title: Long-term outcome of the humoral and cellular immune response of an H5N1 adjuvanted influenza vaccine in elderly persons: 2-year follow-up of a randomised open-label study.
abstract: BACKGROUND
  Older individuals often have a reduced immune response to influenza vaccination, which might be improved by administering a higher vaccine dose. We compared the immune response to two single doses of the AS03A-adjuvanted H5N1 pandemic vaccine (3.75 μg hemagglutinin of A/Vietnam/1194/2004) with that of two double vaccine doses (7.5 μg hemagglutinin) in adults aged ≥61 years. Here we report the 2-year persistence of the humoral and cellular immune response.
  
  
  METHODS
  In this phase II, open-label study, healthy participants aged 61 to 88 years (median 68 years) were randomised (3:1:3:1) to receive two single doses of the AS03A-adjuvanted vaccine (1xH5N1-AS) or the non-adjuvanted vaccine (1xH5N1), or two double doses of the AS03A-adjuvanted vaccine (2xH5N1-AS) or the non-adjuvanted vaccine (2xH5N1), 21 days apart. Serum haemagglutination inhibition antibodies and cellular immune responses against A/Vietnam/1194/2004 were measured in all groups at months 12 and 24; neutralising antibodies were assessed in a subset of the adjuvanted groups. Serious adverse events and adverse events of specific interest were recorded.
  
  
  RESULTS
  At month 24, haemagglutination inhibition antibody seroprotection rates were 37.2% (95% CI 27.0% to 48.3%) for 1xH5N1-AS, 30.9% (95% CI 21.1% to 42.1%) for 2xH5N1-AS, 16.2% (95% CI 6.2% to 32.0%) for 1xH5N1, and 8.3% (95% CI 1.0% to 27.0%) for 2xH5N1. Haemagglutination inhibition antibody geometric mean titres were 17.6 (95% CI 13.7 to 22.5) for 1xH5N1-AS, 18.4 (95% CI 14.2 to 23.8) for 2xH5N1-AS, 12.3 (95% CI 8.9 to 16.9) for 1xH5N1 and 9.8 (95% CI 6.7 to 14.4) for 2xH5N1. The median frequency of antigen-specific CD4+ T cells per 106 T cells (25th quartile; 75th quartile) was 852 (482; 1477) for 1xH5N1-AS, 1147 (662; 1698) for 2xH5N1-AS, 556 (343; 749) for 1x-H5N1 and 673 (465; 1497) for 2xH5N1. Neutralising antibody geometric mean titres were 391.0 (95% CI 295.5 to 517.5) in the 1xH5N1-AS group and 382.8 (95% CI 317.4 to 461.6) in the 2xH5N1-AS group.
  
  
  CONCLUSIONS
  Antibody levels declined substantially in all groups. Seroprotection rates, geometric mean titres for haemagglutination inhibition antibodies, and CD4+ T-cell responses tended to be higher in the AS03A-adjuvanted groups. There was no clear benefit, in terms of long-term persistence of the immune response, of doubling the dose of the adjuvanted vaccine. No safety concern was observed up to 24 months post-primary vaccination.
  
  
  BACKGROUND
  NCT00397215 (7 November 2006).
authors.affiliation: GSK Vaccines, Wavre, Belgium. paul.gillard@gsk.com.
authors.forename: Paul
authors.initials: P
authors.lastname: Gillard
authors.forename: Didier
authors.initials: D
authors.lastname: Giet
authors.forename: Stéphane
authors.initials: S
authors.lastname: Heijmans
authors.forename: Mamadou
authors.initials: M
authors.lastname: Dramé
authors.forename: Karl
authors.initials: K
authors.lastname: Walravens
authors.forename: François
authors.initials: F
authors.lastname: Roman
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood; D001530:Belgium; D015415:Biomarkers / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000821:virology; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D006385:Hemagglutination Inhibition Tests; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects*; D056724:Immunity, Humoral / Q000187:drug effects*; D007115:Immunization Schedule; D053124:Influenza A Virus, H5N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D007251:Influenza, Human / Q000097:blood / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D008297:Male; D008875:Middle Aged; D011136:Polysorbates / Q000008:administration & dosage* / Q000009:adverse effects; D012698:Serologic Tests; D013185:Squalene / Q000008:administration & dosage* / Q000009:adverse effects; D013997:Time Factors; D016896:Treatment Outcome; D024502:alpha-Tocopherol / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D000276:Adjuvants, Immunologic; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D015415:Biomarkers; D004338:Drug Combinations; D007252:Influenza Vaccines; D011136:Polysorbates; D013185:Squalene; C550253:AS03 adjuvant; D024502:alpha-Tocopherol