Towards broadly protective hantavirus vaccine: Immunological barriers, structural vaccinology and one health perspectives

Abstract

Background Hantaviruses are globally distributed zoonotic pathogens that cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS), yet no broadly protective vaccine is currently available. This review critically examines why broadly protective hantavirus vaccines have remained elusive and presents an integrated framework that combines immunological barriers, structural vaccinology, and One Health perspectives to inform next-generation vaccine development. Methodology A structured critical narrative review was conducted following the Scale for the Assessment of Narrative Review Articles (SANRA) framework. Literature was retrieved from PubMed, Scopus, Web of Science, and Google Scholar (1996-2026). Evidence from human studies, experimental infection models, structural biology investigations, mechanistic immunology studies, and preclinical and clinical vaccine research was critically synthesized to evaluate protective immunity, correlates of protection, antigenic diversity, immune escape, and emerging strategies for broad vaccine protection. Results Current evidence indicates that broadly protective vaccine development is constrained by extensive antigenic diversity, viral immune-evasion mechanisms, incomplete validation of immune correlates of protection, and limited understanding of durable cross-protective immunity. Although neutralizing antibodies remain the leading correlate of homologous protection, accumulating evidence supports composite correlates involving coordinated humoral, cellular, innate, and memory immune responses for broader protection. Recent structural studies identifying conserved glycoprotein epitopes and broadly neutralizing antibodies have strengthened the biological rationale for structure-guided antigen design and rational immunogen engineering. Conclusion This review highlights that the pathway to broadly protective hantavirus vaccines depends less on new vaccine platforms than on integrating structural vaccinology, systems immunology, and One Health principles to target conserved viral vulnerabilities and achieve durable protection against both established and emerging hantaviruses.