Advances and Challenges in Vaccination and Therapeutic Strategies Against Japanese Encephalitis Virus

The Japanese encephalitis virus (JEV) remains a major cause of viral encephalitis in Asia, and recent epidemiological shifts driven by the predominance of genotype I and the re-emergence of genotype V have renewed concerns regarding control efforts. Licensed vaccines have a reduced incidence of more than 90% in several endemic regions; however, evidence of reduced cross-neutralization against heterologous genotypes indicates that vaccines derived from genotype III strains may not fully match the evolving antigenic landscape. This review synthesizes current knowledge on vaccine performance, genotype-driven antigenic variation, and implications for future strain alignment. Emerging platforms, including mRNA, DNA, virus-like particles, and structure-guided recombinant antigens, have been evaluated for their potential to enhance cross-genotype breadth, scalability, and thermostability. We also summarize the progress in antiviral discovery targeting viral nonstructural proteins, host pathways, and monoclonal antibody development, along with immunomodulatory and neuroprotective strategies. Translational challenges, such as blood–brain barrier penetration, therapeutic timing, and durability of immunity, have been highlighted as key barriers to clinical application. By integrating molecular, immunological, and epidemiological evidence, this review outlines strategic directions for developing broad-spectrum vaccines and therapeutics capable of addressing the evolving genetic and ecological landscape of JEV.