Hand, Foot, and Mouth Disease in China: Modeling Epidemic Dynamics of Enterovirus Serotypes and Implications for Vaccination

Using time series susceptible–infected–recovered (TSIR) epidemic models, Saki Takahashi and colleagues investigate hand, foot, and mouth disease dynamics and the projected effect of vaccination in China.

Vyšlo v časopise: Hand, Foot, and Mouth Disease in China: Modeling Epidemic Dynamics of Enterovirus Serotypes and Implications for Vaccination. PLoS Med 13(2): e32767. doi:10.1371/journal.pmed.1001958
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pmed.1001958


Using time series susceptible–infected–recovered (TSIR) epidemic models, Saki Takahashi and colleagues investigate hand, foot, and mouth disease dynamics and the projected effect of vaccination in China.


1. Podin Y, Gias EL, Ong F, Leong Y-W, Yee S-F, Yusof MA, et al. Sentinel surveillance for human enterovirus 71 in Sarawak, Malaysia: lessons from the first 7 years. BMC Public Health. 2006;6:180. doi: 10.1186/1471-2458-6-180 16827926

2. Tseng F-C, Huang H-C, Chi C-Y, Lin T-L, Liu C-C, Jian J-W, et al. Epidemiological survey of enterovirus infections occurring in Taiwan between 2000 and 2005: analysis of sentinel physician surveillance data. J Med Virol. 2007;79:1850–1860. doi: 10.1002/jmv.21006 17935170

3. World Health Organization Western Pacific Region. Emerging disease surveillance and response. Hand, foot and mouth disease information sheet. 2012 Jul 10 [cited 20 Aug 2014]. Manila: World Health Organization Regional Office for the Western Pacific. Available: http://www.wpro.who.int/emerging_diseases/hfmd.information.sheet/en/

4. Chan Y-F, Sam I-C, Wee K-L, Abubakar S. Enterovirus 71 in Malaysia: a decade later. Neurol Asia. 2011;16:1–15.

5. Chan LG, Parashar UD, Lye MS, Ong FGL, Zaki SR, Alexander JP, et al. Deaths of children during an outbreak of hand, foot, and mouth disease in Sarawak, Malaysia: clinical and pathological characteristics of the disease. Clin Infect Dis. 2000;31:678–683. doi: 10.1086/314032 11017815

6. Ho M, Chen E-R, Hsu K-H, Twu S-J, Chen K-T, Tsai S-F, et al. An epidemic of enterovirus 71 infection in Taiwan. Taiwan Enterovirus Epidemic Working Group. N Engl J Med. 1999;341:929–935. doi: 10.1056/NEJM199909233411301 10498487

7. Fujimoto T, Chikahira M, Yoshida S, Ebira H, Hasegawa A, Totsuka A, et al. Outbreak of central nervous system disease associated with hand, foot, and mouth disease in Japan during the summer of 2000: detection and molecular epidemiology of enterovirus 71. Microbiol Immunol. 2002;46:621–627. doi: 10.1111/j.1348-0421.2002.tb02743.x 12437029

8. Chan KP, Goh KT, Chong CY, Teo ES, Lau G, Ling AE. Epidemic hand, foot and mouth disease caused by human enterovirus 71, Singapore. Emerg Infect Dis. 2003;9:78–85. doi: 10.3201/eid1301.020112 12533285

9. Van Tu P, Thao NTT, Perera D, Truong KH, Tien NTK, Thuong TC, et al. Epidemiologic and virologic investigation of hand, foot, and mouth disease, southern Vietnam, 2005. Emerg Infect Dis. 2007;13:1733–1741. doi: 10.3201/eid1311.070632 18217559

10. Zhang Y, Tan X-J, Wang H-Y, Yan D-M, Zhu S-L, Wang D-Y, et al. An outbreak of hand, foot, and mouth disease associated with subgenotype C4 of human enterovirus 71 in Shandong, China. J Clin Virol. 2009;44:262–267. doi: 10.1016/j.jcv.2009.02.002 19269888

11. Zhang Y, Zhu Z, Yang W, Ren J, Tan X, Wang Y, et al. An emerging recombinant human enterovirus 71 responsible for the 2008 outbreak of hand foot and mouth disease in Fuyang city of China. Virol J. 2010;7:94. doi: 10.1186/1743-422X-7-94 20459851

12. Ma E, Chan KC, Cheng P, Wong C, Chuang SK. The enterovirus 71 epidemic in 2008—public health implications for Hong Kong. Int J Infect Dis. 2010;14:e775–e780. doi: 10.1016/j.ijid.2010.02.2265 20599410

13. Ryu W-S, Kang B, Hong J, Hwang S, Kim J, Cheon D-S. Clinical and etiological characteristics of enterovirus 71-related diseases during a recent 2-year period in Korea. J Clin Microbiol. 2010;48:2490–2494. doi: 10.1128/JCM.02369-09 20463159

14. Seiff A. Cambodia unravels cause of mystery illness. Lancet. 2012;380:206.

15. Xing W, Liao Q, Viboud C, Zhang J, Sun J, Wu JT, et al. Hand, foot, and mouth disease in China, 2008–12: an epidemiological study. Lancet Infect Dis. 2014;14:308–318. doi: 10.1016/S1473-3099(13)70342-6 24485991

16. Feng H, Duan G, Zhang R, Zhang W. Time series analysis of hand-foot-mouth disease hospitalization in Zhengzhou: establishment of forecasting models using climate variables as predictors. PLoS ONE. 2014;9:e87916. doi: 10.1371/journal.pone.0087916 24498221

17. Lee BY, Wateska AR, Bailey RR, Tai JHY, Bacon KM, Smith KJ. Forecasting the economic value of an Enterovirus 71 (EV71) vaccine. Vaccine. 2010;28:7731–7736. doi: 10.1016/j.vaccine.2010.09.065 20923711

18. US Centers for Disease Control and Prevention. Non-polio enterovirus: enterovirus D68. [cited 19 Oct 2014]. Atlanta: US Centers for Disease Control and Prevention. Available: http://www.cdc.gov/non-polio-enterovirus/about/ev-d68.html

19. McMinn PC. An overview of the evolution of enterovirus 71 and its clinical and public health significance. FEMS Microbiol Rev. 2002;26:91–107. 12007645

20. De W, Changwen K, Wei L, Monagin C, Jin Y, Cong M, et al. A large outbreak of hand, foot, and mouth disease caused by EV71 and CAV16 in Guangdong, China, 2009. Arch Virol. 2011;156:945–953. doi: 10.1007/s00705-011-0929-8 21305327

21. Liu MY, Liu W, Luo J, Liu Y, Zhu Y, Berman H, et al. Characterization of an outbreak of hand, foot, and mouth disease in Nanchang, China in 2010. PLoS ONE. 2011;6:e25287. doi: 10.1371/journal.pone.0025287 21980416

22. Ma E, Fung C, Yip SHL, Wong C, Chuang SK, Tsang T. Estimation of the basic reproduction number of enterovirus 71 and coxsackievirus A16 in hand, foot, and mouth disease outbreaks. Pediatr Infect Dis J. 2011;30:675–679. doi: 10.1097/INF.0b013e3182116e95 21326133

23. Li R, Liu L, Mo Z, Wang X, Xia J, Liang Z, et al. An inactivated enterovirus 71 vaccine in healthy children. N Engl J Med. 2014;370:829–837. doi: 10.1056/NEJMoa1303224 24571755

24. China Food and Drug Administration. [Announcement on licensed drugs approved by China Food and Drug Administration (No. 4 in 2016).] 2016 Jan 12 [cited 17 Jan 2016]. Available: http://www.sfda.gov.cn/WS01/CL0087/142000.html.

25. Zhu F-C, Meng F-Y, Li J-X, Li X-L, Mao Q-Y, Tao H, et al. Efficacy, safety, and immunology of an inactivated alum-adjuvant enterovirus 71 vaccine in children in China: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2013;381:2024–2032. doi: 10.1016/S0140-6736(13)61049-1 23726161

26. Pitzer VE, Patel MM, Lopman BA, Viboud C, Parashar UD, Grenfell BT. Modeling rotavirus strain dynamics in developed countries to understand the potential impact of vaccination on genotype distributions. Proc Natl Acad Sci U S A. 2011;108:19353–19358. doi: 10.1073/pnas.1110507108 22084114

27. Kamo M, Sasaki A. The effect of cross-immunity and seasonal forcing in a multi-strain epidemic model. Phys Nonlinear Phenom. 2002;165:228–241. doi: 10.1016/S0167-2789(02)00389-5

28. Zhuang L, Cressie N, Pomeroy L, Janies D. Multi-species SIR models from a dynamical Bayesian perspective. Theor Ecol. 2013;6:457–473. doi: 10.1007/s12080-013-0180-x

29. Hovi T, Roivainen M. Peptide antisera targeted to a conserved sequence in poliovirus capsid VP1 cross-react widely with members of the genus Enterovirus. J Clin Microbiol. 1993;31:1083–1087. 8388885

30. Samuelson A, Forsgren M, Johansson B, Wahren B, Sällberg M. Molecular basis for serological cross-reactivity between enteroviruses. Clin Diagn Lab Immunol. 1994;1:336–341. 7496972

31. Deng C, Yang C, Wan J, Zhu L, Leng Q. Irregular poliovirus vaccination correlates to pulmonary edema of hand, foot, and mouth disease. Clin Vaccine Immunol. 2011;18:1589–1590. doi: 10.1128/CVI.05132-11 21752953

32. Yan X-F, Gao S, Xia J-F, Ye R, Yu H, Long J-E. Epidemic characteristics of hand, foot, and mouth disease in Shanghai from 2009 to 2010: enterovirus 71 subgenotype C4 as the primary causative agent and a high incidence of mixed infections with coxsackievirus A16. Scand J Infect Dis. 2012;44:297–305. doi: 10.3109/00365548.2011.634433 22176514

33. Li Y, Zhu R, Qian Y, Deng J, Sun Y, Liu L, et al. Comparing Enterovirus 71 with Coxsackievirus A16 by analyzing nucleotide sequences and antigenicity of recombinant proteins of VP1s and VP4s. BMC Microbiol. 2011;11:246. doi: 10.1186/1471-2180-11-246 22050722

34. Lin Y, Wen K, Pan Y, Wang Y, Che X, Wang B. Cross-reactivity of anti-EV71 IgM and neutralizing antibody in series sera of patients infected with Enterovirus 71 and Coxsackievirus A 16. J Immunoassay Immunochem. 2011;32:233–243. doi: 10.1080/15321819.2011.559297 21574094

35. Chou A-H, Liu C-C, Chang J-Y, Jiang R, Hsieh Y-C, Tsao A, et al. Formalin-inactivated EV71 vaccine candidate induced cross-neutralizing antibody against subgenotypes B1, B4, B5 and C4A in adult volunteers. PLoS ONE. 2013;8:e79783. doi: 10.1371/journal.pone.0079783 24278177

36. Li Y, Zhang J, Zhang X. Modeling and preventive measures of hand, foot and mouth disease (HFMD) in China. Int J Environ Res Public Health. 2014;11:3108–3117. doi: 10.3390/ijerph110303108 24633146

37. Roy N. Mathematical modeling of hand-foot-mouth disease: quarantine as a control measure. Int J Adv Sci Eng Technol Res. 2012;1:34–44.

38. Zhu Y, Xu B, Lian X, Lin W, Zhou Z, Wang W. A hand-foot-and-mouth disease model with periodic transmission rate in Wenzhou, China. Abstr Appl Anal. 2014;2014:e234509. doi: 10.1155/2014/234509

39. Wang Y, Feng Z, Yang Y, Self S, Gao Y, Longini IM, et al. Hand, foot, and mouth disease in China: patterns of spread and transmissibility. Epidemiol Camb Mass. 2011;22:781–792. doi: 10.1097/EDE.0b013e318231d67a

40. Weinberger DM, Malley R, Lipsitch M. Serotype replacement in disease after pneumococcal vaccination. Lancet. 2011;378:1962–1973. doi: 10.1016/S0140-6736(10)62225-8 21492929

41. Hanage WP, Finkelstein JA, Huang SS, Pelton SI, Stevenson AE, Kleinman K, et al. Evidence that pneumococcal serotype replacement in Massachusetts following conjugate vaccination is now complete. Epidemics. 2010;2:80–84. doi: 10.1016/j.epidem.2010.03.005 21031138

42. Lloyd-Smith JO. Vacated niches, competitive release and the community ecology of pathogen eradication. Philos Trans R Soc Lond B Biol Sci. 2013;368. doi: 10.1098/rstb.2012.0150

43. Metcalf CJE, Bjørnstad ON, Grenfell BT, Andreasen V. Seasonality and comparative dynamics of six childhood infections in pre-vaccination Copenhagen. Proc Biol Sci. 2009;276:4111–4118. doi: 10.1098/rspb.2009.1058 19740885

44. National Bureau of Statistics of China. Annual data. [cited 6 Jul 2015]. Available: http://www.stats.gov.cn/english/Statisticaldata/AnnualData/

45. Finkenstädt BF, Bjørnstad ON, Grenfell BT. A stochastic model for extinction and recurrence of epidemics: estimation and inference for measles outbreaks. Biostat Oxf Engl. 2002;3:493–510. doi: 10.1093/biostatistics/3.4.493

46. Reich NG, Shrestha S, King AA, Rohani P, Lessler J, Kalayanarooj S, et al. Interactions between serotypes of dengue highlight epidemiological impact of cross-immunity. J R Soc Interface. 2013;10:20130414. doi: 10.1098/rsif.2013.0414 23825116

47. Zhu F-C, Liang Z-L, Meng F-Y, Zeng Y, Mao Q-Y, Chu K, et al. Retrospective study of the incidence of HFMD and seroepidemiology of antibodies against EV71 and CoxA16 in prenatal women and their infants. PLoS ONE. 2012;7:e37206. doi: 10.1371/journal.pone.0037206 22662137

48. Finkenstädt BF, Grenfell BT. Time series modelling of childhood diseases: a dynamical systems approach. J R Stat Soc Ser C Appl Stat. 2000;49:187–205.

49. Bjørnstad ON, Finkenstädt BF, Grenfell BT. Dynamics of measles epidemics: estimating scaling of transmission rates using a time series SIR model. Ecol Monogr. 2002;72:169–184.

50. Glass K, Xia Y, Grenfell BT. Interpreting time-series analyses for continuous-time biological models—measles as a case study. J Theor Biol. 2003;223:19–25. 12782113

51. Bjørnstad ON, Finkenstädt BF, Grenfell BT. Dynamics of measles epidemics: scaling noise, determinism, and predictability with the TSIR model. Ecol Monogr. 2002;72:185–202.

52. Zhu F, Xu W, Xia J, Liang Z, Liu Y, Zhang X, et al. Efficacy, safety, and immunogenicity of an enterovirus 71 vaccine in China. N Engl J Med. 2014;370:818–828. doi: 10.1056/NEJMoa1304923 24571754

53. Grassly NC, Fraser C. Seasonal infectious disease epidemiology. Proc R Soc Lond B Biol Sci. 2006;273:2541–2550. doi: 10.1098/rspb.2006.3604

54. Bartlett MS. The critical community size for measles in the United States. J R Stat Soc Ser A. 1960;123:37–44. doi: 10.2307/2343186

55. Keeling MJ, Rohani P. Modeling infectious diseases in humans and animals. Princeton (New Jersey): Princeton University Press.

56. He Y-Q, Chen L, Xu W-B, Yang H, Wang H-Z, Zong W-P, et al. Emergence, circulation, and spatiotemporal phylogenetic analysis of coxsackievirus A6- and coxsackievirus A10-associated hand, foot, and mouth disease infections from 2008 to 2012 in Shenzhen, China. J Clin Microbiol. 2013;51:3560–3566. doi: 10.1128/JCM.01231-13 23966496

57. Hongyan G, Chengjie M, Qiaozhi Y, Wenhao H, Juan L, Lin P, et al. Hand, foot and mouth disease caused by coxsackievirus A6, Beijing, 2013. Pediatr Infect Dis J. 2014;33:1302–1303. doi: 10.1097/INF.0000000000000467 25037037

58. Tian H, Zhang Y, Sun Q, Zhu S, Li X, Pan Z, et al. Prevalence of multiple enteroviruses associated with hand, foot, and mouth disease in Shijiazhuang City, Hebei province, China: outbreaks of coxsackieviruses A10 and B3. PLoS ONE. 2014;9:e84233. doi: 10.1371/journal.pone.0084233 24392117

59. Di B, Zhang Y, Xie H, Li X, Chen C, Ding P, et al. Circulation of Coxsackievirus A6 in hand-foot-mouth disease in Guangzhou, 2010–2012. Virol J. 2014;11:157. doi: 10.1186/1743-422X-11-157 25178398

60. Stewart CL, Chu EY, Introcaso CE, Schaffer A, James WD. Coxsackievirus A6-induced hand-foot-mouth disease. JAMA Dermatol. 2013;149:1419–1421. doi: 10.1001/jamadermatol.2013.6777 24172861

61. Bible JM, Pantelidis P, Chan PKS, Tong CYW. Genetic evolution of enterovirus 71: epidemiological and pathological implications. Rev Med Virol. 2007;17:371–379. doi: 10.1002/rmv.538 17487831

62. Huang S-W, Hsu Y-W, Smith DJ, Kiang D, Tsai H-P, Lin K-H, et al. Reemergence of enterovirus 71 in 2008 in Taiwan: dynamics of genetic and antigenic evolution from 1998 to 2008. J Clin Microbiol. 2009;47:3653–3662. doi: 10.1128/JCM.00630-09 19776232

63. Zhang H, An D, Liu W, Mao Q, Jin J, Xu L, et al. Analysis of cross-reactive neutralizing antibodies in human HFMD serum with an EV71 pseudovirus-based assay. PLoS ONE. 2014;9:e100545. doi: 10.1371/journal.pone.0100545 24964084

64. Mao Q, Cheng T, Zhu F, Li J, Wang Y, Li Y, et al. The cross-neutralizing activity of enterovirus 71 subgenotype c4 vaccines in healthy Chinese infants and children. PLoS ONE. 2013;8:e79599. doi: 10.1371/journal.pone.0079599 24260259

65. Huang M-L, Chiang P-S, Chia M-Y, Luo S-T, Chang L-Y, Lin T-Y, et al. Cross-reactive neutralizing antibody responses to enterovirus 71 infections in young children: implications for vaccine development. PLoS Negl Trop Dis. 2013;7:e2067. doi: 10.1371/journal.pntd.0002067 23459633

66. Dushoff J, Plotkin JB, Levin SA, Earn DJD. Dynamical resonance can account for seasonality of influenza epidemics. Proc Natl Acad Sci U S A. 2004;101:16915–16916. doi: 10.1073/pnas.0407293101 15557003

67. Grassly NC, Fraser C, Garnett GP. Host immunity and synchronized epidemics of syphilis across the United States. Nature. 2005;433:417–421. doi: 10.1038/nature03072 15674292

68. Xu M, Su L, Cao L, Zhong H, Dong N, Xu J. Enterovirus genotypes causing hand foot and mouth disease in Shanghai, China: a molecular epidemiological analysis. BMC Infect Dis. 2013;13:489. doi: 10.1186/1471-2334-13-489 24148902

69. Wei S-H, Huang Y-P, Liu M-C, Tsou T-P, Lin H-C, Lin T-L, et al. An outbreak of coxsackievirus A6 hand, foot, and mouth disease associated with onychomadesis in Taiwan, 2010. BMC Infect Dis. 2011;11:346. doi: 10.1186/1471-2334-11-346 22168544

70. Lu Q-B, Zhang X-A, Wo Y, Xu H-M, Li X-J, Wang X-J, et al. Circulation of Coxsackievirus A10 and A6 in hand-foot-mouth disease in China, 2009–2011. PLoS ONE. 2012;7:e52073. doi: 10.1371/journal.pone.0052073 23272213

71. Xia Y, Bjørnstad ON, Grenfell BT. Measles metapopulation dynamics: a gravity model for epidemiological coupling and dynamics. Am Nat. 2004;164:267–281. doi: 10.1086/422341 15278849

72. Smith DJ, Lapedes AS, de Jong JC, Bestebroer TM, Rimmelzwaan GF, Osterhaus ADME, et al. Mapping the antigenic and genetic evolution of influenza virus. Science. 2004;305:371–376. doi: 10.1126/science.1097211 15218094

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