Veterans’ Study Looks at Effects of Infant Vaccination in Adulthood
Click to Expand: Risk ratios and 95% confidence intervals for the association of BCG vaccination in infancy with mortality among COVID-19 cases from the U.S. Department of Veterans Affairs, 2020–21, after variable levels of adjustment for potential confounders
MONTREAL — At an earlier point in the COVID-19 pandemic, hopes were raised that the BCG (Bacillus Calmette-Guérin) vaccine, which stimulates innate immunity, could provide protection against SARS-CoV-2.
In fact, several studies claimed to have identified an association between the vaccine—commonly used against tuberculous in some smaller countries but not the United States—and decreases in the risk of SARS-CoV-2 infection in adulthood and the severity of COVID-19.
That research was trying to explain why low- and middle-income countries (LMICs) —at that point—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. One suggestion was 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.
Now, two new studies were unable to support that position.
The first involved U.S. military veterans and was led by researchers from the VA Northern California Health Care System in Martinez, CA, and the School of Public Health at the, University of California in Berkeley, CA.
“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,” the authors wrote in Human Vaccines and Immune Therapeutics. “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.”1
The articles pointed out that some of the ecologic epidemiological studies supporting an effect from the BCG vaccine were “primarily hypothesis-generating, given their well-known limitations in extrapolating to the individual-person level.”
That’s why the team conducted what was principally a case-control study of COVID-19 infections with a retrospective cohort study of mortality nested within the infections. Anonymized VA records were used to do that.
For the study, the 263,039 controls were a random sample of veterans not recorded as having had COVID-19. Those were compared to 167,664 COVID-19 cases, of whom 5,016 patients died.
No Evidence of Protection
Researchers used a combination of country and year of birth as a surrogate for infant BCG vaccination. “The study did not support the hypothesis that BCG in infancy was protective against COVID-19,” the authors wrote. “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.”
“In summary, in this, the first study involving people born in many LMICs to examine whether there is a protective effect of BCG administration in infancy against COVID-19 in adulthood, we found no evidence to support or confirm study hypotheses of protection against infection and mortality,” the authors explained. “However, our results may have been influenced to some extent by misclassification of whether subjects received BCG vaccination in infancy. Such exposure misclassification would have pushed both odds ratios and risk ratios toward the null value, potentially obscuring a protective effect. Further investigation might be undertaken with another large dataset containing a substantial number of COVID-19 cases, but with more definitive data on BCG vaccination status in infancy.”
Another study, conducted in Quebec, Canada, involved patients with a positive SARS-CoV-2 nucleic acid amplification test performed at two hospitals between March-October 2020. Included were those born in Quebec between 1956 and 1976 and whose vaccine status was accessible in a computerized registry of 4.2 million BCG vaccinations.
In the study published in Vaccine, of the 920 cases and 2,123 controls recruited, 54% of cases (n = 424) and 53% of controls (n = 1,127) had received BCG during childhood (OR: 1.03; 95% CI: 0.89-1.21). About 12% of cases (n = 114) and 11% of controls (n = 235) had received two or more BCG doses (OR: 1.14; 95% CI: 0.88-1.46). 2
Results indicated that, after adjusting for age, sex, material deprivation, recruiting hospital and occupation, no evidence of protection conferred by BCG against SARS-CoV-2 (AOR: 1.01; 95% CI: 0.84-1.21) was found. Among cases, 77 (8.4%) needed hospitalization and 18 (2.0%) died. Those vaccinated with BCG “were as likely as the unvaccinated to require hospitalization (AOR: 1.01, 95% CI: 0.62-1.67) or to die (AOR: 0.85, 95% CI: 0.32-2.39),” according to the researchers, who add, “BCG does not provide long-term protection against symptomatic COVID-19 or severe forms of the disease.”
- Bates MN, Herron TJ, Lwi SJ, Baldo JV. BCG vaccination at birth and COVID-19: a case-control study among U.S. military Veterans. Hum Vaccin Immunother. 2021 Oct 13:1-8. doi: 10.1080/21645515.2021.1981084. Epub ahead of print. PMID: 34643480.
- Pépin J, Labbé AC, Carignan A, Parent ME, Yu J, Grenier C, Beauchemin S, De Wals P, Valiquette L, Rousseau MC. Does BCG provide long-term protection against SARS-CoV-2 infection? A case-control study in Quebec, Canada. Vaccine. 2021 Aug 11:S0264-410X(21)01039-2. doi: 10.1016/j.vaccine.2021.08.019. Epub ahead of print. PMID: 34493410; PMCID: PMC8354805.
