{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T09:32:37Z","timestamp":1790674357592,"version":"4.1.0"},"reference-count":37,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,11,23]],"date-time":"2019-11-23T00:00:00Z","timestamp":1574467200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Annually, influenza A virus (IAV) infects ~5\u201310% of adults and 20\u201330% of children worldwide. The primary resource to protect against infection is by vaccination. However, vaccination only induces strain-specific and transient immunity. Vaccine strategies that induce cross-protective immunity against the broad diversity of IAV are needed. Here we developed and tested a novel mosaic H1 HA immunogen. The mosaic immunogen was optimized in silico to include the most potential B and T cell epitopes (PBTE) across a diverse population of human H1 IAV. Phylogenetic analysis showed that the mosaic HA localizes towards the non-pandemic 2009 strains which encompasses the broadest diversity in the H1 IAV population. We compared the mosaic H1 immunogen to wild-type HA immunogens and the commercial inactivated influenza vaccine, Fluzone. When analyzed by ELISA, the mosaic immunogen induced stronger antibody responses against all four diverse H1 HA proteins. When analyzing T cell responses, again the mosaic immunogen induced stronger cellular immunity against all 4 diverse HA strains. Not only was the magnitude of T cell responses strongest in mosaic immunized mice, the number of epitopes recognized was also greater. The mosaic vaccinated mice showed strong cross-protection against challenges with three divergent IAV strains. These data show that the mosaic immunogen induces strong cross-protective immunity and should be investigated further as a universal influenza vaccine.<\/jats:p>","DOI":"10.3390\/vaccines7040195","type":"journal-article","created":{"date-parts":[[2019,11,25]],"date-time":"2019-11-25T03:10:00Z","timestamp":1574651400000},"page":"195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Influenza H1 Mosaic Hemagglutinin Vaccine Induces Broad Immunity and Protection in Mice"],"prefix":"10.3390","volume":"7","author":[{"given":"Brigette N.","family":"Corder","sequence":"first","affiliation":[{"name":"School of Biological Sciences, Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE 68503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6702-0079","authenticated-orcid":false,"given":"Brianna L.","family":"Bullard","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE 68503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer L.","family":"DeBeauchamp","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8178-0472","authenticated-orcid":false,"given":"Natalia A.","family":"Ilyushina","sequence":"additional","affiliation":[{"name":"Division of Biotechnology Review and Research II, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Webby","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, St. Jude Children\u2019s Research Hospital, Memphis, TN 38105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5029-0662","authenticated-orcid":false,"given":"Eric A.","family":"Weaver","sequence":"additional","affiliation":[{"name":"School of Biological Sciences, Nebraska Center for Virology, University of Nebraska-Lincoln, Lincoln, NE 68503, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1173","DOI":"10.3201\/eid2407.171270","article-title":"Progress and Remaining Gaps in Estimating the Global Disease Burden of Influenza","volume":"24","author":"Bresee","year":"2018","journal-title":"Emerg. Infect. Dis."},{"key":"ref_2","unstructured":"WHO (2019, October 09). Seasonal Influenza and Influenza A(H1N1). Available online: https:\/\/www.who.int\/ith\/diseases\/si_iAh1n1\/en\/."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1007\/s13337-017-0390-8","article-title":"History and current trends in influenza virus infections with special reference to Sri Lanka","volume":"28","author":"Rafeek","year":"2017","journal-title":"Virusdisease"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2605","DOI":"10.1056\/NEJMoa0903810","article-title":"Emergence of a novel swine-origin influenza A (H1N1) virus in humans","volume":"360","author":"Dawood","year":"2009","journal-title":"N. Engl."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1038\/nature08182","article-title":"Origins and evolutionary genomics of the 2009 swine-origin H1N1 influenza A epidemic","volume":"459","author":"Smith","year":"2009","journal-title":"Nature"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1093\/infdis\/jix632","article-title":"Duration of Influenza Vaccine Effectiveness: A Systematic Review, Meta-analysis, and Meta-regression of Test-Negative Design Case-Control Studies","volume":"217","author":"Young","year":"2018","journal-title":"J. Infect. Dis."},{"key":"ref_7","first-page":"544","article-title":"Intraseason waning of influenza vaccine protection: Evidence from the US Influenza Vaccine Effectiveness Network, 2011-12 through 2014-15","volume":"64","author":"Ferdinands","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_8","unstructured":"CDC (2019, September 04). CDC Seasonal Flu Vaccine Effectiveness Studies, Available online: https:\/\/www.cdc.gov\/flu\/vaccines-work\/effectiveness-studies.htm."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1080\/14760584.2017.1379396","article-title":"Vaccine approaches conferring cross-protection against influenza viruses","volume":"16","author":"Vemula","year":"2017","journal-title":"Exp. Rev.Vvaccines"},{"key":"ref_10","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. Virology"},{"key":"ref_11","first-page":"301","article-title":"Advances in universal influenza virus vaccine design and antibody mediated therapies based on conserved regions of the hemagglutinin","volume":"386","author":"Krammer","year":"2015","journal-title":"Curr. Top. Microbiol. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/j.coviro.2013.07.007","article-title":"Influenza virus hemagglutinin stalk-based antibodies and vaccines","volume":"3","author":"Krammer","year":"2013","journal-title":"Curr. Opin. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"18979","DOI":"10.1073\/pnas.1013387107","article-title":"Vaccination with a synthetic peptide from the influenza virus hemagglutinin provides protection against distinct viral subtypes","volume":"107","author":"Wang","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Weaver, E.A., Rubrum, A.M., Webby, R.J., and Barry, M.A. (2011). Protection against divergent influenza H1N1 virus by a centralized influenza hemagglutinin. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0018314"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"14912","DOI":"10.1038\/s41598-017-14891-y","article-title":"Efficacy of an Adenoviral Vectored Multivalent Centralized Influenza Vaccine","volume":"7","author":"Lingel","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1099\/vir.0.033076-0","article-title":"Cross-protective immunity against influenza pH1N1 2009 viruses induced by seasonal influenza A (H3N2) virus is mediated by virus-specific T-cells","volume":"92","author":"Hillaire","year":"2011","journal-title":"J. Gen. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1016\/j.vaccine.2006.08.036","article-title":"Primary influenza A virus infection induces cross-protective immunity against a lethal infection with a heterosubtypic virus strain in mice","volume":"25","author":"Kreijtz","year":"2007","journal-title":"Vaccine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1128\/jb.89.1.170-174.1965","article-title":"Induction of partial specific heterotypic immunity in mice by a single infection with influenza A virus","volume":"89","author":"Schulman","year":"1965","journal-title":"J. Bacteriol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1111\/imm.12548","article-title":"Epitope specific T-cell responses against influenza A in a healthy population","volume":"147","author":"Savic","year":"2016","journal-title":"Immunology"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2486","DOI":"10.4049\/jimmunol.1300954","article-title":"Protective CD8 T cell-mediated immunity against influenza A virus infection following influenza virus-like particle vaccination","volume":"191","author":"Hemann","year":"2013","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1615\/CritRevImmunol.2013010019","article-title":"T-cell immunity to influenza A viruses","volume":"34","author":"Grant","year":"2014","journal-title":"Crit. Rev. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1038\/nm1461","article-title":"Polyvalent vaccines for optimal coverage of potential T-cell epitopes in global HIV-1 variants","volume":"13","author":"Fischer","year":"2007","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.virol.2012.03.012","article-title":"Breadth of cellular and humoral immune responses elicited in rhesus monkeys by multi-valent mosaic and consensus immunogens","volume":"428","author":"Santra","year":"2012","journal-title":"Virology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1016\/j.cell.2013.09.061","article-title":"Protective efficacy of a global HIV-1 mosaic vaccine against heterologous SHIV challenges in rhesus monkeys","volume":"155","author":"Barouch","year":"2013","journal-title":"Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"6771","DOI":"10.1128\/JVI.00730-16","article-title":"Mosaic H5 Hemagglutinin Provides Broad Humoral and Cellular Immune Responses against Influenza Viruses","volume":"90","author":"Kamlangdee","year":"2016","journal-title":"J. Virology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.3389\/fimmu.2019.01429","article-title":"Dengue Mosaic Vaccines Enhance Cellular Immunity and Expand the Breadth of Neutralizing Antibody Against All Four Serotypes of Dengue Viruses in Mice","volume":"10","author":"Hou","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"4876","DOI":"10.1093\/nar\/25.24.4876","article-title":"The CLUSTAL_X windows interface: Flexible strategies for multiple sequence alignment aided by quality analysis tools","volume":"25","author":"Thompson","year":"1997","journal-title":"Nucleic Acids. Res."},{"key":"ref_28","unstructured":"Cummings, M.P. (2014). PAUP: Phylogenetic Analysis Using Parsimony (and Other Methods), Sinauer Associates."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"W296","DOI":"10.1093\/nar\/gky427","article-title":"SWISS-MODEL: Homology modelling of protein structures and complexes","volume":"46","author":"Waterhouse","year":"2018","journal-title":"Nucleic Acids. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"W252","DOI":"10.1093\/nar\/gku340","article-title":"SWISS-MODEL: Modelling protein tertiary and quaternary structure using evolutionary information","volume":"42","author":"Biasini","year":"2014","journal-title":"Nucleic Acids. Res."},{"key":"ref_31","unstructured":"Los Alamos National Laboratory (2017, November 10). Mosaic Vaccine Designer, Available online: https:\/\/www.hiv.lanl.gov\/content\/sequence\/MOSAIC\/makeVaccine.html."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.jviromet.2010.11.024","article-title":"Comparison of hemagglutination inhibition assay, an ELISA-based micro-neutralization assay and colorimetric microneutralization assay to detect antibody responses to vaccination against influenza A H1N1 2009 virus","volume":"171","author":"Grund","year":"2011","journal-title":"J. Virol. Methods"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Jacobsen, H., Rajendran, M., Choi, A., Sjursen, H., Brokstad, K.A., Cox, R.J., Palese, P., Krammer, F., and Nachbagauer, R. (2017). Influenza Virus Hemagglutinin Stalk-Specific Antibodies in Human Serum are a Surrogate Marker for In Vivo Protection in a Serum Transfer Mouse Challenge Model. mBio, 8.","DOI":"10.1128\/mBio.01463-17"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"13300","DOI":"10.1128\/JVI.01532-14","article-title":"Broad protection against avian influenza virus by using a modified vaccinia Ankara virus expressing a mosaic hemagglutinin gene","volume":"88","author":"Kamlangdee","year":"2014","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11756","DOI":"10.1128\/JVI.01460-06","article-title":"Cellular immune responses in children and adults receiving inactivated or live attenuated influenza vaccines","volume":"80","author":"He","year":"2006","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1093\/infdis\/jir436","article-title":"Live and inactivated influenza vaccines induce similar humoral responses, but only live vaccines induce diverse T-cell responses in young children","volume":"204","author":"Hoft","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1517\/14712598.2010.519332","article-title":"Production of adenovirus vectors and their use as a delivery system for influenza vaccines","volume":"10","author":"Vemula","year":"2010","journal-title":"Expert Opin. Biol. Ther."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/7\/4\/195\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:37:02Z","timestamp":1760189822000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/7\/4\/195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,23]]},"references-count":37,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["vaccines7040195"],"URL":"https:\/\/doi.org\/10.3390\/vaccines7040195","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,23]]}}}