Global review of BCG vaccine protection from severe COVID-19

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A epidemiological evidence review suggests a negative association between national bacillus Calmette–Guérin (BCG) vaccination policy and the prevalence and mortality of coronavirus disease. However, the analyses are restricted to coarse-scale signals and should be considered with caution, the authors warn.

The COVID-19 pandemic is one of the most devastating in recent history. The bacillus Calmette−Guérin (BCG) vaccine against tuberculosis also confers broad protection against other infectious diseases, and it has been proposed that it could reduce the severity of COVID-19. This epidemiological study by researchers at the Virginia Polytechnic Institute and State University and the National Institute of Allergy and Infectious Diseases at the National Institutes of Health, assessed the global linkage between BCG vaccination and COVID-19 mortality.

Signals of BCG vaccination effect on COVID-19 mortality are influenced by social, economic, and demographic differences between countries. After mitigating multiple confounding factors, several significant associations between BCG vaccination and reduced COVID-19 deaths were observed.

This study highlights the need for mechanistic studies behind the effect of BCG vaccination on COVID-19, and for clinical evaluation of the effectiveness of BCG vaccination to protect from severe COVID-19.

Abstract
A series of epidemiological explorations has suggested a negative association between national bacillus Calmette–Guérin (BCG) vaccination policy and the prevalence and mortality of coronavirus disease 2019 (COVID-19). However, these comparisons are difficult to validate due to broad differences between countries such as socioeconomic status, demographic structure, rural vs. urban settings, time of arrival of the pandemic, number of diagnostic tests and criteria for testing, and national control strategies to limit the spread of COVID-19. We review evidence for a potential biological basis of BCG cross-protection from severe COVID-19, and refine the epidemiological analysis to mitigate effects of potentially confounding factors (e.g., stage of the COVID-19 epidemic, development, rurality, population density, and age structure). A strong correlation between the BCG index, an estimation of the degree of universal BCG vaccination deployment in a country, and COVID-19 mortality in different socially similar European countries was observed (r2 = 0.88; P = 8 × 10−7), indicating that every 10% increase in the BCG index was associated with a 10.4% reduction in COVID-19 mortality. Results fail to confirm the null hypothesis of no association between BCG vaccination and COVID-19 mortality, and suggest that BCG could have a protective effect. Nevertheless, the analyses are restricted to coarse-scale signals and should be considered with caution. BCG vaccination clinical trials are required to corroborate the patterns detected here, and to establish causality between BCG vaccination and protection from severe COVID-19. Public health implications of a plausible BCG cross-protection from severe COVID-19 are discussed.

Authors
Luis E Escobar, Alvaro Molina-Cruz, Carolina Barillas-Mury

 

Proceedings of the National Academy of Sciences (PNAS) material and abstract

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