Effect of simultaneous vaccination with H1N1 and GAD-alum on GAD65-induced immune response.
AIMS/HYPOTHESIS
A European Phase III trial of GAD formulated with aluminium hydroxide (GAD-alum) failed to reach its primary endpoint (preservation of stimulated C-peptide secretion from baseline to 15 months in type 1 diabetes patients), but subgroup analysis showed a clinical effect when participants from Nordic countries were excluded, raising concern as to whether the mass vaccination of the Swedish and Finnish populations with the Pandemrix influenza vaccine could have influenced the study outcomes. In the current study, we aimed to assess whether Pandemrix vaccination affects the specific immune responses induced by GAD-alum and the C-peptide response.


METHODS
In this secondary analysis, we analysed data acquired from the Swedish participants in the Phase III GAD-alum trial who received subcutaneous GAD-alum vaccination (two doses, n = 43; four doses, n = 46) or placebo (n = 48). GAD autoantibodies (GADA) and H1N1 autoantibodies, GAD65-induced cytokine secretion and change in fasting and stimulated C-peptide levels from baseline to 15 months were analysed with respect to the relative time between H1N1 vaccination and the first injection of GAD-alum.


RESULTS
GADA levels at 15 months were associated with the relative time between GAD-alum and Pandemrix administration in participants who received two doses of the GAD-alum vaccine (p = 0.015, r = 0.4). Both in participants treated with two doses and four doses of GAD-alum, GADA levels were higher when the relative time between vaccines was ≥210 days (p < 0.05). In the group that received two doses of GAD-alum, levels of several GAD65-induced cytokines were higher in participants who received the H1N1 vaccination and the first GAD-alum injection at least 150 days apart, and the change in fasting and stimulated C-peptide at 15 months was associated with the relative time between vaccines. Neither of these effects were observed in individuals who received four doses of GAD-alum.


CONCLUSIONS/INTERPRETATION
In individuals who received two doses of GAD-alum, receiving the Pandemrix vaccine closer to the first GAD-alum injection, i.e. <150 days, seemed to affect both GAD65-induced immune response and C-peptide preservation.


TRIAL REGISTRATION
ClinicalTrials.gov NCT00723411.
['Tavira|Beatriz|B|', 'Cheramy|Mikael|M|', 'Axelsson|Stina|S|', 'Åkerman|Linda|L|', 'Ludvigsson|Johnny|J|', 'Casas|Rosaura|R|']
D000293:Adolescent D000534:Alum Compounds D001323:Autoantibodies D002096:C-Peptide D002648:Child D016207:Cytokines D003922:Diabetes Mellitus, Type 1 D004311:Double-Blind Method D005260:Female D005387:Finland D005968:Glutamate Decarboxylase D006388:Hemagglutinins D006801:Humans D007107:Immune System D053118:Influenza A Virus, H1N1 Subtype D007252:Influenza Vaccines D007251:Influenza, Human D007328:Insulin D000078790:Insulin Secretion D008297:Male D016011:Normal Distribution D013548:Sweden D013997:Time Factors D014611:Vaccination D055815:Young Adult
Vaccine H1N1 GAD Type 1 diabetes Children Immune intervention