Last updated on September 9th, 2020 at 10:51 am
I originally wrote this article about the BCG vaccine for coronavirus about three months ago (that’s about 10 years in non-pandemic time measurement). Of course, as things happen with the coronavirus pandemic, ideas keep returning, and I wanted to make sure that this article is up-to-date with the most recent information about whether the BCG vaccine has any usefulness in preventing or improving outcomes of COVID-19.
I wanted to see if there was any evidence supporting the BCG vaccine for coronavirus, so here’s what I found.
All about the BCG vaccine
Before we jump into this, we should talk about the vaccine itself.
The Bacillus Calmette-Guerin vaccine, or BCG vaccine, was initially developed to prevent tuberculosis. That disease is caused by a bacteria called Mycobacterium tuberculosis. The bacteria usually attack the lungs, but they can also damage other parts of the body. Tuberculosis is treatable with advanced medicines, but it takes a long time and can be expensive. Without treatment, the patient will die.
The BCG vaccine is one of the oldest vaccines available on the market, first used in 1921 (pdf). With the successful eradication of tuberculosis in many countries, the vaccine isn’t used very much anymore, except in countries with endemic tuberculosis. It is still given to about 100 million children every year.
The BCG vaccine works like most vaccines – it is made from an attenuated, live bovine tuberculosis bacillus, Mycobacterium bovis which induces an adaptive immune response against tuberculosis bacterium.
At this point, you’re wondering why this vaccine is still around or important. Well, it seems it has some other purposes.
- There is some very preliminary, but promising, research that the BCG vaccine may help reverse type 1 diabetes. We’re a long way from knowing if it will work, but it is encouraging for researchers looking for a “cure” for type 1 diabetes.
- The BCG vaccine is one of the most successful immunotherapies for some forms of cancer. In fact, the vaccine is the “standard of care with bladder cancer,” specifically for non-muscle-invasive bladder cancer (NIMBC), since about 1977. The vaccine seems to treat and prevent the recurrence of NIMBC. Unfortunately, low supplies of the BCG vaccine have caused a shortage of the vaccine for cancer patients. (Because it wasn’t clear to some, the BCG vaccine is not a vaccine against bladder cancer, it is part of the immunotherapy for the disease – the vaccine is injected directly into the bladder.)
- The vaccine has also been evaluated as a therapy for colorectal cancer. It is being evaluated as an adjuvant to autologous colorectal cancer cells for the treatment of stage II colon cancer. Moreover, a number of other cancer vaccines undergoing development use the BCG vaccine as an adjuvant to provide an initial stimulation of the patient’s immune system.
- In a secondary analysis of a BCG vaccination trial, conducted between 1935-1938 (yes, 1935-38), of 2,963 American Indian/Alaskan Native children age <20 in five states, researchers found BCG vaccine group had a significantly lower rate of lung cancer, after adjusting for a variety of confounders including tobacco smoking history, alcohol abuse, and sex of participants. The BCG vaccine group had approximately 18.2 cases per 100,000 person-years compared to 45.4 cases for the placebo group. That is a 2.5X reduction in the risk of lung cancer. However, there are a lot of concerns about this study, and I don’t think that we’re close to being a standard of care for lung cancer.
- There is some preliminary evidence that the BCG vaccine may reduce the incidence of Alzheimer’s disease. The researchers showed that, among bladder cancer patients, patients who did not receive the BCG vaccine therapy had a 4.7X higher risk of Alzheimer’s disease compared to those who did.
Scientists aren’t sure why the vaccine is effective against some cancers (and please don’t assume that it works as a treatment for the hundreds of other cancers). It is possible that the BCG vaccine stimulates the immune system in such a way that it causes it to attack the bladder cancer. But more research is necessary to determine the mechanisms, which could help improve it for cancer therapy.
Ironically, the vaccine has a very wide range of effectiveness, and we probably should develop a better vaccine. Since it’s mostly used for children in underdeveloped countries, there probably isn’t much incentive to improve it. That’s sad.
BCG vaccine for COVID-19
Despite all of the evidence regarding some amazing clinical uses for the vaccine, how did we get to the point that some people are pushing the BCG vaccine for COVID-19?
This hypothesis was based on a rather simple observation. Dr. Gonzalo Otazu from New York Institute of Technology, College of Osteopathic Medicine stated that:
We found that there was a reduction in the number of deaths attributed to COVID-19 per million inhabitants in countries that have universal BCG vaccination (usually at birth) compared to the countries that never established such policy. The earlier the establishment of such policy, the stronger the reduction in mortality, consistent with a protection to the elderly population which is more severely affected by COVID-19.
Now, there’s a lot to criticize in that statement. I am always uncomfortable with population-level statistics that can be misused. Anti-vaccine activists love to make specious claims comparing the number of vaccines and some random effects between countries while ignoring hundreds of confounding variables.
But with a lot of desperation surrounding the coronavirus, observations like this can lead to interesting hypotheses, which is what we’ve got here. No one thinks that the BCG vaccine is a guaranteed slam dunk to either prevent or treat COVID-19, but this is the start.
What is the biological plausibility that the BCG vaccine for coronavirus might work?
We need to go back to the pre-print from Dr. Otazu:
Several vaccines including the BCG vaccination have been shown to produce positive“heterologous” or non-specific immune effects leading to improved response against other non-mycobacterial pathogens.
For instance, BCG vaccinated mice infected with the vaccinia virus were protected by increased IFN-Y production from CD4+ cells. This phenomenon was named ‘trained immunity’ and is proposed to be caused by metabolic and epigenetic changes leading to promotion of genetic regions encoding for pro-inflammatory cytokines.
BCG vaccination significantly increases the secretion of pro-inflammatory cytokines, specifically IL-1B, which has been shown to play a vital role in antiviral immunity.
In other words, the BCG vaccine may induce certain parts of the immune system to produce more cytokines, which are important to signal the growth and maturation of numerous cells that are part of the immune system’s responses to pathogens.
It is well understood that a cytokine storm was probably responsible for the high mortality during the 1918 flu pandemic. A cytokine storm results from large numbers of white blood cells are activated and release inflammatory cytokines, which in turn activate yet more white blood cells. This can be dangerous.
However, the BCG vaccine does not cause a cytokine storm (or we would have noticed it during the last 100 years of its use).
Thus, there are some plausible reasons why this vaccine might work, but we really need clinical trials to tell us.
BCG vaccine for coronavirus clinical trials
Assistance Publique – Hôpitaux de Paris
Vaccine candidate: BCG vaccine
Status: Phase 3 clinical trial
Clinical trial identifier: NCT04384549
Clinical trial institution: Cochin Hospital, APHP, Paris, France, 75014
Study design: A double-blinded, randomized, placebo-controlled clinical trial with 1120 participants.
Clinical trial status: Will begin May 2020
Date of completion: February 2021
Bandim Health Project
Vaccine candidate: BCG vaccine
Status: Phase 3 clinical trial
Clinical trial identifier: NCT04373291
Clinical trial institution: University of Southern Denmark; Odense, Denmark
Study design: A patient-blinded, randomized clinical trial with 1500 participants.
Clinical trial status: Will begin May 2020
Date of completion: January 2021
Murdoch Children’s Research Institute
Vaccine candidate: BCG vaccine
Status: Phase 3 clinical trial
Clinical trial identifier: NCT04327206
Clinical trial institution: Epworth Victoria Parade, Melbourne, Victoria, Australia; Royal Children’s Hospital, Melbourne, Victoria, Australia; Epworth Richmond, Melbourne, Victoria, Australia
Study design: An open-label, two-group, phase III randomized controlled trial in up to 4170 healthcare workers.
Clinical trial status: Began March 2020, recruiting patients
Date of completion: October 2020
This clinical trial is not for a COVID-19 specific vaccine, but for another vaccine that may prevent or reduce the complications from the disease. The BCG vaccine is one of the oldest vaccines available on the market, first used in 1921 (pdf). With the successful eradication of tuberculosis in many countries, the vaccine isn’t used very much anymore, except in countries with endemic tuberculosis. It is still given to about 100 million children every year.
The BCG vaccine works like most vaccines – it is made from an attenuated, live bovine tuberculosis bacillus, Mycobacterium bovis which induces an adaptive immune response against tuberculosis bacterium. The vaccine is used to treat bladder cancer and may have some usefulness in reversing type 1 diabetes.
Because the BCG vaccine is already on the market, researchers can utilize it in phase 3 clinical trials.
TASK Applied Science
Vaccine candidate: BCG vaccine
Status: Phase 3 clinical trial
Clinical trial identifier: NCT04379336
Clinical trial institution: TASK Foundation Recruiting; Cape Town, Western Cape, South Africa
Study design: A randomized, double-blind clinical trial with 500 healthcare workers.
Clinical trial status: Will begin May 2020
Date of completion: April 2021
Texas A&M University
Vaccine candidate: BCG vaccine
Status: Phase 3 clinical trial
Clinical trial identifier: NCT04348370
Clinical trial institution: Texas A&M University, College Station, TX; Baylor College of Medicine, Houston, TX; The University of Texas MD Anderson Cancer Center, Houston, TX; Cedars-Sinai Medical Center, Los Angeles, CA.
Study design: A randomized, double-blinded, placebo-controlled trial including 1500 participants.
Clinical trial status: Not yet recruiting
Date of completion: November 2021
UMC Utrecht
Vaccine candidate: BCG vaccine
Status: Phase 3 clinical trial
Clinical trial identifier: NCT04328441
Clinical trial institution: Jeroen Bosch ziekenhuis, Den Bosch, Brabant, Netherlands; Canisius Wilhelmina Ziekenhuis, Nijmegen, Gelderland, Netherlands; Radboud UMC, Nijmegen, Gelderland, Netherlands; Sint Maartenskliniek, Nijmegen, Gelderland, Netherlands; Noordwest Ziekenhuisgroep locatie Alkmaar, Alkmaar, Noord Holland, Netherlands; Hagaziekenhuis, Den Haag, Zuid-Holland, Netherlands; Leiden University Medical Center, Leiden, Zuid-Holland, Netherlands; Erasmus Medical Center, Rotterdam, Zuid-Holland, Netherlands; University Medical Center Utrecht, Utrecht, Netherlands.
Study design: A placebo-controlled, adaptive multi-centre randomized controlled trial.
Clinical trial status: Began March 2020, recruiting patients
Date of completion: October-December 2020
Similar to the study described above, this clinical trial is examining whether the BCG vaccine has any effect on the prevention or treatment of COVID-19.
Universidad de Antioquia
Vaccine candidate: BCG vaccine
Status: Phase 3 clinical trial
Clinical trial identifier: NCT04362124
Clinical trial institution: Program for Research and Control in Tropical Diseases – PECET; Medellín, Antioquia, Colombia
Study design: A multicenter, double-blind, randomized, phase III clinical trial, 1000 healthcare workers divided into two groups (vaccine and placebo) using a 1: 1 allocation ratio.
Clinical trial status: Began March 2020, recruiting patients
Date of completion: November 2021
Vakzine Projekt Management GmbH
Vaccine candidate: VPM1002, an improved BCG vaccine
Status: Phase 3 clinical trial
Clinical trial identifier: NCT04387409
Clinical trial institution: FGK Clinical Research GmbH
Study design: A multicenter, double-blind, randomized, phase III clinical trial that will include 1200 healthcare workers.
Clinical trial status: Recruiting patients beginning in May 2020
Date of completion: June 2021
BCG vaccine for coronavirus study
A new study, published in the Proceedings of the National Academy of Sciences (PNAS), by Luis Escobar et al., examined whether the BCG vaccine, when it is routinely given to children in countries with high rates of tuberculosis infection, might play some role in reducing mortality rates from COVID-19.
The researchers collected coronavirus mortality data from around the world. From that data, the team adjusted for various confounders, such as income, access to education and health services, population size and densities, and age distribution. They found a correlation held showing that countries with higher uptake of BCG vaccinations had lower peak mortality rates from COVID-19.
One of the more interesting bits of data in the research was what the saw with the data from Germany. The country had different vaccine schedules for East and West Germany prior to the country’s unification in 1990. West Germany provided BCG vaccines to infants from 1961 to 1998, whereas East Germany started their BCG vaccinations a decade earlier, but stopped in 1975.
This meant that older East Germans, which, of course, is the population most at risk from COVID-19, would have more protection from the current pandemic than the same cohort in western German states. This research showed that western German states have experienced mortality rates that are 2.9 times higher than those in eastern Germany.
This is one of those studies that may show correlation, but I don’t know if it establishes causation. That’s why we have clinical trials.
Summary
We don’t know if the BCG vaccine for coronavirus will have any effect on the disease. We don’t know if it will prevent an infection from the SARS-CoV-2 virus or improve outcomes.
There is some intriguing population-level evidence that those who have received the vaccine are at lower risk from COVID-19. We have a large body of evidence that the BCG vaccine has several non-specific effects that could induce the immune system to attack the SARS-CoV-2 virus.
We will get some information about whether the BCG vaccine will work for COVID-19 well before we have any other vaccine to prevent the disease. The BCG vaccine for COVID-19 is a much better bet than that ridiculous chloroquine fantasy. So we’ll see.
Citations
- BCG vaccines: WHO position paper – February 2018. Vaccins BCG: Note de synthèse de l’OMS – Février 2018. Wkly Epidemiol Rec. 2018;93(8):73–96. Published 2018 Feb 23.
- Escobar LE, Molina-Cruz A, Barillas-Mury C. BCG vaccine protection from severe coronavirus disease 2019 (COVID-19). Proc Natl Acad Sci U S A. 2020 Jul 9:202008410. doi: 10.1073/pnas.2008410117. Epub ahead of print. PMID: 32647056.
- Gofrit ON, Klein BY, Cohen IR, Ben-Hur T, Greenblatt CL, Bercovier H. Bacillus Calmette-Guérin (BCG) therapy lowers the incidence of Alzheimer’s disease in bladder cancer patients. PLoS One. 2019;14(11):e0224433. doi: 10.1371/journal.pone.0224433. eCollection 2019. PubMed PMID: 31697701; PubMed Central PMCID: PMC6837488.
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