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Vaccines against JEV and DENV are currently available. However, the dengue vaccine possibly increases the risk of severe dengue due to antibody-dependent enhancement (ADE). Moreover, the Japanese encephalitis (JE) vaccine reportedly induces cross-reactive ADE-prone antibodies against DENV, potentially leading to symptomatic dengue. Therefore, it is necessary to eliminate the risk of ADE through vaccination. In this study, we attempted to develop a JE vaccine that does not induce ADE of DENV infection using an epitope modification strategy. We found that an ADE-prone monoclonal antibody cross-reactive to DENV and JEV recognizes the 106th amino acid residue of the E protein of JEV (E-106). The JE DNA vaccine with a mutation at E-106 (E-106 vaccine) induced comparable neutralizing antibody titers against JEV to those induced by the wild-type JE DNA vaccine. Meanwhile, the E-106 vaccine induced 64-fold less cross-reactive ADE-prone antibodies against DENV. The mutation did not compromise the protective efficacy of the vaccine in the lethal JEV challenge experiment. Altogether, the modification of a single amino acid residue identified in this study helped in the development of an ADE-free JE vaccine.<\/jats:p>","DOI":"10.3390\/vaccines10091411","type":"journal-article","created":{"date-parts":[[2022,8,31]],"date-time":"2022-08-31T02:09:36Z","timestamp":1661911776000},"page":"1411","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Japanese Encephalitis DNA Vaccines with Epitope Modification Reduce the Induction of Cross-Reactive Antibodies against Dengue Virus and Antibody-Dependent Enhancement of Dengue Virus Infection"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0284-8278","authenticated-orcid":false,"given":"Tomohiro","family":"Kotaki","sequence":"first","affiliation":[{"name":"Department of Public Health, Kobe University Graduate School of Health Sciences, Kobe 654-0142, Japan"},{"name":"Department of Virology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yurie","family":"Nagai","sequence":"additional","affiliation":[{"name":"Department of Public Health, Kobe University Graduate School of Health Sciences, Kobe 654-0142, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2757-2792","authenticated-orcid":false,"given":"Atsushi","family":"Yamanaka","sequence":"additional","affiliation":[{"name":"BIKEN Endowed Department of Dengue Vaccine Development, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand"},{"name":"Mahidol-Osaka Center for Infectious Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eiji","family":"Konishi","sequence":"additional","affiliation":[{"name":"BIKEN Endowed Department of Dengue Vaccine Development, Faculty of Tropical Medicine, Mahidol University, Bangkok 10400, Thailand"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5525-9915","authenticated-orcid":false,"given":"Masanori","family":"Kameoka","sequence":"additional","affiliation":[{"name":"Department of Public Health, Kobe University Graduate School of Health Sciences, Kobe 654-0142, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"766","DOI":"10.2471\/BLT.10.085233","article-title":"Estimated global incidence of Japanese encephalitis: A systematic review","volume":"89","author":"Campbell","year":"2011","journal-title":"Bull World Health Organ"},{"key":"ref_2","unstructured":"Japanese Encephalitis Vaccines (2022, June 20). 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