Phase 3 Study on Immunogenicity and Safety of High-Dose MF59-Adjuvanted Quadrivalent Influenza Vaccine in Adults Aged 50+ with Stable Comorbidities

The primary objective of this Phase 3, randomized, observer-blind, controlled, multicenter clinical study is to demonstrate the clinical lot-to-lot consistency of three consecutive lots of the high-dose MF59-adjuvanted quadrivalent subunit cell-derived influenza vaccine (**aQIVc HD**) in terms of **immunogenicity** for each vaccine strain in adults aged 50 years and older. This is measured by the hemagglutination inhibition (HI) assay using cell-derived target viruses at Day 29. Additionally, the study aims to establish the immunological noninferiority of aQIVc HD compared to a non-adjuvanted quadrivalent recombinant influenza vaccine (QIVr) and an MF59-adjuvanted quadrivalent subunit egg-derived influenza vaccine (aQIV) for each vaccine strain in the same age group, as measured by HI geometric mean titers (GMTs) and seroconversion rates (SCRs) at Day 29. The clinical relevance of this objective lies in ensuring the consistent efficacy of the vaccine across different production lots, which is crucial for maintaining public health safety and confidence in influenza vaccination programs.

Secondary objectives include: - Demonstrating the immunological noninferiority of aQIVc HD versus aQIV for each vaccine strain in subjects aged 65 years and older, as measured by HI GMTs and SCRs at Day 29. - Comparing the immunogenicity of aQIVc HD versus QIVr for each vaccine strain in subjects aged 50 years and older, in terms of superiority as measured by the HI assay at Day 29. - Comparing the immunogenicity of aQIVc HD versus aQIV for each vaccine strain in subjects aged 50 years and older, in terms of superiority as measured by the HI assay at Day 29. - Comparing the immunogenicity of aQIVc HD versus aQIV for each vaccine strain in subjects aged 65 years and older, in terms of superiority as measured by the HI assay at Day 29. - Assessing the reactogenicity from Day 1 to Day 7 and the safety from Day 1 to Day 365 of aQIVc HD, QIVr, and aQIV in subjects aged 50 years and older, overall and by age subgroup (50-64 years; 65 years and older).

The clinical trial involves a total of **4200 participants** who are either **healthy individuals** or those with stable comorbidities that increase their risk of complications from **influenza** infection. The study population consists of both male and female subjects aged **50 years and older**. Participants were selected based on their ability to comply with all study procedures and their health status, which includes either being healthy or having stable comorbidities. The trial does not specify any particular lifestyle considerations such as diet or physical activity. The population includes a vulnerable group, as it involves individuals with conditions that may predispose them to higher risks from influenza. The selection criteria ensure that the participants are representative of the target demographic for the study's objectives.

The clinical trial is designed as a **randomized**, observer-blind, controlled, multicenter study to evaluate the **immunogenicity** and safety of a high-dose MF59-adjuvanted quadrivalent subunit cell-derived influenza vaccine (aQIVc HD) in comparison with a non-adjuvanted quadrivalent recombinant influenza vaccine (QIVr) and an MF59-adjuvanted quadrivalent subunit egg-derived influenza vaccine (aQIV) in adults aged 50 years and older. The trial aims to demonstrate clinical lot-to-lot consistency of three consecutive aQIVc HD lots in terms of immunogenicity for each vaccine strain, as measured by hemagglutination inhibition (HI) assay using cell-derived target viruses at Day 29. Additionally, the trial seeks to establish immunological noninferiority of aQIVc HD compared to QIVr and aQIV for each vaccine strain, using HI geometric mean titers (GMTs) and seroconversion rates (SCRs) at Day 29.

The trial is expected to last until June 28, 2025, with recruitment starting on October 2, 2023. Participants will be involved in the study for a maximum treatment period of one day, with follow-up assessments extending to Day 365 to monitor safety outcomes. The study includes several key visits: an initial screening visit to confirm eligibility based on inclusion criteria, which require participants to be aged 50 years or older and either healthy or with stable comorbidities that increase their risk of complications from **influenza** infection. Participants must also be able to comply with all study procedures. The primary endpoint involves comparing immunogenicity responses of the three lots of aQIVc HD in terms of Day 29 ratio of Geometric Mean Titer (GMTr) and seroconversion rates. Secondary endpoints include safety assessments and further immunogenicity comparisons among the vaccines.

Study visits are structured as follows: the inclusion visit involves screening and baseline assessments, followed by the administration of the vaccine. Participants will return for follow-up visits on Day 29 to assess immunogenicity and safety, with additional safety follow-ups extending to Day 365. The end-of-study visit will conclude the participant's involvement, ensuring all safety data is collected. Conditions that may lead to early termination from the study include the occurrence of serious adverse events, adverse events leading to withdrawal, or any medically attended adverse events that compromise participant safety. The trial is not categorized as low intervention, given its phase 3 status and the use of a vaccine not currently authorized in the population involved.

The clinical trial involves the administration of several **experimental medications** and comparator treatments. The primary experimental medication is the **adjuvanted Quadrivalent Subunit Inactivated Cell-derived Influenza Vaccine** (aQIVc), which is a suspension for injection. This vaccine contains multiple active substances, including A/(H3N2)-like virus antigen, B (Yamagata lineage)-like virus antigen, B (Victoria lineage)-like virus antigen, and A/H1N1 influenza vaccine. The vaccine is administered via injection, with a maximum daily and total dose of 1.0 ml. The treatment period is limited to a single administration. The vaccine is delivered using a pre-filled syringe, which is a single integral product intended for one-time use.

Another experimental treatment in the study is the **A/DARWIN/9/2021 (H3N2) - LIKE STRAIN** (A/DARWIN/6/2021, IVR-227), which is also a suspension for injection. This vaccine is administered via injection with a maximum daily and total dose of 0.5 ml. The treatment period is limited to one administration. The vaccine is provided in a pre-filled syringe, ensuring it is not reusable.

The study also includes the **B/PHUKET/3073/2013-LIKE STRAIN** (B/PHUKET/3073/2013, BVR-1B) as a comparator treatment. This suspension for injection is administered via injection with a maximum daily and total dose of 0.5 ml. The treatment period is limited to one administration. The vaccine is delivered in a pre-filled syringe, designed for single use only.

Additionally, the **INFLUENZA VIRUS B/AUSTRIA/1359417/2021-LIKE STRAIN** (B/AUSTRIA/1359417/2021, BVR-26) is used as a comparator. This suspension for injection is administered via injection with a maximum daily and total dose of 0.5 ml. The treatment period is limited to one administration. The vaccine is provided in a pre-filled syringe, ensuring it is not reusable.

The trial also includes the **INFLUENZA B VIRUS YAMAGATA LINEAGE HAEMAGGLUTININ, RECOMBINANT**, which is a solution for injection. This vaccine is administered via injection with a maximum daily and total dose of 0.5 ml. The treatment period is limited to one administration. The vaccine is delivered in a pre-filled syringe, designed for single use only.

Another comparator treatment is the **INFLUENZA A VIRUS SUBTYPE H1N1 HAEMAGGLUTININ, RECOMBINANT**, which is a solution for injection. This vaccine is administered via injection with a maximum daily and total dose of 0.5 ml. The treatment period is limited to one administration. The vaccine is provided in a pre-filled syringe, ensuring it is not reusable.

The study also includes the **A/VICTORIA/2570/2019 (H1N1)PDM09-LIKE STRAIN** (A/VICTORIA/2570/2019, IVR-215) as a comparator. This suspension for injection is administered via injection with a maximum daily and total dose of 0.5 ml. The treatment period is limited to one administration. The vaccine is delivered in a pre-filled syringe, designed for single use only.

Additionally, the **INFLUENZA A VIRUS SUBTYPE H3N2 HAEMAGGLUTININ, RECOMBINANT** is used as a comparator. This solution for injection is administered via injection with a maximum daily and total dose of 0.5 ml. The treatment period is limited to one administration. The vaccine is provided in a pre-filled syringe, ensuring it is not reusable.

Finally, the **INFLUENZA B VIRUS VICTORIA LINEAGE HAEMAGGLUTININ, RECOMBINANT** is included as a comparator treatment. This solution for injection is administered via injection with a maximum daily and total dose of 0.5 ml. The treatment period is limited to one administration. The vaccine is delivered in a pre-filled syringe, designed for single use only.

The efficacy of the high-dose MF59-adjuvanted quadrivalent subunit cell-derived influenza vaccine (aQIVc HD) will be assessed through a series of immunogenicity endpoints. The primary endpoints include the evaluation of immunogenicity responses of three consecutive lots of aQIVc HD, compared in pairs, by measuring the Day 29 ratio of Geometric Mean Titer (GMTr) from antibodies via the hemagglutination inhibition (HI) assay using cell-derived target viruses for the four vaccine strains. Additionally, the immunogenicity responses of aQIVc HD will be compared to a non-adjuvanted quadrivalent recombinant influenza vaccine (QIVr) and an MF59-adjuvanted quadrivalent subunit egg-derived influenza vaccine (aQIV) in terms of Day 29 Geometric Mean Titer (GMT) and GMTr, as well as the Day 1 to Day 29 Seroconversion Rate (SCR) and SCR difference.

Secondary endpoints will further assess the immunogenicity responses of aQIVc HD in comparison with aQIV in subjects aged 65 years and older, focusing on Day 29 GMT and GMT ratio of antibodies for the A/H1N1, A/H3N2, B/Yamagata, and B/Victoria vaccine strains, along with the Day 1 to Day 29 SCR and SCR difference. The study will also evaluate the safety of aQIVc HD, QIVr, and aQIV by monitoring the percentage of subjects experiencing solicited local and systemic reactions from Day 1 to Day 7, unsolicited adverse events from Day 1 to Day 29, and serious adverse events, adverse events leading to withdrawal, adverse events of special interest, and medically attended adverse events from Day 1 to Day 365.