title: Effect of simultaneous vaccination with H1N1 and GAD-alum on GAD65-induced immune response.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  ClinicalTrials.gov NCT00723411.
authors.affiliation: Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, 581 85, Linköping, Sweden. beatriz.tavira.iglesias@liu.se.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Tavira
authors.affiliation: Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, 581 85, Linköping, Sweden.
authors.forename: Mikael
authors.initials: M
authors.lastname: Cheramy
authors.affiliation: Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, 581 85, Linköping, Sweden.
authors.forename: Stina
authors.initials: S
authors.lastname: Axelsson
authors.affiliation: Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, 581 85, Linköping, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Åkerman
authors.affiliation: Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, 581 85, Linköping, Sweden.
authors.forename: Johnny
authors.initials: J
authors.lastname: Ludvigsson
authors.affiliation: Division of Pediatrics, Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, 581 85, Linköping, Sweden.
authors.forename: Rosaura
authors.initials: R
authors.lastname: Casas
mesh_terms: D000293:Adolescent; D000534:Alum Compounds / Q000737:chemistry*; D001323:Autoantibodies / Q000737:chemistry; D002096:C-Peptide / Q000737:chemistry; D002648:Child; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D004311:Double-Blind Method; D005260:Female; D005387:Finland; D005968:Glutamate Decarboxylase / Q000737:chemistry*; D006388:Hemagglutinins / Q000737:chemistry; D006801:Humans; D007107:Immune System; D053118:Influenza A Virus, H1N1 Subtype; D007252:Influenza Vaccines / Q000627:therapeutic use*; D007251:Influenza, Human / Q000517:prevention & control*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D008297:Male; D016011:Normal Distribution; D013548:Sweden; D013997:Time Factors; D014611:Vaccination; D055815:Young Adult
chemical_list: D000534:Alum Compounds; D001323:Autoantibodies; D002096:C-Peptide; D016207:Cytokines; D006388:Hemagglutinins; D007252:Influenza Vaccines; D007328:Insulin; C556153:pandemrix; C041524:aluminum sulfate; D005968:Glutamate Decarboxylase
keywords: Children; GAD; H1N1; Immune intervention; Type 1 diabetes; Vaccine