The Dengue NS1 epitope landscape: a blueprint for next-generation vaccines and therapeutics

The dengue virus (DENV) nonstructural protein 1 (NS1) is a critical ‘double-edged sword’ in dengue pathogenesis and immunity. While a key driver of vascular pathology, it is also a major target for protective immune responses that lack the risk of antibody-dependent enhancement. Anti-NS1 antibodies can neutralize NS1’s pathogenic functions or clear infected cells; however, pathogenic responses can be driven by cross-reactive antibodies, causing cellular dysfunction or by NS1–antibody immune complexes triggering inflammatory damage. Concurrently, T-cell responses target conserved epitopes to drive viral clearance, though their efficacy is shaped by host HLA diversity. This review deconstructs the NS1 epitope landscape to provide a blueprint for rational countermeasure design. We emphasize how targeting immunogenic ‘hotspots’ can elicit balanced immunity, while also critically assessing the major translational hurdles, particularly the limitations of preclinical models, that must be overcome.