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A vaccine that prevents EBV-driven morbidity and mortality remains an unmet need. EBV is orally transmitted, infecting both B cells and epithelial cells. Several virally encoded proteins are involved in entry. The gH\/gL glycoprotein complex is essential for infectivity irrespective of cell type, while gp42 is essential for infection of B cells. gp350 promotes viral attachment by binding to CD21 or CD35 and is the most abundant glycoprotein on the virion. gH\/gL, gp42 and gp350, are known targets of neutralizing antibodies and therefore relevant immunogens for vaccine development. Here, we developed and optimized the delivery of several alphavirus-derived replicon RNA (repRNA) vaccine candidates encoding gH\/gL, gH\/gL\/gp42 or gp350 delivered by a cationic nanocarrier termed LION\u2122. The lead candidate, encoding full-length gH\/gL, elicited high titers of neutralizing antibodies that persisted for at least 8 months and a vaccine-specific CD8<jats:sup>+<\/jats:sup> T cell response. Transfer of vaccine-elicited IgG protected humanized mice from EBV-driven tumor formation and death following high-dose viral challenge. These data demonstrate that LION\/repRNA-gH\/gL is an ideal candidate vaccine for preventing EBV infection and\/or related malignancies in humans.<\/jats:p>","DOI":"10.1038\/s41541-024-00907-y","type":"journal-article","created":{"date-parts":[[2024,6,26]],"date-time":"2024-06-26T19:21:54Z","timestamp":1719429714000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A gH\/gL-encoding replicon vaccine elicits neutralizing antibodies that protect humanized mice against EBV challenge"],"prefix":"10.1038","volume":"9","author":[{"given":"Kristina R.","family":"Edwards","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harman","family":"Malhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina","family":"Schmidt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6983-3567","authenticated-orcid":false,"given":"Amelia R.","family":"Davis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah J.","family":"Homad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2307-5529","authenticated-orcid":false,"given":"Nikole L.","family":"Warner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Crystal B.","family":"Chhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5905-8862","authenticated-orcid":false,"given":"Samuel C.","family":"Scharffenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Gaffney","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4833-0255","authenticated-orcid":false,"given":"Troy","family":"Hinkley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0699-8863","authenticated-orcid":false,"given":"Nicole B.","family":"Potchen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing Yang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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