Dual-target vaccine for flu, COVID-19 compares favourably with standalone comparators

The investigational influenza–COVID-19 combination vaccine mRNA-1083 has demonstrated noninferiority to recommended standard-care flu and COVID-19 vaccines, with higher immune responses and an acceptable safety profile in adults at least 50 years of age, according to the results of a phase III trial.

“mRNA-1083 increased hemagglutination inhibition and pseudovirus neutralizing antibody geometric mean antibody levels against each influenza (A/H1N1, A/H3N2, B/Victoria, B/Yamagata) and SARS-CoV-2 (Omicron XBB.1.5) strain at day 29 vs baseline,” the investigators said.

Notably, the primary immunogenicity objective of noninferiority was met in the 50–64-year and ≥65-year age cohorts. A single mRNA-1083 dose induced noninferior immune responses against all four influenza strains and SARS-CoV-2 compared with standard-dose quadrivalent inactivated influenza vaccine (SD-IIV4) plus mRNA-1273 and high-dose quadrivalent inactivated influenza vaccine (HD-IIV4) plus mRNA-1273. [JAMA 2025;333:1977-1987]

Furthermore, immune responses against all flu strains and SARS-CoV-2 was rather superior with mRNA-1083 vs SD-IIV4 plus mRNA-1273 in the 50–64-year age cohort. However, in the ≥65-year age cohort, mRNA-1273 did not meet the superiority threshold for the immune response against the B/Yamagata flu strain compared with HD-IIV4 plus mRNA-1273.

It’s worth noting that the WHO does not recommend the inclusion of the B/Yamagata in the 2024–2025 vaccine due to its global disappearance during the COVID-19 pandemic, according to the investigators. “Therefore, for adults 50 and older, mRNA-1083 still produced higher immune responses against the three clinically relevant influenza strains (A/H1N1, A/H3N2, B/Victoria) and SARS-CoV-2 compared with the licensed comparator vaccines in this trial.”

Acceptable tolerability

The dual-target vaccine had acceptable tolerability and a similar safety profile to comparator vaccines. Solicited adverse reactions (ARs) occurred in 83.5 percent of mRNA-1083 recipients and in 78.1 percent of HD-IIV4 plus mRNA-1273 recipients in the ≥65-year age cohort; and in 85.2 percent of mRNA-1083 recipients and 81.8 percent of mRNA-1083 and SD-IIV4 plus mRNA-1273 recipients in the 50–64-year age cohort. These ARs were mostly grade 1 or 2 and included injection site pain, fatigue, myalgia, and headache. Grade 4 fever was documented in ≤0.1 percent of individuals across the vaccine groups.  

Unsolicited adverse events (AEs) within 28 days after vaccination were similar among the vaccine groups, with none leading to study discontinuation. AEs considered to be vaccination-related occurred in 0.8 percent mRNA-1083 recipients and 1.0 percent of HD-IIV4 plus mRNA-1273 recipients in the ≥65-year age cohort; and in 0.9 percent mRNA-1083 recipients and 1.3 percent of SD-IIV4 plus mRNA-1273 recipients in the 50–64-year age cohort. There were no reports of vaccination-related severe or serious AEs, nor were there any reported cases of myocarditis or pericarditis. One recipient of HD-IIV4 plus mRNA-1273 died due to cardiac arrest that was deemed unrelated to vaccination.

The median duration of follow-up after vaccination was 109 days in the ≥65-year age cohort and 112 days in the 50–64-year age cohort.

mRNA-1083

“mRNA-1083 contains 5 mRNA sequences encoding membrane-bound hemagglutinin of four influenza strains (recommended for Northern Hemisphere 2023–2024 season) and the linked N-terminal domain and receptor-binding domain of the SARS-CoV-2 S glycoprotein, encapsulated in lipid nanoparticles,” the investigators said.

They pointed out that the mRNA platform used to develop mRNA-1083 offers several advantages, including avoidance of issues with egg adaptation during vaccine development as well as broad immunity and robust T-cell responses for the influenza component.

“Additionally, the rapid production and flexibility for updates to vaccine composition can ensure close matching to circulating influenza and SARS-CoV-2 virus strains. The platform can quickly adapt to allow for timely and effective public health responses, especially in the face of emerging variants and strains,” the investigators noted.

“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,” they added.

The investigators believed that the dual-target vaccine for flu and COVID-19 holds the potential to improve vaccination coverage and compliance with recommendations, in turn reducing illness among adults aged 50 years and older as well as the associated burden on the healthcare system.

In the randomized controlled study, 4,017 adults in the ≥65-year age cohort (median age 70 years, 54.2 percent female, 18.4 percent a Black or African American) received either mRNA-1083 (n=2,011) or HD-IIV4 plus mRNA-1273 (n=2,006). In the 50–64-year age cohort, 3,998 adults (median age 58 years, 58.8 percent female, 26.7 percent a Black or African American) received either mRNA-1083 (n=1,993) or SD-IIV4 plus mRNA-1273 (n=2,005).

Overall, 10 percent of participants were 75 years or older, 45 percent had received flu vaccination in the prior season, and more than 60 percent had a high-risk comorbid condition.