JMIR Publications

ABSTRACT

Background:

Hand, foot, and mouth disease (HFMD) is a global public health concern, notably within the Asia-Pacific region. In recent years, the primary pathogen causing HFMD outbreaks across numerous countries, inclusive of China, is Coxsackievirus (CV) A6. CVA6 is one of the most prevalent enteroviruses in the world, and a new variant that has undergone genetic recombination and evolution. Such genetic recombination and evolution might not only induce modifications in the clinical manifestations of HFMD but may also heighten its pathogenicity because of nucleotide mutation accumulation.

Objective:

We aimed to characterize the occurrence of CVA6 mutations and gene recombination, to describe the genotypic distribution of CVA6 in China, and to establish the association between disease progression and viral genetic evolution through molecular epidemiological studies.

Methods:

We have analyzed the evolutionary characteristics of all full-length CVA6 sequences in the NCBI database as well as the isolated sequences in Henan, Central China. We found that all viral sequences isolated in Henan were classified into the D3 subtype. Moreover, in China, the D3 subtype began to gradually emerge in 2011. By 2019, all CVA6 virus strains in China were of the D3 subtype. To characterize the molecular evolution of CVA6, we used Bayesian phylogenetic to analyze 279 CVA6 VP1 nucleotide sequences extracted from the NCBI database, as well as 34 CVA6 strains isolated from Henan in 2023. And we used Bio Edit software (version 7.2.5.0) to analyze the isolated strains for mutated or missing amino acid sites with the prototype CVA6 strain.

Results:

Compared to the prototype strains, multiple amino acid points in the strains isolated in 2023 have mutated. The sub-genotype D3 of CVA6, with the most recent common ancestor of CVA6 D3 traced back to 2002, earlier than the outbreak of HFMD in Fuyang, East China's Anhui Province, 2008. This suggests the probable introduction and covert circulation of these viruses within China prior to the recognition of HFMD cases. Our laboratory testing data confirmed the fluctuation and periodic patterns of these viruses.

Conclusions:

This investigation has provided valuable insights into understanding the evolutionary dynamics of CVA6 and has enhanced the selection and development of genotype-compatible vaccines, effectively guiding their implementation.