BCG vaccination at birth and COVID-19: a case-control study among U.S. military Veterans

In the early stages of the COVID-19 global pandemic, caused by the SARS-CoV-2 virus, low- and middle-income countries (LMICs) appeared to be experiencing lower morbidity and mortality rates than high-income countries, particularly the United States. Various suggestions put forward to account for this included the possibility that LMICs might be experiencing off-target benefits of infant vaccination with BCG, intended primarily to protect against tuberculosis. A number of ecologic epidemiological studies that considered COVID-19 morbidity and mortality rates across countries appeared to support this suggestion. Ecologic studies, however, are primarily hypothesis-generating, given their well-known limitations in extrapolating to the individual-person level. The present study, which employed anonymized records of U.S. Military Veterans treated by the Department of Veterans Affairs was principally a case-control study of COVID-19 infections with a retrospective cohort study of mortality nested within the infections. Controls were a random sample of Veterans not recorded as having had COVID-19. There were 263,039 controls and 167,664 COVID-19 cases, of whom 5,016 died. The combination of country and year of birth was used as a surrogate for infant BCG vaccination. The study did not support the hypothesis that BCG in infancy was protective against COVID-19. The odds ratio for infection was 1.07 (95% confidence interval [CI]: 1.03, 1.11) and the risk ratio for mortality among the COVID-19 cases was 0.86 (95% CI: 0.63, 1.18). The potential for non-differential exposure misclassification was a concern, possibly biasing measures of association toward the null value.