title: AS03-adjuvanted versus non-adjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial.
abstract: BACKGROUND
  We aimed to compare AS03-adjuvanted inactivated trivalent influenza vaccine (TIV) with non-adjuvanted TIV for seasonal influenza prevention in elderly people.
  
  
  METHODS
  We did a randomised trial in 15 countries worldwide during the 2008-09 (year 1) and 2009-10 (year 2) influenza seasons. Eligible participants aged at least 65 years who were not in hospital or bedridden and were without acute illness were randomly assigned (1:1) to receive either AS03-adjuvanted TIV or non-adjuvanted TIV. Randomisation was done in an internet-based system, with a blocking scheme and stratification by age (65-74 years and 75 years or older). Participants were scheduled to receive one vaccine in each year, and remained in the same group in years 1 and 2. Unmasked personnel prepared and gave the vaccines, but participants and individuals assessing any study endpoint were masked. The coprimary objectives were to assess the relative efficacy of the vaccines and lot-to-lot consistency of the AS03-adjuvanted TIV (to be reported elsewhere). For the first objective, the primary endpoint was relative efficacy of the vaccines for prevention of influenza A (excluding A H1N1 pdm09) or B, or both, that was confirmed by PCR analysis in year 1 (lower limit of two-sided 95% CI had to be greater than zero to establish superiority). From Nov 15, to April 30, in both years, participants were monitored by telephone or site contact and home visits every week or 2 weeks to identify cases of influenza-like illness. After onset of suspected cases, we obtained nasal and throat swabs to identify influenza RNA with real-time PCR. Efficacy analyses were done per protocol. This trial is registered with ClinicalTrials.gov, number NCT00753272.
  
  
  RESULTS
  We enrolled 43 802 participants, of whom 21 893 were assigned to and received the AS03-adjuvanted TIV and 21 802 the non-adjuvanted TIV in year 1. In the year 1 efficacy cohort, fewer participants given AS03-adjuvanted than non-adjuvanted TIV were infected with influenza A or B, or both (274 [1·27%, 95% CI 1·12-1·43] of 21 573 vs 310 [1·44%, 1·29-1·61] of 21 482; relative efficacy 12·11%, 95% CI -3·40 to 25·29; superiority not established). Fewer participants in the year 1 efficacy cohort given AS03-adjuvanted TIV than non-adjuvanted TIV were infected with influenza A (224 [1·04%, 95% CI 0·91-1·18] vs 270 [1·26, 1·11-1·41]; relative efficacy 17·53%, 95% CI 1·55-30·92) and influenza A H3N2 (170 [0·79, 0·67-0·92] vs 205 [0·95, 0·83-1·09]; post-hoc analysis relative efficacy 22·0%, 95% CI 5·68-35·49).
  
  
  CONCLUSIONS
  AS03-adjuvanted TIV has a higher efficacy for prevention of some subtypes of influenza than does a non-adjuvanted TIV. Future influenza vaccine studies in elderly people should be based on subtype or lineage-specific endpoints.
  
  
  BACKGROUND
  GlaxoSmithKline Biologicals SA.
authors.affiliation: Health Sciences North and Advanced Medical Research Institute of Canada, Sudbury, ON, Canada.
authors.forename: Janet E
authors.initials: JE
authors.lastname: McElhaney
authors.forename: Jiri
authors.initials: J
authors.lastname: Beran
authors.forename: Jeanne-Marie
authors.initials: JM
authors.lastname: Devaster
authors.forename: Meral
authors.initials: M
authors.lastname: Esen
authors.forename: Odile
authors.initials: O
authors.lastname: Launay
authors.forename: Geert
authors.initials: G
authors.lastname: Leroux-Roels
authors.forename: Guillermo M
authors.initials: GM
authors.lastname: Ruiz-Palacios
authors.forename: Gerrit A
authors.initials: GA
authors.lastname: van Essen
authors.forename: Adrian
authors.initials: A
authors.lastname: Caplanusi
authors.forename: Carine
authors.initials: C
authors.lastname: Claeys
authors.forename: Christelle
authors.initials: C
authors.lastname: Durand
authors.forename: Xavier
authors.initials: X
authors.lastname: Duval
authors.forename: Mohamed
authors.initials: M
authors.lastname: El Idrissi
authors.forename: Ann R
authors.initials: AR
authors.lastname: Falsey
authors.forename: Gregory
authors.initials: G
authors.lastname: Feldman
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Frey
authors.forename: Florence
authors.initials: F
authors.lastname: Galtier
authors.forename: Shinn-Jang
authors.initials: SJ
authors.lastname: Hwang
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Innis
authors.forename: Martina
authors.initials: M
authors.lastname: Kovac
authors.forename: Peter
authors.initials: P
authors.lastname: Kremsner
authors.forename: Shelly
authors.initials: S
authors.lastname: McNeil
authors.forename: Andrzej
authors.initials: A
authors.lastname: Nowakowski
authors.forename: Jan Hendrik
authors.initials: JH
authors.lastname: Richardus
authors.forename: Andrew
authors.initials: A
authors.lastname: Trofa
authors.forename: Lidia
authors.initials: L
authors.lastname: Oostvogels
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000368:Aged; D000369:Aged, 80 and over; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D009980:Influenza A virus / Q000276:immunology* / Q000302:isolation & purification; D009981:Influenza B virus / Q000276:immunology* / Q000302:isolation & purification; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology* / Q000517:prevention & control* / Q000821:virology; D008297:Male; D008875:Middle Aged; D011136:Polysorbates / Q000008:administration & dosage*; D012621:Seasons; D013185:Squalene / Q000008:administration & dosage* / Q000276:immunology; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology; D024502:alpha-Tocopherol / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D004338:Drug Combinations; D007252:Influenza Vaccines; D011136:Polysorbates; D015164:Vaccines, Inactivated; D013185:Squalene; C550253:AS03 adjuvant; D024502:alpha-Tocopherol