Protective envelope dimer epitope–like antibodies are elicited against dengue virus in children after infection and vaccination

Cross-reactive antibodies to epitopes that span envelope proteins on the virion surface are hypothesized to protect against dengue virus (DENV) infection and disease. Here, we measured antibodies targeting a quaternary epitope called the envelope dimer epitope (EDE) as well as neutralizing and binding antibodies and evaluated their association with DENV infection, vaccine response, and disease outcome in dengue-vaccinated ( n = 164) and dengue-unvaccinated children ( n = 88) within a longitudinal cohort in Cebu, Philippines ( n = 2996). Antibodies targeting EDE were prevalent and associated with broad neutralization of mature DENV1 to DENV4 virions in those with evidence of at least two prior DENV infections but were mostly absent in those with only one prior infection. Subsequent infection and vaccination boosted titers of EDE-like antibodies, neutralizing antibodies, and DENV-binding antibodies. EDE-like antibodies were associated with reduced risk of symptomatic dengue and more severe dengue and statistically explained the protective effect of binding and neutralizing antibodies on dengue. Thus, antibodies targeting quaternary epitopes help explain the broad cross-protection observed in those with multiple prior DENV exposures, making them useful for evaluation and development of future vaccines and therapeutics.