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Coxsackievirus A6 (CV-A6) has emerged as the predominant causative agent of hand, foot, and mouth disease (HFMD) in young children. Since the declaration of coronavirus disease 2019 (COVID-19) as a global pandemic, the incidence of infectious diseases, including HFMD, has decreased markedly. When social mitigation was relaxed during the COVID-19 pandemic in 2022, the re-emergence of HFMD was observed in Gwangju, South Korea, and seasonal characteristics of the disease appeared to have changed. To investigate the molecular characteristics of enterovirus (EV) associated with HFMD during 2022, 277 specimens were collected. Children aged younger than 5 years accounted for the majority of affected individuals. EV detection and genotyping were performed using real-time RT-PCR and nested RT-PCR followed by sequence analysis. The EV detection rate was found to be 82.3%, and the main genotype identified was CV-A6. Sixteen CV-A6 samples were selected for whole genome sequencing. According to phylogenetic analysis, all CV-A6 strains from this study belonged to the sub-genotype D3 clade based on VP1 sequences. Analysis of 3D polymerase phylogeny showed that only the recombinant RF-A group was identified. In conclusion, circulating EV types should be continuously monitored to understand pathogen emergence and evolution during the post-pandemic era. [ABSTRACT FROM AUTHOR]

• 73 nearly full-length CVA6 sequences were obtained from HFMD samples in China. • Frequent recombination in CVA6 P3 coding region resulted in 24 recombinant forms. • widespread transmission of CVA6 in East and Southeast Asia, Europe and Australia. • The eastern China region plays a key role in the dissemination of CVA6 in China. The increasing incidence of hand, foot, and mouth disease (HFMD) associated with Coxsackievirus A6 (CVA6) has become a very significant public health problem. The aim of this study is to investigate the recombination, geographic transmission, and evolutionary characteristics of the global CVA6. From 2019 to 2022, 73 full-length CVA6 sequences were obtained from HFMD patients in China and analyzed in combination with 1032 published whole genome sequences. Based on this dataset, the phylogenetic features, recombinant diversity, Bayesian phylodynamic characteristics, and key amino acid variations in CVA6 were analyzed. The four genotypes of CVA6, A, D, E, and F, are divided into 24 recombinant forms (RFs, RF-A – RF-X) based on differences in the P3 coding region. The eastern China region plays a key role in the dissemination of CVA6 in China. VP1–137 and VP1–138 are located in the DE loop on the surface of the CVA6 VP1 protein, with the former being a highly variable site and the latter having more non-synonymous substitutions. Based on whole genome sequences, this study contributes to the CVA6 monitoring, early warning, and the pathogenic mechanism by studying recombination diversity, geographical transmission characteristics, and the variation of important amino acid sites. [Display omitted] [ABSTRACT FROM AUTHOR]

To investigate the evolution and genetic characteristics of Coxsackievirus A6 (CVA6) which acted as the predominant pathogen of hand, foot and mouth disease (HFMD) in children in Beijing, China, 2017–2019. Throat swab specimens were collected for general Enterovirus (EV), enterovirus A71 (EV-A71) and CVA16 detection by Real-time PCR. These general EV-positive samples were identified by semi-nested RT-PCR method and sequencing. The CVA6 VP1 gene and genome sequences were amplified and sequenced. The phylogenetic, variation and recombination analyses were performed. A total of 1721 HFMD patients were enrolled in this study, with the male to female ratio of 1.62:1. The majority of cases were less than five years, which accounted for 73.50%. The overall detection rate of EV was 88.32% (1520/1721). A total of 8 EV types were identified, including CVA6 (55.86%), CVA16 (26.32%), EV-A71 (2.24%), CVA10 (2.04%), CVA4 (1.05%), CVA5 (0.59%), CVA2 (0.33%), and CVA8 (0.07%), while 175 (11.51%) EV were untyped. The main pathogen of HFMD was CVA6 from 2017 to 2018, while CVA6 and CVA16 were the main causative pathogens in 2019. The nucleotide and amino acid sequence identities of the 120 CVA6 complete VP1 gene sequences in this study were 91.2%–100.0% and 97.7%–100.0%, respectively. Compared with the prototype strain (Gdula) of CVA6, the nucleotide and amino acid sequence identities were 81.7%–84% and 94.7%–96.3%, respectively. The phylogenetic tree indicated that all 120 CVA6 sequences belonged to sub-genotype D3, while 119 CVA6 sequences belonged to evolutionary branch D3a, except one from 2017 belonged to D3b. Recombination analysis based on the complete genome sequences showed that potential multiple recombination may have occurred in 2B and 3D protein coding regions with EV-A114. The main pathogens of HFMD were CVA6 and CVA16 in Beijing, China, 2017–2019; while these CVA6, as recombination strains, belonged to the D3a evolutionary branch. • The predominant serotypes of HFMD were CVA6 and CVA16 in Beijing, 2017−2019. • CVA6 D3a was the predominant sub-genotype caused HFMD in Beijing. [ABSTRACT FROM AUTHOR]