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Although recent reports indicate that three vaccine candidates are effective against SARS-CoV-2, more time is needed to generate enough doses for the general population. Meanwhile, frontline healthcare workers are at high risk of SARS-CoV-2 exposure. To avoid collapse of the medical care system, there is a need to develop novel approaches to limit SARS-CoV-2 spread. Through a process called trained immunity, the Bacillus Calmette-Guerin (BCG) vaccine boosts the action of innate immune cells, resulting in a nonspecific reduction in the incidence of viral infections. Due to this immunomodulatory action, the BCG vaccine is currently used as a therapeutic in bladder cancer. Data collected from epidemiological and observational studies indicate that BCG vaccination might provide protection against COVID-19. While these observations do not provide evidence of causality and are limited by cofounding and intrinsic biases, it is crucial to explore the hypothesis that BCG vaccination may provide a nonspecific innate immune boost and therefore protect against COVID-19 in randomized controlled clinical trials, particularly for people at higher risk of developing COVID-19, such as frontline healthcare workers.<\/jats:p>","DOI":"10.3233\/blc-201529","type":"journal-article","created":{"date-parts":[[2021,2,23]],"date-time":"2021-02-23T13:13:58Z","timestamp":1614086038000},"page":"121-131","source":"Crossref","is-referenced-by-count":1,"title":["Rationale for Randomized Clinical Trials Investigating the Potential of BCG Vaccination in Preventing COVID-19 Infection"],"prefix":"10.1177","volume":"7","author":[{"given":"Magali","family":"Noval Rivas","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Division of Infectious Diseases and Immunology, Infectious and Immunologic Diseases 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