BCG Vaccine Does Not Protect Healthcare Workers Against COVID-19: Results from International Trial
A large international trial has found that the bacille Calmette–Guérin (BCG) vaccine, which is used to prevent tuberculosis, does not protect healthcare workers against COVID-19. The multisite, double-blind, randomized, controlled trial involved healthcare workers in five countries and found that vaccination with BCG-Denmark did not result in a lower risk of COVID-19 within six months than placebo. In fact, the risk of an episode of COVID-19 was higher in the BCG group than in the placebo group, although the confidence interval around this estimate was wide and crossed zero.
The trial had two primary outcomes: the incidence of symptomatic COVID-19 and the incidence of severe COVID-19 by six months after randomization. The Supplementary Appendix, which can be accessed at NEJM.org, contains comprehensive explanations of the primary and secondary outcomes. In brief, symptomatic COVID-19 was defined, in accordance with the case definition used internationally at the start of the trial, as an episode of illness with fever or at least one symptom of respiratory disease (including sore throat, cough, and shortness of breath) and evidence of SARS-CoV-2 infection on PCR assay, rapid antigen test, or serologic test. Severe COVID-19 was defined as an episode of illness with evidence of SARS-CoV-2 infection (on PCR assay, rapid antigen test, or serologic test) plus at least one of the following as a consequence of COVID-19: death, hospitalization, or severe disease without hospitalization (defined, for the purpose of this trial, as being confined to bed or unable to work for ≥3 consecutive days, not resulting from quarantine or other restrictions).
In prespecified subgroup analyses, there was little evidence that the treatment effect differed across most of the subgroups. With respect to the influence of previous BCG vaccination, the results are consistent with the possibility of a greater risk of severe COVID-19 in the BCG group than in the placebo group among participants who had not previously received BCG vaccination but not among those who received BCG revaccination. The probability of symptomatic or severe COVID-19 by six months appeared to be slightly higher in the BCG group than in the placebo group among participants with cardiovascular disease, those with hypertension, and those with chronic respiratory disease. In the sex subgroup analysis, although there was minimal evidence of an interaction between sex and the effect of BCG vaccination, the disease-free survival curves separated earlier in the male subgroup than in the female subgroup.
The inconsistent results from this and other trials of the off-target effects of the BCG vaccine are probably explained by a number of factors, including differing study designs; varying age (infants, adults, and older adults), sex distribution, and proportion of participants who had previously received BCG vaccine; use of different BCG strains (with varying CFUs or dose) and number of doses; and different periods before pathogen exposure. Further investigation is warranted for all of these factors. The effects induced by BCG may differ depending on the pathogen.
It is important to note that the findings of this trial should not be extrapolated beyond the effect of BCG-Denmark vaccine on COVID-19 in healthcare workers. Several studies show beneficial off-target effects of the BCG vaccine in other situations, particularly among infants in high-mortality geographic settings, and ongoing research is examining potential underlying immunologic mechanisms.
Overall, this trial provides important information on the potential use of the BCG vaccine for COVID-19 prevention and highlights the need for further research to better understand the factors that influence its effectiveness.
0. “BCG vaccine does not protect against COVID-19 in health care workers, finds clinical trial” Medical Xpress, 26 Apr. 2023, https://medicalxpress.com/news/2023-04-bcg-vaccine-covid-health-workers.html
1. “Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers | NEJM” nejm.org, 26 Apr. 2023, https://www.nejm.org/doi/full/10.1056/NEJMoa2212616