{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:30:45Z","timestamp":1790951445560,"version":"4.1.0"},"reference-count":34,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T00:00:00Z","timestamp":1750377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["75N93019C00052"],"award-info":[{"award-number":["75N93019C00052"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Georgia Research Alliance","award":["75N93019C00052"],"award-info":[{"award-number":["75N93019C00052"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives: There is a need for effective seasonal influenza virus vaccines that provide broad and long-lasting protection against influenza virus infections. Methods: In this study, next-generation influenza hemagglutinin (HA) and neuraminidase (NA) vaccine candidates designed using the computationally optimized broadly reactive antigen (COBRA) methodology were formulated with the TLR9 agonist, CpG 1018. These adjuvanted COBRA HA\/NA vaccines were administered intramuscularly or intranasally to mice with pre-existing anti-influenza immunity or immunologically na\u00efve mice. Results: Mice with pre-existing immune responses to historical influenza virus strains vaccinated intranasal (IN) with COBRA HA\/NA vaccines adjuvanted with CpG 1018 had enhanced IgG titers in their bronchoalveolar lavages (BALF) compared to unadjuvanted vaccines. These mice also had increased serum IgG titers that were like antibody titers observed in mice that were vaccinated intramuscularly. Mice that were vaccinated intranasally with this adjuvanted vaccine also had antibodies with significantly higher hemagglutination inhibition activity against a broad range of H1N1 and H3N2 influenza viruses and more HA and NA specific antibody-secreting cells compared to unadjuvanted vaccine. Following the H1N1 influenza virus challenge, pre-immune mice that were vaccinated with the COBRA HA\/NA vaccine with CpG 1018 were protected from morbidity and mortality and had no detectable viral lung titers. Conclusions: Overall, CpG 1018 adjuvanted COBRA HA\/NA elicited enhanced protective antibodies compared to the unadjuvanted vaccine against several drifted H1N1 and H3N2 influenza viruses in pre-immune mice that were either intramuscularly or intranasally vaccinated with a balanced Th1\/Th2 immune response.<\/jats:p>","DOI":"10.3390\/vaccines13070662","type":"journal-article","created":{"date-parts":[[2025,6,20]],"date-time":"2025-06-20T06:10:27Z","timestamp":1750399827000},"page":"662","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Multivalent COBRA Hemagglutinin and Neuraminidase Influenza Vaccines Adjuvanted with TLR9 Agonist CpG 1018"],"prefix":"10.3390","volume":"13","author":[{"given":"Pedro L.","family":"Sanchez","sequence":"first","affiliation":[{"name":"Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA"},{"name":"Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL 34987, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5210-9563","authenticated-orcid":false,"given":"Amanda","family":"Lynch","sequence":"additional","affiliation":[{"name":"Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL 34987, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1947-7469","authenticated-orcid":false,"given":"Ted M.","family":"Ross","sequence":"additional","affiliation":[{"name":"Center for Vaccines and Immunology, University of Georgia, Athens, GA 30602, USA"},{"name":"Florida Research and Innovation Center, Cleveland Clinic, Port Saint Lucie, FL 34987, USA"},{"name":"Department of Infection Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Department of Infectious Diseases, College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1080\/08820139.2021.1909617","article-title":"Better, Faster, Stronger: mRNA Vaccines Show Promise for Influenza Vaccination in Older Adults","volume":"50","author":"Bartley","year":"2021","journal-title":"Immunol. 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