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

Amanda K Rudman Spergel; Iris Wu; Weiping Deng; Jose Cardona; Kimball Johnson; Ivette Espinosa-Fernandez; Melissa Sinkiewicz; Veronica Urdaneta; Lizbeth Carmona; Kristin Schaefers; Bethany Girard; Yamuna D Paila; Darshan Mehta; Benoit Callendret; Lusine Kostanyan; Jintanat Ananworanich; Jacqueline Miller; Rituparna Das; Christine A Shaw

doi:10.1001/jama.2025.5646

. 2025 May 7;333(22):1977–1987. doi: 10.1001/jama.2025.5646

Immunogenicity and Safety of Influenza and COVID-19 Multicomponent Vaccine in Adults ≥50 Years

A Randomized Clinical Trial

Amanda K Rudman Spergel ^1,^✉, Iris Wu ¹, Weiping Deng ¹, Jose Cardona ², Kimball Johnson ³, Ivette Espinosa-Fernandez ⁴, Melissa Sinkiewicz ¹, Veronica Urdaneta ¹, Lizbeth Carmona ¹, Kristin Schaefers ¹, Bethany Girard ¹, Yamuna D Paila ¹, Darshan Mehta ¹, Benoit Callendret ¹, Lusine Kostanyan ¹, Jintanat Ananworanich ¹, Jacqueline Miller ¹, Rituparna Das ¹, Christine A Shaw ¹

¹Moderna Inc, Cambridge, Massachusetts

²Indago Research and Health Center, Hialeah, Florida

³CenExel iResearch, Decatur, Georgia

⁴Revival Research Corporation, Doral, Florida

Accepted for Publication: March 19, 2025.

Published Online: May 7, 2025. doi:10.1001/jama.2025.5646

^✉

Corresponding Author: Amanda K. Rudman Spergel, MD, Moderna Inc, 325 Binney St, Cambridge, MA 02142 (Amanda.RudmanSpergel@modernatx.com).

Author Contributions: Drs Rudman Spergel and Shaw had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Rudman Spergel, Wu, Deng, Carmona, Schaefers, Mehta, Ananworanich, Miller, Das, Shaw.

Acquisition, analysis, or interpretation of data: Rudman Spergel, Wu, Deng, Cardona, Johnson, Espinosa-Fernandez, Sinkiewicz, Urdaneta, Schaefers, Girard, Paila, Mehta, Callendret, Kostanyan, Ananworanich, Miller, Das, Shaw.

Drafting of the manuscript: Rudman Spergel, Sinkiewicz, Girard, Mehta, Ananworanich, Das.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Rudman Spergel, Wu, Deng, Urdaneta, Mehta, Kostanyan.

Administrative, technical, or material support: Rudman Spergel, Cardona, Johnson, Sinkiewicz, Schaefers, Girard, Paila.

Supervision: Rudman Spergel, Espinosa-Fernandez, Carmona, Schaefers, Callendret, Kostanyan, Ananworanich, Miller, Das.

Other - Overseeing of clinical operations: Carmona.

Conflict of Interest Disclosures: Drs Rudman Spergel, Wu, Deng, Sinkiewicz, Urdaneta, Girard, Paila, Mehta, Callendret, Kostanyan, Ananworanich, Miller, Das, and Shaw and Ms Carmona and Ms Schaefers may hold stock/stock options in Moderna, Inc as employees. Dr Johnson may hold stock/stock options in CenExel as an employee.

Funding/Support: This study was funded by Moderna, Inc.

Role of the Funder/Sponsor: Moderna, Inc was involved in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and the decision to submit the manuscript for publication.

Meeting Presentation: Results of this study were presented at OPTIONS XII for the Control of Influenza, Brisbane, Australia; September 29, 2024.

Data Sharing Statement: See Supplement 4.

Additional Contributions: Medical writing and editorial assistance were provided by Kate Russin, PhD, Renee Gordon, PhD, and Andy Kerr, PhD, of MEDiSTRAVA in accordance with Good Publication Practice guidelines, funded by Moderna, Inc, and under the direction of the authors.

^✉

Corresponding author.

PMCID: PMC12060023 PMID: 40332892

Key Points

Question

Is a multicomponent vaccine against seasonal influenza and SARS-CoV-2 (mRNA-1083) immunogenic and well-tolerated in adults 50 years and older?

Findings

In this phase 3 study, mRNA-1083 elicited noninferior immune responses against standard care immunization: licensed standard-dose or high-dose seasonal influenza vaccine (A/H1N1, A/H3N2, B/Victoria, B/Yamagata) coadministered with licensed SARS-CoV-2 (Omicron XBB.1.5) vaccine. The multicomponent vaccine mRNA-1083 had an acceptable tolerability and safety profile.

Meaning

mRNA-1083 was demonstrated to be at least as immunogenic as recommended standard care vaccines against both seasonal influenza and COVID-19 and well-tolerated in adults 50 years and older.

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

This study examines the immunogenicity and safety of an investigational mRNA-based vaccine against seasonal influenza and SARS-CoV-2 in adults 50 years and older.

Introduction

Seasonal influenza and SARS-CoV-2 viruses are global health concerns, causing approximately 1 billion influenza cases and 2.3 billion COVID-19 cases worldwide annually.^1,2 Hospitalizations and deaths from influenza and COVID-19 are higher among adults 50 years and older.^3,4,5 During the 2023-2024 season in the US, influenza and COVID-19 were associated with 2.7-fold and 4.2-fold higher hospitalization rates, respectively, among adults 65 years and older compared with the population overall.³ Despite available vaccines, vaccine uptake for influenza and COVID-19 remains suboptimal.^6,7,8 Given the annual circulation and continuous evolution of influenza and SARS-CoV-2, there remains a need to improve vaccine uptake and harmonize vaccine recommendations.

Influenza and COVID-19 vaccine coadministration is currently recommended by the World Health Organization and US Centers for Disease Control and Prevention,^9,10 which likely helps improve coverage rates,¹¹ and is supported by data from randomized clinical trials.^{12,13,14,15,16} However, a multicomponent vaccine may be a preferable option to vaccinate against both diseases with a single injection,¹⁷ potentially increasing compliance with immunization guidelines and ultimately mitigating disease.

mRNA-1083 is an investigational mRNA-based multicomponent vaccine that combines the components of a hemagglutinin-based influenza vaccine (mRNA-1010) and a second-generation SARS-CoV-2 vaccine encoding for spike (S) glycoprotein N-terminal domain and receptor-binding domain (NTD-RBD; mRNA-1283), which have independently shown acceptable safety profiles and robust immunogenicity noninferior to licensed comparators in phase 3 studies, with noninferior relative vaccine efficacy also demonstrated for mRNA-1283 (vs mRNA-1273).^18,19,20 In a phase 1/2 study (NCT05827926), mRNA-1083 was well-tolerated, had an acceptable safety profile, and induced immune responses that were similar to or higher than those following licensed influenza and COVID-19 vaccines.²¹

This article presents interim phase 3 immunogenicity and safety results of 40-μg mRNA-1083 in adults 50 years and older compared with standard care licensed influenza (standard dose [50-64 years] or high dose [≥65 years]) and SARS-CoV-2 vaccines. Health-related quality of life (QoL) assessments are also described.

Methods

Trial Design and Participants

This phase 3, randomized, observer-blinded, active-controlled study was conducted at 146 US sites in adults 50 years and older (NCT06097273). The study protocol is provided in Supplement 1 and the statistical analysis plan is provided in Supplement 2. Blinding and inclusion and exclusion criteria are described in the eMethods in Supplement 3. The study was conducted in 2 age cohort substudies: those 65 years and older and those aged 50 to 64 years. Each substudy had separate hypotheses and analyses because recommended licensed influenza vaccines differ between these 2 age groups. Participants in each age cohort substudy were randomized in a 1:1 ratio using interactive response technology by a centralized randomization procedure to receive mRNA-1083 plus placebo (henceforth referred to as mRNA-1083) or active comparator vaccines for seasonal influenza and COVID-19. In both substudies, randomization was stratified by influenza vaccine status in the prior influenza season (received or not received since September 2022). Additionally, randomization in the substudy of those 65 years and older was also stratified into those aged 65 to 74 years or 75 years and older. This report summarizes safety and immunogenicity findings of the planned interim analyses after all participants had completed the day 91 visit. Safety and immunogenicity findings of the final analysis (through the day 181 visit) will be reported separately.

This study was conducted in accordance with the protocol, applicable laws and regulatory requirements, International Council for Harmonisation Good Clinical Practice guidelines, and consensus ethical principles derived from international guidelines, including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines. The protocol was approved by the central institutional review board (Advarra, Inc). All participants provided written informed consent before enrollment. This report follows the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for randomized trials. Race and ethnicity of participants were self-reported according to multiple prefixed categories and were included to provide a sense of the applicability of the findings.

Vaccines

mRNA-1083 contained 5 mRNA sequences encoding membrane-bound hemagglutinin of 4 influenza strains (recommended for Northern Hemisphere 2023-2024 season) and the linked NTD-RBD of the SARS-CoV-2 S glycoprotein (Omicron XBB.1.5), encapsulated in lipid nanoparticles. Placebo was 0.9% sodium chloride. Licensed quadrivalent inactivated influenza vaccine (IIV4) comparators were standard-dose Fluarix (SD-IIV4; GlaxoSmithKline) for those aged 50 to 64 years and high-dose Fluzone (HD-IIV4; Sanofi Pasteur, Inc) for those 65 years and older; the licensed SARS-CoV-2 comparator for both cohorts was Spikevax (mRNA-1273; Moderna, Inc), compliant with recommendations for the Northern Hemisphere 2023-2024 season. On day 1, participants received coadministered intramuscular injections of mRNA-1083 or SD-IIV4 plus mRNA-1273 or HD-IIV4 plus mRNA-1273, according to group assignment.

Trial Objectives

Primary objectives were to evaluate humoral responses to mRNA-1083 for noninferiority relative to active comparators against vaccine-matched strains for influenza and SARS-CoV-2 at day 29 and safety and reactogenicity of study vaccines. Secondary objectives included evaluation of humoral responses to mRNA-1083 for superiority relative to active comparators at day 29.

Immunogenicity Assessments

Blood samples for immunogenicity assessments were collected from participants on days 1 (baseline) and 29, with an additional collection planned for more than 800 participants in each cohort on day 181 (end of study). Immunogenicity data from days 1 and 29 are reported. Co–primary (noninferiority) and secondary (superiority) immunogenicity end points were geometric mean (GM) antibody levels by hemagglutination inhibition assay (influenza) and pseudovirus neutralization assay (PsVNA; SARS-CoV-2) and percentage of participants with seroconversion of antihemagglutinin antibodies for influenza or seroresponse of neutralizing antibodies for SARS-CoV-2. Seroconversion was defined as a day 29 antihemagglutinin antibody titer of greater than or equal to 1:40 if baseline was less than 1:10 or as a greater than or equal to 4-fold rise in antihemagglutinin antibody titer if baseline was greater than or equal to 1:10, measured by hemagglutination inhibition (HAI) assay. Seroresponse was defined as a day 29 neutralizing antibody level of greater than or equal to 4-fold if the baseline level was greater than or equal to the lower limit of quantification (LLOQ) or as greater than or equal to 4 × LLOQ if the baseline level was less than the LLOQ. GM fold increases from baseline by hemagglutination inhibition assay and PsVNA were calculated. Additionally, influenza GM antibody levels and GM fold increases were measured by a validated microneutralization assay in a randomized participant subset. Assay methodologies are shown in Supplement 3.

Safety Assessments

Safety assessments included solicited local and systemic adverse reactions (ARs) through 7 days after vaccination (eTable 1 in Supplement 3); unsolicited adverse events (AEs) and severe AEs through 28 days after vaccination; and serious AEs, medically attended AEs, AEs of special interest, and AEs leading to discontinuation from day 1 through to study end (day 181). Safety data through the cutoff date (February 26, 2024) are reported.

Health-Related QoL Assessments

Characterizing other health outcomes during the first 7 days after vaccination was an exploratory objective (Supplement 3). Self-reported EuroQol 5-Dimension 5-Level (EQ-5D-5L) questionnaire responses were used to assess the impact of vaccination on participant QoL for participants in both substudies and Work Productivity and Activity Impairment (WPAI) questionnaire responses were used for the substudy of individuals aged 50 to 64 years.

Statistical Analyses

The sample size was considered to provide sufficient power for noninferiority testing based on GM antibody levels and seroconversion/seroresponse rates at day 29 for hemagglutination inhibition (4 influenza strains) and PsVNA (SARS-CoV-2) (Supplement 3). Populations for statistical evaluations are shown in Supplement 3.

For the primary immunogenicity objective, hypothesis testing was performed to compare strain-matched immune responses against influenza and SARS-CoV-2 for mRNA-1083 vs respective comparator group in each substudy (Supplement 3). There were 5 co–primary end points for GM antibody level (4 influenza strains and 1 SARS-CoV-2 strain) and 5 co–primary end points for seroconversion/seroresponse rate. For each influenza and SARS-CoV-2 strain, noninferiority of GM antibody level was demonstrated if the lower bound of the 97.5% CI of the GM ratio (GMR) was greater than 0.667. Noninferiority of the seroconversion/seroresponse rate was demonstrated if the lower bound of the 97.5% CI of the seroconversion/seroresponse rate difference was greater than −10%. If all co–primary end points for GM antibody level and seroconversion/seroresponse rate met the noninferiority criteria, the primary noninferiority objective was achieved. Secondary superiority testing was sequentially performed in a hierarchical order: (1) GM antibody level for 4 influenza strains, (2) GM antibody level for SARS-CoV-2, (3) seroconversion rate for 4 influenza strains, and (4) seroresponse rate for SARS-CoV-2 (Supplement 3). If the superiority testing failed at any step, the testing sequence would stop. Superiority of GM antibody level of a strain was considered demonstrated if the lower bound of the 95% CI of the GMR was greater than 1.0; superiority of seroconversion/seroresponse rate of a strain was considered demonstrated if the lower bound of the 95% CI of the seroconversion/seroresponse rate difference was greater than 0%. An ad hoc subgroup analysis of immunogenicity by comorbidity status (high risk vs low risk) was performed. Descriptive immunogenicity, correlation, and health-related QoL analyses are described in Supplement 3.

Results

Participants

Enrollment occurred between October 19, 2023, and November 21, 2023 (eTable 2 in Supplement 3). As of the data cutoff (February 26, 2024), 4037 adults 65 years and older were randomized to receive mRNA-1083 (n = 2025) or HD-IIV4 plus mRNA-1273 (n = 2012) and 4024 adults aged 50 to 64 years were randomized to receive mRNA-1083 (n = 2009) or SD-IIV4 plus mRNA-1273 (n = 2015) (Figure 1). More than 99% of randomized participants in each group received vaccination.

Figure 1. — ^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.

Demographic and baseline characteristics of participants in the safety population were balanced between the 2 groups in each substudy (Table 1). Among adults 65 years and older, the median (IQR) age was 70 (67-74) years, 20.7% were 75 or older years, 54.2% were female, 18.4% were Black or African American, 13.9% were Hispanic or Latino, 65.2% had a high-risk comorbid condition, and 50.7% received the previous season’s influenza vaccine. Among adults aged 50 to 64 years, the median (IQR) age was 58 (54-61) years, 58.8% were female, 26.7% were Black or African American, 19.3% were Hispanic or Latino, 61.9% had a high-risk comorbid condition, and 39.2% received the previous season’s influenza vaccine. Demographic and baseline characteristics of participants in the per-protocol immunogenicity population were similarly balanced between the 2 groups in each substudy (eTable 3 in Supplement 3).

Table 1. Participant Demographics and Baseline Characteristics (Safety Population)^a.

	Age ≥65 y		Age 50-64 y
	mRNA-1083 (n = 2011)	HD-IIV4 + mRNA-1273 (n = 2006)	mRNA-1083 (n = 1993)	SD-IIV4 + mRNA-1273 (n = 2005)
Age, y
Mean (SD)	70.9 (5.0)	70.7 (4.7)	57.5 (4.3)	57.4 (4.2)
Median (IQR)	70 (67-74)	70 (67-74)	58 (54-61)	58 (54-61)
Age group, No. (%)
50-64 y	2 (<0.1)^b	0	1991 (99.9)	2004 (99.9)
65-74 y	1593 (79.2)	1591 (79.3)	1 (<0.1)^b	0
≥75 y	416 (20.7)	415 (20.7)	1 (<0.1)^b	1 (<0.1)^b
Sex, No. (%)
Male	933 (46.4)	908 (45.3)	837 (42.0)	811 (40.4)
Female	1078 (53.6)	1098 (54.7)	1156 (58.0)	1194 (59.6)
Race, No. (%)^c	n = 2000	n = 1994	n = 1978	n = 1981
American Indian or Alaska Native	9 (0.5)	12 (0.6)	12 (0.6)	13 (0.7)
Asian	25 (1.3)	36 (1.8)	50 (2.5)	39 (2.0)
Black or African American	370 (18.5)	370 (18.6)	517 (26.1)	552 (27.9)
Native Hawaiian or Other Pacific Islander	1 (0.1)	4 (0.2)	3 (0.2)	5 (0.3)
White	1577 (78.9)	1565 (78.5)	1373 (69.4)	1343 (67.8)
Multiple	14 (0.7)	4 (0.2)	19 (1.0)	21 (1.1)
Other	4 (0.2)	3 (0.2)	4 (0.2)	8 (0.4)
Ethnicity, No. (%)
Hispanic or Latino	283 (14.1)	275 (13.7)	392 (19.7)	381 (19.0)
Not Hispanic or Latino	1688 (83.9)	1689 (84.2)	1576 (79.1)	1603 (80.0)
Unknown or not reported	40 (2.0)	42 (2.1)	25 (1.3)	21 (1.0)
BMI
Mean (SD)	30.3 (6.2)	30.1 (6.1)	31.1 (7.1)	31.6 (7.3)
Median (IQR)	29.4 (25.9-33.8)	29.2 (25.7-33.6)	30.2 (26.2-34.9)	30.5 (26.6-35.4)
BMI group, No. (%)^d	n = 1995	n = 1984	n = 1963	n = 1980
<30	1077 (54.0)	1096 (55.2)	951 (48.4)	927 (46.8)
≥30	918 (46.0)	888 (44.8)	1012 (51.6)	1053 (53.2)
Comorbidity group, No. (%)
High risk^e	1312 (65.2)	1292 (64.4)	1233 (61.9)	1264 (63.0)
Low risk	699 (34.8)	714 (35.6)	760 (38.1)	741 (37.0)
Influenza vaccine received since Sept 2022, No. (%)	1019 (50.7)	1016 (50.6)	783 (39.3)	784 (39.1)
COVID-19 vaccine received since Sept 2022, No. (%)	853 (42.4)	854 (42.6)	632 (31.7)	611 (30.5)

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Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HD-IIV4, high-dose quadrivalent inactivated influenza vaccine; SD-IIV4, standard-dose quadrivalent inactivated influenza vaccine.

^{^a}

The safety population included all participants who were randomized and received the study vaccination. Participants were included in the vaccine group corresponding to the vaccine they received.

^{^b}

Due to misrandomization, 2 participants aged 50-64 years were enrolled in the ≥65 years cohort and 3 participants aged ≥65 years were enrolled in the 50-64 years cohort.

^{^c}

Race and ethnicity of participants was self-reported according to multiple categories. The total number of participants with a reported race (excluding participants with race unknown or unreported); percentages are based on this total.

^{^d}

The total number of participants with a reported BMI group (excluding participants with unknown BMI group); percentages are based on this total.

^{^e}

High-risk comorbidity included having any medical history of autoimmune/immune-mediated disease, blood disorders, cardiac disorders, nervous system disorders, diabetes mellitus, kidney disorders, hepatic disorders, mental impairment disorders, pulmonary disorders, or metabolism and nutritional disorders. Comorbidities based on self-report or review of medical records.

Immunogenicity

mRNA-1083 increased hemagglutination inhibition and PsVNA GM antibody levels against each influenza (A/H1N1, A/H3N2, B/Victoria, B/Yamagata) and SARS-CoV-2 strain at day 29 vs baseline (eFigure 1; eTable 4 in Supplement 3). The primary immunogenicity objective was achieved in both substudies. Noninferiority of mRNA-1083 vs SD-IIV4 plus mRNA-1273 and HD-IIV4 plus mRNA-1273 was demonstrated against all vaccine-matched influenza and SARS-CoV-2 strains based on prespecified success criteria for GMR (97.5% CI lower bound >0.667) and seroconversion/seroresponse rate difference (97.5% CI lower bound >−10%) (Figure 2). In both substudies, immune responses among participants with high-risk comorbid conditions were comparable to participants without such conditions (eFigure 2 in Supplement 3). Immune response by prior vaccine receipt since September 2022 is shown in eFigure 3 in Supplement 3.

Figure 2. — 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%.

The secondary immunogenicity objective of superiority of mRNA-1083 vs SD-IIV4 plus mRNA-1273 was demonstrated in adults aged 50 to 64 years for all 4 influenza strains and SARS-CoV-2 based on GMRs and seroconversion/seroresponse rate differences (Figure 2). For mRNA-1083 vs HD-IIV4 plus mRNA-1273 in adults 65 years and older, the lower bound of the 95% CI for the GMR was greater than 1.0 for 3 influenza strains (A/H1N1, A/H3N2, B/Victoria); however, the GMR for B/Yamagata did not meet the superiority threshold (95% CI lower bound of 0.973). This precluded formal superiority testing for GMR of SARS-CoV-2, although the lower bound of the 95% CI exceeded 1.0 (1.53) and the lower bound of the 956% CI of the seroconversion/seroresponse rate difference exceeded 0% for 3 influenza strains (2.4%, 1.0%, and 1.9%; exception of B/Yamagata [−3.3%]) and for SARS-CoV-2 (10.0%) (eTable 4 in Supplement 3).

mRNA-1083 elicited robust influenza-specific antibody responses at day 29 as measured by microneutralization assay in a random participant subset of 146 to 147 participants per vaccine group (eTable 5 and eFigure 4 in Supplement 3). GM fold increases were numerically similar or higher for mRNA-1083 than SD-IIV4 plus mRNA-1273 and HD-IIV4 plus mRNA-1273 in each substudy for all influenza strains except B/Yamagata in the cohort of participants 65 years and older. A positive correlation between microneutralization and hemagglutination inhibition titers was observed (Pearson correlation coefficients of 0.5285-0.7539; eFigure 5 in Supplement 3).

Safety

Solicited ARs were reported by 83.5% and 78.1% of mRNA-1083 and HD-IIV4 plus mRNA-1273 recipients, respectively, 65 years and older and in 85.2% and 81.8% of mRNA-1083 and SD-IIV4 plus mRNA-1273 recipients, respectively, aged 50 to 64 years (Figure 3; eTable 6 in Supplement 3). Most solicited local and systemic ARs were grade 1 or 2 across vaccine groups. Grade 4 ARs were reported only for systemic events (all fever) by 2 (<0.1%) mRNA-1083 and 1 (<0.1%) HD-IIV4 plus mRNA-1273 recipient in adults 65 years and older and by 2 (0.1%) mRNA-1083 and 1 (<0.1%) SD-IIV4 plus mRNA-1273 recipients in adults aged 50 to 64 years. Across age cohort substudies, the most reported ARs were injection site pain, fatigue, myalgia, and headache, and the median duration of ARs was 3 to 4 days.

Figure 3. — 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.

In each substudy, rates of unsolicited AEs within 28 days after vaccination were balanced between vaccine groups, with no AEs leading to study discontinuation (Table 2). Among adults 65 years and older, AEs within 28 days considered to be vaccination-related by the investigator occurred in 16 (0.8%) mRNA-1083 recipients and 21 (1.0%) HD-IIV4 plus mRNA-1273 recipients. Medically attended AEs considered by the investigator to be vaccination-related were reported by 3 (0.1%) and 5 (0.2%) participants, respectively. No severe or serious AEs were considered vaccination-related by the investigator (eTables 7 and 8 in Supplement 3). No cases of myocarditis or pericarditis were reported. AEs of special interest were reported in 2 (<0.1%) mRNA-1083 recipients and 4 (0.2%) HD-IIV4 plus mRNA-1273 recipients. An event of confusional state that occurred in an mRNA-1083 recipient was designated as an AE of special interest and considered vaccination-related by the investigator; however, this was not a protocol-defined AE of special interest and there were several confounders (ie, advanced age, history of posttraumatic stress disorder and hypertension, and concurrent SARS-CoV-2 infection). One death (cardiac arrest) was reported on day 7 in the HD-IIV4 plus mRNA-1273 group and was assessed by the investigator to be unrelated to vaccination.

Table 2. Unsolicited Adverse Events (AEs) After Study Vaccination Among the Safety Population^a.

Participants	Age, No. (%)
	≥65 y		50-64 y
	mRNA-1083 n = 2011)	HD-IIV4 + mRNA-1273 (n = 2006)	mRNA-1083 (n = 1993)	SD-IIV4 + mRNA-1273 (n = 2005)
Unsolicited AEs within 28 d^b
Regardless of relationship to study vaccination
Any AE	239 (11.9)	245 (12.2)	193 (9.7)	189 (9.4)
Severe^c	15 (0.7)	11 (0.5)	7 (0.4)	4 (0.2)
Serious^d	18 (0.9)	13 (0.6)	10 (0.5)	5 (0.2)
Fatal	0	1 (<0.1)	0	0
Medically attended	132 (6.6)	139 (6.9)	99 (5.0)	95 (4.7)
Leading to study discontinuation	0	0	0	0
AESI	2 (<0.1)	4 (0.2)	2 (0.1)	2 (<0.1)
Related to study vaccination^e
Any AE	16 (0.8)	21 (1.0)	17 (0.9)	26 (1.3)
Severe^c	0	0	0	0
Serious^d	0	0	0	0
Fatal	0	0	0	0
Medically attended	3 (0.1)	5 (0.2)	2 (0.1)	3 (0.1)
Leading to study discontinuation	0	0	0	0
AESI	1 (<0.1)	0	0	0
Unsolicited AEs to data cutoff ^b ^, ^f
Regardless of relationship to study vaccination
Any AE	406 (20.2)	414 (20.6)	316 (15.9)	320 (16.0)
Severe^c	38 (1.9)	27 (1.3)	14 (0.7)	14 (0.7)
Serious^d	41 (2.0)	27 (1.3)	18 (0.9)	20 (1.0)
Fatal	0	1 (<0.1)	0	1 (<0.1)
Medically attended	306 (15.2)	315 (15.7)	212 (10.6)	210 (10.5)
Leading to study discontinuation	0	0	0	0
AESI	11 (0.5)	9 (0.4)	3 (0.2)	6 (0.3)
Related to study vaccination^e
Any AE	17 (0.8)	22 (1.1)	18 (0.9)	29 (1.4)
Severe^c	0	0	0	0
Serious^d	0	0	0	0
Fatal	0	0	0	0
Medically attended	4 (0.2)	6 (0.3)	2 (0.1)	3 (0.1)
Leading to study discontinuation	0	0	0	0
AESI	1 (<0.1)	0	0	0

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Abbreviations: AESI, adverse event of special interest; HD, high dose; IIV4, quadrivalent inactivated influenza vaccine, SD, standard dose.

^{^a}

The safety population consisted of all participants who were randomly assigned and received the study vaccination. Participants were included in the vaccine group corresponding to what they received.

^{^b}

An unsolicited AE is any AE reported by the participant that is not specified as a solicited adverse reaction in the protocol, or is specified as a solicited adverse reaction in the protocol but starts outside the protocol-defined period for solicited adverse reaction reporting (>7 days after vaccination). AEs were collected on days 8 (telephone call), 29 (physical examination), 91 (telephone call), and 181 (telephone call), by unsolicited reporting, observation, or by using open-ended and nonleading verbal questioning.

^{^c}

Severe AEs were defined as any AE that prevents the participant’s daily activities and requires intensive therapeutic intervention.

^{^d}

Serious AEs were defined as any AE that is life threatening, results in death, requires/prolongs inpatient hospitalization, results in persistent/significant disability/incapacity, results in congenital anomaly/birth defect, or is considered to be a medically important event by the study investigator.

^{^e}

Per the study protocol, the investigator assessed each occurrence of an AE and reported it as related (a reasonable possibility) or not related (not a reasonable possibility) to study vaccination.

^{^f}

At the data cutoff date (February 26, 2024), the median (IQR) duration of follow-up after vaccination was 109 (103-113) days in the cohort ≥65 years of age and 112 (109-117) days in the cohort 50-64 years of age.

Among adults aged 50 to 64 years, AEs within 28 days considered related to vaccination occurred in 17 (0.9%) mRNA-1083 recipients and 26 (1.3%) SD-IIV4 plus mRNA-1273 recipients. Medically attended AEs considered by the investigator to be vaccination related were reported by 2 (0.1%) and 3 (0.1%) participants, respectively. No severe or serious AEs (eTables 7 and 8 in Supplement 3) or AE of special interest were considered vaccination related and no deaths or cases of myocarditis or pericarditis were reported.

Throughout the current analyses’ data cutoff date, the median (IQR) duration of follow-up after vaccination was 109 (103-113) days in the cohort of individuals 65 years and older and 112 (109-117) days in the cohort of individuals aged 50 to 64 years. No safety concerns were identified through the data cutoff date (Table 2); 1 additional death (unknown cause) was reported outside the 28-day window (day 61 after vaccination with SD-IIV4 plus mRNA-1273), which was assessed to be unrelated to vaccination by the investigator.

Health-Related QoL

Overall, 97.5% of the safety population completed the baseline EQ-5D-5L and Work Productivity and Activity Impairment questionnaires and were included in each age cohort analysis set (eTables 9-11 in Supplement 3). In each substudy, both vaccine groups experienced a transient decline in EQ-5D-5L utility scores on day 2 after vaccination, which resolved by day 3 (eFigures 6-7 in Supplement 3). The observed decline on day 2 was higher for mRNA-1083 recipients; however, the change was less than the instrument-defined meaningful threshold (0.078).²² There was no difference in EQ-5D-5L utility scores across both substudies from days 4 to 7. Among Work Productivity and Activity Impairment respondents in the cohort of participants aged 50 to 64 years, both vaccine groups reported an increase in worktime missed at day 8 (7-day lookback period) (eTable 12 in Supplement 3).

Discussion

This pivotal phase 3 trial of an mRNA multicomponent vaccine against seasonal influenza and SARS-CoV-2 met all prespecified primary immunogenicity objectives in adults 50 years and older. The trial demonstrated that a single mRNA-1083 dose induced noninferior immune responses to licensed comparators (≥65 years: HD-IIV4 plus mRNA-1273; 50-64 years: SD-IIV4 plus mRNA-1273) against 4 influenza strains (A/H1N1, A/H3N2, B/Victoria, B/Yamagata) and SARS-CoV-2 (XBB.1.5). Although immunogenicity against B/Yamagata was evaluated (as a component of the Northern Hemisphere 2023-2024 vaccine), this strain is not recommended by the World Health Organization for inclusion in the 2024-2025 vaccine due to its global disappearance during the COVID-19 pandemic.²³ Thus, mRNA-1083 induced higher immune responses against the 3 clinically relevant influenza strains (A/H1N1, A/H3N2, B/Victoria) and SARS-CoV-2 than licensed comparator vaccines evaluated in this trial (including the enhanced HD-IIV4 vaccine) in adults 50 years and older. Further, mRNA-1083 had acceptable tolerability and a similar safety profile to comparator vaccines. mRNA-1083 had an overall favorable benefit/risk profile among study participants 50 years and older, of whom 10% were 75 years or older, 45% had received influenza vaccination in the prior season, and more than 60% had a high-risk comorbid condition.

The mRNA platform used to develop mRNA-1083 has numerous advantages, including avoidance of egg adaptation–related changes²⁴ as well as the breadth of immunity and T-cell responses for the influenza component (mRNA-1010).²⁵ Additionally, the rapid production and flexibility for updates to vaccine composition can ensure close matching to circulating influenza and SARS-CoV-2 virus strains.²⁶ Further, the platform can quickly adapt to allow for timely and effective public health responses, especially in the face of emerging variants and strains.²⁶ As such, an annual vaccination campaign with a multicomponent vaccine could occur during the seasonal period when the burden of respiratory hospitalizations is the greatest while allowing for a standalone COVID-19 vaccine option for additional doses or if the vaccine is updated in the interim should any antigenically divergent strain emerge. In addition, a multicomponent vaccine against influenza and COVID-19 has potential to improve coverage and increase compliance with recommendations, therefore reducing COVID-19–related and influenza-related outcomes and health care system burden in adults 50 years and older.

The present study showed that mRNA-1083 induced higher hemagglutination inhibition GM titers than licensed comparators against 3 clinically relevant influenza strains. Hemagglutination inhibition titers are considered a surrogate marker of protection that reasonably predicts clinical benefit in adults, including for older adults.^27,28 Microneutralization GM titers were evaluated as a second assay for verification of immunogenicity; these data were consistent with hemagglutination inhibition results and correlation between assays was observed. Additionally, mRNA-1083 induced higher immune responses than a licensed mRNA COVID-19 comparator (mRNA-1273) based on PsVNA GMCs. Because PsVNA levels provide a surrogate marker of protection against COVID-19, mRNA-1083 is expected to provide meaningful protection against COVID-19.^29,30,31 Further, mRNA-1283, the COVID-19 component of the vaccine, has been observed to have similar or higher efficacy than mRNA-1273.¹⁹ Altogether, the results of these interim analyses suggest that mRNA-1083 has the potential to provide protection against 2 respiratory pathogens in a single injection and, hence, positively impact public health.

The health-related QoL analyses suggest that mRNA-1083 is generally associated with transient, minor decrements in QoL that are not clinically meaningful, in alignment with observations for trivalent adjuvanted or high-dose inactivated influenza vaccines in older adults.³² Overall, the observed impairment was lower than that for currently available COVID-19 vaccines.³³

Study strengths include the randomized, observer-blinded, active comparator-controlled design that allowed for noninferiority and superiority comparisons with licensed vaccines. The placebo vaccination administered to the mRNA-1083 group lessened the likelihood that participants could determine their vaccine group because both groups received an mRNA vaccination and a non-mRNA vaccination. The study was also strengthened by evaluating mRNA-1083 among some participants with a high-risk comorbid condition.

Limitations

This study has limitations. First, efficacy of mRNA-1083 has not been established and warrants future investigation. However, this study evaluated immunogenicity of mRNA-1083 using hemagglutination inhibition and PsVNA, which are well established correlates of protection for influenza and COVID vaccine efficacy, respectively. Second, although the diversity of the study population mirrors that of the general US population, the results may not be generalizable to other geographic areas.

Conclusions

This pivotal phase 3 study demonstrated the noninferiority of a single mRNA-1083 dose in adults 50 years and older in terms of immune responses for 4 influenza strains (A/H1N1, A/H3N2, B/Victoria, B/Yamagata) and SARS-CoV-2 (XBB.1.5) vs licensed seasonal influenza (standard or high dose) and SARS-CoV-2 vaccines.

Supplement 1.

Trial protocol

jama-e255646-s001.pdf^{(899.4KB, pdf)}

Supplement 2.

Statistical analysis plan

jama-e255646-s002.pdf^{(681.9KB, pdf)}

Supplement 3.

eMethods

eTable 1. Classification of Solicited Adverse Reactions by Grade

eTable 2. Participants by Study Site

eTable 3. Participant Demographics and Baseline Characteristics of the Per-Protocol Immunogenicity Population

eTable 4. Summary of Influenza Antibody Responses by HAI and SARS-CoV-2 Antibody Responses by PsVNA by Vaccine and Age Cohort (Per Protocol Immunogenicity Population)

eTable 5. MN assay GMTs and GMFRs at Day 1 and Day 29 by Age Cohort (Per-Protocol Immunogenicity Population for MN Assay)

eTable 6. Solicited Adverse Reactions Within 7 Days After Study Vaccination

eTable 7. Severe Adverse Events Within 28 Days After Study Vaccination By System Organ Class and Preferred Term

eTable 8. Serious Adverse Events Within 28 Days After Study Vaccination By System Organ Class and Preferred Term

eTable 9. Participant Demographics and Baseline Characteristics of EQ-5D-5L Analysis Population in ≥65 Years Cohort

eTable 10. Participant Demographics and Baseline Characteristics of EQ-5D-5L Analysis Population in 50-64 Years Cohort

eTable 11. Participant Demographics and Baseline Characteristics of WPAI Analysis Population in 50-64 Years Cohort

eTable 12. WPAI Scores For Participants Aged 50-64 Years

eFigure 1. Influenza HAI and SARS-CoV-2 PsVNA GM levels and GMFRs at Day 1 and Day 29 by Age Cohort (Per-Protocol Immunogenicity Population)

eFigure 2. GMRs and SCR/SRR Differences of Antibody Levels Against Influenza and SARS-CoV-2 Strains at Day 29 by Comorbidity Status

eFigure 3. GMRs and SCR/SRR Differences of Antibody Levels Against Influenza and SARS-CoV-2 Strains at Day 29 by Prior Vaccine Status Since September 2022

eFigure 4. MN Assay GMTs and GMFRs at Day 1 and Day 29 by Age Cohort (Per-Protocol Immunogenicity Population for MN Assay)

eFigure 5. Correlation Between Influenza HAI and MN titers at Day 1 and Day 29

eFigure 6. Adjusted Change from Baseline in EQ-5D-5L Health State Utilities for Cohort A (Aged ≥65 Years)

eFigure 7. Adjusted Change From Baseline in EQ-5D-5L Health State Utilities for Cohort B (Aged 50-64 Years)

Supplemental References

jama-e255646-s003.pdf^{(2.8MB, pdf)}

Supplement 4.

Data sharing statement

jama-e255646-s004.pdf^{(18.2KB, pdf)}

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Supplementary Materials