Poxvirus antigenic proteins: from fundamental biology to translational applications

Abstract Poxviruses (family Poxviridae ) infect a wide range of human and animal hosts, causing diseases of substantial concern in both public health and veterinary medicine. Although smallpox was eradicated by global vaccination, the multicountry spread of mpox since 2022 and the continuing burden of capripox and parapox infections underscore the need for sustained poxvirus research and preparedness. Poxviruses have a complex virion architecture with two infectious forms, the intracellular mature virion (IMV) and extracellular enveloped virion (EEV), and large DNA genomes encoding more than 200 proteins, creating an antigenic landscape that complicates cross-genus comparison and application-oriented target prioritization. To define the biological basis for rational poxvirus antigen selection, we provide a cross-genus comparative synthesis of antigenic proteins in Orthopoxvirus , Capripoxvirus , and Parapoxvirus , integrating biological function, sequence conservation, antibody recognition, and published immunogenicity data. We delineate major antigen classes associated with IMV, EEV, and core structures and evaluate how their conserved and variable features influence immunodominance, neutralization, cross-protection, and serological discrimination. By relating these antigen-level features to translational application, this review establishes an antigen-centered framework that connects fundamental biology with practical relevance and provides a comparative basis for vaccine candidate selection, serological differentiation, and antibody-based intervention.