Reducing COVID-19 burden: could Bacille Calmette-Guérin (BCG) vaccines confer protection?

By Pooja Toshniwal PahariaReviewed by Lily Ramsey, LLMMay 1 2023

In a recent study in The New England Journal of Medicine, researchers performed a randomized controlled trial (RCT) to investigate whether Bacille Calmette-Guérin (BCG) vaccines could lower coronavirus disease 2019 (COVID-19) burden among healthcare workers.

Study: Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers. Image Credit: BernardChantal/Shutterstock.com

Background

BCG vaccines have been known to prevent the target disease, tuberculosis, for decades. The vaccine's immunomodulatory 'off-target' effects may confer protection against unrelated infections, including those caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Previous studies have reported that BCG vaccines may lower respiratory disease risks among teenagers and adult individuals and lower mortality risks among newborns.

About the study

In the present international phase 3 RCT, researchers evaluated BCG Vaccination to Reduce the Impact of COVID-19 on Healthcare Workers (BRACE) effects.

The double-blinded and placebo-controlled multicenter trial included healthcare workers who were randomized in a 1:1 ratio to receive 0.10 ml intradermal injections of Bacille Calmette-Guérin-Denmark vaccines (equivalent to 2.0 to 8.0 ×10⁵ colony-forming units of the 1,331 Danish strain of Mycobacterium bovis) or normal saline as a placebo.

During the one-year follow-up, the participants filled out questionnaires every three months concerning SARS-CoV-2 symptoms and any associated illnesses that developed. The primary study outcomes were the incidence rates of symptomatic and/or severe SARS-CoV-2 infections.

The primary analysis involved the modified intention-to-treat (ITT) population, limited to individuals with SARS-CoV-2-negative test results at baseline. Secondary study outcomes were the number of days to COVID-19 onset, COVID-19 episodes, symptomatic COVID-19 duration, duration of being bedridden or unable to work, COVID-19-associated adverse events (AEs) and complications, and asymptomatic infections.

The complications included pneumonia, hospitalization, critical care unit admission, mechanical ventilation, oxygen supplementation, and death. The primary and secondary outcomes were evaluated after six months of randomization.

All participants provided blood samples at study initiation, three months, six months, nine months, and twelve months post-randomization to determine antibody titers against the nucleocapsid (N) protein of SARS-CoV-2.

In addition, in Brazil, the SARS-CoV-2 polymerase chain reaction (PCR) was performed using respiratory swabs obtained from the participants.

The trial was conducted in two stages: in the initial stage, individuals were recruited between March 2020 and May 2020 in Australia; in the subsequent stage, individuals were recruited between May 2020 and April 2021 across Australia, Spain, the Netherlands, Brazil, and the United Kingdom (UK).

The team excluded individuals with prior SARS-CoV-2-positive test reports; individuals contraindicated for BCG vaccination; individuals who were administered BCG vaccines in the previous year; individuals who received live-attenuated vaccines in the previous month; individuals who received any COVID-19 vaccines; and individuals who participated in any other trial on COVID-19 prevention.

Results and conclusions

In total, 3,988 individuals underwent randomization; recruitment ceased before attaining the initially decided sample population (7,244 individuals) due to COVID-19 vaccine availability.

The modified ITT population included 85% of the randomized participants: 1,703 and 1,683 individuals in the vaccine recipient group and placebo recipient group, respectively. Among the participants, 74% were women, and the mean participant age was 42.0 years.

At six months, in the modified ITT population, symptomatic SARS-CoV-2 infection occurred among 132 BCG vaccine recipients and 106 placebo recipients. At six months, the estimated risk of symptomatic SARS-CoV-2 infection was 15% among BCG vaccinees and 12% among placebo recipients (2.40 percent point-risk difference).

Severe SARS-CoV-2 infection occurred among 75 vaccinees and 61 placebo recipients, with risk estimates of 7.60% among BCG vaccinees and 6.50% among placebo recipients (1.10-percent point risk difference).

Most participants satisfying the severe SARS-CoV-2 infection definition were not hospitalized but could not resume their jobs for ≥3.0 consecutive days. The sensitivity analysis and supplementary analysis findings showed relative risk differences.

The analyses included results from rapid antigen testing and PCR only (no serologic data) and analysis that didn't consider SARS-CoV-2-specific vaccines. The adjusted hazard ratio (aHR) for any SARS-CoV-2 infection episode following BCG vaccination compared to the placebo receipt was 1.2. Five individuals had COVID-19-associated hospitalizations in each group (and a placebo recipient died).

In the sensitivity analysis based on rapid antigen testing and PCR results (aHR 1.4) and the analysis not accounting for SARS-CoV-2-specific vaccinations (aHR 1.2), increased follow-up times yielded more accurate estimates, indicating no significant differences in the study groups. BCG vaccines were considered safe for administration.

In total, 30.0 serious-type adverse events (AEs) were reported, of which BCG vaccinees reported 20. However, besides a painful abscess at the injection site and lethargy, no serious AEs were considered related to the BCG vaccination.

Post-hoc analysis findings indicated that among individuals aged ≥60.0 years, the BCG vaccinees had fewer symptomatic days compared to the placebo recipients [incidence rate ratio (IRR) of 0.3].

Among individuals without comorbidities, BCG group individuals had fewer symptomatic days than the placebo recipients (IRR 0.7), whereas, among individuals with comorbidities, placebo recipients had fewer days with symptoms (IRR 1.5).

Concerning the impact of prior BCG vaccinations, the results indicated higher risks of COVID-19 severity among BCG vaccinees than placebo recipients among individuals with no BCG vaccination history. The BCG vaccines were slightly more likely to develop symptomatic or severe SARS-CoV-2 infections at six months than placebo recipients among individuals with cardiovascular, hypertension, or chronic pulmonary diseases.

Overall, the study findings showed that vaccination with BCG-Denmark did not reduce the risk of COVID-19 among healthcare workers compared to the placebo.