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.

Trial registration: These trials were registered at ClinicalTrials.gov: NCT01440387; NCT01153685.

Figures

Figure 1

Subject flow. QIV, inactivated quadrivalent influenza vaccine. TIV, inactivated trivalent influenza vaccine

Figure 2

Seroprotection rates 21 days after QIV (A) or TIV (B) in the per-protocol immunogenicity cohort. QIV, inactivated quadrivalent influenza vaccine; TIV, inactivated trivalent influenza vaccine; Seroprotection rate defined as proportion with post-vaccination titer ≥1:40; European Union Committee for Medicinal Products for Human Use (CHMP) licensure threshold for seroprotection rate: ≥70% in the 18–60 years group, and ≥60% in the >60 years group [17].

Figure 3

Seroconversion rates 21 days after QIV (A) or TIV (B) in the per-protocol immunogenicity cohort. QIV, inactivated quadrivalent influenza vaccine; TIV, inactivated trivalent influenza vaccine; Seroconversion rate defined as the proportion with antibody titer <1:10 at baseline and with post-vaccination titer of ≥1:40, or pre-vaccination titer of ≥1:10 and a ≥4-fold post-vaccination increase in titer; European Union Committee for Medicinal Products for Human Use (CHMP) licensure threshold for seroconversion: >40% in the 18–60 years group, and >30% in the >60 years group [17].