"Longterm followup of participants in clinical trials of a generic vaccine to reverse advanced type  diabetes finds significant clinical benefits including restoration of nearnormal blood sugar levels. Three years after receiving two administrations of the bacillus CalmetteGurin BCG vaccine four weeks apart all members of a group of adults with longstanding type  diabetes showed an improvement in HbAc to near normal levels  improvement that persisted for the following five years. The study from a Massachusetts General Hospital MGH research team  published in npj Vaccines http  also reports that the effects of BCG vaccine on blood sugar control appear to depend on a totally novel metabolic mechanism that increases cellular consumption of glucose.  This is clinical validation of the potential to stably lower blood sugars to near normal levels with a safe vaccine even in patients with longstanding disease says Denise Faustman MD PhD director of the MGH Immunobiology Laboratory  https principal investigator of BCG clinical trials http at MGH and senior author of the npj Vaccines report. In addition to the clinical outcomes we now have a clear understanding of the mechanisms through which limited BCG vaccine doses can make permanent beneficial changes to the immune system and lower blood sugars in type  diabetes.  Faustman will also present fiveyear followup results of a separate group of BCG clinical trial participants with longstanding type  diabetes on Saturday June  at the th Scientific Sessions of the American Diabetes Association in Orlando.  Used for almost a century to prevent tuberculosis BCG has been known for more than  years to boost production of a cytokine called tumor necrosis factor TNF which may be beneficial in autoimmune diseases both by eliminating the autoreactive T cells that attack an individuals tissues  in the case of type  diabetes pancreatic islets  and by inducing production of regulatory T cells Tregs that could prevent an autoimmune reaction. Faustmans team first reported in  that inducing TNF production could cure type  diabetes in mice but since TNF dosing is toxic in humans clinical trials have utilized BCG for its ability to elevate TNF levels safely.  Initial clinical trial results published in a  PLOS One https paper reported that two doses of BCG spaced four weeks apart led to reductions in autoreactive T cells an increase in Tregs and what turned out to be a transient increase in insulin production. But by the end of that short week trial there was no reduction in HbAc the established measure of blood sugar levels over time. An extension and expansion of that trial with long term followup the current results are based on data from  human study participants   with type  diabetes who participated in the BCG clinical trials and  who contributed blood samples for mechanistic studies.  Regular monitoring of clinical trial participants found that HbAc levels of those receiving BCG had dropped by more than  percent at three years after treatment and by more than  percent at four years. That reduction was maintained over the next four years with treated participants having an average HbAc of . close to the . considered the threshold for diabetes diagnosis and with no reports of severe hypoglycemia. Participants in the placebo group and in a comparison group of patients receiving no treatment experienced consistent HbAc elevations over the same eightyear time period.  In investigating how BCG administration produces its beneficial effects the research team identified a mechanism never previously seen in humans in response to treatment with any drug  a shifting of the process of glucose metabolism from oxidative phosphorylation the most common pathway by which cells convert glucose into energy to aerobic glycolysis a process that involves significantly greater glucose consumption by cells. The researchers also found that BCG could reduce blood sugar elevations in mice that were caused by means other than autoimmune attack raising the possibility that BCG vaccines could also be beneficial against type  diabetes.  Mihai G. Netea PhD professor in the Department of Internal Medicine at Radboud University Medical Center in the Netherlands says of this study The clinical effects and the proposed mechanism demonstrated are exciting and add to the emerging consensus that the BCG vaccine can have a lasting and valuable impact on the immune system. We know and this study shows that BCG vaccination induces epigenetic reprogramming at the chromatin architecture level and functional alterations indicative of a permanent change in immunity. The MGH trials and other larger prevention and intervention trials underway around the globe may lead to a major shift in the prevention and treatment of infections and autoimmunity. Netea was not involved in the current study.   The MGH teams findings set the stage for further testing of BCG administration including the FDAapproved phase  study currently underway testing multiple BCG doses in a large group of participants with longstanding type  diabetes. That trial is fully enrolled and there are seven additional BCG clinical trial groups currently recruiting or enrolling at MGH with a pediatric trial in the planning stages. The MGH BCG clinical trial program is entirely funded by private philanthropy from individuals and family foundations including the Iacocca Foundation. Additional information about clinical trials including information for potential participants and financial supporters is available at http or by emailing DiabetesTrialpartners.org mailtoDiabetesTrialpartners.org.  The lead author of the npj Vaccines paper is Willem M. Khtreiber PhD MGH Immunobiology Laboratories. Additional coauthors are Lisa Tran Taesoo Kim Michael Dybala Brian Nguyen Sara Plager Daniel Huang Sophie Janes Audrey Defusco and Danielle Baum MGH Immunobiology and Hui Zheng PhD MGH Biostatistics.  Massachusetts General Hospital founded in  is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute http conducts the largest hospitalbased research program in the nation with an annual research budget of more than  million and major research centers in HIVAIDS cardiovascular research cancer computational and integrative biology cutaneous biology genomic medicine medical imaging neurodegenerative disorders regenerative medicine reproductive biology systems biology photomedicine and transplantation biology. The MGH topped the  Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious  Foster G. McGaw Prize for Excellence in Community Service. In August  the MGH was once again named to the Honor Roll in the U.S. News  World Report list of Americas Best Hospitals."