DISCUSSION
infection, infections, long-term loss of smell and/or taste), SARS-CoV-2 infections
ACUTE INFECTION, SARS-COV-2 INFECTION, CNS INFECTIONS, INFECTIONS, INFECTION, REGRESSION, HIGH BLOOD PRESSURE
This is the most comprehensive analysis of a placebo-controlled BCG trial with SARS-CoV-2 endpoints to date, including both participant-reported positive tests as well as serology to identify infections and in-depth characterization of infection episodes using daily symptoms data. Serology detected an additional 74 endpoints on top of the 224 participant-reported endpoints. Unadjusted and adjusted logistic regression (cumulative incidence) and Cox proportional hazards (time-to-first-event) models showed no differences between BCG and placebo vaccination for SARS-CoV-2 infections of any severity, nor for asymptomatic, mild (subdivided into mild and very mild), or moderate infections separately. Mean infection durations and the proportions of participants with infections who developed long-COVID or long-term loss of smell and/or taste did not differ between the randomization groups either.Our findings corroborated the results of several placebo-controlled BCG trials with SARS-CoV-2 endpoints. A South African trial in HCWs (SARS-CoV-2 risk in HCWs increased with the proportion of work hours with patient contact. This suggests that the risk is mostly due to a high probability of exposure rather than a higher risk of infection once exposed. Interestingly, working in intensive or medium care unit was associated with a lower risk of infection than working in urgent care, which may be related to better infection control measures, including availability of personal protective equipment, in the former. Using antihypertensive medication was also consistently associated with higher infection risk. Patients diagnosed with high blood pressure have increased levels of angiotensin-converting enzyme 2 (ACE2), which acts as the entry receptor for SARS-CoV-2 (The BCG-Corona trial was initiated in March 2020, early in the first epidemic wave in the Netherlands, and therefore captured SARS-CoV-2 exposures and infections in an immunologically naive population. This may explain why the mean acute infection episode duration was long (15.7 days) and a substantial proportion of infected individuals developed lingering symptoms (10% long-COVID plus an additional 4% long-term loss of smell and/or taste). Studies in the United Kingdom showed that median episode duration declined as the pandemic progressed, from a median of 11 days in 2020 (The percentage of participants with SARS-CoV-2 seroconversion at month 3 (7.8% versus 2.8%; Important strengths of this trial are the large number and comprehensive nature of the endpoints. Anti-S1 antibodies are highly sensitive and specific for the presence of the SARS-CoV-2 Spike protein but are induced by both natural infection as well as COVID-19 vaccines (Supplementary background and methods. Download In conclusion, BCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (on a scale from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection, but this remains to be confirmed.