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We constructed an intranasal (IN) replication-competent adenovirus type 4 recombinant platform to express SARS-CoV-2 Spike variants (Ad4-S) and assessed immunogenicity and efficacy in the Syrian hamster model. Although both IN Ad4-S and intramuscular (IM) vaccines (Ad26.CoV2.S and mRNA-1273) induced serum binding antibodies, only Ad4-S induced a robust mucosal response in the nasal cavity. IN Ad4-S vaccination induced serum neutralizing titers equivalent to or greater than IM vaccination but more durable up to 6 months. Upon challenge, IN immunization also resulted in less weight loss, greater breadth and durability of restriction of viral replication, and less lung pathology than IM immunization up to 268 days after immunization. These data support the potential of the IN Ad4 vaccine platform to reduce transmission of SARS-CoV-2 and other respiratory viruses with pandemic potential.<\/jats:p>","DOI":"10.64898\/2026.02.04.703921","type":"posted-content","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T02:45:13Z","timestamp":1770345913000},"source":"Crossref","is-referenced-by-count":1,"title":["Intranasal Replicating Adenovirus type 4-SARS-CoV-2 Recombinants Induce Superior Immune Response Durability and Efficacy in Preclinical Testing Compared to Standard Intramuscular Vaccines"],"prefix":"10.64898","author":[{"given":"Breanna","family":"Kim","sequence":"first","affiliation":[{"name":"HIV-Specific Immunity Section of the Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, 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