Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers

Abstract

Background: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19).

Methods: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline.

Results: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified.

Conclusions: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

Figure 1. Screening and Randomization.

BCG denotes bacille Calmette–Guérin, and SARS-CoV-2 severe acute respiratory syndrome coronavirus 2.

Figure 2. Primary Outcomes.

The primary outcomes were symptomatic coronavirus disease 2019 (Covid-19) and severe Covid-19. Panels A and C show Kaplan–Meier curves with 95% confidence intervals in shaded areas (unadjusted primary analyses in the modified intention-to-treat population). Insets show the same data on an expanded y axis. In Panels B and D, forest plots show the between-group difference in the percentage of participants with symptomatic or severe Covid-19, with 95% confidence intervals (adjusted for stratification factors used in randomization; primary, sensitivity, and supplementary analyses). The widths of the confidence intervals for sensitivity and supplementary analyses have not been adjusted for multiplicity and may not be used in place of hypothesis testing. PCR denotes polymerase chain reaction, and RAT rapid antigen test.

Figure 3. Subgroup Analyses.

Subgroup analyses of the primary outcomes — symptomatic Covid-19 (Panel A) and severe Covid-19 (Panel B) — are shown with the use of forest plots of the difference in percentage points and 95% confidence intervals, with adjustment for stratification factors used in randomization. The widths of the confidence intervals have not been adjusted for multiplicity and may not be used in place of hypothesis testing. The body-mass index is the weight in kilograms divided by the square of the height in meters. We did not estimate the treatment effect within the geographic region of Australia because there were no episodes of symptomatic Covid-19 or severe Covid-19 there.