Immunogenicity and safety of an MF59-adjuvanted cell-derived higher-dose quadrivalent influenza vaccine (aQIVc) in adults aged 50 years or older: a phase 3 randomised controlled trial.

BACKGROUND: Combining the benefits of adjuvant, cell-based manufacturing and a higher dose of antigen could boost immune responses in older adults. We aimed to evaluate the immunogenicity and safety of an MF59-adjuvanted cell-derived higher-dose quadrivalent influenza vaccine (aQIVc) compared with MF59-adjuvanted egg-derived quadrivalent influenza vaccine (aQIV) and recombinant quadrivalent influenza vaccine (QIVr) in adults aged 50 years or older. METHODS: This phase 3, randomised, observer-blind, parallel-group, multicentre study randomly assigned (3:2:2) healthy adults aged 50 years or older to aQIVc, aQIV, or QIVr via an interactive response technology system, using a permuted block randomisation method (block size of seven), with stratification by age group (50-64 or ≥65 years), history of any influenza vaccination (previous three influenza seasons), and study site. aQIVc contains haemagglutinin (HA; 45 μg per strain) and MF59 (19·5 mg squalene); aQIV contains 15 μg HA per strain and MF59 (9·75 mg squalene); and QIVr contains 45 μg HA per strain. Participants received one vaccine dose (day 1; intramuscular injection). Primary immunogenicity objectives were lot-to-lot consistency of three batches of aQIVc (met if the 95% CI of the day-29 geometric mean titre [GMT] ratios was 0·67-1·5 for the pairwise comparison of each vaccine strain) and non-inferiority of aQIVc versus aQIV and QIVr (met if the lower bound 97·5% CI for day-29 GMT ratio and seroconversion rate differences were 0·67 or higher and -10% or higher, respectively, per strain) in the per-protocol set. Safety was assessed through solicited (days 1-7) and unsolicited (days 1-29) adverse events, with a subset of unsolicited adverse events collected until end of study (day 365). This trial was registered with ClinicalTrials.gov (NCT06015282). FINDINGS: Between Nov 3, 2023, and Jan 30, 2024, 7699 adults aged 50 years or older were randomly assigned, of whom 7677 were included in the all exposed set (aQIVc, n=3283; aQIV, n=2205; QIVr, n=2189; as randomised) and 7419 were in the per-protocol set (aQIVc, n=3175; aQIV, n=2129; QIVr, n=2115). Lot-to-lot consistency criteria were fully met. aQIVc was non-inferior and superior (lower bound 97·5% CI of day-29 GMT ratio was more than 1·0; secondary objective) to aQIV at day 29: GMT ratio was 1·53 (97·5% CI 1·43 to 1·64) for A/H1N1, 1·22 (1·15 to 1·30) for A/H3N2, 1·73 (1·63 to 1·85) for B/Victoria, and 1·71 (1·63 to 1·80) for B/Yamagata, and corresponding seroconversion rate differences were 16·8% (97·5% CI 13·9 to 19·8), 9·5% (6·4 to 12·5), 21·9% (18·8 to 24·9), and 24·3% (21·3 to 27·2), respectively. Compared with QIVr, non-inferiority criteria were met for three strains, but not A/H3N2: GMT ratio was 0·93 (97·5% CI 0·87 to 1·00) for A/H1N1, 0·69 (0·65 to 0·74) for A/H3N2, 1·41 (1·33 to 1·50) for B/Victoria, and 1·33 (1·27 to 1·40) for B/Yamagata, and seroconversion rate differences were 1·5% (97·5% CI -1·2 to 4·3), -7·4% (-10·3 to -4·6), 11·6% (8·5 to 14·7), and 13·4% (10·3 to 16·5), respectively. aQIVc was well tolerated; despite higher rates of local and systemic adverse events versus aQIV and QIVr, most were mild-to-moderate, transient, and self-resolved. Serious adverse events were low across all vaccine groups (days 1-181; 91 [2·8%] of 3282 with aQIVc; 78 [3·5%] of 2204 with aQIV; and 64 [2·9%] of 2191 with QIVr). INTERPRETATION: In adults aged 50 years or older, aQIVc was non-inferior and superior to aQIV for all four influenza strains and non-inferiority criteria for aQIVc versus QIVr were met for A/H1N1 and both B strains, but not A/H3N2. No safety concerns were identified. FUNDING: CSL Seqirus.