A phase III randomized clinical trial has demonstrated that mRNA-1083, an investigational multicomponent mRNA vaccine targeting seasonal influenza and SARS-CoV-2, met noninferiority immunogenicity criteria compared with licensed standard-of-care vaccines in adults aged 50 years and older. Researchers also found that mRNA-1083 induced superior immune responses against multiple vaccine-matched strains in some subgroups, while maintaining an acceptable safety profile.
In the pivotal trial of 8,015 participants conducted across 146 U.S. sites, mRNA-1083 demonstrated immunogenicity and safety comparable to coadministered licensed quadrivalent influenza vaccines (high-dose for adults aged ≥ 65 years, standard-dose for adults aged 50 to 64 years) and COVID-19 (mRNA-1273) vaccines.
“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 four influenza strains (among those aged 50 [to] 64 years), the three clinically relevant influenza strains (among those older than 65 years), and SARS-CoV-2 (all ages), with an acceptable tolerability and safety profile,” the study authors reported.
The multicomponent vaccine combined hemagglutinin-based influenza components (mRNA-1010) with a second-generation SARS-CoV-2 vaccine component encoding spike glycoprotein N-terminal domain and receptor-binding domain (NTD-RBD; mRNA-1283).
Trial Design and Demographics
The participants were stratified into two age cohorts (65 years and older and 50 to 64 years) and randomly assigned 1:1 to receive either mRNA-1083 plus placebo or coadministered licensed vaccines. Among 4,017 adults aged 65 years and older and 3,998 adults aged 50 to 64 years, the participants received either mRNA-1083 or comparator vaccines containing high-dose quadrivalent inactivated influenza vaccine (HD-IIV4) plus mRNA-1273, or standard-dose IIV4 (SD-IIV4) plus mRNA-1273, respectively.
The study population was diverse, with 54.2% and 58.8% female participants in the ≥ 65– and 50-to-64–year cohorts, respectively. Black participants represented 18.4% and 26.7% of the respective cohorts, while Hispanic participants comprised 13.9% and 19.3%. More than 60% of the participants had high-risk comorbid conditions.
Immunogenicity Results
The primary noninferiority endpoints were met for all vaccine-matched strains. Noninferiority was determined based on the lower bound of the 97.5% confidence interval (CI) of the geometric mean ratio being greater than 0.667 and the lower bound of the 97.5% CI of the seroconversion/seroresponse rate difference being greater than −10%.
For secondary superiority objectives, mRNA-1083 elicited significantly higher immune responses than SD-IIV4 for all 4 influenza strains in adults aged 50 to 64 years. Among adults aged older than 65 years, mRNA-1083 demonstrated superior immune responses compared with HD-IIV4 for A/H1N1, A/H3N2, and B/Victoria; responses against B/Yamagata didn't meet the superiority threshold, which precluded formal superiority testing for SARS-CoV-2 in this cohort. Nevertheless, SARS-CoV-2 responses in both age groups were significantly higher with mRNA-1083 compared with mRNA-1273.
Safety Profile
Solicited adverse reactions occurred in 83.5% of mRNA-1083 recipients vs 78.1% of HD-IIV4 plus mRNA-1273 recipients among adults ≥ 65 years, and in 85.2% vs 81.8% in adults aged 50 to 64 years, respectively. Most of the reactions were grade 1 or 2 in severity and resolved within 3 to 4 days. Grade 4 adverse reactions were rare (< 0.1%), and no cases of myocarditis or pericarditis were reported.
The most common adverse reactions were injection-site pain, fatigue, myalgia, and headache. Rates of unsolicited adverse events, medically attended events, and serious adverse events were similar across groups, and no adverse events led to study discontinuation.
Clinical and Public Health Implications
The researchers noted that the mRNA platform could offer advantages, including avoidance of egg adaptation–related changes and the potential for broad immunity and robust T-cell responses. The rapid production timeline and flexibility of mRNA vaccines may allow for close matching to circulating influenza and SARS-CoV-2 strains.
In addition to immunogenicity and safety outcomes, the researchers evaluated health-related quality of life. A transient decline in EQ-5D-5L utility scores was observed on day 2 postvaccination, which resolved by day 3; the change was below the threshold considered clinically meaningful. Given the suboptimal uptake of influenza and COVID-19 vaccines, a single-injection multicomponent vaccine may improve coverage and compliance with immunization guidelines and help reduce disease burden and strain on health care systems.
The authors concluded: "[This pivotal study] demonstrated the noninferiority of a single mRNA-1083 dose in adults 50 years and older in terms of immune responses for four 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.” While efficacy data are pending, the use of hemagglutination inhibition and pseudovirus neutralization assays could provide surrogate markers for clinical protection against influenza and COVID-19 infections.
Source: JAMA