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Developing a ZIKV mucosal vaccine that can elicit both systemic and mucosal immune responses is of particular interest. In this study, we constructed a recombinant ZIKV envelope DIII (ZDIII) protein genetically fused with Salmonella typhimurium flagellin (FliC-ZDIII) as a novel mucosal antigen for intranasal immunization. The results indicated that the FliC-ZDIII fusion proteins formulated with E. coli heat-labile enterotoxin B subunit (LTIIb-B5) adjuvant greatly increased the ZDIII-specific IgG, IgA, and neutralizing titers in sera, and the ZDIII-specific IgA titers in bronchoalveolar lavage and vaginal fluids. Protective immunity was further assessed by subcutaneous and intravaginal ZIKV challenges. The second-generation FliC\u0394D3-2ZDIII was shown to result in a reduced titer of anti-FliC IgG antibodies in sera and still retained the same levels of serum IgG, IgA, and neutralizing antibodies and mucosal IgA antibodies without compromising the vaccine antigenicity. Therefore, intranasal immunization with FliC\u0394D3-2ZDIII fusion proteins formulated with LTIIb-B5 adjuvant elicited the greatest protective immunity against subcutaneous and intravaginal ZIKV challenges. Our findings indicated that the combination of FliC\u0394D3-2ZDIII fusion proteins and LTIIb-B5 adjuvant for intranasal immunization can be used for developing ZIKV mucosal vaccines.<\/jats:p>","DOI":"10.3390\/pharmaceutics14051014","type":"journal-article","created":{"date-parts":[[2022,5,8]],"date-time":"2022-05-08T21:31:20Z","timestamp":1652045480000},"page":"1014","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Intranasal Immunization with Zika Virus Envelope Domain III-Flagellin Fusion Protein Elicits Systemic and Mucosal Immune Responses and Protection against Subcutaneous and Intravaginal Virus Challenges"],"prefix":"10.3390","volume":"14","author":[{"given":"Chi-Hsun","family":"Chen","sequence":"first","affiliation":[{"name":"Institute of Biotechnology, National Tsing Hua University, Hsinchu 30013, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4415-7811","authenticated-orcid":false,"given":"Chung-Chu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, MacKay Memorial Hospital, Hsinchu 30071, Taiwan"},{"name":"Teaching Center of Natural Science, Minghsin University of Science and Technology, Hsinchu 30401, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Bo","family":"Wang","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, National Tsing Hua University, Hsinchu 30013, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vania","family":"Lionel","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, National Tsing Hua University, Hsinchu 30013, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Chyi","family":"Liu","sequence":"additional","affiliation":[{"name":"National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Zhunan 35053, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9291-260X","authenticated-orcid":false,"given":"Li-Min","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, National Taiwan University Hospital, Taipei 10041, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suh-Chin","family":"Wu","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, National Tsing Hua University, Hsinchu 30013, Taiwan"},{"name":"Department of Medical Science, National Tsing Hua University, Hsinchu 30013, Taiwan"},{"name":"Adimmune Corporation, Taichung 42723, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0065-3527(03)59002-9","article-title":"Molecular biology of flaviviruses","volume":"59","author":"Lindenbach","year":"2003","journal-title":"Adv. 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