Molecular Epidemiology Of Enterovirus 71 In China, 1998-2011

Nationwide outbreak of HFMD emerged since 2008 in mainland China, which becomes a severe problem of public health since then. Accordingly, HFMD was increased as the 38th notifiable disease on May 2,2008, managed as C class. The nationwide surveillance for HFMD is initiated since 2008, both on epidemiology and virology.Case information reported during Jan 1,2008 to Dec 31,2011, was collected from the National Notifiable Disease Reporting System (NNDRS) and analyzed. It’s indicated that totally,1,155,491-1,619,689 cases are reported annually in 2009-2011, including 13,481-27,043 severe cases with neural system involvement, and 355-904 fatalities. Young children 1-2-years old show the highest incidence (1,211-2,953 per 100,000) and fatality (0.61-2.12 per 100,000). Virology surveillance showed that enterovirus (EV71) and Coxsackievirus A16 (CA16) are the primary pathogen. However, EV71 infections respond for most of the severe (79%-82%) and fatal (92%-95%) cases.For molecular epidemiological analysis on EV71, VP1 encoding sequences of the 3435, and whole genome sequences of 129 native EV71 isolates are determined by this study or download from GenBank. Bioinformatics tools are used for sequence analyses. C4 subgenotype became the predominant one circulating in mainland China, since 1998, originating in-1994 and evolving at 4.6×10-3 substitutions per site per year. During the persistent circulation in China, the evolutionary distance of C4 isolates to SHZH98 got larger through the years. A clade transition occurred in 2002-2004, from C4b to C4a. Analyses based on whole genome indicate that recombinations between the native EV71 isolates and other HEV-A members are common. Both phylogenetic and evolutionary distance indicated that except PI, all the non-structural region (P2, P3 and UTR) originate from other HEV-A than EV71. Although the origin and the potential breakpoint of recombination are diversiform, most of the C4 subgenotype of EV71 clusters with each other on phylogenetic tree, and show a small pairwise distances (0.019-0.041) throughout all the genes, suggesting that the C4 isolates circulating in mainland China are of a group with high genetic homology. The natural selection analyses indicate high purified selection through the genome, with only 2 pervasive positive site identified (codon 93 in VP3, and codon 98 in VP1).From the results in this study, it’s concluded that:1) young children especially less than 3 years old should be the aimed population for HFMD control and prevention; 2) to fight against the threaten from HFMD, EV71 should be the prior target; 3) C4 subgenotype isolates have evolved during persistent circulation, through both mutations and recombinations, however, advanced researches are necessary to determine whether any biological phenotype is achived through evolution; 4) high purified selection on EV71 might cast a bright future for the development of EV71 vaccine.