A recent study published in The Latest England Journal of Medicine evaluated whether the bacilli Calmette–Guérin (BCG) vaccine could protect healthcare staff (HCWs) against coronavirus disease 2019 (COVID-19).

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

Background

The BCG vaccine has off-target immunomodulatory effects, which could moreover protect against other infections. The vaccine is related to a lower mortality risk from any cause in infants and a lower risk of respiratory infections in adults/adolescents.

Within the early COVID-19 pandemic, BCG vaccine repurposing was proposed to guard against COVID-19. The hypothesis was that the vaccine might augment protection against SARS-CoV-2 until vaccines for the pathogen were available.

Concerning the study

In the current study, researchers evaluated whether COVID-19 incidence and severity can be lower in BCG-vaccinated HCWs in a randomized controlled trial. The study was conducted in two phases.

In the primary phase, only Australian HCWs were recruited between March and May 2020. Within the second phase, HCWs were recruited from Brazil, Spain, the Netherlands, and the UK between May 2020 and April 2021.

Subjects were excluded if previously they were SARS-CoV-2-positive, immunized with the BCG vaccine up to now yr or other live-attenuated vaccines up to now month, involved in other COVID-19 trials, or had contraindications to the BCG vaccine.

Participants within the double-blind second phase were randomized to receive the BCG vaccine or a saline placebo and were followed for one yr.

The present evaluation focused on the second phase because community transmission of SARS-CoV-2 was negligible in the primary phase. Blood samples were collected at baseline and each three months after randomization for serologic testing.

Respiratory swab samples were also obtained from Brazilian HCWs for the SARS-CoV-2 reverse-transcription polymerase chain response (RT-PCR) assay.

Randomization was stratified by age group, geographic region, and the presence/absence of coexisting conditions.

A dose of 0.1 ml BCG-Denmark vaccine or placebo was intradermally injected. Primary outcomes were the incidence of symptomatic COVID-19 and severe illness at six months post-randomization.

Severe illness is a COVID-19 episode with severe disease without hospitalization or death. Secondary outcomes were asymptomatic infection, time to COVID-19 onset, variety of days with symptoms, variety of days confined to bed or absent from work, variety of COVID-19 episodes, and complications.

Findings

Within the second phase, 3,988 HCWs were randomized to receive the BCG vaccine or placebo. Baseline characteristics were similar between vaccine and placebo recipients, apart from the marginally higher proportion of females amongst placebo recipients.

Most participants (64%) were recruited in Brazil. At baseline, 14% of participants were positive for SARS-CoV-2 antibodies, and a pair of.7% of swabs from Brazilian participants were positive for SARS-CoV-2.

As such, the modified intention-to-treat population included 1,703 subjects within the BCG group and 1,683 within the placebo group. Symptomatic COVID-19 was recorded in 132 BCG recipients and 106 placebo recipients. Severe COVID-19 occurred in 75 and 61 subjects in BCG and placebo groups, respectively.

Most patients with severe illness couldn’t work for a minimum of three days. The probability of any episode of COVID-19 was higher amongst BCG recipients than placebo participants. Five hospitalizations occurred in each group. BCG recipients aged 60 or older had fewer days with symptoms than those within the placebo group.

In a subgroup of HCWs without coexisting conditions, BCG recipients had fewer days with symptoms than placebo recipients. In a subset of those with coexisting conditions, placebo recipients had fewer symptomatic days than BCG recipients.

Twenty BCG participants and nine placebo recipients reported 30 adversarial events overall. Investigators deemed all serious adversarial events as unrelated to the intervention.

Conclusions

The researchers found that the BCG vaccine didn’t reduce COVID-19 risk inside six months post-vaccination in comparison with the placebo. Notably, the COVID-19 episode(s) risk was higher in BCG recipients than in placebo subjects.

Greater than a 3rd of the participants were previously vaccinated with the BCG, and it has been suggested that off-target effects is perhaps higher in previously vaccinated subjects.

Further, it is feasible that (BCG) revaccination may not increment off-target advantages beyond those provided by the previous vaccination.

Interestingly, there was weak evidence of increased severe COVID-19 incidence within the BCG group amongst those that weren’t previously vaccinated but not in those revaccinated with BCG. In sum, BCG vaccination didn’t decrease COVID-19 risk in HCWs, and the potential for increased risk couldn’t be excluded.