The Re-Emergence of Hepatitis E Virus in Europe and Vaccine Development

Hepatitis E virus (HEV) is one of the leading causes of acute viral hepatitis. Transmission of HEV mainly occurs via the fecal-oral route (ingesting contaminated water or food) or by contact with infected animals and their raw meat products. Some animals, such as pigs, wild boars, sheep, goats, rabbits, camels, rats, etc., are natural reservoirs of HEV, which places people in close contact with them at increased risk of HEV disease. Although hepatitis E is a self-limiting infection, it could also lead to severe illness, particularly among pregnant women, or chronic infection in immunocompromised people. A growing number of studies point out that HEV can be classified as a re-emerging virus in developed countries. Preventative efforts are needed to reduce the incidence of acute and chronic hepatitis E in non-endemic and endemic countries. There is a recombinant HEV vaccine, but it is approved for use and commercially available only in China and Pakistan. However, further studies are needed to demonstrate the necessity of applying a preventive vaccine and to create conditions for reducing the spread of HEV. This review emphasizes the hepatitis E virus and its importance for public health in Europe, the methods of virus transmission and treatment, and summarizes the latest studies on HEV vaccine development.

[1]  J. Pawlotsky,et al.  Orthohepevirus C hepatitis, an underdiagnosed disease? , 2023, Journal of hepatology.

[2]  M. Tambuwala,et al.  The Plant Viruses and Molecular Farming: How Beneficial They Might Be for Human and Animal Health? , 2023, International journal of molecular sciences.

[3]  N. Ravin,et al.  High-Yield Production of Chimeric Hepatitis E Virus-Like Particles Bearing the M2e Influenza Epitope and Receptor Binding Domain of SARS-CoV-2 in Plants Using Viral Vectors , 2022, International journal of molecular sciences.

[4]  N. Ravin,et al.  Rapid Transient Expression of Receptor-Binding Domain of SARS-CoV-2 and the Conserved M2e Peptide of Influenza A Virus Linked to Flagellin in Nicotiana benthamiana Plants Using Self-Replicating Viral Vector , 2022, Plants.

[5]  V. Martella,et al.  Current Knowledge of Hepatitis E Virus (HEV) Epidemiology in Ruminants , 2022, Pathogens.

[6]  M. Purdy,et al.  ICTV Virus Taxonomy Profile: Hepeviridae 2022. , 2022, The Journal of general virology.

[7]  M. Groschup,et al.  Co-Circulation of Different Hepatitis E Virus Genotype 3 Subtypes in Pigs and Wild Boar in North-East Germany, 2019 , 2022, Pathogens.

[8]  A. Qin,et al.  Novel Pegylated Interferon for the Treatment of Chronic Viral Hepatitis , 2022, Viruses.

[9]  R. D. de Man,et al.  Chronic hepatitis E: advancing research and patient care. , 2022, Journal of hepatology.

[10]  Wenhai Yu,et al.  Rat Hepatitis E virus is a potential zoonotic pathogen to humans. , 2022, Journal of hepatology.

[11]  N. Pyrsopoulos,et al.  Hepatitis E in immunocompromised individuals , 2022, World journal of hepatology.

[12]  G. Lomonossoff,et al.  Plant‐based expression and characterization of SARS‐CoV‐2 virus‐like particles presenting a native spike protein , 2022, Plant biotechnology journal.

[13]  J. Meng,et al.  Efficient production and characterization of immunogenic HEV-PCV2 chimeric virus-like particles. , 2022, Veterinary microbiology.

[14]  J. Hübschen,et al.  Prevalence of hepatitis E virus antibodies in cattle in Burkina Faso associated with swine mixed farming , 2022, Journal of veterinary science.

[15]  J. Pineda,et al.  Orthohepevirus C infection as an emerging cause of acute hepatitis in Spain: first report in Europe. , 2022, Journal of hepatology.

[16]  M. Muramatsu,et al.  Experimental Cross-Species Transmission of Rat Hepatitis E Virus to Rhesus and Cynomolgus Monkeys , 2022, Viruses.

[17]  A. Andonov,et al.  Plant-Derived Recombinant Vaccines against Zoonotic Viruses , 2022, Life.

[18]  D. Todt,et al.  Beyond the Usual Suspects: Hepatitis E Virus and Its Implications in Hepatocellular Carcinoma , 2021, Cancers.

[19]  A. Guercio,et al.  Hepatitis E Virus seroprevalence among cows in a rural area of southern Italy , 2021, Veterinarski arhiv.

[20]  N. Ravin,et al.  Development and Optimization of an Enzyme Immunoassay to Detect Serum Antibodies against the Hepatitis E Virus in Pigs, Using Plant-Derived ORF2 Recombinant Protein , 2021, Vaccines.

[21]  Meifen Li,et al.  Immunological Manifestations of Hepatitis E-Associated Acute and Chronic Liver Failure and Its Regulatory Mechanisms , 2021, Frontiers in Medicine.

[22]  A. Mrzljak,et al.  Hepatitis E virus in professionally exposed: A reason for concern? , 2021, World journal of hepatology.

[23]  M. Bortolanza,et al.  Extrahepatic manifestations related to hepatitis E virus infection and their triggering mechanisms. , 2021, The Journal of infection.

[24]  Yong-Lin Yang,et al.  Open reading frame 3 protein of hepatitis E virus: Multi-function protein with endless potential , 2021, World journal of gastroenterology.

[25]  Marc‐André D'Aoust,et al.  Phase 1 randomized trial of a plant-derived virus-like particle vaccine for COVID-19 , 2021, Nature Medicine.

[26]  I. Tsachev,et al.  Seroprevalence of Hepatitis E Virus Infection among Blood Donors in Bulgaria , 2021, Viruses.

[27]  I. Tsachev,et al.  Seroprevalence of Hepatitis E Virus Infection Among Wild Boars in Western Bulgaria. , 2021, Vector borne and zoonotic diseases.

[28]  C. Yip,et al.  Multimodal investigation of rat hepatitis E virus antigenicity: implications for infection, diagnostics, and vaccine efficacy. , 2021, Journal of hepatology.

[29]  S. Schillberg,et al.  Plant molecular farming for the production of valuable proteins - Critical evaluation of achievements and future challenges. , 2021, Journal of plant physiology.

[30]  G. Lomonossoff,et al.  Efficient Production of Chimeric Hepatitis B Virus-Like Particles Bearing an Epitope of Hepatitis E Virus Capsid by Transient Expression in Nicotiana benthamiana , 2021, Life.

[31]  R. Girones,et al.  Unveiling Viruses Associated with Gastroenteritis Using a Metagenomics Approach , 2020, Viruses.

[32]  S. Sridhar,et al.  Hepatitis E virus infection and its associated adverse feto-maternal outcomes among pregnant women in Qinhuangdao, China , 2020, The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians.

[33]  T. Vesikari,et al.  Efficacy, immunogenicity, and safety of a plant-derived, quadrivalent, virus-like particle influenza vaccine in adults (18–64 years) and older adults (≥65 years): two multicentre, randomised phase 3 trials , 2020, The Lancet.

[34]  A. Aslan,et al.  Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment , 2020, World journal of gastroenterology.

[35]  N. Ravin,et al.  A plant-based transient expression system for the rapid production of highly immunogenic Hepatitis E virus-like particles , 2020, Biotechnology letters.

[36]  I. Minkov,et al.  Increasing Hepatitis E Virus Seroprevalence in Domestic Pigs and Wild Boar in Bulgaria , 2020, Animals : an open access journal from MDPI.

[37]  X. Meng,et al.  Hepatitis E virus: host tropism and zoonotic infection. , 2020, Current opinion in microbiology.

[38]  J. Meng,et al.  Design and development of a chimeric vaccine candidate against zoonotic hepatitis E and foot-and-mouth disease , 2020, Microbial Cell Factories.

[39]  M. Peppelenbosch,et al.  The global epidemiology of hepatitis E virus infection: A systematic review and meta‐analysis , 2020, Liver international : official journal of the International Association for the Study of the Liver.

[40]  Xīnglóu Yáng,et al.  Orthohepevirus C: An Expanding Species of Emerging Hepatitis E Virus Variants , 2020, Pathogens.

[41]  I. Jacobson,et al.  Hepatitis E Virus Infection in the United States: Current Understanding of the Prevalence and Significance in the Liver Transplant Patient Population and Proposed Diagnostic and Treatment Strategies , 2020, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[42]  Manidipa Banerjee,et al.  Expression, Purification and Characterization of the Hepatitis E Virus Like-Particles in the Pichia pastoris , 2020, Frontiers in Microbiology.

[43]  Prashanth Rawla,et al.  A Systematic Review of the Extra-Hepatic Manifestations of Hepatitis E Virus Infection , 2020, Medical sciences.

[44]  O. Tsang,et al.  Transmission of Rat Hepatitis E Virus Infection to Humans in Hong Kong: A Clinical and Epidemiological Analysis , 2020, Hepatology.

[45]  C. L. Heffron,et al.  The U-Rich Untranslated Region of the Hepatitis E Virus Induces Differential Type I and Type III Interferon Responses in a Host Cell-Dependent Manner , 2020, mBio.

[46]  Kotsev Stanislav,et al.  Spread of Hepatitis E Viral Infection among Hemodialysis Patients in Pazardzhik District, Bulgaria , 2020, International Journal of Current Microbiology and Applied Sciences.

[47]  N. Ravin,et al.  Rapid High-Yield Transient Expression of Swine Hepatitis E ORF2 Capsid Proteins in Nicotiana benthamiana Plants and Production of Chimeric Hepatitis E Virus-Like Particles Bearing the M2e Influenza Epitope , 2019, Plants.

[48]  J. Izopet,et al.  Hepatitis E virus infections in Europe. , 2019, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[49]  R. Johne,et al.  No Evidence of Hepatitis E Virus Infection in Farmed Deer in Germany , 2019, Food and Environmental Virology.

[50]  D. Christodoulou,et al.  Extrahepatic manifestations of hepatitis E virus: An overview , 2019, Clinical and molecular hepatology.

[51]  I. Di Bartolo,et al.  Detection of hepatitis E virus RNA in rats caught in pig farms from Northern Italy , 2019, Zoonoses and public health.

[52]  M. Manns,et al.  Hepatitis E Virus (HEV)-Specific T Cell Receptor Cross-Recognition: Implications for Immunotherapy , 2019, Front. Immunol..

[53]  A. Andonov,et al.  Rat hepatitis E virus linked to severe acute hepatitis in an immunocompetent patient. , 2019, The Journal of infectious diseases.

[54]  T. Nishizawa,et al.  Screening of novel drugs for inhibiting hepatitis E virus replication. , 2019, Journal of virological methods.

[55]  V. Savić,et al.  Epidemiology of hepatitis E in South-East Europe in the "One Health" concept , 2019, World journal of gastroenterology.

[56]  A. Lohse,et al.  The Clinical Perspective on Hepatitis E , 2019, Viruses.

[57]  N. Kamar,et al.  Acute and Persistent Hepatitis E Virus Genotype 3 and 4 Infection: Clinical Features, Pathogenesis, and Treatment. , 2019, Cold Spring Harbor perspectives in medicine.

[58]  D. Glebe,et al.  Why all blood donations should be tested for hepatitis E virus (HEV) , 2019, BMC Infectious Diseases.

[59]  S. P. Kenney,et al.  The Current Host Range of Hepatitis E Viruses , 2019, Viruses.

[60]  D. Semela,et al.  Rabbit HEV in immunosuppressed patients with hepatitis E acquired in Switzerland. , 2019, Journal of hepatology.

[61]  K. Watt,et al.  Sofosbuvir and Ribavirin Eradication of Refractory Hepatitis E in an Immunosuppressed Kidney Transplant Recipient , 2019, Hepatology.

[62]  S. Vasudevan,et al.  Antiviral Candidates for Treating Hepatitis E Virus Infection , 2019, Antimicrobial Agents and Chemotherapy.

[63]  S. Berger,et al.  Transmission of hepatitis E virus by water: An issue still pending in industrialized countries. , 2019, Water research.

[64]  N. O'Flaherty,et al.  Blood Donor Screening for Hepatitis E Virus in the European Union , 2019, Transfusion Medicine and Hemotherapy.

[65]  A. C. Mulder,et al.  HEVnet: a One Health, collaborative, interdisciplinary network and sequence data repository for enhanced hepatitis E virus molecular typing, characterisation and epidemiological investigations , 2019, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[66]  I. Ushiro-Lumb,et al.  Hepatitis E virus in blood donors in England, 2016 to 2017: from selective to universal screening , 2019, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[67]  J. Denner Hepatitis E virus (HEV)—The Future , 2019, Viruses.

[68]  M. Groschup,et al.  Different Outcomes of Experimental Hepatitis E Virus Infection in Diverse Mouse Strains, Wistar Rats, and Rabbits , 2018, Viruses.

[69]  P. Woo,et al.  Rat Hepatitis E Virus as Cause of Persistent Hepatitis after Liver Transplant , 2018, Emerging infectious diseases.

[70]  I. Bekeredjian-Ding,et al.  Impact of hepatitis E virus testing on the safety of blood components in Germany – results of a simulation study , 2018, Vox sanguinis.

[71]  J. Dubuisson,et al.  New insights into the ORF2 capsid protein, a key player of the hepatitis E virus lifecycle , 2018, bioRxiv.

[72]  S. De Vliegher,et al.  Absence of zoonotic hepatitis E virus infection in Flemish dairy cows. , 2018, International journal of food microbiology.

[73]  D. Todt,et al.  The natural compound silvestrol inhibits hepatitis E virus (HEV) replication in vitro and in vivo , 2018, Antiviral Research.

[74]  A. Zvirbliene,et al.  Detection of rat hepatitis E virus, but not human pathogenic hepatitis E virus genotype 1-4 infections in wild rats from Lithuania. , 2018, Veterinary microbiology.

[75]  M. Groschup,et al.  Hepatitis E virus in feral rabbits along a rural-urban transect in Central Germany. , 2018, Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases.

[76]  K. Stark,et al.  Hepatitis E virus seroprevalence, seroincidence and seroreversion in the German adult population , 2018, Journal of viral hepatitis.

[77]  R. Charrel,et al.  Hepatitis E in High-Income Countries: What Do We Know? And What Are the Knowledge Gaps? , 2018, Viruses.

[78]  C. Walker,et al.  Origin, antigenicity, and function of a secreted form of ORF2 in hepatitis E virus infection , 2018, Proceedings of the National Academy of Sciences.

[79]  Nan Wang,et al.  Characterization of capsid protein (p495) of hepatitis E virus expressed in Escherichia coli and assembling into particles in vitro. , 2018, Vaccine.

[80]  M. Michalak,et al.  Comparative Seroprevalence of Hepatitis A And E Viruses in Blood Donors from Wielkopolska Region, West-Central Poland , 2018 .

[81]  J. Mesquita,et al.  Hepatitis E Virus Genotype 1 Cases Imported to Portugal from India, 2016. , 2018, Annals of hepatology.

[82]  Jingmin Zhao,et al.  Chronic Hepatitis E in a Renal Transplant Recipient: The First Report of Genotype 4 Hepatitis E Virus Caused Chronic Infection in Organ Recipient. , 2018, Gastroenterology.

[83]  C. Yip,et al.  Genotype 4 hepatitis E virus is a cause of chronic hepatitis in renal transplant recipients in Hong Kong , 2018, Journal of viral hepatitis.

[84]  C. Knabbe,et al.  Transfusion-Transmitted Hepatitis E: NAT Screening of Blood Donations and Infectious Dose , 2018, Front. Med..

[85]  Sukhen Das Mandal,et al.  Host-Virus Protein Interaction Network Reveals the Involvement of Multiple Host Processes in the Life Cycle of Hepatitis E Virus , 2018, mSystems.

[86]  N. Gardinali,et al.  Hepatitis E: Update on Prevention and Control , 2018, BioMed research international.

[87]  M. Michalak,et al.  Comparative Seroprevalence of Hepatitis A And E Viruses in Blood Donors from Wielkopolska Region, West-Central Poland , 2018, Polish journal of microbiology.

[88]  Lin Liu,et al.  An overview: Rabbit hepatitis E virus (HEV) and rabbit providing an animal model for HEV study , 2018, Reviews in medical virology.

[89]  M. Groschup,et al.  Hepatitis E virus in wild rabbits and European brown hares in Germany , 2017, Zoonoses and public health.

[90]  N. Pavio,et al.  Recent knowledge on hepatitis E virus in Suidae reservoirs and transmission routes to human , 2017, Veterinary Research.

[91]  M. Purdy,et al.  ICTV Virus Taxonomy Profile: Hepeviridae , 2017, The Journal of general virology.

[92]  T. Nishizawa,et al.  Characterization of the Quasi-Enveloped Hepatitis E Virus Particles Released by the Cellular Exosomal Pathway , 2017, Journal of Virology.

[93]  J. Meng,et al.  A phase 1 randomized open-label clinical study to evaluate the safety and tolerability of a novel recombinant hepatitis E vaccine. , 2017, Vaccine.

[94]  M. Groschup,et al.  Detection of rat hepatitis E virus in wild Norway rats (Rattus norvegicus) and Black rats (Rattus rattus) from 11 European countries. , 2017, Veterinary microbiology.

[95]  Jinyuan Wu,et al.  A Recombinant HAV Expressing a Neutralization Epitope of HEV Induces Immune Response against HAV and HEV in Mice , 2017, Viruses.

[96]  Milan Surjit,et al.  Zinc Salts Block Hepatitis E Virus Replication by Inhibiting the Activity of Viral RNA-Dependent RNA Polymerase , 2017, Journal of Virology.

[97]  J. Izopet,et al.  Rabbit Hepatitis E Virus Infections in Humans, France , 2017, Emerging infectious diseases.

[98]  L. Tavoschi,et al.  Hepatitis E virus infection in Europe: surveillance and descriptive epidemiology of confirmed cases, 2005 to 2015 , 2017, Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin.

[99]  E. Zhou,et al.  Evaluation of recombinant Chinese avian hepatitis E virus (CaHEV) ORF2 and ORF3 proteins for protection of chickens against CaHEV infection. , 2017, Vaccine.

[100]  M. Andraud,et al.  From the epidemiology of hepatitis E virus (HEV) within the swine reservoir to public health risk mitigation strategies: a comprehensive review , 2017, Veterinary Research.

[101]  G. Tantillo,et al.  Occurrence of hepatitis A and E and norovirus GI and GII in ready-to-eat vegetables in Italy. , 2017, International journal of food microbiology.

[102]  A. Lohse,et al.  Hepatitis E virus: Infection beyond the liver? , 2017, Journal of hepatology.

[103]  C. Jiang,et al.  [Fermentation, purification and immunogenicity evaluation of hepatitis E virus-like particles expressed in Hansenula polymorpha]. , 2017, Sheng wu gong cheng xue bao = Chinese journal of biotechnology.

[104]  G. Lomonossoff,et al.  Detection of Serum Antibodies to Hepatitis E Virus Based on HEV Genotype 3 ORF2 Capsid Protein Expressed in Nicotiana benthamiana , 2017, Annals of laboratory medicine.

[105]  M. Janssen,et al.  Cost‐effectiveness of the screening of blood donations for hepatitis E virus in the Netherlands , 2017, Transfusion.

[106]  M. Buti,et al.  Red blood cell transfusion‐transmitted acute hepatitis E in an immunocompetent subject in Europe: a case report , 2017, Transfusion.

[107]  Q. Ding,et al.  Hepatitis E virus ORF3 is a functional ion channel required for release of infectious particles , 2017, Proceedings of the National Academy of Sciences.

[108]  U. Schotte,et al.  Hepatitis E Virus in Wild Boars and Spillover Infection in Red and Roe Deer, Germany, 2013–2015 , 2017, Emerging infectious diseases.

[109]  P. Becher,et al.  No evidence for zoonotic hepatitis E virus infection through dairy milk in Germany , 2017, Hepatology.

[110]  Liang Chen,et al.  Clinical features of acute hepatitis E super-infections on chronic hepatitis B , 2016, World journal of gastroenterology.

[111]  P. Woo,et al.  New Hepatitis E Virus Genotype in Bactrian Camels, Xinjiang, China, 2013 , 2016, Emerging infectious diseases.

[112]  N. Pavio,et al.  Zoonotic Hepatitis E Virus: Classification, Animal Reservoirs and Transmission Routes , 2016, Viruses.

[113]  K. Borgen,et al.  Hepatitis E in Norway: seroprevalence in humans and swine , 2016, Epidemiology and Infection.

[114]  Yanjin Zhang,et al.  Molecular Biology and Infection of Hepatitis E Virus , 2016, Front. Microbiol..

[115]  J. Mesquita,et al.  Hepatitis E virus subgenotypes 3i and 3f in wastewater of treatment plants of Portugal , 2016 .

[116]  A. Lohse,et al.  Hepatitis E Seroprevalence in Europe: A Meta-Analysis , 2016, Viruses.

[117]  Zhenglun Liang,et al.  Hepatitis E virus: Current epidemiology and vaccine , 2016, Human vaccines & immunotherapeutics.

[118]  S. Spencer,et al.  Detection of hepatitis E virus and other livestock-related pathogens in Iowa streams , 2016, Science of The Total Environment.

[119]  J. Izopet,et al.  Conventional and innate lymphocytes response at the acute phase of HEV infection in transplanted patients. , 2016, The Journal of infection.

[120]  J. Izopet,et al.  Detection of Hepatitis E Virus in Sewage After an Outbreak on a French Island , 2016, Food and Environmental Virology.

[121]  Matthias Filter,et al.  Thermal Stability of Hepatitis E Virus as Estimated by a Cell Culture Method , 2016, Applied and Environmental Microbiology.

[122]  Milan Surjit,et al.  Endoplasmic Reticulum Stress Induced Synthesis of a Novel Viral Factor Mediates Efficient Replication of Genotype-1 Hepatitis E Virus , 2016, PLoS pathogens.

[123]  P. Gallian,et al.  A nationwide survey of hepatitis E viral infection in French blood donors , 2016, Hepatology.

[124]  J. Meng,et al.  Immunogenicity difference between two hepatitis E vaccines derived from genotype 1 and 4. , 2016, Antiviral research.

[125]  F. Ruggeri,et al.  Serological survey of hepatitis E virus infection in farmed and pet rabbits in Italy , 2016, Archives of Virology.

[126]  Zongdi Feng,et al.  Distinct Entry Mechanisms for Nonenveloped and Quasi-Enveloped Hepatitis E Viruses , 2016, Journal of Virology.

[127]  Dianjun Cao,et al.  A trivalent vaccine candidate against hepatitis E virus, norovirus, and astrovirus. , 2016, Vaccine.

[128]  G. Lee,et al.  Chronic Infection With Camelid Hepatitis E Virus in a Liver Transplant Recipient Who Regularly Consumes Camel Meat and Milk. , 2016, Gastroenterology.

[129]  V. Vaillant,et al.  High Proportion of Asymptomatic Infections in an Outbreak of Hepatitis E Associated With a Spit-Roasted Piglet, France, 2013. , 2016, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[130]  Aijaz Ahmed,et al.  Hepatitis E virus infection in the liver transplant recipients: Clinical presentation and management. , 2016, World journal of hepatology.

[131]  P. Simmonds,et al.  Proposed reference sequences for hepatitis E virus subtypes. , 2016, The Journal of general virology.

[132]  A. Lasson,et al.  Diagnostic Performance of Five Assays for Anti-Hepatitis E Virus IgG and IgM in a Large Cohort Study , 2015, Journal of Clinical Microbiology.

[133]  L. Scobie,et al.  Hepatitis E virus in patients with decompensated chronic liver disease: a prospective UK/French study , 2015, Alimentary pharmacology & therapeutics.

[134]  Å. Lundkvist,et al.  Hepatitis E Virus in Domestic Pigs, Wild Boars, Pig Farm Workers, and Hunters in Estonia , 2015, Food and Environmental Virology.

[135]  R. Bruni,et al.  Hepatitis A and E Viruses in Wastewaters, in River Waters, and in Bivalve Molluscs in Italy , 2015, Food and Environmental Virology.

[136]  M. Myrmel,et al.  A 1-Year Quantitative Survey of Noro-, Adeno-, Human Boca-, and Hepatitis E Viruses in Raw and Secondarily Treated Sewage from Two Plants in Norway , 2015, Food and Environmental Virology.

[137]  Y. Yi,et al.  Enhanced Mucosal Immune Responses Induced by a Combined Candidate Mucosal Vaccine Based on Hepatitis A Virus and Hepatitis E Virus Structural Proteins Linked to Tuftsin , 2015, PloS one.

[138]  David G. Karlin,et al.  Sequence analysis reveals a conserved extension in the capping enzyme of the alphavirus supergroup, and a homologous domain in nodaviruses , 2015, Biology Direct.

[139]  Qinjian Zhao,et al.  The development of a recombinant hepatitis E vaccine HEV 239 , 2015, Human vaccines & immunotherapeutics.

[140]  Xiang‐Jin Meng,et al.  Zoonotic origin of hepatitis E. , 2015, Current opinion in virology.

[141]  M. Manns,et al.  Chronic hepatitis E virus infection beyond transplantation or human immunodeficiency virus infection , 2014, Hepatology.

[142]  Yanjin Zhang,et al.  Hepatitis E Virus Inhibits Type I Interferon Induction by ORF1 Products , 2014, Journal of Virology.

[143]  L. Rostaing,et al.  Characterization of the Polyproline Region of the Hepatitis E Virus in Immunocompromised Patients , 2014, Journal of Virology.

[144]  P. Simmonds,et al.  Consensus proposals for classification of the family Hepeviridae , 2014, The Journal of general virology.

[145]  L. Rostaing,et al.  Hepatitis E virus reinfections in solid-organ-transplant recipients can evolve into chronic infections. , 2014, The Journal of infectious diseases.

[146]  Shoujun Li,et al.  Hepatitis E Virus Serosurvey among Pet Dogs and Cats in Several Developed Cities in China , 2014, PloS one.

[147]  P. Woo,et al.  New Hepatitis E Virus Genotype in Camels, the Middle East , 2014, Emerging infectious diseases.

[148]  M. Peppelenbosch,et al.  Calcineurin inhibitors stimulate and mycophenolic acid inhibits replication of hepatitis E virus. , 2014, Gastroenterology.

[149]  A. Kamen,et al.  Development of a vectored vaccine against hepatitis E virus. , 2014, Vaccine.

[150]  T. Nishizawa,et al.  The membrane on the surface of hepatitis E virus particles is derived from the intracellular membrane and contains trans-Golgi network protein 2 , 2014, Archives of Virology.

[151]  K. Nelson,et al.  Fetal and neonatal health consequences of vertically transmitted hepatitis E virus infection. , 2014, The American journal of tropical medicine and hygiene.

[152]  J. Izopet,et al.  Hepatitis E: An emerging infection in high income countries. , 2014, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[153]  T. Shimizu,et al.  Chronic hepatitis E: a review of the literature , 2014, Journal of viral hepatitis.

[154]  J. Izopet,et al.  Hepatitis E Virus Infection , 2014, Clinical Microbiology Reviews.

[155]  Martin D'Agostino,et al.  Tracing enteric viruses in the European berry fruit supply chain. , 2013, International journal of food microbiology.

[156]  Danielle M. Yugo,et al.  Hepatitis E Virus: Foodborne, Waterborne and Zoonotic Transmission , 2013, International journal of environmental research and public health.

[157]  H. Cao,et al.  Influence of chronic HBV infection on superimposed acute hepatitis E. , 2013, World journal of gastroenterology.

[158]  H. Wedemeyer,et al.  Hepatitis E virus infection: multiple faces of an underestimated problem. , 2013, Journal of hepatology.

[159]  Bhupinder Singh,et al.  Hepatitis E virus: the current scenario. , 2013, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[160]  H. Te,et al.  Hepatitis E virus infection in a liver transplant recipient in the United States: a case report. , 2013, Transplantation proceedings.

[161]  Bernadette A. Thomas,et al.  Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010 , 2012, The Lancet.

[162]  Y. Takeuchi,et al.  Hepatitis E Virus Genotype 3 in Shellfish, United Kingdom , 2012, Emerging infectious diseases.

[163]  T. Opriessnig,et al.  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. , 2012, Vaccine.

[164]  N. Cook,et al.  Harmonised Investigation of the Occurrence of Human Enteric Viruses in the Leafy Green Vegetable Supply Chain in Three European Countries , 2012, Food and Environmental Virology.

[165]  U. Beuers,et al.  Chronic hepatitis E after solid organ transplantation. , 2012, The Netherlands journal of medicine.

[166]  J. Lack,et al.  Hepatitis E Virus Genotype 3 in Wild Rats, United States , 2012, Emerging infectious diseases.

[167]  M. Purdy Evolution of the Hepatitis E Virus Polyproline Region: Order from Disorder , 2012, Journal of Virology.

[168]  Qinjian Zhao,et al.  Hepatitis E vaccine development , 2012, Human vaccines & immunotherapeutics.

[169]  A. Singh,et al.  Hepatitis E Virus Infection Causing Isolated Fetal Ascites: A Case Report , 2012, Fetal Diagnosis and Therapy.

[170]  M. Manns,et al.  Pathogenesis and treatment of hepatitis e virus infection. , 2012, Gastroenterology.

[171]  M. Groschup,et al.  Seroprevalence study in forestry workers from eastern Germany using novel genotype 3- and rat hepatitis E virus-specific immunoglobulin G ELISAs , 2012, Medical Microbiology and Immunology.

[172]  Gretchen A. Stevens,et al.  The global burden of hepatitis E virus genotypes 1 and 2 in 2005 , 2012, Hepatology.

[173]  L. Rostaing,et al.  Hepatitis E Virus and the Kidney in Solid-Organ Transplant Patients , 2012, Transplantation.

[174]  R. Ulrich,et al.  Hepatitis E Virus in Pork Liver Sausage, France , 2012, Emerging infectious diseases.

[175]  B. Schlosser,et al.  Liver transplant from a donor with occult HEV infection induced chronic hepatitis and cirrhosis in the recipient. , 2012, Journal of hepatology.

[176]  J. Izopet,et al.  Hepatitis E Virus Antibodies in Blood Donors, France , 2011, Emerging infectious diseases.

[177]  Y. Matsuura,et al.  Structure of hepatitis E viral particle. , 2011, Virus research.

[178]  Yao-Wei Huang,et al.  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. , 2011, Virus research.

[179]  S. Yun,et al.  A novel member of the family Hepeviridae from cutthroat trout (Oncorhynchus clarkii). , 2011, Virus research.

[180]  J. Dumortier,et al.  Factors associated with chronic hepatitis in patients with hepatitis E virus infection who have received solid organ transplants. , 2011, Gastroenterology.

[181]  A Rajić,et al.  A systematic review/meta-analysis of primary research investigating swine, pork or pork products as a source of zoonotic hepatitis E virus , 2011, Epidemiology and Infection.

[182]  S. Baylis,et al.  Standardization of Hepatitis E Virus (HEV) Nucleic Acid Amplification Technique-Based Assays: an Initial Study To Evaluate a Panel of HEV Strains and Investigate Laboratory Performance , 2011, Journal of Clinical Microbiology.

[183]  S. Emerson,et al.  Cross-species infections of cultured cells by hepatitis E virus and discovery of an infectious virus–host recombinant , 2011, Proceedings of the National Academy of Sciences.

[184]  A. Lavazza,et al.  Prevalence of hepatitis E virus antibodies in pigs in Northern Italy , 2011, Infection ecology & epidemiology.

[185]  J. Segalés,et al.  Increasing Contact with Hepatitis E Virus in Red Deer, Spain , 2010, Emerging infectious diseases.

[186]  J. Segalés,et al.  Hepatitis E virus is highly prevalent in the Danish pig population. , 2010, Veterinary microbiology.

[187]  L. Rostaing,et al.  Ribavirin therapy inhibits viral replication on patients with chronic hepatitis e virus infection. , 2010, Gastroenterology.

[188]  J. Izopet,et al.  Hepatitis E virus excretion can be prolonged in patients with hematological malignancies. , 2010, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[189]  N. Xia,et al.  Efficacy and safety of a recombinant hepatitis E vaccine in healthy adults: a large-scale, randomised, double-blind placebo-controlled, phase 3 trial , 2010, The Lancet.

[190]  M. Bouwknegt,et al.  Seroprevalence and molecular detection of hepatitis E virus in wild boar and red deer in The Netherlands. , 2010, Journal of virological methods.

[191]  L. Xing,et al.  Structure of Hepatitis E Virion-sized Particle Reveals an RNA-dependent Viral Assembly Pathway* , 2010, The Journal of Biological Chemistry.

[192]  L. Rostaing,et al.  Three-month pegylated interferon-alpha-2a therapy for chronic hepatitis E virus infection in a haemodialysis patient. , 2010, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[193]  E. Thervet,et al.  Brief Communication: Case Reports of Ribavirin Treatment for Chronic Hepatitis E , 2010, Annals of Internal Medicine.

[194]  Alimuddin Zumla Mandell, Douglas, and Bennett's principles and practice of infectious diseases , 2010, The Lancet Infectious Diseases.

[195]  A. Zarei,et al.  Hepatitis E Virus Infection: A General Review with a Focus on Hemodialysis and Kidney Transplant Patients , 2010, American Journal of Nephrology.

[196]  L. Rostaing,et al.  Pegylated interferon-alpha for treating chronic hepatitis E virus infection after liver transplantation. , 2010, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[197]  X. Meng,et al.  Hepatitis E virus: animal reservoirs and zoonotic risk. , 2010, Veterinary microbiology.

[198]  R. Tedder,et al.  Persistent carriage of hepatitis E virus in patients with HIV infection. , 2009, The New England journal of medicine.

[199]  A. Walsh,et al.  Hepatitis E Outbreak on Cruise Ship , 2009, Emerging infectious diseases.

[200]  J. Echevarría,et al.  Imported and autochthonous hepatitis E virus strains in Spain , 2009, Journal of medical virology.

[201]  H. Vennema,et al.  Prevalence of hepatitis E virus infection in liver transplant recipients , 2009, Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society.

[202]  W. Kong,et al.  Immunogenicity and efficacy of a bacterially expressed HEV ORF3 peptide, assessed by experimental infection of primates , 2009, Archives of Virology.

[203]  T. Tsukihara,et al.  Biological and immunological characteristics of hepatitis E virus-like particles based on the crystal structure , 2009, Proceedings of the National Academy of Sciences.

[204]  S. Kamili,et al.  Clinical course and duration of viremia in vertically transmitted hepatitis E virus (HEV) infection in babies born to HEV‐infected mothers , 2009, Journal of viral hepatitis.

[205]  D. Melzer,et al.  National mortality rates from chronic liver disease and consumption of alcohol and pig meat , 2009, Epidemiology and Infection.

[206]  H. Mizuo,et al.  Development and Characterization of a Genotype 4 Hepatitis E Virus Cell Culture System Using a HE-JF5/15F Strain Recovered from a Fulminant Hepatitis Patient , 2009, Journal of Clinical Microbiology.

[207]  P. Colson,et al.  Hepatitis E virus as an emerging cause of chronic liver disease in organ transplant recipients. , 2009, Journal of hepatology.

[208]  K. Lole,et al.  Challenge studies in Rhesus monkeys immunized with candidate hepatitis E vaccines: DNA, DNA-prime-protein-boost and DNA-protein encapsulated in liposomes. , 2009, Vaccine.

[209]  U. Navaneethan,et al.  Hepatitis E and pregnancy: understanding the pathogenesis , 2008, Liver international : official journal of the International Association for the Study of the Liver.

[210]  M. Kumar,et al.  Hepatitis E virus as an etiology of acute exacerbation of previously unrecognized asymptomatic patients with hepatitis B virus‐related chronic liver disease , 2008, Journal of gastroenterology and hepatology.

[211]  H. Dalton,et al.  Autochthonous hepatitis E in Southwest England: a comparison with hepatitis A , 2008, European Journal of Clinical Microbiology & Infectious Diseases.

[212]  L. Rostaing,et al.  Hepatitis E virus and chronic hepatitis in organ-transplant recipients. , 2008, The New England journal of medicine.

[213]  P. Colson,et al.  Chronic hepatitis E with cirrhosis in a kidney-transplant recipient. , 2008, The New England journal of medicine.

[214]  S. Basu,et al.  Hepatitis E vaccine. , 2007, The New England journal of medicine.

[215]  K. Lole,et al.  Immunogenicity of candidate hepatitis E virus DNA vaccine expressing complete and truncated ORF2 in mice. , 2007, Vaccine.

[216]  N. Xia,et al.  Difference of T cell and B cell activation in two homologous proteins with similar antigenicity but great distinct immunogenicity. , 2007, Molecular immunology.

[217]  S. Hazeldine,et al.  Locally acquired hepatitis E in chronic liver disease , 2007, The Lancet.

[218]  D. Vaughn,et al.  Safety and efficacy of a recombinant hepatitis E vaccine. , 2007, The New England journal of medicine.

[219]  T. Opriessnig,et al.  Initiation at the Third In-Frame AUG Codon of Open Reading Frame 3 of the Hepatitis E Virus Is Essential for Viral Infectivity In Vivo , 2007, Journal of Virology.

[220]  J. Meng,et al.  [Expression, purification and immunogenicity of a novel hepatitis E virus-like particle]. , 2006, Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology.

[221]  C. Teo,et al.  Transfusion‐transmitted hepatitis E in a ‘nonhyperendemic’ country , 2006, Transfusion medicine.

[222]  E. Lam,et al.  A truncated hepatitis E virus ORF2 protein expressed in tobacco plastids is immunogenic in mice. , 2006, World journal of gastroenterology.

[223]  L. Xing,et al.  Essential Elements of the Capsid Protein for Self-Assembly into Empty Virus-Like Particles of Hepatitis E Virus , 2005, Journal of Virology.

[224]  J. Andrews U.S. Military Sponsored Vaccine Trials and La Resistance in Nepal , 2005, The American journal of bioethics : AJOB.

[225]  N. Xia,et al.  A bacterially expressed particulate hepatitis E vaccine: antigenicity, immunogenicity and protectivity on primates. , 2005, Vaccine.

[226]  T. Miyamura,et al.  Challenges in creating a vaccine to prevent hepatitis E. , 2005, Vaccine.

[227]  N. Xia,et al.  Mutational Analysis of Essential Interactions Involved in the Assembly of Hepatitis E Virus Capsid* , 2005, Journal of Biological Chemistry.

[228]  S. Emerson,et al.  Capped RNA Transcripts of Full-Length cDNA Clones of Swine Hepatitis E Virus Are Replication Competent When Transfected into Huh7 Cells and Infectious When Intrahepatically Inoculated into Pigs , 2005, Journal of Virology.

[229]  K. Masuko,et al.  Simultaneous Detection of Immunoglobulin A (IgA) and IgM Antibodies against Hepatitis E Virus (HEV) Is Highly Specific for Diagnosis of Acute HEV Infection , 2005, Journal of Clinical Microbiology.

[230]  Huub Schellekens,et al.  Structure-Immunogenicity Relationships of Therapeutic Proteins , 2004, Pharmaceutical Research.

[231]  N. S. Murthy,et al.  Hepatitis E in pregnancy , 2004 .

[232]  R. Aggarwal,et al.  Hepatitis E virus is responsible for decompensation of chronic liver disease in an endemic region. , 2004, Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology.

[233]  G. Kang,et al.  Hepatitis E superinfection produces severe decompensation in patients with chronic liver disease , 2004, Journal of gastroenterology and hepatology.

[234]  S. Kamili,et al.  Protective efficacy of hepatitis E virus DNA vaccine administered by gene gun in the cynomolgus macaque model of infection. , 2004, The Journal of infectious diseases.

[235]  T. Miyamura,et al.  Protection of cynomolgus monkeys against HEV infection by oral administration of recombinant hepatitis E virus-like particles. , 2004, Vaccine.

[236]  N. Xia,et al.  Expression of ORF2 partial gene of hepatitis E virus in tomatoes and immunoactivity of expression products. , 2003, World journal of gastroenterology.

[237]  Teresa Mitchell,et al.  Production of Complex Human Glycoproteins in Yeast , 2003, Science.

[238]  A. Kumar,et al.  Prevalence and severity of acute viral hepatitis and fulminant hepatitis during pregnancy: a prospective study from north India. , 2003, Indian journal of medical microbiology.

[239]  M. Shapiro,et al.  Pre-clinical immunogenicity and efficacy trial of a recombinant hepatitis E vaccine. , 2003, Vaccine.

[240]  N. Xia,et al.  [The immuno-protect study of a hepatitis E virus ORF2 peptide expressed in E. coli]. , 2003, Wei sheng wu xue bao = Acta microbiologica Sinica.

[241]  M. Khuroo,et al.  Aetiology, clinical course and outcome of sporadic acute viral hepatitis in pregnancy * , 2003, Journal of viral hepatitis.

[242]  S. Kamili,et al.  DNA vaccination against hepatitis E virus infection in cynomolgus macaques , 2002, Journal of gastroenterology and hepatology.

[243]  S. Hamid,et al.  Hepatitis E virus superinfection in patients with chronic liver disease , 2002, Hepatology.

[244]  S. Emerson,et al.  Immunogenicity and protective efficacy of a vaccine prepared from 53 kDa truncated hepatitis E virus capsid protein expressed in insect cells. , 2001, Vaccine.

[245]  Michael Ruogu Zhang,et al.  Recombinant hepatitis E virus genomes infectious for primates: Importance of capping and discovery of a cis-reactive element , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[246]  J. Meng,et al.  Identification and characterization of the neutralization epitope(s) of the hepatitis E virus. , 2001, Virology.

[247]  P. Auvinen,et al.  Virus-Specific mRNA Capping Enzyme Encoded by Hepatitis E Virus , 2001, Journal of Virology.

[248]  N. Xia,et al.  A bacterially expressed peptide prevents experimental infection of primates by the hepatitis E virus. , 2001, Vaccine.

[249]  A. Jain,et al.  Viral hepatitis during pregnancy , 2001, International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics.

[250]  S. Emerson,et al.  Identification by Phage Display and Characterization of Two Neutralizing Chimpanzee Monoclonal Antibodies to the Hepatitis E Virus Capsid Protein , 2000, Journal of Virology.

[251]  S. Emerson,et al.  Structural characterization of recombinant hepatitis E virus ORF2 proteins in baculovirus-infected insect cells. , 1998, Protein expression and purification.

[252]  S. Jacobson,et al.  Prevalence of antibodies to hepatitis E virus among hemodialysis patients in Sweden , 1998, Journal of medical virology.

[253]  T. Miyamura,et al.  Expression and self-assembly of empty virus-like particles of hepatitis E virus , 1997, Journal of virology.

[254]  A. W. Tam,et al.  Expression, characterization, and immunoreactivities of a soluble hepatitis E virus putative capsid protein species expressed in insect cells , 1997, Clinical and diagnostic laboratory immunology.

[255]  T. Fuerst,et al.  Purification of a soluble hepatitis E open reading frame 2-derived protein with unique antigenic properties. , 1996, Protein expression and purification.

[256]  S. Locarnini,et al.  Persistent and transient antibody responses to hepatitis E virus detected by western immunoblot using open reading frame 2 and 3 and glutathione S-transferase fusion proteins , 1994, Journal of clinical microbiology.

[257]  D. Bradley,et al.  Preliminary evidence that a trpE‐HEV fusion protein protects cynomolgus macaques against challenge with wild‐type hepatitis e virus (HEV) , 1993, Journal of medical virology.

[258]  S. Emerson,et al.  ELISA for antibody to hepatitis E virus (HEV) based on complete open-reading frame-2 protein expressed in insect cells: identification of HEV infection in primates. , 1993, The Journal of infectious diseases.

[259]  G. Reyes,et al.  Solid-phase enzyme-linked immunosorbent assay for hepatitis E virus IgG and IgM antibodies utilizing recombinant antigens and synthetic peptides. , 1992, Journal of virological methods.

[260]  A. W. Tam,et al.  Hepatitis E virus (HEV): Molecular cloning and sequencing of the full-length viral genome , 1991, Virology.

[261]  A. Nanji,et al.  RELATIONSHIP BETWEEN PORK CONSUMPTION AND CIRRHOSIS , 1985, The Lancet.

[262]  M. Khuroo CHRONIC LIVER DISEASE AFTER NON-A, NON-B HEPATITIS , 1980, The Lancet.

[263]  M. Khuroo Study of an epidemic of non-A, non-B hepatitis. Possibility of another human hepatitis virus distinct from post-transfusion non-A, non-B type. , 1980, The American journal of medicine.

[264]  J. Dubuisson,et al.  Hepatitis E Virus Lifecycle and Identification of 3 Forms of the ORF2 Capsid Protein. , 2018, Gastroenterology.

[265]  S. Mondal,et al.  Hepatitis E Virus Genotype 3 in Shellfi sh , United Kingdom , 2018 .

[266]  A. Zvirbliene,et al.  Generation in yeast and antigenic characterization of hepatitis E virus capsid protein virus-like particles , 2017, Applied Microbiology and Biotechnology.

[267]  C. Rice,et al.  Sofosbuvir Inhibits Hepatitis E Virus Replication In Vitro and Results in an Additive Effect When Combined With Ribavirin. , 2016, Gastroenterology.

[268]  P. Gallian,et al.  [Hepatitis E virus: Blood transfusion implications]. , 2014, Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine.

[269]  A. Ganser,et al.  Hepatitis E virus infection in a hematopoietic stem cell donor , 2014, Bone Marrow Transplantation.

[270]  N. de Deus,et al.  Distribution of hepatitis E virus infection and its prevalence in pigs on commercial farms in Spain. , 2008, Veterinary journal.

[271]  N. Xia,et al.  Clinical Significance of Anti-HEV IgA in Diagnosis of Acute Genotype 4 Hepatitis E Virus Infection Negative for Anti-HEV IgM , 2008, Digestive Diseases and Sciences.

[272]  G. Makar Safety and Efficacy of a Recombinant Hepatitis E Vaccine , 2007 .

[273]  Ping Zhang,et al.  [Expression of ORF2 protein of HEV genotype IV in Hansenula polymorpha]. , 2007, Sheng wu gong cheng xue bao = Chinese journal of biotechnology.

[274]  T. Tucker,et al.  Hepatitis E. , 1994, South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde.

[275]  A. W. Tam,et al.  Molecular organization and replication of hepatitis E virus (HEV). , 1993, Archives of virology. Supplementum.

[276]  C. Czerny,et al.  Unconventional Agents and Unclassified Viruses , 1993, Archives of Virology.