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Influenza poses a significant global healthcare burden, with up to 1 billion infections annually, and poorer outcomes in vulnerable populations such as older adults. Vaccination effectiveness is often lower in elderly individuals. By adding an adjuvant and using cell-based vaccine production methods, the MF59-adjuvanted quadrivalent cell-based influenza vaccine (aQIVc) may boost immunogenicity and vaccine effectiveness in this population. We report the results of a randomised proof-of-concept study, investigating the immunogenicity and safety of aQIVc. Eligible participants aged ≥50 years were randomised 1: 1:1:1 to receive aQIVc (n = 116), a non-adjuvanted quadrivalent cell-based influenza vaccine (QIVc; n = 119), an MF59-adjuvanted quadrivalent egg-based influenza vaccine (aQIV; n = 116), or a high-dose quadrivalent recombinant influenza vaccine (QIVr; n = 120). The primary objective was to assess immunogenicity of aQIVc vs the comparators by haemagglutination inhibition (HI) assay 28 days post-vaccination. Secondary objectives included immunogenicity of aQIVc vs comparators 28 days and 180 post-vaccination by microneutralisation assay and 180 days post-vaccination by HI assay; and reactogenicity and safety of all study vaccines. Compared with QIVc and aQIV, aQIVc elicited a higher immune response (adjusted geometric mean titre [GMT] ratio range 1.18–1.85) against all four influenza strains at Day 29. Against QIVr, aQIVc elicited lower responses against A strains (adjusted GMT ratio range 0.79–0.84), and higher responses against B strains (adjusted GMT ratio range 1.15–1.26). Estimated GMT ratios were generally higher in the subgroup of participants aged ≥65 years vs those aged 50–64 years. aQIVc was well tolerated, eliciting similar rates of solicited local adverse events (AE) and slightly higher rates of solicited systemic AE than aQIV, and a higher rate of all solicited AE than QIVc and QIVr. No safety concern was identified. These data support further investigation of additional formulations of aQIVc in adults aged ≥50 years. Clinical trial registry:NCT04576702 •We assessed an adjuvanted, cell-based influenza vaccine (aQIVc) in adults ≥50 years•aQIVc elicited higher immune responses than a non-adjuvanted comparator•aQIVc elicited higher immune responses than an egg-based adjuvanted comparator•aQIVc showed an acceptable safety profile; no safety concerns were identified•These data are proof-of-concept for seasonal aQIVc vaccination in adults ≥50 years

The optimal formulation of an adjuvanted cell-based quadrivalent influenza vaccine (aQIVc) was investigated in Phase 2, observer-blind, multicentre, dose-finding (V201_01, NCT04782323) and dose-confirmation (V201_07, NCT05501561) studies in participants aged ≥50 years. In V201_01, participants were randomised to one of seven investigational aQIVc formulations or non-adjuvanted QIVc (15 μg haemagglutinin antigen [HA] per strain). Investigational formulations contained 15, 30, or 45 μg HA per strain, and 1×, 2×, and 3× the dose of MF59 adjuvant included in Fluad®. In V201_07, participants were randomised to aQIVc [45,1×], aQIVc [45,2×], QIVc [45,0×: 45 μg HA, 0×MF59] or QIVc [15,0×: 15 μg HA, 0× MF59]. Primary objective: to assess the immunogenicity of aQIVc formulations vs. QIVc 28 days post-vaccination. In V201_01, 838 participants (47.3% aged ≥65 years; 56.6% female; 55.9% White) were exposed. Generally, covariate-adjusted geometric mean titre ratios (GMTr) of aQIVc vs. QIVc at Day 29 (per-protocol set [PPS; n = 810]) increased with antigen and adjuvant dose but were similar between 2× and 3× adjuvant. In V201_07, 1051 participants (47.9% aged ≥65 years; 58.0% female; 83.7% White) were exposed (PPS; n = 1022). GMTr for aQIVc [45,2×] vs. QIVc [15,0×] ranged from 1.27 (95% confidence interval [CI], 1.04, 1.55) to 1.86 (1.52, 2.27) and were superior (lower limit of 95% CI >1.0) for all strains. GMTr of aQIVc [45,2×] vs. QIVc [45,0×] were superior for A/H1N1, A/H3N2, and B/Yamagata, and non-inferior for B/Victoria. Neither study presented safety concerns. In V201_07, rates of solicited adverse events (Day 1–7 post-vaccination) were highest with aQIVc [45,2×] (71.1%) and lowest with QIVc [15,0×] (50.4%); most events were mild (Grade 1) or moderate (Grade 2) severity across all groups. aQIVc [45,2×] demonstrated the highest immune response of all formulations tested, with no safety concerns, and was selected for further investigation in a Phase 3 study (NCT06015282). Clinical trial registry: NCT04782323 (https://clinicaltrials.gov/study/NCT04782323; registered date 2021-03-01), NCT05501561 (https://clinicaltrials.gov/study/NCT05501561; registered date 2022-08-11). [Display omitted] •Enhanced flu vaccines that avoid egg adaptation are needed for those aged ≥50 years.•We sought the ideal formulation of aQIVc vaccine: adjuvanted, cell-based, higher-dose.•aQIVc [45 μg HA, 2×MF59] showed the highest immune response of all those tested.•Two dose-ranging studies showed the favourable benefit:risk profile of aQIVc [45,2×].•aQIVc [45,2×] was selected for investigation in a Phase 3 study.

► Vero cell-derived whole-virus H1N1 vaccine was well tolerated, inducing low adverse reaction rates (overall fever rate: 6% after the first vaccination; 7% after the second vaccination) in children and adolescents. ► Two vaccinations with the 7.5μg dose induced high seroprotection rates in all subjects ranging from 84.2% to 100%. ► Persistence of antibodies against the vaccine strain was demonstrated at 6 months (GMTs ranging from 65.6 to 212.8) and at 12 months (GMTs ranging from 33.6 to 124.1) after primary vaccination. ► Vaccination with a seasonal influenza vaccine induced a strong booster response to the A/California/07/2009 strain reaching 100% seroprotection in all age groups, with GMTs ranging from 640.0 to 886.3. This phase 1/2 open-label, randomized clinical study investigated the safety and immunogenicity of a non-adjuvanted, whole virus, Vero cell-derived H1N1 pandemic influenza vaccine (A/H1N1/California/07/2009) in children and adolescents (6 months to 17 years). Subjects were stratified by age (6–11 months, 12–35 months, 3–8 years, 9–17 years) to receive two vaccinations 21 days apart of either the 3.75μg or 7.5μg dose. A booster with a licensed trivalent seasonal (2010/2011) influenza vaccine was administered one year after the first vaccination to a subgroup that had previously received the 7.5μg dose. A single vaccination with the 7.5μg dose induced high seroprotection rates in all subjects, namely: 88.0% (9–17 years); 68.0% (3–8 years); 42.9% (12–35 months); and 50.0% (6–11 months). Following a second vaccination, seroprotection rates ranged from 84.2% to 100%. GMTs after two vaccinations with the 7.5μg dose (as determined by HI) were also substantial: reaching 210.0 (9–17 years), 196.2 (3–8 years), 118.9 (12–35 months) and 99.6 (6–11 months). Antibody persistence was demonstrated at 6 months (GMTs ranging from 65.6 to 212.8 with the 7.5μg dose) and at 12 months (GMTs ranging from 33.6 to 124.1 with the 7.5μg dose) after primary vaccination. The booster vaccination induced a strong response to the A/California/07/2009 strain, reaching 100% seroprotection in all age groups, with GMTs ranging from 640.0 to 886.3. The vaccine was well tolerated, inducing low adverse reaction rates (overall fever rate: 6% after the first vaccination; 7% after the second vaccination), even in young children. These data confirm that the H1N1 whole-virus Vero cell-derived pandemic influenza vaccine is suitable for use in children and adolescents; a 2-dose primary vaccination induces a memory response in a naïve population that can be effectively boosted with the A/H1N1/California/07/2009 component of a seasonal influenza vaccine. ClinicalTrials.gov Identifier: NCT00976469.