The FLARE Four
- The "trained immunity" hypothesis holds that a prior infection can influence the innate immune response to a new infection
- Some evidence suggests BCG vaccination can generate innate immune memory that protects against non-mycobacterial infections, but this is far from established
- Studies reporting an association between national BCG vaccination rates and COVID-19 outcomes have not been peer-reviewed and have methodologic flaws
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There's no credible evidence yet that national childhood Bacille Calmette–Guérin (BCG) vaccination programs protect against COVID-19, Vladimir Vinarsky, MD, a physician in the Division of Pulmonary and Critical Care at Massachusetts General Hospital, concludes in a fast literature update posted on April 12, 2020.
Background on the Vaccine
The World Health Organization recommends routine newborn BCG vaccination in regions of the world with a high incidence of tuberculosis. Some countries also have booster programs. Some countries have initiated these programs over the last 50 years while many others have abandoned them.
The BCG vaccine has variable efficacy against TB infection, ranging from 15% to 30% in various studies. It has higher efficacy, up to 90%, in preventing TB disease, especially in children and especially TB meningitis. The results in adults are more variable and less effective against TB infection and disease.
There's growing evidence that innate immunity, like adaptive immunity, can develop memory-like properties. The "trained immunity" hypothesis holds that a prior infection can influence the innate immune response to a new infection.
Some evidence suggests BCG vaccination can generate innate immune memory that protects against non-mycobacterial infections. However, this is far from established. Furthermore, in mouse and human studies, trained immunity has not persisted beyond several years.
BCG Vaccination and COVID-19
To date, studies reporting an association between BCG vaccination and COVID-19 outcomes appear only on online preprint servers and appear to have methodological concerns.
One study, published on medRxiv, found an inverse correlation between the duration of universal BCG vaccination program and COVID-19 mortality.
This study and others were marred by poor sourcing of vaccination data and failed to account for:
- Additional confounders, including tourism and duration of infection
- Differences in SARS-CoV-2 testing across countries
- Rise in cases as countries progress along the epidemiologic trajectory
- Differences in COVID-19 burden within each country
- Total disease burden in each country (unknown until this wave of the pandemic ends)
In the most recent study that touted positive results, published by medRxiv, the researchers tried to improve the study by adjusting for gross national product and population age in comparing 50 countries to see whether nationwide BCG immunization affected COVID-19 mortality. The researchers also corrected for the timing of the entry of SARS-CoV-2 into each country by starting analyses with the 100th reported case (but did not mention that the total number of people with the disease is unknown before the end of this wave).
The Bottom Line
It is much too early in the pandemic to analyze whether national BCG vaccination programs affect COVID-19 outcomes.
View all COVID-19 updates
Learn more about research in the Division of Pulmonary and Critical Care