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Its broad host range, tropism for human\u2010origin cells, and limited vaccine availability underscore the importance of defining viral determinants of pathogenicity. The accessory protein ORF3 has been linked to CoV virulence, but its role in SADS\u2010CoV infection in vivo and its impact on maternally transferred protection have not been fully established. Here, we used reverse genetics to generate rSADS\u2010\u0394ORF3\/GFP, a recombinant virus with ORF3 replaced by GFP, and compared it with parental rSADS\u2010CoV in suckling BALB\/c mice. ORF3 depletion markedly attenuated disease and reduced viral RNA burdens across tissues relative to parental rSADS\u2010CoV. Because maternally derived immunity is critical to protection against swine enteric CoV infection in newborn animals, we further evaluated whether rSADS\u2010\u0394ORF3\/GFP, as a potential live attenuated vaccine (LAV), could elicit maternal protection transferred from inoculated dams to their offspring. Compared with parental rSADS\u2010CoV, rSADS\u2010\u0394ORF3\/GFP induced lower maternal neutralizing antibody titers and provided less robust protection in challenged offspring. Nevertheless, offspring from rSADS\u2010\u0394ORF3\/GFP\u2010inoculated dams showed improved survival, weight gain, milder intestinal pathology, and lower tissue viral RNA burdens than offspring from DMEM\u2010inoculated dams, indicating retained protective immunogenicity. Together, these findings support a contribution of ORF3 to SADS\u2010CoV virulence and demonstrate that ORF3 depletion yields an attenuated virus that retains partial maternally mediated protective efficacy. The residual immunogenicity of rSADS\u2010\u0394ORF3\/GFP, combined with its reduced virulence, supports its further evaluation as a LAV candidate.<\/jats:p>","DOI":"10.1155\/tbed\/6713584","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T11:56:54Z","timestamp":1790855814000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ORF3 Depletion Attenuates SADS\u2010CoV Virulence and Retains Partial Maternally Mediated Protection in Suckling Mice"],"prefix":"10.1155","volume":"2026","author":[{"given":"Nian-Qi","family":"Zhang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Animal Disease Control and Prevention Guangdong Laboratory for Lingnan Modern Agriculture College of Veterinary Medicine South China Agricultural University  Guangzhou China  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