Efficacy and Safety Evaluation of MF59-Adjuvanted Influenza Vaccine Versus Non-Adjuvanted Vaccine in Adults Aged 65 and Older

The primary objective of this study is to demonstrate the **efficacy** of the MF59-adjuvanted influenza vaccine in preventing RT-PCR-confirmed influenza A and/or B disease due to any influenza strain when compared to a non-adjuvanted influenza vaccine in adults aged 65 years and older. This is clinically relevant as it addresses the need for effective influenza prevention in an older population, which is at higher risk for severe influenza-related complications.

Secondary objectives include:

• Evaluating the efficacy of the MF59-adjuvanted influenza vaccine in preventing influenza A and/or B disease due to strains antigenically matched to the seasonal vaccine strains, compared to a non-adjuvanted vaccine.
• Assessing the efficacy in preventing culture-confirmed influenza A and/or B disease due to any strain, regardless of antigenic match, compared to a non-adjuvanted vaccine.
• Evaluating the efficacy in preventing RT-PCR-confirmed influenza A and/or B disease using modified CDC and WHO ILI definitions.
• Assessing the efficacy in preventing influenza A and/or B disease due to strains antigenically unmatched to the seasonal vaccine strains.
• Evaluating the **immunogenicity** of the MF59-adjuvanted vaccine compared to the non-adjuvanted vaccine, measured by HI assay against homologous vaccine strains before and 21 days after vaccination.
• Assessing the **safety** of the MF59-adjuvanted vaccine compared to the non-adjuvanted vaccine, determined by the occurrence of adverse events, serious adverse events, and adverse events of special interest during the study period.

The clinical trial involved a total of **30,650** participants, focusing on the prevention of **influenza virus** infections. The study population comprised adults aged **65 years and older**, including both male and female subjects. Participants were selected based on their ability to comply with study procedures and their voluntary provision of written informed consent. The trial did not specify any particular lifestyle considerations such as diet or physical activity. The study included a vulnerable population, emphasizing the importance of careful monitoring and ethical considerations. The primary objective was to assess the efficacy of an MF59-adjuvanted influenza vaccine compared to a non-adjuvanted vaccine in preventing RT-PCR-confirmed influenza A and/or B disease.

The clinical trial is a **randomized**, observer-blind, multicenter study designed to evaluate the efficacy, safety, and immunogenicity of an MF59-adjuvanted subunit inactivated **influenza vaccine** compared to a non-adjuvanted influenza vaccine in adults aged 65 years and older. The trial aims to demonstrate the efficacy of the adjuvanted vaccine in preventing RT-PCR-confirmed influenza A and/or B disease. The study is expected to commence on October 2, 2023, and conclude by May 31, 2026, with the primary endpoint being the first occurrence of RT-PCR-confirmed influenza from 14 days post-vaccination until the end of the influenza season.

Participants will be involved in the study for the duration of the influenza season, with the primary endpoint assessed from 14 days after vaccination. The study visits will include an initial screening visit to confirm eligibility based on criteria such as age and informed consent. Following the screening, participants will receive a single dose of either the adjuvanted or non-adjuvanted vaccine via **intramuscular use**. Subsequent follow-up visits will monitor the occurrence of influenza-like illness (ILI) and assess safety through the reporting of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs). The end-of-study visit will occur at the conclusion of the influenza season to evaluate the final outcomes and collect any remaining data.

Participant involvement is expected to last for the duration of the influenza season, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The study will utilize a pre-filled syringe for vaccine administration, and the maximum daily and total dose is 0.5 ml. The trial will adhere to protocol-defined ILI definitions and utilize both the modified CDC and WHO ILI definitions for secondary endpoints. The study will also assess immunogenicity through serum HI10 antibody titers on Day 1 and Day 22 for selected subjects. The trial is not classified as low intervention and is conducted under the authorization of Seqirus UK Limited.

The clinical trial involves the administration of two influenza vaccines. The **Adjuvanted Trivalent Influenza Vaccine (aTIV)** is a suspension for injection, designed for **intramuscular use**. It contains the following active substances: **Influenza Virus B/Austria/1359417/2021-like strain (B/Austria/1359417/2021, BVR-26)**, **A/Victoria/4897/2022 (H1N1)pdm09-like strain (A/Victoria/4897/2022, IVR-238)**, and **Influenza Virus A/Thailand/8/2022 (H3N2) IVR-237-like strain (A/Thailand/8/2022)**. The vaccine is provided in a pre-filled syringe and is administered at a dosage of 0.5 ml. The maximum treatment period is one day, with a single dose being the total dose administered. This vaccine is produced by Seqirus UK Limited and is classified as a biological vaccine.

The comparator in the study is the **FLUARIX (Influenza Vaccine)**, also a suspension for injection intended for **intramuscular use**. It contains the same active substances as the aTIV: **Influenza Virus B/Austria/1359417/2021-like strain (B/Austria/1359417/2021, BVR-26)**, **A/Victoria/4897/2022 (H1N1)pdm09-like strain (A/Victoria/4897/2022, IVR-238)**, and **Influenza Virus A/Thailand/8/2022 (H3N2) IVR-237-like strain (A/Thailand/8/2022)**. This vaccine is also provided in a pre-filled syringe, with a dosage of 0.5 ml, and the maximum treatment period is one day, with a single dose being the total dose administered. It is also produced by Seqirus UK Limited and classified as a biological vaccine.

Both vaccines are not pediatric formulations and are not classified as orphan drugs. Participant compliance with the dosing schedule is monitored to ensure adherence to the protocol. The trial aims to evaluate the efficacy, safety, and immunogenicity of the MF59-adjuvanted subunit inactivated influenza vaccine compared to the non-adjuvanted influenza vaccine in adults aged 65 years and older.

The efficacy of the MF59-adjuvanted influenza vaccine will be assessed in a Phase 3/3b, randomized, observer-blind, multicenter clinical trial. The primary endpoint for evaluating efficacy is the first occurrence of **RT-PCR-confirmed influenza** due to any influenza Type A and/or B virus, regardless of antigenic match, occurring from 14 days after vaccination until the end of the influenza season. This will be measured using the protocol-defined influenza-like illness (ILI) definition.

Secondary endpoints include the first occurrence of culture-confirmed influenza due to influenza Type A and/or B virus antigenically matched to the vaccine strains, and the first occurrence of culture-confirmed influenza due to any influenza Type A and/or B virus, regardless of antigenic match. These occurrences will also be measured from 14 days post-vaccination until the end of the influenza season, using both the protocol-defined ILI definition and the modified CDC and WHO ILI definitions. Additionally, immunogenicity will be assessed by measuring serum HI10 antibody titers on Day 1 and Day 22 for four vaccine homologous influenza strains in a subset of subjects.