BACILLUS CALMETTEGUÉRIN VACCINATION TO PREVENT SERIOUS RESPIRATORY TRACT INFECTION AND COVID-19 IN VULNERABLE ELDERLY - AN ADAPTIVE RANDOMIZED CONTROLLED TRIAL (BCG-PRIME)'

Rationale: On March 11 2020 the World Health Organization (WHO) declared the coronavirus (SARS-CoV-2) outbreak a pandemic. Worldwide, the number of confirmed cases continues to rise, leading to significant morbidity and mortality. In the Netherlands, although the incidence is currently low due to social distancing measures, recurrence of infections is expected once measures are going to be lifted. Although individuals of any age can acquire SARS-CoV-2, adults of middle and older age are at highest risk for developing severe COVID-19 disease. Moreover, recent reports demonstrate that mortality rates rise significantly among patients 60 years and older. Therefore, strategies to prevent SARS-CoV-2 infection or to reduce its clinical consequences in vulnerable populations are urgently needed. Bacille Calmette-Guérin (BCG) vaccine not only protects against tuberculosis, but also induces protection against various respiratory infections, including those with a viral etiology. We hypothesize that BCG vaccination reduces clinically relevant respiratory tract infections requiring medical intervention, including COVID-19, in vulnerable elderly. Objective: To determine the impact of BCG vaccination on the incidence of clinically relevant respiratory infections or COVID-19 in vulnerable elderly. Study design: An adaptive multi-center double-blind randomized placebo-controlled trial. Study population: 5,200 to 7,000 vulnerable elderly, defined as =60 years of age being discharged from hospital in the last 6 weeks, or visiting a medical outpatient clinic, thrombosis care services, or chronic renal replacement departments. Patients with contraindications to BCG vaccination as stipulated in the Summary of Product Characteristics (SPC) and patients with a history of COVID-19 will be excluded. Intervention: Participants will be randomized between intracutaneous administration of BCG vaccine (Danish strain 1331) or placebo (0.1ml 0.9% NaCl) in a 1:1 ratio. Main study parameters/endpoints: The trial has an adaptive primary endpoint. Based on accrual of the two endpoints, the primary endpoint will be either (a) COVID-19 or (b) clinically relevant respiratory tract infection requiring medical intervention, potentially including COVID-19 episodes. The other will be declared secondary endpoint. Other secondary endpoints include: all SARS-CoV-2 infections (including asymptomatic infections), influenza infection, acute respiratory infection (ARI; all infections regardless of medical intervention), ARI-related hospital admission, COVID-19 related hospital admission, pneumonia, mental, physical and social functioning, serious adverse events and adverse events, and death. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Based on previous experience in published and ongoing randomized controlled trials in adults and elderly, the risks of BCG vaccination are considered negligible. Vaccination could cause local pain, suppuration and scarring at the site of injection. The size of the trial will ensure rapid availability of results that can inform policy-making during the ongoing pandemic and may be of benefit for participants that received no intervention, as well as individuals who did not participate in the trial.