Molecular epidemiological and genetic characteristics of coxsackievirus A6 circulating in mainland China from 1992 to 2023

Hand, foot, and mouth disease (HFMD) is a common global infectious disease in children. Coxsackievirus A6 (CVA6) has emerged as the most important pathogen of HFMD. Molecular epidemiological and evolutionary surveillance of CVA6 is vital for the prevention and control of HFMD outbreaks. This study comprehensively analyzed the molecular epidemiology and genetic characteristics of CVA6 circulating in mainland China during 1992-2023. Phylogenetic analysis based on VP1 sequences revealed that in addition to the previously reported subgenotypes B1, B2, C1, D2, D3a, and D3b, genotype A was first identified in mainland China. Phylogenetic analysis based on the P3 region identified ten evolutionary lineages (defined as recombination forms, RFs) in mainland China, including previously reported lineages (RF-I, -C, -D, -K1, -A, -J, -L, and -K2) and two new lineages, RF-K2.1 and RF-Z. Recombination analysis revealed that RF-C and RF-A acted as the major parents and generated 2 derived lineages (-D and -K1) and 5 derived lineages (-J, -L, -K2, -K2.1 and -Z), respectively, by recombination with other enteroviruses in nonstructural regions. Furthermore, amino acid variations in 3D proteins were predicted across CVA6 lineages. Polymorphism in 3D might partially account for differences in pathogenicity among CVA6 lineages within the same subgenotypes. The residues at the site 3D-259 may be associated with the high-frequency recombination of CVA6. The findings reveal the longitudinal molecular epidemiological and evolutionary characteristics of CVA6 in mainland China, providing critical insights for the continuous monitoring of CVA6-associated HFMD and the development of antiviral drugs and vaccines.