Proof-of-Concept, Randomized, Controlled Clinical Trial of Bacillus-Calmette-Guerin for Treatment of Long-Term Type 1 Diabetes

Study Questions:

What is the safety of two low-dose Bacillus Calmette-Guerin (BCG) vaccinations and their effects on four serially studied biomarkers in long-term type 1 diabetes?

Methods:

Translating preclinical findings to humans, the investigators administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean, 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6), or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending on the outcome measure. The authors monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion.

Results:

BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus (EBV) infection, a known tumor necrosis factor (TNF) inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means, 3.49 pmol/L [95% confidence interval (CI), 2.95–3.8]; 2.57 [95% CI 1.65–3.49]) and the EBV-infected subject (3.16 [95% CI, 2.54–3.69]) vs.1.65 [95% CI, 1.55–3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95th percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level.

Conclusions:

The authors concluded that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response.

Perspective:

This study reports that repeated BCG vaccination at low doses was safe and well tolerated, and that BCG vaccination and an unexpected EBV infection in a placebo-treated diabetic subject, both known triggers of innate immunity, caused rapid increases in circulating insulin-autoreactive T cells that were mostly dead. This pilot study provides proof-of-principle evidence that insulin-autoreactive T cells can be specifically targeted and eliminated, albeit briefly, in vivo, even in long-standing disease with a transient restoration of C-peptide. Additional studies with either higher doses or more frequent BCG administered may be reasonable in patients with advanced disease to maintain or restore C-peptide levels.

Clinical Topics: Prevention

Keywords: North America, Insulin, Glutamate Decarboxylase, Bacillus, C-Peptide, T-Lymphocytes, Regulatory, Tumor Necrosis Factor-alpha, Signal Transduction, Mycobacterium bovis, Autoantibodies, Insulin-Secreting Cells, Epstein-Barr Virus Infections, Biological Markers, Herpesvirus 4, Human, BCG Vaccine, Confidence Intervals, Vaccination, Immunity, Innate, Diabetes Mellitus, Type 1


< Back to Listings