GAD vaccine reduces insulin loss in recently diagnosed type 1 diabetes: findings from a Bayesian meta-analysis

Abstract

Aims/hypothesis GAD is a major target of the autoimmune response that occurs in type 1 diabetes mellitus. Randomised controlled clinical trials of a GAD + alum vaccine in human participants have so far given conflicting results. Methods In this study, we sought to see whether a clearer answer to the question of whether GAD65 has an effect on C-peptide could be reached by combining individual-level data from the randomised controlled trials using Bayesian meta-analysis to estimate the probability of a positive biological effect (a reduction in C-peptide loss compared with placebo approximately 1 year after the GAD vaccine). Results We estimate that there is a 98% probability that 20 μg GAD with alum administered twice yields a positive biological effect. The effect is probably a 15–20% reduction in the loss of C-peptide at approximately 1 year after treatment. This translates to an annual expected loss of between −0.250 and −0.235 pmol/ml in treated patients compared with an expected 2 h AUC loss of −0.294 pmol/ml at 1 year for untreated newly diagnosed patients. Conclusions/interpretation The biological effect of this vaccination should be developed further in order to reach clinically desirable reductions in insulin loss in patients recently diagnosed with type 1 diabetes.

ISPAD Clinical Practice Consensus Guidelines 2018: Stages of type 1 diabetes in children and adolescents

“…Randomized controlled trials of GAD alum vaccine have produced inconsistent results. Bayesian meta‐analysis indicated a high probability that GAD with alum administered twice in stage 3 diabetes reduces the loss of C‐peptide by 15% to 20% at 1 year after treatment …”

“…Bayesian meta-analysis indicated a high probability that GAD with alum administered twice in stage 3 diabetes reduces the loss of C-peptide by 15% to 20% at 1 year after treatment. 67 Short-term administration of immune modulation therapies that can delay the loss of β-cell function (rate of decline of C-peptide) in patients with recent onset type 1 diabetes includes the anti-CD3 monoclonal antibodies Teplizumab 68 and otelixizumab, Abatacept (CTLA4-Ig), 69,70 Alefacept, 71 and the anti-CD20 monoclonal antibody, rituximab. 72,73 Children and adolescents were participants in these trials and in general had a better c-peptide response to the intervention than adults.…”

A Novel Quantitative Approach to Staging and Assessing Recovery from Type 1 Diabetes Mellitus: The Type 1 Diabetes Mellitus Metabolic Recovery Index

“…Oral insulin has been tried in a prevention setting [17] and post hoc analysis indicated some preventive effect in a subgroup [17]. GAD in alum in T1DM patients showed modest beneficial effects in a recent metanalysis [18]. Insulin B-chain in incomplete Freund's adjuvant (IFA) in a phase 1 clinical trial showed a desirable immune effect by increasing insulin B-chain specific regulatory T cells [19].…”

Autoantigen Treatment in Type 1 Diabetes: Unsolved Questions on How to Select Autoantigen and Administration Route

“…The preservation of C-peptide was better the longer the time interval between GAD-alum treatment and the H1N1 vaccination was [93]. Moreover, efficacy was statistically significant in the rather few Swedish patients who were never given the H1N1 vaccination [94]. The results also seemed to be better in patients with high and moderate HLA risk and high GADA concentrations, but less good in patients with low HLA risk and low GADA.…”