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Among the latter, the conserved fusion loop epitope (FLE) within domain II is a major target for flavivirus cross-reactive and poorly neutralizing responses. To eliminate unwanted FLE targeting, we redesigned ZIKV E using a reverse vaccinology approach, excising domain II and allowing domains I and III (DI-DIII) to fold into an independent subunit harboring key neutralizing epitopes.\n                    <jats:italic>Ifnar1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>-\/-<\/jats:italic>\n                    <\/jats:sup>\n                    mice vaccinated with ZIKV DI-DIII elicited high ZIKV neutralizing antibodies and were protected from weight loss and death. In addition, sera from DI-DIII vaccinated mice demonstrated a reduced capacity to enhance DENV 1-4 infection in vitro, compared to mice vaccinated with full-length E. This study identifies DI-DIII as a promising immunogen, focusing antibody responses to protective epitopes on ZIKV and minimizing the elicitation of unwanted responses.\n                  <\/jats:p>","DOI":"10.1038\/s41541-026-01442-8","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T13:07:07Z","timestamp":1776172027000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting the Zika virus envelope domains I and III as a recombinant vaccine protects mice from lethal challenge"],"prefix":"10.1038","volume":"11","author":[{"given":"Vincent","family":"Dussupt","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime L.","family":"Jensen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ang\u00e9lica Pe\u00f1a","family":"Rosado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa","family":"Donofrio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill","family":"Pflugheber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Letzibeth","family":"Mendez-Rivera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajeshwer S.","family":"Sankhala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Hung","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bonnie M.","family":"Slike","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annika","family":"Schmid","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ursula","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily","family":"Metzger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline E.","family":"Peterson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia K.","family":"Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandhya","family":"Vasan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie D.","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron","family":"Farmer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nelson L.","family":"Michael","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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(The Henry M. Jackson Foundation (HJF) for the advancement of Military Medicine) and S.J.K. (United States Government) are named inventors on US pending patent 18\/866,371 \u201cImmunogens and Vaccine Compositions Against Flavivirus\u201d describing the design and use of flavivirus envelope DI-DIII flavivirus immunogens. All other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"118"}}