A systematic review of rodent-borne orthohantaviruses: Discovery, epidemiology, evolution, pathogenicity, vaccines, and therapeutics

Rodent-borne orthohantaviruses currently comprise 37 species and 69 strains according to the International Committee on Taxonomy of Viruses (ICTV; Feb 2026 release, MSL #41). Among these, six species are etiologic agents of hemorrhagic fever with renal syndrome (HFRS), and six others cause hantavirus pulmonary syndrome (HPS). In the absence of widely available specific therapeutics or licensed vaccines, the World Health Organization (WHO) has designated orthohantaviruses as priority pathogens with a high risk of precipitating a public health emergency of international concern. This narrative review systematically synthesizes seven decades of orthohantavirus research across six thematic sections, taxonomy and discovery history, epidemiological characteristics, viral biology and evolutionary dynamics, pathogenic mechanisms, and recent advances in vaccine development and therapeutic strategies. We highlight the discovery trajectories and epidemiological profiles of six representative Old World and New World orthohantaviruses. To elucidate host-virus interplay, we summarize the immune evasion tactics employed by orthohantaviruses and multifactorial basis underlying vascular hyperpermeability. Eight vaccine platforms are critically appraised, ranging from licensed inactivated vaccines to mRNA-based candidates that have demonstrated single-dose protection in lethal animal challenge models. Therapeutic approaches, including neutralizing antibodies, direct-acting antivirals, entry inhibitors, and host-targeted agents, are systematically evaluated. Finally, we identify critical knowledge gaps and priority research directions to inform accelerated development of effective medical countermeasures against this globally significant yet underrecognized viral threat.