Data from: Safety and efficacy of BCG re-vaccination in relation to COVID-19 morbidity in healthcare workers: A double-blind, randomised, controlled, phase 3 trial

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.