The long-term follow-up of participants with Type 1 diabetes in a clinical trial of a cheap, generic vaccine has shown lasting improvements in blood glucose control, according to results published on June 21 in the journal npj Vaccines.
Members of the treatment group — all of whom had longstanding diabetes — received two administrations of the bacillus Calmette-Guérin (BCG) vaccine four weeks apart. Three years later, everyone in the group showed reductions in HbA1c to near-normal levels, and this improvement continued for five additional years of follow-up.
“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, senior author of the study and director of the Massachusetts General Hospital (MGH) Immunobiology Laboratory.
HbA1c reductions without greater insulin use
Initial results from the clinical trial, published in 2012 in PLOS One, showed reductions in autoreactive T cells but no effect on HbA1c 20 weeks after administration of the BCG vaccine. The current results are based on an extension and expansion of that trial, and include 52 participants. An additional 230 patients with Type 1 diabetes contributed blood samples for in vitro mechanistic studies.
The current results from the clinical trial show that among participants who received BCG, HbA1c dropped by more than 10 percent after three years and by more than 18 percent after four years. This reduction was largely maintained over the next four years, with an average HbA1c level of 6.65 percent in the treatment group at eight years compared with 7.22 percent in the control group.
While Phase I of the trial did not track participants’ insulin use and was not designed to see if they could stop taking insulin, researchers observed no evidence of increased insulin use in the treatment group. In fact, they documented instances of participants significantly reducing or stopping insulin use for short periods of time.
Phase II of the trial, currently in progress, will closely monitor insulin use in all participants, according to an MGH press release.
Novel mechanism for lowering blood glucose
BCG is a live vaccine and one of the oldest vaccines in existence. Widely used around the world to protect against tuberculosis (TB), it’s an attenuated version of a highly virulent Myobacterium species. As noted in the current study, humans and Myobacterium have experienced coevolution for some 90,000 years, and the past decade has seen a resurgence in clinical trials of BCG for autoimmune and allergic conditions.
In early studies of BCG in mice at the MGH Immunobiology Lab, researchers found that blood glucose improvements were driven by restored insulin production due to pancreatic islet regeneration. They sought to demonstrate a similar mechanism in the current human study, but found instead that endogenous insulin (as measured by cosecreted C-peptide) was no higher in participants who received BCG.
Instead of being driven by restored insulin production or reduced insulin resistance, the BCG group’s improved HbA1c levels were due to improved glucose metabolism, the researchers found. Specifically, there was a difference at the cellular level in white blood cells — a switch from primarily a low glucose utilization state (oxidative phosphorylation) to a higher glucose utilization state (augmented aerobic glycolysis).
Because it doesn’t rely on regeneration of pancreatic islets or any other insulin-mediated effect, inducing aerobic glycolysis by administering BCG could prove to be effective at reducing all forms of hyperglycemia, the researchers note — including elevated blood glucose in Type 2 diabetes.
Faustman stresses that further trials of BCG are key to understanding its potential for diabetes-related applications. “More global studies, as well as advancing our own studies, are central,” she says.
Cautious response from ADA and JDRF
The American Diabetes Association (ADA) and JDRF (formerly Juvenile Diabetes Research Foundation) issued a joint statement in response to the study’s results and the attention it has received.
The statement points out that the number of participants involved in the study was small — especially before it was expanded, meaning those on whom the long-term results are based — and that while the results may be statistically significant, they don’t represent a dramatic reduction in HbA1c.
Other limitations of the study, according to the statement, include that it didn’t track insulin use or the standard of care followed by participants, and that it didn’t explore alternative explanations for lowered HbA1c, such as natural variability over time.
“We will be monitoring the progress made by Dr. Faustman and want every researcher in our field to be successful,” the statement concludes. “We will continue to focus our resources on projects that we believe give us the best opportunity to create a world without T1D.”
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