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.
Keywords: BCG; COVID-19; SARS-CoV-2; Veterans; case-control study; off-target effects; retrospective cohort study.
PLAIN LANGUAGE SUMMARYLow- and middle-income countries (LMICs) have appeared to be much less affected by the COVID-19 pandemic, caused by the SARS-CoV-2 virus, than might have been expected from the effects of the virus in more-developed countries. It has been suggested that BCG vaccination of infants against tuberculosis in LMICs might be providing cross-protection against COVID-19. BCG has never been routinely administered in the United States and is not currently administered in most other developed countries.Some epidemiology studies, known as “ecologic” studies have provided support for the idea that BCG is protecting against COVID-19. However, ecologic studies, with group (i.e., country) measures of exposure and health outcomes, are difficult to interpret in terms of cause and effect.More interpretable are studies that use individual-person measures of exposure and health outcome. We carried out such a study using data from several hundred-thousand U.S. military Veterans, many of whom were born in LMICs and would have received BCG vaccination as infants. Many U.S. Veterans have had COVID-19, and many of those have died of it.Our study, the first of its kind, found no evidence to support the idea that infant BCG vaccination protects against infection or death from COVID-19.