The epitope arrangement on flavivirus particles contributes to Mab C10’s extraordinary neutralization breadth across Zika and dengue viruses

The human monoclonal antibody C10 exhibits extraordinary cross-reactivity, potently neutralizing Zika virus (ZIKV) and the four serotypes of dengue virus (DENV1–DENV4). Here we describe a comparative structure-function analysis of C10 bound to the envelope (E) protein dimers of the five viruses it neutralizes. We demonstrate that the C10 Fab has high affinity for ZIKV and DENV1 but not for DENV2, DENV3, and DENV4. We further show that the C10 interaction with the latter viruses requires an E protein conformational landscape that limits binding to only one of the three independent epitopes per virion. This limited affinity is nevertheless counterbalanced by the particle’s icosahedral organization, which allows two different dimers to be reached by both Fab arms of a C10 immunoglobulin. The epitopes’ geometric distribution thus confers C10 its exceptional neutralization breadth. Our results highlight the importance not only of paratope/epitope complementarity but also the topological distribution for epitope-focused vaccine design. [Display omitted] •The C10 Fab’s orientation on E dimers allows bivalent IgG binding to each virion raft•C10 binding to DENV2 induces E dimer rearrangement by hitting a spring-loaded segment•Only E dimers with asymmetric environment on DENV2 virions can bind C10•Bivalent binding to two different E dimers expands C10 neutralization breadth Comparative structure-function analyses reveal how the topological distribution of epitopes explains the cross-reactivity and neutralization of Zika and dengue viruses by the human monoclonal antibody C10.