ORF2 of hepatitis E virus: genetic and antigenic variation across genotypes and implications for immunity, diagnostics and vaccine development

Hepatitis E virus (HEV) causes over 19 million infections annually, yet the molecular determinants governing its diverse clinical phenotypes and cross-genotype immunity remain incompletely synthesized. The ORF2 capsid protein is the sole structural component of the virion, the primary neutralizing antibody target and the basis for all commercial diagnostics and the only licensed vaccine (Hecolin®). While current literature often treats HEV as a monolithic antigenic entity, ORF2 sequences diverge by 15–25% across the eight recognized genotypes (GT1–GT8), with critical substitutions concentrated in the protruding (P) domain neutralizing epitopes. This comprehensive review integrates recent structural, virological and clinical data to evaluate the multidimensional impact of ORF2 variability. We highlight how the differential expression of three ORF2 isoforms (infectious ORF2i, secreted decoy ORF2g and cleaved ORF2c) complicates immune recognition. Furthermore, we critically analyse the functional consequences of P domain divergence, which results in 2–4-fold reduced cross-genotype neutralization by GT1-derived vaccines against the globally emerging GT3 and drives false-negative rates of 12–30% in commercial serological assays. Finally, we map ORF2 genetic signatures to distinct clinical phenotypes, including GT1-associated pregnancy mortality and GT3-driven chronicity in transplant recipients. By synthesizing these fragmented domains, this review identifies critical knowledge gaps, particularly concerning the zoonotic emergence of GT7/GT8 and provides a prioritized research roadmap for the development of true pan-genotype vaccines and universal diagnostic algorithms.