Morbidity and mortality attributable to COVID-19 is devastating global health systems and economies. Bacillus Calmette Guérin (BCG) vaccination has been in use for many decades to prevent severe forms of tuberculosis in children. Studies have also shown a combination of improved long-term innate or trained immunity (through epigenetic reprogramming of myeloid cells) and adaptive responses after BCG vaccination, which leads to non-specific protective effects in adults. Observational studies have shown that countries with routine BCG vaccination programs have significantly less reported cases and deaths of COVID-19, but such studies are prone to significant bias and need confirmation. To date, in the absence of direct evidence, WHO does not recommend BCG for the prevention of COVID-19. This project aims to investigate in a timely manner whether and why BCG-revaccination can reduce infection rate and/or disease severity in health care workers during the SARS-CoV-2 outbreak in South Africa. 

These objectives will be achieved with a blinded, randomised controlled trial of BCG revaccination versus placebo in exposed front-line staff in hospitals in Cape Town. Observations will include the rate of infection with COVID-19 as well as the occurrence of mild, moderate or severe ambulatory respiratory tract infections, hospitalisation, need for oxygen, mechanical ventilation or death. HIV-positive individuals will be excluded. Safety of the vaccines will be monitored. A secondary endpoint is the occurrence of latent or active tuberculosis. Initial sample size and follow-up duration is at least 500 workers and 52 weeks. Statistical analysis will be model-based and ongoing in real time with frequent interim analyses and optional increases of both sample size or observation time, based on the unforeseeable trajectory of the South African COVID-19 epidemic, available funds and recommendations of an independent data and safety monitoring board. The study will be supported by a novel 3D lung organoid model of SARS-CoV-2 infection system that can mimic the cascade of immunological events after SARS-CoV-2 infection to determine and analyse the contribution of cellular components to the impact of BCG revaccination in this study.

Given the immediate threat of the SARS-CoV-2 epidemic the trial has been designed as a pragmatic study with highly feasible endpoints that can be continuously measured. This allows for the most rapid identification of a beneficial outcome that would lead to immediate dissemination of the results, vaccination of the control group and outreach to the health authorities to consider BCG vaccination for all qualifying health care workers.

This dataset was collected in a clinical randomised control trial under the TASK008-BCG CORONA protocol. The trial was conducted in South Africa. This trial was registered with ClinicalTrials.gov, NCT04379336.