Repeat BCG Vaccination Creates Lasting Reductions of HbA1c in Type 1 Diabetic Subjects: Long-Term Clinical Trial Follow Up and Novel Mechanistic Insights

Background;This is a study of 282 research subjects in vivo (n=52) and in vitro (n=230) related to the clinical and metabolic effects of repeat BCG vaccines in type 1 diabetic subjects (T1D). Methods:We report on a randomized, placebo-controlled examination of adult subjects with long-term type 1 diabetes who received 2-BCG vaccines, 4-weeks apart and studied for up to 5 years (n=46) or followed beyond 8 years (n=6). All enrolled subjects had disease >10 years duration without complications. T1D subjects (n=230) were used for parallel metabolomic, mRNAseq, and epigenetic evaluations of the BCG effect. Results:For all clinical trial groups, starting after year 4 and persisting up to 8 years, only BCG vaccinated subjects had lowered HbA1c. The 8 years long and BCG-treated T1Ds showed a reduction in HbA1c levels of greater than 10% after Year 03, 18% at Year 04, and the HbA1c remained low for the next 5 years (p=0.0002 at Year 8). For BCG treated subjects compared to placebo of reference subjects followed up to Year 05: BCG-treated HbA1c were 6.18+/-.34, placebo 7.07+/-.41, reference subjects with type 1 diabetes 7.22+/-.17 [p=0.02]. Stable reductions in HbA1c were not associated with hypoglycemia. The long-lasting impact of BCG on blood sugars in humans with type 1 diabetes was a result of a novel mechanism, 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 a cellular level. BCG via epigenetics also resets all 6 T-regulatory genes for genetic reprogramming of tolerance. Conclusion:This data shows durable blood sugar control with BCG vaccines. The identification of a novel mechanisms for how BCG lowers HbA1c opens up future trials in T1D/T2D with this safe affordable vaccine.