J Vet Sci.  2016 Mar;17(1):1-11. 10.4142/jvs.2016.17.1.1.

Hepatitis E virus as an emerging zoonotic pathogen

• Park WJ
• Park BJ
• Ahn HS
• Lee JB
• Park SY
• Song CS
• Lee SW
• Yoo HS
• Choi IS

• KMID: 2363329
• DOI: http://doi.org/10.4142/jvs.2016.17.1.1

Abstract

Hepatitis E outbreaks are a serious public health concern in developing countries. The disease causes acute infections, primarily in young adults. The mortality rate is approximately 2%; however, it can exceed 20% in pregnant women in some regions in India. The causative agent, hepatitis E virus (HEV), has been isolated from several animal species, including pigs. HEV genotypes 3 and 4 have been isolated from both humans and animals, and are recognized as zoonotic pathogens. Seroprevalence studies in animals and humans indirectly suggest that HEV infections occur worldwide. The virus is primarily transmitted to humans via undercooked animal meats in developed countries. Moreover, transfusion- and transplantation-mediated HEV infections have recently been reported. This review summarizes the general characteristics of hepatitis E, HEV infection status in animals and humans, the zoonotic transmission modes of HEV, and HEV vaccine development status.

Keyword

hepatitis E; hepatitis E virus; pig; transmission; zoonotic pathogen

MeSH Terms

Animals
Genotype
Hepatitis E/*epidemiology/mortality/*transmission/virology
Hepatitis E virus/genetics/*physiology
Humans
Zoonoses/epidemiology/mortality/*transmission/virology

Reference

1. Abid M, O'Brien SJ, Boxall EH, Skidmore SJ. Hepatitis and travel abroad: a case report. J Travel Med. 1997; 4:187–188.

2. Aggarwal R. Hepatitis E: epidemiology and natural history. J Clin Exp Hepatol. 2013; 3:125–133.

3. Ahn JM, Kang SG, Lee DY, Shin SJ, Yoo HS. Identification of novel human hepatitis E virus (HEV) isolates and determination of the seroprevalence of HEV in Korea. J Clin Microbiol. 2005; 43:3042–3048.

4. Arankalle VA, Chobe LP. Retrospective analysis of blood transfusion recipients: evidence for post-transfusion hepatitis E. Vox Sang. 2000; 79:72–74.

5. Arankalle VA, Joshi MV, Kulkarni AM, Gandhe SS, Chobe LP, Rautmare SS, Mishra AC, Padbidri VS. Prevalence of anti-hepatitis E virus antibodies in different Indian animal species. J Viral Hepat. 2001; 8:223–237.

6. Berto A, Grierson S, Hakze-van der Honing R, Martelli F, Johne R, Reetz J, Ulrich RG, Pavio N, Van der Poel WHM, Banks M. Hepatitis E virus in pork liver sausage, France. Emerg Infect Dis. 2013; 19:264–266.

7. Bilic I, Jaskulska B, Basic A, Morrow CJ, Hess M. Sequence analysis and comparison of avian hepatitis E viruses from Australia and Europe indicate the existence of different genotypes. J Gen Virol. 2009; 90:863–873.

8. Birke L, Cormier SA, You D, Stout RW, Clement C, Johnson M, Thompson H. Hepatitis E antibodies in laboratory rabbits from 2 US vendors. Emerg Infect Dis. 2014; 20:693–696.

9. Borgen K, Herremans T, Duizer E, Vennema H, Rutjes S, Bosman A, de Roda Husman AM, Koopmans M. Non-travel related hepatitis E virus genotype 3 infections in the Netherlands; a case series 2004-2006. BMC Infect Dis. 2008; 8:61.

10. Brost S, Wenzel JJ, Ganten TM, Filser M, Flechtenmacher C, Boehm S, Astani A, Jilg W, Zeier M, Schnitzler P. Sporadic cases of acute autochthonous hepatitis E virus infection in Southwest Germany. J Clin Virol. 2010; 47:89–92.

11. Centers for Disease Control and Prevention (US). Hepatitis E among U.S. travelers, 1989-1992. MMWR Morb Mortal Wkly Rep. 1993; 42:1–4.

12. Chaussade H, Rigaud E, Allix A, Carpentier A, Touzé A, Delzescaux D, Choutet P, Garcia-Bonnet N, Coursaget P. Hepatitis E virus seroprevalence and risk factors for individuals in working contact with animals. J Clin Virol. 2013; 58:504–508.

13. Chiu DMY, Chan MCW, Yeung ACM, Ngai KLK, Chan PKS. Seroprevalence of hepatitis E virus in Hong Kong, 2008-2009. J Med Virol. 2013; 85:459–461.

14. Choi IS, Kwon HJ, Shin NR, Yoo HS. Identification of swine hepatitis E virus (HEV) and prevalence of anti-HEV antibodies in swine and human populations in Korea. J Clin Microbiol. 2003; 41:3602–3608.

15. Clayson ET, Innis BL, Myint KSA, Narupiti S, Vaughn DW, Giri S, Ranabhat P, Shrestha MP. Detection of hepatitis E virus infections among domestic swine in the Kathmandu Valley of Nepal. Am J Trop Med Hyg. 1995; 53:228–232.

16. Clayson ET, Shrestha MP, Vaughn DW, Snitbhan R, Shrestha KB, Longer CF, Innis BL. Rates of hepatitis E virus infection and disease among adolescents and adults in Kathmandu, Nepal. J Infect Dis. 1997; 176:763–766.

17. Colson P, Borentain P, Queyriaux B, Kaba M, Moal V, Gallian P, Heyries L, Raoult D, Gerolami R. Pig liver sausage as a source of hepatitis E virus transmission to humans. J Infect Dis. 2010; 202:825–834.

18. Colson P, Coze C, Gallian P, Henry M, De Micco P, Tamalet C. Transfusion-associated hepatitis E, France. Emerg Infect Dis. 2007; 13:648–649.

19. Cossaboom CM, Córdoba L, Cao D, Ni YY, Meng XJ. Complete genome sequence of hepatitis E virus from rabbits in the United States. J Virol. 2012; 86:13124–13125.

20. Dalton HR, Thurairajah PH, Fellows HJ, Hussaini HS, Mitchell J, Bendall R, Banks M, Ijaz S, Teo CG, Levine DF. Autochthonous hepatitis E in southwest England. J Viral Hepat. 2007; 14:304–309.

21. Ditah I, Ditah F, Devaki P, Ditah C, Kamath PS, Charlton M. Current epidemiology of hepatitis E virus infection in the United States: low seroprevalence in the National Health and Nutrition Evaluation Survey. Hepatology. 2014; 60:815–822.

22. Dong C, Dai X, Shao JS, Hu K, Meng JH. Identification of genetic diversity of hepatitis E virus (HEV) and determination of the seroprevalence of HEV in eastern China. Arch Virol. 2007; 152:739–746.

23. Dong C, Meng J, Dai X, Liang JH, Feagins AR, Meng XJ, Belfiore NM, Bradford C, Corn JL, Cray C, Glass GE, Gordon ML, Hesse RA, Montgomery DL, Nicholson WL, Pilny AA, Ramamoorthy S, Shaver DD, Drobeniuc J, Purdy MA, Fields HA, Kamili S, Teo CG. Restricted enzooticity of hepatitis E virus genotypes 1 to 4 in the United States. J Clin Microbiol. 2011; 49:4164–4172.

24. Faber MS, Wenzel JJ, Jilg W, Thamm M, Höhle M, Stark K. Hepatitis E virus seroprevalence among adults, Germany. Emerg Infect Dis. 2012; 18:1654–1657.

25. Fogeda M, Avellón A, Cilla CG, Echevarría JM. Imported and autochthonous hepatitis E virus strains in Spain. J Med Virol. 2009; 81:1743–1749.

26. Galiana C, Fernández-Barredo S, García A, Gómez MT, Pérez-Gracia MT. Occupational exposure to hepatitis E virus (HEV) in swine workers. Am J Trop Med Hyg. 2008; 78:1012–1015.

27. Gao S, Li D, Zha E, Zhou T, Wang S, Yue X. Surveillance of hepatitis E virus contamination in shellfish in China. Int J Environ Res Public Health. 2015; 12:2026–2036.

28. Geng J, Fu H, Wang L, Bu Q, Liu P, Wang M, Sui Y, Wang X, Zhu Y, Zhuang H. Phylogenetic analysis of the full genome of rabbit hepatitis E virus (rbHEV) and molecular biologic study on the possibility of cross species transmission of rbHEV. Infect Genet Evol. 2011; 11:2020–2025.

29. Haagsma EB, Niesters HGM, van den Berg AP, Riezebos-Brilman A, Porte RJ, Vennema H, Reimerink JHJ, Koopmans MPG. Prevalence of hepatitis E virus infection in liver transplant recipients. Liver Transpl. 2009; 15:1225–1228.

30. Haagsma EB, Riezebos-Brilman A, van den Berg AP, Porte RJ, Niesters HGM. Treatment of chronic hepatitis E in liver transplant recipients with pegylated interferon alpha-2b. Liver Transpl. 2010; 16:474–477.

31. Halac U, Béland K, Lapierre P, Patey N, Ward P, Brassard J, Houde A, Alvarez F. Chronic hepatitis E infection in children with liver transplantation. Gut. 2012; 61:597–603.

32. Han J, Lei Y, Liu L, Liu P, Xia J, Zhang Y, Zeng H, Wang L, Wang L, Zhuang H. SPF rabbits infected with rabbit hepatitis E virus isolate experimentally showing the chronicity of hepatitis. PLoS One. 2014; 9:e99861.

33. Haqshenas G, Shivaprasad HL, Woolcock PR, Read DH, Meng XJ. Genetic identification and characterization of a novel virus related to human hepatitis E virus from chickens with hepatitis–splenomegaly syndrome in the United States. J Gen Virol. 2001; 82:2449–2462.

34. Hauser L, Roque-Afonso AM, Beylouné A, Simonet M, Deau Fischer B, Burin des Roziers N, Mallet V, Tiberghien P, Bierling P. Hepatitis E transmission by transfusion of intercept blood system-treated plasma. Blood. 2014; 123:796–797.

35. Herremans M, Vennema H, Bakker J, van der Veer B, Duizer E, Benne CA, Waar K, Hendrixks B, Schneeberger P, Blaauw G, Kooiman M, Koopmans MP. Swine-like hepatitis E viruses are a cause of unexplained hepatitis in the Netherlands. J Viral Hepat. 2007; 14:140–146.

36. Hewitt PE, Ijaz S, Brailsford SR, Brett R, Dicks S, Haywood B, Kennedy ITR, Kitchen A, Patel P, Poh J, Russell K, Tettmar KI, Tossell J, Ushiro-Lumb I, Tedder RS. Hepatitis E virus in blood components: a prevalence and transmission study in southeast England. Lancet. 2014; 384:1766–1773.

37. Hinjoy S, Nelson KE, Gibbons RV, Jarman RG, Mongkolsirichaikul D, Smithsuwan P, Fernandez S, Labrique AB, Patchanee P. A cross-sectional study of hepatitis E virus infection in healthy people directly exposed and unexposed to pigs in a rural community in northern Thailand. Zoonoses Public Health. 2013; 60:555–562.

38. Huang FF, Haqshenas G, Shivaprasad HL, Guenette DK, Woolcock PR, Larsen CT, Pierson FW, Elvinger F, Toth TE, Meng XJ. Heterogeneity and seroprevalence of a newly identified avian hepatitis E virus from chickens in the United States. J Clin Microbiol. 2002; 40:4197–4202.

39. Huang FF, Sun ZF, Emerson SU, Purcell RH, Shivaprasad HL, Pierson FW, Toth TE, Meng XJ. Determination and analysis of the complete genomic sequence of avian hepatitis E virus (avian HEV) and attempts to infect rhesus monkeys with avian HEV. J Gen Virol. 2004; 85:1609–1618.

40. Huang WJ, Zhang HY, Harrison TJ, Lan HY, Huang GY, Wang YC. Immunogenicity and protective efficacy in rhesus monkeys of a recombinant ORF2 protein from hepatitis E virus genotype 4. Arch Virol. 2009; 154:481–488.

41. Huzly D, Umhau M, Bettinger D, Cathomen T, Emmerich F, Hasselblatt P, Hengel H, Herzog R, Kappert O, Maassen S, Schorb E, Schulz-Huotari C, Thimme R, Unmüssig R, Wenzel JJ, Panning M. Transfusion-transmitted hepatitis E in Germany, 2013. Euro Surveill. 2014; 19:20812.

42. Ijaz S, Vyse AJ, Morgan D, Pebody RG, Tedder RS, Brown D. Indigenous hepatitis E virus infection in England: more common than it seems. J Clin Virol. 2009; 44:272–276.

43. Ishida S, Yoshizumi S, Ikeda T, Miyoshi M, Goto A, Matsubayashi K, Ikeda H. Detection and molecular characterization of hepatitis E virus in clinical, environmental and putative animal sources. Arch Virol. 2012; 157:2363–2368.

44. Jardi R, Crespo M, Homs M, van den Eynde E, Girones R, Rodriguez-Manzano J, Caballero A, Buti M, Esteban R, Rodriguez-Frias F. HIV, HEV and cirrhosis: evidence of a possible link from eastern Spain. HIV Med. 2012; 13:379–383.

45. Jia Z, Yi Y, Liu J, Cao J, Zhang Y, Tian R, Yu T, Wang H, Wang X, Su Q, Zhou W, Cui F, Liang X, Bi S. Epidemiology of hepatitis E virus in China: results from the Third National Viral Hepatitis Prevalence Survey, 2005-2006. PLoS One. 2014; 9:e110837.

46. Jilani N, Das BC, Husain SA, Baweja UK, Chattopadhya D, Gupta RK, Sardana S, Kar P. Hepatitis E virus infection and fulminant hepatic failure during pregnancy. J Gastroenterol Hepatol. 2007; 22:676–682.

47. Jirintai S, Jinshan , Tanggis , Manglai D, Mulyanto , Takahashi M, Nagashima S, Kobayashi T, Nishizawa T, Okamoto H. Molecular analysis of hepatitis E virus from farm rabbits in Inner Mongolia, China and its successful propagation in A549 and PLC/PRF/5 cells. Virus Res. 2012; 170:126–137.

48. Jothikumar N, Aparna K, Kamatchiammal S, Paulmurugan R, Saravanadevi S, Khanna P. Detection of hepatitis E virus in raw and treated wastewater with the polymerase chain reaction. Appl Environ Microbiol. 1993; 59:2558–2562.

49. Juhl D, Baylis SA, Blümel J, Görg S, Hennig H. Seroprevalence and incidence of hepatitis E virus infection in German blood donors. Transfusion. 2014; 54:49–56.

50. Kaba M, Richet H, Ravaux I, Moreau J, Poizot-Martin I, Motte A, Nicolino-Brunet C, Dignat-George F, Ménard A, Dhiver C, Brouqui P, Colson P. Hepatitis E virus infection in patients infected with the human immunodeficiency virus. J Med Virol. 2011; 83:1704–1716.

51. Kamar N, Abravanel F, Garrouste C, Cardeau-Desangles I, Mansuy JM, Weclawiak H, Izopet J, Rostaing L. Three-month pegylated interferon-alpha-2a therapy for chronic hepatitis E virus infection in a haemodialysis patient. Nephrol Dial Transplant. 2010; 25:2792–2795.

52. Kamar N, Abravanel F, Selves J, Garrouste C, Esposito L, Lavayssière L, Cointault O, Ribes D, Cardeau I, Nogier MB, Mansuy JM, Muscari F, Peron JM, Izopet J, Rostaing L. Influence of immunosuppressive therapy on the natural history of genotype 3 hepatitis-E virus infection after organ transplantation. Transplantation. 2010; 89:353–360.

53. Kamar N, Garrouste C, Haagsma EB, Garrigue V, Pischke S, Chauvet C, Dumortier J, Cannesson A, Cassuto-Viguier E, Thervet E, Conti F, Lebray P, Dalton HR, Santella R, Kanaan N, Essig M, Mousson C, Radenne S, Roque-Afonso AM, Izopet J, Rostaing L. Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. Gastroenterology. 2011; 140:1481–1489.

54. Kamar N, Izopet J, Tripon S, Bismuth M, Hillaire S, Dumortier J, Radenne S, Coilly A, Garrigue V, D'Alteroche L, Buchler M, Couzi L, Lebray P, D'harancy S, Minello A, Hourmant M, Roque-Afonso AM, Abravanel F, Pol S, Rostaing L, Mallet V. Ribavirin for chronic hepatitis E virus infection in transplant recipients. N Engl J Med. 2014; 370:1111–1120.

55. Kamar N, Rostaing L, Abravanel F, Garrouste C, Esposito L, Cardeau-Desangles I, Mansuy JM, Selves J, Peron JM, Otal P, Muscari F, Izopet J. Pegylated interferon-alpha for treating chronic hepatitis E virus infection after liver transplantation. Clin Infect Dis. 2010; 50:e30–e33.

56. Kamar N, Rostaing L, Abravanel F, Garrouste C, Lhomme S, Esposito L, Basse G, Cointault O, Ribes D, Nogier MB, Alric L, Peron JM, Izopet J. Ribavirin therapy inhibits viral replication on patients with chronic hepatitis e virus infection. Gastroenterology. 2010; 139:1612–1618.

57. Kar P, Jilani N, Husain SA, Pasha ST, Anand R, Rai A, Das BC. Does hepatitis E viral load and genotypes influence the final outcome of acute liver failure during pregnancy? Am J Gastroenterol. 2008; 103:2495–2501.

58. Kasorndorkbua C, Thacker BJ, Halbur PG, Guenette DK, Buitenwerf RM, Royer RL, Meng XJ. Experimental infection of pregnant gilts with swine hepatitis E virus. Can J Vet Res. 2003; 67:303–306.

59. Kim YM, Jeong SH, Kim JY, Song JC, Lee JH, Kim JW, Yun H, Kim JS. The first case of genotype 4 hepatitis E related to wild boar in South Korea. J Clin Virol. 2011; 50:253–256.

60. Koizumi Y, Isoda N, Sato Y, Iwaki T, Ono K, Ido K, Sugano K, Takahashi M, Nishizawa T, Okamoto H. Infection of a Japanese patient by genotype 4 hepatitis E virus while traveling in Vietnam. J Clin Microbiol. 2004; 42:3883–3885.

61. Koning L, Pas SD, de Man RA, Balk AHMM, de Knegt RJ, ten Kate FJ, Osterhaus ADME, van der Eijk AA. Clinical implications of chronic hepatitis E virus infection in heart transplant recipients. J Heart Lung Transplant. 2013; 32:78–85.

62. Krumbholz A, Mohn U, Lange J, Motz M, Wenzel JJ, Jilg W, Walther M, Straube E, Wutzler P, Zell R. Prevalence of hepatitis E virus-specific antibodies in humans with occupational exposure to pigs. Med Microbiol Immunol. 2012; 201:239–244.

63. Kumar A, Beniwal M, Kar P, Sharma JB, Murthy NS. Hepatitis E in pregnancy. Int J Gynaecol Obstet. 2004; 85:240–244.

64. Kumar S, Subhadra S, Singh B, Panda BK. Hepatitis E virus: the current scenario. Int J Infect Dis. 2013; 17:e228–e233.

65. Kwon HM, Sung HW, Meng XJ. Serological prevalence, genetic identification, and characterization of the first strains of avian hepatitis E virus from chickens in Korea. Virus Genes. 2012; 45:237–245.

66. Lagler H, Poeppl W, Winkler H, Herkner H, Faas A, Mooseder G, Burgmann H. Hepatitis E virus seroprevalence in Austrian adults: a nationwide cross-sectional study among civilians and military professionals. PLoS One. 2014; 9:e87669.

67. La Rosa G, Muscillo M, Vennarucci VS, Garbuglia AR, La Scala P, Capobianchi MR. Hepatitis E virus in Italy: molecular analysis of travel-related and autochthonous cases. J Gen Virol. 2011; 92:1617–1626.

68. Lee JT, Shao PL, Chang LY, Xia NS, Chen PJ, Lu CY, Huang LM. Seroprevalence of hepatitis E virus infection among swine farmers and the general population in rural Taiwan. PLoS One. 2013; 8:e67180.

69. Li S, Tang X, Seetharaman J, Yang C, Gu Y, Zhang J, Du H, Shih JW, Hew CL, Sivaraman J, Xia N. Dimerization of hepatitis E virus capsid protein E2s domain is essential for virus-host interaction. PLoS Pathog. 2009; 5:e1000537.

70. Li SW, Zhang J, Li YM, Ou SH, Huang GY, He ZQ, Ge SX, Xian YL, Pang SQ, Ng MH, Xia NS. A bacterially expressed particulate hepatitis E vaccine: antigenicity, immunogenicity and protectivity on primates. Vaccine. 2005; 23:2893–2901.

71. Liang H, Chen J, Xie J, Sun L, Ji F, He S, Zheng Y, Liang C, Zhang G, Su S, Li S. Hepatitis E virus serosurvey among pet dogs and cats in several developed cities in China. PLoS One. 2014; 9:e98068.

72. Liang H, Su S, Deng S, Gu H, Ji F, Wang L, Liang C, Wang H, Zhang G. The prevalence of hepatitis E virus infections among swine, swine farmers and the general population in Guangdong Province, China. PLoS One. 2014; 9:e88106.

73. Liu P, Bu QN, Wang L, Han J, Du RJ, Lei YX, Ouyang YQ, Li J, Zhu YH, Lu FM, Zhuang H. Transmission of hepatitis E virus from rabbits to cynomolgus macaques. Emerg Infect Dis. 2013; 19:559–565.

74. Liu P, Du R, Wang L, Han J, Liu L, Zhang Y, Xia J, Lu F, Zhuang H. Management of hepatitis E virus (HEV) zoonotic transmission: protection of rabbits against HEV challenge following immunization with HEV 239 vaccine. PLoS One. 2014; 9:e87600.

75. Ma H, Zheng L, Liu Y, Zhao C, Harrison TJ, Ma Y, Sun S, Zhang J, Wang Y. Experimental infection of rabbits with rabbit and genotypes 1 and 4 hepatitis E viruses. PLoS One. 2010; 5:e9160.

76. Masclaux FG, Hotz P, Friedli D, Savova-Bianchi D, Oppliger A. High occurrence of hepatitis E virus in samples from wastewater treatment plants in Switzerland and comparison with other enteric viruses. Water Res. 2013; 47:5101–5109.

77. Matsubayashi K, Nagaoka Y, Sakata H, Sato S, Fukai K, Kato T, Takahashi K, Mishiro S, Imai M, Takeda N, Ikeda H. Transfusion-transmitted hepatitis E caused by apparently indigenous hepatitis E virus strain in Hokkaido, Japan. Transfusion. 2004; 44:934–940.

78. Meng J, Dai X, Chang JC, Lopareva E, Pillot J, Fields HA, Khudyakov YE. Identification and characterization of the neutralization epitope(s) of the hepatitis E virus. Virology. 2001; 288:203–211.

79. Meng XJ, Dea S, Engle RE, Friendship R, Lyoo YS, Sirinarumitr T, Urairong K, Wang D, Wong D, Yoo D, Zhang Y, Purcell RH, Emerson SU. Prevalence of antibodies to the hepatitis E virus in pigs from countries where hepatitis E is common or is rare in the human population. J Med Virol. 1999; 59:297–302.

80. Meng XJ, Halbur PG, Shapiro MS, Govindarajan S, Bruna JD, Mushahwar IK, Purcell RH, Emerson SU. Genetic and experimental evidence for cross-species infection by swine hepatitis E virus. J Virol. 1998; 72:9714–9721.

81. Meng XJ, Purcell RH, Halbur PG, Lehman JR, Webb DM, Tsareva TS, Haynes JS, Thacker BJ, Emerson SU. A novel virus in swine is closely related to the human hepatitis E virus. Proc Natl Acad Sci U S A. 1997; 94:9860–9865.

82. Meng XJ, Wiseman B, Elvinger F, Guenette DK, Toth TE, Engle RE, Emerson SU, Purcell RH. Prevalence of antibodies to hepatitis E virus in veterinarians working with swine and in normal blood donors in the United States and other countries. J Clin Microbiol. 2002; 40:117–122.

83. Mirazo S, Ramos N, Mainardi V, Gerona S, Arbiza J. Transmission, diagnosis, and management of hepatitis E: an update. Hepat Med. 2014; 6:45–59.

84. Miyashita K, Kang JH, Saga A, Takahashi K, Shimamura T, Yasumoto A, Fukushima H, Sogabe S, Konishi K, Uchida T, Fujinaga A, Matsui T, Sakurai Y, Tsuji K, Maguchi H, Taniguchi M, Abe N, Fazle Akbar SM, Arai M, Mishiro S. Three cases of acute or fulminant hepatitis E caused by ingestion of pork meat and entrails in Hokkaido, Japan: zoonotic food-borne transmission of hepatitis E virus and public health concerns. Hepatol Res. 2012; 42:870–878.

85. Moal V, Legris T, Burtey S, Morange S, Purgus R, Dussol B, Garcia S, Motte A, Gérolami R, Berland Y, Colson P. Infection with hepatitis E virus in kidney transplant recipients in southeastern France. J Med Virol. 2013; 85:462–471.

86. Patra S, Kumar A, Trivedi SS, Puri M, Sarin SK. Maternal and fetal outcomes in pregnant women with acute hepatitis E virus infection. Ann Intern Med. 2007; 147:28–33.

87. Péron JM, Mansuy JM, Poirson H, Bureau C, Dupuis E, Alric L, Izopet J, Vinel JP. Hepatitis E is an autochthonous disease in industrialized countries: analysis of 23 patients in South-West France over a 13-month period and comparison with hepatitis A. Gastroenterol Clin Biol. 2006; 30:757–762.

88. Pina S, Jofre J, Emerson SU, Purcell RH, Girones R. Characterization of a strain of infectious hepatitis E virus isolated from sewage in an area where hepatitis E is not endemic. Appl Environ Microbiol. 1998; 64:4485–4488.

89. Pischke S, Suneetha PV, Baechlein C, Barg-Hock H, Heim A, Kamar N, Schlue J, Strassburg CP, Lehner F, Raupach R, Bremer B, Magerstedt P, Cornberg M, Seehusen F, Baumgaertner W, Klempnauer J, Izopet J, Manns MP, Grummer B, Wedemeyer H. Hepatitis E virus infection as a cause of graft hepatitis in liver transplant recipients. Liver Transpl. 2010; 16:74–82.

90. Preiss JC, Plentz A, Engelmann E, Schneider T, Jilg W, Zeitz M, Duchmann R. Autochthonous hepatitis E virus infection in Germany with sequence similarities to other European isolates. Infection. 2006; 34:173–175.

91. Renou C, Moreau X, Pariente A, Cadranel JF, Maringe E, Morin T, Causse X, Payen JL, Izopet J, Nicand E, Bourlière M, Penaranda G, Hardwigsen J, Gerolami R, Péron JM, Pavio N. ANGH, France. A national survey of acute hepatitis E in France. Aliment Pharmacol Ther. 2008; 27:1086–1093.

92. Reuter G, Fodor D, Forgách P, Kátai A, Szucs G. Characterization and zoonotic potential of endemic hepatitis E virus (HEV) strains in humans and animals in Hungary. J Clin Virol. 2009; 44:277–281.

93. Riveiro-Barciela M, Buti M, Homs M, Campos-Varela I, Cantarell C, Crespo M, Castells L, Tabernero D, Quer J, Esteban R, Rodriguez-Frías F. Cirrhosis, liver transplantation and HIV infection are risk factors associated with hepatitis E virus infection. PLoS One. 2014; 9:e103028.

94. Robinson RA, Burgess WH, Emerson SU, Leibowitz RS, Sosnovtseva SA, Tsarev S, Purcell RH. Structural characterization of recombinant hepatitis E virus ORF2 proteins in baculovirus-infected insect cells. Protein Expr Purif. 1998; 12:75–84.

95. Safary A. Perspectives of vaccination against hepatitis E. Intervirology. 2001; 44:162–166.

96. Sanford BJ, Dryman BA, Huang YW, Feagins AR, Leroith T, Meng XJ. Prior infection of pigs with a genotype 3 swine hepatitis E virus (HEV) protects against subsequent challenges with homologous and heterologous genotypes 3 and 4 human HEV. Virus Res. 2011; 159:17–22.

97. Sanford BJ, Emerson SU, Purcell RH, Engle RE, Dryman BA, Cecere TE, Buechner-Maxwell V, Sponenberg DP, Meng XJ. Serological evidence for a hepatitis E virus-related agent in goats in the United States. Transbound Emerg Dis. 2013; 60:538–545.

98. Sanford BJ, Opriessnig T, Kenney SP, Dryman BA, Córdoba L, Meng XJ. Assessment of the cross-protective capability of recombinant capsid proteins derived from pig, rat, and avian hepatitis E viruses (HEV) against challenge with a genotype 3 HEV in pigs. Vaccine. 2012; 30:6249–6255.

99. Schofield DJ, Glamann J, Emerson SU, Purcell RH. Identification by phage display and characterization of two neutralizing chimpanzee monoclonal antibodies to the hepatitis E virus capsid protein. J Virol. 2000; 74:5548–5555.

100. Shrestha MP, Scott RM, Joshi DM, Mammen MP Jr, Thapa GB, Thapa N, Myint KS, Fourneau M, Kuschner RA, Shrestha SK, David MP, Seriwatana J, Vaughn DW, Safary A, Endy TP, Innis BL. Safety and efficacy of a recombinant hepatitis E vaccine. N Engl J Med. 2007; 356:895–903.

101. Shuval H. Estimating the global burden of thalassogenic diseases: human infectious diseases caused by wastewater pollution of the marine environment. J Water Health. 2003; 1:53–64.

102. Smith DB, Simmonds P, Jameel S. International Committee on Taxonomy of Viruses Hepeviridae Study Group. Emerson SU, Harrison TJ, Meng XJ, Okamoto H, Van der Poel WHM, Purdy MA. Consensus proposals for classification of the family Hepeviridae. J Gen Virol. 2014; 95:2223–2232.

103. Song YJ, Jeong HJ, Kim YJ, Lee SW, Lee JB, Park SY, Song CS, Park HM, Choi IS. Analysis of complete genome sequences of swine hepatitis E virus and possible risk factors for transmission of HEV to humans in Korea. J Med Virol. 2010; 82:583–591.

104. Stoszek SK, Abdel-Hamid M, Saleh DA, El Kafrawy S, Narooz S, Hawash Y, Shebl FM, El Daly M, Said A, Kassem E, Mikhail N, Engle RE, Sayed M, Sharaf S, Fix AD, Emerson SU, Purcell RH, Strickland GT. High prevalence of hepatitis E antibodies in pregnant Egyptian women. Trans R Soc Trop Med Hyg. 2006; 100:95–101.

105. Takahashi K, Kitajima N, Abe N, Mishiro S. Complete or near-complete nucleotide sequences of hepatitis E virus genome recovered from a wild boar, a deer, and four patients who ate the deer. Virology. 2004; 330:501–505.

106. Takeda H, Matsubayashi K, Sakata H, Sato S, Kato T, Hino S, Tadokoro K, Ikeda H. A nationwide survey for prevalence of hepatitis E virus antibody in qualified blood donors in Japan. Vox Sang. 2010; 99:307–313.

107. Tam AW, Smith MM, Guerra ME, Huang CC, Bradley DW, Fry KE, Reyes GR. Hepatitis E virus (HEV): molecular cloning and sequencing of the full-length viral genome. Virology. 1991; 185:120–131.

108. Tamura A, Shimizu YK, Tanaka T, Kuroda K, Arakawa Y, Takahashi K, Mishiro S, Shimizu K, Moriyama M. Persistent infection of hepatitis E virus transmitted by blood transfusion in a patient with T-cell lymphoma. Hepatol Res. 2007; 37:113–120.

109. Taniguchi M, Kim SR, Mishiro S, Takahashi K, Shin MH, Yun H, Park MS, Li ZM, Kim MK, Fang J, Hayashi Y. Epidemiology of hepatitis E in Northeastern China, South Korea and Japan. J Infect. 2009; 58:232–237.

110. Tsarev SA, Tsareva TS, Emerson SU, Govindarajan S, Shapiro M, Gerin JL, Purcell RH. Recombinant vaccine against hepatitis E: dose response and protection against heterologous challenge. Vaccine. 1997; 15:1834–1838.

111. Wang Y, Zhou X, Debing Y, Chen K, Van Der Laan LJW, Neyts J, Janssen HLA, Metselaar HJ, Peppelenbosch MP, Pan Q. Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus. Gastroenterology. 2014; 146:1775–1783.

112. Wei M, Zhang X, Yu H, Tang ZM, Wang K, Li Z, Zheng Z, Li S, Zhang J, Xia N, Zhao Q. Bacteria expressed hepatitis E virus capsid proteins maintain virion-like epitopes. Vaccine. 2014; 32:2859–2865.

113. Widén F, Sundqvist L, Matyi-Toth A, Metreveli G, Belák S, Hallgren G, Norder H. Molecular epidemiology of hepatitis E virus in humans, pigs and wild boars in Sweden. Epidemiol Infect. 2011; 139:361–371.

114. Wu T, Li SW, Zhang J, Ng MH, Xia NS, Zhao Q. Hepatitis E vaccine development: a 14 year odyssey. Hum Vaccin Immunother. 2012; 8:823–827.

115. Wu T, Zhu FC, Huang SJ, Zhang XF, Wang ZZ, Zhang J, Xia NS. Safety of the hepatitis E vaccine for pregnant women: a preliminary analysis. Hepatology. 2012; 55:2038.

116. Xia J, Liu L, Wang L, Zhang Y, Zeng H, Liu P, Zou Q, Wang L, Zhuang H. Experimental infection of pregnant rabbits with hepatitis E virus demonstrating high mortality and vertical transmission. J Viral Hepat. 2015; 22:850–857.

117. Xia NS, Zhang J, Zheng YJ, Ge SX, Ye XZ, Ou SH. Transfusion of plasma from a blood donor induced hepatitis E in rhesus monkey. Vox Sang. 2004; 86:45–47.

118. Xu C, Wang RY, Schechterly CA, Ge S, Shih JW, Xia NS, Luban NL, Alter HJ. An assessment of hepatitis E virus (HEV) in US blood donors and recipients: no detectable HEV RNA in 1939 donors tested and no evidence for HEV transmission to 362 prospectively followed recipients. Transfusion. 2013; 53:2505–2511.

119. Yamashita T, Mori Y, Miyazaki N, Cheng RH, Yoshimura M, Unno H, Shima R, Moriishi K, Tsukihara T, Li TC, Takeda N, Miyamura T, Matsuura Y. Biological and immunological characteristics of hepatitis E virus-like particles based on the crystal structure. Proc Natl Acad Sci U S A. 2009; 106:12986–12991.

120. Yoon Y, Jeong HS, Yun H, Lee H, Hwang YS, Park B, Lee CJ, Lee S, Hyeon JY. Hepatitis E virus (HEV) seroprevalence in the general population of the Republic of Korea in 2007-2009: a nationwide cross-sectional study. BMC Infect Dis. 2014; 14:517.

121. Zhao C, Ma Z, Harrison TJ, Feng R, Zhang C, Qiao Z, Fan J, Ma H, Li M, Song A, Wang Y. A novel genotype of hepatitis E virus prevalent among farmed rabbits in China. J Med Virol. 2009; 81:1371–1379.

122. Zhu FC, Zhang J, Zhang XF, Zhou C, Wang ZZ, Huang SJ, Wang H, Yang CL, Jiang HM, Cai JP, Wang YJ, Ai X, Hu YM, Tang Q, Yao X, Yan Q, Xian YL, Wu T, Li YM, Miao J, Ng MH, Shih JW, Xia NS. Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial. Lancet. 2010; 376:895–902.