BCG Vaccine Flops Again for COVID-19 Prevention

Another large randomized trial testing a bacillus Calmette-Guérin (BCG) vaccine as a means of thwarting COVID-19 failed to show any benefit, researchers reported.

In the multinational BRACE study, healthcare workers were just as likely to contract symptomatic COVID-19 through 6 months whether they received a BCG-Denmark vaccine or placebo shot (14.7% vs 12.3%, P=0.13), according to Nigel Curtis, MBBS, PhD, of the University of Melbourne in Australia, and colleagues.

In terms of severe illness, 7.6% of patients in the vaccine arm met the trial’s definition versus 6.5% of those in the placebo group (P=0.34), though the vast majority didn’t require hospitalization, the group wrote in the New England Journal of Medicine.

Results of the nearly 4,000-participant trial, which was primarily conducted before the widespread availability of COVID vaccines, “did not exclude the possibility of an increased risk” with the BCG vaccine, the researchers said, but they cautioned against extrapolating the findings beyond the trial parameters, given the vaccine’s known benefits.

Why test the BCG vaccine in the first place?

“In addition to protecting against its target disease, tuberculosis, the [BCG] vaccine has immunomodulatory ‘off-target’ effects that may protect against unrelated infections,” explained Curtis and colleagues.

Given past studies showing reduced deaths from any cause in infants and a reduced risk for respiratory infections in older children and adults receiving the BCG vaccine, the thinking early in the pandemic was that it could be repurposed against the novel coronavirus.

“It was hypothesized that the immunomodulatory properties of this vaccine might enhance protection against SARS-CoV-2, thus bridging the gap until pathogen-specific vaccines were available,” the authors wrote.

Their findings mirror those of another large negative trial in older adults with comorbidities, but join a host of conflicting studies involving BCG vaccination for COVID-19.

BRACE (BCG Vaccination to Reduce the Impact of COVID-19 in Healthcare Workers) was a double-blind trial conducted across 36 sites in five countries (Brazil, Australia, the U.K., the Netherlands, and Spain). A total of 3,988 participants were randomized 1:1 to either the BCG-Denmark vaccine or saline placebo. The trial was initially launched in March 2020 and continued on through April 2021, but recruitment was ultimately halted following the availability of COVID vaccines.

A modified intent-to-treat (mITT) population restricted to participants with a negative SARS-CoV-2 serologic status at baseline was used for the primary analyses, leaving 1,703 in the vaccine arm and 1,683 in the placebo arm. The primary endpoints were symptomatic COVID illness or severe disease, with the latter defined as any COVID-related hospitalization or death along with cases where patients were sick enough that they were unable to work for 3 straight days or more.

Participants in the mITT population had an average age of 43 years, about three-fourths were women, 20% had coexisting conditions (diabetes, heart disease/hypertension, or chronic respiratory disease), and 21% had obesity. Most (74%) had previously received a BCG vaccine at some point in their lives.

Through 6 months, 132 cases of symptomatic COVID-19 occurred in the BCG vaccine group compared with 106 in the placebo group, with severe cases in 75 and 61, respectively. Most participants meeting the definition of severe illness didn’t require hospitalization; however, 71% were too sick to go to work and 22% were too sick to get out of bed.

No significant differences were seen for a host of secondary outcomes, including pneumonia due to COVID-19 (seven cases in each arm) and hospitalization for COVID (five in each arm), among others. One placebo arm participant died due to COVID-19.

Between-group differences were small, but most outcomes appeared to show a slight trend favoring placebo, and the only hint of benefit with the BCG vaccine turned up in post hoc analyses: a quicker time to recovery in people 60 and older and in those without coexisting conditions.

Curtis and co-authors suggested several possible factors that may have affected the off-target effects of the BCG vaccine, including “the predominance of female participants (in whom off-target effects are proposed to differ as compared with males) and the underrepresentation of participants who had not previously received the BCG vaccine.”

There were no safety concerns identified in the trial, with serious adverse events reported in 20 participants in the BCG group and nine in the placebo group.

Main limitations cited by the researchers were the failure to fully enroll at the planned trial size, the definition used for severe COVID-19 (which now typically refers to COVID-related hospitalization or death), and the fact that blinding is difficult with the BCG vaccine due to injection-site reactions, though they attempted to mitigate this last one by telling participants that vaccination does not always cause a reaction.