ADA: TB vaccine repurposed in Type 1 diabetes restores gene expression in key immune cells

A team of diabetes researchers at Massachusetts General Hospital has spent the last two decades building up data to support their idea of repurposing the old tuberculosis vaccine bacillus Calmette-Guérin (BCG) in Type 1 diabetes. They’ve been testing it in adults and hope to launch a pediatric trial of the vaccine later this year. Now they have new evidence that starting the treatment early in life could quickly reset patients’ immune systems and restore blood sugar to normal levels.

The ability of BCG to alter blood sugar centers around its effect on regulatory T cells (Tregs) in the immune system. Tregs prevent the destruction of insulin-producing pancreatic islets, and the MGH team previously showed that BCG alters gene expression in a way that restores the key immune cells.

During the Annual Scientific Sessions of the American Diabetes Association, the MGH team reported new insights from an ongoing mid-stage trial of BCG in 143 patients with Type 1 diabetes. They showed that three years after receiving two doses or more of BCG, patients in the trial exhibited Treg gene expression consistent with that of healthy volunteers. 

The MGH team reported that BCG treatment corrects the "over-methylation" of the Treg gene Foxp3, a characteristic of the autoimmune form of diabetes. After three years, the Foxp3 gene had stabilized "to a level close to non-diabetic controls," they said in the conference presentation.

The HbA1c response was even faster in people who developed the disease before age 21. Those patients had a bigger change in HbA1c, showing a response at two years that matched the three-year response shown in older subjects.

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The MGH team, led by Denise Faustman, M.D., Ph.D., has been collecting DNA and RNA from patients throughout the study to determine how BCG acts in the body to improve blood sugar. In early animal and human studies, they demonstrated that the TB vaccine raises levels of the immune system modulator tumor necrosis factor. They went on to show that in addition to restoring Tregs, BCG shifts cell metabolism, prompting cells to consume more glucose and improving the body’s elimination of sugar from the bloodstream.

The latest data “adds the growing understanding of how BCG changes the way the body responds to autoimmune” disease, said Nigel Curtis, M.D., Ph.D., of the Murdoch Children’s Research Institute in Australia, in a statement. Curtis was not involved in the MGH studies.

The MGH research has drawn financial support from diabetes associations, including the late Chrysler CEO Lee Iacocca’s family foundation. In 2018, the MGH researchers reported that BCG-treated people maintained HbA1C improvements for eight years. They expect to complete the five-year, phase 2 study in 2023. 

Meanwhile, MGH is awaiting approval from the FDA to start the pediatric trial, and Faustman hopes the new data will support her team’s belief that starting BCG early could benefit young Type 1 diabetics. “We have continued evidence of BCG’s ability to reset and restore the immune system,” she said in the statement.