Project Summary/ Abstract BCG can induce epigenetic changes in the innate immune system with non-specific memory characteristics, termed `trained immunity', associated with enhanced immune responses to heterologous infections and vaccines. We hypothesize that the enhanced immunity induced by BCG vaccination will provide protection for high-risk individuals against COVID-19 and other viral respiratory infections. This hypothesis will be assessed by conducting a Phase II double blind, randomized, placebo (vehicle)-controlled clinical trial of BCG Tokyo 172-1 (BCG-Japan) vaccine for the prevention of COVID-19 in healthcare workers (HCWs at high-risk for infection. BCG-Japan is one of the most potent formulations of BCG vaccine demonstrating relatively high microbial viability and human innate immune activation, and offering robust protection against TB and multiple off-target infections. This study will test the hypothesis that administration of BCG-Japan vaccine to HCWs at high-risk for infection will enhance innate antiviral immunity to reduce the risk for SARS-CoV-2 .infection and/or severity of COVID-19. Two thousand and eight hundred (2,800) eligible volunteer HCWs will be randomly assigned to either a placebo vaccination or BCG-Japan, conducted at Brigham & Women's Hospital and up to four additional clinical sites. Subjects will be monitored for two years with assessments for viral illness and serological and molecular monitoring for SARS-CoV-2. A subset of subjects will be intensively studied using a suite of systems biology analyses, which will be integrated with clinical data to gain insight into the impact of BCG on human immunity in relation to SARS-CoV-2 infection and/or incidence or severity of COVID. Overall this aspect will provide information regarding how BCG may reshape the human blood and nasal mucosal compartments in a manner that may correlate with protection against SARS-CoV-2 infection and/or incidence and severity of COVID.