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We developed intranasal rare-serotype chimpanzee adenovirus 68 (AdC68)\u2013based vaccines expressing heterologous tandem receptor-binding domains from SARS-CoV-2, SARS-CoV, and MERS-CoV, fused to the SARS-CoV-2 nucleocapsid (AdC68-4RBD(XBB.1.5)-N) to enhance both B and T cell responses. Antigen integrity was confirmed by receptor binding and recognition by multiple conformation-sensitive monoclonal antibodies. In mice, intranasal AdC68-4RBD(XBB.1.5)-N elicited potent and durable mucosal and systemic immunity, including serum\/saliva IgA and broad neutralizing antibodies persisting up to 40 weeks, alongside tissue-localized B and T cells. Monoclonal antibodies from long-lived bone marrow antibody-secreting cells demonstrated broad and strain-specific neutralization, providing mechanistic insight into the breadth and longevity of the antibody response. In Syrian hamsters, intranasal immunization protected against SARS-CoV-2 XBB.1.5 replication in nasal turbinates and lungs and blocked transmission for up to four months post-vaccination. Robust protection against SARS-CoV challenge was demonstrated in K18-hACE2 transgenic mice, further confirming its broad efficacy. These findings support AdC68-4RBD(XBB.1.5)-N as a promising mucosal vaccine candidate to prevent infection and transmission of pathogenic coronaviruses.<\/jats:p>","DOI":"10.1371\/journal.ppat.1014436","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T17:40:59Z","timestamp":1784914859000},"page":"e1014436","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Broad and durable protection against SARS-CoV-2 and SARS-CoV by an intranasal chimpanzee adenovirus vaccine expressing tandem RBDs and nucleocapsid"],"prefix":"10.1371","volume":"22","author":[{"given":"Yaping","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runhong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoke","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junxian","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqing","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Bai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanling","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4931-509X","authenticated-orcid":true,"given":"Linqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"issue":"5","key":"ppat.1014436.ref001","doi-asserted-by":"crossref","DOI":"10.1016\/j.cell.2022.02.005","article-title":"Respiratory 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