The BCG Vaccine & COVID-19OVERVIEW
The bacillus Calmette-Guérin (BCG) vaccine, best known for its role in helping to prevent tuberculosis infection, also
appears to protect recipients from a variety of non-tuberculosis-related infections, including respiratory infections,as seen in global studies. Further, two recent studies suggest that the impact of COVID-19 is more severe—with
more illness and more death—in countries that do not routinely administer the BCG vaccination to their populations.
For this reason, the BCG vaccine is now being investigated in Australia and Europe to protect individuals at high-riskof serious COVID-19 infection, such as the elderly and healthcare workers. A trial in Boston is also underway to test
BCG in healthcare workers at risk for COVID-19 infection.

WHAT IS THE BCG VACCINE?
BCG is a live, attenuated (“weakened”) bacterial vaccine. It contains a strain ofbacteria called Mycobacterium bovis (a relative of the bacteria responsible fortuberculosis in humans) that has been weakened so that it cannot cause diseasein people with a healthy immune system. Instead, it prompts the immune
system to prepare for a protective response against future infection. BCG
has historically been given as a vaccination to prevent tuberculosis infection.
Since the introduction of the BCG vaccine in 1921, it has been the most widely
administered vaccine in the history of medicine. BCG is typically considered
to be very safe. It is on the World Health Organization’s Model List of Essential
Medicines for both adults and children, and it is given to roughly 100 million
children per year globally, typically in places where there may be a high risk oftuberculosis.

WHY DO WE THINK BCG COULD PROTECT FROM COVID-19 INFECTION AND COMPLICATIONS?
A large body of data suggests that BCG vaccination may have broad benefits beyond the prevention of tuberculosis,
including protection from respiratory infections that are unrelated to tuberculosis, as well as a reduced risk of deathfrom such infections. In addition, new and very preliminary data suggests that large-scale BCG vaccination may havea role in preventing COVID-19 illness and death, and may explain the variability in COVID-19 infection and outcomesseen across borders and age groups (Figure 1).
Collectively, these studies highlight the potential of the BCG vaccine to protect against diverse diseases, including,possibly, COVID-19.
Figure 1. Association between BCG vaccinationand death from COVID-19. Countries that have
not had a universal BCG policy currently have thehighest number of COVID-19 cases and deaths permillion inhabitants. Deaths per million inhabitants
are shown here. (Source: Miller A, et al. Correlation
between universal BCG vaccination policy andreduced morbidity and mortality for COVID-19:
an epidemiological study. MedRxiv. 2020.
Reprinted with permission.)

Lower middle income countries
with universal BCG policy

Upper middle income and high income
countries with universal BCG policy

Upper middle income and high income
countries that never had universal BCG policy

1BCG WORKS DIFFERENTLY THAN VACCINES BEING DESIGNED TO TARGET COVID-19 DIRECTLY
Historically, vaccine design has involved the identification of the “perfect” antigen that generates long-term,
infection-specific immune responses and provides protective immunity upon reencounter with the same diseasecausing agent later. However, this approach can take months to years to develop, and has yet to lead to a successful
vaccine against coronaviruses. Another approach may be to more broadly boost the immune system to fightinfection, by triggering a form of “non-specific” immune memory, called trained immunity, which can arm cells
against broad range of infectious diseases.
BCG appears to trigger this form of immunity. Multiple clinical trials have demonstrated the beneficial “off target”
effects of BCG as it relates to infections. For example, in a randomized study, BCG vaccination induced trained
immunity in healthy adults who were exposed to an attenuated strain of the yellow fever virus. In newborn
children, BCG vaccination provides protection not only against tuberculosis, but also against viral infections of therespiratory tract and against neonatal sepsis—while also significantly reducing mortality. BCG vaccination also has
been shown to alter the immune system so that it produces white blood cells that provide enhanced protection
against pulmonary infection.
EVIDENCE OF HETEROLOGOUS PROTECTIVE EFFECTS OF BCG AGAINST VIRAL INFECTIONS IN HUMANS.
Virus		Setting

ExampleComments

RSV (Respiratory syncytial virus)

Guinea-BissauFewer RSV infections inBCG-vaccinated childrenChildren 0-5 years oldInfluenza

Netherlands

Enhanced antibody titers against Healthy adult volunteers
the 2009 pandemic influenza A(H1N1) vaccine strain

Unspecified respiratory viruses

SpainFewer hospitalizations due toChildren 0-15 years old
respiratory infections and sepsis

COVID-19

GlobalFewer cases in countries withlongstanding universal BCGvaccination policies

All ages

Long-term effects of vaccines on innate immune function. Upon vaccination, the innate immune system becomes activated by the vaccine. The stimulationof innate immunity can lead to long-term effects leading to an increase response to a (nonrelated) infection. For example, BCG vaccination leads to trainingof innate immunity and a more effective host immune response, accompanied by a reduced mortality, as a result of nonrelated infections.

CONCLUSIONS
BCG’s safety profile, ease of administration and demonstrated potential
to prevent respiratory infections make it an ideal candidate to test as
an agent for protection against COVID-19 infection and subsequent
complications. Multiple clinical trials as well as retrospective studies ofBCG and COVID-19 are underway. The data from these trials will help us
understand the role of BCG in current and future pandemics.

CONTACT INFORMATION
For more information about ourBCG trial programs (including
COVID-19 and type 1 diabetes)or to support our research, pleasecontact us:
Immunobiology Lab,
Massachusetts General Hospital
Bld 149, 13th Street, Rm 3602
Charlestown, MA 02129
Diabetestrial@partners.org

REFERENCES
A full list of references can be found at www.bcgandautoimmunity.org

617-726-4084

www.faustmanlab.org

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