Current status on encephalitic alphavirus vaccines development: Advances, challenges, and global health perspectives

• Comprehensive review on vaccine R&D for all major encephalitic alphaviruses (VEEV/EEEV/WEEV). • In-depth comparison of vaccine platforms from inactivated to novel nanotechnologies. • Proposes a rational roadmap for developing next-generation broad-spectrum vaccines. Alphaviruses are a globally distributed group of arboviruses responsible for two distinct disease manifestations, namely inflammatory polyarthritis and encephalitis. Among the arthritogenic viruses, chikungunya virus (CHIKV) is the most prevalent and has caused epidemics in 119 countries. Notably, two human vaccines have now received FDA approval. In contrast, the encephalitic alphaviruses, including Venezuelan equine encephalitis virus (VEEV), eastern equine encephalitis virus (EEEV), and western equine encephalitis virus (WEEV), are associated with substantially higher case fatality rates. These neurovirulent pathogens cause acute encephalitis in humans and animals, instigate outbreaks in endemic regions, and pose a severe public health threat. Currently, there are no licensed vaccines available for this group of viruses. However, several candidate vaccine platforms, including inactivated, live-attenuated, viral vector, and subunit vaccines, have shown promising immunogenicity and efficacy in preclinical studies, with several advancing to clinical trials. This review summarizes the current progress in vaccine development against encephalitic alphaviruses, aiming to inform future research directions.