Whole-genome analysis of CVA4 in children with herpangina in two cities of China

Sporadic epidemics of coxsackievirus A4 (CVA4) have been reported worldwide, but there are relatively few studies on CVA4. This study successfully obtained 60 VP1 region sequences and 50 complete genome sequences of CVA4. Phylogenetic analysis based on the complete genome revealed that these strains clustered within the same evolutionary branch as CVA4 strains from other regions of China. Analysis of the VP1-based phylogenetic tree demonstrated that all 60 strains belonged to the C2 genetic subgenotype. Recombination analysis indicated high sequence identity (85.1–85.7%) between the study strains and the CVA4 prototype strain within the P1 region. In contrast, significant sequence similarities were observed in the P2 and P3 regions with prototype strains of CVA4, CVA5, CVA14, and CVA16. Bootscan analysis further identified recombination signals in the 5′ untranslated region (5′ UTR), P2, and P3 regions, suggesting recombination events with non-CVA4 enterovirus A (EV-A) prototype strains. This study provides evidence of genetic recombination in circulating CVA4 strains in Shandong Province, China, highlighting their complex evolutionary dynamics within the EV-A species.