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In this study, the E2 protein nanoparticle (NP) platform is engineered to synthesize vaccines that simultaneously co\u2010deliver influenza hemagglutinin (H5) antigen, TLR5 agonist flagellin (FliCc), and TLR9 agonist CpG 1826 (CpG) all on one particle (termed H5\u2010FliCc\u2010CpG\u2010E2), with uniform molecular orientation significant for immunomodulation. Antigen\u2010bound NP formulations elicit higher IgG antibody responses and broader homosubtypic cross\u2010reactivity against different H5 variants than unconjugated antigen alone. IgG1\/IgG2c skewing is modulated by adjuvant type and NP attachment. Conjugation of flagellin to the NP causes significant IgG1 (Th2) skewing while attachment of CpG yields significant IgG2c (Th1) skewing, and simultaneous conjugation of both flagellin and CpG results in a balanced IgG1\/IgG2c (Th2\/Th1) response. 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This investigation highlights that NP\u2010based delivery of antigen and multiple adjuvants can be designed to effectively modulate the strength, breadth toward variants, and bias of an immune response against influenza viruses.<\/jats:p>","DOI":"10.1002\/adhm.202404335","type":"journal-article","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T00:47:35Z","timestamp":1739234855000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Co\u2010Delivery of Multiple Toll\u2010Like Receptor Agonists and Avian Influenza Hemagglutinin on Protein Nanoparticles Enhances Vaccine Immunogenicity and Efficacy"],"prefix":"10.1002","volume":"14","author":[{"given":"Aaron","family":"Ramirez","sequence":"first","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering University of California  Irvine CA 92697 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jenny E.","family":"Hernandez\u2010Davies","sequence":"additional","affiliation":[{"name":"Vaccine Research and Development Center Department of Physiology and Biophysics University of California  Irvine CA 92697 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aarti","family":"Jain","sequence":"additional","affiliation":[{"name":"Vaccine Research and Development Center Department of Physiology and Biophysics University of California  Irvine CA 92697 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Chemical and Biomolecular Engineering University of California  Irvine CA 92697 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwin","family":"Strahsburger","sequence":"additional","affiliation":[{"name":"Vaccine Research and Development Center Department of Physiology and Biophysics University of California  Irvine CA 92697 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D. 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