The effect of BCG vaccination on infection and antibody levels against SARS-CoV-2—The results of ProBCG: a multicenter randomized clinical trial in Brazil

•Bacillus Calmette-Guérin (BCG) could be effective against SARS-CoV-2 based on the concept of trained immunity.•COVID-19 vaccines and BCG can enhance the immune response represented by immunoglobulin G levels.•The cumulative incidence of COVID-19 was smaller in BCG-vaccinated participants.•Immunoglobulin G levels tend to be higher and longer in the group submitted to BCG vaccination. Evatuate if Bacillus Calmette-Guérin (BCG) vaccine could be used as a tool against SARS-CoV-2 based on the concept of trained immunity. A multicenter, double-blinded, randomized clinical trial recruited health care workers (HCWs) in Brazil. The incidence rates of COVID-19, clinical manifestations, absenteeism, and adverse events among HCWs receiving BCG vaccine (Moreau or Moscow strains) or placebo were compared. BCG vaccine-mediated immune response before and after implementing specific vaccines for COVID-19 (CoronaVac or COVISHIELD) was analyzed. Cox proportional hazard and linear mixed effect modeling were used. A total of 264 volunteers were included for analysis (BCG = 134 and placebo = 130). The placebo group presented a COVID-19 cumulative incidence of 0.75% vs 0.52% of BCG. The Moreau strain also presented a higher incidence rate (1.60% × 0.22%). BCG did not show a protective hazard ratio against COVID-19. In addition, the log (immunoglobulin G) level against SARS-CoV-2 presented a higher increase in the BCG group, whether or not participants had COVID-19, but also without statistical significance. Our results suggest that BCG has a tendency of protection against SARS-CoV-2 and higher immunoglobulin G levels than placebo. The clinical trial was registered at https://clinicaltrials.gov/ (NCT04659941).