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Echovirus 11 (E11) has gained attention owing to its association with severe neonatal infections. From 2018 to 2023, a surge in severe neonatal cases and fatalities linked to a novel variant of genotype D5 was documented in China, France, and Italy. However, the prevention and control of E11 variants have been hampered by limited background data on the virus circulation and genetic variance. Therefore, the present study investigated the circulating dynamics of E11 and the genetic variation and molecular evolution of genotype D5 through the collection of strains from the national acute flaccid paralysis (AFP) and hand, foot, and mouth disease (HFMD) surveillance system in China during 2000–2022 and genetic sequences published in the GenBank database. The results of this study revealed a prevalent dynamic of E11 circulation, with D5 being the predominant genotype worldwide. Further phylogenetic analysis of genotype D5 indicated that it could be subdivided into three important geographic clusters (D5-CHN1: 2014–2019, D5-CHN2: 2016–2022, and D5-EUR: 2022–2023). Additionally, variant-specific (144) amino acid mutation sites and positive-selection pressure sites (132, 262) were identified in the VP1 region. Cluster-specific recombination patterns were also identified, with CVB5, E6, and CVB4 as the major recombinant viruses. These findings provide a preliminary landscape of E11 circulation worldwide and basic scientific data for further study of the pathogenicity of E11 variants.

As the proportion of non-enterovirus 71 and non-coxsackievirus A16 which proportion of composition in the hand, foot, and mouth pathogenic spectrum gradually increases worldwide, the attention paid to other enteroviruses has increased. As a member of the species enterovirus A, coxsackievirus A14 (CVA14) has been epidemic around the world until now since it has been isolated. However, studies on CVA14 are poor and the effective population size, evolutionary dynamics, and recombination patterns of CVA14 are not well understood. In this study, 15 CVA14 strains were isolated from HFMD patients in mainland China from 2009 to 2019, and the complete sequences of CVA14 in GenBank as research objects were analyzed. CVA14 was divided into seven genotypes A-G based on an average nucleotide difference of the full-length VP1 coding region of more than 15%. Compared with the CVA14 prototype strain, the 15 CVA14 strains showed 84.0–84.7% nucleotide identity in the complete genome and 96.9–97.6% amino acid identity in the encoding region. Phylodynamic analysis based on 15 CVA14 strains and 22 full-length VP1 sequences in GenBank showed a mean substitution rate of 5.35 × 10−3 substitutions/site/year (95% HPD: 4.03–6.89 × 10−3) and the most recent common ancestor (tMRCA) of CVA14 dates back to 1942 (95% HPD: 1930–1950). The Bayesian skyline showed that the effective population size had experienced a decrease–increase–decrease fluctuation since 2004. The phylogeographic analysis indicated two and three possible migration paths in the world and mainland China, respectively. Four recombination patterns with others of species enterovirus A were observed in 15 CVA14 strains, among which coxsackievirus A2 (CVA2), coxsackievirus A4 (CVA4), coxsackievirus A6 (CVA6), coxsackievirus A8 (CVA8), and coxsackievirus A12 (CVA12) may act as recombinant donors in multiple regions. This study has filled the gap in the molecular epidemiological characteristics of CVA14, enriched the global CVA14 sequence database, and laid the epidemiological foundation for the future study of CVA14 worldwide. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the global genetic diversity and transmission dynamics of coxsackievirus B4 (CVB4) and to propose future directions for disease surveillance. Next-generation sequencing was performed to obtain the complete genome sequence of CVB4, and the genetic diversity and transmission dynamics of CVB4 worldwide were analyzed using bioinformatics methods such as phylogenetic analysis, evolutionary dynamics, and phylogeographic analysis. Forty complete genomes of CVB4 were identified from asymptomatic infected individuals and hand, foot, and mouth disease (HFMD) patients. Frequent recombination between CVB4 and EV-B multiple serotypes in the 3Dpol region was found and formed 12 recombinant patterns (A-L). Among these, the CVB4 isolated from asymptomatic infected persons and HFMD patients belonged to lineages H and I, respectively. Transmission dynamics analysis based on the VP1 region revealed that CVB4 epidemics in countries outside China were dominated by the D genotype, whereas the E genotype was dominant in China, and both genotypes evolved at a rate of > 6.50 × 10−3 substitutions/site/year. CVB4 spreads through the population unseen, with the risk of disease outbreaks persisting as susceptible individuals accumulate. Our findings add to publicly available CVB4 genomic sequence data and deepen our understanding of CVB4 molecular epidemiology. [ABSTRACT FROM AUTHOR]

Coxsackievirus B5 (CVB5) is an important enterovirus B species (EV-Bs) type. We used the full-length genomic sequences of 53 viral sequences from the national hand, foot, and mouth disease surveillance network in the Chinese mainland (2001–2021). Among them, 69 entire VP1 coding region nucleotide sequences were used for CVB5 genotyping and genetic evolution analysis. Phylogenetic analysis based on a data set of 448 complete VP1 sequences showed that CVB5 could be divided into four genotypes (A-D) worldwide. Sequences from this study belonged to genotypes B and D, which dominated transmission in the Chinese mainland. Two transmission lineages of CVB5 have been discovered in the Chinese mainland, lineage 2 was predominant. Markov chain Monte Carlo analysis indicated that the tMRCA of CVB5 in the Chinese mainland could be traced to 1955, while the global trend could be traced to 1862, 93 years earlier than China. The evolution rate of CVB5 was higher in the Chinese mainland than worldwide. The spatiotemporal dynamics analysis of CVB5 assessed that virus transportation events were relatively active in Central, Northeast, North and Northwest China. Recombination analysis revealed frequent intertypic recombination in the non-structural region of CVB5 genotypes B and D with the other EV-Bs, revealing eight recombination lineages. Our study showed the molecular evolution and phylogeography of CVB5 that could provide valuable information for disease prevention. [ABSTRACT FROM AUTHOR]

Nineteen CVA9 isolates were obtained between 2010 and 2019 from six provinces of mainland China, using the HFMD surveillance network established in China. Nucleotide sequencing revealed that the full-length VP1 of 19 CVA9 isolates was 906 bases encoding 302 amino acids. The combination of the thresholds of the phylogenetic tree and nucleotide divergence of different genotypes within the same serotype led to a value of 15–25%, and enabled CVA9 worldwide to be categorized into ten genotypes: A–J. The phylogenetic tree showed that the prototype strain was included in genotype A, and that the B, C, D, E, H, and J genotypes disappeared during virus evolution, whereas the F, I, and G genotypes showed co-circulation. Lineage G was the dominant genotype of CVA9 and included most of the strains from nine countries in Asia, North America, Oceania, and Europe. Most Chinese strains belonged to the G genotype, suggesting that the molecular epidemiology of China is consistent with that observed worldwide. The 165 partial VP1 strains (723 nt) showed a mean substitution rate of 3.27 × 10−3 substitution/site/year (95% HPD range 2.93–3.6 × 10−3), dating the tMRCA of CVA9 back to approximately 1922 (1911–1932). The spatiotemporal dynamics of CVA9 showed the spread of CVA9 obviously increased in recent years. Most CVA9 isolates originated in USA, but the epidemic areas of CVA9 are now concentrated in the Asia–Pacific region, European countries, and North America. Recombination analysis within the enterovirus B specie (59 serotypes) revealed eight recombination patterns in China at present, CVB4, CVB5, E30, CVB2, E11, HEV106, HEV85, and HEV75. E14, and E6 may act as recombinant donors in multiple regions. Comparison of temperature sensitivity revealed that temperature-insensitive strains have more amino acid substitutions in the RGD motif of the VP1 region, and the sites T283S, V284M, and R288K in the VP1 region may be related to the temperature tolerance of CVA9. [ABSTRACT FROM AUTHOR]