Localized adaptive evolution in VP1 drives antigenic divergence of feline calicivirus despite high sequence conservation.

Feline calicivirus (FCV) evolves rapidly under immune pressure, yet the genetic basis of antigenic escape remains poorly understood, particularly when sequence divergence is limited. We isolated 13 FCV strains from cats in Jilin Province, China, between 2018 and 2024, and characterized their genetic and antigenic properties. Phylogenetic analysis of the major capsid protein VP1 revealed the co-circulation of multiple lineages, including isolates clustering within clades associated with virulent systemic disease (VSD) and grouping with strains previously identified in dogs. Cross-neutralization assays demonstrated that the vaccine-induced antiserum neutralized most isolates but exhibited markedly reduced neutralizing activity against JL1907 and JL2103, both of which were isolated from vaccinated cats. Notably, despite sharing 91.9% amino acid identity in VP1, JL2103 and JL2104 exhibited highly asymmetric cross-neutralization: Antiserum raised against JL2103 failed to neutralize JL2104, whereas antiserum raised against JL2104 potently neutralized JL2103. Comparative sequence analysis identified nonsynonymous substitutions concentrated in E region (the hypervariable region of VP1), particularly within predicted B cell epitopes and residues proximal to the feline junctional adhesion molecule A (fJAM-A) binding interface. Our findings indicate that minor amino acid substitutions at critical antigenic sites are sufficient to disrupt cross-neutralization, even among closely related FCV strains, thereby providing a mechanistic basis for antigenic escape under constrained genetic divergence.