DISCUSSION
consequent reduced hospitalisations, comorbidity, death, non-febrile, deaths
BCG VACCINE, ASYMPTOMATIC COVID-19, DISEASE, RECRUITMENT, INJECTION SITE REACTION, EVENTS, INFLUENZA
In this multi-site RCT in healthcare workers in five countries, BCG-Denmark did not reduce the occurrence of COVID-19 within 6 months compared with placebo. It is notable that the risk of an episode of COVID-19 was increased in BCG-vaccinated participants, although the confidence interval around this estimate was wide and crossed zero. In elderly participants and those without a comorbidity, however, episodes were shorter in those in the BCG group.Previous studies investigating the ability of BCG vaccine to protect against COVID-19 in adultsThe inconsistent results from these and other trials of BCG’s off-target effects are likely explained by a number of factors, including: differing study designs; varying age (infants, adults, elderly), sex distribution and proportion of previously BCG-vaccinated participants; use of different BCG strains (with varying CFUs/dose)Off-target effects of BCG are proposed to, at least in part, be underpinned by epigenetic modifications in immune cells which induce a pro-inflammatory state and stronger cytokine responses to subsequent challenge with unrelated pathogens.In our trial, over three-quarters of participants had previously received a BCG vaccine. It has been proposed that the off-target effects of BCG vaccination might be greater in those who have previously received the vaccine compared with those who are BCG-naïve.Strengths of our trial include its design, larger size, recruitment in 36 sites across 3 continents, blinding of group allocation, stringent COVID-19 case definitions, close active follow-up of participants with daily data collection during illnesses, 3-monthly serology tests, 98% follow-up rate and statistical analysis accounting for COVID-19-specific vaccination.Main limitations of our trial were the inability to recruit the planned sample size and reduced participant observation time for the primary analysis resulting from the earlier-than-expected availability of COVID-19-specific vaccines. This means the trial was underpowered and susceptible to type II error, and therefore it is possible that BCG increases the risk of COVID-19. Another limitation is that the trial definition of severe COVID-19 differed to that more widely used in COVID-19 studies, which commonly includes only hospitalisations and deaths. Over 90% of participants categorised as severe COVID-19 were captured solely by virtue of being ‘too sick to go to work’ (71%) or ‘unable to get out of bed’ (22%) for ≥3 consecutive days. The effect on severe COVID-19 as more commonly defined by hospitalisation or death could not be meaningfully analysed due to the infrequency of these events. The possibility that BCG induces a more robust immune response that leads to more symptomatic disease, but more rapid clearance of SARS-CoV-2 and consequent reduced hospitalisations and deaths therefore could not be assessed. Another limitation was that our definition of symptomatic COVID-19 was confined to the original case definition which did not include non-febrile episodes without respiratory symptoms. Finally, blinding is a challenge in BCG trials, even with a placebo, due to the injection site reaction that develops in most people. This limitation was mitigated by informing participants that BCG vaccination does not always cause a reaction so that group allocation could not be inferred from the absence of a reaction/scar, using objective primary outcomes and blinding study staff involved with data collection and analysis. However, participant presumption of allocation group might have influenced adherence to COVID-19 control measures, decisions to get influenza or COVID-19-specific vaccines, self-reporting of symptoms or SARS-CoV-2 testing.In summary, BCG-Denmark vaccination did not reduce, and possibly increased the likelihood of COVID-19 in healthcare workers. Any effect on severe disease as defined by hospitalisation or death could not be assessed. A differential treatment effect of BCG vaccination was found in the duration of COVID-19 episodes in relation to age and presence of comorbidity in post-hoc analyses. It is important that our findings are not extrapolated beyond the effect of BCG-Denmark on COVID-19 in healthcare workers. Several studies report beneficial ‘off-target’ effects of BCG in other situations, particularly infants in high- mortality settings