Late in the US pandemic, multi-dose BCG vaccines protect against COVID-19 and infectious diseases

The Bacillus Calmette-Guérin vaccine has many off-target benefits, including protection from diverse infectious diseases. As SARS-CoV-2 evolved, COVID-19 disease became more transmissible and less lethal. In this Phase III double-blinded, placebo-controlled trial conducted late in the pandemic, we tested at-risk US adults with type 1 diabetes if multi-dose BCG protected against COVID-19 and other infectious disease, co-primary outcomes. From April 2021 to November 2022, Tokyo-strain BCG vaccines provided significant protection against COVID-19 disease (p = 0.023) and strong platform protection against all infectious diseases (p < 0.0001). Over the course of the study, commercial COVID-19 vaccines were rolled out, most of which were mRNA-based. In contrast to the protection afforded by BCG, as reported by others, COVID-19 mRNA vaccine alone provided no protection from COVID-19 disease (p = 0.43). BCG vaccination efficacy was unaffected by concurrent COVID-19 vaccinations; COVID-19 vaccines neither helped nor hindered BCG protection.