaccine can provide protection against a range of infections other than its main target, tuberculosis.”

Oswaldo Cruz Foundation’s Dr Julio Croda said the majority of COVID-19 symptomatic cases were recorded in the Brazil trial arm.

“This demonstrates the high burden of the disease in Brazil during the entire pandemic,” he said. Although BCG does not protect against symptomatic COVID-19, we will also use the data to assess whether BCG protects healthcare workers for latent tuberculosis infection. An open question, especially for populations at high risk of acquiring the disease.”

Professor Curtis said trials of this size and complexity normally took about eight to 12 months to organise and recruit, but BRACE was able to start within three weeks due to the dedicated researchers and support teams at the Murdoch Children’s, together with generous philanthropic support.

“This trial highlights the importance of large-scale randomised controlled trials to test hypotheses and evaluate the effectiveness of new or repurposed drugs or vaccines,” he said. The importance of this was highlighted early in the pandemic by The Director General of the World Health Organization Tedros Ghebreyesus who stressed the need for the BCG vaccine to be given only in the context of clinical trials.”

Professor Curtis said trial data analysis was ongoing with further results on the effect of BCG expected later this year, including the impact of the vaccine on other infections, such as respiratory illnesses and the effect on COVID-19 vaccine responses. The trial team is also using blood samples collected from participants to discover biomarkers for COVID-19 risk.

BRACE trial donations included a $AU18 million grant from the Bill & Melinda Gates Foundation, $AU700,000 from Sarah and Lachlan Murdoch, $AU400,000 from The Royal Children’s Hospital Foundation, $AU1.5 million from The Minderoo Foundation, $AU200,000 from the South Australian Government and $AU250,000 from UK Peter Sowerby Foundation.

The publication is entitled ‘Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers’ New England Journal of Medicine. Authors are Laure F. Pittet, Nicole L. Messina, Francesca Orsini, Cecilia Moore, Rhian Bonnici, Marc Bonten, John Campbell, Julio Croda, Margareth Dalcolmo, Susie Germano, Kaya Gardiner, Casey Goodall, Amanda Gwee, Richard Hall, Tenaya Jamieson, Bruno Jardim, Tobias R Kollman, Marcus VG Lacerda, Katherine J. Lee, Michaela Lucas, David J. Lynn, Ellie McDonald, Laurens Manning, Craig F. Munns, Suellen Nicholson, Susan Perlen, Kirsten P. Perrett, Cristina Prat Aymerich, Peter Richmond, ‪Jesus Rodriguez-Baño, Glauce dos Santos, Jia Wei Teo, Patricia Vieira da Silva, Paola Villanueva, Adilia Warris, Nicholas J. Wood, Andrew Davidson, Nigel Curtis and the BRACE trial Consortium Group.