Evaluation of Safety, Efficacy, and Immunogenicity of mRNA-1010 Influenza Vaccine Versus Inactivated Influenza Vaccine in Adults Aged 50 Years and Older

The primary objective of this study is to evaluate the **safety** and **reactogenicity** of the mRNA-1010 vaccine, as well as to assess its relative vaccine efficacy (rVE) compared to an active comparator against protocol-defined influenza-like illness (ILI) caused by any influenza A or B strains. This is clinically relevant as it aims to determine the safety profile and effectiveness of the mRNA-1010 vaccine in preventing influenza, which is crucial for public health, especially in adults aged 50 years and older.

Secondary objectives include:

• Evaluating the rVE of mRNA-1010 versus an active comparator against modified CDC-defined ILI caused by any influenza A or B strains.
• Assessing the rVE of mRNA-1010 versus an active comparator against protocol-defined ILI or modified CDC-defined ILI caused by influenza A or B strains with similarity or antigenic match to the vaccine strains.
• Evaluating the humoral immunogenicity of mRNA-1010 relative to that of an active comparator against vaccine-matched influenza A and B strains.
• Assessing hemagglutination inhibition (HAI) titers as a surrogate of risk and protection against protocol-defined ILI for mRNA-1010 and an active comparator.

The clinical trial involves a total of **42,700 participants** who are being evaluated for the safety and reactogenicity of mRNA-1010, as well as its relative vaccine efficacy (rVE) against influenza-like illness (ILI) caused by any influenza A or B strains. The study population includes both **male and female subjects** within the **age range of 18 to 64 years**. Participants were selected based on their ability to provide informed consent and meet specific criteria related to reproductive health, particularly for those assigned female at birth or who can become pregnant. The trial does not include a vulnerable population. Participants' general health status is not specified, nor are there any particular lifestyle considerations such as diet or physical activity mentioned. The sponsor has not provided additional information regarding the selection process or specific health conditions of the participants beyond the focus on influenza.

The clinical trial is a **Phase 3**, randomized, observer-blind, active-controlled, case-driven study designed to evaluate the safety, efficacy, and immunogenicity of the mRNA-1010 candidate seasonal influenza vaccine compared to a licensed inactivated seasonal influenza vaccine in adults aged 50 years and older. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on specific inclusion criteria, such as the ability to provide informed consent and, for participants who can become pregnant, the use of acceptable contraceptive methods. The trial is expected to commence recruitment on September 2, 2024, and conclude by February 1, 2027, with participant involvement lasting up to approximately 181 days.

Participants will be randomly assigned to receive either the investigational mRNA-1010 vaccine or the comparator vaccine via **intramuscular injection**. The trial will include several follow-up visits to monitor for adverse reactions and assess immunogenicity. Primary endpoints include the number of participants with solicited local and systemic adverse reactions from day 1 to day 7, unsolicited adverse events from day 1 to day 28, and medically attended adverse events, serious adverse events, or adverse events of special interest from day 1 to day 181. Secondary endpoints will evaluate the number of participants with RT-PCR confirmed influenza-like illness (ILI) and various immunogenicity measures at day 29.

The study will conclude with an end-of-study visit to collect final data and ensure participant safety. Participants may be withdrawn from the study early if they experience adverse events that necessitate discontinuation or if they fail to comply with study procedures. The trial's design ensures rigorous assessment of the investigational vaccine's performance against influenza, contributing valuable data to the field of influenza prevention.

The clinical trial involves the administration of two treatments to evaluate their safety, efficacy, and immunogenicity in adults aged 50 years and older. The first treatment is the **Influsplit Tetra 2024/2025**, a licensed inactivated seasonal influenza vaccine. This vaccine is presented as a **suspension for injection** in a pre-filled syringe. It contains the following active substances: B/Phuket/3073/2013-like virus, Influenza virus B/Austria/1359417/2021-like strain, A/Victoria/4897/2022 (H1N1)pdm09-like strain, and Influenza virus A/Thailand/8/2022 (H3N2) IVR-237-like strain. The vaccine is administered via **intramuscular injection** with a dosage of 0.5 ml per administration. The maximum treatment period is one day, and the vaccine is produced by GlaxoSmithKline GmbH & Co. KG.

The second treatment is the experimental vaccine **mRNA-1010**, developed by ModernaTX, Inc. This vaccine is also administered as an **injection** via the **intramuscular route**. The active substances in mRNA-1010 include CX-039776, CX-044933, and CX-037231, all of which are nucleic acids. The dosing schedule for mRNA-1010 is not specified in terms of volume, but the maximum treatment period is one day. This investigational product is being evaluated as a potential seasonal influenza vaccine.

Both treatments are administered under observer-blind conditions, with mRNA-1010 serving as the test product and Influsplit Tetra 2024/2025 as the active comparator. Participant compliance with the dosing schedule is monitored throughout the study to ensure accurate assessment of the vaccines' safety and efficacy. The trial aims to provide insights into the relative vaccine efficacy (rVE) of mRNA-1010 compared to the licensed inactivated vaccine against influenza-like illness (ILI) caused by any influenza A or B strains.

The efficacy of the mRNA-1010 candidate seasonal influenza vaccine will be assessed in a Phase 3, randomized, observer-blind, active-controlled, case-driven study. The primary efficacy endpoint is the time to the first episode of reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed protocol-defined **influenza-like illness (ILI)** caused by any influenza A or B strain, from day 14 up to the end of the season, approximately day 181. Secondary efficacy endpoints include the number of participants with the first episode of RT-PCR confirmed modified US Centers for Disease Control and Prevention (CDC)-defined ILI, and the number of participants with first episode of RT-PCR-confirmed protocol-defined ILI or modified CDC-defined ILI with similarity and/or antigenic match to the vaccine strains, from day 14 up to the end of the season.

Additional secondary endpoints involve immunogenicity measures such as the geometric mean titer (GMT) of hemagglutination inhibition (HAI) at day 29, the number of participants reaching seroconversion as measured by HAI at day 29, and the number of participants with an HAI titer ≥1:40 at day 29. The geometric mean fold rise (GMFR) of HAI titers at day 1 and day 29, as well as HAI titer measurements at these timepoints, will also be evaluated. The study will further assess the number of participants with the first episode of RT-PCR-confirmed protocol-defined ILI, correlates of risk (CoR), and correlates of protection (CoP) from day 14 up to the end of the season.