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Trial Shows Generic Vaccine Helps Reverse Type 1 Diabetes

Denise Faustman (Jon Chase, Harvard University)

Denise Faustman (Jon Chase, Harvard University)

An early clinical trial indicates a generic vaccine that raises levels of an immune system modulator can kill autoimmune cells targeting the pancreas and temporarily restore insulin secretion in type 1 diabetes patients. Findings from the trial, conducted by researchers at Massachusetts General Hospital and Harvard Medical School in Boston, appear in the online journal PLoS ONE.

The team led by Denise Faustman, director of Mass General’s Immunobiology Laboratory (pictured left), tested the bacillus Calmette-Guérin vaccine, a generic vaccine in use for more than 90 years, and approved by the the Food and Drug Administration to protect against tuberculosis and as a treatment of bladder cancer. The double-blind phase 1 trial enrolled six long-term type 1 diabetes patients — diagnosed for an average of 15 years — who were randomly assigned to receive two doses of either bacillus Calmette-Guérin (BCG) or a placebo, spaced four weeks apart.

In earlier research Faustman and colleagues induced the expression of tumor necrosis factor (TNF) that destroys insulin-autoreactive T cells in mice. The expression of TNF made it possible to regenerate islets in the pancreas of test mice with type 1 diabetes, and restore their insulin production. High doses of TNF are toxic to humans, however, thus the use of the bacillus Calmette-Guérin vaccine, which safely elevates TNF levels.

In the 20-week clinical trial, blood samples from the six participants with diabetes were also compared with samples from six nondiabetic control participants and with samples from 75 additional individuals with diabetes and 15 people without diabetes. Frequent blood tests measured participants’ blood levels of insulin-autoreactive T cells, of an autoantibody, of regulatory T cells that help control the immune response, and of C-peptide, a marker of pancreatic insulin secretion.

During the study, two of the three participants treated with bacillus Calmette-Guérin showed increases in the death of insulin-autoreactive T cells and in levels of protective regulatory T cells. Researchers also observed a temporary but statistically significant elevation in C-peptide levels in the patients receiving the vaccine, suggesting a restoration of insulin production. The same responses were seen in one of the placebo-treated patients who, after enrolling in the study, developed an infection with the Epstein-Barr virus, which is known to induce expression of TNF.

The team reports no significant adverse events. The researchers expect that more frequent or larger doses of bacillus Calmette-Guérin than was used in this trial will be needed for long-term elimination of insulin-autoreactive T cells and a sustained restoration of C-peptide secretion and insulin production.

“We are trying to create a regimen that will actually reverse type 1 diabetes in people who are living with the disease,” says Faustman. “We anticipate that the phase 2 trial will give us more direction for turning BCG into a more sustained treatment, including the right dose and the frequency of vaccination needed to sustain a therapeutic response.”

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