Epigenetics of HFRS: Linking Immunity, Pathogenesis, and Vaccine-Induced Protection

Haemorrhagic fever with renal syndrome (HFRS), caused by Old World hantaviruses, including Hantaan virus (HTNV) and Seoul virus (SEOV), is an important public-health concern, particularly in Asia. Clinical manifestations range from febrile illness to vascular leakage, thrombocytopenia, haemorrhage and acute kidney injury. The mechanisms underlying variation in disease severity and the variability and durability of vaccine-induced immunity remain incompletely understood. Epigenetic mechanisms, including DNA methylation, histone modifications, chromatin regulation and non-coding RNA-mediated regulation, can influence antiviral immunity and immune-cell function in several biological settings; however, their specific contributions to HFRS remain insufficiently characterized. This structured narrative review examines hantavirus-specific evidence alongside relevant findings from other viral infections and vaccination settings, focusing on inflammatory responses, endothelial dysfunction, regulatory non-coding RNAs, trained immunity and potential applications in vaccinology. Experimental HTNV studies and clinical investigations of regulatory RNAs have identified candidate pathways associated with hantavirus-host interactions; however, these findings do not establish that epigenetic mechanisms determine HFRS severity or clinical outcomes. Similarly, preclinical hantavirus vaccine studies and early clinical evaluations provide evidence regarding immunogenicity and safety but do not demonstrate epigenetic mediation of protective immunity. Findings from Andes virus (ANDV), associated primarily with hantavirus cardiopulmonary syndrome (HCPS), and other viral systems are therefore considered comparative or contextual evidence, not directly generalizable to HFRS. This review identifies critical knowledge gaps and outlines how longitudinal, cell-resolved epigenomic profiling, functional validation and integrated multi-omics could clarify causal mechanisms, explain interindividual variation in disease outcomes and vaccine responses, and establish the potential translational value of epigenetic biomarkers and interventions.