Diverse contributions of avidity to the broad neutralization of Dengue virus by antibodies targeting the E dimer epitope

Antibodies (Abs) recognizing the Dengue virus (DENV) E dimer epitope (EDE) that potently neutralize all DENV serotypes are promising templates for vaccine design. As an important feature for some Abs is their bivalency, we sought to define the role avidity plays in neutralization by EDE Abs. We compared neutralization activity between bivalent IgGs and monovalent Ab fragments (Fabs) for two EDE Abs, A11 and C10. IgG forms of both Abs exhibited more potent neutralization activity than their counterpart Fabs, yet only for C10 was this enhanced activity associated with bivalent binding. A11 and C10 also exhibited differential binding profiles to DENV virus-like particles under acidic conditions mimicking the environment that triggers viral membrane fusion, suggesting that EDE Abs employ diverse neutralization mechanisms despite sharing an epitope. Delineating the full range of Ab binding modes and neutralization mechanisms against a single epitope may inform therapeutic approaches and refine vaccine design.