Confirmation that BCG vaccine reverses advanced type 1 diabetes

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VaccineLong-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 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 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.

“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,” says Dr Denise Faustman, director of the MGH Immunobiology Laboratory, principlal investigator of the BCG clinical trials at MGH and senior author of the study. “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.”

Faustman, an associate professor of medicine at Harvard Medical School, will also present five-year follow-up results of a separate group of BCG clinical trial participants with longstanding type 1 diabetes at the 78th Scientific Sessions of the American Diabetes Association in Orlando.

Used for almost a century to prevent tuberculosis, BCG has been known for more than 30 years to boost production of a cytokine called tumour 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 utilised BCG for its ability to elevate TNF levels safely.

Initial clinical trial results 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, the established measure of blood sugar levels over time. 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.

Regular monitoring of clinical trial participants found that HbA1c levels of those receiving BCG had dropped by more than 10% at three years after treatment and by more than 18% at four years. That reduction was maintained over the next four years, with treated participants having an average HbA1c of 6.65, close to the 6.5 considered the threshold for diabetes diagnosis, and with no reports of severe hypoglycaemia. 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.

In investigating how BCG administration produces its beneficial effects, the research team 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.

Dr Mihai G Netea, professor in the department of internal medicine at Radboud University Medical Centre 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 long-standing 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 paediatric trial in the planning stages.

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

Abstract
Mycobacterium are among the oldest co-evolutionary partners of humans. The attenuated Mycobacterium bovis Bacillus Calmette Guérin (BCG) strain has been administered globally for 100 years as a vaccine against tuberculosis. BCG also shows promise as treatment for numerous inflammatory and autoimmune diseases. Here, we report on a randomized 8-year long prospective examination of type 1 diabetic subjects with long-term disease who received two doses of the BCG vaccine. After year 3, BCG lowered hemoglobin A1c to near normal levels for the next 5 years. The BCG impact on blood sugars appeared to be driven by a novel systemic and blood sugar lowering mechanism in diabetes. We observe a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, a state of high glucose utilization. Confirmation is gained by metabolomics, mRNAseq, and functional assays of cellular glucose uptake after BCG vaccinations. To prove BCG could induce a systemic change to promote accelerated glucose utilization and impact blood sugars, murine data demonstrated reduced blood sugars and aerobic induction in non-autoimmune mice made chemically diabetic. BCG via epigenetics also resets six central T-regulatory genes for genetic re-programming of tolerance. These findings set the stage for further testing of a known safe vaccine therapy for improved blood sugar control through changes in metabolism and durability with epigenetic changes even in advanced Type 1 diabetes.

Authors
Willem M Kühtreiber, Lisa Tran, Taesoo Kim, Michael Dybala, Brian Nguyen, Sara Plager, Daniel Huang, Sophie Janes, Audrey Defusco, Danielle Baum, Hui Zheng, Denise L Faustman

 

Commenting on the research, Professor Helen McShane, professor of vaccinology, at the University of Oxford, said in a report in The Daily Telegraph: “The finding that two doses of BCG, a safe vaccine that is almost 100 years old, can significantly improve the control of blood glucose in patients with established type-1 diabetes, is very exciting.

“This well conducted study provides data to support a plausible immunological mechanism for this durable effect and adds to an increasing body of knowledge on the effects of BCG on autoimmune diseases.

“The effects observed here, which intriguingly increase over time, may provide a highly cost-effective way to reduce the significant morbidity and mortality associated with this disease.”

Massachusetts General Hospital material
npj Vaccines abstract
The Daily Telegraph report


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