Immunogenicity and Safety of Influenza and COVID-19 Multicomponent Vaccine in Adults ≥50 Years: A Randomized Clinical Trial

Abstract

Importance: Uptake of recommended seasonal influenza and COVID-19 vaccines remains suboptimal.

Objective: To assess the immunogenicity and safety of an investigational mRNA-1083 vaccine against seasonal influenza and SARS-CoV-2 in adults 50 years and older.

Design, setting, and participants: This phase 3, randomized, observer-blinded trial was conducted across 146 US sites in adults 50 years and older enrolled between October 19, 2023, and November 21, 2023. Data extraction was complete on April 9, 2024.

Interventions: Participants in 2 age cohorts (≥65 years and 50-64 years) were randomly assigned (1:1) to receive mRNA-1083 plus placebo or coadministered licensed quadrivalent seasonal influenza (≥65 years: high-dose quadrivalent inactivated influenza vaccine [HD-IIV4]; 50-64 years: standard-dose IIV4 [SD-IIV4]) and COVID-19 (all ages: mRNA-1273) vaccines.

Main outcomes and measures: The primary objectives were to demonstrate the noninferiority of humoral immune responses following mRNA-1083 vs comparators against vaccine-matched strains at day 29 and to evaluate the reactogenicity and safety of mRNA-1083. Secondary objectives included demonstration of superiority of humoral immune responses elicited by mRNA-1083 relative to comparators at day 29.

Results: Overall, 8015 participants were enrolled and vaccinated (4017 aged ≥65 y and 3998 aged 50-64 y). Among adults 65 years and older and 50 to 64 years, the median age was 70 and 58 years, 54.2% and 58.8% were female, 18.4% and 26.7% were Black or African American, and 13.9% and 19.3% were Hispanic or Latino, respectively. Noninferior immunogenicity of mRNA-1083 was demonstrated against all vaccine-matched influenza and SARS-CoV-2 strains based on lower bound of the 97.5% CI of the geometric mean ratio greater than 0.667 and lower bound of the 97.5% CI of the seroconversion/seroresponse rate difference greater than -10%. mRNA-1083 elicited higher immune responses than SD-IIV4 (50-64 years) for all 4 influenza strains and HD-IIV4 (≥65 years) for 3 influenza strains (A/H1N1, A/H3N2, B/Victoria) and against SARS-CoV-2 (all ages). Solicited adverse reactions were numerically higher in frequency and severity after mRNA-1083 vaccination than comparators in both age cohorts (≥65 y: 83.5% and 78.1%; 50-64 y: 85.2% and 81.8%); most were grade 1 or 2 in severity and of short duration. No safety concerns were identified.

Conclusions and relevance: In this study, mRNA-1083 met noninferiority criteria and induced higher immune responses than recommended standard care influenza (standard and high dose) and COVID-19 vaccines against all 4 influenza strains (among those ages 50-64 y), the 3 clinically relevant influenza strains (among those aged ≥65 y), and SARS-CoV-2 (all ages), with an acceptable tolerability and safety profile.

Trial registration: ClinicalTrials.gov Identifier: NCT06097273.

Figure 1.. Participant Flow Throughout the Trial

^aParticipants were randomized 1:1 in 2 age cohort substudy groups to receive mRNA-1083 or active comparator vaccines for seasonal influenza and COVID-19. Randomization was stratified by prior influenza season vaccine status (received or not received since September 2022). In the cohort ≥65 years, randomization was also stratified into those aged 65-74 years or 75 years and older age groups. ^bA total of 92 (mRNA-1083) and 97 (HD-IIV4 plus mRNA-1273) participants in the ≥65 years substudy, and 77 (mRNA-1083) and 86 (SD-IIV4 plus mRNA-1273) participants in the 50-64 substudy were excluded from the per-protocol immunogenicity population. Participants were excluded for reverse transcription polymerase chain reaction–confirmed or missing influenza or SARS-CoV-2 status on day 1 (≥65 years substudy: n = 41 and n = 49; 50-64 years substudy: n = 42 and n = 41), failure to comply with timing of immunogenicity blood sampling (≥65 years substudy: n = 10 and n = 7; 50-64 years substudy: n = 8 and n = 10), and significant protocol deviations that impact key data (≥65 years substudy: n = 41 and n = 40; 50-64 years substudy: n = 27 and n = 35) for the mRNA-1083 and active comparator vaccine groups, respectively. One participant in the group aged 65 years or older had a major dosing error (HD-IIV4 plus mRNA-1273 group). EQ-5D-5L indicates EuroQol 5-Dimension, 5-Level; HD, high dose; IIV4, quadrivalent inactivated influenza vaccine; SD, standard dose; WPAI, Work Productivity and Activity Impairment.

Figure 2.. GMRs and Seroconversion/Seroresponse Rate Differences of Antibody Levels Against Influenza and SARS-CoV-2 Strains at Day 29

ANCOVA–modeled geometric mean (GM) antibody levels and GM ratios (GMRs) are shown. The dotted lines indicate noninferiority thresholds. The prespecified superiority threshold for the lower bound of the 95% CI of the GMR was >1.0 and for the seroconversion/seroresponse difference was >0%.

Figure 3.. Summary of Solicited Local and Systemic Adverse Reactions Within 7 Days After Vaccination

Severity grading occurred automatically based on participant entry into the eDiary according to the grading scales modified from the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (US Department of Health and Human Services, FDA, 2007). HD indicates high dose; IIV4, inactivated influenza vaccine, quadrivalent; SD, standard dose.