A world-leading international trial into the immune boosting benefits of the tuberculosis vaccine, BCG, has found it does not protect healthcare workers against COVID-19.
The BRACE trial, led by Murdoch Children's Research Institute, to test whether the BCG vaccine could protect healthcare workers against SARS-CoV-2 in the first six months after vaccination found it didn't 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 over 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 3988 of the almost 7000 healthcare workers who signed up across 36 sites in Australia, the Netherlands, UK, Spain and Brazil. UMC Utrecht in the Netherlands, University of Exeter in the UK and the Oswaldo Cruz Foundation in Brazil helped to oversee the international arms of the trial.
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 altered the immune response to COVID-19," he said.
"Symptoms reflect the immune system working hard to fight the virus. A stronger response induced by BCG 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, in whom COVID-19 symptoms were shorter in the BCG-vaccinated group."
Professor Curtis said because COVID-19 vaccines had been developed and rolled out at lightning speed and healthcare workers prioritised, less participants were recruited than originally envisioned. As a result, lower 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 last year using blood samples from BRACE participants, also showed that the BCG vaccine did provide an immune response consistent with protection against severe COVID-19.
University of Exeter Professor John Campbell, who led the UK arm of BRACE, said the trial represented an important opportunity to test the potential of the BCG vaccine.
"The findings raise important questions about how BCG can modify the course of different 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," he said.
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.
Publication: L.F. Pittet, N.L. Messina, F. Orsini, C.L. Moore, V. Abruzzo, S. Barry, R. Bonnici, M. Bonten, J. Campbell, J. Croda, M. Dalcolmo, K. Gardiner, G. Gell, S. Germano, A. Gomes‐Silva, C. Goodall, A. Gwee, T. Jamieson, B. Jardim, T.R. Kollmann, M.V.G. Lacerda, K.J. Lee, M. Lucas, D.J. Lynn, L. Manning, H.S. Marshall, E. McDonald, C.F. Munns, S. Nicholson, A. O'Connell, R.D. de Oliveira, S. Perlen, K.P. Perrett, C. Prat‐Aymerich, P.C. Richmond, J. Rodriguez‐Baño, G. dos Santos, P.V. da Silva, J.W. Teo, P. Villanueva, A. Warris, N.J. Wood, A. Davidson and N. Curtis for the BRACE Trial Consortium Group. 'Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers,' New England Journal of Medicine. DOI: 10.1056/NEJMoa2212616.
*The content of this communication is the sole responsibility of Murdoch Children's and does not reflect the views of the NHMRC.
