The persistent circulation of enterovirus 71 in People's Republic of China: causing emerging nationwide epidemics since 2008

Abstract

Emerging epidemics of hand-foot-and-mouth disease (HFMD) associated with enterovirus 71 (EV71) has become a serious concern in mainland China. It caused 126 and 353 fatalities in 2008 and 2009, respectively. The epidemiologic and pathogenic data of the outbreak collected from national laboratory network and notifiable disease surveillance system. To understand the virological evolution of this emerging outbreak, 326 VP1 gene sequences of EV71 detected in China from 1987 to 2009 were collected for genetic analyses. Evidence from both traditional and molecular epidemiology confirmed that the recent HFMD outbreak was an emerging one caused by EV71 of subgenotype C4. This emerging HFMD outbreak is associated with EV71 of subgenotype C4, circulating persistently in mainland China since 1998, but not attributed to the importation of new genotype. Originating from 1992, subgenotype C4 has been the predominant genotype since 1998 in mainland China, with an evolutionary rate of 4.6∼4.8×10⁻³ nucleotide substitutions/site/year. The phylogenetic analysis revealed that the majority of the virus during this epidemic was the most recent descendant of subgenotype C4 (clade C4a). It suggests that the evolution might be one of the potential reasons for this native virus to cause the emerging outbreak in China. However, strong negative selective pressure on VP1 protein of EV71 suggested that immune escape might not be the evolving strategy of EV71, predicting a light future for vaccine development. Nonetheless, long-term antigenic and genetic surveillance is still necessary for further understanding.

Figure 1. Phylogenetic analyses based on all the available VP1 Nt sequences of EV71 in China.

(A) Phylogenetic tree showed that subgenotype C4 was the predominant one in mainland China. The branches of sequences from China were highlighted in red color. The sequences marked with blue block were selected and used for Baysian MCMC computations and natural selection inference. (B) Phylogenetic tree showed the evolutionary tendency of subgenotype C4 strains in China since 1998. The branches were colored differently by years. A ladder-like topology revealed the adaptation of EV71 occurred during the epidemic history , . (C) Illustration of genetic evolution over years for all the strains of subgenotype C4 in China with distance measured to SHZH98 (AF302996; the first C4 strain isolated in China mainland). The distances conformed to tree distance in (A) and (B). The red line is the best-fit regression curve fitted all the data point to indicate the trend through time.

Figure 2. Baysian skyline plot was estimated to reconstruct the demographic history of subgenotype C4 EV71 in China .

The x axis is in units of years before 2009, and the y axis is equal to N_eτ (the product of the effective population size and the generation length in years). The thick solid line is the mean estimates, the 95% HPD credible region is showed by blue areas.