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In this study, we compared three recombinant chimeric viruses developed as candidate vaccine prototypes (rJEV\/ZIKVMR-766, rJEV\/ZIKVP6-740, and rJEV\/ZIKVPRVABC-59), in which the two neutralizing antibody-inducing prM and E genes from each of three genetically distinct ZIKV strains were used to replace the corresponding genes of the clinically proven live-attenuated Japanese encephalitis virus vaccine SA14-14-2 (rJEV). In WHO-certified Vero cells (a cell line suitable for vaccine production), rJEV\/ZIKVP6-740 exhibited the slowest viral growth, formed the smallest plaques, and displayed a unique protein expression profile with the highest ratio of prM to cleaved M when compared to the other two chimeric viruses, rJEV\/ZIKVMR-766 and rJEV\/ZIKVPRVABC-59, as well as their vector, rJEV. In IFNAR\u2212\/\u2212 mice, an animal model of ZIKV infection, subcutaneous inoculation of rJEV\/ZIKVP6-740 caused a low-level localized infection limited to the spleen, with no clinical signs of infection, weight loss, or mortality; in contrast, the other two chimeric viruses and their vector caused high-level systemic infections involving multiple organs, consistently leading to clear clinical signs of infection, rapid weight loss, and 100% mortality. Subsequently, subcutaneous immunization with rJEV\/ZIKVP6-740 proved highly effective, offering complete protection against a lethal intramuscular ZIKV challenge 28 days after a single-dose immunization. This protection was specific to ZIKV prM\/E and likely mediated by neutralizing antibodies targeting ZIKV prM\/E. Therefore, our data indicate that the chimeric virus rJEV\/ZIKVP6-740 is a highly promising vaccine prototype for developing a safe and effective vaccine for inducing neutralizing antibody-mediated protective immunity against ZIKV.<\/jats:p>","DOI":"10.3390\/ijms26010195","type":"journal-article","created":{"date-parts":[[2024,12,31]],"date-time":"2024-12-31T07:34:19Z","timestamp":1735630459000},"page":"195","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Comparison of Three Chimeric Zika Vaccine Prototypes Developed on the Genetic Background of the Clinically Proven Live-Attenuated Japanese Encephalitis Vaccine SA14-14-2"],"prefix":"10.3390","volume":"26","author":[{"given":"Byung-Hak","family":"Song","sequence":"first","affiliation":[{"name":"Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan C.","family":"Frank","sequence":"additional","affiliation":[{"name":"Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sang-Im","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin G.","family":"Julander","sequence":"additional","affiliation":[{"name":"Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA"},{"name":"Institute for Antiviral Research, Utah State University, Logan, UT 84322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2459-1186","authenticated-orcid":false,"given":"Jeffrey B.","family":"Mason","sequence":"additional","affiliation":[{"name":"Department of Veterinary Clinical and Life Sciences, College of Veterinary Medicine, Center for Integrated BioSystems, Utah State University, Logan, UT 84322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0858-5889","authenticated-orcid":false,"given":"Irina A.","family":"Polejaeva","sequence":"additional","affiliation":[{"name":"Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0368-886X","authenticated-orcid":false,"given":"Kenneth L.","family":"White","sequence":"additional","affiliation":[{"name":"Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8821-0042","authenticated-orcid":false,"given":"Xin","family":"Dai","sequence":"additional","affiliation":[{"name":"Utah Agricultural Experiment Station, Utah State University, Logan, UT 84322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3974-3405","authenticated-orcid":false,"given":"Young-Min","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Animal Dairy and Veterinary Sciences, College of Agriculture and Applied Sciences, Utah State University, Logan, UT 84322, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1099\/jgv.0.000672","article-title":"ICTV virus taxonomy profile: Flaviviridae","volume":"98","author":"Simmonds","year":"2017","journal-title":"J. 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