The 100-year-old BCG vaccine, developed to prevent tuberculosis, may be useful in treating cancer, type 1 diabetes, and Alzheimer’s disease. Its usefulness may be expanded beyond those diseases.
I’m not saying that the BCG vaccine is some sort of miracle drug, but it seems to have some non-specific effects on the immune system which may turn it into a powerful tool for medicine.
Let’s take a look at this vaccine and its effects on other diseases (other than tuberculosis, of course).
What is this BCG vaccine?
The Bacillus Calmette-Guérin 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 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.
Tuberculosis (TB) is a leading cause of infectious disease deaths worldwide, second only to COVID. The vaccine’s development began in Lille, France in 1900, when Albert Calmette, an army physician, was working with Camille Guérin, a veterinarian, to understand how TB was transmitted.
Calmette and Guérin cultured TB bacteria on potato slices and found that after several passages of the microbes from one slice to a fresh one, they became less virulent over time. The researchers started to vaccinate calves with this live, weakened form of TB to protect cattle. By 1921, after over 200 generations of this weakened bacteria, the TB strain was stable and did not cause the disease in all animals they tested it on.
At the time of the vaccine’s development, French children born in a family in which someone had TB faced a 25 percent chance of dying from the disease within their first year of life. In 1921, Calmette and Guérin gave the first dose of BCG to a child born into a family with TB, and the child survived.
In 1924, a large clinical trial of more than 5,000 French children showed that the BCG vaccine had 93% effectiveness in preventing death in the first year of life. Based on the results of the clinical trial, France quickly adopted the vaccine, and soon thereafter, many more countries developed their version of the BCG vaccine and began mass vaccination of children.
As a result of the vaccine, tuberculosis was successfully eradicated in many countries, and the vaccine is rarely used in those countries. However, it is still given to about 100 million children every year in countries where tuberculosis is still endemic.
A 1927 trial in very young Swedish children showed that BCG reduced early-life mortality by 1931, and the benefit could not be explained by just the reduction in TB deaths. A lot of researchers of the BCG vaccine have hypothesized that the vaccine might trigger some nonspecific immunity, that is, it may protect against other causes of death.
Laboratory-based immunological studies, epidemiological studies, and clinical trials have documented that this nonspecific immunity appears to be evidence-based. The MMR vaccine for measles also seems to have a nonspecific effect on other diseases.
This nonspecific effect was used as the basis to try to use the BCG vaccine to stop COVID-19. It didn’t work, which is why we do clinical trials.
BCG vaccine and type 1 diabetes
I have written extensively about the potential of this vaccine in reversing type 1 diabetes, a disease that is currently incurable and can only be treated with regular insulin injections.
Type 1 diabetes is an autoimmune disease that is characterized by autoreactive T lymphocytes (T-cells) that destroy pancreatic islet cells, which are critical to glucose metabolism since these cells produce insulin. These lymphocytes mistakenly attack the islet cells as if they were a foreign body, as they do with a viral or bacterial infection.
Insulin is a small peptide hormone that signals cells to store insulin when blood sugars increase, usually immediately after eating. Then, in between meals, another hormone, glucagon, tells the cells to slowly release stores of glucose, which is the basic energy source for most cells.
Regulatory T-cells (which are often called Tregs) are supposed to modulate the immune system and would normally reduce the effect of an autoimmune attack. Tregs act like brakes that normally prevent mistaken attacks by the immune system, such as the autoimmune attack on the pancreatic islet cells, without affecting the whole immune system. A branch of diabetes research has hypothesized that abnormal Tregs could be the key to finding treatments to reverse type 1 diabetes.
Once the pancreatic islet cells are damaged, they can no longer produce insulin, thereby impairing control of levels of glucose in the blood. Uncontrolled blood glucose levels can lead to long-term damage to eyesight, kidneys, limbs, heart, and other organs.
The BCG vaccine induces a response in the immune system that is driven, in part, by tumor necrosis factor (TNF). Since many people think that “tumor necrosis factor” means it kills cancer, that’s not quite what it does. TNF induces an inflammatory response, it doesn’t kill tumor cells.
The vaccine’s induction of TNF has two important potential effects that may reverse type 1 diabetes – first, it causes selective death of the autoreactive T cells (which are destroying the pancreatic islet cells), and second, it causes the expansion of the beneficial Tregs. Now, both of these claims are fairly controversial, but early clinical trial results are promising.
Dr. Denise Faustman, MD Ph.D., Harvard University and Massachusetts General Hospital, has been leading this clinical research into the BCG vaccine’s effects on type 1 diabetes. The research is just entering phase 2 clinical trials, so it will be a few years before we know if the vaccine works.
Additionally, there is a compelling 2022 epidemiological study from Canada that used records from Canada’s national health registry to determine the risk of diabetes in individuals who received the BCG vaccine as a child. Even though it did not appear to reduce the risk of type 1 diabetes in adolescents, it showed that 30 years and older adults had a 35% lower risk of diabetes compared to individuals of the same age cohort who had not received the vaccine.
If the BCG vaccine can reverse or “cure” type 1 diabetes, it would be one of the greatest advances in medicine of the past 100 years (right up there with isolating insulin to treat diabetes).
Cancer
I have written previously about the BCG vaccine being used to treat bladder cancer. The BCG vaccine is one of the most successful immunotherapies for some forms of cancer. 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.
To be clear, the vaccine doesn’t destroy bladder cancer by itself, it is used as part of the immunotherapy against bladder cancer. It is hypothesized that the nonspecific immune effects help enhance the treatment of NIMBC.
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, several 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 aged <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.
Alzheimer’s disease
Although research into the effect of the BCG vaccine on the risk of Alzheimer’s disease is very early, an interesting 2019 analysis of patients who did not receive the vaccine for the treatment of bladder cancer showed a nearly 5X increased risk of developing Alzheimer’s than those who received the vaccine. To be fair, this result may be affected by confounding data, but the difference is so large, it is more than compelling.
Multiple sclerosis
In a 2014 clinical trial that used the BCG vaccine versus placebo in multiple sclerosis, an autoimmune disease that damages the myelin lining of the nerves, patients, the results showed that there was a significant reduction in damage to the myelin sheath. Depending on the type of damage, there was up to an 85% reduction in lesions on the myelin.
This is really important data that can lead to a potential reduction in damage to the nerves from the disease. Again, researchers don’t know the exact cause, but it may be similar to what the vaccine does to the immune system in diabetes.
The miracle BCG vaccine?
Because of the huge amount of research ongoing with the BCG vaccine, scientists across the world are beginning to coalesce around to considering new public health policies regarding the vaccine. If it prevents some types of cancer, prevents or reverses diabetes, reduces the risk of Alzheimer’s disease, or has other nonspecific benefits, then maybe we should consider bringing the vaccine back to areas where the vaccination has stopped.
Of course, that leads to a significant issue — supply. There is only one BCG manufacturer in the USA and there is limited supply in other countries since most of the developed world does not regularly give the vaccine. If there is a change in public health strategies with the vaccine, it could be a long time before an adequate supply is available.
Sometimes the vaccine is in such short supply that bladder cancer patients have to wait for treatment.
But right now, we are early in research on the effects of this “miracle vaccine.” If it works for these diseases (and many more), we will have a sea change in medicine. I’m hopeful, but like I always say, “show me the evidence.”
Citations
- ARONSON JD, ARONSON CF. Appraisal of protective value of BCG vaccine. J Am Med Assoc. 1952 May 24;149(4):334-43. doi: 10.1001/jama.1952.02930210018006. PMID: 14927352.
- Corsenac P, Parent MÉ, Mansaray H, Benedetti A, Richard H, Stäger S, Rousseau MC. Early life Bacillus Calmette-Guerin vaccination and incidence of type 1, type 2, and latent autoimmune diabetes in adulthood. Diabetes Metab. 2022 May;48(3):101337. doi: 10.1016/j.diabet.2022.101337. Epub 2022 Mar 1. PMID: 35245655.
- Faustman DL. TNF, TNF Inducers and TNFR2 Agonists: A New Path to Type 1 Diabetes Treatment. Diabetes Metab Res Rev. 2018 Jan;34(1). doi: 10.1002/dmrr.2941. Epub 2017 Sep 29. PMID: 28843039.
- 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 Nov 7;14(11):e0224433. doi: 10.1371/journal.pone.0224433. PMID: 31697701; PMCID: PMC6837488.
- Moradi-Marjaneh R, Hassanian SM, Fiuji H, Soleimanpour S, Ferns GA, Avan A, Khazaei M. Toll like receptor signaling pathway as a potential therapeutic target in colorectal cancer. J Cell Physiol. 2018 Aug;233(8):5613-5622. doi: 10.1002/jcp.26273. Epub 2018 Mar 1. PMID: 29150944.
- Rentsch CA, Birkhäuser FD, Biot C, Gsponer JR, Bisiaux A, Wetterauer C, Lagranderie M, Marchal G, Orgeur M, Bouchier C, Bachmann A, Ingersoll MA, Brosch R, Albert ML, Thalmann GN. Bacillus Calmette-Guérin strain differences have an impact on clinical outcome in bladder cancer immunotherapy. Eur Urol. 2014 Oct;66(4):677-88. doi: 10.1016/j.eururo.2014.02.061. Epub 2014 Mar 12. PMID: 24674149.
- Ristori G, Romano S, Cannoni S, Visconti A, Tinelli E, Mendozzi L, Cecconi P, Lanzillo R, Quarantelli M, Buttinelli C, Gasperini C, Frontoni M, Coarelli G, Caputo D, Bresciamorra V, Vanacore N, Pozzilli C, Salvetti M. Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS. Neurology. 2014 Jan 7;82(1):41-8. doi: 10.1212/01.wnl.0000438216.93319.ab. Epub 2013 Dec 4. PMID: 24306002; PMCID: PMC3873620.
