Structural basis of broadly neutralizing human antibodies targeting diverse dengue virus forms

Abstract Dengue virus (DENV) is a global health threat, with four antigenically distinct serotypes impeding vaccine and therapeutic development. We describe here, structural features of patient-derived, heavy chain–driven E-dimer–recognizing (HEDR) antibodies that achieve potent, pan-serotype activity by binding a conserved quaternary epitope on DENV’s envelope (E) glycoprotein dimer. Single-particle cryo–EM structures of three HEDR broadly neutralizing antibodies (bnAbs) complexed to DENV delineate epitope engagement via E-glycoprotein’s fusion loop region and conserved glycans. We also identify capsule-shaped DENV, with helical cryo-EM reconstructions of Fab-bound tubular DENV from different strains revealing that the E-glycoprotein arrangement is determined by virus strain, not bnAb identity. Our findings elucidate key binding features of HEDR bnAbs and signify the need for intervention strategies capable of neutralizing diverse DENV morphologies.