title: Challenge of conducting a placebo-controlled randomized efficacy study for influenza vaccine in a season with low attack rate and a mismatched vaccine B strain: a concrete example.
abstract: BACKGROUND
  Our aim was to determine the efficacy of a trivalent inactivated split virus influenza vaccine (TIV) against culture-confirmed influenza A and/or B in adults 18 to 64 years of age during the 2005/2006 season in the Czech Republic.
  
  
  METHODS
  6203 subjects were randomized to receive TIV (N = 4137) or placebo (N = 2066). The sample size was based on an assumed attack rate of 4% which provided 90% power to reject the hypothesis that vaccine efficacy (VE) was > or = 45%. Cases of influenza like illness (defined as fever (oral temperature > or =37.8 degrees C) plus cough and/or sore throat) were identified both by active (biweekly phone contact) and passive (self reporting) surveillance and nasal and throat swabs were collected from subjects for viral culture.
  
  
  RESULTS
  TIV was well tolerated and induced a good immune response. The 2005/2006 influenza season was exceptionally mild in the study area, as it was throughout Europe, and only 46 culture-confirmed cases were found in the study cohort (10 influenza A and 36 influenza B). Furthermore among the B isolates, 35 were identified as B/Hong Kong 330/2001-like (B/Victoria/2/87 lineage) which is antigenically unrelated to the vaccine B strain (B/Yamagata/16/88 lineage). The attack rate in the vaccine group (0.7%) was not statistically significantly different from the attack rate in the placebo group (0.9%).
  
  
  CONCLUSIONS
  Due to the atypical nature of the influenza season during this study we were unable to assess TIV efficacy. This experience illustrates the challenge of conducting a prospective influenza vaccine efficacy trial during a single season when influenza attack rates and drift in circulating strains or B virus lineage match can be difficult to estimate in advance.
  
  
  BACKGROUND
  Clinical trial registery: NCT00197223.
authors.affiliation: The Vaccination and Travel Medicine Center, Hradec Kralove, Czech Republic. jiri.beran@vakcinace.cz
authors.forename: Jirí
authors.initials: J
authors.lastname: Beran
authors.forename: Veronika
authors.initials: V
authors.lastname: Wertzova
authors.forename: Karel
authors.initials: K
authors.lastname: Honegr
authors.forename: Eva
authors.initials: E
authors.lastname: Kaliskova
authors.forename: Martina
authors.initials: M
authors.lastname: Havlickova
authors.forename: Jirí
authors.initials: J
authors.lastname: Havlik
authors.forename: Helena
authors.initials: H
authors.lastname: Jirincova
authors.forename: Pascale
authors.initials: P
authors.lastname: Van Belle
authors.forename: Varsha
authors.initials: V
authors.lastname: Jain
authors.forename: Bruce
authors.initials: B
authors.lastname: Innis
authors.forename: Jeanne-Marie
authors.initials: JM
authors.lastname: Devaster
mesh_terms: D000293:Adolescent; D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology; D018153:Czech Republic / Q000453:epidemiology; D004311:Double-Blind Method; D005260:Female; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D053122:Influenza A Virus, H3N2 Subtype / Q000276:immunology; D009981:Influenza B virus / Q000276:immunology; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D007251:Influenza, Human / Q000453:epidemiology* / Q000517:prevention & control*; D008297:Male; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D015164:Vaccines, Inactivated