Structural determinants of broadly neutralizing human antibodies binding to morphological dengue virus variants.

Dengue virus (DENV) is a global disease threat with tropical regions bearing the bulk of disease burden. Presence of four DENV serotypes with varying antigenicity has complicated development of effective, pan-serotype strategies for prevention and treatment of dengue disease. Here, we report single-particle cryo-electron microscopy (cryo-EM) structures of DENV in complex with three human-derived broadly neutralizing antibodies (bnAbs), revealing an antibody class which preferentially uses its heavy chain for potency and antigen recognition. These heavy chain-driven E-dimer recognizing (HEDR) bnAbs potently neutralize all DENV serotypes by binding to a quaternary epitope encompassing the critical fusion loop and conserved glycans on DENVs surface E-glycoprotein dimer. We also demonstrate the presence of capsule-shaped DENV, with HEDR antibodies binding such tubular morphologies in addition to spherical virions. Cryo-EM helical reconstructions of Fab-bound tubular virions from different DENV strains establishes that the pattern of E-glycoproteins helical arrangement is dependent solely on the virus strain. The structural data also demonstrate that binding of highly potent HEDR bnAb D14.F25.S02 causes distortion of DENV particles. Collectively, these results elucidate key features of HEDR bnAbs while illustrating the importance of eliciting immune responses that can neutralize diverse DENV morphologies.