Pandemic-driven immune imprinting accelerates evolution of human coronavirus OC43

Global pandemic interventions have reshaped host-virus dynamics, potentially altering the evolution of endemic pathogens. Here, we report accelerated genomic evolution of human coronavirus OC43 (HCoV-OC43)—a close relative of pandemic-associated coronaviruses—following recent worldwide epidemiological shifts. Bayesian analysis of longitudinal surveillance data revealed a 3.76-fold increase (8.9403 × 10 ⁻ ⁴ nucleotide substitutions/site/year, 95% HPD: 4.9075 × 10 ⁻ ⁴, 1.3053 × 10 ⁻ ³) in the spike gene substitution rate of the currently dominant genotype K post-2020. Positively selected mutations were mainly located in the spike protein, and some colocalize with antigenic epitopes. Crucially, structural modeling demonstrated that broadly neutralizing antibodies targeting conserved stem-helix (S2P6) and fusion-peptide (COV44–62/79, 76E1) epitopes of high-pathogenicity betacoronaviruses cross-bind HCoV-OC43 spike protein, establishing a mechanistic basis for immune-driven selection. These findings suggest that population-level immune imprinting may play a potential driving role in mutations within key domains of HCoV-OC43, although further validation is required. Sustained co-surveillance of co-circulating coronaviruses is imperative to anticipate emergent variants with altered pathogenicity.