{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T18:37:27Z","timestamp":1781548647672,"version":"3.54.5"},"reference-count":36,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T00:00:00Z","timestamp":1735689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"NIAID","doi-asserted-by":"publisher","award":["AI154656"],"award-info":[{"award-number":["AI154656"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Current influenza vaccines are not effective in conferring protection against antigenic variants and pandemics. To improve cross-protection of influenza vaccination, we developed a 5xM2e messenger RNA (mRNA) vaccine encoding the tandem repeat conserved ectodomain (M2e) of ion channel protein M2 derived from human, swine, and avian influenza A viruses. The lipid nanoparticle (LNP)\u2013encapsulated 5xM2e mRNA vaccine was immunogenic, eliciting high levels of M2e-specific IgG antibodies, IFN-\u03b3+ T cells, T follicular helper cells, germinal center phenotypic B cells, and plasma cells. The mice with 5xM2e mRNA vaccination were broadly protected against lethal infection regardless of hemagglutinin (H1, H3, H5) subtypes by preventing severe weight loss. Injection of 5xM2e mRNA LNP vaccine induced acute innate responses recruiting monocytes, macrophages, and diverse subsets of dendritic cells. A single dose of combined 5xM2e mRNA LNP and split vaccines resulted in significantly enhanced and sustainable IgG antibody responses to viral antigens and protection against homologous and heterologous viruses. This study provides a new strategy of combined mRNA and seasonal vaccination, significantly enhancing vaccine protective efficacy.<\/jats:p>","DOI":"10.1093\/jimmun\/vkae013","type":"journal-article","created":{"date-parts":[[2025,1,31]],"date-time":"2025-01-31T11:27:18Z","timestamp":1738322838000},"page":"104-114","source":"Crossref","is-referenced-by-count":9,"title":["Influenza 5xM2e mRNA lipid nanoparticle vaccine confers broad immunity and significantly enhances the efficacy of inactivated split vaccination when coadministered"],"prefix":"10.1093","volume":"214","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6779-1703","authenticated-orcid":false,"given":"Phillip","family":"Grovenstein","sequence":"first","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9260-3957","authenticated-orcid":false,"given":"Noopur","family":"Bhatnagar","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ki-Hye","family":"Kim","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Surya Sekhar","family":"Pal","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8540-2767","authenticated-orcid":false,"given":"Chau Thuy Tien","family":"Le","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jannatul Ruhan","family":"Raha","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Liu","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6385-5992","authenticated-orcid":false,"given":"Chong Hyun","family":"Shin","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo Ryoung","family":"Park","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5955-1294","authenticated-orcid":false,"given":"Lanying","family":"Du","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7983-1215","authenticated-orcid":false,"given":"Jeeva","family":"Subbiah","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bao-Zhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Moo","family":"Kang","sequence":"additional","affiliation":[{"name":"Center for Inflammation, Immunity and Infection, Institute for Biomedical Sciences, Georgia State University , Atlanta, GA,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,1,31]]},"reference":[{"key":"2025020515594537500_vkae013-B1","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1093\/cid\/ciw635","article-title":"2014-2015 influenza vaccine effectiveness in the United States by vaccine type","volume":"63","author":"Zimmerman","year":"2016","journal-title":"Clin Infect Dis"},{"key":"2025020515594537500_vkae013-B2","doi-asserted-by":"crossref","first-page":"ofab069","DOI":"10.1093\/ofid\/ofab069","article-title":"Decline in seasonal influenza vaccine effectiveness with vaccination program maturation: a systematic review and meta-analysis","volume":"8","author":"Okoli","year":"2021","journal-title":"Open Forum Infect Dis"},{"key":"2025020515594537500_vkae013-B3","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1093\/infdis\/jiy103","article-title":"A universal influenza vaccine: the strategic plan for the national institute of allergy and infectious diseases","volume":"218","author":"Erbelding","year":"2018","journal-title":"J Infect Dis"},{"key":"2025020515594537500_vkae013-B4","doi-asserted-by":"crossref","first-page":"344","DOI":"10.3389\/fcimb.2019.00344","article-title":"The quest for a truly universal influenza vaccine","volume":"9","author":"Jang","year":"2019","journal-title":"Front Cell Infect Microbiol"},{"key":"2025020515594537500_vkae013-B5","doi-asserted-by":"crossref","first-page":"6542","DOI":"10.1128\/JVI.00641-13","article-title":"Chimeric hemagglutinin influenza virus vaccine constructs elicit broadly protective stalk-specific antibodies","volume":"87","author":"Krammer","year":"2013","journal-title":"J Virol"},{"key":"2025020515594537500_vkae013-B6","doi-asserted-by":"crossref","first-page":"e02810","DOI":"10.1128\/mBio.02810-18","article-title":"Design of nanoparticulate group 2 influenza virus hemagglutinin stem antigens that activate unmutated ancestor B cell receptors of broadly neutralizing antibody lineages","volume":"10","author":"Corbett","year":"2019","journal-title":"mBio"},{"key":"2025020515594537500_vkae013-B7","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1080\/17460441.2020.1801629","article-title":"Call for a paradigm shift in the design of universal influenza vaccines by harnessing multiple correlates of protection","volume":"15","author":"Jang","year":"2020","journal-title":"Expert Opin Drug Discov"},{"key":"2025020515594537500_vkae013-B8","doi-asserted-by":"crossref","first-page":"105","DOI":"10.3390\/vaccines3010105","article-title":"M2e-Based universal influenza A vaccines","volume":"3","author":"Deng","year":"2015","journal-title":"Vaccines"},{"key":"2025020515594537500_vkae013-B9","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1080\/14760584.2017.1240041","article-title":"M2-based influenza vaccines: recent advances and clinical potential","volume":"16","author":"Kolpe","year":"2017","journal-title":"Expert Rev Vaccines"},{"key":"2025020515594537500_vkae013-B10","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/j.micinf.2004.10.006","article-title":"Sequence comparison between the extracellular domain of M2 protein human and avian influenza A virus provides new information for bivalent influenza vaccine design","volume":"7","author":"Liu","year":"2005","journal-title":"Microbes Infect"},{"key":"2025020515594537500_vkae013-B11","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1038\/mt.2012.246","article-title":"Virus-like particles containing multiple M2 extracellular domains confer improved cross-protection against various subtypes of influenza virus","volume":"21","author":"Kim","year":"2013","journal-title":"Mol Ther J Am Soc Gene Ther"},{"key":"2025020515594537500_vkae013-B12","doi-asserted-by":"crossref","first-page":"1569","DOI":"10.1016\/j.ymthe.2020.04.018","article-title":"A multi-targeting, nucleoside-modified mRNA influenza virus vaccine provides broad protection in mice","volume":"28","author":"Freyn","year":"2020","journal-title":"Mol Ther"},{"key":"2025020515594537500_vkae013-B13","doi-asserted-by":"crossref","first-page":"e2206333119","DOI":"10.1073\/pnas.2206333119","article-title":"Assessment of a quadrivalent nucleoside-modified mRNA vaccine that protects against group 2 influenza viruses","volume":"119","author":"McMahon","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025020515594537500_vkae013-B14","doi-asserted-by":"crossref","first-page":"4677","DOI":"10.1038\/s41467-022-32149-8","article-title":"Development of a pentavalent broadly protective nucleoside-modified mRNA vaccine against influenza B viruses","volume":"13","author":"Pardi","year":"2022","journal-title":"Nat Commun"},{"key":"2025020515594537500_vkae013-B15","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41541-020-0163-z","article-title":"Modified mRNA\/lipid nanoparticle-based vaccines expressing respiratory syncytial virus F protein variants are immunogenic and protective in rodent models of RSV infection","volume":"5","author":"Espeseth","year":"2020","journal-title":"NPJ Vaccines"},{"key":"2025020515594537500_vkae013-B16","doi-asserted-by":"crossref","first-page":"2877","DOI":"10.1016\/j.immuni.2021.11.001","article-title":"Lipid nanoparticles enhance the efficacy of mRNA and protein subunit vaccines by inducing robust T follicular helper cell and humoral responses","volume":"54","author":"Alameh","year":"2021","journal-title":"Immunity"},{"key":"2025020515594537500_vkae013-B17","doi-asserted-by":"crossref","first-page":"105229","DOI":"10.1016\/j.antiviral.2021.105229","article-title":"Comparison of the effects of different potent adjuvants on enhancing the immunogenicity and cross-protection by influenza virus vaccination in young and aged mice","volume":"197","author":"Bhatnagar","year":"2022","journal-title":"Antiviral Res"},{"key":"2025020515594537500_vkae013-B18","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1016\/j.omtn.2022.10.024","article-title":"cGAMP-adjuvanted multivalent influenza mRNA vaccines induce broadly protective immunity through cutaneous vaccination in mice","volume":"30","author":"Zhu","year":"2022","journal-title":"Mol Ther Nucleic Acids"},{"key":"2025020515594537500_vkae013-B19","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1016\/j.antiviral.2018.06.004","article-title":"MPL and CpG combination adjuvants promote homologous and heterosubtypic cross protection of inactivated split influenza virus vaccine","volume":"156","author":"Ko","year":"2018","journal-title":"Antiviral Res"},{"key":"2025020515594537500_vkae013-B20","doi-asserted-by":"crossref","first-page":"3514","DOI":"10.1128\/JVI.02052-06","article-title":"Virus-like particle vaccine induces protective immunity against homologous and heterologous strains of influenza virus","volume":"81","author":"Quan","year":"2007","journal-title":"J Virol"},{"key":"2025020515594537500_vkae013-B21","article-title":"Virus-like particles are a superior platform for presenting M2e epitopes to prime humoral and cellular immunity against influenza virus","volume":"6","author":"Kim","year":"2018","journal-title":"Vaccines (Basel)"},{"key":"2025020515594537500_vkae013-B22","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1038\/s41590-022-01163-9","article-title":"Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine","volume":"23","author":"Li","year":"2022","journal-title":"Nat Immunol"},{"key":"2025020515594537500_vkae013-B23","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/j.cell.2020.12.039","article-title":"Messenger RNA vaccines against SARS-CoV-2","volume":"184","author":"Topol","year":"2021","journal-title":"Cell"},{"key":"2025020515594537500_vkae013-B24","doi-asserted-by":"crossref","first-page":"5598","DOI":"10.4049\/jimmunol.172.9.5598","article-title":"Influenza A vaccine based on the extracellular domain of M2: weak protection mediated via antibody-dependent NK cell activity","volume":"172","author":"Jegerlehner","year":"2004","journal-title":"J Immunol"},{"key":"2025020515594537500_vkae013-B25","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1126\/science.abm0271","article-title":"A multivalent nucleoside-modified mRNA vaccine against all known influenza virus subtypes","volume":"378","author":"Arevalo","year":"2022","journal-title":"Science"},{"key":"2025020515594537500_vkae013-B26","doi-asserted-by":"crossref","first-page":"3361","DOI":"10.1038\/s41467-018-05482-0","article-title":"Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies","volume":"9","author":"Pardi","year":"2018","journal-title":"Nat Commun"},{"key":"2025020515594537500_vkae013-B27","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/s41467-021-21037-2","article-title":"A single-dose mRNA vaccine provides a long-term protection for hACE2 transgenic mice from SARS-CoV-2","volume":"12","author":"Huang","year":"2021","journal-title":"Nat Commun"},{"key":"2025020515594537500_vkae013-B28","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.4049\/jimmunol.1501637","article-title":"A novel vaccination strategy mediating the induction of lung-resident memory CD8 T cells confers heterosubtypic immunity against future pandemic influenza virus","volume":"196","author":"Lee","year":"2016","journal-title":"J Immunol"},{"key":"2025020515594537500_vkae013-B29","doi-asserted-by":"crossref","first-page":"362","DOI":"10.3390\/vaccines12040362","article-title":"Multivalent and sequential heterologous spike protein vaccinations effectively induce protective humoral immunity against SARS-CoV-2 variants","volume":"12","author":"Liu","year":"2024","journal-title":"Vaccines (Basel)"},{"key":"2025020515594537500_vkae013-B30","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1038\/13484","article-title":"A universal influenza A vaccine based on the extracellular domain of the M2 protein","volume":"5","author":"Neirynck","year":"1999","journal-title":"Nat Med"},{"key":"2025020515594537500_vkae013-B31","doi-asserted-by":"crossref","first-page":"2405","DOI":"10.4049\/jimmunol.2100637","article-title":"Cutting edge: circulating exosomes with COVID spike protein are induced by BNT162b2 (Pfizer-BioNTech) vaccination prior to development of antibodies: a novel mechanism for immune activation by mRNA vaccines","volume":"207","author":"Bansal","year":"2021","journal-title":"J Immunol"},{"key":"2025020515594537500_vkae013-B32","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1084\/jem.20171450","article-title":"Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses","volume":"215","author":"Pardi","year":"2018","journal-title":"J Exp Med"},{"key":"2025020515594537500_vkae013-B33","doi-asserted-by":"crossref","first-page":"12","DOI":"10.7774\/cevr.2014.3.1.12","article-title":"New vaccines against influenza virus","volume":"3","author":"Lee","year":"2014","journal-title":"Clin Exp Vaccine Res"},{"key":"2025020515594537500_vkae013-B34","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1073\/pnas.1012199108","article-title":"Vaccination inducing broad and improved cross protection against multiple subtypes of influenza A virus","volume":"108","author":"Song","year":"2011","journal-title":"Proc Natl Acad Sci USA"},{"key":"2025020515594537500_vkae013-B35","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.hipert.2021.11.003","article-title":"Monocyte chemoattractant protein-1 and hypertension: An overview","volume":"39","author":"Cortez","year":"2022","journal-title":"Hipertens Riesgo Vasc"},{"key":"2025020515594537500_vkae013-B36","doi-asserted-by":"crossref","first-page":"103479","DOI":"10.1016\/j.isci.2021.103479","article-title":"The mRNA-LNP platform's lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory","volume":"24","author":"Ndeupen","year":"2021","journal-title":"iScience"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/advance-article-pdf\/doi\/10.1093\/jimmun\/vkae013\/61706817\/vkae013.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/advance-article-pdf\/doi\/10.1093\/jimmun\/vkae013\/61706817\/vkae013.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T16:00:23Z","timestamp":1738771223000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/214\/1\/104\/7991292"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,1]]},"references-count":36,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,1,1]]}},"URL":"https:\/\/doi.org\/10.1093\/jimmun\/vkae013","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,1]]},"published":{"date-parts":[[2025,1,1]]}}}