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Antibody-dependent enhancement is linked to antibodies targeting the fusion loop (FL) motif of the envelope protein, which is completely conserved in mosquito-borne flaviviruses and required for viral entry and fusion. In the current study, we utilized saturation mutagenesis and directed evolution to engineer a functional variant with a mutated FL (D2-FL), which is not neutralized by FL-targeting monoclonal antibodies. The FL mutations were combined with our previously evolved prM cleavage site to create a mature version of D2-FL (D2-FLM), which evades both prM- and FL-Abs but retains sensitivity to other type-specific and quaternary cross-reactive (CR) Abs. CR serum from heterotypic (DENV4)-infected non-human primates (NHP) showed lower neutralization titers against D2-FL and D2-FLM than isogenic wildtype DENV2 while similar neutralization titers were observed in serum from homotypic (DENV2)-infected NHP. We propose D2-FL and D2-FLM as valuable tools to delineate CR Ab subtypes in serum as well as an exciting platform for safer live-attenuated DENV vaccines suitable for na\u00efve individuals and children.<\/jats:p>","DOI":"10.7554\/elife.87555","type":"journal-article","created":{"date-parts":[[2023,7,12]],"date-time":"2023-07-12T11:31:52Z","timestamp":1689161512000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.87555","source":"Crossref","is-referenced-by-count":2,"title":["Evolution of a functionally intact but antigenically distinct DENV fusion loop"],"prefix":"10.7554","volume":"12","author":[{"given":"Rita M","family":"Meganck","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01p7jjy08","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Molecular Microbiology and Immunology, Saint Louis University","place":["Saint Louis, United 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