[CLARIFICATION: The results of this study were based on a small sample of patients who continued insulin treatment, and further research is needed. A previous version of this article seemed to imply that the BCG vaccine alone restored normal blood sugar levels. That is not the case; we regret the error.]
Long-term follow-up of participants in clinical trials of a generic vaccine to reverse advanced type 1 diabetes finds significant clinical benefits, including restoration of near-normal blood sugar levels. Three years after receiving two administrations of the bacillus Calmette-Guérin (BCG) vaccine four weeks apart, all members of a small group of adults with longstanding type 1 diabetes showed an improvement in HbA1c to near normal levels – improvement that persisted for the following five years. The study from a Massachusetts General Hospital (MGH) research team – published in npj Vaccines – also reports that the effects of BCG vaccine on blood sugar control appear to depend on a totally novel metabolic mechanism that increases cellular consumption of glucose.
Researchers led by Denise Faustman, MD, PhD, director of the MGH Immunobiology Laboratory, point out that BCG is one of the oldest vaccines in the world. It was used for almost a century to prevent tuberculosis and has been known for more than 30 years to boost production of a cytokine called tumor necrosis factor (TNF), which may be beneficial in autoimmune diseases both by eliminating the autoreactive T cells that attack an individual’s tissues – in the case of type 1 diabetes, pancreatic islets – and by inducing production of regulatory T cells (Tregs) that could prevent an autoimmune reaction. Faustman’s team first reported in 2001 that inducing TNF production could cure type 1 diabetes in mice, but since TNF dosing is toxic in humans, clinical trials have utilized BCG for its ability to elevate TNF levels safely.
“This is clinical validation of the potential to stably lower blood sugars to near normal levels with a safe vaccine, even in patients with longstanding disease,” Faustman says. “In addition to the clinical outcomes, we now have a clear understanding of the mechanisms through which limited BCG vaccine doses can make permanent, beneficial changes to the immune system and lower blood sugars in type 1 diabetes.”
Initial clinical trial results, published in a 2012 PLOS One paper, reported that two doses of BCG spaced four weeks apart led to reductions in autoreactive T cells, an increase in Tregs and what turned out to be a transient increase in insulin production. But by the end of that short, 20-week trial, there was no reduction in HbA1c. An extension and expansion of that trial with long term follow-up, the current results are based on data from 282 human study participants – 52 with type 1 diabetes who participated in the BCG clinical trials and 230 who contributed blood samples for mechanistic studies.
For five years, the researchers followed nine patients with type 1 diabetes who were treated with the BCG vaccine to prevent tuberculosis, as well as three people in a placebo group and 40 patients in a type 1 diabetes reference group. They followed three of the BCG-treated patients with type 1 diabetes for eight years. The researchers report that HbA1c levels of the BCG-treated patients in the eight-year follow-up dropped by more than 10 percent at three years after treatment and by more than 18 percent at four years. That reduction was maintained over the next four years, with treated participants having an average HbA1c of 6.65 and with no reports of severe hypoglycemia. Participants in the placebo group and in a comparison group of patients receiving no treatment experienced consistent HbA1c elevations over the same eight-year time period.
But skepticism in the community remains. Those patients were returned to the care of their practitioners and remained on insulin during follow-up, and those differences in blood-sugar levels could have come from any small change in insulin dosing or adherence.
In investigating how BCG administration produces its beneficial effects, the research team may have identified a mechanism never previously seen in humans in response to treatment with any drug – a shifting of the process of glucose metabolism from oxidative phosphorylation, the most common pathway by which cells convert glucose into energy, to aerobic glycolysis, a process that involves significantly greater glucose consumption by cells. The researchers also found that BCG could reduce blood sugar elevations in mice that were caused by means other than autoimmune attack, raising the possibility that BCG vaccines could also be beneficial against type 2 diabetes.
Mihai G. Netea, PhD, professor in the Department of Internal Medicine at Radboud University Medical Center in the Netherlands, says of this study, “The clinical effects and the proposed mechanism demonstrated are exciting and add to the emerging consensus that the BCG vaccine can have a lasting and valuable impact on the immune system. We know, and this study shows, that BCG vaccination induces epigenetic reprogramming at the chromatin architecture level and functional alterations indicative of a permanent change in immunity. The MGH trials and other, larger prevention and intervention trials underway around the globe may lead to a major shift in the prevention and treatment of infections and autoimmunity.” Netea was not involved in the current study.
The MGH team’s findings set the stage for further testing of BCG administration, including the FDA-approved phase 2 study currently underway, testing multiple BCG doses in a large group of participants with longstanding type 1 diabetes. That trial is fully enrolled, and there are seven additional BCG clinical trial groups currently recruiting or enrolling at MGH, with a pediatric trial in the planning stages. The MGH BCG clinical trial program is entirely funded by private philanthropy from individuals and family foundations, including the Iacocca Foundation.
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