Development of NS1 antigen-CAPture assays for accurate diagnosis of neurotropic FLAVIviruses

Neurotropic flaviviruses such as West Nile virus (WNV), Usutu virus (USUV), tick-borne encephalitis virus (TBEV), and Japanese encephalitis virus (JEV) are expanding across Europe and Asia, causing unpredictable outbreaks with high morbidity and mortality. Vaccines are only available for JEV and TBEV, while no preventive or therapeutic strategies exist for WNV and USUV. Their diagnosis and management remain highly challenging due to co-circulation in the same regions, antigenic similarity, and overlapping clinical manifestations. Current diagnostic methods rely mainly on serology, which suffers from severe crossreactivity, hampering outbreak detection and surveillance. A major obstacle for progress is the lack of highly specific monoclonal antibodies (mAbs) against the nonstructural protein 1 (NS1), a secreted viral protein detectable early in infection and implicated in blood–brain barrier (BBB) disruption. With this project, we will generate and validate NS1-specific mAbs for WNV, USUV, JEV, and advance these tools to robust laboratory validation with infected cell supernatants and patient samples. In parallel, we will explore the therapeutic potential of WNV mAbs in preventing NS1-induced BBB disruption using a unique 3D human BBB model. This approach will provide the first insights into NS1-targeted interventions for neurotropic flaviviruses. By combining innovative antibody discovery, diagnostic assay development, and therapeutic exploration, this project will deliver highly specific tools for early detection and open new avenues for prevention and treatment of emerging flavivirus infections.