{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T10:08:47Z","timestamp":1789380527867,"version":"build-2803163510"},"reference-count":178,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T00:00:00Z","timestamp":1789344000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Available seasonal influenza vaccines, most of which are still produced in eggs, have several limitations. Messenger RNA (mRNA) technology has emerged as a transformative approach capable of overcoming some of these shortcomings. This overview synthesizes clinical trials evaluating the immunogenicity, efficacy, and safety of standalone and combination mRNA influenza vaccines. Moderna\u2019s mRNA-1010 (now approved in the United States) and Pfizer\u2019s modified-nucleoside RNA candidate (modRNA) represent the most advanced standalone platforms, while Moderna\u2019s combination influenza and COVID-19 vaccine, mRNA-1083, was recently granted European authorization. Following iterative platform optimization, these vaccines induce robust humoral and cell-mediated responses, especially against influenza A strains, characterized by extended germinal center reactions, continuous somatic hypermutation, enhanced Fc-mediated effector functions, and strong T helper 1 engagement. In phase III relative efficacy trials, an optimized mRNA-1010 formulation achieved superiority over standard-dose vaccines with a relative efficacy of 26.6% (95% CI: 16.7%, 35.4%) in adults aged \u226550 years. Pfizer\u2019s first-generation quadrivalent modRNA candidate showed 34.5% (95% CI: 7.4%, 53.9%) relative efficacy against a standard-dose comparator in younger adults aged 18\u201364 years, but failed to demonstrate non-inferiority in older adults (\u226565 years), showing a relative efficacy of \u22125.8% (95% CI: \u221247.2%, 23.8%). However, whether mRNA platforms offer incremental benefits over enhanced formulations (such as high-dose, adjuvanted, or recombinant vaccines), which are the preferred options in some countries for older adults, remains to be established. The safety profile aligns with licensed COVID-19 mRNA vaccines; although reactogenicity is higher than with conventional vaccines, adverse reactions are predominantly mild-to-moderate and transient. Operationally, transitioning to single-dose pre-filled syringes alongside expanding refrigerated stability data significantly mitigates historical cold-chain bottlenecks. However, while standalone and combination mRNA platforms represent a major technological advance, real-world implementation challenges may affect their broader global health impact.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1965512","type":"journal-article","created":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T09:55:31Z","timestamp":1789379731000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["mRNA-based seasonal influenza vaccines: an overview of immunogenicity, efficacy, and safety"],"prefix":"10.3389","volume":"17","author":[{"given":"Alexander","family":"Domnich","sequence":"first","affiliation":[{"name":"AOM \u2013 IRCCS Ospedale Policlinico San Martino","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Orsi","sequence":"additional","affiliation":[{"name":"AOM \u2013 IRCCS Ospedale Policlinico San Martino","place":["Genoa, Italy"]},{"name":"Department of Health Sciences (DISSAL), University of Genoa","place":["Genoa, Italy"]},{"name":"Interuniversity Research Centre on Influenza and Other Transmissible Infections (CIRI-IT)","place":["Genoa, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"17","DOI":"10.2807\/1560-7917.ES.2018.23.16.17-00454","article-title":"Impact of infectious diseases on population health using incidence-based disability-adjusted life years (DALYs): results from the Burden of Communicable Diseases in Europe study, European Union and European Economic Area countries, 2009 to 2013","volume":"23","author":"Cassini","year":"2018","journal-title":"Euro Surveill"},{"key":"B2","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1016\/S2213-2600(18)30496-X","article-title":"Mortality, morbidity, and hospitalisations due to influenza lower 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