Study: BCG Vaccine Increased Risk of Severe COVID-19 in Certain Populations

The bacille Calmette– Guérin (BCG) vaccine did not lower risk of COVID-19 infection more than placebo in health care workers, according to authors of a recent study published in the New England Journal of Medicine (NEJM). Patients with BCG vaccination had a 7.6% risk of contracting severe COVID-19 in 6 months, while the risk with placebo was 6.5%.

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“The probability of any COVID-19 episode within 6 months was greater in the BCG group than in the placebo group, although the confidence interval was wide and included no difference between the 2 groups,” wrote study authors in the NEJM article.

Originally, BCG was created to target tuberculosis. However, it has immunomodulatory “off-target” effects that may protect against other infections, such as severe COVID-19. The belief was that CBG could increase protection against COVID-19 as a pathogen-specific vaccine.

Study investigators aimed to understand if the BCG-Denmark vaccine (corresponding to 2 to 8×105 colony-forming units [CFUs] of Mycobacterium bovis, Danish strain 1331; AJ Vaccines) decreased incidence and severity of COVID-19 in adult patients more than placebo. Primary outcomes were symptomatic COVID-19 and severe COVID-19 assessed at 6 months. Secondary outcomes included time to onset of COVID-19, number of COVID-19 episodes, symptom days, days off work, and complications.

The investigative team randomized a modified intention-to-treat population of 3988 participants in the international, double-blind, placebo-controlled, and multistage clinical trial BRACE study. In the study, 1703 patients received the intradermal BCG-Denmark vaccine and 1683 received a saline placebo. Participants were evaluated for primary outcomes at 6 months during a 12-month follow up.

Data showed that the adjusted estimated risk of getting symptomatic COVID-19 was 14.7% in the BCG group and 12.3% in the placebo group. Most of the 7.6% and 6.5% of participants who contracted severe COVID-19 were not hospitalized (BCG and placebo, respectively), and investigators did not observe new safety concerns.

The likelihood of having a COVID-19 episode within the 6-month assessment period was higher in the BCG group. However, BCG was associated with fewer symptom days in adults aged 60 years and older, but there was not a significant difference between symptom days in participants aged 40 to 59 years, or those younger than age 40 years.

In addition, BCG patients with preexisting conditions were likely to experience a greater number of symptom days than those in the placebo group; they also had a higher probability of severe or symptomatic COVID-19 as well, so “the results did not exclude the possibility of an increased risk,” study authors wrote in the article.

The study authors noted that limitations of the study included the inability to recruit the planned sample size and reduced observation time, which makes the study susceptible to error. The study authors also noted that the definitions of “severe” and “symptomatic” COVID-19 could be limited and were different from more traditional definitions. Additionally, the study included blinding.

“It is important that our findings are not extrapolated beyond the effect of BCG-Denmark vaccine on COVID-19 in health care workers,” study authors wrote. “Several studies show beneficial off-target effects of the BCG vaccine in other situation.”

Reference

Pittet L, Messina N, Orsini F, et al. Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers. N Engl J Med. 2023. doi:10.1056/NEJMoa2212616