Preliminary study finds countries with BCG vaccine programs have lower Covid-19 mortality

Preliminary research examining country-specific trends suggests a link between vaccination against tuberculosis and protection from severe Covid-19, and researchers say clinical trials are needed to confirm the association.

In an analysis published Thursday in the Proceedings of the National Academy of Sciences, researchers showed a correlation between higher tuberculosis vaccination rates by country with the bacillus Calmette-Guerin (BCG) vaccine and lower rates of mortality from Covid-19.

Countries with stronger BCG vaccination policies tended to have significantly lower Covid-19 deaths per million population. Countries with BCG programs in place for many years had lower Covid-19 death rates than countries with no BCG vaccination programs or interrupted vaccination programs.

The analysis was conducted by researchers with the National Institute of Allergy and Infectious Diseases (NIAID) and Virginia Polytechnic Institute and State University.

Social, economic and demographic differences between countries have been shown to have a profound effect on Covid-19 mortality, with variables such as older populations and urbanization associated with higher death rates.

Lead researcher Carolina Barillas-Mury, MD, PhD, said higher standard of living, as measured by the human development index (HDI), is also consistently associated with higher Covid-19 mortality.

“We were puzzled by the observation that Covid-19 related deaths were higher in developed countries with higher HDI, but these are also countries that have eradicated tuberculosis and often no longer have BCG vaccination programs.”

After factoring country-specific variables associated with higher Covid-19 mortality into their modeling, researcher Carolina Barillas-Mury, MD, PhD, and colleagues, identified 22 socially similar countries, including 14 socially similar countries in Europe, in an effort to control for these differences.

They also limited their analysis to deaths per million during the first 30 days after the first fatality was reported in a given country, in an effort to control for time of arrival of the pandemic.

In an interview with BreakingMED, Barillas-Mury, who serves as chief of the NIAID Laboratory of Malaria and Vector Research, said tuberculosis coverage in the 14 socially similar European countries ranged from a 75-years of universal vaccination in Ukraine (highest coverage) to no history of BCG vaccination at all in Italy, the Netherlands and Belgium (lowest coverage).

Barillas-Mury explained that the U.S., Canada and certain Western European countries have no universal TB vaccination programs, but most other countries do, with vaccination typically occurring at birth.

She said there is extensive evidence in vaccinated children that BCG vaccination confers some protection from other, non-TB respiratory and viral infections, possibly by training the immune system to respond to dangerous organisms.

“The immune system becomes more vigilant to other infections that might occur because it has experienced an assault (BCG vaccination),” she said.

The analysis showed a strong correlation between a BCG index developed by the researchers to estimate the degree of universal vaccination in an area, and Covid-19 deaths in European countries with similar socioeconomic conditions and differing TB vaccination policies.

The mean Covid-19 mortality rate in Western Europe was close to 10-times higher than in Eastern Europe, where universal BCG vaccination programs are more prevalent and have been in place for decades.

Of the 14 socially similar European countries, Ukraine, Poland and Hungary, in Eastern Europe, had the fewest Covid-19 deaths per million population in the month after the first deaths were reported in those countries, and Italy, the Netherlands, Sweden and Switzerland had the most deaths per million.

Barillas-Mury and colleagues wrote that while a consistent association was shown in the analysis between BCG vaccination and reduced Covid-19 severity, it is “not sufficient to establish causality between BCG vaccination and protection from severe Covid-19.”

Several ongoing clinical trials, including one in Holland and another in Australia, are currently exploring whether BCG vaccination can confer protection against Covid-19 in at-risk health care workers.

The researchers noted that if the BCG protection hypothesis is confirmed, “it would have great implications for regions with ongoing universal vaccination programs, including most developing countries, as they may experience lower morbidity and mortality during the pandemic than in Europe and North America.”

“Our understanding of the biology of innate immune training is in its infancy,” the researchers wrote. “Little is known about the capacity of BCG vaccination to confer broad immune enhancement and the functional correlates of protection. Our inability to confirm the null hypothesis of no effect of BCG on Covid-19 mortality could be explained by an alternative hypothesis of cross-protection mediated by BCG vaccination.”

Study limitations included the epidemiological design, with “important sampling biases.” The researchers added that country level data may not explain Covid-19 mortality at a local level.

“The possibility that a single exposure to an attenuated pathogen during infancy could result in lifelong enhancement in immune surveillance is remarkable, but the available epidemiological data, in the absence of direct evidence from clinical trials, is not sufficient to recommend the use of BCG for the control and prevention of Covid-19 or other emerging infectious diseases,” they concluded.

  1. Preliminary research examining country-specific trends suggests a link between vaccination against tuberculosis and protection from severe Covid-19.
  2. Countries with stronger BCG vaccination policies tended to have significantly lower Covid-19 deaths per million population.

Salynn Boyles, Contributing Writer, BreakingMED™

The researchers declared no funding source nor competing interests associated with this study.


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