title: Phase II, randomized, open, controlled study of AS03-adjuvanted H5N1 pre-pandemic influenza vaccine in children aged 3 to 9 years: follow-up of safety and immunogenicity persistence at 24 months post-vaccination.
abstract: BACKGROUND
  An AS03-adjuvanted H5N1 influenza vaccine elicited broad and persistent immune responses with an acceptable safety profile up to 6 months following the first vaccination in children aged 3-9 years.
  
  
  METHODS
  In this follow-up of the Phase II study, we report immunogenicity persistence and safety at 24 months post-vaccination in children aged 3-9 years. The randomized, open-label study assessed two doses of H5N1 A/Vietnam/1194/2004 influenza vaccine (1·9 μg or 3·75 μg hemagglutinin antigen) formulated with AS03A or AS03B (11·89 mg or 5·93 mg tocopherol, respectively). Control groups received seasonal trivalent influenza vaccine. Safety was assessed prospectively and included potential immune-mediated diseases (pIMDs). Immunogenicity was assessed by hemagglutination-inhibition assay 12 and 24 months after vaccination; cross-reactivity and cell-mediated responses were also assessed. (NCT00502593).
  
  
  RESULTS
  The safety population included 405 children. Over 24 months, five events fulfilled the criteria for pIMDs, of which four occurred in H5N1 vaccine recipients, including uveitis (n = 1) and autoimmune hepatitis (n = 1), which were considered to be vaccine-related. Overall, safety profiles of the vaccines were clinically acceptable. Humoral immune responses at 12 and 24 months were reduced versus those observed after the second dose of vaccine, although still within the range of those observed after the first dose. Persistence of cell-mediated immunity was strong, and CD4(+) T cells with a TH 1 profile were observed.
  
  
  CONCLUSIONS
  Two doses of an AS03-adjuvanted H5N1 influenza vaccine in children showed low but persistent humoral immune responses and a strong persistence of cell-mediated immunity, with clinically acceptable safety profiles up to 24 months following first vaccination.
authors: FISABIO-Public Health, Valencia, Spain.
authors: Javier
authors: J
authors: Díez-Domingo
authors: José-María
authors: JM
authors: Baldó
authors: Maria Victoria
authors: MV
authors: Planelles-Catarino
authors: María
authors: M
authors: Garcés-Sánchez
authors: Isabel
authors: I
authors: Ubeda
authors: Angels
authors: A
authors: Jubert-Rosich
authors: Josep
authors: J
authors: Marès
authors: Pilar
authors: P
authors: Garcia-Corbeira
authors: Philippe
authors: P
authors: Moris
authors: Maurice
authors: M
authors: Teko
authors: Carline
authors: C
authors: Vanden Abeele
authors: Paul
authors: P
authors: Gillard
mesh_terms: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D006385:Hemagglutination Inhibition Tests; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000032:analysis / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007223:Infant; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology; D007251:Influenza, Human / Q000517:prevention & control*; D008297:Male; D011136:Polysorbates; D013185:Squalene / Q000276:immunology*; D014611:Vaccination; D024502:alpha-Tocopherol / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D004338:Drug Combinations; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D011136:Polysorbates; D013185:Squalene; C550253:AS03 adjuvant; D024502:alpha-Tocopherol
keywords: AS03-adjuvanted; H5N1 influenza vaccine; cell-mediated immunity; children; pre-pandemic
references: J Clin Immunol. 2000 Nov;20(6):391-9
references: 11202228
references: Lancet Infect Dis. 2014 Mar;14(3):227-38
references: 24360892
references: J Immunol. 1998 Nov 15;161(10):5284-95
references: 9820501
references: Nat Immunol. 2006 May;7(5):449-55
references: 16622432
references: Immunol Rev. 2006 Jun;211:8-22
references: 16824113
references: Immunity. 2008 Jul 18;29(1):138-49
references: 18599325
references: Lancet Infect Dis. 2008 Oct;8(10):650-8
references: 18922487
references: Expert Opin Biol Ther. 2009 Aug;9(8):1057-71
references: 19555313
references: Am J Epidemiol. 2009 Sep 15;170(6):679-86
references: 19679750
references: Pediatr Infect Dis J. 2010 Jun;29(6):e35-46
references: 20375709
references: J Clin Immunol. 2011 Jun;31(3):443-54
references: 21174144
references: PLoS One. 2011;6(8):e23698
references: 21887299
references: Ann Neurol. 2011 Sep;70(3):410-7
references: 21866560
references: J Immunol. 2011 Dec 1;187(11):5510-4
references: 22058417
references: Nat Med. 2012 Feb;18(2):274-80
references: 22286307
references: J Clin Invest. 2012 Aug;122(8):2847-56
references: 22820287
references: Virus Res. 2004 Jul;103(1-2):91-5
references: 15163495