Ignoring quackery and Trump’s ignorance about chloroquine, it seems like everyone is throwing stuff at the wall to see if it works. Recently, while researching an article on coronavirus vaccines, I noticed that some were pushing the BCG vaccine for COVID-19.
I wanted to see if there was any evidence supporting the BCG vaccine for COVID-19, so here’s what I found.
All about the BCG vaccine
The Bacillus Calmette-Guerin vaccine, or BCG vaccine, was initially developed to prevent tuberculosis. The disease is caused by 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?
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.
As a result of these observations, the Australian Murdoch Children’s Research Institute has begun Phase 3 clinical trials, which include up to 4170 healthcare workers in an open-label, two-group, placebo-controlled, randomized trial. Because the vaccine is already approved across almost all of the world, researchers can jump straight to a phase 3 study. Preliminary results may be available by November 2020.
Additionally, the University Medical Center Utrecht in the Netherlands has registered a phase 3 study that includes up to 1000 healthcare workers in a single-blinded, randomized, placebo-controlled study. This study should be completed by December 2020, and we could have published results within a few months.
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).
We don’t know if the BCG vaccine for COVID-19 will work. 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.
- 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.
- 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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