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Safety and Efficacy of BCG Re-Vaccination in Reducing COVID-19 Morbidity in Healthcare Workers: A Double-Blind, Randomised, Controlled, Phase 3 Trial
20 Pages Posted: 18 Jan 2022
More...Abstract
Background: Bacille Calmette-Guérin (BCG) vaccination prevents severe childhood tuberculosis and was in use in South Africa from the 1950’s. 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 randomized, double-blinded, placebo-controlled trial recruited healthcare workers at three facilities in the Western Cape, South Africa, unless unwell, pregnant, breastfeeding, immunocompromised, allergic, or undergoing experimental COVID-19 treatment. Participants received BCG or saline intradermally (1:1) and were contacted four-weekly for one year. COVID-19 testing was guided by symptoms. Hospitalization, COVID-19, and respiratory tract infections were assessed with Cox proportional hazard modelling and time-to-event analyses, and event severity with Markovian analysis. This study is registered at ClinicalTrials.gov, NCT04379336.
Findings: Between May 4 and October 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. Hospitalization due to COVID-19 occurred in 15 participants (1·5%); 10 (66·7%) on BCG and 5 (33·3%) on placebo, hazard ratio 2·0 (95% CI 0·69-5·9, p=0·20), indicating no significant protection. Similarly, BCG had no effect on all-cause hospitalisation (p=0·31), COVID-19 (p=0·63), or respiratory tract infections (p=0·40). Markovian modelling showed an increased probability of more severe respiratory tract infections with BCG (p=0·02). Two participants (0·2%) died from COVID-19 and 2 (0·2%) from other reasons, all on placebo.
Interpretation: BCG did not protect healthcare workers from SARS-CoV-2 infection or related severe COVID-19 disease and hospitalization.
Clinical Trial Registration: This study is registered at ClinicalTrials.gov, NCT04379336.
Funding: EDCTP, Mediclinic, Calavera Capital, Thys Du Toit, Louis Stassen, The Ryan Foundation, Dream World Investments, SNIC, Swedish Research Council.
Declaration of Interest: Authors have no conflicts of interest to declare.
Ethical Approval: The study was approved by the South African Health Products Regulatory Authority (ref: 20200402), Pharma-Ethics (ref: 200423268) and UCT Human Research Ethics Committee (ref: 237/2020).
Keywords: COVID-19, BCG, respiratory tract infection, vaccine, tuberculosis, trained immunity, pandemic
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