West Nile virus: epidemiology, prevention, clinical features, diagnosis, treatment, and open research questions

Background: West Nile virus (WNV) is among the most widespread arboviruses and has become a seasonal threat in temperate regions. Sustained in an enzootic bird–mosquito cycle, with humans and horses as incidental hosts, its geographic range has expanded in recent decades due to ongoing climatic and ecological changes. While most infections are asymptomatic or mild, a minority progress to neuroinvasive disease with high morbidity and long-term sequelae. This review summarizes current knowledge on epidemiology, pathogenesis, clinical spectrum, diagnostic challenges, therapeutic options, prevention, and research gaps. Discussion: Lineages 1 and 2 co-circulate in Europe, where repeated large outbreaks highlight WNV adaptability to warmer summers, altered rainfall, and expanded mosquito habitats driven by recent ecological shifts. After inoculation, replication occurs in keratinocytes and dendritic cells, amplification in lymph nodes, and dissemination to visceral organs and the central nervous system. Neuroinvasion depends on viral proteins and host immune responses. Severe disease is associated with advanced age, immunosuppression, comorbidities, and genetic susceptibility. Clinical manifestations range from febrile illness to meningitis, encephalitis, or acute flaccid myelitis. Persistent neurological and functional sequelae are common, adding to disease burden. Diagnosis relies on molecular and serological tests, limited by short viremia and cross-reactivity with other flaviviruses. No approved antiviral therapy exists; management is supportive. Experimental antivirals, monoclonal antibodies, and interferon have shown mixed results. Vaccine candidates have progressed to phase 1–2 trials, but none are licensed for humans. Prevention relies on integrated vector control, veterinary surveillance, and donor screening, framed within a One Health approach. Conclusion: WNV exemplifies the impact of global ecological change on zoonotic diseases. Strengthening surveillance, refining diagnostics, and advancing antivirals and vaccines through multidisciplinary collaboration are essential to mitigate future outbreaks.