MON-179 Repeat BCG Vaccination Creates Lasting HbA1c Reductions in Adult Subjects with Longstanding Type 1 Diabetes by Correcting Immune-Metabolic Defects

The move to cleaner and more urban environments is speculated to be involved in not just how type 1 diabetes develops, but also in the increased incidence of many immune diseases. The bacillus Calmette-Guérin (BCG) vaccine, originally developed to prevent tuberculosis and recently shown to reduce blood sugar levels in humans with advanced type 1 diabetes, may safely mimic the microbial exposures modern societies have lost. We investigated how the BCG vaccine impacts the immune system and lowers blood sugars by analyzing data from 282 adult human research participants from in vivo clinical trial studies (n=52) and in vitro mechanistic studies (n=230). Of these subjects, 211 had type 1 diabetes and 71 were non-diabetic controls. Participants with type 1 diabetes were followed for 8 years (Phase I trial subjects) or up to 5 years (additional subjects) after receiving BCG vaccinations, and all had disease >10 years duration without complications at enrollment. Mechanistic studies of RNAseq, metabolomics and epigenetics were performed in parallel to the clinical trial to track the systemic and mechanistic effects of BCG vaccinations. Subjects with type 1 diabetes had cellular metabolism consistent with fewer microbial exposures, resulting in white blood cells that use minimal blood sugar compared to non-diabetic control subjects. BCG led to a systemic shift in glucose metabolism from oxidative phosphorylation to aerobic glycolysis, which corrected metabolism to normal within the lymphoid compartment. Exposing the patients to microbes through the BCG vaccine exerted major epigenetic effects on the immune system related to Treg tolerance and resulted in white blood cells using more blood sugar by increasing aerobic glycolysis. Starting after Year 03 follow up, only BCG vaccinated subjects had lowered HbA1c for >1 year (p=0.02) and BCG lowering of blood sugar was maintained for 5 continuous years (p=0.0002). BCG-treated subjects had no post-enrollment change in insulin pump use, none utilized a CGM device, and insulin usage was reduced. We conclude that microbial exposure through BCG vaccination appears to result in white blood cells using more serum sugar by increasing aerobic glycolysis, a process of high cellular glucose utilization. After an onset delay, repeat BCG vaccination was associated with stable, long-term lowering of HbA1c in type 1 diabetes for > 5 years without hypoglycemia. These findings support the hygiene hypothesis, which suggests that early life exposure to microbes is actually beneficial to the development of the immune system and is an important determinant of sensitivity to autoimmune diseases such as type 1 diabetes. The discovery that individuals with type 1 diabetes have too little lymphoid sugar utilization sets the stage for more clinical trials using the BCG vaccine, even in advanced type 1 diabetes, to stably and safely lower blood sugars.