A pediatric phase 2 clinical trial using bacillus Calmette-Guerin vaccine, or BCG vaccine, to reverse even advanced type 1 diabetes mellitus has begun. Type 1 diabetes is considered irreversible, so if phase 2 and 3 clinical trials show that the vaccine is safe and effective in reversing diabetes, it would be one of the most important advances in medicine.

Let’s take a look at what is type 1 diabetes (since a lot of people confuse it with type 2 diabetes), the clinical trial, and other information. Maybe one of you is close enough to the trial centers so that you may, if you have type 1 diabetes, can sign up to participate in the trial.

I am very hopeful about this clinical trial, but I also know that it will take many years before we know if it works.

First, what is type 1 diabetes mellitus?

I know that a lot of people don’t quite understand what diabetes is, so I hope that this helps. For those of you who have a lot of knowledge about diabetes (because you or a loved one has it), this explanation might be boring.

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.

Type 1 diabetes can be deadly if uncontrolled blood sugar leads to a life-threatening condition called diabetic ketoacidosis. Without regular insulin injections, a patient has little chance of living beyond a short period of time, and even then it could be a horrifically painful demise.

It is not known what causes this autoimmune disease, although there is strong evidence that genetics is the most important factor. However, other things may be implicated, like vaccine-preventable diseases or some other pathogen that could be important triggers to the autoimmune disease.

Just to be clear, vaccines are not linked to type 1 diabetes.

Currently, there are no known cures for type 1 diabetes. The only treatment for the disease is regular injections of human insulin, manufactured from genetically engineered E. coli cultures. In addition, careful diet and lifestyle management help regulate blood glucose levels, although it cannot replace insulin injections. (See Note 1)

BCG vaccine to reverse type 1 diabetes – early results

The BCG vaccine was initially developed to prevent tuberculosis. It 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.

One of the great things about biomedical research is that there is almost always an assumption that with an improved understanding of the disease through research, better treatments may be uncovered. This is the case with type 1 diabetes.

In a 2017 article, authored by Denise Faustman, MD Ph.D. and published in Diabetes Metabolism Research and Reviews (a respected journal with a good impact factor of 6.36), Dr. Faustman reported that the BCG vaccine induces a response in the immune system that is driven, in part, by tumor necrosis factor (TNF, see Note 2).

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, which we will discuss below with the new article by Dr. Faustman.

This “proof of concept” study, think preliminary Phase 1 clinical trial, included six adult volunteers with type 1 diabetes, who received two BCG vaccinations spaced 4 weeks apart. It appeared that the vaccine selectively eliminated the autoreactive T cells, positively induced Tregs, and cause a small restoration of insulin production. However, this paper was probably written more to make a case for biological plausibility rather than the clinical trial (although stay tuned, we will get to that).

It’s important to underline that this Phase 1 trial is very small – the goals were not to show the effectiveness of the vaccine, it’s more to show the safety. However, this preliminary data provide intriguing, though not convincing, evidence that the BCG vaccine may reverse type 1 diabetes.

According to Dr. Faustman,

Many groups are looking at the ability of BCG vaccination to reverse autoimmunity. We and other global efforts have known for some time that restoring beneficial Treg cells might halt the abnormal self-reactivity in type 1 diabetes and other autoimmune diseases, but therapies to restore this immune balance have not achieved long-lasting results. The discovery that BCG restores Tregs through epigenetics a process that modulates whether or not genes are expressed is exciting. This now provides a better idea of how BCG vaccination appears to work by powerfully modulating Treg induction and resetting the immune system to halt the underlying cause of the disease.

But do these results provide us with convincing evidence that the vaccine can reverse type 1 diabetes? Did Dr. Faustman provide a viable case for biological plausibility? I’m undecided on both points.

One more point that needs to be made clear — the BCG vaccine is not being used as preventative medicine, it’s a treatment. Two epidemiological studies, one in Preventative Medicine and the other in Paediatric and Perinatal Epidemiology, showed that there probably was no link between the BCG vaccine and preventing type 1 diabetes. So, it may not be useful in preventing type 1 diabetes but could be extremely useful in treating it.

BCG vaccine to reverse type 1 diabetes – more results

Dr. Faustman first published the results of this “proof of concept” phase 1 clinical trial over six years ago. Although the results were intriguing, it wasn’t from a large, randomized study that would be convincing evidence. The clinical evidence wasn’t sufficient for science-based medicine to suddenly start using the vaccine to reverse type 1 diabetes.

Recently, Dr. Faustman presented long-term evidence, eight years after the patients received the vaccine, that the vaccine does lower blood sugar in type 1 diabetics. The paper, published in npj Vaccines, a Nature journal, seems to indicate that the vaccine may take several years to show an effect.

This study enrolled 282 human research participants for both in vivo BCG vaccine clinical trial studies (52) and in vitro mechanistic studies (230). Of these enrolled patients,  211 had type 1 diabetes and 71 were non-diabetic (controls). The patients who received the vaccine, on average, had “near-normal” blood glucose levels for 8 years after vaccination. The average HbA1c level (which is a long-term measurement for average blood glucose levels) fell to 6.65%, just above the level considered to be indicative of diabetes, 6.5%.

The authors concluded:

…we show that re-introduced avirulent Mycobacterium bovis in the form of BCG vaccine holds benefits for human disease blood sugar control and re-establishment of tolerance through Treg cells. Although this study is centered on T1D this novel mechanism might be speculated to also be applicable to T2D. The limitations of this therapy as it is currently formatted as intradermal vaccinations are the almost 3+ year lag time for a systemic effect. Also to prove efficacy in the broadest T1D subject populations, including pediatric subjects, there is now the need to expand the trial to larger number of subjects of all ages and durations of diabetes. The advantages of this therapy are its durability, simplicity, safety, and cost-effectiveness. Exploitation of safe versions of Mycobacterium for systemic changes in immune-metabolism may recapitulate the immense benefit of co-evolution of the virulent genetic organisms, genomic modeling by epigenetics and restoration of a beneficial host partnership in modern societies. Perhaps attenuated Mycobacterium are primary organisms for reestablishing host-environment interactions for improved health.

Dr. Faustman states that this kind of delayed result is seen with treatments for other autoimmune diseases like multiple sclerosis.

At the recent 2021 Annual Scientific Sessions of the American Diabetes Association, researchers from Massachusetts General Hospital presented positive updates on their trials of the bacillus Calmette-Guérin vaccine to safely and significantly lower blood sugars.

Currently, 143 type 1 diabetics have received at least two doses of the BCG vaccine, including 25 patients enrolled in a recently launched trial of adults who had pediatric onset. Pending FDA approval, MGH aims to launch a multi-center pediatric trial later this year.

The new data presented at the ADA include:

• Type 1 diabetics with age of onset younger than 21 years have a faster response time and greater change in HbA1c than adult onset type 1 diabetics.
• Over a period of three years BCG returns gene expression in Tregs in type 1 diabetics to a pattern consistent with non-type 1 control subjects.
• The HbA1c response at two years in juvenile onset subjects is consistent with the three-year response seen in the Phase 1 study.

Phase 2 clinical trials

The Massachusetts General Hospital (MGH) team already has an ongoing five-year phase 2 study for adults and is anticipated to be completed within two years. The phase 2 trial is double-blinded and randomized and will include 150 patients divided between the BCG vaccine and placebo groups. (Note that the study is fully enrolled, although you might be able to register for participation in future clinical trials.)

MGH, in partnership with NYU Langone Health, announced on March 1, 2022, a multi-center phase 2 clinical trial has launched to investigate a new BCG vaccine treatment for pediatric type 1 diabetes, even in subjects with established disease. Right now, only Massachusetts General Hospital and NYU Langone Health are listed as study centers, but more may be included in the future.

There will be 150 participants with type 1 diabetes, 75 in the BCG vaccine group and 75 in a saline control group. Their primary outcome will be HbA1c values at 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 years after initial BCG/placebo injection. Their secondary outcome will be changes in hypoglycemia, C-peptide levels, and insulin usage at 1, 2, 3, 4, and 5 years after initial BCG/placebo injection.

This study will only include pediatric patients 12-17 years old who have been diagnosed with type 1 diabetes 24 months previous to enrollment.

This is an important study that could end type 1 diabetes in children. I can’t help but take off my science hat and get excited about the potential. But I know that many phase 2 clinical trials fail.

My analysis

Despite my trepidation about data derived from a Phase 1 clinical trial, this research is not outside the mainstream science concerning new treatments that may reverse type 1 diabetes. The islet cells in the pancreas are not completely killed off by the autoimmune disease. Even if just a few of these cells survive the autoimmune disease, they could repopulate the pancreas, if the original autoimmune disease could be suppressed. Of course, this “repopulation” (my words, not Dr. Faustman’s) would take time, maybe up to a decade.

It’s important to note that, over time, these remaining islet cells will be destroyed eventually, precluding any ability to repopulate the pancreas and produce insulin. We don’t know how long this destructive process may last, but the BCG vaccine’s ability to reverse type 1 diabetes may decrease over time.

Furthermore, in support of Dr. Faustman’s hypothesis on how the BCG vaccine might treat diabetes, she showed that levels of autoreactive T-cells fell in two out of three patients. This supports her hypothesis on the mechanism of action.

Dr. Faustman has been laser-focused on this route of treating diabetes. She first published a study in 2001, using a mouse model, describing how TNF might be critical to a treatment that will reverse type 1 diabetes. At first, her ideas weren’t exactly embraced, but these early results may start to change minds.

Now, she’s becoming mainstream, although there is still some skepticism. The CEO of the JDRF, Jeffrey Brewer, said:

It’s certainly interesting and worth further investigation, but it’s really important to be careful about how we interpret early results.

One last thing – the research team did not observe any serious adverse events. Like most vaccines.

The future of the BCG vaccine for diabetes

As I mentioned, Dr. Faustman’s team at MGH has entered the BCG vaccine into a phase 2 clinical trial that will include 150 patients followed over 5 years, and they are starting to enroll patients for the pediatric version of the study (which may show more profound results since the pancreas of these children may be less “damaged” than adult ones). These studies will examine whether BCG vaccinations can clinically improve type 1 diabetes outcomes in adults with the disease.

Unusually, these phase 2 trials are privately funded with no involvement of any pharmaceutical companies. However, the phase 3 trial, which will provide definitive data on the effectiveness of the BCG vaccine, is significantly more expensive and will probably require the participation of a corporation.

At this time, the BCG vaccine is generic (it’s over 100 years old, so patents had expired decades ago). There is only one licensed manufacturer of the vaccine in the USA, Organon Teknika Corporation, a division of Merck. Even though the vaccine is generic, only pharmaceutical companies with vaccine manufacturing facilities, requiring large capital investment, would probably get involved.

Unfortunately, this BCG vaccine is in short supply. It’s used as a treatment for one type of bladder cancer, and sometimes those patients aren’t able to get the vaccine. If it becomes a mainstream treatment for type diabetes, Merck is going to have to substantially increase production (and probably increase prices substantially).

If the BCG vaccine shows more promise in the proposed phase 2 trial, you can bet good money that one or more of the major vaccine manufacturers will fund the phase 3 trial to get an indication for treating (or preventing) type 1 diabetes. They may also improve the vaccine to increase the immune response which might improve the effectiveness short- and long-term.

There’s one more reason that the manufacturer of the BCG vaccine needs to eventually be involved in the trial. The whole purpose of phase 1, 2, and 3 clinical trials is to eventually gain FDA approval for a new drug, or, in this case, for a new indication. Even if Dr. Faustman’s research shows that the vaccine can prevent diabetes, without FDA approval for a change in the labeling of the vaccine, it technically cannot be used for type 1 diabetes. And legally, Organon Teknika cannot promote it for type 1 diabetes without FDA approval.

Finally, there are several things we don’t know that need to be fully researched before this vaccine becomes a medical tool:

1. How long does it last? Does the autoimmune disease return after a few years or decades?
2. Does the patient still need to use insulin (even at a lower dose) to maintain proper blood glucose levels? Faustman’s team was unable to determine actual levels of insulin since currently available analytical techniques cannot tell the difference between injected and endogenous insulin.
3. What dose of BCG vaccine will be most effective to reverse type 1 diabetes?
4. Are there significant adverse events after the appropriate dose is determined?
5. Will this vaccine have any effect on reversing type 2 diabetes? There are some forms of type 2 diabetes that might be associated with a late-onset autoimmune disease.

Summary

We need to set proper expectations with this vaccine, although entering phase 2 clinical trials does get me more excited than I usually am about these things. Although the preclinical research on the BCG vaccine and type 1 diabetes provides a strong possibility for the effectiveness of the vaccine, we still lack definitive evidence that it will work in humans.

The positive results of the phase 1 trial included only a relatively small group of patients, and the study was not powered in a way to determine effectiveness – it was not a double-blind, randomized clinical trial

Results for a phase 2 trial, which will give us a better idea of whether the vaccine is effective, could be several years away. Moreover, a definitive phase 3 trial, which will be the absolute best evidence of the safety and effectiveness of the vaccine in treating or reversing type 1 diabetes, will require another 5 years after that. So, we are looking at the late 2020s before we are ready to conclusively include the BCG vaccine in the armamentarium for the prevention and treatment of type 1 diabetes.

At this moment, no diabetic should run to their physician and demand a BCG vaccination. I doubt any physician would give it based on this very early evidence. The results are so preliminary, it would be dangerous to consider this as a “cure.” I doubt that Dr. Faustman would ever say that right now.

It will be a decade, maybe more, before we can proclaim that the BCG vaccine will reverse type 1 diabetes. It’s not a sprint, it’s a marathon, and we’re just a few hundred meters past the starting line. I almost always say this when someone tells me about some new drug or treatment – call me when the phase 3 clinical trial results have been published.

And let’s ponder another question. What will the anti-vaccine crowd say about this vaccine when it is approved to reverse diabetes? I predict that every parent with a diabetic child will run as fast as they can to their pediatrician.

Notes

1. Type 2 diabetes is a substantially different disease from type 1. Mostly, type 2 diabetics produce insulin, just an insufficient amount to regulate glucose levels, or their cells have become resistant to insulin because of lifestyle issues. There is almost no relationship between type 1 and type 2 diabetes, except they share the same symptoms of high blood sugar.
2. There are memes and articles all over the internet that make the bogus claim that ripe bananas contain TNF, so eating them will prevent cancer. First, bananas do not contain TNF. Second, TNF induces an inflammatory response, it doesn’t kill tumor cells.

Citations

• Corsenac P, Parent MÉ, Benedetti A, Richard H, Stäger S, Rousseau MC. Association between Bacillus Calmette-Guerin vaccination and type 1 diabetes in adolescence: A population-based birth cohort study in Quebec, Canada. Prev Med. 2022 Jan;154:106893. doi: 10.1016/j.ypmed.2021.106893. Epub 2021 Nov 17. PMID: 34798196.
• Faustman DL, Wang L, Okubo Y, Burger D, Ban L, Man G, Zheng H, Schoenfeld D, Pompei R, Avruch J, Nathan DM. Proof-of-concept, randomized, controlled clinical trial of Bacillus-Calmette-Guerin for treatment of long-term type 1 diabetes. PLoS One. 2012;7(8):e41756. doi: 10.1371/journal.pone.0041756. Epub 2012 Aug 8. PubMed PMID: 22905105; PubMed Central PMCID: PMC3414482.
• Faustman DL. TNF, TNF Inducers and TNFR2 Agonists: A New Path to Type 1 Diabetes Treatment. Diabetes Metab Res Rev. 2017 Aug 26. doi: 10.1002/dmrr.2941. [Epub ahead of print] Review. PubMed PMID: 28843039.
• Kühtreiber WM, Tran L, Taesoo K, Dvbala M, Nguyen B, Plager S, Huang D, Jones S, Defusco A, Baum D, Zheng H, Faustman DL. Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations. npj Vaccines 3:23; 21 June 2018.
• Petzold A, Solimena M, Knoch KP. Mechanisms of Beta Cell Dysfunction Associated With Viral Infection. Curr Diab Rep. 2015 Oct;15(10):73. doi: 10.1007/s11892-015-0654-x. Review. PubMed PMID: 26280364; PubMed Central PMCID: PMC4539350.
• Rousseau MC, El-Zein M, Conus F, Legault L, Parent ME. Bacillus Calmette-Guérin (BCG) Vaccination in Infancy and Risk of Childhood Diabetes. Paediatr Perinat Epidemiol. 2016 Mar;30(2):141-8. doi: 10.1111/ppe.12263. Epub 2015 Nov 20. PMID: 26584963.
• Ryu S, Kodama S, Ryu K, Schoenfeld DA, Faustman DL. Reversal of established autoimmune diabetes by restoration of endogenous beta cell function. J Clin Invest. 2001 Jul;108(1):63-72. PubMed PMID: 11435458; PubMed Central PMCID: PMC209340.