ACTIVATE-2: A Double-Blind Randomized Trial of BCG Vaccination Against COVID-19 in Individuals at Risk

Abstract

In a recent study of our group with the acronym ACTIVATE, Bacillus Calmete-Guérin (BCG) vaccination reduced the occurrence of new infections compared to placebo vaccination in the elderly. Most benefit was found for respiratory infections. The ACTIVATE-2 study was launched to assess the efficacy of BCG vaccination against coronavirus disease 2019 (COVID-19). In this multicenter, double-blind trial, 301 volunteers aged 50 years or older were randomized (1:1) to be vaccinated with BCG or placebo. The trial end points were the incidence of COVID-19 and the presence of anti–severe acute respiratory syndrome coronavirus 2 (anti–SARS-CoV-2) antibodies, which were both evaluated through 6 months after study intervention. Results revealed 68% relative reduction of the risk to develop COVID-19, using clinical criteria or/and laboratory diagnosis, in the group of BCG vaccine recipients compared with placebo-vaccinated controls, during a 6-month follow-up (OR 0.32, 95% CI 0.13-0.79). In total, eight patients were in need of hospitalization for COVID-19: six in the placebo group and two in the BCG group. Three months after study intervention, positive anti–SARS-CoV-2 antibodies were noted in 1.3% of volunteers in the placebo group and in 4.7% of participants in BCG-vaccinated group. These data indicate that BCG vaccination confers some protection against possible COVID-19 among patients older than 50 years with comorbidities. BCG vaccination may be a promising approach against the COVID-19 pandemic.

Trained immunity — basic concepts and contributions to immunopathology

“…These analyses also demonstrated that BCG had a cross-protective effect against C. albicans and Staphylococcus aureus infections for at least 3 months after vaccination. A 6-month follow-up phase III placebo-controlled randomized clinical trial of BCG vaccination against SARS-CoV-2 demonstrated a 68% relative reduction in the risk of developing COVID-19 in older individuals 6 months after vaccination compared with those in the placebo group 32 . Another study demonstrated that BCG induces an increase in the peripheral blood mononuclear cell production of TNF and IL-1β after LPS stimulation in vitro 1 year after vaccination compared with pre-vaccination levels, which supports the sustained training effects of BCG vaccination 33 .…”

Beneficial non-specific effects of live vaccines against COVID-19 and other unrelated infections

“…By contrast, a Greek RCT showed protective effects of BCG in older adults. 63 The lack of effect in some RCTs could be related to a lack of previous BCG vaccination and the rapid implementation of COVID-19 vaccines. Importantly, all RCTs suggested a beneficial effect of BCG on overall survival ( table 3 ).…”

“…Ongoing RCTs are testing whether live attenuated vaccines reduce the incidence of COVID-19. 62 , 63 , 64 However, the non-specific effects of live attenuated vaccines might have little effect on the risk of infection but change the severity of infection. For example, RCTs of BCG administered to newborn babies found little effect on hospital admissions for sepsis, but the case fatality was reduced by 42% (95% CI 6–65%).…”

Spurious early ecological association suggesting BCG vaccination effectiveness for COVID-19

“…As of March 2021, there were more than two dozen clinical trials underway across the globe to evaluate whether BCG protects against COVID-19. Completed assessments to date include a case-control study [ 8 ] that did not demonstrate effectiveness and an unpublished RCT [ 9 ] conducted in elderly patients in Greece claiming effectiveness that is limited by small sample size and high loss to follow-up. In the interim, we aimed to evaluate whether the early ecologic findings that BCG appeared to protect against COVID-19 persisted as the pandemic progressed.…”