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Yan XL, Li J, Ma QQ, Wang HJ, Li L, Zhao H, Qin CF, Li XF. Identification of mutations in viral proteins involved in cell adaptation using a reverse genetic system of the live attenuated hepatitis A virus vaccine H2 strain. Virol Sin 2024; 39:882-891. [PMID: 39151705 PMCID: PMC11738778 DOI: 10.1016/j.virs.2024.08.004] [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: 04/10/2024] [Accepted: 08/12/2024] [Indexed: 08/19/2024] Open
Abstract
The live attenuated hepatitis A virus vaccine H2 strain was developed by passaging a wild-type H2w isolate in cell cultures. Currently, the mechanism underlying its attenuation phenotype remain largely unknown. In this study, we generated a full-length infectious cDNA clone of the H2 strain using in-fusion techniques. The recovered H2 strain (H2ic) from the cDNA clone exhibited an efficient replication in both the hepatoma cell line Huh7.5.1 and the 2BS cell line used for vaccine production, similar to the parental H2 strain. Additionally, H2ic did not cause disease in Ifnar1-/- C57 mice, consistent with the H2 strain. To explore the cell-adaptive mutations of the H2 strain, chimeric viruses were generated by replacing its non-structural proteins with corresponding regions from H2w using the infectious cDNA clone as a genetic backbone. The chimeric viruses carrying the 3C or 3D proteins from H2w showed decreased replication in Huh7.5.1 and 2BS cell lines compared to H2ic. Other chimeric viruses containing the 2B, 2C, or 3A proteins from H2w failed to be recovered. Furthermore, there were no significant differences in disease manifestation in mice between H2ic and the recovered chimeric viruses. These results demonstrate that adaptive mutations in the 2B, 2C, and 3A proteins are essential for efficient replication of the H2 strain in cell cultures. Mutations in the 3C and 3D proteins contribute to enhanced replication in cell cultures but did not influence the attenuated phenotypes in mice. Together, this study presents the first reverse genetic system of the H2 strain and identifies viral proteins essential for adaptation to cell cultures.
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Affiliation(s)
- Xiu-Li Yan
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, China; Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, 100071, China
| | - Jian Li
- Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, 100071, China; School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Qing-Qing Ma
- Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, 100071, China
| | - Hong-Jiang Wang
- Department of Research, The Chinese People's Liberation Army Strategic Support Force Medical Center, Beijing, 100101, China
| | - Lin Li
- Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, 100071, China; School of Medicine, Tsinghua University, Beijing, 100084, China
| | - Hui Zhao
- Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, 100071, China
| | - Cheng-Feng Qin
- Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, 100071, China.
| | - Xiao-Feng Li
- School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, China; Department of Virology, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, 100071, China.
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The infectivity and pathogenicity of Hepatitis A virus live-attenuated vaccine strain H2 in type I interferon receptor-deficient mice. Virol Sin 2022; 37:740-745. [PMID: 35863604 PMCID: PMC9583102 DOI: 10.1016/j.virs.2022.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 05/23/2022] [Indexed: 11/30/2022] Open
Abstract
Hepatitis A virus (HAV) live-attenuated vaccine H2 strain has been approved for clinical use for decades with ideal safety profiles in nonhuman primate models and humans. Recently, type I interferon (IFN) receptor-deficient mice were shown to be susceptible to HAV infection. Herein, we sought to determine the infection and replication dynamics of the H2 in Ifnar−/− mice that lack type I IFN receptor. Following intravenous injection, the H2 failed to cause obvious clinical symptoms in Ifnar−/− mice, and no significant upregulation in serum alanine aminotransferase (ALT) levels was observed. Notably, the histopathological examination showed that there were significant focal infiltrations of lymphocytes and neutrophils in the portal area, but no focal necrosis was observed in liver tissues. Viral RNAs sustained in the liver, and the infectious virus could be recovered from the liver tissue until 42 days post-infection. More importantly, H2 infection induced obvious viremia and persistent viral shedding in feces. In addition, robust HAV-specific humoral immune responses were induced in Ifnar−/− mice. Overall, our study revealed the safety profile of H2 in Ifnar−/− mice, which not only helps understand the attenuation mechanism of H2, but also expands the application of the Ifnar−/− mouse model for HAV studies.
We described the characteristics of Ifnar−/− mice infected by HAV H2 strain infection. H2 fails to induce ALT elevationand obvious liver damage in Ifnar−/− mice. H2 causes viremia, persistent viral shedding in feces, and replication in mice liver. H2 induces robust HAV-specific humoral immune responses in Ifnar−/− mice.
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Migueres M, Lhomme S, Izopet J. Hepatitis A: Epidemiology, High-Risk Groups, Prevention and Research on Antiviral Treatment. Viruses 2021; 13:1900. [PMID: 34696330 PMCID: PMC8540458 DOI: 10.3390/v13101900] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Revised: 09/15/2021] [Accepted: 09/20/2021] [Indexed: 12/17/2022] Open
Abstract
The hepatitis A virus (HAV) is a leading cause of acute viral hepatitis worldwide. It is transmitted mainly by direct contact with patients who have been infected or by ingesting contaminated water or food. The virus is endemic in low-income countries where sanitary and sociodemographic conditions are poor. Paradoxically, improving sanitary conditions in these countries, which reduces the incidence of HAV infections, can lead to more severe disease in susceptible adults. The populations of developed countries are highly susceptible to HAV, and large outbreaks can occur when the virus is spread by globalization and by increased travel and movement of foodstuffs. Most of these outbreaks occur among high-risk groups: travellers, men who have sex with men, people who use substances, and people facing homelessness. Hepatitis A infections can be prevented by vaccination; safe and effective vaccines have been available for decades. Several countries have successfully introduced universal mass vaccination for children, but high-risk groups in high-income countries remain insufficiently protected. The development of HAV antivirals may be important to control HAV outbreaks in developed countries where a universal vaccination programme is not recommended.
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Affiliation(s)
- Marion Migueres
- Virology Laboratory, Hôpital Purpan, CHU Toulouse, 31300 Toulouse, France; (S.L.); (J.I.)
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), INSERM UMR1291-CNRS UMR5051, 31300 Toulouse, France
- Université Toulouse III Paul-Sabatier, 31062 Toulouse, France
| | - Sébastien Lhomme
- Virology Laboratory, Hôpital Purpan, CHU Toulouse, 31300 Toulouse, France; (S.L.); (J.I.)
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), INSERM UMR1291-CNRS UMR5051, 31300 Toulouse, France
- Université Toulouse III Paul-Sabatier, 31062 Toulouse, France
| | - Jacques Izopet
- Virology Laboratory, Hôpital Purpan, CHU Toulouse, 31300 Toulouse, France; (S.L.); (J.I.)
- Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), INSERM UMR1291-CNRS UMR5051, 31300 Toulouse, France
- Université Toulouse III Paul-Sabatier, 31062 Toulouse, France
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Bhave S, Sapru A, Bavdekar A, Jain R, Debnath K, Kapatkar V. Long term Immunogenicity of Single Dose of Live Attenuated Hepatitis A Vaccine in Indian Children - Results of 15-Year Follow-up. Indian Pediatr 2021; 58:749-752. [PMID: 33612491 PMCID: PMC8384096] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/28/2020] [Accepted: 02/12/2021] [Indexed: 08/29/2024]
Abstract
OBJECTIVES To measure anti-HAV antibodies 15 years after a single dose of live attenuated hepatitis A vaccine in Indian children. METHODS Of the 143 children vaccinated in 2004, 109 were evaluated in 2019, clinically and for anti-HAV antibodies. These children have been assessed clinically every year, and for anti-HAV antibodies in 2004, 2007, 2010 and 2014. RESULTS Of the 109 children who came for the present assessment, 11 had received additional doses of hepatitis A vaccine in 2004/2007 because of low anti-HAV titre (<20 mIU/mL). In the remaining 98 children, 94 (96%) had seroprotective levels with a geometric mean titre of 79.6 mIU/mL. Seroprotection rate in all 109 children was 86.2%. CONCLUSIONS Single dose of live attenuated hepatitis A vaccine in Indian children demonstrated robust immunogenicity at 15 years post vaccination.
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Affiliation(s)
- Sheila Bhave
- Department of Pediatrics, KEM Hospital Research Centre, Pune, Maharashtra. Correspondence to: Dr Sheila Bhave, Consultant in Pediatric Research, Department of Pediatrics, KEM Hospital Research Centre, Rasta Peth, Pune 411 011, India.
| | - Amita Sapru
- Department of Pediatrics, KEM Hospital Research Centre, Pune, Maharashtra
| | - Ashish Bavdekar
- Department of Pediatrics, KEM Hospital Research Centre, Pune, Maharashtra
| | - Rishi Jain
- Department of Medical Affairs, Wockhardt Limited, Mumbai, Maharashtra
| | - Khokan Debnath
- Department of Medical Affairs, Wockhardt Limited, Mumbai, Maharashtra
| | - Vaibhavi Kapatkar
- Department of Medical Affairs, Wockhardt Limited, Mumbai; Maharashtra
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Bhave S, Sapru A, Bavdekar A, Jain R, Debnath K, Kapatkar V. Long term Immunogenicity of Single Dose of Live Attenuated Hepatitis A Vaccine in Indian Children — Results of 15-Year Follow-up. Indian Pediatr 2021. [PMID: 33612491 PMCID: PMC8384096 DOI: 10.1007/s13312-021-2285-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Objectives Methods Results Conclusions
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Affiliation(s)
- Sheila Bhave
- Department of Pediatrics, KEM Hospital Research Centre, Pune, Maharashtra. Correspondence to: Dr Sheila Bhave, Consultant in Pediatric Research, Department of Pediatrics, KEM Hospital Research Centre, Rasta Peth, Pune 411 011, India.
| | - Amita Sapru
- Department of Pediatrics, KEM Hospital Research Centre, Pune, Maharashtra
| | - Ashish Bavdekar
- Department of Pediatrics, KEM Hospital Research Centre, Pune, Maharashtra
| | - Rishi Jain
- Department of Medical Affairs, Wockhardt Limited, Mumbai, Maharashtra
| | - Khokan Debnath
- Department of Medical Affairs, Wockhardt Limited, Mumbai, Maharashtra
| | - Vaibhavi Kapatkar
- Department of Medical Affairs, Wockhardt Limited, Mumbai; Maharashtra
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Yang T, Xie T, Li H, Song X, Yue L, Wang X, Shen D, Ma K, Jiang Q, Long R, Yang R, He X, Zhang Y, Xie Z, Li Q. Immune responses of a CV-A16 live attenuated candidate strain and its protective effects in rhesus monkeys. Emerg Microbes Infect 2020; 9:2136-2146. [PMID: 32930072 PMCID: PMC7580583 DOI: 10.1080/22221751.2020.1823889] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 09/07/2020] [Accepted: 09/09/2020] [Indexed: 12/27/2022]
Abstract
Coxsackievirus A16 (CV-A16) is a major causative pathogen of hand, foot, and mouth diseases (HFMDs). The licensed HFMD vaccine targets EV-A71 without cross-protection against CV-A16. Thus, a CV-A16 vaccine is needed. In this study, the immunogenicity and protective efficacy of a live attenuated CV-A16 candidate, K168-8Ac, were evaluated in a rhesus monkey model. Four passages of this strain (P35, P50, P60, and P70) were administered to monkeys, and its protective effect was identified. The immunized monkeys were clinically asymptomatic, except for slight fever. Weak viraemia was observed, and two doses of vaccination were found to significantly reduce virus shedding. High levels of antibody responses were observed (1:1024-1:2048), along with a significant increase in plasma IL-8. The I.M. group showed a much stronger humoural immunity. Pathological damage was detected mainly in lung tissues, although thalamus, spinal cord, lymph nodes, and livers were involved. After the viral challenge, it was found that two doses of vaccine reduced virus shedding, and the degree of lung damage and the number of organs involved decreased as the passage number increased. Overall, a robust immune response and partial protection against CV-A16, triggered by the K168-8Ac strain, were demonstrated. This study provides valuable data for CV-A16 vaccine development.
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Affiliation(s)
- Ting Yang
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Tianhong Xie
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Hua Li
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Xia Song
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Lei Yue
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Xi Wang
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Dong Shen
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Kaili Ma
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Qinfang Jiang
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Runxiang Long
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Rong Yang
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Xin He
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Ye Zhang
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Zhongping Xie
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
| | - Qihan Li
- Institute of Medical Biology, Chinese Academic Medical Sciences and Peking Union Medical College, Kunming, People’s Republic of China
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Shah N, Faridi MMA, Mitra M, Bavdekar A, Karadkhele A, Puppalwar G, Jain R. Review of long term immunogenicity and tolerability of live hepatitis A vaccine. Hum Vaccin Immunother 2020; 16:2816-2821. [PMID: 32243237 PMCID: PMC7746250 DOI: 10.1080/21645515.2020.1741997] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 03/09/2020] [Indexed: 12/20/2022] Open
Abstract
Hepatitis A represents one of the major public health problems worldwide including India. Vaccination is the most effective way to prevent hepatitis A infection. Two types of hepatitis A vaccines-live attenuated (H2 strain) and inactivated (killed) are available for use in clinical practice in India with former having advantage of a single-dose compared to two-dose killed vaccine. One of the important characteristic of an ideal vaccine includes its ability to provide life-long protection. In this article we reviewed the available long-term (≥10 years follow-up) published data on live attenuated hepatitis A (H2 strain) vaccine. The data from country of origin of the vaccine (China) and India establish the long-term immunogenicity, protection, and tolerability. Based on the results of several clinical trials showing long-term protection, single dose of live attenuated hepatitis vaccine can be widely used to protect high-risk population against hepatitis A virus infection and related complications.
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Affiliation(s)
- Nitin Shah
- Pediatrics Department, PD Hinduja Hospital, Mumbai, India
| | - MMA Faridi
- Pediatrics Department, ERA’s Lucknow Medical College & Hospital, Lucknow, India
| | - Monjori Mitra
- Pediatrics Department, Institute of Child Health, Kolkata, India
| | | | | | | | - Rishi Jain
- Medical Affairs Department, Wockhardt Ltd., Mumbai, India
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Abstract
Hepatitis A is an important public health issue worldwide. Hepatitis A vaccine (HepA) was first licensed in 1992. Both inactivated HepA (HepA-I) and live attenuated HepA (HepA-L) are highly immunogenic and well tolerated, and immune protection postvaccination can persist for at least 20 y. HepA is effective for both preexposure and postexposure prophylaxis, especially among children and young adults. The strategy of HepA vaccination varies in different countries and mainly includes vaccination among high-risk populations, regional childhood vaccination and universal childhood vaccination. The incidence of hepatitis A has decreased greatly in many countries in the last 30 y, but hepatitis A outbreaks frequently occur among high-risk populations and those who have not been covered by universal child vaccination programs in recent years. Disease surveillance and serosurveys are suggested to clarify the shift in the epidemiology of hepatitis A. The long-term persistence of immune protection after one dose of HepA should be further studied, as well as the cost-effective evaluation of different strategies of HepA vaccination. Based on this evidence, the recommendation on HepA vaccination should be put forward scientifically and updated in a timely and well-implemented manner.
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Affiliation(s)
- Li Zhang
- Academy of Preventive Medicine, Shandong University , Jinan, China.,Shandong Provincial Key Laboratory of Infectious Disease Control and Prevention, Shandong Center for Disease Control and Prevention , Jinan, China
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Yang T, Xie T, Song X, Shen D, Li H, Yue L, Jiang Q, Zhu F, Meng H, Long R, Yang R, Luo F, Xie Z. Safety and immunogenicity of an experimental live combination vaccine against enterovirus 71 and coxsackievirus A16 in rhesus monkeys. Hum Vaccin Immunother 2020; 16:1586-1594. [PMID: 32159429 DOI: 10.1080/21645515.2019.1709353] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Enterovirus 71 (EV-A71) and Coxsackievirus A16 (CV-A16) are the two most common pathogens causing hand, foot, and mouth disease (HFMD). Previously, we obtained one candidate live attenuated strain each for EV-A71 and CV-A16; here, we evaluated the safety and immunogenicity of a combinedlive vaccine against EV-A71 and CV-A16 generated from these two candidate strains. Rhesus monkeys were intramuscularly treated with a live combinationvaccine against both EV-A71 and CV-A16 or with either vaccine alone. No fever or atypical clinical signs were observed in any animals. Monkeys vaccinated with the combinationlive vaccine presented no notable pathological changes in the brain, spinal cord, lung, and liver; in contrast, these regions showed inflammatory cell infiltration in monkeys treated with EV-A71 alone or CV-A16 alone. Weak viremia was detected in plasma after inoculation with the combinationvaccine; however, the duration of viral shedding in feces was increased. Biochemical studies revealed a slight increase in aspartate aminotransferase levels in monkeys inoculated with the live combination vaccine; however, histopathological findings did not attribute this change to liver damage. We also found that the live combinationvaccine induced a dual humoral immune response. Cytokine analysis indicated that the combined EV-A71/CV-A16 vaccine significantly down-regulated interleukin-8 production. Here, we have demonstrated that the live attenuated EV-A71/CV-A16 vaccine was safe and could trigger a dual specific immune response. However, its immune protection efficacy requires further investigation.
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Affiliation(s)
- Ting Yang
- The Institute of Medical Biology, Chinese Academic Medical Sciences & Peking Union Medical College , Kunming, China
| | - Tianhong Xie
- The Institute of Medical Biology, Chinese Academic Medical Sciences & Peking Union Medical College , Kunming, China
| | - Xia Song
- The Institute of Medical Biology, Chinese Academic Medical Sciences & Peking Union Medical College , Kunming, China
| | - Dong Shen
- The Institute of Medical Biology, Chinese Academic Medical Sciences & Peking Union Medical College , Kunming, China
| | - Hua Li
- The Institute of Medical Biology, Chinese Academic Medical Sciences & Peking Union Medical College , Kunming, China
| | - Lei Yue
- The Institute of Medical Biology, Chinese Academic Medical Sciences & Peking Union Medical College , Kunming, China
| | - Qinfang Jiang
- The Institute of Medical Biology, Chinese Academic Medical Sciences & Peking Union Medical College , Kunming, China
| | - Fanli Zhu
- The Institute of Medical Biology, Chinese Academic Medical Sciences & Peking Union Medical College , Kunming, China
| | - Huaqing Meng
- Hospital Infection Control Department, The Affiliated Hospital of GuiZhou Medical University , Guiyang, China
| | - Runxiang Long
- The Institute of Medical Biology, Chinese Academic Medical Sciences & Peking Union Medical College , Kunming, China
| | - Rong Yang
- The Institute of Medical Biology, Chinese Academic Medical Sciences & Peking Union Medical College , Kunming, China
| | - Feiyu Luo
- The Institute of Medical Biology, Chinese Academic Medical Sciences & Peking Union Medical College , Kunming, China
| | - Zhongping Xie
- The Institute of Medical Biology, Chinese Academic Medical Sciences & Peking Union Medical College , Kunming, China
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Irving GJ, Holden J, Yang R, Pope D, Cochrane Hepato‐Biliary Group. Hepatitis A immunisation in persons not previously exposed to hepatitis A. Cochrane Database Syst Rev 2019; 12:CD009051. [PMID: 31846062 PMCID: PMC6916710 DOI: 10.1002/14651858.cd009051.pub3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
This review is withdrawn because it is outdated. A new review is to be published by the end of 2019.
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Affiliation(s)
- Greg J Irving
- University of CambridgeDepartment of Public Health and Primary CareForvie Site, Robinson WayCambridge Biomedical CampusCambridgeCambridgeshireUKCB2 0SR
| | - John Holden
- Garswood SurgeryStation RoadGarswoodSt. HelensMerseysideUKWND 0SD
| | - Rongrong Yang
- Peking UniversityInstitute of Population ResearchYiheyuanroad 5Haidian DistrictBeijingChina100871
| | - Daniel Pope
- University of LiverpoolHealth Inequalities and the Social Determinants of HealthLiverpoolUKL69 3GB
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11
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Rasche A, Sander AL, Corman VM, Drexler JF. Evolutionary biology of human hepatitis viruses. J Hepatol 2019; 70:501-520. [PMID: 30472320 PMCID: PMC7114834 DOI: 10.1016/j.jhep.2018.11.010] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 11/09/2018] [Accepted: 11/10/2018] [Indexed: 02/06/2023]
Abstract
Hepatitis viruses are major threats to human health. During the last decade, highly diverse viruses related to human hepatitis viruses were found in animals other than primates. Herein, we describe both surprising conservation and striking differences of the unique biological properties and infection patterns of human hepatitis viruses and their animal homologues, including transmission routes, liver tropism, oncogenesis, chronicity, pathogenesis and envelopment. We discuss the potential for translation of newly discovered hepatitis viruses into preclinical animal models for drug testing, studies on pathogenesis and vaccine development. Finally, we re-evaluate the evolutionary origins of human hepatitis viruses and discuss the past and present zoonotic potential of their animal homologues.
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Affiliation(s)
- Andrea Rasche
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany,German Center for Infection Research (DZIF), Germany
| | - Anna-Lena Sander
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany
| | - Victor Max Corman
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany,German Center for Infection Research (DZIF), Germany
| | - Jan Felix Drexler
- Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Virology, 10117 Berlin, Germany; German Center for Infection Research (DZIF), Germany.
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12
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Chen Y, Zhou CL, Zhang XJ, Hao ZY, Zhang YH, Wang SM, Ma JC, Zhao G, Qiu C, Zhao YL, Wang B, Wang XY. Immune memory at 17-years of follow-up of a single dose of live attenuated hepatitis A vaccine. Vaccine 2017; 36:114-121. [PMID: 29183734 DOI: 10.1016/j.vaccine.2017.11.036] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2017] [Revised: 09/28/2017] [Accepted: 11/13/2017] [Indexed: 11/26/2022]
Abstract
BACKGROUND In recent years, hepatitis A virus (HAV) infection has declined considerably in China, associated with wide deployment of HAV vaccines and improvement in socio-economic indicators. Towards the elimination of HA in the country, we assessed the duration and characteristics of immunity conferred by the widely used, locally manufactured HAV vaccine. METHODS This is a longitudinal cohort study that followed recipients of a live attenuated HAV vaccine 17 years after the initial administration. Blood samples were collected from participants pre- and two-week post-booster HAV vaccine dose. Serum anti-HAV antibody was measured by ELISA method. Memory B and T cells were determined by ELISPOT and Flow Cytometry assays, respectively. RESULTS A robust anamnestic response was observed two-week post-challenge. Both HAV-specific memory B cell and T cells remained, and responded quickly when re-encountering HAV. The magnitude of recall responses was present, regardless of the status of the serum anti-HAV antibody pre-booster. CONCLUSIONS We demonstrated long-term immunity from the live attenuated HAV vaccine, including antibody persistence and immunological memory. Considering the conditions that make elimination of infectious diseases feasible, following polio, hepatitis A could be targeted for elimination in China.
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Affiliation(s)
- Ying Chen
- Key Laboratory of Medical Molecular Virology of MoE & MoH, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chen-Liang Zhou
- Key Laboratory of Medical Molecular Virology of MoE & MoH, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Xin-Jiang Zhang
- Zhengding County Center for Disease Control and Prevention, Zhengding, Hebei, China
| | - Zhi-Yong Hao
- Zhengding County Center for Disease Control and Prevention, Zhengding, Hebei, China
| | - Yan-Hong Zhang
- Zhengding County Center for Disease Control and Prevention, Zhengding, Hebei, China
| | - Song-Mei Wang
- Laboratory of Molecular Biology, Training Center of Medical Experiments, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jing-Chen Ma
- Hebei Province Center for Disease Control and Prevention, Shijiazhuang, Hebei, China
| | - Gan Zhao
- Key Laboratory of Medical Molecular Virology of MoE & MoH, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Chao Qiu
- Key Laboratory of Medical Molecular Virology of MoE & MoH, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Yu-Liang Zhao
- Hebei Province Center for Disease Control and Prevention, Shijiazhuang, Hebei, China
| | - Bin Wang
- Key Laboratory of Medical Molecular Virology of MoE & MoH, School of Basic Medical Sciences, Fudan University, Shanghai, China.
| | - Xuan-Yi Wang
- Key Laboratory of Medical Molecular Virology of MoE & MoH, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
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13
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Rao S, Mao JS, Motlekar S, Fangcheng Z, Kadhe G. A review of immunogenicity and tolerability of live attenuated Hepatitis A vaccine in children. Hum Vaccin Immunother 2017; 12:3160-3165. [PMID: 27532370 PMCID: PMC5215502 DOI: 10.1080/21645515.2016.1216286] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Changing epidemiology of Hepatitis A virus (HAV) has led to an increased susceptibility of adolescents and adults to the infection. Vaccination can remarkably reduce the incidence and associated morbidity of HAV infection. This review is focused on the safety and efficacy of H2 strain derived live attenuated Hepatitis A vaccine. We found the vaccine to be highly immunogenic with minimal or negligible safety issues. Moreover, a single dose of live attenuated vaccine persists a long term immune response and can be a preferred option for developing countries. In 2014, Indian Academy of Paediatrics (IAP) also updated their recommendations for H2 vaccine as a single dose as against the previous 2 dose schedule. A focused approach to include the vaccine in national immunization program should be explored.
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Affiliation(s)
- Sameer Rao
- a Medical Affairs Department , Wockhardt Ltd , Bandra (East), Mumbai , India
| | - J S Mao
- b Institute of Viral Diseases, Zhejiang Academy of Medical Sciences , Hangzhou , China
| | - Salman Motlekar
- a Medical Affairs Department , Wockhardt Ltd , Bandra (East), Mumbai , India
| | - Zhuang Fangcheng
- b Institute of Viral Diseases, Zhejiang Academy of Medical Sciences , Hangzhou , China
| | - Ganesh Kadhe
- a Medical Affairs Department , Wockhardt Ltd , Bandra (East), Mumbai , India
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14
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Ye C, Luo J, Wang X, Xi J, Pan Y, Chen J, Yang X, Li G, Sun Q, Yang J. Development of a peptide ELISA to discriminate vaccine-induced immunity from natural infection of hepatitis A virus in a phase IV study. Eur J Clin Microbiol Infect Dis 2017. [PMID: 28631170 DOI: 10.1007/s10096-017-3040-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Hepatitis A virus (HAV) is a highly infectious agent that causes acute liver disease. The infection can trigger the production of antibodies against the structural and non-structural proteins of HAV. Nonetheless, vaccination with an HAV vaccine leads to the production of a primary antibody against the structural proteins. Because the non-structural proteins are only produced during active virus replication, there is no or very little antibody production against the non-structural proteins. However, the current commercial immunoassay cannot distinguish between antibodies produced during natural infection and those from vaccination against HAV. In our study, six immune-dominant epitopes from the non-structural proteins were designed, synthesized, linked together and cloned into pGEX-5X-1 plasmid. The recombinant protein was expressed in E. coli and purified by Ni2+-coated magnetic agarose beads. Then the purified recombinant protein was used as an ELISA antigen to detect antibodies for HAV non-structural proteins in serum samples. Seventy-seven attenuated and 89 inactivated vaccinated samples collected from our previous phase IV study of HAV vaccines were detected by peptide ELISA developed in this study. The mean OD450 value for the vaccination samples and acute infection samples were 0.529 (0.486 for the attenuated group and 0.567 for the inactivated group) and 1.187, respectively. According to the receiver operating characteristic (ROC) curve, the sensitivity and specificity of the peptide ELISA were 93.80% and 91.00%, respectively. This peptide ELISA was confirmed to discriminate vaccine-induced immunity from natural infection of HAV in a phase IV study with high sensitivity and specificity.
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Affiliation(s)
- C Ye
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), 935 Jiao Ling Road, Kunming, Yunnan Province, 650118, People's Republic of China.,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, 650118, People's Republic of China.,Kunming Medical University, Kunming, 650500, People's Republic of China
| | - J Luo
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), 935 Jiao Ling Road, Kunming, Yunnan Province, 650118, People's Republic of China.,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, 650118, People's Republic of China.,Kunming Medical University, Kunming, 650500, People's Republic of China
| | - X Wang
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), 935 Jiao Ling Road, Kunming, Yunnan Province, 650118, People's Republic of China.,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, 650118, People's Republic of China
| | - J Xi
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), 935 Jiao Ling Road, Kunming, Yunnan Province, 650118, People's Republic of China.,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, 650118, People's Republic of China
| | - Y Pan
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), 935 Jiao Ling Road, Kunming, Yunnan Province, 650118, People's Republic of China.,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, 650118, People's Republic of China
| | - J Chen
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), 935 Jiao Ling Road, Kunming, Yunnan Province, 650118, People's Republic of China.,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, 650118, People's Republic of China
| | - X Yang
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), 935 Jiao Ling Road, Kunming, Yunnan Province, 650118, People's Republic of China.,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, 650118, People's Republic of China
| | - G Li
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), 935 Jiao Ling Road, Kunming, Yunnan Province, 650118, People's Republic of China.,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, 650118, People's Republic of China
| | - Q Sun
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), 935 Jiao Ling Road, Kunming, Yunnan Province, 650118, People's Republic of China. .,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, 650118, People's Republic of China.
| | - J Yang
- Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), 935 Jiao Ling Road, Kunming, Yunnan Province, 650118, People's Republic of China. .,Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Kunming, 650118, People's Republic of China.
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15
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Shi J, Sun J, Wu M, Wang H, Hu N, Hu Y. Comprehensive profiling and characterization of cellular miRNAs in response to hepatitis A virus infection in human fibroblasts. INFECTION GENETICS AND EVOLUTION 2016; 45:176-186. [DOI: 10.1016/j.meegid.2016.08.035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 08/01/2016] [Accepted: 08/29/2016] [Indexed: 11/27/2022]
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16
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Ma F, Yang J, Kang G, Sun Q, Lu P, Zhao Y, Wang Z, Luo J, Wang Z. Comparison of the safety and immunogenicity of live attenuated and inactivated hepatitis A vaccine in healthy Chinese children aged 18 months to 16 years: results from a randomized, parallel controlled, phase IV study. Clin Microbiol Infect 2016; 22:811.e9-811.e15. [PMID: 27345175 DOI: 10.1016/j.cmi.2016.06.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 06/10/2016] [Accepted: 06/11/2016] [Indexed: 11/25/2022]
Abstract
For large-scale immunization of children with hepatitis A (HA) vaccines in China, accurately designed studies comparing the safety and immunogenicity of the live attenuated HA vaccine (HA-L) and inactivated HA vaccine (HA-I) are necessary. A randomized, parallel controlled, phase IV clinical trial was conducted with 6000 healthy children aged 18 months to 16 years. HA-L or HA-I was administered at a ratio of 1: 1 to randomized selected participants. The safety and immunogenicity were evaluated. Both HA-L and HA-I were well tolerated by all participants. The immunogenicity results showed that the seroconversion rates (HA-L versus HA-I: 98.0% versus 100%, respectively, p >0.05), and geometric mean concentrations in participants negative for antibodies against HA virus IgG (anti-HAV IgG) before vaccination did not differ significantly between the two types of vaccines (HA-L versus HA-I first dose: 898.9 versus 886.2 mIU/mL, respectively, p >0.05). After administration of the booster dose of HA-I, the geometric mean concentrations of anti-HAV IgG (HA-I booster dose: 2591.2 mIU/mL) was higher than that after the first dose (p <0.05) and that reported in participants administered HA-L (p <0.05). Additionally, 12 (25%) of the 48 randomized selected participants who received HA-L tested positive for HA antigen in stool samples. Hence, both HA-L and HA-I could provide acceptable immunogenicity in children. The effects of long-term immunogenicity after natural exposure to wild-type HA virus and the possibility of mutational shifts of the live vaccine virus in the field need to be studied in more detail.
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Affiliation(s)
- F Ma
- Jiangsu Provincial Centre of Disease Control and Prevention, Nanjing, Jiangsu Province, China
| | - J Yang
- Institute of Medical Biology, Chinese Academy of Medical Sciences, Kunming, Yunnan Province, China
| | - G Kang
- Jiangsu Provincial Centre of Disease Control and Prevention, Nanjing, Jiangsu Province, China.
| | - Q Sun
- Institute of Medical Biology, Chinese Academy of Medical Sciences, Kunming, Yunnan Province, China
| | - P Lu
- Jiangsu Provincial Centre of Disease Control and Prevention, Nanjing, Jiangsu Province, China
| | - Y Zhao
- Institute of Medical Biology, Chinese Academy of Medical Sciences, Kunming, Yunnan Province, China
| | - Z Wang
- Jiangsu Provincial Centre of Disease Control and Prevention, Nanjing, Jiangsu Province, China
| | - J Luo
- Institute of Medical Biology, Chinese Academy of Medical Sciences, Kunming, Yunnan Province, China
| | - Z Wang
- Xiangshui County Centre of Disease Control and Prevention, Jiangsu Province, China
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17
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Shi J, Sun J, Wu M, Hu N, Hu Y. Hepatitis A virus-encoded miRNAs attenuate the accumulation of viral genomic RNAs in infected cells. Virus Genes 2016; 52:317-24. [DOI: 10.1007/s11262-016-1306-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 02/16/2016] [Indexed: 11/30/2022]
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18
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Xu M, Liang Z, Xu Y, Wang J. Chinese vaccine products go global: vaccine development and quality control. Expert Rev Vaccines 2015; 14:763-73. [PMID: 25697690 DOI: 10.1586/14760584.2015.1012503] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Through the continuous efforts of several generations, China has become one of the few countries in the world that is capable of independently addressing all the requirements by the Expanded Program on Immunization. Regulatory science is applied to continuously improve the vaccine regulatory system. Passing the prequalification by WHO has allowed Chinese vaccine products to go global. Chinese vaccine products not only secure disease prevention and control domestically but also serve the needs for international public health. This article describes the history of Chinese vaccine development, the current situation of Chinese vaccine industry and its contribution to the prevention and control of infectious diseases. We also share our experience of national quality control and vaccine regulation during the past decades. China's experience in vaccine development and quality control can benefit other countries and regions worldwide, including the developing countries.
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Affiliation(s)
- Miao Xu
- Key Laboratory of the Ministry of Health for Research on Quality and Standardization of Biotech Products, National Institutes for Food and Drug Control, No.2, Tiantan Xili, Dongcheng District, Beijing 100050, People's Republic of China
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19
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Waning of anti-HAV immunity in Shijiazhuang prefecture, Hebei province, China: A comparison of seroprevalence between 1992 and 2011. Vaccine 2014; 32:6227-32. [DOI: 10.1016/j.vaccine.2014.09.022] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Revised: 08/28/2014] [Accepted: 09/08/2014] [Indexed: 11/18/2022]
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20
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Shi J, Duan Z, Sun J, Wu M, Wang B, Zhang J, Wang H, Hu N, Hu Y. Identification and validation of a novel microRNA-like molecule derived from a cytoplasmic RNA virus antigenome by bioinformatics and experimental approaches. Virol J 2014; 11:121. [PMID: 24981144 PMCID: PMC4087238 DOI: 10.1186/1743-422x-11-121] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2014] [Accepted: 06/24/2014] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND It is generally believed that RNA virus replicating in the cell cytoplasm would not encode microRNAs (miRNAs) due to nucleus inaccessibility. Recent studies have described cytoplasmic RNA virus genome-derived miRNAs in West Nile virus (WNV) and Dengue virus (DENV). However, naturally occurring miRNAs derived from the antigenome of a cytoplasmic RNA virus have not been described. METHODS Hepatitis A virus (HAV) was served as a model virus to investigate whether the antigenome of a cytoplasmic RNA virus would be processed into miRNAs or miRNA-like small RNAs upon infection. HAV antigenome was queried for putative miRNA precursors (pre-miRNA) with the VMir analyzer program. Mature miRNA prediction was performed using MatureBayes and Bayes-SVM-MiRNA web server v1.0. Finally, multiple experimental approaches, including cloning and sequencing-, RNAi-, plasmid-based miRNA expression- and luciferase reporter assays, were performed to identify and validate naturally occurring viral antigenome-derived miRNAs. RESULTS Using human HAV genotype IA (isolate H2) (HAVH2), a virally encoded miRNA-like small RNA was detected on the antigenome and named hav-miR-N1-3p. Transcription of viral pre-miRNA in KMB17 and HEK293T cells led to mature hav-miR-N1-3p production. In addition, silencing of the miRNA-processing enzyme Dicer or Drosha caused a dramatic reduction in miRNA levels. Furthermore, artificial target of hav-miR-N1-3p was silenced by synthesized viral miRNA mimics and the HAVH2 naturally-derived hav-miR-N1-3p. CONCLUSION These results suggested that the antigenome of a cytoplasmic RNA virus could be processed into functional miRNAs. Our findings provide new evidence supporting the hypothesis that cytoplasmic RNA viruses naturally encode miRNAs through cellular miRNA processing machinery.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Yunzhang Hu
- Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Diseases, Institute of Medical Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Kunming 650118, China.
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21
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Shi J, Sun J, Wang B, Wu M, Zhang J, Duan Z, Wang H, Hu N, Hu Y. Novel microRNA-like viral small regulatory RNAs arising during human hepatitis A virus infection. FASEB J 2014; 28:4381-93. [PMID: 25002121 DOI: 10.1096/fj.14-253534] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
MicroRNAs (miRNAs), including host miRNAs and viral miRNAs, play vital roles in regulating host-virus interactions. DNA viruses encode miRNAs that regulate the viral life cycle. However, it is generally believed that cytoplasmic RNA viruses do not encode miRNAs, owing to inaccessible cellular miRNA processing machinery. Here, we provide a comprehensive genome-wide analysis and identification of miRNAs that were derived from hepatitis A virus (HAV; Hu/China/H2/1982), which is a typical cytoplasmic RNA virus. Using deep-sequencing and in silico approaches, we identified 2 novel virally encoded miRNAs, named hav-miR-1-5p and hav-miR-2-5p. Both of the novel virally encoded miRNAs were clearly detected in infected cells. Analysis of Dicer enzyme silencing demonstrated that HAV-derived miRNA biogenesis is Dicer dependent. Furthermore, we confirmed that HAV mature miRNAs were generated from viral miRNA precursors (pre-miRNAs) in host cells. Notably, naturally derived HAV miRNAs were biologically and functionally active and induced post-transcriptional gene silencing (PTGS). Genomic location analysis revealed novel miRNAs located in the coding region of the viral genome. Overall, our results show that HAV naturally generates functional miRNA-like small regulatory RNAs during infection. This is the first report of miRNAs derived from the coding region of genomic RNA of a cytoplasmic RNA virus. These observations demonstrate that a cytoplasmic RNA virus can naturally generate functional miRNAs, as DNA viruses do. These findings also contribute to improved understanding of host-RNA virus interactions mediated by RNA virus-derived miRNAs.
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Affiliation(s)
- Jiandong Shi
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China; and
| | - Jing Sun
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China; and
| | - Bin Wang
- Department of Life Science and Biotechnology, Kunming University, Kunming, China
| | - Meini Wu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China; and
| | - Jing Zhang
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China; and
| | - Zhiqing Duan
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China; and
| | - Haixuan Wang
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China; and
| | - Ningzhu Hu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China; and
| | - Yunzhang Hu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, China; and
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22
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Cui F, Liang X, Wang F, Zheng H, Hutin YJ, Yang W. Development, production, and postmarketing surveillance of hepatitis A vaccines in China. J Epidemiol 2014; 24:169-77. [PMID: 24681843 PMCID: PMC4000763 DOI: 10.2188/jea.je20130022] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023] Open
Abstract
China has long experience using live attenuated and inactivated vaccines against hepatitis A virus (HAV) infection. We summarize this experience and provide recent data on adverse events after immunization (AEFIs) with hepatitis A vaccines in China. We reviewed the published literature (in Chinese and English) and the published Chinese regulatory documents on hepatitis A vaccine development, production, and postmarketing surveillance of AEFI. We described the safety, immunogenicity, and efficacy of hepatitis A vaccines and horizontal transmission of live HAV vaccine in China. In clinical trials, live HAV vaccine was associated with fever (0.4%–5% of vaccinees), rash (0%–1.1%), and elevated alanine aminotransferase (0.015%). Inactivated HAV vaccine was associated with fever (1%–8%), but no serious AEFIs were reported. Live HAV vaccine had seroconversion rates of 83% to 91%, while inactivated HAV vaccine had seroconversion rates of 95% to 100%. Community trials showed efficacy rates of 90% to 95% for live HAV and 95% to 100% for inactivated HAV vaccine. Postmarketing surveillance showed that HAV vaccination resulted in an AEFI incidence rate of 34 per million vaccinees, which accounted for 0.7% of adverse events reported to the China AEFI monitoring system. There was no difference in AEFI rates between live and inactivated HAV vaccines. Live and inactivated HAV vaccines manufactured in China were immunogenic, effective, and safe. Live HAV vaccine had substantial horizontal transmission due to vaccine virus shedding; thus, further monitoring of the safety of virus shedding is warranted.
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Affiliation(s)
- Fuqiang Cui
- Chinese Center for Disease Control and Prevention
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23
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Xu ZY, Wang XY. Live attenuated hepatitis A vaccines developed in China. Hum Vaccin Immunother 2013; 10:659-66. [PMID: 24280971 PMCID: PMC4130259 DOI: 10.4161/hv.27124] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2013] [Revised: 10/30/2013] [Accepted: 11/08/2013] [Indexed: 11/19/2022] Open
Abstract
Two live, attenuated hepatitis A vaccines, H 2 and LA-1 virus strains, were developed through serial passages of the viruses in cell cultures at 32 °C and 35 °C respectively. Both vaccines were safe and immunogenic, providing protection against clinical hepatitis A in 95% of the vaccinees, with a single dose by subcutaneous injection. The vaccine recipients were not protected from asymptomatic, subclinical hepatitis A virus (HAV) infection, which induced a similar antibody response as for unvaccinated subjects. A second dose caused anamnestic response and can be used for boosting. Oral immunization of human with H 2 vaccine or of marmoset with LA-1 vaccine failed, and no evidence was found for person-to-person transmission of the H 2 strain or for marmoset-to-marmoset transmission of LA-1 strain, by close contact. H 2 strain was genetically stable when passaged in marmosets, humans or cell cultures at 37 °C; 3 consecutive passages of the virus in marmosets did not cause virulence mutation. The live vaccines offer the benefits of low cost, single dose injection, long- term protection, and increased duration of immunity through subclinical infection. Improved sanitation and administration of 150 million doses of the live vaccines to children had led to a 90% reduction in the annual national incidence rate of hepatitis A in China during the 16-year period, from 1991 to 2006. Hepatitis A immunization with both live and inactivated HA vaccines was implemented in the national routine childhood immunization program in 2008 and around 92% of the 16 million annual births received the affordable live, attenuated vaccines at 18 months of age. Near elimination of the disease was achieved in China for 14 years following introduction of the H 2 live vaccine into the Expanded Immunization Program (EPI) in 1992.
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Affiliation(s)
- Zhi-Yi Xu
- Institutes of Biomedical Sciences; Shanghai Medical College; Fudan University; Shanghai, PR China
- Department of Epidemiology; School of Public Health, Shanghai Medical College; Fudan University; Shanghai, PR China
| | - Xuan-Yi Wang
- Institutes of Biomedical Sciences; Shanghai Medical College; Fudan University; Shanghai, PR China
- Key Laboratory of Medical Molecular Virology MoE/MoH; Shanghai Medical College; Fudan University; Shanghai, PR China
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24
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Tsai TF, Bock H, Xu ZY. Immunization in the Asia-Pacific region. Vaccines (Basel) 2013. [PMCID: PMC7152305 DOI: 10.1016/b978-1-4557-0090-5.00069-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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25
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26
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Irving GJ, Holden J, Yang R, Pope D. Hepatitis A immunisation in persons not previously exposed to hepatitis A. Cochrane Database Syst Rev 2012; 2012:CD009051. [PMID: 22786522 PMCID: PMC6823267 DOI: 10.1002/14651858.cd009051.pub2] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND In many parts of the world, hepatitis A infection represents a significant cause of morbidity and socio-economic loss. Whilst hepatitis A vaccines have the potential to prevent disease, the degree of protection afforded against clinical outcomes and within different populations remains uncertain. There are two types of hepatitis A virus (HAV) vaccine, inactivated and live attenuated. It is important to determine the efficacy and safety for both vaccine types. OBJECTIVES To determine the clinical protective efficacy, sero-protective efficacy, and safety and harms of hepatitis A vaccination in persons not previously exposed to hepatitis A. SEARCH METHODS We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and China National Knowledge Infrastructure (CNKI) up to November 2011. SELECTION CRITERIA Randomised clinical trials comparing HAV vaccine with placebo, no intervention, or appropriate control vaccines in participants of all ages. DATA COLLECTION AND ANALYSIS Data extraction and risk of bias assessment were undertaken by two authors and verified by a third author. Where required, authors contacted investigators to obtain missing data. The primary outcome was the occurrence of clinically apparent hepatitis A (infectious hepatitis). The secondary outcomes were lack of sero-protective anti-HAV immunoglobulin G (IgG), and number and types of adverse events. Results were presented as relative risks (RR) with 95% confidence intervals (CI). Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence interval (CI), using intention-to-treat analysis. We conducted assessment of risk of bias to evaluate the risk of systematic errors (bias) and trial sequential analyses to estimate the risk of random errors (the play of chance). MAIN RESULTS We included a total of 11 clinical studies, of which only three were considered to have low risk of bias; two were quasi-randomised studies in which we only addressed harms. Nine randomised trials with 732,380 participants addressed the primary outcome of clinically confirmed hepatitis A. Of these, four trials assessed the inactivated hepatitis A vaccine (41,690 participants) and five trials assessed the live attenuated hepatitis A vaccine (690,690 participants). In the three randomised trials with low risk of bias (all assessing inactivated vaccine), clinically apparent hepatitis A occurred in 9/20,684 (0.04%) versus 92/20,746 (0.44%) participants in the HAV vaccine and control groups respectively (RR 0.09, 95% CI 0.03 to 0.30). In all nine randomised trials, clinically apparent hepatitis A occurred in 31/375,726 (0.01%) versus 505/356,654 (0.18%) participants in the HAV vaccine and control groups respectively (RR 0.09, 95% CI 0.05 to 0.17). These results were supported by trial sequential analyses. Subgroup analyses confirmed the clinical effectiveness of both inactivated hepatitis A vaccines (RR 0.09, 95% CI 0.03 to 0.30) and live attenuated hepatitis A vaccines (RR 0.07, 95% CI 0.03 to 0.17) on clinically confirmed hepatitis A. Inactivated hepatitis A vaccines had a significant effect on reducing the lack of sero-protection (less than 20 mIU/L) (RR 0.01, 95% CI 0.00 to 0.03). No trial reported on a sero-protective threshold less than 10 mIU/L. The risk of both non-serious local and systemic adverse events was comparable to placebo for the inactivated HAV vaccines. There were insufficient data to draw conclusions on adverse events for the live attenuated HAV vaccine. AUTHORS' CONCLUSIONS Hepatitis A vaccines are effective for pre-exposure prophylaxis of hepatitis A in susceptible individuals. This review demonstrated significant protection for at least two years with the inactivated HAV vaccine and at least five years with the live attenuated HAV vaccine. There was evidence to support the safety of the inactivated hepatitis A vaccine. More high quality evidence is required to determine the safety of live attenuated vaccines.
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Affiliation(s)
- Greg J Irving
- Division of Primary Care, University of Liverpool, Liverpool, UK.
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27
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Dotzauer A, Kraemer L. Innate and adaptive immune responses against picornaviruses and their counteractions: An overview. World J Virol 2012; 1:91-107. [PMID: 24175214 PMCID: PMC3782268 DOI: 10.5501/wjv.v1.i3.91] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2011] [Revised: 02/22/2012] [Accepted: 05/20/2012] [Indexed: 02/05/2023] Open
Abstract
Picornaviruses, small positive-stranded RNA viruses, cause a wide range of diseases which is based on their differential tissue and cell type tropisms. This diversity is reflected by the immune responses, both innate and adaptive, induced after infection, and the subsequent interactions of the viruses with the immune system. The defense mechanisms of the host and the countermeasures of the virus significantly contribute to the pathogenesis of the infections. Important human pathogens are poliovirus, coxsackievirus, human rhinovirus and hepatitis A virus. These viruses are the best-studied members of the family, and in this review we want to present the major aspects of the reciprocal effects between the immune system and these viruses.
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Affiliation(s)
- Andreas Dotzauer
- Andreas Dotzauer, Leena Kraemer, Department of Virology, University of Bremen, 28359 Bremen, Germany
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Fangcheng Z, Xuanyi W, Mingding C, Liming J, Jie W, Qi J, Yuanping G, Wen Q, Yajuan X, Jiangsen M. Era of vaccination heralds a decline in incidence of hepatitis A in high-risk groups in China. HEPATITIS MONTHLY 2012; 12:100-5. [PMID: 22509186 PMCID: PMC3321316 DOI: 10.5812/hepatmon.838] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2011] [Revised: 12/21/2011] [Accepted: 01/15/2012] [Indexed: 12/11/2022]
Abstract
BACKGROUND Hepatitis A was ranked first among all of the different types of viral hepatitis in China, which occurred an average of 500,000 cases annually during the 1980's. A live attenuated hepatitis A vaccine was applied in preventing of the disease in 1992, large scale used in vaccination program in 1995, and incorporated in the Expanded Program of Immunization in 2008 in China. OBJECTIVE The objective of this study was to determine whether, and to what extent, the decline in the incidence of hepatitis A in China was the result of hepatitis A (HA) vaccination. MATERIALS AND METHODS Official documents and longitudinal serological follow-up studies were reviewed to compare the incidence of HA before and after the introduction of the vaccine. RESULTS National trends in the incidence of HA in China saw rates decrease by 92.7% in 2009, compared to the levels seen in 1992. A mass vaccination program was carried out in 3-18 year old children (Wuhan City, China), and its protective efficacy was 85.4%. In a mass vaccination program of an entire population (Shenshi County, China), the annual HA incidence decreased from 359.7/100,000 to 17.7/100,000 (almost 20.3 times). There was a significant relationship found between vaccine coverage and the incidence of HA, the correlation of the negative regression was significant at the 1% (Kendall rank correlation, significant level P < 0.05). CONCLUSIONS In summary, this study highlights the important role of implementing a vaccination program in decreasing the incidence of HA, and the large protective efficacy of such a strategy, as demonstrated in China.
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Affiliation(s)
- Zhuang Fangcheng
- Institute of Viral Disease, Zhejiang Academy of Medical Sciences, Hangzhou, China; Key Lab for Bio-tech Vaccine Research, Hangzhou, China.
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Era of Vaccination Heralds a Decline in Incidence of Hepatitis A in High-Risk Groups in China. HEPATITIS MONTHLY 2012. [DOI: 10.5812/hepatmon.4907] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
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Xu ZY, Wang XY, Liu CQ, Li YT, Zhuang FC. Decline in the risk of hepatitis A virus infection in China, a country with booming economy and changing lifestyles. J Viral Hepat 2008; 15 Suppl 2:33-7. [PMID: 18837831 DOI: 10.1111/j.1365-2893.2008.01026.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The objective of the study was to identify the protective factors for the rapid decline in the risk of hepatitis A virus (HAV) infection in China between 1990 and 2006. Results of serological follow-up and data on annual hepatitis A incidence were analysed and correlated with economic growth and HAV vaccine output during the same period. In conclusion, both HAV vaccination and changing lifestyles associated with the booming economy contributed to the rapid risk decline. Changing lifestyles played a major role in the decline especially in the areas with booming economy.
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Affiliation(s)
- Zhi-Yu Xu
- International Vaccine Institute, Seoul, Korea.
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31
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Immunization in the Asia-Pacific region. Vaccines (Basel) 2008. [DOI: 10.1016/b978-1-4160-3611-1.50073-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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32
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Tang CH, Mao JS, Chai SA, Chen Y, Zhuang FC. Molecular evolution of hepatitis A virus in a human diploid cell line. World J Gastroenterol 2007; 13:4630-5. [PMID: 17729420 PMCID: PMC4611841 DOI: 10.3748/wjg.v13.i34.4630] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the hotspots, direction, and the time course of evolution of hepatitis A virus in the process of consecutive cell culture passage in human KMB17 diploid cells.
METHODS: Wild type hepatitis A virus H2w was serially propagated in KMB17 cells until passage 30, and the full-length genomes of H2w and its six chosen progenies were determined by directly sequencing RT-PCR products amplified from viral genomic RNA. Alignment comparison of sequences from H2w with its six progenies and phylogenetic analysis of the whole VP1 region from H2w, progenies of H2w, and other cell culture adapted hepatitis A virus were then carried out to obtain data on the molecular evolution of hepatitis A virus in the process of consecutive passage in KMB17 cells.
RESULTS: Most of the mutations occurred by passage 5 and several hotspots related to adaptation of the virus during cell growth were observed. After that stage, few additional mutations occurred through the remaining duration of passage in KMB17 cells except for mutation in the virulence determinants, which occurred in the vicinity of passage 15. The phylogenetic analysis of the whole VP1 region suggested that the progenies of H2w evolved closely to other cell culture adapted hepatitis A virus, i.e. MBB, L-A-1, other than its progenitor H2w.
CONCLUSION: Hepatitis A virus served as a useful model for studying molecular evolution of viruses in a given environment. The information obtained in this study may provide assistance in cultivating the next generation of a seed virus for live hepatitis A vaccine production.
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Affiliation(s)
- Cai-Hua Tang
- Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang Province, China
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Abstract
When first introduced in 1992 the hepatitis A vaccine was recommended for individuals at high risk of exposure. This policy was not expected to have a significant impact on disease incidence at population level in view of the epidemiology of the hepatitis A virus (HAV). More recently two countries, Israel and Bahrain, and regions or subpopulations in others (Australia, China, Byelorussia, Italy, Spain, US) have embarked upon more ambitious vaccination programmes that aim to immunize whole birth cohorts. After a brief survey of the virology and epidemiology of HAV, the disease burden it inflicts and a short history of the development of HAV vaccines--both live (in China) and killed vaccines are available--he vaccination programmes introduced in the countries mentioned above are described. The results have been spectacular: disease incidence, not only in the vaccinated cohorts but also in the whole population, have plummeted within a few years of the start of mass vaccination. There is now convincing evidence that the vaccine confers herd immunity if the main spreaders of the virus are targeted for immunization. This finding should encourage other countries to start mass vaccination programmes against HAV, particularly as pharmacoeconomic studies are beginning to show that such a strategy could be a cost-effective way of controlling the disease. It is now even conceivable to eradicate HAV. In fact, this should be easier to achieve than polio eradication as HAV vaccines confer more durable immunity than polio vaccines. However, the global disease burden of HAV is generally thought not to be high enough to justify such an undertaking in the foreseeable future.
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Wang XY, Xu ZY, Ma JC, von Seidlein L, Zhang Y, Hao ZY, Han OP, Zhang YL, Tian MY, Ouyang PY, Zhang ZY, Han CQ, Xing ZC, Chen JC. Long-term immunogenicity after single and booster dose of a live attenuated hepatitis A vaccine: Results from 8-year follow-up. Vaccine 2007; 25:446-9. [PMID: 16949710 DOI: 10.1016/j.vaccine.2006.08.004] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2006] [Revised: 07/28/2006] [Accepted: 08/03/2006] [Indexed: 11/23/2022]
Abstract
Live, attenuated hepatitis A vaccines are used widely in China but there is uncertainty regarding the persistence of vaccine-induced anti-HAV antibodies after single dose and booster dose administrated at month 12. A large scale clinical trial to evaluate the live, attenuated hepatitis A vaccine was conducted in Hebei province between 1996 and 1999. Five years after the trials, children in single dose and booster dose groups were bled and followed. Seventy two percent (61/85) of children who received a single trial dose had detectable anti-HAV antibodies for 96 months (GMC at 96 months: 89.0 mIU/mL). In the booster group 98% (48/49) children remained anti-HAV positive with GMC of 262.8 mIU/mL at month 96. The reinjection with live attenuated HAV vaccine can elicit a booster effect. Results from single dose group seems not to support the need for booster doses of live attenuated hepatitis A vaccine in immunocompetent individuals regarding the persisting anti-HAV and anamnestic response of a single dose vaccine. Continued monitoring of anti-HAV antibodies is needed for a rational hepatitis A immunization strategy in China.
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Affiliation(s)
- Xuan-Yi Wang
- International Vaccine Institute, San 4-8 Bongcheon-7-dong, Kwanak-gu, Seoul 151-818, Republic of Korea.
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Jiang YJ, Liao GY, Zhao W, Sun MB, Qian Y, Bian CX, Jiang SD. Detection of infectious hepatitis A virus by integrated cell culture/strand-specific reverse transcriptase-polymerase chain reaction. J Appl Microbiol 2004; 97:1105-12. [PMID: 15479428 DOI: 10.1111/j.1365-2672.2004.02413.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
AIMS A novel integrated cell culture/strand-specific reverse transcriptase-polymerase chain reaction (RT-PCR) assay was established for detection of infectious hepatitis A virus (HAV). METHODS AND RESULTS The specificity of tagged RT-PCR was assessed using HAV genomic positive-strand RNA extracted from HAV virions as reference. Water samples artificially contaminated with infectious or formalin-inactivated HAV were subjected to integrated cell culture (ICC)/RT-PCR and ICC/strand-specific RT-PCR assays respectively. The tagged RT-PCR had high specificity for HAV negative-strand RNA. By demonstrating the formation of negative-strand RNA replicative intermediate, ICC/strand-specific RT-PCR can distinguish between infectious and non-infectious HAV. The described method detected infectious HAV at inoculation level of 10(0) TCID50 per flask within 4 days. CONCLUSIONS The ICC/strand-specific RT-PCR is a novel, rapid, sensitive and reliable method for detection of infectious HAV. SIGNIFICANCE AND IMPACT OF THE STUDY Coupled with a suitable virus concentration and purification system, ICC/strand-specific RT-PCR will provide a novel and rapid method for detection of infectious HAV in clinical, environmental and food samples. This assay may be used as an alternative method to test the effective inactivation of inactivated virus vaccines. It may also be adapted to assess the efficacy of disinfection of HAV and enteric viruses in foods and water.
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Affiliation(s)
- Y-J Jiang
- Laboratory of Vaccine Research, Institute of Medical Biology, Chinese Academy of Medical Science, Kunming, Yunnan Province
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36
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Wang XY, Xu Z, Yao X, Tian M, Zhou L, He L, Wen Y. Immune responses of anti-HAV in children vaccinated with live attenuated and inactivated hepatitis A vaccines. Vaccine 2004; 22:1941-5. [PMID: 15121306 DOI: 10.1016/j.vaccine.2003.11.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2003] [Accepted: 11/06/2003] [Indexed: 12/12/2022]
Abstract
The immunogenicity of a live attenuated HAV vaccine and an inactivated HAV vaccine was compared. Altogether 117 children were vaccinated with either the inactivated or the live attenuated vaccine. Children were bled at months 1, 6, 7, 12 and 24, and the anti-HAV total IgG antibody and IgG subclass profile were assessed. In both vaccinated groups, the geometric mean titer (GMT) of anti-HAV peaked 7 months after the initial dose and declined during the following months. The IgG subclass profiles in both vaccinated groups were highly restricted to IgG1 and IgG3. Both vaccines have been shown highly effective in preventing viral hepatitis A in former studies.
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Affiliation(s)
- Xuan-Yi Wang
- Department of Medical Molecular Virology, 138 Yi Xue Yuan Road, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Rezende G, Roque-Afonso AM, Samuel D, Gigou M, Nicand E, Ferre V, Dussaix E, Bismuth H, Féray C. Viral and clinical factors associated with the fulminant course of hepatitis A infection. Hepatology 2003; 38:613-8. [PMID: 12939587 DOI: 10.1053/jhep.2003.50366] [Citation(s) in RCA: 126] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Fulminant hepatitis is a severe complication of hepatitis A virus infection. Its mechanism is unknown. Liver transplantation can be necessary, but spontaneous recovery is frequent. There are no data on the level of viral replication according to the clinical form of hepatitis A. We reviewed the files of 50 patients with acute hepatitis A. Nineteen patients had fulminant hepatitis (defined by encephalopathy and factor V <50%), and, from them, 10 patients underwent transplantation. Hepatitis A virus (HAV) RNA was quantified by real-time PCR on sera obtained at admission. The genotype was determined by phylogenetic analysis of HAV RNA. HAV RNA was detected in serum by RT-PCR in 39 out of 50 patients. Encephalopathy and low factor V level were significantly related to female gender, HAV PCR negativity (9/19 vs. 5/31, respectively; P =.03), a low serum HAV RNA level (log, 3.6 +/- 0.6 vs. 4.4 +/- 0.9, respectively; P =.02), genotypes other than IA, and acetaminophen intake. In multivariate analysis, low or undetectable HAV viral load and a high bilirubin level were independently associated with both low factor V levels and fulminant hepatitis and also with death or transplantation. In conclusion, HAV-related liver failure is due to an excessive host response associated with a marked reduction in viral load. Serum HAV RNA assay could be of help in the management of severe hepatitis A.
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Affiliation(s)
- Guilhermo Rezende
- Centre Hépato-Biliaire, Equipe Propre de l'Institut National de la Santé, Unité propre de recherche de l'enseignement supérieur No. 3541, Formation de recherche associée à l'Association Claude Bernard, Villejuif, France
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Hu NZ, Hu YZ, Shi HJ, Liu GD, Qu S. Mutational characteristics in consecutive passage of rapidly replicating variants of hepatitis A virus strain H2 during cell culture adaptation. World J Gastroenterol 2002; 8:872-8. [PMID: 12378633 PMCID: PMC4656578 DOI: 10.3748/wjg.v8.i5.872] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the molecular mechanism of cell adaptation and rapid replication of hepatitis A virus strain H2 in KBM17 cells.
METHODS: Virus of strain H2 at passage 7 was consecutively passaged in KBM17 cells for 22 passages, every passage was incubated for 14 d. Antigenic and infectious titers of every passage and one-step growth dynamics of passage 22 were determined with ELISA. Genomes of passage 6, passage 12, passage 18 and passage 22 were sequenced and compared with H2K7.
RESULTS: During continuous passage of vaccine strain H2 at passage K7 in KMB17 cells, infectious and antigenic titers increased with the increase of passages, infectious titers at day 14 reached 6.77 LgCCID50ml-1 for passage 6 (P6), 7.0 LgCCID50ml-1 for passage 12 (P12), 7.33 LgCCID50ml-1 for passage 18 (P18) and 7.83 LgCCID50ml-1 for passage 22 (P22), respectively. The one-step growth dynamics showed that replicating peak of P22 appeared at day 14 with infectious titers of 7.83 LgCCID50ml-1 and antigenic titer of 1:1024. After passage 22 a new cell-adapted variant (P22) of H2K7 with rapid and shortened replication cycle from 28 d to 14 d was obtained. Sequencing and comparisons of genomes of P6, P12, P18 and P22 showed that mutational numbers in genomes of different passages increased with adaptive passages, and mutations scattered over the genome. In comparison with that of K7, P6 had only 6 nucleotides (nt) mutations, P12 had 7 mutational changes, in addition to 6 same mutations with P6, there appeared a new mutation in 5'NTR at nucleotide position 591 resulting in a nucleotide exchange from A to G. P18 had 10 nt mutations, among the 10 mutations, 7 mutational changes were same as with P12, three new mutational changes appeared in the genome, one in 5'NTR, one in 3C coding region, one in 3D coding region, at P22 there appeared 18 nucleotide changes in the genome, on the basis of P18, there occured additional 8 nucleotide mutations, two in 5'NTR, three in 2C, one in 3A, one in 3C and one in 3D. The results suggested that although H2K7 was already an attenuated strain, the mutations of genome is not sufficient to completely adapt the KMB17, further mutations caused rapid replication adaptation.
CONCLUSION: 18-nt changes scattering over the genome are cooperatively responsible for further adaptation characterized by rapid and shortened replication cycle from 28 d to 14 d in KMB17 cells. The mutations in 2C coding region play more important role in increase of infectious titer than other mutations, the mutations in 2B coding region show less important role than it usually does in cell adaptation, nucleotide changes in 5’NTR seem to be not relevant to cell adaptation during initial stages (before P6), but do in late stages.
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Affiliation(s)
- Ning-Zhu Hu
- Department of Vaccine Research, Institute of Medical Biology, Chinese Academy of Medical Sciences, Peking Union of Medical College, Kunming, 650118, Yunnan Province, China
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Abstract
Several useful animal models for both hepatitis A and E have been identified, characterized, and refined. At present, all of the best models utilize nonhuman primates: chimpanzees, tamarin species, and owl monkeys for hepatitis A; and macaque species, chimpanzees, and owl monkeys for hepatitis E. Pigs may prove useful for some studies of hepatitis E, and it is hoped that serological evidence of widespread infection of rats with an HEV-like agent may lead to the development of an animal model based on laboratory rats. As has been the case for each of the hepatitis viruses as they have been discovered, the development of useful and reproducible animal model systems has been critical for moving the field forward as expeditiously as possible.
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Affiliation(s)
- R H Purcell
- Hepatitis Viruses and Molecular Hepatitis Sections, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA
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Kabrane-Lazizi Y, Emerson SU, Herzog C, Purcell RH. Detection of antibodies to HAV 3C proteinase in experimentally infected chimpanzees and in naturally infected children. Vaccine 2001; 19:2878-83. [PMID: 11282198 DOI: 10.1016/s0264-410x(00)00560-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Commercial assays for the diagnosis of hepatitis A detect antibody to hepatitis A virus (anti-HAV), but they cannot discriminate between antibody resulting from infection and antibody induced by inactivated vaccine. With the licensing and increasing use of inactivated hepatitis A vaccines, there is a need for a test to distinguish between infection and vaccination. Since antibodies to viral non-structural proteins are elicited by infection but not by vaccination with inactivated vaccine, we developed and evaluated a test for such antibodies. The antibody response to the non-structural 3C proteinase (anti-3C) of virus HAV was studied by ELISA in chimpanzees experimentally infected with virulent (wild type) or with attenuated HAV strains and in children who received inactivated HAV vaccine or placebo during a vaccination trial in Nicaragua. Anti-3C was detected in 89% of 18 chimpanzees infected with wild-type HAV strains and 27% of 26 chimpanzees infected with attenuated HAV strains. There was a direct correlation between severity of hepatitis and magnitude of the anti-3C response. In the vaccine trial, anti-3C was detected only in children who were infected with HAV during the study; IgG anti-3C persisted for at least 15 months after infection in one child. Vaccinated and uninfected children remained negative for anti-3C. The anti-3C response can be regarded as an indicator of viral replication. Its detection should be useful for distinguishing between antibody acquired in response to HAV infection and antibody induced by immunization with inactivated vaccine.
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Affiliation(s)
- Y Kabrane-Lazizi
- Hepatitis Viruses and Molecular Hepatitis Sections, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Zhao YL, Meng ZD, Xu ZY, Guo JJ, Chai SA, Duo CG, Wang XY, Yao JF, Liu HB, Qi SX, Zhu HB. H2 strain attenuated live hepatitis A vaccines: Protective efficacy in a hepatitis A outbreak. World J Gastroenterol 2000; 6:829-832. [PMID: 11819704 PMCID: PMC4728270 DOI: 10.3748/wjg.v6.i6.829] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the protective efficacy of H2 strain attenuated live hepatitis A vaccines (H2-strain vaccines) in hepatitis A (HA) out breaks.
METHODS: With the permission of their parents, 5551 pre-school and grade 1-3 primary school children were inoculated with 1 dose (106.5TCID50) of H2-strain vaccines in a nonrandomized, controlled trial conducted in Fucheng County, Hebei Province in May 1997. Another 6485 children in the same grades and compatible in gender and age were enrolled as controls. Epidemiological and serological survey was conducted to evaluate the protective efficacy of the vaccines. ELISA was used to detect serum IgM anti-HAV.
RESULTS: HA outbreak started in early May 1998, peaked in the middle of the same month, and lasted about 80 d. Overall 302 HA cases were found, 192 (63.58%) were 5-9 years old. One vaccinee and 25 control cases were found to have hepatitis A, which account for 0.28% (1/356) and 5.92% (25/422) of all vaccinees and controls in the 14 villages, respectively. The protective efficacy of vaccines was 95.27% (95%CI: 85.83%-104.72%). In subjects tested for anti-HAV IgM from 13 villages, 1 (0.40%) overt and 11 (4.06%) asymptomatic HAV cases were found in 271 vaccinees，but 21 (6.69%) of overt and asymptomatic ones were found in 314 controls.
CONCLUSION: H2 strain vaccines were excellent in preventing overt hepatitis A, but not so effective in preventing asymptomatic hepatitis A virus infection. A booster dose might be needed to get permanent reliable immunity.
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Lee A, Cheng F, Lau L, Lo A, Fabb WE. Should adolescents be vaccinated against hepatitis A: the Hong Kong experience. Vaccine 1999; 18:941-6. [PMID: 10580208 DOI: 10.1016/s0264-410x(99)00339-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Hong Kong is a well developed city in the center of an endemic region for hepatitis A. The age at which hepatitis A occurs has shifted from childhood and adolescence to adults like many western countries. There is a high chance of outbreaks with the introduction of infection from neighbouring countries. Reducing the susceptibility of a population by vaccination can eliminate the diseases but updated sero-epidemiological data is needed to analyse the level of natural immunity, and identify those susceptible to infection for preventive measures. This study conducted amongst secondary school children seeks to identify those who are at risk and to obtain data on the present sero-prevalence of anti-HAV. Overall prevalence of anti-HAV in this age group was 7% increasing with age. Analysed by multiple regression model, those students living in mainland China over 3 years had odds ratio of 31.6 (95% c. i. 17.4-57.3) compared with those born in Hong Kong. Students with a father in a skilled occupation and an education level of secondary school or above, and both parents with secondary education or above, had an odds ratio of 0.22 (95% c.i. 0.07-0.7) and 0.35 (95% c.i. 0. 17-0.72) associated with presence of anti-HAV, respectively. Improved socio-economic state exposes higher proportion of the population at risk. Immunisation is worthwhile to be considered for the adolescents in Hong Kong. Prevaccination screening is cost effective only for those adolescents who are most likely to have natural immunity.
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Affiliation(s)
- A Lee
- Chinese University of Hong Kong, Lek Yuen Health Centre, Department of Community and Family Medicine, 4th Floor, Shatin, Hong Kong.
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Ashur Y, Adler R, Rowe M, Shouval D. Comparison of immunogenicity of two hepatitis A vaccines--VAQTA and HAVRIX--in young adults. Vaccine 1999; 17:2290-6. [PMID: 10403597 DOI: 10.1016/s0264-410x(98)00480-0] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Two new hepatitis A vaccines have been developed, and their immunogenicity tested using different immunoassays. The present study was designed to compare the immunogenicity of these two hepatitis A virus (HAV) vaccines--VAQTA and HAVRIX--as determined by seroconversion rates and anti-HAV titers, and using the same immunoassay. Healthy volunteers (15-30 y), seronegative for anti-HAV, were randomized in an open single center study to four groups of 20-21 vaccinees each, to receive either a 25 U or a 50 U dose of VAQTA, or HAVRIX at 720 EU or 1440 EU/dose, administered at 0, 1 and 6 m or at 0 and 6 m, respectively. Four weeks after primary immunization, seroconversion rates were 100% for VAQTA and 95% for HAVRIX, following injection of 50 U or 1440 EU, respectively (p = NS) and anti-HAV GMTs were 40 and 37 mIU/ml for VAQTA and HAVRIX, respectively. At 6 months, prior to the booster dose, seroconversion rates were 100% for both vaccines, with anti-HAV GMTs of 111 and 70 mIU/ml for VAQTA and HAVRIX, respectively (P < 0.05). At month 7, four weeks after the only booster injection, using the two dose regimen, anti-HAV titers were 2212 and 1511 mIU/ml for VAQTA and HAVRIX, respectively (P < NS). Using three doses of 25 U/dose of VAQTA or 720 EU/dose of HAVRIX at 0, 1 and 6 m did not produce any clinically evaluable advantage over the two dose regimen for either vaccine. No significant adverse events were observed using either vaccine. In summary, both vaccines have similar immunogenicity demonstrated using identical immunoassays for evaluation. These results also confirm the outstanding immunogenicity of a single dose of either of the HAV vaccines and support their use in pre- and possibly postexposure prophylaxis against hepatitis A virus infection.
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Affiliation(s)
- Y Ashur
- Division of Medicine, Hadassah University Hospital, Jerusalem, Israel
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Raychaudhuri G, Govindarajan S, Shapiro M, Purcell RH, Emerson SU. Utilization of chimeras between human (HM-175) and simian (AGM-27) strains of hepatitis A virus to study the molecular basis of virulence. J Virol 1998; 72:7467-75. [PMID: 9696843 PMCID: PMC109981 DOI: 10.1128/jvi.72.9.7467-7475.1998] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/1997] [Accepted: 06/15/1998] [Indexed: 11/20/2022] Open
Abstract
Chimeras between human (HM-175) and simian (AGM-27) strains of hepatitis A virus (HAV) were constructed to evaluate the effect of the 2C gene of AGM-27 on HAV replication in cell culture and virulence in tamarins (Saguinus mystax) and chimpanzees (Pan troglodytes). Kinetic studies and radioimmunofocus assays demonstrated that replacement of the 2C gene of HAV/7, a cell culture-adapted strain of HM-175, with that of AGM-27 drastically reduced the ability of the virus to replicate in cultured cells. Intragenic chimeras containing AGM-27 sequences in either the 5' or 3' half of the 2C gene replicated in cell culture at an intermediate level. Whereas HAV/7 is attenuated for tamarins, a chimera containing the simian virus 2C gene in the HAV/7 background was virulent in tamarins, demonstrating that the simian virus 2C gene alone can confer the phenotype of virulence to an otherwise attenuated virus. Clusters of AGM-27-specific residues near both ends of the 2C protein were required for virulence since a chimera containing AGM-27 sequences in the carboxy-terminal half of 2C was partially attenuated for tamarins while one containing AGM-27 sequences only in the amino-terminal half of 2C was even more attenuated. Chimeras containing either the entire or only the 3' half of the simian virus 2C gene in the HAV/7 background were attenuated for chimpanzees.
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Affiliation(s)
- G Raychaudhuri
- Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland 20892, USA.
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Abstract
At the end of the 20th century active immunization against hepatitis A and B has been introduced into routine medical practice. Therefore, patients at risk, and especially those with coagulation disorders, should be immunized at the earliest age possible. In contrast, development of an efficacious vaccine against hepatitis C remains an important goal for the next decade.
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Affiliation(s)
- D Shouval
- Liver Unit, Hadassah University Hospital, Jerusalem, Israel
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Mao JS, Chai SA, Xie RY, Chen NL, Jiang Q, Zhu XZ, Zhang SY, Huang HY, Mao HW, Bao XN, Liu CJ. Further evaluation of the safety and protective efficacy of live attenuated hepatitis A vaccine (H2-strain) in humans. Vaccine 1997; 15:944-7. [PMID: 9261939 DOI: 10.1016/s0264-410x(96)00304-0] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
A study on the possibility of transmission of live hepatitis A vaccine (H2-strain) from vaccinees to nonvaccinees was conducted. As a result, no seroconversion was found among 87 seronegative nonvaccinees, who had a close contact with their 141 subcutaneously vaccinated classmates nor was it found among 101 seronegative children administered the vaccine orally. The above fundings suggest that by losing the ability to be transmitted orally the vaccine virus may result in a decreasing possibility of dissemination among contacts. A 4-year study on the protective efficacy of the H2-strain vaccine was done at 11 primary schools starting at 1991 in Shaoxing County. Since then, there has been no hepatitis A reported among 18102 cumulative person-years in the vaccination group, while 495 cases occurred among 242168 cumulative person-years in the control groups. A large scale vaccination with a cumulative vaccination coverage of 89.45% was carried out in Jiaojiang City among children 1-15 years old. Hepatitis A in this age group in the city, which had 12-87 cases per annum with an average of 32 for 8 years before vaccination, decreased drastically to 0-1 cases after vaccination. The protective efficacy of H2-strain vaccine proved to be satisfactory.
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Affiliation(s)
- J S Mao
- Zhejiang Academy of Medical Sciences, Hangzhou, People's Republic of China
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49
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Chen XQ, Bülbül M, de Gast GC, van Loon AM, Nalin DR, van Hattum J. Immunogenicity of two versus three injections of inactivated hepatitis A vaccine in adults. J Hepatol 1997; 26:260-4. [PMID: 9059944 DOI: 10.1016/s0168-8278(97)80039-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
AIM To investigate the immunogenicity of two versus three injections of inactivated strain CR326F-derived hepatitis A vaccine in healthy adults. METHODS Healthy adult volunteers (n = 105) at Utrecht University Hospital, The Netherlands, were randomly assigned to receive intramuscular injections (deltoid muscle) of 25 Units (U) at 0 and 6 months (group A, n = 53), or at 0, 2 and 6 months (group B, n = 52). Blood was drawn before and at various time points after vaccination for determination of serum antibody to hepatitis A (anti-HAV). RESULTS One month after the first injection, the seroconversion rates (> or = 10 mIU/ml, international units) were 88% for group A and 90% for group B. Only 2/ 103 (one in each group) showed IgM anti-HAV. One month after the second injection, seroconversion rates were 100% in both groups. At months 3, 6 and 7, anti-HAV geometric mean titers were significantly different because of the different vaccination schedules, but they were similar at months 1, 2 and 12. The anti-HAV geometric mean titer increase after the second injection was higher when the interval between the two doses was of longer duration. Anti-HAV titers of females were significantly higher than those of males and vaccinees < or = 30 years had higher titers than those > 30 years. CONCLUSIONS Two 25 U doses of the vaccine investigated given at 0 and 6 months, induce adequate anti-HAV titers in all adult healthy vaccinees and are as immunogenic as three doses given at 0, 2 and 6 months.
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Affiliation(s)
- X Q Chen
- Department of Gastroenterology, University Hospital of Utrecht, The Netherlands
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50
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Affiliation(s)
- S M Lemon
- Department of Medicine, University of North Carolina at Chapel Hill, 27599-7030, USA
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