title: Hand, Foot, and Mouth Disease in China: Modeling Epidemic Dynamics of Enterovirus Serotypes and Implications for Vaccination.
abstract: BACKGROUND
  Hand, 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.
  
  
  RESULTS
  Weekly 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, R0, 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.
  
  
  CONCLUSIONS
  The 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 eliminate the ongoing transmission of EV-A71, but serotype replacement by CV-A16 following EV-A71 vaccination is likely to be transient and minor compared to the corresponding reduction in the burden of EV-A71-associated HFMD. Therefore, a mass EV-A71 vaccination program of infants and young children should provide significant benefits in terms of a reduction in overall HFMD burden.
authors.affiliation: Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Saki
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Division of Infectious Disease, Key Laboratory of Surveillance and Early Warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Qiaohong
authors.initials: Q
authors.lastname: Liao
authors.affiliation: Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Van Boeckel
authors.affiliation: Division of Infectious Disease, Key Laboratory of Surveillance and Early Warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Weijia
authors.initials: W
authors.lastname: Xing
authors.affiliation: Division of Infectious Disease, Key Laboratory of Surveillance and Early Warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Junling
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: Victor Y
authors.initials: VY
authors.lastname: Hsiao
authors.affiliation: Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.|Woodrow Wilson School of Public and International Affairs, Princeton University, Princeton, New Jersey, United States of America.
authors.forename: C Jessica E
authors.initials: CJ
authors.lastname: Metcalf
authors.affiliation: Division of Infectious Disease, Key Laboratory of Surveillance and Early Warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Zhaorui
authors.initials: Z
authors.lastname: Chang
authors.affiliation: Division of Infectious Disease, Key Laboratory of Surveillance and Early Warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Fengfeng
authors.initials: F
authors.lastname: Liu
authors.affiliation: Division of Infectious Disease, Key Laboratory of Surveillance and Early Warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Wu
authors.affiliation: WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Cowling
authors.affiliation: WHO Collaborating Centre for Infectious Disease Epidemiology and Control, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Gabriel M
authors.initials: GM
authors.lastname: Leung
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam.
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Farrar
authors.affiliation: Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam.|Centre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: H Rogier
authors.initials: HR
authors.lastname: van Doorn
authors.affiliation: Department of Ecology and Evolutionary Biology, Princeton University, Princeton, New Jersey, United States of America.|Fogarty International Center, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Bryan T
authors.initials: BT
authors.lastname: Grenfell
authors.affiliation: Division of Infectious Disease, Key Laboratory of Surveillance and Early Warning on Infectious Disease, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yu
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002681:China / Q000453:epidemiology; D004770:Enterovirus / Q000276:immunology*; D058872:Epidemics / Q000517:prevention & control*; D005260:Female; D006232:Hand, Foot and Mouth Disease / Q000453:epidemiology* / Q000517:prevention & control; D006801:Humans; D007223:Infant; D008297:Male; D011446:Prospective Studies; D065288:Serogroup; D014611:Vaccination / Q000379:methods*