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While inactivated vaccines have contributed to FMD control worldwide, recent outbreaks in Europe and Asia highlight the need for new control strategies. Live-attenuated virus (LAV) vaccines provide strong and long-lasting protection. We previously demonstrated that deoptimization of various viral coding regions results in attenuated foot-and-mouth disease virus (FMDV). Here, an FMDV A24Cruzeiro LAV with codon deoptimized P2\/P3 regions (A24-P2\/P3Deopt) and markers differentiating infected from vaccinated animals (DIVA) was tested for safety\/efficacy in cattle. Animals inoculated intradermolingually (IDL) with 10\n                    <jats:sup>6<\/jats:sup>\n                    or 10\n                    <jats:sup>7<\/jats:sup>\n                    pfu of A24-P2\/P3Deopt for safety testing exhibited no clinical signs, viremia or viral shedding for 28 days post inoculation (DPI). To assess efficacy, cattle were subcutaneously inoculated either once with 10\n                    <jats:sup>5<\/jats:sup>\n                    pfu or twice (0- and 14-dpi) with 10\n                    <jats:sup>4<\/jats:sup>\n                    , 10\n                    <jats:sup>5<\/jats:sup>\n                    or 10\n                    <jats:sup>6<\/jats:sup>\n                    pfu A24-P2\/P3Deopt. No animal developed signs of disease post-inoculation. All prime-boost vaccinated animals developed strong neutralizing antibody responses that were protective against challenge with WT FMDV A24. Moreover, vaccinated sera showed strong cross-reactivity against several A strains and serotype Asia1. Our work demonstrates that codon deoptimization is a viable technology to derive novel LAV candidates that are safe, immunogenic and efficacious against FMD in cattle.\n                  <\/jats:p>","DOI":"10.1038\/s41541-025-01368-7","type":"journal-article","created":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T07:04:18Z","timestamp":1769238258000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Live-attenuated foot-and-mouth disease virus vaccine engineered by codon deoptimization induces a strong protective immune response in cattle"],"prefix":"10.1038","volume":"11","author":[{"given":"Sarah E.","family":"Attreed","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christina","family":"Silva","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monica","family":"Rodriguez-Calzada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan D.","family":"Heimroth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Oldakowski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carolina","family":"Stenfeldt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Azzinaro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward","family":"Spinard","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aishwarya","family":"Mogulothu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steffen","family":"Mueller","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bruce","family":"Taillon","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonathan","family":"Arzt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth","family":"Rieder","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Teresa","family":"de los Santos","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fayna","family":"D\u00edaz-San Segundo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gisselle N.","family":"Medina","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,1,24]]},"reference":[{"key":"1368_CR1","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1128\/CMR.17.2.465-493.2004","volume":"17","author":"MJ Grubman","year":"2004","unstructured":"Grubman, M. 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