Immunogenicity, reactogenicity and safety of an inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine: a phase III, randomized trial in adults aged ≥18 years

Abstract

BackgroundTwo antigenically distinct influenza B lineages have co-circulated since the 1980s, yet inactivated trivalent influenza vaccines (TIVs) include strains of influenza A/H1N1, A/H3N2, and only one influenza B from either the Victoria or Yamagata lineage. This means that exposure to B-lineage viruses mismatched to the TIV is frequent, reducing vaccine protection. Formulations including both influenza B lineages could improve protection against circulating influenza B viruses. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages versus TIV in adults in stable health.MethodsA total of 4659 adults were randomized 5:5:5:5:3 to receive one dose of QIV (one of three lots) or a TIV containing either a B/Victoria or B/Yamagata strain. Hemagglutination-inhibition assays were performed pre-vaccination and 21-days after vaccination. Lot-to-lot consistency of QIV was assessed based on geometric mean titers (GMT). For QIV versus TIV, non-inferiority against the three shared strains was demonstrated if the 95% confidence interval (CI) upper limit for the GMT ratio was ≤1.5 and for the seroconversion difference was ≤10.0%; superiority of QIV versus TIV for the alternate B lineage was demonstrated if the 95% CI lower limit for the GMT ratio was > 1.0 and for the seroconversion difference was > 0%. Reactogenicity and safety profile of each vaccine were assessed. Clinicaltrials.gov: NCT01204671.ResultsConsistent immunogenicity was demonstrated for the three QIV lots. QIV was non-inferior to TIV for the shared vaccine strains, and was superior for the added alternate-lineage B strains. QIV elicited robust immune responses against all four vaccine strains; the seroconversion rates were 77.5% (A/H1N1), 71.5% (A/H3N2), 58.1% (B/Victoria), and 61.7% (B/Yamagata). The reactogenicity and safety profile of QIV was consistent with TIV.ConclusionsQIV provided superior immunogenicity for the additional B strain compared with TIV, without interfering with antibody responses to the three shared antigens. The additional antigen did not appear to alter the safety profile of QIV compared with TIV. This suggests that the candidate QIV is a viable alternative to TIV for use in adults, and could potentially improve protection against influenza B.Trial registrationClinical Trials.gov: NCT01204671/114269

Epidemiology of influenza B in Australia: 2001‐2014 influenza seasons

“…Since 2012, following recommendations by WHO, a quadrivalent influenza vaccine (QIV) (with two A strains and two B lineages) became available to avoid the risk of B lineage vaccine mismatches. The QIV offers improved protection against unmatched influenza B infections and has comparable safety measures to TIV in both children and adults 38, 39, 40…”

Evaluating the case for trivalent or quadrivalent influenza vaccines

“…There were no differences between the trivalent and quadrivalent preparations with regard to safety and reactogenicity. [36][37][38][39][40][41] There is an increased cost associated with the use of quadrivalent vaccines but modeling studies suggest a significant societal cost saving even if the cost is significantly higher than the trivalent preparation. [42][43][44] …”

Evidence update: GlaxoSmithKline’s inactivated quadrivalent influenza vaccines

“…[63] Importantly, D-IIV4 manufacturing consistency was confirmed by demonstrating equivalent immunogenicity per strain for three consecutive vaccine lots. [63] A Reactogenicity and safety IIV4s contain 25% more inactivated split virus antigen quantified as hemagglutinin than do IIV3s; therefore, increased reactogenicity change in its safety profile were risks that had to be assessed in the clinical trial program. Overall, D-IIV4 had an acceptable safety profile in all four studies (Supplementary File 2).…”

“…Clinical studies were conducted in adults aged 18-60 years, [62] adults aged ≥18 years, [63] children aged 18-47 months, [64] In a sub-group analysis by age, though immune responses were generally lower for subjects aged ≥65 years than those aged 18-65 years, the D-IIV4 candidate was immunogenic for all four vaccine strains, and HI antibody responses against all strains fulfilled CBER immunogenicity acceptance criteria in both age strata (18-65 years, and ≥65 years). [63] Importantly, D-IIV4 manufacturing consistency was confirmed by demonstrating equivalent immunogenicity per strain for three consecutive vaccine lots. [63] A Reactogenicity and safety IIV4s contain 25% more inactivated split virus antigen quantified as hemagglutinin than do IIV3s; therefore, increased reactogenicity change in its safety profile were risks that had to be assessed in the clinical trial program.…”

“…Most injection site and general adverse events (AEs) were transient in nature, mild to moderate in severity, and similar in frequency between D-IIV4 and IIV3 groups. In all studies, [62][63][64][65] the rates of unsolicited AEs over 21-28 days after vaccination and of medically attended and serious AE (SAE) during the entire clinical trials were comparable between D-IIV4 and IIV3 groups. These outcomes provided assurance that D-IIV4 posed no incremental safety risk relative to IIV3s.…”