Effectiveness of mCOMBRIAX influenza‑COVID‑19 vaccine versus high‑dose influenza vaccine and mRNA‑1273 COVID‑19 vaccine in adults 65 years and older

The primary objective is to determine the comparative vaccine effectiveness of the investigational mCombriax (mRNA‑1083) administered alone versus same‑day co‑administration of a high‑dose influenza vaccine (Efluelda) and an mRNA‑1273 COVID‑19 vaccine (Spikevax) in adults ≥ 65 years for prevention of (1) medically attended influenza and/or SARS‑CoV‑2 infection and (2) hospitalization due to influenza and/or COVID‑19. Secondary objectives assess the same comparative effectiveness for additional clinically relevant outcomes, including medically attended influenza, influenza‑related hospitalization, medically attended COVID‑19, COVID‑19‑related hospitalization, all‑cause cardio‑respiratory hospitalization, all‑cause hospitalization, and hospitalization for any respiratory tract disease.

The trial enrolled adults aged ≥ 65 years, including both females and males, drawn from the general community and clinical settings. Participants comprised healthy volunteers as well as patients, and may have a history of SARS-CoV-2 infection or influenza infection. The sponsor did not provide the total number of participants. Enrollment was based on principal inclusion criteria requiring age ≥ 65 years at vaccination, self‑reported ability to understand written and spoken English, Danish (Denmark), Spanish or Galician (Spain), and a signed informed consent form. No additional lifestyle or exclusion information was supplied.

The study is a Phase 4 pragmatic randomized controlled trial evaluating the comparative vaccine effectiveness of the investigational mCombriax (mRNA‑1083) versus same‑day co‑administration of a high‑dose influenza vaccine (Efluelda) and an mRNA COVID‑19 vaccine (Spikevax) in adults aged 65 years or older. Recruitment is planned to begin on 15 September 2026 and continue until 30 September 2029, with each participant remaining in the protocol from the screening visit through the end‑of‑study visit. After obtaining informed consent, eligible individuals attend a screening visit to confirm age, language ability, and consent criteria; eligible participants receive the allocated vaccine(s) on the same day (baseline visit). Subsequent follow‑up visits are scheduled at predefined intervals to capture medically attended influenza and/or COVID‑19 events, hospitalizations, and secondary safety outcomes, with the final visit occurring at the conclusion of the observation period to document all endpoints. The primary endpoints are the occurrence of (1) medically attended influenza and/or COVID‑19 and (2) influenza and/or COVID‑19 hospitalization. Participant involvement therefore extends for the duration of the follow‑up period, which terminates at the end‑of‑study visit. Early termination may occur if a participant withdraws consent, experiences a serious adverse event related to the investigational product, exhibits significant protocol non‑compliance, or is lost to follow‑up, in which case data collection ceases for that individual.

The investigational vaccine, identified as mCOMBRIAX dispersion for injection in a pre‑filled syringe, is a multi‑antigen mRNA formulation containing encoded hemagglutinin proteins from influenza A (H1N1, strain A/Wisconsin/67/2022; H3N2, strain A/Darwin/6/2021), influenza B (strain B/Austria/1359417/2021, Victoria lineage), and the receptor‑binding domain of the SARS‑CoV‑2 spike protein (XBB.1.5). Each 1 mg dose is administered as a single intramuscular injection into the deltoid muscle. The vaccine is provided in a sterile dispersion for injection and is given once on the study day, with participants observed for at least 15 minutes post‑administration. Compliance is assessed by documented administration in the study record and follow‑up visits at predefined intervals.

The COVID‑19 mRNA comparator, Spikevax JN.1, is supplied as a 50 µg dispersion for injection in a pre‑filled syringe. One 1 µg dose is delivered as a single intramuscular injection into the deltoid muscle on the same day as the test vaccine. The product contains SARS‑CoV‑2 JN.1 mRNA and is administered in accordance with the approved labeling. Observation after injection and documentation of receipt constitute the primary compliance monitoring measures.

The influenza vaccine comparator, Efluelda Tetra, is provided as a suspension for injection in a filled syringe. A single 1 µg dose is given by intramuscular injection into the deltoid muscle, containing inactivated virus strains B/Phuket/3073/2013 (wild type), B/Michigan/01/2021, influenza A H1N1 (A/Victoria/4897/2022, IVR‑238), and influenza A H3N2 (A/Croatia/10136RV/2023, X‑425A). The vaccine is administered once on the study day, with standard post‑vaccination observation and recording of administration to ensure adherence to the dosing schedule.

The efficacy assessment will be based on the occurrence of medically attended influenza and/or COVID-19 and the occurrence of influenza and/or COVID-19 hospitalization as the primary efficacy parameters. These events will be identified through health care utilization records during the follow‑up period after vaccination.

Secondary efficacy parameters include medically attended influenza, influenza hospitalization, medically attended COVID‑19, COVID‑19 hospitalization, all‑cause cardio‑respiratory hospitalization, all‑cause hospitalization, and all‑cause respiratory tract disease hospitalization. Each endpoint will be captured using standard case definitions applied to routine clinical and administrative data sources.