BCG vaccine leads to lasting improvement in blood sugar in type 1 diabetes

By Megan Brooks

NEW YORK (Reuters Health) - Three years after receiving bacillus Calmette-Guerin (BCG) vaccine, adults with longstanding type 1 diabetes showed improvement in hemoglobin A1c to near-normal levels and the improvement persisted over the next five years, with no reports of severe hypoglycemia.

"This is significant because a durable change without risk of hypoglycemia as never been demonstrated in patients with established type 1 diabetes. And, it was done with a safe, generic vaccine," Dr. Denise Faustman, director of the Massachusetts General Hospital (MGH) Immunobiology Laboratory and principal investigator of the BCG clinical trials at MGH, told Reuters Health by email.

"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," Dr. Faustman added in a news release.

The study is scheduled for publication in npjVaccines and will be presented this weekend at the American Diabetes Association annual meeting in Orlando, Florida.

Dr. Faustman's group was the first to document reversal of advanced type 1 diabetes in mice and subsequently completed a phase I human clinical trial of BCG vaccination in six adults with long-term type 1 diabetes.

In that trial, they showed that BCG-treated subjects with type 1 diabetes had statistically significant increases in regulatory T cells (Tregs) four to six weeks after repeat BCG vaccination and what turned out to be a transient increase in insulin production. (https://bit.ly/2tp0C6V) But by the end of the 20-week trial, there was no reduction in HbA1c.

The new results are an extension and expansion of that trial with follow-up lasting eight years. Fifty-two adults with advanced type 1 diabetes received two doses of BCG vaccine four weeks apart as part of BCG vaccine clinical trials and 230 contributed blood samples for mechanistic studies.

With BCG vaccination, HbA1c levels dropped by greater than 10% at three years and 18% at four years, and HbA1c remained stable over the next four years, with BCG-treated adults having an average HbA1c of 6.65, close to the 6.5 considered the threshold for diabetes diagnosis, with no hypoglycemic episodes. Adults in the placebo group and in a comparison group of patients receiving no treatment experienced consistent HbA1c elevations over the eight-year period.

BCG vaccination produced "prolonged persistent and stable lower blood sugars in people with long-term type 1 diabetes, which is remarkable," Dr. Faustman noted in a phone interview.

In their paper, the investigators say it's unclear why BCG's reduction of HbA1c takes three years to show up. "This crucial question cannot be directly answered by our clinical trial. We can speculate that since autoimmune disease takes years to develop, the reversal or halt of autoimmunity may share similar time dependence. It is important to note that the 3-year lag time was also found in a human clinical trial of BCG's benefits for multiple sclerosis," they write.

Mechanistic studies suggest that the impact of BCG administration blood sugar appears to be driven by a novel systemic and blood sugar lowering mechanism in diabetes – namely, a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, a state of high glucose utilization. "We spent five years defining this new mechanism of how this ancient microorganism lowers blood sugar in people who are exposed," Dr. Faustman said by phone.

This new mechanism suggests that BCG might have broader applicability to other forms of hyperglycemia like type 2 diabetes. There are no studies yet in adults with type 2 diabetes, Dr. Faustman said, but a series of studies in type 2 diabetic mouse models show "very clear" benefits of BCG administration.

"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," Dr. Mihai Netea, from Radboud University Medical Center in the Netherlands, who wasn't involved in the study, said in the news release.

"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," added Dr. Netea.

Dr. Faustman said a "fully enrolled Phase II pivotal FDA approved clinical trial testing six doses of BCG (versus two in the Phase I) is underway."

The BCG clinical trial program at MGH is entirely funded by private philanthropy from individuals and family foundations, including the Iacocca Foundation.

SOURCE: https://go.nature.com/2K7aysU

npjVaccines 2018.