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

Background BCG vaccination prevents severe childhood tuberculosis (TB) and was introduced in South Africa in the 1950s. It is hypothesised that BCG trains the innate immune system by inducing epigenetic and functional reprogramming, thus providing non-specific protection from respiratory tract infections. We evaluated BCG for reduction of morbidity and mortality due to COVID-19 in healthcare workers in South Africa. Methods This randomised, double-blind, placebo-controlled trial recruited healthcare workers at three facilities in the Western Cape, South Africa, unless unwell, pregnant, breastfeeding, immunocompromised, hypersensitivity to BCG, or undergoing experimental COVID-19 treatment. Participants received BCG or saline intradermally (1:1) and were contacted once every 4 weeks for 1 year. COVID-19 testing was guided by symptoms. Hospitalisation, COVID-19, and respiratory tract infections were assessed with Cox proportional hazard modelling and time-to-event analyses, and event severity with post hoc Markovian analysis. This study is registered with ClinicalTrials.gov, NCT04379336. Findings Between May 4 and Oct 23, 2020, we enrolled 1000 healthcare workers with a median age of 39 years (IQR 30-49), 70.4% were female, 16.5% nurses, 14.4% medical doctors, 48.5% had latent TB, and 15.3% had evidence of prior SARS-CoV-2 exposure. Hospitalisation due to COVID-19 occurred in 15 participants (1.5%); ten (66.7%) in the BCG group and five (33.3%) in the placebo group, hazard ratio (HR) 2.0 (95% CI 0.69-5.9, p= 0.20), indicating no statistically significant protection. Similarly, BCG had no statistically significant effect on COVID-19 (p= 0.63, HR = 1.08, 95% CI 0.82-1.42). Two participants (0.2%) died from COVID-19 and two (0.2%) from other reasons, all in the placebo group. Interpretation BCG did not protect healthcare workers from SARS-CoV-2 infection or related severe COVID-19 disease and hospitalisation. Copyright (c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)