Dengue virus envelope epitope-specific antibodies are associated with protection from severe dengue

Our understanding of a protective humoral immune response to dengue virus (DENV) remains limited. The envelope (E) protein is the main antibody (Ab) target. While anti-fusion loop (FL) epitope monoclonal Abs (mAbs) can induce antibody dependent enhancement (ADE) in vitro, some mAbs targeting quaternary epitopes can cross-neutralize different DENV serotypes. However, the contribution of each Ab subset to disease outcome remains poorly characterized. We defined DENV2 E epitope-specific Abs dynamics and assessed their association with disease outcome in a cohort of hospitalized and subclinical dengue patients during post-primary DENV2 infection. We quantified and isolated anti-E epitope-specific Abs and tested their enhancing and neutralizing capacity. During the critical phase, FL-targeting antibodies were increased in hospitalized patients compared to subclinical cases. Antibodies targeting quaternary epitopes were reduced in severe dengue compared to classical dengue fever patients. Functionally, quaternary epitope-targeting antibodies showed stronger neutralization and cross-neutralization properties, while FL-binding antibodies displayed stronger in vitro enhancement. These findings show that anti-DENV2 E epitope-specific Ab proportions correlate with disease susceptibility and severity, with important implications for novel vaccine design.