title: A historically-controlled Phase III study in adults to characterize the acceptability of a process change for manufacturing inactivated quadrivalent influenza vaccine.
abstract: BACKGROUND
  An inactivated quadrivalent influenza vaccine (QIV) was recently licenced in the US as a thimerosal-free formulation presented in a pre-filled syringe. A multidose presentation is preferred in some settings due to reduced acquisition and cold storage costs. We assessed the immunogenicity and safety of a thimerosal-containing QIV formulated using a new manufacturing process for presentation in multidose vials.
  
  
  METHODS
  Two Phase III non-randomized studies separately evaluated inactivated trivalent influenza vaccine (TIV; 2010-2011; historical control) and a QIV (2011-2012). The QIV contained the same strains as the TIV plus an additional B strain. Both vaccines contained thimerosal to allow multidose presentation: this preservative was added to the QIV during the final formulation step using a new process, whereas it was added to the TIV early in the manufacturing process using an established method. The TIV study included 50 and 70 subjects aged 18-60 and >60 years, respectively; the QIV study included 56 subjects in each age stratum. Immunogenicity was assessed using hemagglutination-inhibition (HI) assays. Reactogenicity was assessed during the 4-day post-vaccination periods and unsolicited adverse events (AEs) were assessed during the 21-day post-vaccination periods.
  
  
  RESULTS
  The TIV and QIV were immunogenic in both age strata. With the QIV and TIV respectively, the seroconversion rates were 48.2-62.7% and 71.4-83.7% for influenza A, and 33.9-62.5% and 67.3-72.9% for influenza B. With the QIV and TIV respectively, the seroprotection rates were 92.9-98.2% and 98.2-100% for influenza A, and 88.6-100% and 95.9-98.6% for influenza B. Pre-vaccination titers were higher in the QIV versus TIV study which confounds a direct comparison and likely explains the lower seroconversion rates observed in the QIV study. There were no safety concerns raised with TIV or QIV.
  
  
  CONCLUSIONS
  The thimerosal-containing QIV formulated using a new process was immunogenic, conforming to regulatory acceptance criteria, with a reactogenicity and safety profile in line with the TIV manufactured using a licensed process. These results support acceptability of a manufacturing process change in which the thimerosal preservative is added at the point at which batches are filled into multidose vials.
  
  
  BACKGROUND
  These trials were registered at ClinicalTrials.gov: NCT01440387; NCT01153685.
authors.affiliation: GlaxoSmithKline Vaccines, GCDC Non Ops, King of Prussia, PA, USA. Varsha.K.Jain@gsk.com.
authors.forename: Varsha K
authors.initials: VK
authors.lastname: Jain
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Chandrasekaran
authors.forename: Long
authors.initials: L
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Aixue
authors.initials: A
authors.lastname: Liu
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Innis
mesh_terms: D000293:Adolescent; D000328:Adult; D004339:Drug Compounding; D005260:Female; D065386:Historically Controlled Study; D006801:Humans; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry*; D007251:Influenza, Human / Q000276:immunology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D013849:Thimerosal / Q000008:administration & dosage / Q000009:adverse effects / Q000737:chemistry; D055815:Young Adult
chemical_list: D007252:Influenza Vaccines; D013849:Thimerosal