BCG vaccine protection from severe coronavirus disease 2019 (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.

Keywords: BCG vaccination policy; COVID-19 coronavirus; cross-protection; mortality; pandemic.

Fig. 1.

COVID-19 mortality, human development, and BCG vaccination policy by country. (A) Map showing the COVID-19 mortality per million inhabitants in countries worldwide. COVID-19−related deaths per country per million inhabitants denoting countries with low (yellow) to high (red) mortality. (B) COVID-19 mortality per million inhabitants (log) vs. HDI in different countries worldwide. United States data appear by state. (C) Map showing the BCG vaccination policy in countries that currently have universal BCG vaccination program (Current), countries with interrupted BCG vaccination programs (Interrupted), and countries that never implemented a universal vaccination program (Never). Countries without information appear in white.

Fig. 2.

Linkage between COVID-19 mortality and BCG vaccination. (A) Coarse analysis of COVID-19 mortality per million inhabitants in countries with current, interrupted, or that never had BCG vaccination programs. United States data appear by state. (B) Filtered analysis of COVID-19 mortality per million inhabitants in countries with current, interrupted, or that never had BCG vaccination programs and similar social, economic, and epidemic stage conditions. (C) Filtered analysis of COVID-19 mortality per million inhabitants in countries with current vs. interrupted or that never had BCG vaccination programs, including only countries with similar social, economic, and epidemic stage conditions. (D) Negative association between percentage of vaccination coverage (mean) between 1980 and 2018, as a proxy of population protection, and maximum COVID-19 deaths per million inhabitants registered by country in a day, as a proxy of COVID-19 severity. Full list of analyses is available in SI Appendix, Tables S2–S4.

Fig. 3.

COVID-19 mortality in comparable regions that have had different BCG vaccination policies. (A) COVID-19 mortality by time in populous North and South American States. (Left) COVID-19 mortality per 10 million inhabitants in a 3-d centered average. Time adjusted according to the day with the first death in each region as day 1, up to 25 d of the epidemic. (Right) Table shows population density and COVID-19 mortality by day 25 of the epidemic for each region. Regions that have had BCG vaccination (blue) had lower mortality than regions without BCG vaccination (red; r² = 0.84, P < 0.001; t [237] = 14.274, P < 0.001). (B) Estimated age range of people that received BCG vaccination in East and West Germany. (C) Map illustrating the regions of East and West Germany included in the analysis. (D) Mean COVID-19 mortality in East Germany was lower than mortality in West Germany (t [11] = −2.592, P = 0.025).

Fig. 4.

Variation in COVID-19 mortality and BCG vaccination policy in different European countries. (A) Map illustrating COVID-19 deaths per million inhabitants in European countries. (B) Map illustrating BCG vaccination policy in European countries that currently have universal BCG vaccination program (Current), countries that interrupted in the past a BCG vaccination program (Interrupted), and countries that never implemented a universal vaccination program (Never). (C) BCG index = (age of oldest vaccinated cohort × total number of years of vaccination campaign)/standardization parameter (5,625) × Mean BCG vaccination coverage. (D) Correlation between BCG index and COVID-19 mortality per million inhabitants and in European countries with different BCG vaccination policy. (E) Correlation between BCG index and COVID-19 mortality per million inhabitants during the first month of the pandemic in socially similar European countries with different BCG vaccination policy.