Repeat BCG Vaccination Creates Lasting Reductions of HbA1c in Subjects with Long-Term Type 1 Diabetes—Long-Term Clinical Trial Follow-up

Abstract

We report on a randomized, placebo-controlled prospective examination of adult subjects with long-term type 1 diabetes who received 2 bacillus Calmette-Guerin (BCG) vaccine doses 4 weeks apart and were studied for up to 5 years. All enrolled subjects had disease >10 years duration without complications. Starting after year 3 of follow-up, only BCG vaccinated subjects had lowered HbA1c for 1 year (Year 05 data: BCG-treated HbA1c 6.18+/-.34 [n=9], placebo 7.07+/-.41 [n=3], reference subjects with type 1 diabetes 7.22+/-.17 [n=34, p=0.02]). Continuing follow-up of 6 subjects who have been followed for a total of 8 years, 4 years after the first documented lowering of HbA1c (Phase 1 trial participants), confirms the ability of repeat BCG vaccination to maintain lowered HbA1c levels without hypoglycemia in long-term disease (BCG-treated HbA1c 6.65+/-.26 vs. placebo 7.22+/-.38, p=0.0002) for a total of 5 continuous years. For all BCG-treated subjects, the stable reductions in HbA1c were not associated with hypoglycemia. BCG-treated subjects had no change in their enrollment use of insulin pumps and none utilized a CGM device. The apparent stable and long-lasting impact of BCG on blood sugars in humans with type 1 diabetes appears to be the result of a novel mechanism, as documented with metabolomics, mRNAseq, and epigenetic methods; namely, a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, a state of high glucose utilization on cellular levels. BCG via epigenetics also resets T-regulatory genes for genetic reprogramming of tolerance. Trials are being designed to confirm the value of BCG for blood sugar control in humans. The identification of a novel mechanism for blood sugar lowering with BCG opens the door for future trials in both type 1 and 2 diabetes with a safe, novel and affordable approach.