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

Caryn M Upton; Rob C van Wijk; Laurynas Mockeliunas; Ulrika S H Simonsson; Kirsten McHarry; Gerben van den Hoogen; Chantal Muller; Arné von Delft; Helene-Mari van der Westhuizen; Reinout van Crevel; Gerhard Walzl; Pedro M Baptista; Jonathan Peter; Andreas H Diacon; BCG CORONA Consortium

doi:10.1016/j.eclinm.2022.101414

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

EClinicalMedicine. 2022 Jun:48:101414. doi: 10.1016/j.eclinm.2022.101414. Epub 2022 May 12.

Authors

Affiliations

¹ TASK HQ, Cape Town 7500, South Africa.
² Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
³ TASK Eden, George, South Africa.
⁴ Department of Medicine, University of Cape Town Lung Institute and Division of Allergy and Clinical Immunology, University of Cape Town, Cape Town, South Africa.
⁵ Centre for Infectious Diseases Research in Africa, Cape Town, South Africa.
⁶ TB Proof, Cape Town, South Africa.
⁷ Radboud University Medical Center, Nijmegen, the Netherlands.
⁸ DST/NRF Centre of Excellence for Biomedical TB Research, and SAMRC Centre for TB Research, Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Francie Van Zijl Drive, Parow 7505, South Africa.
⁹ Spain and ARAID Foundation, Institute of Health Research Aragon (IIS Aragon), Zaragoza, Spain.

Abstract

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.

Funding: Funding provided by EDCTP, grant number RIA2020EF-2968. Additional funding provided by private donors including: Mediclinic, Calavera Capital (Pty) Ltd, Thys Du Toit, Louis Stassen, The Ryan Foundation, and Dream World Investments 401 (Pty) Ltd. The computations were enabled by resources in project SNIC 2020-5-524 provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, partially funded by the Swedish Research Council through grant agreement No. 2018-05,973.

Keywords: BCG; COVID-19; Pandemic; Respiratory tract infection; Trained immunity; Tuberculosis; Vaccine.

Associated data

ClinicalTrials.gov/NCT04379336