An international trial has investigated the potential immune-boosting effects of the tuberculosis BCG vaccine against COVID-19. The results show that the risk of developing the disease during the first six months after vaccination was not reduced in participants as originally hoped for. Nearly 4,000 healthcare workers took part in the BRACE trial across 36 sites from five countries, including the Germans Trias Hospital. Researchers from IGTP's tuberculosis research groups were involved in the development of the study, which has been published in the New England Journal of Medicine.

The Bacillus Calmette-Guerin (BCG) vaccine, primarily developed to prevent tuberculosis, is administered to over 130 million babies worldwide each year. Despite some studies suggesting that BCG may enhance immunity against other respiratory infections in adolescents and adults, the World Health Organization did not endorse its use for COVID-19 at the onset of the pandemic, citing a lack of evidence regarding its efficacy. To address this uncertainty, the BRACE trial started in March 2020 to test the efficacy of the BCG vaccine in protecting against COVID-19, at a time when no vaccines specifically for this coronavirus were available.

This double-blind, placebo-controlled trial involved 3,988 healthcare workers, a highly exposed group, across 36 centres and hospitals in Australia, Brazil, the UK, the Netherlands, and Spain. It was led by the Murdoch Children's Research Institute (MCRI) in Melbourne and brought to Europe with the support of the Bill & Melinda Gates Foundation and coordinated by the University Medical Centre (UMC) in Utrecht.

In the fall of 2020, the Germans Trias i Pujol University Hospital (HUGTiP), along with five other Spanish hospitals, joined the clinical trial. This Can Ruti institution contributed 46 participants who underwent regular check-ups every three months, with a survey and a blood sample collection. The final visits concluded in July 2021, marking the end of a 12-month follow-up period which was adhered to by 95% of the participants.

The Germans Trias i Pujol University Hospital and Research Institute (IGTP) collaborated in this project, which had a strong multidisciplinary component. The trial involved the Pulmonology and Preventive Medicine services, and the Hospital Pharmacy and Multipurpose Clinical Research (UPIC) units at HUGTiP, in conjunction with the Innovation in Respiratory Infections and Tuberculosis Diagnosis research group at IGTP.

"This is a large size, international trial that highlights the importance of testing proposed interventions through carefully designed randomised trials, even in the midst of a pandemic. The hypothesis was worth to be evaluated in such a critical situation while maintaining a rigorous methodology. The setting up was quite challenging, spanning five countries across three continents. Both the data and samples collected are very important in terms of allowing a better understanding of BCG response." explains Dr. Cristina Prat-Aymerich, co-leader of an IGTP research group dedicated to tuberculosis and head of the Respiratory and Mycobacterial Infection section in the Microbiology service at HUGTiP, currently on leave from this position and working in UMC Utrecht, the Netherlands.

The recent study published in the New England Journal of Medicine analyses the results of the second stage of the trial. Researchers found that BCG vaccination did not reduce the incidence of COVID-19. In fact, it increased the risk of symptomatic disease during the first six months following enrolment in the trial, which was 14.7% in the BCG group compared to 12.3% in the placebo group, a difference deemed not statistically significant.

The increase in symptomatic COVID-19 among those vaccinated with BCG could possibly be due to a stronger immune response to the virus, but it is unclear whether this had any impact on protection against severe cases or re-infections. Interestingly, older participants who were vaccinated had shorter illness durations, hinting at potentially more efficient virus clearance.

Recruitment for the trial was stopped prematurely and follow-up period was reduced, which affected the number of episodes recorded. Consequently, the lack of significant difference between the studied groups could be caused by the trial not being powerful enough to detect a real effect - a phenomenon sometimes referred to as a 'type 2 error' in statistics.

Dr. Antoni Rosell, clinical director of the Thorax Institute at HUGTiP, states that "very few people in the trial were hospitalised or died, so the trial could not test whether BCG reduced the risk of severe types of COVID-19. This is partly due to the earlier-than-expected availability of COVID-19 vaccines (with health care workers prioritised) leading to recruitment stopping before target number was reached as well as shorter follow-up period."

Although the BCG vaccine did not protect against symptomatic COVID-19, this research provides valuable insights into the immune response to the virus and the potential benefits and drawbacks of repurposing existing vaccines. Dr José Domínguez, co-leader of an IGTP research group, is positive about the future. "There remains strong evidence that BCG protects against tuberculosis and has important beneficial effects against other infections in infants. The trial allowed to further explore the safety of revaccination in adults and soon will be reported whether BCG protected against infections other than SARS-CoV-2."

The BRACE Trial Consortium Group will continue to analyse data and will share further results on the impact of the BCG vaccine on other infections and the effect on COVID-19 vaccine responses later this year.