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- W4384072064 abstract "A hallmark of Dengue virus (DENV) pathogenesis is the potential for antibody-dependent enhancement, which is associated with deadly DENV secondary infection, complicates the identification of correlates of protection, and negatively impacts the safety and efficacy of DENV vaccines. 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 fusion-loop (D2-FL) which is not neutralized by fusion-loop-targeting monoclonal antibodies. The fusion-loop mutations were combined with our previously evolved pre-membrane cleavage site to create a mature version of D2-FL (D2-FLM), which evades both pre-membrane and fusion-loop antibodies but retains sensitivity to other type-specific and quaternary cross-reactive antibodies. Cross-reactive serum from heterotypic (DENV4) infected non-human primates 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 non-human primates. We propose D2-FL and D2-FLM as valuable tools to delineate cross-reactive antibody subtypes in serum as well as an exciting platform for safer live attenuated DENV vaccines suitable for naïve individuals and children." @default.
- W4384072064 created "2023-07-13" @default.
- W4384072064 creator A5035044575 @default.
- W4384072064 date "2023-07-12" @default.
- W4384072064 modified "2023-09-28" @default.
- W4384072064 title "eLife assessment: Evolution of a Functionally Intact but Antigenically Distinct DENV Fusion Loop" @default.
- W4384072064 doi "https://doi.org/10.7554/elife.87555.1.sa0" @default.
- W4384072064 hasPublicationYear "2023" @default.
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