Evolution of a functionally intact but antigenically distinct DENV fusion loop

• DOI: 10.7554/elife.87555.3
• Publication Date: 2023-09-19T14:16:32Z
• Authors: Rita M Meganck; Deanna Zhu; Stephanie Dong; Lisa J Snoderly-F...; Yago R Dalben; Devina Thiono; Laura J White; Arivianda M DeSilva; Ralph S Baric; Longping V Tse
• Keywords: Dengue vaccine; Chimera (genetics)

A hallmark of dengue virus (DENV) pathogenesis is the potential for antibody-dependent enhancement, which associated with deadly DENV secondary infection, complicates identification correlates protection, and negatively impacts safety efficacy vaccines. Antibody-dependent enhancement linked to antibodies targeting fusion loop (FL) motif envelope protein, completely conserved in mosquito-borne flaviviruses required viral entry fusion. In current study, we utilized saturation mutagenesis directed evolution engineer a functional variant mutated FL (D2-FL), not neutralized by FL-targeting monoclonal antibodies. The mutations were combined our previously evolved prM cleavage site create mature version D2-FL (D2-FLM), evades both prM- FL-Abs but retains sensitivity other type-specific quaternary cross-reactive (CR) Abs. CR serum from heterotypic (DENV4)-infected non-human primates (NHP) showed lower neutralization titers against D2-FLM than isogenic wildtype DENV2 while similar observed homotypic (DENV2)-infected NHP. We propose as valuable tools delineate Ab subtypes well an exciting platform safer live-attenuated vaccines suitable naïve individuals children.