GAD Vaccine for Type 1 Diabetes Shows Continued Promise

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When to Intervene?

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 ( 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.


KEYSTONE, Colo. – Right now, the Diamyd Medical’s GAD vaccine is in the sweet spot in the developmental pipeline – an interim period of enormous optimism that this novel autoantigen-based immunotherapy will safely prevent many cases of type 1 diabetes.

The results of three phase II studies are in and they look quite promising. Two large phase III clinical trials are well underway in Europe and the United States. The safety experience with the 65-kD isoform of GAD (glutamic acid decarboxylase-65) vaccine has been outstanding. The subcutaneous two-injection series is easy to administer. Acceptance of the vaccine by patients and their families is high. The vaccine targets a serious disease whose incidence is steadily climbing by 3%-5% per year in developed countries. And most patients with recently diagnosed type 1 diabetes possess GAD autoantibodies, so the Diamyd vaccine would be widely applicable.

Dr. Johnny L. Ludvigsson

All of that was good enough for Johnson and Johnson, which in June inked a huge development and marketing deal for the GAD vaccine with small Swedish biotech company Diamyd Medical. Under the deal, Diamyd receives $45 million upfront, milestone payments of up to $580 million, and tiered royalties after that. The Federal Trade Commission’s antitrust division has already approved the deal.

But during this blissful interlude, one key question remains: Is the Diamyd vaccine effective?

“It’s too early to say if this works. Absolutely too early. We have a phase III trial in Europe with results due next spring. And the TrialNet study [is] going on here in the U.S. So we will know in a year or 2,” Dr. Johnny L. Ludvigsson said at a conference on management of diabetes in youth sponsored by the Children’s Diabetes Foundation at Denver.

Dr. Ludvigsson, professor of pediatrics at the University of Linkoping (Sweden), led the phase III European trial evaluating whether the GAD vaccine preserves beta-cell function and residual insulin secretion in patients with type 1 diabetes diagnosed within 3 months of starting treatment. He also headed a phase II study that caused a favorable buzz within the diabetes research community (N. Engl. J. Med. 2008;359:1909-20) and for which he is now analyzing 5-year follow-up data.

And while the forthcoming phase III trial results will tell the tale as to clinical efficacy, at this time some useful interim observations can be made about the GAD vaccine, according to Dr. Ludvigsson:

The vaccine has demonstrated excellent safety. Experience with the vaccine to date totals 850 patient-years in adults and 350 patient-years in children, with no adverse events reported. This is enormously reassuring because GAD transforms glutamate into GABA, an important neurotransmitter. Lack of GAD in the CNS leads to muscle rigidity and convulsions, while stimulation of CNS GAD results in inhibition of neurotransmission. The absence of any such adverse events indicates the vaccine is working, as designed, to affect only a very small part of the immune system: namely, the activated T cells that have targeted pancreatic beta-cells for destruction, Dr. Ludvigsson said.

The vaccine has demonstrated prolonged immunologic effects. The immunologic response to the Diamyd vaccine lasts surprisingly long – approaching 5 years and still counting. It’s a GAD-specific, cell-mediated, and humoral immune response characterized by increased GAD autoantibodies, a Th2 shift marked by reduction in activated T cells and an increase in regulatory T cells, a sharp and sustained rise in levels of interleukins-2, -5, -10, -13, and -17, and GAD tolerance. “We see this response still after 4 years. The memory is there,” Dr. Ludvigsson observed.

“The earlier we treat, the better the outcome.” That’s why the phase III European trial is restricted to patients diagnosed with type 1 diabetes within the past 3 months. It’s also the impetus for ongoing prevention trials in individuals at very high genetic risk for type 1 diabetes who have GAD autoantibodies but have not developed overt disease.

The vaccine probably won’t work in diabetic patients without GAD autoantibodies. No studies have been carried out in such patients, but Dr. Ludvigsson said it’s his impression that the vaccine is more effective in individuals with higher than lower titers of GAD autoantibodies.

For the future, the GAD vaccine alone probably is not the solution to type 1 diabetes, Dr. Ludvigsson said candidly.

“I believe this opens the door to using different antigens, like in allergy. Allergists don’t use just cat antigen in patients who have cat, dog, and house dust mite allergies. I suppose we may also learn to combine autoantigens, together with possible stimulation of beta-cells in combination with drugs that promote beta-cell regeneration,” he continued.


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