Summary Background Hand–foot–and–mouth disease (HFMD) is a common childhood illness caused by enteroviruses. Increasingly it imposes a substantial disease burden throughout East and Southeast Asia. To better inform vaccine and other interventions, we characterized the epidemiology of HFMD in China based on enhanced surveillance. Methods We extracted epidemiological, clinical and laboratory data from reported HFMD cases during 2008–2012 and compiled climatic, geographic and demographic information. All analyses were stratified by age, disease severity, laboratory confirmation status and enterovirus subtype. Findings The surveillance registry captured 7,200,092 probable HFMD cases (annualized incidence, 1·2 per 1,000), of whom 3·7% were laboratory–confirmed and 0·03% died. Incidence and mortality were highest in children aged 12–23 months (in 2012: 38·2 cases per 1,000 and 1·5 death per 100,000). Median durations from onset to diagnosis and death were 1·5 days and 3·5 days respectively. The risk of cardiopulmonary or neurological complications was 1·1% and the severe-case fatality risk was 3·0%, with >90% of deaths associated with enterovirus 71. HFMD peaked annually in June in the North, whereas Southern China experienced semi-annual outbreaks in May and September/October. Geographic differences in seasonal patterns were weakly associated with climate and demographic factors (variance explained 8-23% and 3–19%, respectively). Interpretation This is the largest population-based study to date of the epidemiology of HFMD. Future mitigation policies should take full account of the heterogeneities of disease burden identified. Additional epidemiologic and serologic studies are warranted to elucidate local HFMD dynamics and immunity patterns and optimize interventions. Funding China–US Collaborative Program on Emerging and Re-emerging Infectious Diseases; World Health Organization; The Li Ka Shing Oxford Global Health Programme and Wellcome Trust; Harvard Center for Communicable Disease Dynamics; Health and Medical Research Fund, Government of the Hong Kong Special Administrative Region.

Background The novel influenza A(H7N9) virus recently emerged, while influenza A(H5N1) virus has infected humans since 2003 in mainland China. Both infections are thought to be predominantly zoonotic. We compared the epidemiologic characteristics of the complete series of laboratory-confirmed cases of both viruses in mainland China to date. Methods An integrated database was constructed with information on demographic, epidemiological, and clinical variables of laboratory-confirmed A(H7N9) and A(H5N1) cases that were reported to the Chinese Center for Disease Control and Prevention up to May 24, 2013. We described disease occurrence by age, sex and geography and estimated key epidemiologic parameters. Findings Among 130 and 43 patients with confirmed A(H7N9) and A(H5N1) respectively, the median ages were 62y and 26y. In urban areas, 74% of cases of both viruses were male whereas in rural areas the proportions were 62% for A(H7N9) and 33% for A(H5N1). Among cases of A(H7N9) and A(H5N1), 75% and 71% reported recent exposure to poultry. The mean incubation periods of A(H7N9) and A(H5N1) were 3.1 and 3.3 days, respectively. On average, 21 and 18 contacts were traced for each A(H7N9) case in urban and rural areas respectively; compared to 90 and 63 for A(H5N1). The hospitalization fatality risk was 35% (95% CI: 25%, 44%) for A(H7N9) and 70% (95% CI: 56%, 83%) for A(H5N1). Interpretation The sex ratios in urban compared to rural cases are consistent with poultry exposure driving the risk of infection. However the difference in susceptibility to serious illness with the two different viruses remains unexplained, given that most A(H7N9) cases were in older adults while most A(H5N1) cases were in younger individuals. Funding Ministry of Science and Technology, China; Research Fund for the Control of Infectious Disease and University Grants Committee, Hong Kong Special Administrative Region, China; and the US National Institutes of Health.

BackgroundHand, foot, and mouth disease (HFMD) is a common childhood illness caused by serotypes of the Enterovirus A species in the genus Enterovirus of the Picornaviridae family. The disease has had a substantial burden throughout East and Southeast Asia over the past 15 y. China reported 9 million cases of HFMD between 2008 and 2013, with the two serotypes Enterovirus A71 (EV-A71) and Coxsackievirus A16 (CV-A16) being responsible for the majority of these cases. Three recent phase 3 clinical trials showed that inactivated monovalent EV-A71 vaccines manufactured in China were highly efficacious against HFMD associated with EV-A71, but offered no protection against HFMD caused by CV-A16. To better inform vaccination policy, we used mathematical models to evaluate the effect of prospective vaccination against EV-A71-associated HFMD and the potential risk of serotype replacement by CV-A16. We also extended the model to address the co-circulation, and implications for vaccination, of additional non-EV-A71, non-CV-A16 serotypes of enterovirus.Methods and FindingsWeekly reports of HFMD incidence from 31 provinces in Mainland China from 1 January 2009 to 31 December 2013 were used to fit multi-serotype time series susceptible–infected–recovered (TSIR) epidemic models. We obtained good model fit for the two-serotype TSIR with cross-protection, capturing the seasonality and geographic heterogeneity of province-level transmission, with strong correlation between the observed and simulated epidemic series. The national estimate of the basic reproduction number, R 0, weighted by provincial population size, was 26.63 for EV-A71 (interquartile range [IQR]: 23.14, 30.40) and 27.13 for CV-A16 (IQR: 23.15, 31.34), with considerable variation between provinces (however, predictions about the overall impact of vaccination were robust to this variation). EV-A71 incidence was projected to decrease monotonically with higher coverage rates of EV-A71 vaccination. Across provinces, CV-A16 incidence in the post-EV-A71-vaccination period remained either comparable to or only slightly increased from levels prior to vaccination. The duration and strength of cross-protection following infection with EV-A71 or CV-A16 was estimated to be 9.95 wk (95% confidence interval [CI]: 3.31, 23.40) in 68% of the population (95% CI: 37%, 96%). Our predictions are limited by the necessarily short and under-sampled time series and the possible circulation of unidentified serotypes, but, nonetheless, sensitivity analyses indicate that our results are robust in predicting that the vaccine should drastically reduce incidence of EV-A71 without a substantial competitive release of CV-A16.ConclusionsThe ability of our models to capture the observed epidemic cycles suggests that herd immunity is driving the epidemic dynamics caused by the multiple serotypes of enterovirus. Our results predict that the EV-A71 and CV-A16 serotypes provide a temporary immunizing effect against each other. Achieving high coverage rates of EV-A71 vaccination would be necessary to eli...

Children who have received the enterovirus A71 vaccine are still at risk for disease with infections of enteroviruses of other serotypes.

IntroductionHand, foot and mouth disease (HFMD) is usually caused by several serotypes from human enterovirus A species, including enterovirus 71 (EV-A71) and coxsackievirus A16 (CV-A16). Two inactivated monovalent EV-A71 vaccines have been recently licensed in China and monovalent CV-A16 vaccine and bivalent EV-A71 and CV-A16 vaccine are under development. Methods: Using notifications from the national surveillance system, we describe the epidemiology and dynamics of HFMD in the country, before the introduction of EV-A71 vaccination, from 2008 through 2015. Results: Laboratory-identified serotype categories, i.e. CV-A16, EV-A71 and other enteroviruses, circulated annually. EV-A71 remained the most virulent serotype and was the major serotype for fatal cases (range: 88.5–95.4%) and severe cases (range: 50.7–82.3%) across years. Except for 2013 and 2015, when other enteroviruses were more frequently found in mild HFMD (48.8% and 52.5%), EV-A71 was more frequently detected from mild cases in the rest of the years covered by the study (range: 39.4–52.6%). The incidence rates and severity risks of HFMD associated with all serotype categories were the highest for children aged 1 year and younger, and decreased with increasing age. Discussion/conclusion: This study provides baseline epidemiology for evaluation of vaccine impact and potential serotype replacement.