Animal models illuminate dengue immunopathogenesis to guide vaccine and therapeutic developments.

Abstract

Dengue virus (DENV) infection affects over 390 million people annually, and its severe forms, including dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), occur as a result of antibody-dependent enhancement (ADE), T-cell dysregulation, and a cytokine storm. This review integrates the results of human immunopathology with those reported by animal models, consolidating the findings in a systematic manner to validate these mechanisms. Research on AG129 interferon receptor-deficient mice consistently demonstrates ADE-mediated viremia and vascular leakage. However, humanized NSG-BLT mice recapitulate the classic antigenic sin of human T cells after heterotypic challenge with DENV. Cynomolgus macaque models are physiologically relevant for testing tetravalent vaccines under near-human circulatory conditions, and diet-induced obese mice are used to phenotype the effects of metabolic comorbidities on IL-1β-driven immunopathology. Data using standardized methods, including Evans blue extravasation assays, multiplex cytokine panels, and endpoints compliant with the ARRIVE 2.0 guidelines for animal research reporting, were associated with human clinical results. ARRIVE 2.0 is a set of guidelines to improve the transparency and reproducibility of animal research. It is worth noting that early experimental studies on the effectiveness and safety of Dengvaxia reported breakthrough viremia in macaque models. The protection provided by the monoclonal antibody C10 was shown to mitigate antibody-dependent enhancement (ADE) in murine models, though it is not associated with the Dengvaxia vaccine. The further development of these animal models will be necessary to expedite the safe development of next-generation dengue vaccines (TAK-003, TV003/TV005), antivirals (favipiravir, sofosbuvir), and immune modulators (IL-6 and TNF-α blockers) for use in endemic areas.