GAD Vaccine for Type 1 Diabetes Shows Continued Promise

Type 1 diabetes (T1D) is an autoimmune disease caused by interplay of genetic and environmental factors. The incidence of childhood T1D has doubled worldwide over the past 20-25 years. Elimination of the environmental agent(s) responsible for this epidemic would be the most efficient approach to primary prevention; however, more work is needed to identify the environmental agents and to develop effective interventions.

Blocking progression from islet autoimmunity to clinical diabetes or secondary prevention has been attempted, so far to no avail, by a number of groups, including large randomized trials: the Diabetes Prevention Trial – Type 1, the European Nicotinamide Diabetes Intervention Trial, and the Type 1 Diabetes Prediction and Prevention Project.

Trials in patients with newly diagnosed T1D aim at tertiary prevention, such as preservation of remaining islet beta-cells to induce and prolong partial remission. Unfortunately, most islets have already been destroyed by the time diabetes is diagnosed and complete reversal of diabetes is highly unlikely. Benefits may include a simpler insulin regimen, lower HbA1c, and reduced risk of hypoglycemia and microvascular complications. The gain may be even greater if the intervention is applied as soon as the patient shows asymptomatic “dysglycemia,” detected by oral glucose tolerance test or A1c, before overt symptoms of diabetes.

While new interventions are often tested first in patients with established diabetes, and, when proven safe, applied to patients with pre-T1D, efficacy after diagnosis of diabetes is not to be a precondition to application in pre-T1D, as there may be a “point of no return” in the destruction of the islets, rendering some interventions effective only at the earlier stages of the process.

Antigen-specific vaccines

Among several approaches to prevention of T1D, “vaccination” using islet autoantigens (intact or altered peptides derived from insulin, GAD65 or other proteins) stands out as potentially inducing long-term tolerance by induction of regulatory T-cells that down-regulate immunity to autoantigens. Until recently, trials of insulin administered parenterally, orally, or intranasally have been unsuccessful. Therefore, the initial results from trials of the Diamyd vaccine, as reviewed here, were greeted with huge interest and excitement. The vaccine includes the whole recombinant human GAD65 (rhGAD65) molecule suspended in alum. The protective effect was most pronounced in patients treated within 3 months of diagnosis, and no serious side effects were observed.

Insulin-related molecules continue to attract great interest in vaccine development. Phase I studies have been completed or are nearing completion for a proinsulin peptide C19-A3, an insulin peptide with incomplete Freund adjuvant, and a plasmid encoding proinsulin.

Combination therapies may enhance efficacy while lowering risk of adverse events if utilizing therapies from different treatment pathways. While more targeted therapies are being employed, immunomodulatory agents are still relatively nonspecific and potentially toxic to some of the trial participants. Some may carry an unacceptable risk of long-term complications. This direction is important; however, multiple scientific and logistic issues remain, for example, the anticipated duration, toxicity, and complexity of immunotherapy.

In the long run, primary prevention will likely be the optimal approach to the prevention of T1D. Once more than one islet autoantibody is present, most individuals progress to diabetes in 5-10 years. The TrialNet consortium (www.diabetestrialnet.org) systematically evaluates therapies in new-onset patients as well as in pre-diabetic subjects, and invites proposals from the research community at large.

Marian Rewers, M.D., Ph.D., is professor of pediatrics and preventive medicine at the Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver.