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Brüggemann Y, Klöhn M, Wedemeyer H, Steinmann E. Hepatitis E virus: from innate sensing to adaptive immune responses. Nat Rev Gastroenterol Hepatol 2024; 21:710-725. [PMID: 39039260 DOI: 10.1038/s41575-024-00950-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/29/2024] [Indexed: 07/24/2024]
Abstract
Hepatitis E virus (HEV) infections are a major cause of acute viral hepatitis in humans worldwide. In immunocompetent individuals, the majority of HEV infections remain asymptomatic and lead to spontaneous clearance of the virus, and only a minority of individuals with infection (5-16%) experience symptoms of acute viral hepatitis. However, HEV infections can cause up to 30% mortality in pregnant women, become chronic in immunocompromised patients and cause extrahepatic manifestations. A growing body of evidence suggests that the host immune response to infection with different HEV genotypes is a critical determinant of distinct HEV infection outcomes. In this Review, we summarize key components of the innate and adaptive immune responses to HEV, including the underlying immunological mechanisms of HEV associated with acute and chronic liver failure and interactions between T cell and B cell responses. In addition, we discuss the current status of vaccines against HEV and raise outstanding questions regarding the immune responses induced by HEV and treatment of the disease, highlighting areas for future investigation.
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Affiliation(s)
- Yannick Brüggemann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany
| | - Heiner Wedemeyer
- Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
- German Center for Infection Research (DZIF), Partner Sites Hannover-Braunschweig, Hannover, Germany
- Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr University Bochum, Bochum, Germany.
- German Center for Infection Research (DZIF), External Partner Site, Bochum, Germany.
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Yadav KK, Kenney SP. Hepatitis E virus immunosuppressed animal models. BMC Infect Dis 2024; 24:965. [PMID: 39266958 PMCID: PMC11395946 DOI: 10.1186/s12879-024-09870-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Accepted: 09/03/2024] [Indexed: 09/14/2024] Open
Abstract
Hepatitis E virus (HEV) is an important emerging pathogen producing significant morbidity in immunosuppressed patients. HEV has been detrimental to solid organ transplant (SOT) patients, cancer patients, and HIV-positive patients, where chronic HEV infections occur. Blood-borne transfusions and multiple cases of chronic HEV infection in transplant patients have been reported in the past few decades, necessitating research on HEV pathogenesis using immunosuppressed animal models. Numerous animal species with unique naturally occurring HEV strains have been found, several of which have the potential to spread to humans and to serve as pathogenesis models. Host immunosuppression leads to viral persistence and chronic HEV infection allows for genetic adaptation to the human host creating new strains with worse disease outcomes. Procedures necessary for SOT often entail blood transfusions placing immunosuppressive patients into a "high risk group" for HEV infection. This scenario requires an appropriate immunosuppressive animal model to understand disease patterns in these patients. Hence, this article reviews the recent advances in the immunosuppressed animal models for chronic HEV infection with emphasis on pathogenesis, immune correlates, and the liver pathology associated with the chronic HEV infections.
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Affiliation(s)
- Kush Kumar Yadav
- Center for Food Animal Health, Department of Animal Sciences, The Ohio State University, 1680 Madison Ave, Wooster, OH, 44691, USA
- Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, 43210, USA
| | - Scott P Kenney
- Center for Food Animal Health, Department of Animal Sciences, The Ohio State University, 1680 Madison Ave, Wooster, OH, 44691, USA.
- Department of Veterinary Preventive Medicine, The Ohio State University, Columbus, 43210, USA.
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Kanda T, Li TC, Takahashi M, Nagashima S, Primadharsini PP, Kunita S, Sasaki-Tanaka R, Inoue J, Tsuchiya A, Nakamoto S, Abe R, Fujiwara K, Yokosuka O, Suzuki R, Ishii K, Yotsuyanagi H, Okamoto H. Recent advances in hepatitis E virus research and the Japanese clinical practice guidelines for hepatitis E virus infection. Hepatol Res 2024; 54:1-30. [PMID: 38874115 DOI: 10.1111/hepr.14062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 04/22/2024] [Accepted: 05/09/2024] [Indexed: 06/15/2024]
Abstract
Acute hepatitis E was considered rare until reports emerged affirming the existence of hepatitis E virus (HEV) genotypes 3 and 4 infections in Japan in the early 2000s. Extensive studies by Japanese researchers have highlighted the pivotal role of pigs and wild animals, such as wild boars and deer, as reservoirs for HEV, linking them to zoonotic infections in Japan. Currently, when hepatitis occurs subsequent to the consumption of undercooked or grilled pork, wild boar meat, or offal (including pig liver and intestines), HEV infection should be considered. Following the approval of anti-HEV immunoglobulin A antibody as a diagnostic tool for hepatitis E by Japan's Health Insurance System in 2011, the annual number of diagnosed cases of HEV infection has surged. Notably, the occurrence of post-transfusion hepatitis E promoted nationwide screening of blood products for HEV using nucleic acid amplification tests since 2020. Furthermore, chronic hepatitis E has been observed in immunosuppressed individuals. Considering the significance of hepatitis E, heightened preventive measures are essential. The Japan Agency for Medical Research and Development Hepatitis A and E viruses (HAV and HEV) Study Group, which includes special virologists and hepatologists, held a virtual meeting on February 17, 2024. Discussions encompassed pathogenesis, transmission routes, diagnosis, complications, severity factors, and ongoing and prospective vaccination or treatments for hepatitis E. Rigorous assessment of referenced studies culminated in the formulation of recommendations, which are detailed within this review. This comprehensive review presents recent advancements in HEV research and Japanese clinical practice guidelines for HEV infection.
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Affiliation(s)
- Tatsuo Kanda
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Minamiuonuma, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Tian-Cheng Li
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Masaharu Takahashi
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Shigeo Nagashima
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Putu Prathiwi Primadharsini
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Satoshi Kunita
- Center for Experimental Medicine, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
| | - Reina Sasaki-Tanaka
- Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Jun Inoue
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsunori Tsuchiya
- Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan
| | - Shingo Nakamoto
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Ryuzo Abe
- Department of Emergency Medicine, Oita University, Oita, Japan
| | - Keiichi Fujiwara
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Osamu Yokosuka
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chuo-ku, Chiba, Japan
| | - Ryosuke Suzuki
- Department of Virology II, National Institute of Infectious Diseases, Tokyo, Japan
| | - Koji Ishii
- Department of Quality Assurance and Radiological Protection, National Institute of Infectious Diseases, Tokyo, Japan
| | - Hiroshi Yotsuyanagi
- Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
- Department of Infectious Diseases and Applied Immunology, Hospital of the Institute of Medical Science, University of Tokyo, Tokyo, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, Shimotsuke, Tochigi, Japan
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Lorusso P, Pandiscia A, Manfredi A, Tantillo GM, Terio V. Evaluation of hepatitis E virus RNA persistence in experimentally contaminated cured pork liver sausages. Ital J Food Saf 2024; 13:12286. [PMID: 38846049 PMCID: PMC11154169 DOI: 10.4081/ijfs.2024.12286] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Accepted: 03/11/2024] [Indexed: 06/09/2024] Open
Abstract
Hepatitis E is a disease sustained by RNA viruses, which have four different genotypes, all of which are responsible for acute forms of hepatitis. Genotypes 1 and 2 infect only humans, causing epidemics mainly transmitted by contaminated water, while geno-types 3 and 4 are zoonotic, and the infection is linked to the consumption of raw or undercooked meat or meat products. Hepatitis E virus (HEV) genotypes 3 and 4 have been detected in domestic Suidae, considered the asymptomatic reservoir of HEV, and in wild animals such as wild boar and deer. Despite scientific studies that have highlighted the presence of HEV in cured meat products, such as pork liver sausages, the viral persistence in the different production steps of curing has not been evaluated. Therefore, this study aimed to evaluate the persistence of HEV genotype 3 during the different curing and storage times of experimentally contaminated pork liver sausages using biomolecular methods. The sausages tested positive at all curing and storage times. This study confirms the potential risk attributed to pork liver sausages in HEV transmission. However, to guarantee an efficient risk assessment, future studies will be performed to correlate the presence of HEV RNA with infectious viral particles.
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Caballero-Gómez J, Rivero-Juárez A, Cano-Terriza D, Fajardo T, Buono F, Jose-Cunilleras E, García J, Alguacil E, Rivero A, García-Bocanegra I. Epidemiological survey and risk factors associated with Paslahepevirus balayani in equines in Europe. One Health 2023; 17:100619. [PMID: 38024277 PMCID: PMC10665168 DOI: 10.1016/j.onehlt.2023.100619] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 08/21/2023] [Accepted: 08/21/2023] [Indexed: 12/01/2023] Open
Abstract
Paslahepevirus balayani (HEV) is an important emerging zoonotic virus in Europe. Although domestic pigs and wild boar are the main reservoirs of this pathogen, susceptibility to this virus has been confirmed in a growing number of animal species, including equines. However, their role in the epidemiology of this virus remains poorly understood. Our aim was to assess HEV circulation and identify potential risk factors associated with exposure in equid species in different European countries. A total of 596 equines, including 496 horses, 63 donkeys and 37 mules/hinnies bred in four European countries (Spain, Italy, United Kingdom and Ireland) were sampled. Thirty-three animals (5.5%; 95%CI: 3.7-7.4) had anti-HEV antibodies. Seropositivity was found in 4.6% of horses, 11.1% of donkeys and 8.1% of mules/hinnies tested. By country, 6.3%, 5.4%, 5.0% and 4.0% of the equines sampled in Spain, Italy, United Kingdom and Ireland, respectively, were seropositive, respectively. Statistical analysis showed that "species" and "drinking water from ponds and streams" were potential risk factors associated with HEV seropositivity in equines in Europe. HEV RNA was not detected in any (0.0%; 95%CI: 0.0-1.8) of the 202 equines tested. Our results provide evidence of a low, spatially homogeneous and widespread viral circulation that is not equal across species in equid populations in the European countries analyzed and indicate that these species appear to play a limited role in the epidemiology of this virus. Further studies are required to elucidate the differences in seroprevalence between donkeys, mules/hinnies and horses and to determine the risk of zoonotic transmission of this pathogen from equid species.
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Affiliation(s)
- Javier Caballero-Gómez
- Grupo de Virología Clínica y Zoonosis, Unidad de Enfermedades Infecciosas, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain
- Departamento de Sanidad Animal, Grupo de Investigación GISAZ, UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Córdoba, Spain
- CIBERINFEC, ISCIII – CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Antonio Rivero-Juárez
- Grupo de Virología Clínica y Zoonosis, Unidad de Enfermedades Infecciosas, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain
- CIBERINFEC, ISCIII – CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - David Cano-Terriza
- Departamento de Sanidad Animal, Grupo de Investigación GISAZ, UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Córdoba, Spain
- CIBERINFEC, ISCIII – CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Tomás Fajardo
- Grupo de Virología Clínica y Zoonosis, Unidad de Enfermedades Infecciosas, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain
- Departamento de Sanidad Animal, Grupo de Investigación GISAZ, UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Córdoba, Spain
- CIBERINFEC, ISCIII – CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Francesco Buono
- Department of Veterinary Medicine and Animal Productions, Università degli Studi di Napoli Federico II, Naples, Italy
| | - Eduard Jose-Cunilleras
- Servei de Medicina Interna Equina, Departament de Medicina Cirurgia Animals, Facultat de Veterinària, Universitat Autònoma de Barcelona, Barcelona, Spain
| | | | | | - Antonio Rivero
- Grupo de Virología Clínica y Zoonosis, Unidad de Enfermedades Infecciosas, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain
- CIBERINFEC, ISCIII – CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Ignacio García-Bocanegra
- Departamento de Sanidad Animal, Grupo de Investigación GISAZ, UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Córdoba, Spain
- CIBERINFEC, ISCIII – CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, 28029 Madrid, Spain
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Gremmel N, Keuling O, Eiden M, Groschup MH, Johne R, Becher P, Baechlein C. Hepatitis E virus neutralization by porcine serum antibodies. J Clin Microbiol 2023; 61:e0037323. [PMID: 37823649 PMCID: PMC10662371 DOI: 10.1128/jcm.00373-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 08/26/2023] [Indexed: 10/13/2023] Open
Abstract
The consumption of raw or undercooked meat products poses a serious risk for human hepatitis E virus (HEV) infections. In many high-income countries, domestic pigs and wild boars represent the main animal reservoirs for HEV and are usually identified by reverse transcription-PCR and antibody enzyme-linked immunosorbent assay (ELISA). In order to characterize the humoral immune response in more detail, a cell culture-based serum neutralization assay using a culture-adapted HEV strain was established here. Measurement of neutralizing antibodies was only possible after removing the viral quasi-envelope by detergent treatment. Serum samples of 343 wild boars from Northern Germany were first analyzed for anti-HEV IgG using an in-house ELISA, resulting in 19% positive samples. Subsequently, a subset of 41 representative samples was tested with the neutralization assay, and the results correlated well with those obtained by ELISA. Not only the human HEV strain 47832c but also two porcine HEV strains were shown to be neutralized by porcine serum antibodies. Neutralizing activity was also found in samples containing both HEV-specific antibodies and HEV RNA. Testing of serum samples derived from two experimentally infected domestic pigs showed a steep increase in neutralizing activity at 24 or 51 days post infection, dependent on the used infectious dose. The developed assay can be useful for characterization of the humoral immune response after HEV infection and for assessing the efficiency of HEV vaccine candidates.
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Affiliation(s)
- Nele Gremmel
- Department of Infectious Diseases, Institute of Virology, University of Veterinary Medicine, Hannover, Germany
| | - Oliver Keuling
- Institute for Terrestrial and Aquatic Wildlife Research, University of Veterinary Medicine, Hannover, Germany
| | - Martin Eiden
- Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald, Insel Riems, Germany
| | - Martin H. Groschup
- Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald, Insel Riems, Germany
| | - Reimar Johne
- Department of Biological Safety, German Federal Institute for Risk Assessment, Berlin, Germany
| | - Paul Becher
- Department of Infectious Diseases, Institute of Virology, University of Veterinary Medicine, Hannover, Germany
| | - Christine Baechlein
- Department of Infectious Diseases, Institute of Virology, University of Veterinary Medicine, Hannover, Germany
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Animal Models for Studying Congenital Transmission of Hepatitis E Virus. Microorganisms 2023; 11:microorganisms11030618. [PMID: 36985191 PMCID: PMC10057890 DOI: 10.3390/microorganisms11030618] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023] Open
Abstract
One of the most intriguing issues in the hepatitis E virus (HEV) field is the significant increase in mortality rates of the mother and fetus when infection occurs in the second and third trimesters of gestation. A virus that is normally self-limiting and has a mortality rate of less than one percent in otherwise healthy individuals steeply rises by up to 30% in these pregnant populations. Answering this pivotal question has not been a simple task. HEV, in general, has been a difficult pathogen to understand in the laboratory setting. A historical lack of ability to efficiently propagate the virus in tissue culture models has led to many molecular aspects of the viral lifecycle being understudied. Although great strides have been made in recent years to adapt viruses to cell culture, this field remains behind other viruses that are much easier to replicate efficiently in vitro. Some of the greatest discoveries regarding HEV have come from using animal models for which naturally occurring strains of HEV have been identified, including pigs and chickens, but key limitations have made animal models imperfect for studying all aspects of human HEV infections. In addition to the difficulties working with HEV, pregnancy is a very complicated biological process with an elaborate interplay between many different host systems, including hormones, cardiovascular, kidneys, respiratory, gastrointestinal, epithelial, liver, metabolic, immune, and others. Significant differences between the timing and interplay of these systems are notable between species, and making direct comparisons between animals and humans can be difficult at times. No simple answer exists as to how HEV enhances mortality in pregnant populations. One of the best approaches to studying HEV in pregnancy is likely a combinatorial approach that uses the best combination of emerging in vitro and in vivo systems while accounting for the deficiencies that are present in each model. This review describes many of the current HEV animal model systems and the strengths and weaknesses of each as they apply to HEV pregnancy-associated mortality. We consider factors that are critical to analyzing HEV infection within the host and how, despite no perfect animal model for human pregnancy mortality existing, recent developments in HEV models, both in vitro and in vivo, are advancing our overall understanding of HEV in the pregnant host.
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Zhang J, Zheng Z, Xia N. Prophylactic Hepatitis E Vaccine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:227-245. [PMID: 37223870 DOI: 10.1007/978-981-99-1304-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
The hepatitis E has been increasingly recognized as an underestimated global disease burden in recent years. Subpopulations with more serious infection associated damage or death include pregnant women, patients with basic liver diseases, and elderly persons. Vaccine would be the most effective means for prevention of HEV infection. The lack of an efficient cell culture system for HEV makes the development of classic inactive or attenuated vaccine infeasible. Hence, the recombinant vaccine approaches are explored deeply. The neutralizing sites are located almost exclusively in the capsid protein, pORF2, of the virion. Based on pORF2, many vaccine candidates showed potential of protecting primate animals, two of them were tested in human and evidenced to be well-tolerated in adults and highly efficacious in preventing hepatitis E. The world's first hepatitis E vaccine, Hecolin® (HEV 239 vaccine), was licensed in China and launched in 2012.
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Affiliation(s)
- Jun Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China.
| | - Zizheng Zheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
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Harvey W, Hutto EH, Chilton JA, Chamanza R, Mysore JV, Parry NM, Dick E, Wojcinski ZW, Piaia A, Garcia B, Flandre TD, Pardo ID, Cramer S, Wright JA, Bradley AE. Infectious diseases of non-human primates. SPONTANEOUS PATHOLOGY OF THE LABORATORY NON-HUMAN PRIMATE 2023:15-69. [DOI: 10.1016/b978-0-12-813088-9.00020-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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10
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Zhou YH, Zhao H. Immunobiology and Host Response to HEV. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:93-118. [PMID: 37223861 DOI: 10.1007/978-981-99-1304-6_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Hepatitis E virus (HEV) usually causes acute self-limiting hepatitis but sometimes leads to chronic infection in immunocompromised persons. HEV is not directly cytopathic. Immunologically mediated events after HEV infection are believed to play important roles in the pathogenesis and clearance of infection. The anti-HEV antibody responses have been largely clarified since the determination of major antigenic determinant of HEV, which is located in the C-terminal portion of ORF2. This major antigenic determinant also forms the conformational neutralization epitopes. Robust anti-HEV immunoglobulin M (IgM) and IgG responses usually develop 3-4 weeks after infection in experimentally infected nonhuman primates. In humans, potent specific IgM and IgG responses occur in the very early phase of the disease and are critical in eliminating the virus, in concert with the innate and adaptive T-cell immune responses. Testing anti-HEV IgM is valuable in the diagnosis of acute hepatitis E. The long-term persistence and protection of anti-HEV IgG provide the basis for estimating the prevalence of HEV infection and for the development of a hepatitis E vaccine. Although human HEV has four genotypes, all the viral strains are considered to belong to a single serotype. It is becoming increasingly clear that the innate and adaptive T-cell immune responses play critical roles in the clearance of the virus. Potent and multispecific CD4+ and CD8+ T cell responses to the ORF2 protein occur in patients with acute hepatitis E, and weaker HEV-specific CD4+ and CD8+ T cell responses appear to be associated with chronic hepatitis E in immunocompromised individuals.
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Affiliation(s)
- Yi-Hua Zhou
- Departments of Experimental Medicine and Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Hong Zhao
- Department of Infectious Diseases, Second Hospital of Nanjing, Southeast University School of Medicine, Nanjing, China
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Caballero-Gómez J, García-Bocanegra I, Cano-Terriza D, Beato-Benítez A, Ulrich RG, Martínez J, Guerra R, Martínez-Valverde R, Martínez-Nevado E, Ángel Quevedo-Muñoz M, Sierra-Arqueros C, Planas J, de Castro-García N, Rivero A, Rivero-Juarez A. Monitoring of hepatitis E virus in zoo animals from Spain, 2007-2021. Transbound Emerg Dis 2022; 69:3992-4001. [PMID: 36083467 PMCID: PMC10087427 DOI: 10.1111/tbed.14702] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 08/24/2022] [Accepted: 09/04/2022] [Indexed: 02/07/2023]
Abstract
Hepatitis E virus (HEV, family Hepeviridae) is an important emerging and zoonotic pathogen. In recent decades, the number of human cases of zoonotic hepatitis E has increased considerably in industrialized countries and HEV has been detected in an expanding range of mammal species. Although domestic pigs and wild boar are considered the main reservoirs of zoonotic HEV genotypes, the role of other susceptible animals in the epidemiology of the virus is still poorly understood. A large-scale, long-term study was carried out (1) to assess HEV exposure in captive zoo animals in Spain and (2) to determine the dynamics of seropositivity in individuals that were sampled longitudinally during the study period. Between 2007 and 2021, serum samples from 425 zoo animals belonging to 109 animal species (including artiodactyls, carnivores, perissodactyls, proboscideans and rodents) were collected from 11 different zoological parks in Spain. Forty-six of these animals at seven of these zoos were also longitudinally sampled. Anti-HEV antibodies were detected in 36 (8.5%; 95% CI: 5.8-11.1) of 425 sampled zoo animals. Specific antibodies against HEV-3 and HEV-C1 antigens were confirmed in ELISA-positive animals using western blot assay. Two of 46 longitudinally surveyed animals seroconverted during the study period. Seropositivity was significantly higher in carnivores and perissodactyls than in artiodactyls, and also during the period 2012-2016 compared with 2007-2011. HEV RNA was not detected in any of the 262 animals that could be tested by RT-PCR. To the best of the author's knowledge, this is the first large-scale, long-term surveillance on HEV in different orders of zoo mammals. Our results indicate exposure to HEV-3 and HEV-C1 in zoo animals in Spain and confirm a widespread but not homogeneous spatiotemporal circulation of HEV in captive species in this country. Further studies are required to determine the role of zoo species, particularly carnivores and perissodactyls, in the epidemiology of HEV and to clarify the origins of infection in zoological parks.
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Affiliation(s)
- Javier Caballero-Gómez
- Departamento Sanidad Animal, Grupo de Investigación en Sanidad Animal y Zoonosis (GISAZ), UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Campus de Rabanales, Edificio Sanidad Animal, Córdoba, España.,Grupo de Virología Clínica y Zoonosis, Unidad de Enfermedades Infecciosas, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain.,CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain
| | - Ignacio García-Bocanegra
- Departamento Sanidad Animal, Grupo de Investigación en Sanidad Animal y Zoonosis (GISAZ), UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Campus de Rabanales, Edificio Sanidad Animal, Córdoba, España.,CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain
| | - David Cano-Terriza
- Departamento Sanidad Animal, Grupo de Investigación en Sanidad Animal y Zoonosis (GISAZ), UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Campus de Rabanales, Edificio Sanidad Animal, Córdoba, España.,CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain
| | - Adrián Beato-Benítez
- Departamento Sanidad Animal, Grupo de Investigación en Sanidad Animal y Zoonosis (GISAZ), UIC Zoonosis y Enfermedades Emergentes ENZOEM, Universidad de Córdoba, Campus de Rabanales, Edificio Sanidad Animal, Córdoba, España
| | - Rainer G Ulrich
- Institute of Novel and Emerging Infectious Diseases, Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Greifswald-Insel Riems, Germany.,German Centre for Infection Research (DZIF), partner site Hamburg-Lübeck-Borstel-Riems, Greifswald-Insel Riems, Germany
| | | | | | | | | | | | | | | | | | - Antonio Rivero
- Grupo de Virología Clínica y Zoonosis, Unidad de Enfermedades Infecciosas, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain.,CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain
| | - Antonio Rivero-Juarez
- Grupo de Virología Clínica y Zoonosis, Unidad de Enfermedades Infecciosas, Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Hospital Universitario Reina Sofía, Universidad de Córdoba, Córdoba, Spain.,CIBERINFEC, ISCIII - CIBER de Enfermedades Infecciosas, Instituto de Salud Carlos III, Spain
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12
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Sayed IM, Karam-Allah Ramadan H, Hafez MHR, Elkhawaga AA, El-Mokhtar MA. Hepatitis E virus (HEV) open reading frame 2: Role in pathogenesis and diagnosis in HEV infections. Rev Med Virol 2022; 32:e2401. [PMID: 36209386 DOI: 10.1002/rmv.2401] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/12/2022]
Abstract
Hepatitis E virus (HEV) infection occurs worldwide. The HEV genome includes three to four open reading frames (ORF1-4). ORF1 proteins are essential for viral replication, while the ORF3 protein is an ion channel involved in the exit of HEV from the infected cells. ORF2 proteins form the viral capsid required for HEV invasion and assembly. They also suppress interferon production and inhibit antibody-mediated neutralisation of HEV, allowing the virus to hijack the host immune response. ORF2 is the only detectable viral protein in the human liver during HEV infection and it is secreted in the plasma, stool, and urine of HEV-infected patients, making it a reliable diagnostic marker. The plasma HEV ORF2 antigen level can predict the outcome of HEV infections. Hence, monitoring HEV ORF2 antigen levels may be useful in assessing the efficacy of anti-HEV therapy. The ORF2 antigen is immunogenic and includes epitopes that can induce neutralising antibodies; therefore, it is a potential HEV vaccine candidate. In this review, we highlighted the different forms of HEV ORF2 protein and their roles in HEV pathogenesis, diagnosis, monitoring the therapeutic efficacy, and vaccine development.
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Affiliation(s)
- Ibrahim M Sayed
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Haidi Karam-Allah Ramadan
- Department of Tropical Medicine and Gastroenterology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mahmoud H R Hafez
- International Scholar, African Leadership Academy, Johannesburg, South Africa
| | - Amal A Elkhawaga
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt
| | - Mohamed A El-Mokhtar
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Assiut University, Assiut, Egypt.,Microbiology and Immunology Department, Faculty of Pharmacy, Sphinx University, Assiut, Egypt
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13
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Shata MTM, Hetta HF, Sharma Y, Sherman KE. Viral hepatitis in pregnancy. J Viral Hepat 2022; 29:844-861. [PMID: 35748741 PMCID: PMC9541692 DOI: 10.1111/jvh.13725] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 12/17/2021] [Accepted: 06/13/2022] [Indexed: 12/09/2022]
Abstract
Viral hepatitis is caused by a heterogenous group of viral agents representing a wide range of phylogenetic groups. Many viruses can involve the liver and cause liver injury but only a subset are delineated as 'hepatitis viruses' based upon their primary site of replication and tropism for hepatocytes which make up the bulk of the liver cell population. Since their discovery, beginning with the agent that caused serum hepatitis in the 1960s, the alphabetic designations have been utilized. To date, we have five hepatitis viruses, A through E, though it is postulated that others may exist. This chapter will focus on those viruses. Note that hepatitis D is included as a subset of hepatitis B, as it cannot exist without concurrent hepatitis B infection. Pregnancy has the potential to affect all aspects of these viral agents due to the unique immunologic and physiologic changes that occur during and after the gestational period. In this review, we will discuss the most common viral hepatitis and their effects during pregnancy.
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Affiliation(s)
- Mohamed Tarek M. Shata
- Division of Digestive Disease, Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA
| | - Helal F. Hetta
- Division of Digestive Disease, Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA,Department of Medical Microbiology and Immunology, Faculty of MedicineAssiut UniversityAssiutEgypt
| | - Yeshika Sharma
- Division of Digestive Disease, Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA
| | - Kenneth E. Sherman
- Division of Digestive Disease, Department of Internal MedicineUniversity of CincinnatiCincinnatiOhioUSA
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14
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Collignon L, Verhoye L, Hakze-Van der Honing R, Van der Poel WHM, Meuleman P. Study of Hepatitis E Virus-4 Infection in Human Liver-Chimeric, Immunodeficient, and Immunocompetent Mice. Front Microbiol 2022; 13:819877. [PMID: 35295314 PMCID: PMC8919074 DOI: 10.3389/fmicb.2022.819877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 01/14/2022] [Indexed: 11/13/2022] Open
Abstract
The hepatitis E virus (HEV) is responsible for 20 million infections worldwide per year. Although, HEV infection is mostly self-limiting, immunocompromised individuals may evolve toward chronicity. The lack of an efficient small animal model has hampered the study of HEV and the discovery of anti-HEV therapies. Furthermore, new HEV strains, infectious to humans, are being discovered. Human liver-chimeric mice have greatly aided in the understanding of HEV, but only two genotypes (HEV-1 and HEV-3) have been studied in this model. Moreover, the immunodeficient nature of this mouse model does not allow full investigation of the virus and all aspects of its interaction with the host. Recent studies have shown the susceptibility of regular and nude Balb/c mice to a HEV-4 strain (KM01). This model should allow the investigation of the interplay between HEV and the adaptive immune system of its host, and potential immune-mediated complications. Here, we assess the susceptibility of human liver-chimeric and non-humanised mice to a different HEV-4 strain (BeSW67HEV4-2008). We report that humanised mice could be readily infected with this isolate, resulting in an infection pattern comparable to HEV-3 infection. Despite these results and in contrast to KM01, non-humanised mice were not susceptible to infection with this viral strain. Further investigation, using other HEV-4 isolates, is needed to conclusively determine HEV-4 tropism and mouse susceptibility.
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Affiliation(s)
- Laura Collignon
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | - Lieven Verhoye
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
| | | | - Wim H. M. Van der Poel
- Wageningen Bioveterinary Research, Wageningen University and Research, Lelystad, Netherlands
| | - Philip Meuleman
- Laboratory of Liver Infectious Diseases, Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, Ghent University, Ghent, Belgium
- *Correspondence: Philip Meuleman,
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15
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Hansda A, Biswas D, Bhatta A, Chakravorty N, Mukherjee G. Plasma therapy: a passive resistance against the deadliest. Hum Vaccin Immunother 2021; 18:2006026. [PMID: 34886756 PMCID: PMC9116411 DOI: 10.1080/21645515.2021.2006026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Convalescent plasma therapy provides a useful therapeutic tool to treat infectious diseases, especially where no specific therapeutic strategies have been identified. The ongoing pandemic puts back the spotlight on this age-old method as a viable treatment option. In this review, we discuss the usage of this therapy in different diseases including COVID-19, and the possible mechanisms of action. The current review also discusses the progress of therapeutic applications of blood-derivatives, from the simple transfer of immunized animal sera, to the more target-specific intravenous administration of human immunoglobulins from a pool of convalescent individuals, in both infectious and non-infectious diseases of various etiologies.
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Affiliation(s)
- Anita Hansda
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, India
| | - Debarati Biswas
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, India
| | - Aishwarya Bhatta
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, India
| | - Nishant Chakravorty
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, India
| | - Gayatri Mukherjee
- School of Medical Science and Technology, Indian Institute of Technology Kharagpur, India
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16
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Kupke P, Werner JM. Hepatitis E Virus Infection-Immune Responses to an Underestimated Global Threat. Cells 2021; 10:cells10092281. [PMID: 34571931 PMCID: PMC8468229 DOI: 10.3390/cells10092281] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 08/23/2021] [Accepted: 08/30/2021] [Indexed: 12/19/2022] Open
Abstract
Infection with the hepatitis E virus (HEV) is one of the main ubiquitous causes for developing an acute hepatitis. Moreover, chronification plays a predominant role in immunocompromised patients such as transplant recipients with more frequent severe courses. Unfortunately, besides reduction of immunosuppression and off-label use of ribavirin or pegylated interferon alfa, there is currently no specific anti-viral treatment to prevent disease progression. So far, research on involved immune mechanisms induced by HEV is limited. It is very difficult to collect clinical samples especially from the early phase of infection since this is often asymptomatic. Nevertheless, it is certain that the outcome of HEV-infected patients correlates with the strength of the proceeding immune response. Several lymphoid cells have been identified in contributing either to disease progression or achieving sustained virologic response. In particular, a sufficient immune control by both CD4+ and CD8+ T cells is necessary to prevent chronic viral replication. Especially the mechanisms underlying fulminant courses are poorly understood. However, liver biopsies indicate the involvement of cytotoxic T cells in liver damage. In this review, we aimed to highlight different parts of the lymphoid immune response against HEV and point out questions that remain unanswered regarding this underestimated global threat.
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17
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Castaneda D, Gonzalez AJ, Alomari M, Tandon K, Zervos XB. From hepatitis A to E: A critical review of viral hepatitis. World J Gastroenterol 2021; 27:1691-1715. [PMID: 33967551 PMCID: PMC8072198 DOI: 10.3748/wjg.v27.i16.1691] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 03/02/2021] [Accepted: 04/09/2021] [Indexed: 02/06/2023] Open
Abstract
Viral infections affecting the liver have had an important impact on humanity, as they have led to significant morbidity and mortality in patients with acute and chronic infections. Once an unknown etiology, the discovery of the viral agents triggered interest of the scientific community to establish the pathogenesis and diagnostic modalities to identify the affected population. With the rapid scientific and technological advances in the last centuries, controlling and even curing the infections became a possibility, with a large focus on preventive medicine through vaccination. Hence, a comprehensive understanding of hepatitis A, B, C, D and E is required by primary care physicians and gastroenterologists to provide care to these patients. The review article describes the epidemiology, pathogenesis, clinical presentation, diagnostic tools and current medication regimens, with a focus on upcoming treatment options and the role of liver transplantation.
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Affiliation(s)
- Daniel Castaneda
- Digestive Disease Institute, Cleveland Clinic Florida, Weston, FL 33331, United States
| | | | - Mohammad Alomari
- Digestive Disease Institute, Cleveland Clinic Florida, Weston, FL 33331, United States
| | - Kanwarpreet Tandon
- Digestive Disease Institute, Cleveland Clinic Florida, Weston, FL 33331, United States
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18
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Engmann C, Fleming JA, Khan S, Innis BL, Smith JM, Hombach J, Sobanjo-Ter Meulen A. Closer and closer? Maternal immunization: current promise, future horizons. J Perinatol 2020; 40:844-857. [PMID: 32341454 PMCID: PMC7223555 DOI: 10.1038/s41372-020-0668-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 03/26/2020] [Accepted: 03/27/2020] [Indexed: 12/16/2022]
Abstract
This state-of-the art manuscript highlights our current understanding of maternal immunization-the practice of vaccinating pregnant women to confer protection on them as well as on their young infants, and thereby reduce vaccine-preventable morbidity and mortality. Advances in our understanding of the immunologic processes that undergird a normal pregnancy, studies from vaccines currently available and recommended for pregnant women, and vaccines for administration in special situations are beginning to build the case for safe scale-up of maternal immunization. In addition to well-known diseases, new diseases are emerging which pose threats. Several new vaccines are currently under development and increasingly include pregnant women. In this manuscript, targeted at clinicians, vaccinologists, scientists, public health practitioners, and policymakers, we also outline key considerations around maternal immunization introduction and delivery, discuss noninfectious horizons for maternal immunization, and provide a framework for the clinician faced with immunizing a pregnant woman.
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Affiliation(s)
- Cyril Engmann
- Maternal, Newborn, Child Health and Nutrition, PATH, Seattle, WA, USA.
- Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
- Department of Global Health, University of Washington School of Public Health, Seattle, WA, USA.
| | | | - Sadaf Khan
- Maternal, Newborn, Child Health and Nutrition, PATH, Seattle, WA, USA
| | - Bruce L Innis
- Center for Vaccine Innovation and Access, PATH, Seattle, WA, USA
| | - Jeffrey M Smith
- Maternal, Newborn and Child Health, Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - Joachim Hombach
- Immunization, Vaccines and Biologicals, World Health Organization, Geneva, Switzerland
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19
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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. PLANTS 2019; 9:plants9010029. [PMID: 31878256 PMCID: PMC7020208 DOI: 10.3390/plants9010029] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Revised: 12/12/2019] [Accepted: 12/21/2019] [Indexed: 12/27/2022]
Abstract
The Hepatitis E virus (HEV) is a causative agent of acute hepatitis, mainly transmitted by the fecal-oral route or zoonotic. Open reading frame (ORF) 2 encodes the viral capsid protein, which is essential for virion assembly, host interaction, and inducing neutralizing antibodies. In this study, we investigated whether full-length and N- and C-terminally modified versions of the capsid protein transiently expressed in N. benthamiana plants could assemble into highly-immunogenic, virus-like particles (VLPs). We also assessed whether such VLPs can act as a carrier of foreign immunogenic epitopes, such as the highly-conserved M2e peptide from the Influenza virus. Plant codon-optimized HEV ORF2 capsid genes were constructed in which the nucleotides coding the N-terminal, the C-terminal, or both parts of the protein were deleted. The M2e peptide was inserted into the P2 loop after the residue Gly556 of HEV ORF2 protein by gene fusion, and three different chimeric constructs were designed. Plants expressed all versions of the HEV capsid protein up to 10% of total soluble protein (TSP), including the chimeras, but only the capsid protein consisting of aa residues 110 to 610 (HEV 110–610) and chimeric M2 HEV 110–610 spontaneously assembled in higher order structures. The chimeric VLPs assembled into particles with 22–36 nm in diameter and specifically reacted with the anti-M2e antibody.
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20
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Walker CM. Adaptive Immune Responses in Hepatitis A Virus and Hepatitis E Virus Infections. Cold Spring Harb Perspect Med 2019; 9:cshperspect.a033472. [PMID: 29844218 DOI: 10.1101/cshperspect.a033472] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Both hepatitis A virus (HAV) and hepatitis E virus (HEV) cause self-limited infections in humans that are preventable by vaccination. Progress in characterizing adaptive immune responses against these enteric hepatitis viruses, and how they contribute to resolution of infection or liver injury, has therefore remained largely frozen for the past two decades. How HAV and HEV infections are so effectively controlled by B- and T-cell immunity, and why they do not have the same propensity to persist as HBV and HCV infections, cannot yet be adequately explained. The objective of this review is to summarize our understanding of the relationship between patterns of virus replication, adaptive immune responses, and acute liver injury in HAV and HEV infections. Gaps in knowledge, and recent studies that challenge long-held concepts of how antibodies and T cells contribute to control and pathogenesis of HAV and HEV infections, are highlighted.
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Affiliation(s)
- Christopher M Walker
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's, Columbus, Ohio 43004
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21
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Park BJ, Ahn HS, Han SH, Go HJ, Lee JB, Park SY, Song CS, Lee SW, Paik HJ, Choi YK, Choi IS. Evaluation of the protective effects of a nanogel-based vaccine against rabbit hepatitis E virus. Vaccine 2019; 37:5972-5978. [PMID: 31455586 DOI: 10.1016/j.vaccine.2019.08.029] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2019] [Revised: 08/03/2019] [Accepted: 08/17/2019] [Indexed: 12/13/2022]
Abstract
Infection with hepatitis E virus (HEV) has raised serious public health concerns worldwide. In this study, a nanogel-based vaccine encapsulating the capsid protein of rabbit HEV was developed and its protective efficacy was compared with a subunit vaccine. A total of 23 rabbits were divided into 5 groups: (1) negative control (n = 4), (2) positive control (n = 4), (3) nanogel control (n = 5), (4) nanogel vaccine (n = 5), and (5) subunit vaccine (n = 5). Rabbits were vaccinated two times, at weeks 0 and 1, with nanogel and subunit vaccines, respectively, and challenged with rabbit HEV at week 4. By week 11, rabbits vaccinated with the nanogel vaccine produced higher antibodies than those vaccinated with the subunit vaccine. Fecal viral shedding and viremia were identified in rabbits of the positive and nanogel control groups at weeks 6-10. However, there was no viral shedding and viremia in rabbits immunized with both the nanogel and subunit vaccines. Alanine aminotransferase and aspartate aminotransferase levels were not elevated in any rabbit. However, histopathological examination revealed much less hepatic inflammation in rabbits of the nanogel vaccine group compared to the positive and nanogel control groups. Significant increases in IL-12 and IFN-γlevels were identified from rabbits immunized with the nanogel vaccine. Collectively, these results indicate that the newly developed nanogel vaccine induced sufficient immunity leading to complete protection from HEV infection in rabbits. Application of this vaccine should be considered as a preventive measure against HEV infection in other animal species and humans.
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Affiliation(s)
- Byung-Joo Park
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Hee-Seop Ahn
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Sang-Hoon Han
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Hyeon-Jeong Go
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Joong-Bok Lee
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Seung-Yong Park
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Chang-Seon Song
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Sang-Won Lee
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - Hyun-Jong Paik
- Department of Polymer Science and Engineering, Pusan National University, San 30 Jangjeon 2-dong Geumjeong-gu, Busan 609-735, Republic of Korea
| | - Yang-Kyu Choi
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea
| | - In-Soo Choi
- Department of Infectious Diseases, College of Veterinary Medicine, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 05029, Republic of Korea.
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22
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Ankcorn M, Gallacher J, Ijaz S, Taha Y, Harvala H, Maclennan S, Thomson EC, Davis C, Singer JB, da Silva Filipe A, Smollett K, Niebel M, Semple MG, Tedder RS, McPherson S. Convalescent plasma therapy for persistent hepatitis E virus infection. J Hepatol 2019; 71:434-438. [PMID: 31075322 PMCID: PMC7126959 DOI: 10.1016/j.jhep.2019.04.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 04/17/2019] [Accepted: 04/22/2019] [Indexed: 12/18/2022]
Affiliation(s)
- Michael Ankcorn
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, Colindale, London, UK; Transfusion Microbiology, National Health Service Blood and Transplant, London, UK.
| | - Jennifer Gallacher
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Samreen Ijaz
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, Colindale, London, UK
| | - Yusri Taha
- Departments of Virology and Infectious Diseases, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK
| | - Heli Harvala
- Transfusion Microbiology, National Health Service Blood and Transplant, London, UK
| | - Sheila Maclennan
- Transfusion Medicine, National Health Service Blood and Transplant, Leeds, UK
| | - Emma C. Thomson
- MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
| | - Chris Davis
- MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
| | - Joshua B. Singer
- MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
| | | | | | - Marc Niebel
- MRC-University of Glasgow Centre for Virus Research, Glasgow, UK
| | - Malcolm G. Semple
- Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - Richard S. Tedder
- Blood Borne Virus Unit, Virus Reference Department, National Infection Service, Public Health England, Colindale, London, UK,Transfusion Microbiology, National Health Service Blood and Transplant, London, UK,Department of Medicine, Imperial College London, London, UK
| | - Stuart McPherson
- Liver Unit, Freeman Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK; Institute of Cellular Medicine, Faculty of Medical Sciences, Newcastle University, UK.
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23
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Animal Models for Hepatitis E virus. Viruses 2019; 11:v11060564. [PMID: 31216711 PMCID: PMC6630473 DOI: 10.3390/v11060564] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Revised: 06/11/2019] [Accepted: 06/12/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus (HEV) is an underdiagnosed pathogen with approximately 20 million infections each year and currently the most common cause of acute viral hepatitis. HEV was long considered to be confined to developing countries but there is increasing evidence that it is also a medical problem in the Western world. HEV that infects humans belongs to the Orthohepevirus A species of the Hepeviridae family. Novel HEV-like viruses have been observed in a variety of animals and some have been shown to be able to cross the species barrier, causing infection in humans. Several cell culture models for HEV have been established in the past years, but their efficiency is usually relatively low. With the circulation of this virus and related viruses in a variety of species, several different animal models have been developed. In this review, we give an overview of these animal models, indicate their main characteristics, and highlight how they may contribute to our understanding of the basic aspects of the viral life cycle and cross-species infection, the study of pathogenesis, and the evaluation of novel preventative and therapeutic strategies.
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The Current Host Range of Hepatitis E Viruses. Viruses 2019; 11:v11050452. [PMID: 31108942 PMCID: PMC6563279 DOI: 10.3390/v11050452] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2019] [Revised: 05/08/2019] [Accepted: 05/14/2019] [Indexed: 01/01/2023] Open
Abstract
Hepatitis E virus (HEV) is an emerging zoonotic pathogen transmitting both human to human via the fecal oral route and from animals to humans through feces, direct contact, and consumption of contaminated meat products. Understanding the host range of the virus is critical for determining where potential threats to human health may be emerging from and where potential reservoirs for viral persistence in the environment may be hiding. Initially thought to be a human specific disease endemic to developing countries, the identification of swine as a primary host for genotypes 3 and 4 HEV in industrialized countries has begun a long journey of discovering novel strains of HEV and their animal hosts. As we continue identifying new strains of HEV in disparate animal species, it is becoming abundantly clear that HEV has a broad host range and many of these HEV strains can cross between differing animal species. These cross-species transmitting strains pose many unique challenges to human health as they are often unrecognized as sources of viral transmission.
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Caballero-Gómez J, Rivero-Juarez A, Cano-Terriza D, Risalde MA, Lopez-Lopez P, Frias M, Jiménez-Ruiz S, Rivero A, García-Bocanegra I. Survey for Hepatitis E virus infection in non-human primates in zoos in Spain. Transbound Emerg Dis 2019; 66:1771-1775. [PMID: 30959551 DOI: 10.1111/tbed.13196] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 03/19/2019] [Accepted: 04/02/2019] [Indexed: 11/28/2022]
Abstract
Hepatitis E virus (HEV) is an emerging zoonotic pathogen that has been detected in different animal species. A survey study was carried out to assess HEV infection in non-human primates (NHPs) housed in zoos in Spain. Anti-HEV antibodies were detected in eight of the 181 NHPs tested (4.4%; 95%CI: 1.4-7.4). At least one seropositive animal was detected in five of the 33 species sampled (15.2%). This is the first report of seropositivity in black-and-white ruffed lemurs (Varecia variegata), common chimpanzees (Pan troglodytes), and Barbary macaques (Macaca sylvanus). Anti-HEV antibodies were found in six of the eight zoos included in the study (75.0%). Seroconversion was detected in one chimpanzee, which confirms HEV circulation in one zoo between 2015 and 2016. Seropositivity was significantly higher in hominids than in other NHP families. HEV RNA was not detected in any of the serum samples tested. The results indicate susceptibility of NHPs to HEV infection. Further studies are required to elucidate the role of these species in the epidemiology of HEV.
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Affiliation(s)
- Javier Caballero-Gómez
- Animal Health Department, University of Cordoba, Cordoba, Spain.,Infectious Diseases Unit and Clinical Virology and Zoonoses Unit, Maimonides Institute for Biomedical Research, Reina Sofia Hospital, University of Cordoba, Cordoba, Spain
| | - Antonio Rivero-Juarez
- Infectious Diseases Unit and Clinical Virology and Zoonoses Unit, Maimonides Institute for Biomedical Research, Reina Sofia Hospital, University of Cordoba, Cordoba, Spain
| | | | - Maria A Risalde
- Infectious Diseases Unit and Clinical Virology and Zoonoses Unit, Maimonides Institute for Biomedical Research, Reina Sofia Hospital, University of Cordoba, Cordoba, Spain.,Animal Pathology Department, University of Cordoba, Cordoba, Spain
| | - Pedro Lopez-Lopez
- Infectious Diseases Unit and Clinical Virology and Zoonoses Unit, Maimonides Institute for Biomedical Research, Reina Sofia Hospital, University of Cordoba, Cordoba, Spain
| | - Mario Frias
- Infectious Diseases Unit and Clinical Virology and Zoonoses Unit, Maimonides Institute for Biomedical Research, Reina Sofia Hospital, University of Cordoba, Cordoba, Spain
| | - Saúl Jiménez-Ruiz
- Animal Health Department, University of Cordoba, Cordoba, Spain.,Health & Biotechnology (SaBio) Group, Spanish Wildlife Research Institute (IREC; CSIC-UCLM-JCCCM), Ciudad Real, Spain
| | - Antonio Rivero
- Infectious Diseases Unit and Clinical Virology and Zoonoses Unit, Maimonides Institute for Biomedical Research, Reina Sofia Hospital, University of Cordoba, Cordoba, Spain
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26
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Lanford RE, Walker CM, Lemon SM. Nonhuman Primate Models of Hepatitis A Virus and Hepatitis E Virus Infections. Cold Spring Harb Perspect Med 2019; 9:a031815. [PMID: 29686041 PMCID: PMC6360867 DOI: 10.1101/cshperspect.a031815] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Although phylogenetically unrelated, human hepatitis viruses share an exclusive or near exclusive tropism for replication in differentiated hepatocytes. This narrow tissue tropism may contribute to the restriction of the host ranges of these viruses to relatively few host species, mostly nonhuman primates. Nonhuman primate models thus figure prominently in our current understanding of the replication and pathogenesis of these viruses, including the enterically transmitted hepatitis A virus (HAV) and hepatitis E virus (HEV), and have also played major roles in vaccine development. This review draws comparisons of HAV and HEV infection from studies conducted in nonhuman primates, and describes how such studies have contributed to our current understanding of the biology of these viruses.
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Affiliation(s)
- Robert E Lanford
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas 782227
| | - Christopher M Walker
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children's Hospital and College of Medicine, The Ohio State University, Columbus, Ohio 43205
| | - Stanley M Lemon
- Departments of Medicine and Microbiology & Immunology, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7030
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27
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Life cycle and morphogenesis of the hepatitis E virus. Emerg Microbes Infect 2018; 7:196. [PMID: 30498191 PMCID: PMC6265337 DOI: 10.1038/s41426-018-0198-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 11/01/2018] [Accepted: 11/05/2018] [Indexed: 12/19/2022]
Abstract
Hepatitis E virus (HEV) is transmitted primarily via contaminated water and food by the fecal oral route and causes epidemics in developing countries. In industrialized countries, zoonotic transmission of HEV is prevalent. In addition, HEV is the major cause of acute hepatitis in healthy adults and can cause chronic hepatitis in immunocompromised patients, with pregnant HEV-infected women having increased mortality rates of approximately 25%. HEV was once an understudied and neglected virus. However, in recent years, the safety of blood products with respect to HEV has increasingly been considered to be a public health problem. The establishment of HEV infection models has enabled significant progress to be made in understanding its life cycle. HEV infects cells via a receptor (complex) that has yet to be identified. The HEV replication cycle is initiated immediately after the (+) stranded RNA genome is released into the cell cytosol. Subsequently, infectious viral particles are released by the ESCRT complex as quasi-enveloped viruses (eHEVs) into the serum, whereas feces and urine contain only nonenveloped infectious viral progeny. The uncoating of the viral envelope takes place in the biliary tract, resulting in the generation of a nonenveloped virus that is more resistant to environmental stress and possesses a higher infectivity than that of eHEV. This review summarizes the current knowledge regarding the HEV life cycle, viral morphogenesis, established model systems and vaccine development.
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28
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Abstract
Soon after the 1991 molecular cloning of hepatitis E virus (HEV), recombinant viral capsid antigens were expressed and tested in nonhuman primates for protection against liver disease and infection. Two genotype 1 subunit vaccine candidates entered clinical development: a 56 kDA vaccine expressed in insect cells and HEV 239 vaccine expressed in Escherichia coli Both were highly protective against hepatitis E and acceptably safe. The HEV 239 vaccine was approved in China in 2011, but it is not yet prequalified by the World Health Organization, a necessary step for introduction into those low- and middle-income countries where the disease burden is highest. Nevertheless, the stage is set for the final act in the hepatitis E vaccine story-policymaking, advocacy, and pilot introduction of vaccine in at-risk populations, in which it is expected to be cost-effective.
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Affiliation(s)
- Bruce L Innis
- Center for Vaccine Innovation and Access, PATH, Washington, D.C. 20001
| | - Julia A Lynch
- International Vaccine Institute, SNU Research Park, Gwanak-gu, Seoul 08826, Korea
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29
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Ankcorn M, Moreira F, Ijaz S, Symes A, Buckland MS, Workman S, Warburton F, Tedder RS, Lowe DM. Absence of Persistent Hepatitis E Virus Infection in Antibody-Deficient Patients Is Associated With Transfer of Antigen-Neutralizing Antibodies From Immunoglobulin Products. J Infect Dis 2018; 219:245-253. [DOI: 10.1093/infdis/jiy504] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 08/16/2018] [Indexed: 02/07/2023] Open
Affiliation(s)
- Mike Ankcorn
- Blood Borne Virus Unit, Virus Reference Department, Public Health England
- Transfusion Microbiology, National Health Service Blood and Transplant
| | - Fernando Moreira
- Department of Clinical Immunology, Royal Free London National Health Service Foundation Trust
| | - Samreen Ijaz
- Blood Borne Virus Unit, Virus Reference Department, Public Health England
| | - Andrew Symes
- Department of Clinical Immunology, Royal Free London National Health Service Foundation Trust
| | - Matthew S Buckland
- Department of Clinical Immunology, Royal Free London National Health Service Foundation Trust
- Institute of Immunity and Transplantation, University College London, Royal Free Campus
| | - Sarita Workman
- Department of Clinical Immunology, Royal Free London National Health Service Foundation Trust
| | - Fiona Warburton
- Statistics, Modelling, and Economics Department, Public Health England
| | - Richard S Tedder
- Blood Borne Virus Unit, Virus Reference Department, Public Health England
- Transfusion Microbiology, National Health Service Blood and Transplant
- Division of Infection and Immunity, University College London, London, United Kingdom
| | - David M Lowe
- Department of Clinical Immunology, Royal Free London National Health Service Foundation Trust
- Institute of Immunity and Transplantation, University College London, Royal Free Campus
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Abstract
Hepatitis E virus (HEV) infection is an emerging zoonotic disease posing a severe threat to public health in the world, especially to pregnant women. Currently, no specific treatments are available for HEV infection. Therefore, it is crucial to develop vaccine to prevent this infection. Although several potential candidate vaccines against HEV have been studied for their immunogenicity and efficacy, only Hecolin® which is developed by Xiamen Innovax Biotech Co., Ltd. and approved by China Food and Drug Administration (CFDA) in 2012, is the licensed HEV vaccine in the world so far. Extensive studies on safety, immunogenicity and efficacy in phase III clinical trials have shown that Hecolin® is a promising vaccine for HEV prevention and control. In this article, the advances on HEV vaccine development and research are briefly reviewed.
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Affiliation(s)
- Yufeng Cao
- a College of Veterinary Medicine, Jilin University , Changchun , Jilin , PR China.,b Changchun Institute of Biological Products Co. Ltd. , Changchun , Jilin , PR China
| | - Zhenhong Bing
- c Changchun Institute of Biological Products , Changchun , Jilin , PR China
| | - Shiyu Guan
- c Changchun Institute of Biological Products , Changchun , Jilin , PR China
| | - Zecai Zhang
- a College of Veterinary Medicine, Jilin University , Changchun , Jilin , PR China.,d Key laboratory for Zoonosis , Ministry of Education, and Institute for Zoonosis of Jilin University , Changchun , Jilin , PR China
| | - Xinping Wang
- a College of Veterinary Medicine, Jilin University , Changchun , Jilin , PR China.,d Key laboratory for Zoonosis , Ministry of Education, and Institute for Zoonosis of Jilin University , Changchun , Jilin , PR China
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31
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Characterization of Three Novel Linear Neutralizing B-Cell Epitopes in the Capsid Protein of Swine Hepatitis E Virus. J Virol 2018; 92:JVI.00251-18. [PMID: 29669835 DOI: 10.1128/jvi.00251-18] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 04/10/2018] [Indexed: 01/13/2023] Open
Abstract
Hepatitis E virus (HEV) causes liver disease in humans and is thought to be a zoonotic infection, with domestic animals, including swine and rabbits, being a reservoir. One of the proteins encoded by the virus is the capsid protein. This is likely the major immune-dominant protein and a target for vaccination. Four monoclonal antibodies (MAbs), three novel, 1E4, 2C7, and 2G9, and one previously characterized, 1B5, were evaluated for binding to the capsid protein from genotype 4 swine HEV. The results indicated that 625DFCP628, 458PSRPF462, and 407EPTV410 peptides on the capsid protein comprised minimal amino acid sequence motifs recognized by 1E4, 2C7, and 2G9, respectively. The data suggested that 2C7 and 2G9 epitopes were partially exposed on the surface of the capsid protein. Truncated genotype 4 swine HEV capsid protein (sp239, amino acids 368 to 606) can exist in multimeric forms. Preincubation of swine HEV with 2C7, 2G9, or 1B5 before addition to HepG2 cells partially blocked sp239 cell binding and inhibited swine HEV infection. The study indicated that 2C7, 2G9, and 1B5 partially blocked swine HEV infection of rabbits better than 1E4 or normal mouse IgG. The cross-reactivity of antibodies suggested that capsid epitopes recognized by 2C7 and 2G9 are common to HEV strains infecting most host species. Collectively, MAbs 2C7, 2G9, and 1B5 were shown to recognize three novel linear neutralizing B-cell epitopes of genotype 4 HEV capsid protein. These results enhance understanding of HEV capsid protein structure to guide vaccine and antiviral design.IMPORTANCE Genotype 3 and 4 HEVs are zoonotic viruses. Here, genotype 4 HEV was studied due to its prevalence in human populations and pig herds in China. To improve HEV disease diagnosis and prevention, a better understanding of the antigenic structure and neutralizing epitopes of HEV capsid protein are needed. In this study, the locations of three novel linear B-cell recognition epitopes within genotype 4 swine HEV capsid protein were characterized. Moreover, the neutralizing abilities of three MAbs specific for this protein, 2C7, 2G9, and 1B5, were studied in vitro and in vivo Collectively, these findings reveal structural details of genotype 4 HEV capsid protein and should facilitate development of applications for the design of vaccines and antiviral drugs for broader prevention, detection, and treatment of HEV infection of diverse human and animal hosts.
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32
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Abstract
Humans have a close phylogenetic relationship with nonhuman primates (NHPs) and share many physiological parallels, such as highly similar immune systems, with them. Importantly, NHPs can be infected with many human or related simian viruses. In many cases, viruses replicate in the same cell types as in humans, and infections are often associated with the same pathologies. In addition, many reagents that are used to study the human immune response cross-react with NHP molecules. As such, NHPs are often used as models to study viral vaccine efficacy and antiviral therapeutic safety and efficacy and to understand aspects of viral pathogenesis. With several emerging viral infections becoming epidemic, NHPs are proving to be a very beneficial benchmark for investigating human viral infections.
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Affiliation(s)
- Jacob D Estes
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, MD, USA
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, USA
| | - Scott W Wong
- Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR, USA
| | - Jason M Brenchley
- Barrier Immunity Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
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33
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Abstract
At least 20 million hepatitis E virus (HEV) infections occur annually, with >3 million symptomatic cases and ∼60,000 fatalities. Hepatitis E is generally self-limiting, with a case fatality rate of 0.5-3% in young adults. However, it can cause up to 30% mortality in pregnant women in the third trimester and can become chronic in immunocompromised individuals, such as those receiving organ transplants or chemotherapy and individuals with HIV infection. HEV is transmitted primarily via the faecal-oral route and was previously thought to be a public health concern only in developing countries. It is now also being frequently reported in industrialized countries, where it is transmitted zoonotically or through organ transplantation or blood transfusions. Although a vaccine for HEV has been developed, it is only licensed in China. Additionally, no effective, non-teratogenic and specific treatments against HEV infections are currently available. Although progress has been made in characterizing HEV biology, the scarcity of adequate experimental platforms has hampered further research. In this Review, we focus on providing an update on the HEV life cycle. We will further discuss existing cell culture and animal models and highlight platforms that have proven to be useful and/or are emerging for studying other hepatotropic (viral) pathogens.
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Affiliation(s)
- Ila Nimgaonkar
- Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey 08544, USA
| | - Qiang Ding
- Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey 08544, USA
| | - Robert E Schwartz
- Division of Gastroenterology and Hepatology, Department of Medicine, Weill Medical College of Cornell University, New York, New York 10021, USA
| | - Alexander Ploss
- Department of Molecular Biology, Princeton University, Lewis Thomas Laboratory, Washington Road, Princeton, New Jersey 08544, USA
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34
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Melgaço JG, Gardinali NR, de Mello VDM, Leal M, Lewis-Ximenez LL, Pinto MA. Hepatitis E: Update on Prevention and Control. BIOMED RESEARCH INTERNATIONAL 2018; 2018:5769201. [PMID: 29546064 PMCID: PMC5818934 DOI: 10.1155/2018/5769201] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 11/28/2017] [Accepted: 12/13/2017] [Indexed: 12/20/2022]
Abstract
Hepatitis E virus (HEV) is a common etiology of acute viral hepatitis worldwide. Recombinant HEV vaccines have been developed, but only one is commercially available and licensed in China since 2011. Epidemiological studies have identified genotype 3 as the major cause of chronic infection in immunocompromised individuals. Ribavirin has been shown to be effective as a monotherapy to induce HEV clearance in chronic patients who have undergone solid organ transplant (SOT) under immunosuppressive therapy. Efforts and improvements in prevention and control have been made to reduce the instances of acute and chronic hepatitis E in endemic and nonendemic countries. However, this review shows that further studies are required to demonstrate the importance of preventive vaccination and treatment worldwide, with emphasis on hepatitis E infection in the public health system.
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Affiliation(s)
- Juliana Gil Melgaço
- Ambulatório/Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Noemi Rovaris Gardinali
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Vinicius da Motta de Mello
- Ambulatório/Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Mariana Leal
- Ambulatório/Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Lia Laura Lewis-Ximenez
- Ambulatório/Laboratório de Hepatites Virais, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
| | - Marcelo Alves Pinto
- Laboratório de Desenvolvimento Tecnológico em Virologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, RJ, Brazil
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35
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36
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Hakim MS, Ikram A, Zhou J, Wang W, Peppelenbosch MP, Pan Q. Immunity against hepatitis E virus infection: Implications for therapy and vaccine development. Rev Med Virol 2017; 28. [PMID: 29272060 DOI: 10.1002/rmv.1964] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 11/10/2017] [Accepted: 11/14/2017] [Indexed: 12/20/2022]
Abstract
Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis worldwide and an emerging cause of chronic infection in immunocompromised patients. As with viral infections in general, immune responses are critical to determine the outcome of HEV infection. Accumulating studies in cell culture, animal models and patients have improved our understanding of HEV immunopathogenesis and informed the development of new antiviral therapies and effective vaccines. In this review, we discuss the recent progress on innate and adaptive immunity in HEV infection, and the implications for the devolopment of effective vaccines and immune-based therapies.
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Affiliation(s)
- Mohamad S Hakim
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.,Department of Microbiology, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Aqsa Ikram
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.,Atta-Ur-Rahman School of Applied Biosciences, National University of Science and Technology, Islamabad, Pakistan
| | - Jianhua Zhou
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.,State Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, PR China
| | - Wenshi Wang
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands
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37
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Spahr C, Knauf-Witzens T, Vahlenkamp T, Ulrich RG, Johne R. Hepatitis E virus and related viruses in wild, domestic and zoo animals: A review. Zoonoses Public Health 2017; 65:11-29. [PMID: 28944602 DOI: 10.1111/zph.12405] [Citation(s) in RCA: 84] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Indexed: 01/15/2023]
Abstract
Hepatitis E is a human disease mainly characterized by acute liver illness, which is caused by infection with the hepatitis E virus (HEV). Large hepatitis E outbreaks have been described in developing countries; however, the disease is also increasingly recognized in industrialized countries. Mortality rates up to 25% have been described for pregnant women during outbreaks in developing countries. In addition, chronic disease courses could be observed in immunocompromised transplant patients. Whereas the HEV genotypes 1 and 2 are mainly confined to humans, genotypes 3 and 4 are also found in animals and can be zoonotically transmitted to humans. Domestic pig and wild boar represent the most important reservoirs for these genotypes. A distinct subtype of genotype 3 has been repeatedly detected in rabbits and a few human patients. Recently, HEV genotype 7 has been identified in dromedary camels and in an immunocompromised transplant patient. The reservoir animals get infected with HEV without showing any clinical symptoms. Besides these well-known animal reservoirs, HEV-specific antibodies and/or the genome of HEV or HEV-related viruses have also been detected in many other animal species, including primates, other mammals and birds. In particular, genotypes 3 and 4 infections are documented in many domestic, wildlife and zoo animal species. In most cases, the presence of HEV in these animals can be explained by spillover infections, but a risk of virus transmission through contact with humans cannot be excluded. This review gives a general overview on the transmission pathways of HEV to humans. It particularly focuses on reported serological and molecular evidence of infections in wild, domestic and zoo animals with HEV or HEV-related viruses. The role of these animals for transmission of HEV to humans and other animals is discussed.
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Affiliation(s)
- C Spahr
- Wilhelma Zoological-Botanical Gardens, Stuttgart, Germany.,Faculty of Veterinary Medicine, Institute of Virology, University of Leipzig, Leipzig, Germany
| | | | - T Vahlenkamp
- Faculty of Veterinary Medicine, Institute of Virology, University of Leipzig, Leipzig, Germany
| | - R G Ulrich
- Friedrich-Loeffler-Institut, Federal Research Institute for Animal Health, Institute of Novel and Emerging Infectious Diseases, Greifswald-Insel Riems, Germany.,German Center for Infection Research (DZIF), partner site Hamburg-Luebeck-Borstel-Insel Riems, Braunschweig, Germany
| | - R Johne
- Department Biological Safety, German Federal Institute for Risk Assessment, Berlin, Germany
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38
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Zhang J, Zhao Q, Xia N. Prophylactic Hepatitis E Vaccine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 948:223-246. [PMID: 27738988 DOI: 10.1007/978-94-024-0942-0_13] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatitis E has been increasingly recognized as an underestimated global disease burden in recent years. Subpopulations with more serious infection-associated damage or death include pregnant women, patients with basic liver diseases, and elderly persons. Vaccine would be the most effective means for prevention of HEV infection. The lack of an efficient cell culture system for HEV makes the development of classic inactive or attenuated vaccine infeasible. Hence, the recombinant vaccine approaches are explored deeply. The neutralizing sites are located almost exclusively in the capsid protein, pORF2, of the virion. Based on pORF2, many vaccine candidates showed potential of protecting primate animals; two of them were tested in human and evidenced to be well tolerated in adults and highly efficacious in preventing hepatitis E. The world's first hepatitis E vaccine, Hecolin® (HEV 239 vaccine), was licensed in China and launched in 2012.
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Affiliation(s)
- Jun Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China.
| | - Qinjian Zhao
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
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39
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Abstract
Hepatitis E virus (HEV) is globally prevalent with relatively high percentages of anti-HEV immunoglobulin G-positive individuals in the populations of developing and developed countries. There are two distinct epidemiologic patterns of hepatitis E. In areas with high disease endemicity, primarily developing countries in Asia and Africa, this disease is caused mainly by genotype 1 or 2 HEV, both of which transmit predominantly through contaminated water and occur as either outbreaks or as sporadic cases of acute hepatitis. The acute hepatitis caused by either of these two genotypes has the highest attack rate in young adults, and the disease is particularly severe among pregnant women. In developed countries, sporadic cases of locally acquired genotype 3 or 4 HEV infection are observed. The reservoir of genotype 3 and 4 HEV is believed to be animals, such as pigs, with zoonotic transmission to humans. The affected persons are often elderly, and persistent infection has been well documented among immunosuppressed persons. A subunit vaccine has been shown to be effective in preventing clinical disease and has been licensed in China.
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Affiliation(s)
- Yansheng Geng
- School of Public Health, Hebei University, No. 342 Yuhuadonglu, Baoding, 071000, China.
| | - Youchun Wang
- Division of HIV/AIDS and Sex-transmitted Virus Vaccines, National Institutes for Food and Drug Control, No. 2 Tiantanxili, Dongcheng District, Beijing, 100050, China
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40
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Immunobiology and Host Response to HEV. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 948:113-141. [PMID: 27738982 DOI: 10.1007/978-94-024-0942-0_7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatitis E virus (HEV) causes acute self-limiting hepatitis in most cases and chronic infection in rare circumstances. It is believed to be noncytopathic, so immunologically mediated events should play important roles in its pathogenesis and infection outcomes. The anti-HEV antibody response was clarified when the major antigenic determinants on the ORF2 polypeptide were determined, which are located in its C-terminal portion. This subregion also forms the conformational neutralization epitopes. Robust anti-HEV immunoglobulin M (IgM) and IgG responses usually develop 3-4 weeks after infection in experimentally infected nonhuman primates. In humans, potent specific IgM and IgG responses occur in the very early phase of the disease and are critical in eliminating the virus, in concert with the innate and adaptive T-cell immune responses. They are also very valuable in the diagnosis of acute hepatitis E, when patients are tested for both anti-HEV IgM and IgG. The long-term persistence and protection of anti-HEV IgG provide the basis for estimating the prevalence of HEV infection and for the development of a hepatitis E vaccine. Although HEV has four genotypes, all the viral strains are considered to belong to a single serotype. It is becoming increasingly clear that the innate and adaptive T-cell immune responses play critical roles in the clearance of the virus. Potent and multispecific CD4+ and CD8+ T-cell responses to the ORF2 protein occur in patients with acute hepatitis E, and weaker HEV-specific CD4+ and CD8+ T-cell responses appear to be associated with chronic hepatitis E in immunocompromised individuals.
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Wu X, Chen P, Lin H, Su Y, Hao X, Cao Y, Li L, Zhu F, Liang Z. Dynamics of 8G12 competitive antibody in "prime-boost" vaccination of Hepatitis E vaccine. Hum Vaccin Immunother 2017; 13:1-6. [PMID: 28272983 DOI: 10.1080/21645515.2017.1291105] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus still poses a great threat to public health worldwide. To date, Hecolin® is the only licensed HEV vaccine in China. Total anti-HEV antibody has been used to reflect vaccine induced immune response in clinical trials for the lack of robust HEV neutralizing antibody detection methods. In this study, we applied a broad neutralizing mouse monoclonal antibody 8G12 to develop a competitive ELSIA assay and quantified 8G12 competitive antibody (8G12-like antibody) in serum samples. The presence of 8G12-like antibody was detected both from participants from HEV vaccine clinical trial and mice immunized with HEV vaccine. Furthermore, 8G12-like antibody was found to have a similar dynamic pattern as anti-HEV antibody during "prime-boost" vaccination, and the proportion of 8G12-like antibody in anti-HEV antibody increased along boost vaccination. Together with previously reported finding that 8G12 could block the most binding of HEV vaccine induced serum antibody to vaccine antigen, we proposed that 8G12-like antibody might be a promising surrogate for vaccine induced HEV neutralizing antibody and had potential to be used as a convenient indicator for HEV vaccine potency evaluation.
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Affiliation(s)
- Xing Wu
- a National Institutes for Food and Drug Control , Beijing , China
| | - Pan Chen
- a National Institutes for Food and Drug Control , Beijing , China
| | - Huijuan Lin
- b R&D Department , Shanghai Institute of Biological Products Co., Ltd. , Shanghai , China
| | - Yao Su
- c Changchun Institute of Biological Products Co. Ltd., China National Biotech Corporation , Changchun , China
| | - Xiaotian Hao
- a National Institutes for Food and Drug Control , Beijing , China
| | - Yufeng Cao
- c Changchun Institute of Biological Products Co. Ltd., China National Biotech Corporation , Changchun , China
| | - Li Li
- c Changchun Institute of Biological Products Co. Ltd., China National Biotech Corporation , Changchun , China
| | - Fengcai Zhu
- d Jiangsu Provincial Center for Disease Prevention and Control , Nanjing , China
| | - Zhenglun Liang
- a National Institutes for Food and Drug Control , Beijing , China
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Pelosi E, Clarke I. Hepatitis E: a complex and global disease. EMERGING HEALTH THREATS JOURNAL 2017. [DOI: 10.3402/ehtj.v1i0.7069] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Affiliation(s)
- E Pelosi
- Department of Microbiology and Virology, Health Protection Agency, Southeast Regional Laboratory, Southampton General Hospital, Southampton, UK; and
| | - I Clarke
- Department of Molecular Microbiology, Southampton Medical School, Southampton General Hospital, Southampton, UK
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Su YY, Huang SJ, Guo M, Zhao J, Yu H, He WG, Jiang HM, Wang YJ, Zhang XF, Cai JP, Yang CL, Wang ZZ, Zhu FC, Wu T, Zhang J, Xia NS. Persistence of antibodies acquired by natural hepatitis E virus infection and effects of vaccination. Clin Microbiol Infect 2016; 23:336.e1-336.e4. [PMID: 27836809 DOI: 10.1016/j.cmi.2016.10.029] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 10/15/2016] [Accepted: 10/28/2016] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Naturally acquired anti-hepatitis E virus (HEV) immunity can protect against new HEV infections. The aim of this study was to analyse the persistence of naturally acquired anti-HEV immunoglobulin (Ig) G and anti-HEV IgG concentrations after vaccination. METHODS We examined the seropositivity rates of participants included in a phase 3 clinical efficacy trial (67 months' follow-up) for a HEV vaccine (Hecolin; Xiamen Innovax Biotech, China) and predicted long-term persistence using mixed-effect models. RESULTS The analysis focused on 2242 baseline seropositive participants in a control group (placebo recipients) and 2031 baseline seropositive participants in an vaccine group (vaccine recipients) who received 1 to 3 doses of Hecolin. Naturally acquired anti-HEV IgG levels decreased steadily independent of the initial antibody level; 50% of the placebo recipients were expected to have undetectable antibody concentrations after 14.5 years. After immunization with Hecolin, the power-law model and the modified power-law model predicted that 82.1 and 99.4% of the participants, respectively, would remain seropositive for anti-HEV IgG for 30 years after vaccination. CONCLUSIONS Whereas naturally acquired anti-HEV IgG levels decrease steadily, HEV vaccination induces long-lasting, high-level anti-HEV IgG concentrations.
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Affiliation(s)
- Y-Y Su
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - S-J Huang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - M Guo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - J Zhao
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - H Yu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - W-G He
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - H-M Jiang
- Dongtai Centre for Disease Control and Prevention, Dongtai, China
| | - Y-J Wang
- Dongtai Centre for Disease Control and Prevention, Dongtai, China
| | - X-F Zhang
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - J-P Cai
- Dongtai Centre for Disease Control and Prevention, Dongtai, China
| | - C-L Yang
- Dongtai Centre for Disease Control and Prevention, Dongtai, China
| | - Z-Z Wang
- Dongtai Centre for Disease Control and Prevention, Dongtai, China
| | - F-C Zhu
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - T Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China.
| | - J Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China.
| | - N-S Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
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Kulkarni SP, Thanapati S, Arankalle VA, Tripathy AS. Specific memory B cell response and participation of CD4 + central and effector memory T cells in mice immunized with liposome encapsulated recombinant NE protein based Hepatitis E vaccine candidate. Vaccine 2016; 34:5895-5902. [PMID: 27997340 DOI: 10.1016/j.vaccine.2016.10.046] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 10/14/2016] [Accepted: 10/16/2016] [Indexed: 11/20/2022]
Abstract
BACKGROUND Liposome encapsulated neutralizing epitope protein of Hepatitis E virus (HEV), rNEp, our Hepatitis E vaccine candidate, was shown to be immunogenic and safe in pregnant and non-pregnant mice and yielded sterilizing immunity in rhesus monkeys. METHODS The current study in Balb/c mice assessed the levels and persistence of anti-HEV IgG antibodies by ELISA, frequencies of B, memory B, T and memory T cells by flow cytometry and HEV-specific IgG secreting memory B cells by ELISPOT till 420days post immunization (PI) with 5?g rNEp encapsulated in liposome based adjuvant (2 doses, 4weeks apart). Mice immunized with a lower dose (1?g) were assessed only for anamnestic response post booster dose. RESULTS Vaccine candidate immunized mice (5?g dose) elicited strong anti-HEV IgG response that was estimated to persist for lifetime. At day 120 PI, frequency of memory B cells was higher in immunized mice than those receiving adjuvant alone. Anti-HEV IgG titers were lower in mice immunized with 1?g dose. A booster dose yielded a heightened antibody response in mice with both high (>800GMT, 5?g) and low (?100GMT, 1?g) anti-HEV IgG titers. At day 6th post booster dose, HEV-specific antibody secreting plasma cells (ASCs) were detected in 100% and 50% of mice with high and low anti-HEV IgG titers, respectively, whereas the frequencies of CD4+ central and effector memory T cells were high in mice with high anti-HEV IgG titers only. CONCLUSIONS Taken together, the vaccine candidate effectively generates persistent and anamnestic antibody response, elicits participation of CD4+ memory T cells and triggers memory B cells to differentiate into ASCs upon boosting. This approach of assessing the immunogenicity of vaccine candidate could be useful to explore the longevity of HEV-specific memory response in future HEV vaccine trials in human.
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Affiliation(s)
- Shruti P Kulkarni
- Hepatitis Group, National Institute of Virology, Pune, 130/1, Sus Road, Pashan, Pune 411021, Maharashtra, India
| | - Subrat Thanapati
- Hepatitis Group, National Institute of Virology, Pune, 130/1, Sus Road, Pashan, Pune 411021, Maharashtra, India
| | - Vidya A Arankalle
- Interactive Research School in Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Katraj-Dhankawadi, Pune 411043, Maharashtra, India.
| | - Anuradha S Tripathy
- Hepatitis Group, National Institute of Virology, Pune, 130/1, Sus Road, Pashan, Pune 411021, Maharashtra, India.
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Doceul V, Bagdassarian E, Demange A, Pavio N. Zoonotic Hepatitis E Virus: Classification, Animal Reservoirs and Transmission Routes. Viruses 2016; 8:v8100270. [PMID: 27706110 PMCID: PMC5086606 DOI: 10.3390/v8100270] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 09/22/2016] [Indexed: 12/11/2022] Open
Abstract
During the past ten years, several new hepatitis E viruses (HEVs) have been identified in various animal species. In parallel, the number of reports of autochthonous hepatitis E in Western countries has increased as well, raising the question of what role these possible animal reservoirs play in human infections. The aim of this review is to present the recent discoveries of animal HEVs and their classification within the Hepeviridae family, their zoonotic and species barrier crossing potential, and possible use as models to study hepatitis E pathogenesis. Lastly, this review describes the transmission pathways identified from animal sources.
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Affiliation(s)
- Virginie Doceul
- French Agency for Food, Environmental and Occupational Health & Safety (ANSES), Animal Health Laboratory, UMR (joint research unit) 1161 Virology, 94701 Maisons-Alfort, France.
- French National Institute for Agricultural Research (INRA), UMR (joint research unit) 1161 Virology, 94700 Maisons-Alfort, France.
- Association of Universities and High Education Institutions (ComUE), Paris-Est Créteil Val-de-Marne University, National Veterinary School, UMR (joint research unit) 1161 Virology, 94700 Maisons-Alfort, France.
| | - Eugénie Bagdassarian
- French Agency for Food, Environmental and Occupational Health & Safety (ANSES), Animal Health Laboratory, UMR (joint research unit) 1161 Virology, 94701 Maisons-Alfort, France.
- French National Institute for Agricultural Research (INRA), UMR (joint research unit) 1161 Virology, 94700 Maisons-Alfort, France.
- Association of Universities and High Education Institutions (ComUE), Paris-Est Créteil Val-de-Marne University, National Veterinary School, UMR (joint research unit) 1161 Virology, 94700 Maisons-Alfort, France.
| | - Antonin Demange
- French Agency for Food, Environmental and Occupational Health & Safety (ANSES), Animal Health Laboratory, UMR (joint research unit) 1161 Virology, 94701 Maisons-Alfort, France.
- French National Institute for Agricultural Research (INRA), UMR (joint research unit) 1161 Virology, 94700 Maisons-Alfort, France.
- Association of Universities and High Education Institutions (ComUE), Paris-Est Créteil Val-de-Marne University, National Veterinary School, UMR (joint research unit) 1161 Virology, 94700 Maisons-Alfort, France.
| | - Nicole Pavio
- French Agency for Food, Environmental and Occupational Health & Safety (ANSES), Animal Health Laboratory, UMR (joint research unit) 1161 Virology, 94701 Maisons-Alfort, France.
- French National Institute for Agricultural Research (INRA), UMR (joint research unit) 1161 Virology, 94700 Maisons-Alfort, France.
- Association of Universities and High Education Institutions (ComUE), Paris-Est Créteil Val-de-Marne University, National Veterinary School, UMR (joint research unit) 1161 Virology, 94700 Maisons-Alfort, France.
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Lhomme S, Marion O, Abravanel F, Chapuy-Regaud S, Kamar N, Izopet J. Hepatitis E Pathogenesis. Viruses 2016; 8:E212. [PMID: 27527210 PMCID: PMC4997574 DOI: 10.3390/v8080212] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 07/22/2016] [Accepted: 07/27/2016] [Indexed: 02/08/2023] Open
Abstract
Although most hepatitis E virus (HEV) infections are asymptomatic, some can be severe, causing fulminant hepatitis and extra-hepatic manifestations, including neurological and kidney injuries. Chronic HEV infections may also occur in immunocompromised patients. This review describes how our understanding of the pathogenesis of HEV infection has progressed in recent years.
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Affiliation(s)
- Sébastien Lhomme
- INSERM, UMR1043, Department of Virology, CHU Purpan, Université Paul Sabatier, 31000 Toulouse, France.
| | - Olivier Marion
- INSERM, UMR1043, Department of Virology, CHU Purpan, Université Paul Sabatier, 31000 Toulouse, France.
- INSERM, UMR1043, Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Université Paul Sabatier, 31000 Toulouse, France.
| | - Florence Abravanel
- INSERM, UMR1043, Department of Virology, CHU Purpan, Université Paul Sabatier, 31000 Toulouse, France.
| | - Sabine Chapuy-Regaud
- INSERM, UMR1043, Department of Virology, CHU Purpan, Université Paul Sabatier, 31000 Toulouse, France.
| | - Nassim Kamar
- INSERM, UMR1043, Department of Nephrology, Dialysis and Organ Transplantation, CHU Rangueil, Université Paul Sabatier, 31000 Toulouse, France.
| | - Jacques Izopet
- INSERM, UMR1043, Department of Virology, CHU Purpan, Université Paul Sabatier, 31000 Toulouse, France.
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Garraud O, Heshmati F, Pozzetto B, Lefrere F, Girot R, Saillol A, Laperche S. Plasma therapy against infectious pathogens, as of yesterday, today and tomorrow. Transfus Clin Biol 2016; 23:39-44. [PMID: 26775794 PMCID: PMC7110444 DOI: 10.1016/j.tracli.2015.12.003] [Citation(s) in RCA: 96] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Indexed: 12/20/2022]
Abstract
Plasma therapy consists in bringing to a patient in need – in general suffering a severe, resistant to current therapy, and even lethal infection – plasma or specific, fractioned, antibodies, along with other immunoglobulins and possibly healing factors that can be obtained from immunized blood donors; donors (voluntary and benevolent) can be either actively immunized individuals or convalescent persons. Plasma therapy has been used since the Spanish flu in 1917–1918, and regularly then when viral epidemics threatened vulnerable populations, the last reported occurrence being the 2013–2015 Ebola virus outbreak in West Africa. The precise action mechanism of plasma therapy is not fully delineated as it may function beyond purified, neutralizing antibodies.
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Affiliation(s)
- O Garraud
- Faculté de médecine de Saint-Étienne, université de Lyon, 42023 Saint-Étienne, France; Institut national de la transfusion sanguine, 75015 Paris, France.
| | - F Heshmati
- Hôpital Cochin, Assistance publique des Hôpitaux de Paris, 75005 Paris, France
| | - B Pozzetto
- Faculté de médecine de Saint-Étienne, université de Lyon, 42023 Saint-Étienne, France; Laboratoire des agents infectieux et d'hygiène, CHU de Saint-Étienne, 42055 Saint-Étienne, France
| | - F Lefrere
- Groupe Necker-Enfants malades, Assistance publique des Hôpitaux de Paris, 75015, Paris, France
| | - R Girot
- Hôpital Tenon, Assistance publique des Hôpitaux de Paris, 75020 Paris, France; Université Pierre-et-Marie-Curie-Paris 6, 75005 Paris, France
| | - A Saillol
- Centre de transfusion sanguine des armées, 92140 Clamart, France
| | - S Laperche
- Institut national de la transfusion sanguine, 75015 Paris, France
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Zhao Q, Syed SF, Zhou EM. Antigenic properties of avian hepatitis E virus capsid protein. Vet Microbiol 2015; 180:10-4. [PMID: 26340899 DOI: 10.1016/j.vetmic.2015.08.016] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 08/23/2015] [Accepted: 08/24/2015] [Indexed: 12/23/2022]
Abstract
Avian hepatitis E virus (HEV) is the main causative agent of big liver and spleen disease and hepatitis-splenomegaly syndrome in chickens, and is genetically and antigenically related to mammalian HEVs. HEV capsid protein contains immunodominant epitopes and induces a protective humoral immune response. A better understanding of the antigenic composition of this protein is critically important for the development of effective vaccine and sensitive and specific serological assays. To date, six linear antigenic domains (I-VI) have been characterized in avian HEV capsid protein and analyzed for their applications in the serological diagnosis and vaccine design. Domains I and V induce strong immune response in chickens and are common to avian, human, and swine HEVs, indicating that the shared epitopes hampering differential diagnosis of avian HEV infection. Domains III and IV are not immunodominant and elicit a weak immune response. Domain VI, located in the N-terminal region of the capsid protein, can also trigger an intense immune response, but the anti-domain VI antibodies are transient. The protection analysis showed that the truncated capsid protein containing the C-terminal 268 amino acid residues expressed by the bacterial system can provide protective immunity against avian HEV infection in chickens. However, the synthetic peptides incorporating the different linear antigenic domains (I-VI) and epitopes are non-protective. The antigenic composition of avian HEV capsid protein is altogether complex. To develop an effective vaccine and accurate serological diagnostic methods, more conformational antigenic domains or epitopes are to be characterized in detail.
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Affiliation(s)
- Qin Zhao
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Scientific Observing and Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, Yangling 712100, Shaanxi, China
| | - Shahid Faraz Syed
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Scientific Observing and Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, Yangling 712100, Shaanxi, China
| | - En-Min Zhou
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling 712100, Shaanxi, China; Scientific Observing and Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, Yangling 712100, Shaanxi, China.
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Taherkhani R, Farshadpour F, Makvandi M. Design and production of a multiepitope construct derived from hepatitis E virus capsid protein. J Med Virol 2015; 87:1225-34. [PMID: 25784455 PMCID: PMC7159329 DOI: 10.1002/jmv.24171] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2015] [Indexed: 11/15/2022]
Abstract
The aim of this study was to design a high density multiepitope protein, which can be a promising multiepitope vaccine candidate against Hepatitis E virus (HEV). Initially, conserved and antigenic helper T‐lymphocyte (HTL) epitopes in the HEV capsid protein were predicted by in silico analysis. Subsequently, a multiepitope comprising four HTL epitopes with high‐affinity binding to the HLA molecules was designed, and repeated four times as high density multiepitope construct. This construct was synthesized and cloned into pET‐30a (+) vector. Then, it was transformed and expressed in Escherichia coli BL21 cells. The high density multiepitope protein was purified by Ni‐NTA agarose and concentrated using Amicon filters. Finally, the immunological properties of this high density multiepitope protein were evaluated in vitro. The results showed that the high density multiepitope construct was successfully expressed and purified. SDS‐PAGE and Western blot analyses showed the presence of a high density multiepitope protein band of approximately 33 kDa. Approximately 1 mg of the purified protein was obtained from each liter of the culture media. Moreover, the purified multiepitope protein was capable of induction of proliferation responses, IFN‐γ ELISPOT responses and IFN‐γ and IL‐12 cytokines production in a significant level in peripheral blood mononuclear cells (PBMCs) isolated from HEV‐recovered individuals compared to the control group. In conclusion, the newly produced multiepitope protein can induce significant T helper type 1 responses in vitro, and can be considered as a novel strategy for the development of HEV vaccines in the future. J. Med. Virol. 87:1225–1234, 2015. © 2015 Wiley Periodicals, Inc.
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Affiliation(s)
- Reza Taherkhani
- Department of Microbiology and Parasitology, School of Medicine, Bushehr University of Medical Sciences, Bushehr, Iran; Persian Gulf Biomedical Research Center, Bushehr University of Medical Sciences, Bushehr, Iran
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Characterization of Two Novel Linear B-Cell Epitopes in the Capsid Protein of Avian Hepatitis E Virus (HEV) That Are Common to Avian, Swine, and Human HEVs. J Virol 2015; 89:5491-501. [PMID: 25741007 DOI: 10.1128/jvi.00107-15] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 02/26/2015] [Indexed: 11/20/2022] Open
Abstract
UNLABELLED Antisera raised against the avian hepatitis E virus (HEV) capsid protein are cross-reactive with human and swine HEV capsid proteins. In this study, two monoclonal antibodies (MAbs) against the avian HEV capsid protein, namely, 3E8 and 1B5, were shown to cross-react with the swine HEV capsid protein. The motifs involved in binding both MAbs were identified and characterized using phage display biopanning, peptide synthesis, and truncated or mutated protein expression, along with indirect enzyme-linked immunosorbent assay (ELISA) and Western blotting. The results showed that the I/VPHD motif is a necessary core sequence and that P and H are two key amino acids for recognition by MAb 3E8. The VKLYM/TS motif is the minimal amino acid sequence necessary for recognition by MAb 1B5. Cross-reactivity between the two epitopes and antibodies against avian, swine, and human HEVs in sera showed that both epitopes are common to avian, swine, and human HEVs. In addition, amino acid sequence alignment of the capsid proteins revealed that the key motifs of both novel epitopes are the same in HEVs from different animal species, predicting that they may be common to HEV isolates from boars, rabbits, rats, ferrets, mongooses, deer, and camels as well. Protein modeling analysis showed that both epitopes are at least partially exposed on the surface of the HEV capsid protein. Protective capacity analysis demonstrated that the two epitopes are nonprotective against avian HEV infection in chickens. Collectively, these studies characterize two novel linear B-cell epitopes common to avian, swine, and human HEVs, which furthers the understanding of HEV capsid protein antigenic structure. IMPORTANCE More and more evidence indicates that the host range diversity of hepatitis E virus (HEV) is a global public health concern. A better understanding of the antigenic structure of the HEV capsid protein may improve disease diagnosis and prevention. In this study, binding site mapping and localization as well as the antigenic biology of two novel linear B-cell epitopes common to several different species of HEV were characterized. These findings partially reveal the antigenic structure of the HEV capsid protein and provide potential applications for the development of diagnostics and interventions for HEV infection.
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