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Despite the global implementation of live attenuated vaccines, CSFV remains a persistent threat, with sporadic outbreaks reported annually. A major limitation of the current vaccines is safety concerns and the inability to differentiate infected from vaccinated animals (DIVA). The development of DIVA-compliant vaccines is desirable for effectively controlling or eradicating classical swine fever (CSF). Here, we developed two lipid nanoparticle (LNP)-encapsulated mRNA vaccines encoding either the extracellular domain of the CSFV envelope protein E2 (E2-ECD) or its N-terminal 172-amino acid fragment (E2-ECD-N). Immunological assays in mice revealed high antigenicity and long-lasting protective antibody responses from a single dose of either the E2-ECD or E2-ECD-N mRNA vaccine. Notably, both the E2-ECD and E2-ECD-N mRNA vaccines induced robust T cell responses in mice. Furthermore, a single dose (100\u00a0\u03bcg) of the E2-ECD mRNA vaccine was sufficient to induce long-term (up to 4\u00a0months) protective immunity against CSFV infection in rabbits. Our findings highlight the potential of CSFV-E2-based mRNA vaccines as promising strategies for effective CSF prevention and control while enabling DIVA.<\/jats:p>","DOI":"10.1186\/s13567-025-01581-1","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T23:08:36Z","timestamp":1753139316000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A single-dose mRNA vaccine encoding the classical swine fever virus E2-ECD induces durable protective immunity in rabbits"],"prefix":"10.1186","volume":"56","author":[{"given":"Li-Jun","family":"Bian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Liang","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Zhen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Xia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-Xue","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Bing","family":"Shu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9767-8795","authenticated-orcid":false,"given":"Mi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"1581_CR1","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1017\/S1466252314000024","volume":"15","author":"V Chander","year":"2014","unstructured":"Chander V, Nandi S, Ravishankar C, Upmanyu V, Verma R (2014) Classical swine fever in pigs: recent developments and future perspectives. 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