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?


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.


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.


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.


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

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