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Manne V, Ryan J, Wong J, Vengayil G, Basit SA, Gish RG. Hepatitis C Vaccination: Where We Are and Where We Need to Be. Pathogens 2021; 10:pathogens10121619. [PMID: 34959574 PMCID: PMC8705661 DOI: 10.3390/pathogens10121619] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/07/2021] [Accepted: 12/10/2021] [Indexed: 12/12/2022] Open
Abstract
The hepatitis C virus (HCV) is a common cause of chronic liver disease and liver cancer worldwide. Despite advances in curative therapies for HCV, the incidence of new infections is not decreasing at the expected rate to hit the World Health Organization (WHO) target for the elimination of HCV by 2030. In fact, there are still more new cases of infection in the United States and worldwide than are being cured. The reasons for the rise in new cases include poor access to care and the opioid epidemic. The clinical burden of HCV requires a multimodal approach to eradicating the infection. Vaccination would be an excellent tool to prevent incidence of new infections; however, the genetic diversity of HCV and its ability to generate quasispecies within an infected host make creating a broadly reactive vaccine difficult. Multiple vaccine candidates have been identified, but to date, there has not been a target that has led to a broadly reactive vaccine, though several of the candidates are promising. Additionally, the virus is very difficult to culture and testing candidates in humans or chimpanzees is ethically challenging. Despite the multiple barriers to creating a vaccine, vaccination still represents an important tool in the fight against HCV.
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Affiliation(s)
- Vignan Manne
- HCA Healthcare Graduate Medical Education, Las Vegas, NV 89148, USA; (V.M.); (J.W.); (G.V.)
| | - John Ryan
- Comprehensive Digestive Institute of Nevada, Las Vegas, NV 89148, USA; (J.R.); (S.A.B.)
| | - Jonathan Wong
- HCA Healthcare Graduate Medical Education, Las Vegas, NV 89148, USA; (V.M.); (J.W.); (G.V.)
| | - Gayatri Vengayil
- HCA Healthcare Graduate Medical Education, Las Vegas, NV 89148, USA; (V.M.); (J.W.); (G.V.)
| | - Syed Abdul Basit
- Comprehensive Digestive Institute of Nevada, Las Vegas, NV 89148, USA; (J.R.); (S.A.B.)
| | - Robert G. Gish
- Liver Transplant Clinic, Loma Linda University, Loma Linda, CA 92350, USA
- Correspondence: ; Tel.: +1-866-873-8877
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2
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Shayeghpour A, Kianfar R, Hosseini P, Ajorloo M, Aghajanian S, Hedayat Yaghoobi M, Hashempour T, Mozhgani SH. Hepatitis C virus DNA vaccines: a systematic review. Virol J 2021; 18:248. [PMID: 34903252 PMCID: PMC8667529 DOI: 10.1186/s12985-021-01716-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 11/26/2021] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Vaccination against HCV is an effective measure in reduction of virus-related public health burden and mortality. However, no prophylactic vaccine is available as of yet. DNA-based immunization is a promising modality to generate cellular and humoral immune responses. The objective of this study is to provide a systematic review of HCV DNA vaccines and investigate and discuss the strategies employed to optimize their efficacies. METHODS MEDLINE (PubMed), Web of Science, Scopus, ScienceDirect, and databases in persian language including the Regional Information Centre for Science & Technology (RICeST), the Scientific Information Database and the Iranian Research Institute for Information Science and Technology (IranDoc) were examined to identify studies pertaining to HCV nucleic acid vaccine development from 2000 to 2020. RESULTS Twenty-seven articles were included. Studies related to HCV RNA vaccines were yet to be published. A variety of strategies were identified with the potential to optimize HCV DNA vaccines such as incorporating multiple viral proteins and molecular tags such as HBsAg and Immunoglobulin Fc, multi-epitope expression, co-expression plasmid utilization, recombinant subunit immunogens, heterologous prime-boosting, incorporating NS3 mutants in DNA vaccines, utilization of adjuvants, employment of less explored methods such as Gene Electro Transfer, construction of multi- CTL epitopes, utilizing co/post translational modifications and polycistronic genes, among others. The effectiveness of the aforementioned strategies in boosting immune response and improving vaccine potency was assessed. CONCLUSIONS The recent progress on HCV vaccine development was examined in this systematic review to identify candidates with most promising prophylactic and therapeutic potential.
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Affiliation(s)
- Ali Shayeghpour
- Student Research Committee, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Roya Kianfar
- Department of Medical Virology, Tarbiat Modares University, Tehran, Iran
| | - Parastoo Hosseini
- Department of Virology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
- Research Center for Clinical Virology, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehdi Ajorloo
- Hepatitis Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran
- Department of Clinical Laboratory Sciences, School of Allied Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Sepehr Aghajanian
- Student Research Committee, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Mojtaba Hedayat Yaghoobi
- Department of Infectious Disease, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Tayebeh Hashempour
- Shiraz HIV/AIDS Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sayed-Hamidreza Mozhgani
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran.
- Department of Microbiology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
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Hartlage AS, Kapoor A. Hepatitis C Virus Vaccine Research: Time to Put Up or Shut Up. Viruses 2021; 13:1596. [PMID: 34452460 PMCID: PMC8402855 DOI: 10.3390/v13081596] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 07/27/2021] [Accepted: 07/31/2021] [Indexed: 12/16/2022] Open
Abstract
Unless urgently needed to prevent a pandemic, the development of a viral vaccine should follow a rigorous scientific approach. Each vaccine candidate should be designed considering the in-depth knowledge of protective immunity, followed by preclinical studies to assess immunogenicity and safety, and lastly, the evaluation of selected vaccines in human clinical trials. The recently concluded first phase II clinical trial of a human hepatitis C virus (HCV) vaccine followed this approach. Still, despite promising preclinical results, it failed to protect against chronic infection, raising grave concerns about our understanding of protective immunity. This setback, combined with the lack of HCV animal models and availability of new highly effective antivirals, has fueled ongoing discussions of using a controlled human infection model (CHIM) to test new HCV vaccine candidates. Before taking on such an approach, however, we must carefully weigh all the ethical and health consequences of human infection in the absence of a complete understanding of HCV immunity and pathogenesis. We know that there are significant gaps in our knowledge of adaptive immunity necessary to prevent chronic HCV infection. This review discusses our current understanding of HCV immunity and the critical gaps that should be filled before embarking upon new HCV vaccine trials. We discuss the importance of T cells, neutralizing antibodies, and HCV genetic diversity. We address if and how the animal HCV-like viruses can be used for conceptualizing effective HCV vaccines and what we have learned so far from these HCV surrogates. Finally, we propose a logical but narrow path forward for HCV vaccine development.
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Affiliation(s)
- Alex S. Hartlage
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Medical Scientist Training Program, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43205, USA
| | - Amit Kapoor
- Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA;
- Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43205, USA
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Pisano MB, Giadans CG, Flichman DM, Ré VE, Preciado MV, Valva P. Viral hepatitis update: Progress and perspectives. World J Gastroenterol 2021; 27:4018-4044. [PMID: 34326611 PMCID: PMC8311538 DOI: 10.3748/wjg.v27.i26.4018] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Revised: 04/11/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
Viral hepatitis, secondary to infection with hepatitis A, B, C, D, and E viruses, are a major public health problem and an important cause of morbidity and mortality. Despite the huge medical advances achieved in recent years, there are still points of conflict concerning the pathogenesis, immune response, development of new and more effective vaccines, therapies, and treatment. This review focuses on the most important research topics that deal with issues that are currently being solved, those that remain to be solved, and future research directions. For hepatitis A virus we will address epidemiology, molecular surveillance, new susceptible populations as well as environmental and food detections. In the case of hepatitis B virus, we will discuss host factors related to disease, diagnosis, therapy, and vaccine improvement. On hepatitis C virus, we will focus on pathogenesis, immune response, direct action antivirals treatment in the context of solid organ transplantation, issues related to hepatocellular carcinoma development, direct action antivirals resistance due to selection of resistance-associated variants, and vaccination. Regarding hepatitis D virus, we describe diagnostic methodology, pathogenesis, and therapy. Finally, for hepatitis E virus, we will address epidemiology (including new emerging species), diagnosis, clinical aspects, treatment, the development of a vaccine, and environmental surveillance.
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Affiliation(s)
- María B Pisano
- Virology Institute, CONICET, School of Medical Sciences, National University of Córdoba, Cordoba X5016, Argentina
| | - Cecilia G Giadans
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP) CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children’s Hospital, CABA C1425, Buenos Aires, Argentina
| | - Diego M Flichman
- Institute of Biomedical Investigations in Retrovirus and AIDS (INBIRS), School of Medicine, University of Buenos Aires, CONICET, CABA C1121ABG, Buenos Aires, Argentina
| | - Viviana E Ré
- Virology Institute, CONICET, School of Medical Sciences, National University of Córdoba, Cordoba X5016, Argentina
| | - María V Preciado
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP) CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children’s Hospital, CABA C1425, Buenos Aires, Argentina
| | - Pamela Valva
- Multidisciplinary Institute for Investigation in Pediatric Pathologies (IMIPP) CONICET-GCBA, Laboratory of Molecular Biology, Pathology Division, Ricardo Gutiérrez Children’s Hospital, CABA C1425, Buenos Aires, Argentina
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Abstract
PURPOSE OF REVIEW The WHO has set ambitious targets for hepatitis C virus (HCV) elimination by 2030. In this review, we explore the possibility of HCV micro-elimination in HIV-positive (+) MSM, discussing strategies for reducing acute HCV incidence and the likely interventions required to meet these targets. RECENT FINDINGS With wider availability of directly acting antivirals (DAAs) in recent years, reductions in acute HCV incidence have been reported in some cohorts of HIV+ MSM. Recent evidence demonstrates that treatment in early infection is well tolerated, cost effective and may reduce the risk of onward transmission. Modelling studies suggest that to reduce incidence, a combination approach including behavioural interventions and access to early treatment, targeting both HIV+ and negative high-risk groups, will be required. HCV vaccine trials have not yet demonstrated efficacy in human studies, however phase one and two studies are ongoing. SUMMARY Some progress towards the WHO HCV elimination targets has been reported. Achieving sustained HCV elimination is likely to require a combination approach including early access to DAAs in acute infection and reinfection, validated and reproducible behavioural interventions and an efficacious HCV vaccine.
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Kardani K, Basimi P, Fekri M, Bolhassani A. Antiviral therapy for the sexually transmitted viruses: recent updates on vaccine development. Expert Rev Clin Pharmacol 2020; 13:1001-1046. [PMID: 32838584 DOI: 10.1080/17512433.2020.1814743] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The sexually transmitted infections (STIs) caused by viruses including human T cell leukemia virus type-1 (HTLV-1), human immunodeficiency virus-1 (HIV-1), human simplex virus-2 (HSV-2), hepatitis C virus (HCV), hepatitis B virus (HBV), and human papillomavirus (HPV) are major public health issues. These infections can cause cancer or result in long-term health problems. Due to high prevalence of STIs, a safe and effective vaccine is required to overcome these fatal viruses. AREAS COVERED This review includes a comprehensive overview of the literatures relevant to vaccine development against the sexually transmitted viruses (STVs) using PubMed and Sciencedirect electronic search engines. Herein, we discuss the efforts directed toward development of effective vaccines using different laboratory animal models including mice, guinea pig or non-human primates in preclinical trials, and human in clinical trials with different phases. EXPERT OPINION There is no effective FDA approved vaccine against the sexually transmitted viruses (STVs) except for HBV and HPV as prophylactic vaccines. Many attempts are underway to develop vaccines against these viruses. There are several approaches for improving prophylactic or therapeutic vaccines such as heterologous prime/boost immunization, delivery system, administration route, adjuvants, etc. In this line, further studies can be helpful for understanding the immunobiology of STVs in human. Moreover, development of more relevant animal models is a worthy goal to induce effective immune responses in humans.
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Affiliation(s)
- Kimia Kardani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
| | - Parya Basimi
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
| | - Mehrshad Fekri
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
| | - Azam Bolhassani
- Department of Hepatitis and AIDS, Pasteur Institute of Iran , Tehran, Iran
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Chen F, Nagy K, Chavez D, Willis S, McBride R, Giang E, Honda A, Bukh J, Ordoukhanian P, Zhu J, Frey S, Lanford R, Law M. Antibody Responses to Immunization With HCV Envelope Glycoproteins as a Baseline for B-Cell-Based Vaccine Development. Gastroenterology 2020; 158:1058-1071.e6. [PMID: 31809725 PMCID: PMC7371413 DOI: 10.1053/j.gastro.2019.11.282] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 11/11/2019] [Accepted: 11/12/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS We investigated antibody responses to hepatitis C virus (HCV) antigens E1 and E2 and the relevance of animal models for vaccine development. We compared antibody responses to vaccination with recombinant E1E2 complex in healthy volunteers, non-human primates (NHPs), and mice. METHODS We analyzed 519 serum samples from participants in a phase 1 vaccine trial (ClinicalTrials.gov identifier NCT00500747) and compared them with serum or plasma samples from C57BL/6J mice (n = 28) and rhesus macaques (n = 4) immunized with the same HCV E1E2 antigen. Blood samples were collected at different time points and analyzed for antibody binding, neutralizing activity, and epitope specificity. Monoclonal antibodies from the immunized NHPs were isolated from single plasmablasts and memory B cells, and their immunogenetic properties were characterized. RESULTS Antibody responses of the volunteers, NHPs, and mice to the non-neutralizing epitopes on the E1 N-terminus and E2 hypervariable region 1 did not differ significantly. Antibodies from volunteers and NHPs that neutralized heterologous strains of HCV primarily interacted with epitopes in the antigen region 3. However, the neutralizing antibodies were not produced in sufficient levels for broad neutralization of diverse HCV isolates. Broadly neutralizing antibodies similar to the human VH1-69 class antibody specific for antigen region 3 were produced in the immunized NHPs. CONCLUSIONS In an analysis of vaccinated volunteers, NHPs, and mice, we found that recombinant E1E2 vaccine antigen induces high-antibody titers that are insufficient to neutralize diverse HCV isolates. Antibodies from volunteers and NHPs bind to the same neutralizing epitopes for virus neutralization. NHPs can therefore be used as a preclinical model to develop HCV vaccines. These findings also provide useful baseline values for development of vaccines designed to induce production of neutralizing antibodies.
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Affiliation(s)
- Fang Chen
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Kenna Nagy
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Deborah Chavez
- Southwest National Primate Research Center at Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Shelby Willis
- NGS and Microarray Research Cores, The Scripps Research Institute, La Jolla, California, USA
| | - Ryan McBride
- NGS and Microarray Research Cores, The Scripps Research Institute, La Jolla, California, USA
| | - Erick Giang
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Andrew Honda
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California, USA
| | - Jens Bukh
- Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Hvidovre Hospital, and Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
| | - Phillip Ordoukhanian
- NGS and Microarray Research Cores, The Scripps Research Institute, La Jolla, California, USA
| | - Jiang Zhu
- Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, California, USA
| | - Sharon Frey
- Saint Louis University Center for Vaccine Development, St. Louis, Missouri, USA
| | - Robert Lanford
- Southwest National Primate Research Center at Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Mansun Law
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, California.
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8
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Cox AL. Challenges and Promise of a Hepatitis C Virus Vaccine. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a036947. [PMID: 31548228 DOI: 10.1101/cshperspect.a036947] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
An estimated 1.5-2 million new hepatitis C virus (HCV) infections occur globally each year. Critical to the World Health Organization's (WHO) HCV elimination strategy is an 80% reduction in incidence of HCV infections by 2030. However, even among high-income countries, few are on target to achieve the WHO's incident infection-reduction goal. A preventative vaccine could have a major impact in achieving incidence-reduction targets globally. However, barriers to HCV vaccine development are significant and include at-risk populations that are often marginalized: viral diversity, limited options for testing HCV vaccines, and an incomplete understanding of protective immune responses. In part because of those factors, testing of only one vaccine strategy has been completed in at-risk individuals as of 2019. Despite challenges, immunity against HCV protects against chronic infection in some repeated HCV exposures and an effective HCV vaccine could prevent transmission regardless of risk factors. Ultimately, prophylactic vaccines will likely be necessary to achieve global HCV elimination.
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Affiliation(s)
- Andrea L Cox
- Department of Medicine, Division of Infectious Diseases, Johns Hopkins University, Baltimore, Maryland 21205, USA
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Jansons J, Sominskaya I, Petrakova N, Starodubova ES, Smirnova OA, Alekseeva E, Bruvere R, Eliseeva O, Skrastina D, Kashuba E, Mihailova M, Kochetkov SN, Ivanov AV, Isaguliants MG. The Immunogenicity in Mice of HCV Core Delivered as DNA Is Modulated by Its Capacity to Induce Oxidative Stress and Oxidative Stress Response. Cells 2019; 8:cells8030208. [PMID: 30823485 PMCID: PMC6468923 DOI: 10.3390/cells8030208] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Revised: 02/06/2019] [Accepted: 02/20/2019] [Indexed: 12/16/2022] Open
Abstract
HCV core is an attractive HCV vaccine target, however, clinical or preclinical trials of core-based vaccines showed little success. We aimed to delineate what restricts its immunogenicity and improve immunogenic performance in mice. We designed plasmids encoding full-length HCV 1b core and its variants truncated after amino acids (aa) 60, 98, 152, 173, or up to aa 36 using virus-derived or synthetic polynucleotides (core191/60/98/152/173/36_191v or core152s DNA, respectively). We assessed their level of expression, route of degradation, ability to trigger the production of reactive oxygen species/ROS, and to activate the components of the Nrf2/ARE antioxidant defense pathway heme oxygenase 1/HO-1 and NAD(P)H: quinone oxidoreductase/Nqo-1. All core variants with the intact N-terminus induced production of ROS, and up-regulated expression of HO-1 and Nqo-1. The capacity of core variants to induce ROS and up-regulate HO-1 and Nqo-1 expression predetermined their immunogenicity in DNA-immunized BALB/c and C57BL/6 mice. The most immunogenic was core 152s, expressed at a modest level and inducing moderate oxidative stress and oxidative stress response. Thus, immunogenicity of HCV core is shaped by its ability to induce ROS and oxidative stress response. These considerations are important in understanding the mechanisms of viral suppression of cellular immune response and in HCV vaccine design.
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Affiliation(s)
- Juris Jansons
- Department of Pathology, Riga Stradins University, LV-1007 Riga, Latvia.
- Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia.
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
| | - Irina Sominskaya
- Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia.
| | - Natalia Petrakova
- N.F. Gamaleya Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia.
| | - Elizaveta S Starodubova
- N.F. Gamaleya Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia.
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
| | - Olga A Smirnova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
| | - Ekaterina Alekseeva
- Department of Pathology, Riga Stradins University, LV-1007 Riga, Latvia.
- Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia.
| | - Ruta Bruvere
- Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia.
| | - Olesja Eliseeva
- N.F. Gamaleya Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia.
| | - Dace Skrastina
- Department of Pathology, Riga Stradins University, LV-1007 Riga, Latvia.
- Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia.
| | - Elena Kashuba
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
- RE Kavetsky Institite of Experimental Pathology, Oncology and Radiobiology, The National Academy of Sciences of Ukraine, 03022 Kyiv, Ukraine.
| | - Marija Mihailova
- Latvian Biomedical Research and Study Centre, LV-1067 Riga, Latvia.
| | - Sergey N Kochetkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
| | - Alexander V Ivanov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991 Moscow, Russia.
| | - Maria G Isaguliants
- Department of Pathology, Riga Stradins University, LV-1007 Riga, Latvia.
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
- N.F. Gamaleya Research Center of Epidemiology and Microbiology, Ministry of Health of the Russian Federation, 123098 Moscow, Russia.
- MP Chumakov Center for Research and Development of Immune and Biological Preparations of RAS, 108819 Moscow, Russia.
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Bailey JR, Barnes E, Cox AL. Approaches, Progress, and Challenges to Hepatitis C Vaccine Development. Gastroenterology 2019; 156:418-430. [PMID: 30268785 PMCID: PMC6340767 DOI: 10.1053/j.gastro.2018.08.060] [Citation(s) in RCA: 168] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 08/12/2018] [Accepted: 08/14/2018] [Indexed: 12/16/2022]
Abstract
Risk factors for hepatitis C virus (HCV) infection vary, and there were an estimated 1.75 million new cases worldwide in 2015. The World Health Organization aims for a 90% reduction in new HCV infections by 2030. An HCV vaccine would prevent transmission, regardless of risk factors, and significantly reduce the global burden of HCV-associated disease. Barriers to development include virus diversity, limited models for testing vaccines, and our incomplete understanding of protective immune responses. Although highly effective vaccines could prevent infection altogether, immune responses that increase the rate of HCV clearance and prevent chronic infection may be sufficient to reduce disease burden. Adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins are the only vaccine strategy to be tested in at-risk individuals. Despite development challenges, a prophylactic vaccine is necessary for global control of HCV.
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Affiliation(s)
- Justin R. Bailey
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the Oxford NIHR Biomedical Research Centre, Oxford University, UK
| | - Andrea L. Cox
- Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland,Reprint requests Address requests for reprints to: Andrea L. Cox, MD, PhD, Division of Infectious Diseases, Johns Hopkins University School of Medicine, 551 Rangos Building, 855 N Wolfe Street, Baltimore, Maryland 21205. fax: (443)769-1221.
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11
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Abstract
In spite of the immense progress in hepatitis C virus (HCV) research, efforts to prevent infection, such as generating a vaccine, have not yet been successful. The high price tag associated with current treatment options for chronic infection and the spike in new infections concurrent with growing opioid abuse are strong motivators for developing effective immunization and understanding neutralizing antibodies' role in preventing infection. Humanized mice-both human liver chimeras as well as genetically humanized models-are important platforms for testing both possible vaccine candidates as well as antibody-based therapies. This chapter details the variety of ways humanized mouse technology can be employed in pursuit of learning how HCV infection can be prevented.
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Affiliation(s)
- Jenna M Gaska
- Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ, USA
| | - Qiang Ding
- Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ, USA
- School of Medicine, Tsinghua University, Beijing, China
| | - Alexander Ploss
- Lewis Thomas Laboratory, Department of Molecular Biology, Princeton University, Princeton, NJ, USA.
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12
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Taherkhani R, Farshadpour F. Global elimination of hepatitis C virus infection: Progresses and the remaining challenges. World J Hepatol 2017; 9:1239-1252. [PMID: 29312527 PMCID: PMC5745585 DOI: 10.4254/wjh.v9.i33.1239] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 09/01/2017] [Accepted: 10/10/2017] [Indexed: 02/06/2023] Open
Abstract
Today, with the introduction of interferon-free direct-acting antivirals and outstanding progresses in the prevention, diagnosis and treatment of hepatitis C virus (HCV) infection, the elimination of HCV infection seems more achievable. A further challenge is continued transmission of HCV infection in high-risk population specially injecting drug users (IDUs) as the major reservoir of HCV infection. Considering the fact that most of these infections remain undiagnosed, unidentified HCV-infected IDUs are potential sources for the rapid spread of HCV in the community. The continuous increase in the number of IDUs along with the rising prevalence of HCV infection among young IDUs is harbinger of a forthcoming public health dilemma, presenting a serious challenge to control transmission of HCV infection. Even the changes in HCV genotype distribution attributed to injecting drug use confirm this issue. These circumstances create a strong demand for timely diagnosis and proper treatment of HCV-infected patients through risk-based screening to mitigate the risk of HCV transmission in the IDUs community and, consequently, in the society. Meanwhile, raising general awareness of HCV infection, diagnosis and treatment through public education should be the core activity of any harm reduction intervention, as the root cause of failure in control of HCV infection has been lack of awareness among young drug takers. In addition, effective prevention, comprehensive screening programs with a specific focus on high-risk population, accessibility to the new anti-HCV treatment regimens and public education should be considered as the top priorities of any health policy decision to eliminate HCV infection.
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Affiliation(s)
- Reza Taherkhani
- the Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
| | - Fatemeh Farshadpour
- the Persian Gulf Tropical Medicine Research Center, Bushehr University of Medical Sciences, Bushehr 7514633341, Iran
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Comparative Immunogenicity in Rabbits of the Polypeptides Encoded by the 5' Terminus of Hepatitis C Virus RNA. J Immunol Res 2015; 2015:762426. [PMID: 26609538 PMCID: PMC4644844 DOI: 10.1155/2015/762426] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2015] [Accepted: 09/29/2015] [Indexed: 12/26/2022] Open
Abstract
Recent studies on the primate protection from HCV infection stressed the importance of immune response against structural viral proteins. Strong immune response against nucleocapsid (core) protein was difficult to achieve, requesting further experimentation in large animals. Here, we analyzed the immunogenicity of core aa 1–173, 1–152, and 147–191 and of its main alternative reading frame product F-protein in rabbits. Core aa 147–191 was synthesized; other polypeptides were obtained by expression in E. coli. Rabbits were immunized by polypeptide primes followed by multiple boosts and screened for specific anti-protein and anti-peptide antibodies. Antibody titers to core aa 147–191 reached 105; core aa 1–152, 5 × 105; core aa 1–173 and F-protein, 106. Strong immunogenicity of the last two proteins indicated that they may compete for the induction of immune response. The C-terminally truncated core was also weakly immunogenic on the T-cell level. To enhance core-specific cellular response, we immunized rabbits with the core aa 1–152 gene forbidding F-protein formation. Repeated DNA immunization induced a weak antibody and sustained proliferative response of broad specificity confirming a gain of cellular immunogenicity. Epitopes recognized in rabbits overlapped those in HCV infection. Our data promotes the use of rabbits for the immunogenicity tests of prototype HCV vaccines.
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Verstrepen BE, Boonstra A, Koopman G. Immune mechanisms of vaccine induced protection against chronic hepatitis C virus infection in chimpanzees. World J Hepatol 2015; 7:53-69. [PMID: 25624997 PMCID: PMC4295194 DOI: 10.4254/wjh.v7.i1.53] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2014] [Revised: 10/22/2014] [Accepted: 11/07/2014] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is characterized by a high propensity for development of life-long viral persistence. An estimated 170 million people suffer from chronic hepatitis caused by HCV. Currently, there is no approved prophylactic HCV vaccine available. With the near disappearance of the most relevant animal model for HCV, the chimpanzee, we review the progression that has been made regarding prophylactic vaccine development against HCV. We describe the results of the individual vaccine evaluation experiments in chimpanzees, in relation to what has been observed in humans. The results of the different studies indicate that partial protection against infection can be achieved, but a clear correlate of protection has thus far not yet been defined.
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Affiliation(s)
- Babs E Verstrepen
- Babs E Verstrepen, Gerrit Koopman, Department of Virology, Biomedical Primate Research Centre, 2280GH Rijswijk, The Netherlands
| | - André Boonstra
- Babs E Verstrepen, Gerrit Koopman, Department of Virology, Biomedical Primate Research Centre, 2280GH Rijswijk, The Netherlands
| | - Gerrit Koopman
- Babs E Verstrepen, Gerrit Koopman, Department of Virology, Biomedical Primate Research Centre, 2280GH Rijswijk, The Netherlands
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15
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Shahid I, ALMalki WH, Hafeez MH, Hassan S. Hepatitis C virus infection treatment: An era of game changer direct acting antivirals and novel treatment strategies. Crit Rev Microbiol 2014; 42:535-47. [PMID: 25373616 DOI: 10.3109/1040841x.2014.970123] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Chronic hepatitis C virus infection and associated liver diseases represent a major health care burden all over the world. The current standard of care, i.e. peginterferon-alfa (PEG-IFNα) plus ribavirin (RBV) are associated with frequent and sometimes serious adverse effects and contraindications, which further limit their therapeutic efficacy. The approval of first and second generation HCV protease inhibitors represents a major breakthrough in the development of novel direct acting antivirals (DAAs) against different HCV genotypes and establishes a new standard of care for chronically infected HCV genotypes 1 patients. Similarly, next generation protease inhibitors and HCV RNA polymerase inhibitors have shown better pharmacokinetics and pharmacodynamics in terms of broader HCV genotypes coverage, better safety profile, fewer drug interactions and possible once daily administration than first generation direct acting antivirals. The testing of adenovirus-based vector vaccines, which escalates the innate and acquired immune responses against the most conserved regions of the HCV genome in chimpanzees and humans, may be a promising therapeutic approach against HCV infection in coming future. This review article presents up-to-date knowledge and recent developments in HCV therapeutics, insights the shortcomings of current HCV therapies and key lessons from the therapeutic potential of improved anti-HCV treatment strategies.
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Affiliation(s)
- Imran Shahid
- a Department of Molecular Biology , Applied and Functional Genomics Lab, CEMB, University of the Punjab , Near Thokar Niaz Baig , Lahore , Pakistan .,b Department of Pharmacology and Toxicology , College of Pharmacy, Umm Al Qura University , Al-Abidiyah , Makkah , Saudi Arabia
| | - Waleed Hassan ALMalki
- b Department of Pharmacology and Toxicology , College of Pharmacy, Umm Al Qura University , Al-Abidiyah , Makkah , Saudi Arabia
| | - Muhammad Hassan Hafeez
- c Department of Gastroenterology and Hepatology , Fatima Memorial Hospital and College of Medicine and Dentistry , Shadman , Lahore , Pakistan , and
| | - Sajida Hassan
- a Department of Molecular Biology , Applied and Functional Genomics Lab, CEMB, University of the Punjab , Near Thokar Niaz Baig , Lahore , Pakistan .,d Viral Hepatitis Program, Laboratory of Medicine, University of Washington , Seattle , WA , USA
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16
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Belousova V, Abd-Rabou AA, Mousa SA. Recent advances and future directions in the management of hepatitis C infections. Pharmacol Ther 2014; 145:92-102. [PMID: 25200121 DOI: 10.1016/j.pharmthera.2014.09.002] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2014] [Accepted: 09/02/2014] [Indexed: 02/07/2023]
Abstract
Current estimates indicate that the hepatitis C virus is the leading cause of death in the United States with infection rates steadily increasing. Successful treatment is made difficult by the presence of various host, virus, and treatment-related factors, warranting the development of new approaches to combat the silent epidemic. The addition of telaprevir and boceprevir to the pharmacotherapeutic arsenal drastically improved success rates in genotype 1 infected patients, but rapid development of resistance mechanisms, increases in adverse effects, and a low spectrum activity proved to be barriers to efficacious treatment. In late 2013, two new agents were approved - sofosbuvir and simeprevir - that have higher barriers to resistance, favorable safety profiles, and profoundly improved success rates; however higher costs associated with the new medications could limit their wider utilization. Further strategies to combat the virus are under development, ranging from interferon-free regimens as well as prophylactic and therapeutic vaccines to applications of nanotechnology, helping us get closer to improved treatment of patients infected with hepatitis C.
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Affiliation(s)
- Victoria Belousova
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, One Discovery Drive, Rensselaer, NY 12144, USA
| | - Ahmed A Abd-Rabou
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, One Discovery Drive, Rensselaer, NY 12144, USA; Hormones Department, Medical Research Division, National Research Center, Cairo, Egypt; Center for Aging and Associated Diseases, Zewail City of Science and Technology, 6th of October, Egypt
| | - Shaker A Mousa
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, One Discovery Drive, Rensselaer, NY 12144, USA.
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17
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Ansaldi F, Orsi A, Sticchi L, Bruzzone B, Icardi G. Hepatitis C virus in the new era: Perspectives in epidemiology, prevention, diagnostics and predictors of response to therapy. World J Gastroenterol 2014; 20:9633-9652. [PMID: 25110404 PMCID: PMC4123355 DOI: 10.3748/wjg.v20.i29.9633] [Citation(s) in RCA: 110] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2013] [Revised: 04/18/2014] [Accepted: 05/19/2014] [Indexed: 02/06/2023] Open
Abstract
Despite the great successes achieved in the fields of virology and diagnostics, several difficulties affect improvements in hepatitis C virus (HCV) infection control and eradication in the new era. New HCV infections still occur, especially in some of the poorest regions of the world, where HCV is endemic and long-term sequelae have a growing economic and health burden. An HCV vaccine is still no available, despite years of researches and discoveries about the natural history of infection and host-virus interactions: several HCV vaccine candidates have been developed in the last years, targeting different HCV antigens or using alternative delivery systems, but viral variability and adaption ability constitute major challenges for vaccine development. Many new antiviral drugs for HCV therapy are in preclinical or early clinical development, but different limitations affect treatment validity. Treatment predictors are important tools, as they provide some guidance for the management of therapy in patients with chronic HCV infection: in particular, the role of host genomics in HCV infection outcomes in the new era of direct-acting antivirals may evolve for new therapeutic targets, representing a chance for modulated and personalized treatment management, when also very potent therapies will be available. In the present review we discuss the most recent data about HCV epidemiology, the new perspectives for the prevention of HCV infection and the most recent evidence regarding HCV diagnosis, therapy and predictors of response to it.
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18
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Kwon JS, Yoon J, Kim YJ, Kang K, Woo S, Jung DI, Song MK, Kim EH, Kwon HI, Choi YK, Kim J, Lee J, Yoon Y, Shin EC, Youn JW. Vaccinia-based influenza vaccine overcomes previously induced immunodominance hierarchy for heterosubtypic protection. Eur J Immunol 2014; 44:2360-9. [PMID: 24825439 DOI: 10.1002/eji.201344005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2013] [Revised: 03/21/2014] [Accepted: 05/07/2014] [Indexed: 12/27/2022]
Abstract
Growing concerns about unpredictable influenza pandemics require a broadly protective vaccine against diverse influenza strains. One of the promising approaches was a T cell-based vaccine, but the narrow breadth of T-cell immunity due to the immunodominance hierarchy established by previous influenza infection and efficacy against only mild challenge condition are important hurdles to overcome. To model T-cell immunodominance hierarchy in humans in an experimental setting, influenza-primed C57BL/6 mice were chosen and boosted with a mixture of vaccinia recombinants, individually expressing consensus sequences from avian, swine, and human isolates of influenza internal proteins. As determined by IFN-γ ELISPOT and polyfunctional cytokine secretion, the vaccinia recombinants of influenza expanded the breadth of T-cell responses to include subdominant and even minor epitopes. Vaccine groups were successfully protected against 100 LD50 challenges with PR/8/34 and highly pathogenic avian influenza H5N1, which contained the identical dominant NP366 epitope. Interestingly, in challenge with pandemic A/Cal/04/2009 containing mutations in the dominant epitope, only the group vaccinated with rVV-NP + PA showed improved protection. Taken together, a vaccinia-based influenza vaccine expressing conserved internal proteins improved the breadth of influenza-specific T-cell immunity and provided heterosubtypic protection against immunologically close as well as distant influenza strains.
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Affiliation(s)
- Ji-Sun Kwon
- Vaccine II, Mogam Biotechnology Research Institute, Yongin Si, Republic of Korea
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19
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Cox AL, Thomas DL. Hepatitis C virus vaccines among people who inject drugs. Clin Infect Dis 2014; 57 Suppl 2:S46-50. [PMID: 23884065 DOI: 10.1093/cid/cit329] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Most people who inject drugs (PWID) are infected with hepatitis C virus (HCV), and PWID have the highest risk of HCV infection of any risk group. The incidence of HCV infection is 5%-25% per year, demonstrating continued need for HCV infection prevention in PWID. Existing data in chimpanzees and PWID suggest that protective immunity against persistent HCV infection is achievable. Due to the high incidence of infection, PWID are both the most likely to benefit from a vaccine and a population in which vaccine efficacy could be tested. Challenges to testing a vaccine in PWID are significant. However, the first HCV vaccine trial in at-risk HCV-uninfected PWID was initiated in 2012. The results will likely guide future vaccine development and strategies for vaccination of this and other high-risk populations.
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Affiliation(s)
- Andrea L Cox
- Division of Infectious Diseases, Department of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA.
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20
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Abstract
Prevention of hepatitis C virus (HCV) infection by vaccination has been a priority since discovery of the virus and the need has not diminished over the past 25 years. Infection rates are increasing in developed countries because of intravenous drug use. Reducing transmission will be difficult without a vaccine to prevent persistence of primary infections, and also secondary infections that may occur after cure of chronic hepatitis C with increasingly effective direct-acting antiviral (DAA) regimens. Vaccine need is also acute in resource poor countries where most new infections occur and DAAs may be unaffordable. Spontaneous resolution of HCV infection confers durable protection, but mechanisms of immunity remain obscure and contested in the context of vaccine design. A vaccine must elicit a CD4+ helper T cell response that does not fail during acute infection. The need for neutralizing antibodies versus cytotoxic CD8+ T cells is unsettled and reflected in the design of two very different vaccines evaluated in humans for safety and immunogenicity. Here we review the status of vaccine development and the scientific and practical challenges that must be met if the burden of liver disease caused by HCV is to be reduced or eliminated.
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Affiliation(s)
- Jonathan R Honegger
- The Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, Ohio
| | - Yan Zhou
- The Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, Ohio
| | - Christopher M Walker
- The Center for Vaccines and Immunity, Nationwide Children's Hospital, Columbus, Ohio
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21
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Galal IF, Zakaria Z, Allam WR, Mahmoud MA, Ezzat AR, Osman A, Waked I, Strickland GT, Abdelwahab SF. Cross reactive cellular immune response to HCV genotype 1 and 4 antigens among genotype 4 exposed subjects. PLoS One 2014; 9:e101264. [PMID: 24979366 PMCID: PMC4076338 DOI: 10.1371/journal.pone.0101264] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2014] [Accepted: 06/04/2014] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Hepatitis C Virus (HCV) infection is a global health burden particularly in Egypt, where HCV genotype 4a (GT-4a) predominates. The prevention and control of HCV infection will remain a challenge until the development of an effective vaccine that protects against different genotypes. Several HCV GT-1-based vaccines are in different stages of clinical trials, but antigenic differences could make protection against other genotypes problematic. In this regard, data comparing the cell-mediated immune (CMI) response to different HCV genotypes are limited. We aimed to ex vivo investigate whether GT-1-based vaccine may protect against HCV GT-4 infections. This was carried out on samples collected from genotype 4 infected/exposed subjects. METHODS/PRINCIPAL FINDINGS The CMI responses of 35 subjects; infected with HCV GT-4/or who had spontaneously-resolved the infection and 10 healthy control subjects; to two sets of seven HCV overlapping 15-mer peptide pools derived from both genotypes; and covering most of the viral proteins; were evaluated. This was carried out using an interferon gamma (IFNγ) enzyme-linked immunospot (ELISpot) assay. Peripheral blood mononuclear cells (PBMC) from 17 subjects (48%) responded to at least one peptide pool derived from GT-1b/GT-4a with 13 subjects responding to peptide pools from both genotypes. A strong correlation was found in the responses to both genotypes (r = 0.82, p<0.001; 95% confidence interval = 0.562-0.933). The average IFNγ total spot forming cells (SFC)/10(6) PBMC (±SE) from the responding subjects for GT-1b and GT-4a was 216±56 and 199±55, respectively (p = 0.833). Also, there were no significant differences between those who cleared their HCV infection or who remained HCV-RNA positive (p = 0.8). CONCLUSION/SIGNIFICANCE Our data suggest that an effective GT-1b vaccine could protect from GT-4a infection. These data could help in HCV rationale vaccine design and efficacy studies and further our understanding of HCV cross protection against different genotypes.
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Affiliation(s)
- Iman F. Galal
- Egyptian Company for Blood Transfusion Services (Egyblood)/VACSERA; Agouza, Giza, Egypt
| | - Zainab Zakaria
- Egyptian Company for Blood Transfusion Services (Egyblood)/VACSERA; Agouza, Giza, Egypt
| | - Walaa R. Allam
- Egyptian Company for Blood Transfusion Services (Egyblood)/VACSERA; Agouza, Giza, Egypt
| | - Mohamed A. Mahmoud
- Department of Hepatology, National Liver Institute, Menoufiya University, Menoufiya, Egypt
| | - Ahmed R. Ezzat
- Department of Zoology, Faculty of Science, Ain Shams University, Cairo, Egypt
| | - Ahmed Osman
- Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo
| | - Imam Waked
- Department of Hepatology, National Liver Institute, Menoufiya University, Menoufiya, Egypt
| | - G. Thomas Strickland
- Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America
| | - Sayed F. Abdelwahab
- Egyptian Company for Blood Transfusion Services (Egyblood)/VACSERA; Agouza, Giza, Egypt
- Department of Microbiology and Immunology, Faculty of Medicine, Minia University, Minia, Egypt
- * E-mail:
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Liang TJ. Current progress in development of hepatitis C virus vaccines. Nat Med 2013; 19:869-78. [PMID: 23836237 PMCID: PMC6263146 DOI: 10.1038/nm.3183] [Citation(s) in RCA: 127] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Accepted: 02/22/2013] [Indexed: 12/14/2022]
Abstract
Despite major advances in the understanding and treatment of hepatitis C, a preventive vaccine remains elusive. The marked genetic diversity and multiple mechanisms of persistence of hepatitis C virus, combined with the relatively poor immune response of the infected host against the virus, are major barriers. The lack of robust and convenient model systems further hampers the effort to develop an effective vaccine. Advances in our understanding of virus-host interactions and protective immunity in hepatitis C virus infection provide an important roadmap to develop potent and broadly directed vaccine candidates targeting both humoral and cellular immune responses. Multiple approaches to generating and testing viral immunogens have met with variable success. Several candidates have advanced to clinical trials based on promising results in chimpanzees. The ultimate path to a successful preventive vaccine requires comprehensive evaluations of all aspects of protective immunity, innovative application of state-of-the-art vaccine technology and properly designed vaccine trials that can affirm definitive endpoints of efficacy.
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Affiliation(s)
- T Jake Liang
- Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, US National Institutes of Health, Bethesda, Maryland, USA.
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23
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Wen B, Deng Y, Chen H, Guan J, Chuai X, Ruan L, Kong W, Tan W. The novel replication-defective vaccinia virus (Tiantan strain)-based hepatitis C virus vaccine induces robust immunity in macaques. Mol Ther 2013; 21:1787-95. [PMID: 23774793 DOI: 10.1038/mt.2013.122] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2013] [Accepted: 05/10/2013] [Indexed: 12/13/2022] Open
Abstract
The induction of a robust neutralizing antibody (nAb) response is likely to be as essential as specific cell-mediated immunity (CMI) against multiple antigens for the development of effective preventive and therapeutic vaccines against hepatitis C virus (HCV) infection in humans. To date, no data on the immunogenicity of the replication-defective vaccinia virus (derived from the Tiantan strain) (rNTV)-based HCV vaccine in primates have been reported. This study describes in detail the immunogenicity of various vaccine candidates in rhesus macaques, including rNTV-based and replication-defective recombinant adenoviral (rAd)-based HCV vaccines, as well as HCV pseudotyped virus-like particles (HCVpp). Our data showed that rAd-HCV vaccine boosting induced robust CMI, while priming or boosting with HCVpp enhanced the antigen-specific nAb response after rAd-HCV vaccination; however, CMI was not enhanced. Vaccination includes rNTV-HCV priming induced robust antigen-specific antibody, particularly nAbs, and CMI responses. Furthermore, more robust and longer-lasting CMI and higher cytokine levels (both Th1 and Th2 types, especially IFN-γ) resulted from boosting with rAd-HCV. We conclude that the rNTV-based HCV vaccine induces robust nAbs and CMI when combined with a heterogeneous primer-booster strategy, which shows promise for development of a human HCV vaccine.
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Affiliation(s)
- Bo Wen
- National Engineering Laboratory for AIDS Vaccine, College of Life Science, Jilin University, Changchun, China
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Abstract
Introduction With 3 – 4 million new infections occurring annually, hepatitis C virus (HCV) is a major global health problem. There is increasing evidence to suggest that HCV will be highly amenable to a vaccine approach, and despite advances in treatment, a vaccine remains the most cost-effective and realistic means to significantly reduce the worldwide mortality and morbidity associated with persistent HCV infection. Areas covered In this review we discuss immune responses to HCV during natural infection, and describe how they may inform vaccine design. We introduce the current candidate vaccines for HCV and compare how these fare against the expected requirements of an effective prophylactic HCV vaccine in relation to the breadth, functionality, magnitude and phenotype of the vaccine-induced immune response. Expert opinion Although the correlates of immune protection against HCV are not completely defined, we now have vaccine technologies capable of inducing HCV-specific adaptive immune responses to an order of magnitude that are associated with protection during natural infection. The challenge next is to i) establish well-characterised cohorts of people at risk of HCV infection for vaccine efficacy testing and ii) to better understand the correlates of protection in natural history studies. If these can be achieved, a vaccine against HCV appears a realistic goal.
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Affiliation(s)
- Leo Swadling
- University of Oxford, NDM and Jenner Institute, Peter Medawar Building, South Parks Road, Oxford, OX1 3SY, UK
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Hepatitis C vaccines. Vaccines (Basel) 2013. [DOI: 10.1016/b978-1-4557-0090-5.00051-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Immunization with a recombinant vaccinia virus that encodes nonstructural proteins of the hepatitis C virus suppresses viral protein levels in mouse liver. PLoS One 2012; 7:e51656. [PMID: 23284733 PMCID: PMC3524174 DOI: 10.1371/journal.pone.0051656] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Accepted: 11/05/2012] [Indexed: 12/16/2022] Open
Abstract
Chronic hepatitis C, which is caused by infection with the hepatitis C virus (HCV), is a global health problem. Using a mouse model of hepatitis C, we examined the therapeutic effects of a recombinant vaccinia virus (rVV) that encodes an HCV protein. We generated immunocompetent mice that each expressed multiple HCV proteins via a Cre/loxP switching system and established several distinct attenuated rVV strains. The HCV core protein was expressed consistently in the liver after polyinosinic acid–polycytidylic acid injection, and these mice showed chronic hepatitis C-related pathological findings (hepatocyte abnormalities, accumulation of glycogen, steatosis), liver fibrosis, and hepatocellular carcinoma. Immunization with one rVV strain (rVV-N25), which encoded nonstructural HCV proteins, suppressed serum inflammatory cytokine levels and alleviated the symptoms of pathological chronic hepatitis C within 7 days after injection. Furthermore, HCV protein levels in liver tissue also decreased in a CD4 and CD8 T-cell-dependent manner. Consistent with these results, we showed that rVV-N25 immunization induced a robust CD8 T-cell immune response that was specific to the HCV nonstructural protein 2. We also demonstrated that the onset of chronic hepatitis in CN2-29(+/−)/MxCre(+/−) mice was mainly attributable to inflammatory cytokines, (tumor necrosis factor) TNF-α and (interleukin) IL-6. Thus, our generated mice model should be useful for further investigation of the immunological processes associated with persistent expression of HCV proteins because these mice had not developed immune tolerance to the HCV antigen. In addition, we propose that rVV-N25 could be developed as an effective therapeutic vaccine.
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Park SH, Shin EC, Capone S, Caggiari L, De Re V, Nicosia A, Folgori A, Rehermann B. Successful vaccination induces multifunctional memory T-cell precursors associated with early control of hepatitis C virus. Gastroenterology 2012; 143:1048-60.e4. [PMID: 22705008 PMCID: PMC3458177 DOI: 10.1053/j.gastro.2012.06.005] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2011] [Revised: 05/07/2012] [Accepted: 06/08/2012] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS T cells are an important component for development of a vaccine against hepatitis C virus (HCV), but little is known about the features of successful vaccine-induced T cells. METHODS We compared the phenotype, function, and kinetics of vaccine-induced and infection-induced T cells in chimpanzees with HCV infection using multicolor flow cytometry and real-time polymerase chain reaction. RESULTS In chimpanzees successfully vaccinated with recombinant adenovirus and DNA against HCV NS3-5, HCV-specific T cells appeared earlier, maintained better functionality, and persisted at higher frequencies for a longer time after HCV challenge, than those of mock-vaccinated chimpanzees. Vaccine-induced T cells displayed higher levels of CD127, a marker of memory precursors, and lower levels of programmed death-1 (PD-1) than infection-induced T cells. Vaccine-induced, but not infection-induced, T cells were multifunctional; their ability to secrete interferon gamma and tumor necrosis factor α correlated with early expression of CD127 but not PD-1. Based on a comparison of vaccine-induced and infection-induced T cells from the same chimpanzee, the CD127(+) memory precursor phenotype was induced by the vaccine itself rather than by low viremia. In contrast, induction of PD-1 correlated with viremia, and levels of intrahepatic PD-1, PD-L1, and 2,5-OAS-1 messenger RNAs correlated with peak titers of HCV. CONCLUSIONS Compared with infection, vaccination-induced HCV-specific CD127(+) T cells with high functionality that persisted at higher levels for a longer time. Control of viremia prevented up-regulation of PD-1 on T cells and induction of PD-1, PD-L1, and 2,5-OAS-1 in the liver. Early development of a memory T-cell phenotype and, via control of viremia, attenuation of the inhibitory PD1-PD-L1 pathway might be necessary components of successful vaccine-induced protection against HCV.
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Affiliation(s)
- Su-Hyung Park
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, 10 Center Drive, Bldg. 10, Bethesda, MD 20892
| | - Eui-Cheol Shin
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, 10 Center Drive, Bldg. 10, Bethesda, MD 20892
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, 291 Daehak-ro, Daejeon 305-701, Republic of Korea
| | - Stefania Capone
- Okairos, via dei Castelli Romani 22, 00040, Pomezia, Rome, Italy
| | - Laura Caggiari
- Experimental and Clinical Pharmacology Unit, CRO Centro di Riferimento Oncologico, IRCCS National Cancer Institute, via F. Gallini 2, 33081 AVIANO (PN), Italy
| | - Valli De Re
- Experimental and Clinical Pharmacology Unit, CRO Centro di Riferimento Oncologico, IRCCS National Cancer Institute, via F. Gallini 2, 33081 AVIANO (PN), Italy
| | - Alfredo Nicosia
- Okairos, via dei Castelli Romani 22, 00040, Pomezia, Rome, Italy
- CEINGE, via Gaetano Salvatore 486, 80145, Naples, Italy
| | | | - Barbara Rehermann
- Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, 10 Center Drive, Bldg. 10, Bethesda, MD 20892
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Alvarez-Lajonchere L, Dueñas-Carrera S. Complete definition of immunological correlates of protection and clearance of hepatitis C virus infection: a relevant pending task for vaccine development. Int Rev Immunol 2012; 31:223-42. [PMID: 22587022 DOI: 10.3109/08830185.2012.680552] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Hepatitis C virus (HCV) infects approximately 3% of global population. This pathogen is one of the main causes of chronic viral hepatitis, cirrhosis, and liver cancer, as well as the principal reason for liver transplant in Western countries. Therapy against HCV infection is effective in only half of treated patients. There is no vaccine available against HCV. Some vaccine candidates have reached the clinical trials but several factors, including the incomplete definition of immunological correlates of protection and treatment-related clearance have slowed down vaccine development. Precisely, the present review discusses the state of the art in the establishment of parameters related with immunity against HCV. Validity and limitations of the information accumulated from chimpanzees and other animal models, analysis of studies in humans infected with HCV, and relevance of aspects like type, strength, duration, and specificity of immune response related to successful outcome are evaluated in detail. Moreover, the immune responses induced in some clinical trials with vaccine candidates resemble the theoretical immunological correlates, raising questions about the validity of those correlates. When all facts are taken together, complete definition of immunological correlates for protection or treatment-related clearance is an urgent priority. A limited or wrong criterion with respect to this relevant matter might cause incorrect vaccine design and selection of immunization strategies or erroneous clinical evaluation.
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Xu CH, Shen T, Zheng JJ, Tu J, Zhang WD, Lu FM. Higher dN/dS ratios in the HCV core gene, but not in the E1/HVR1 gene, are associated with human immunodeficiency virus-associated immunosuppression. Arch Virol 2012; 157:2153-62. [PMID: 22825695 DOI: 10.1007/s00705-012-1390-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2011] [Accepted: 05/17/2012] [Indexed: 12/12/2022]
Abstract
Coinfection with HCV and HIV is prevalent among former commercial blood donors in some rural areas in China. Genetic variability of the HCV core and E1/HVR1 was investigated in 23 patients chronically infected with HCV-1b, with or without concomitant HIV infection. Genetic variability in the core sequence was higher under HIV-associated immunocompromised conditions. Both the Shannon entropy values at each nucleotide position and the dN/dS values at each codon were statistically higher in HIV/HCV-coinfected patients with lower CD4+ T cell counts (p-values were <0.0001 and equal to 0.0372, respectively). The more significant difference of dN/dS value occurred in a specific subregion of the core gene that is enriched in CTL/Th epitopes (p = 0.0083). The dN/dS values of full-length core antigen were found to be negatively correlated with the S/CO ratio of plasma anti-HCV antibodies. By contrast, no significant difference in genetic diversity/complexity and dN/dS values in the E1/HVR1 region was found between those two groups. These results suggest that the dN/dS ratio in the core gene, but not in the E1/HVR1 gene, is influenced more by host CD4+ T cell-mediated cellular immunity.
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Affiliation(s)
- Chun-Hui Xu
- Department of Microbiology, Peking University Health Science Center, Beijing 100191, China
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30
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Verardi PH, Titong A, Hagen CJ. A vaccinia virus renaissance: new vaccine and immunotherapeutic uses after smallpox eradication. Hum Vaccin Immunother 2012; 8:961-70. [PMID: 22777090 PMCID: PMC3495727 DOI: 10.4161/hv.21080] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
In 1796, Edward Jenner introduced the concept of vaccination with cowpox virus, an Orthopoxvirus within the family Poxviridae that elicits cross protective immunity against related orthopoxviruses, including smallpox virus (variola virus). Over time, vaccinia virus (VACV) replaced cowpox virus as the smallpox vaccine, and vaccination efforts eventually led to the successful global eradication of smallpox in 1979. VACV has many characteristics that make it an excellent vaccine and that were crucial for the successful eradication of smallpox, including (1) its exceptional thermal stability (a very important but uncommon characteristic in live vaccines), (2) its ability to elicit strong humoral and cell-mediated immune responses, (3) the fact that it is easy to propagate, and (4) that it is not oncogenic, given that VACV replication occurs exclusively within the host cell cytoplasm and there is no evidence that the viral genome integrates into the host genome. Since the eradication of smallpox, VACV has experienced a renaissance of interest as a viral vector for the development of recombinant vaccines, immunotherapies, and oncolytic therapies, as well as the development of next-generation smallpox vaccines. This revival is mainly due to the successful use and extensive characterization of VACV as a vaccine during the smallpox eradication campaign, along with the ability to genetically manipulate its large dsDNA genome while retaining infectivity and immunogenicity, its wide mammalian host range, and its natural tropism for tumor cells that allows its use as an oncolytic vector. This review provides an overview of new uses of VACV that are currently being explored for the development of vaccines, immunotherapeutics, and oncolytic virotherapies.
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Affiliation(s)
- Paulo H Verardi
- Department of Pathobiology and Veterinary Science, College of Agriculture and Natural Resources, University of Connecticut, Storrs, CT, USA.
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31
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Ullah S, Shah MAA, Riaz N. Recent Advances in Development of DNA Vaccines Against Hepatitis C virus. INDIAN JOURNAL OF VIROLOGY : AN OFFICIAL ORGAN OF INDIAN VIROLOGICAL SOCIETY 2012; 23:253-60. [PMID: 24293811 DOI: 10.1007/s13337-012-0058-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2011] [Accepted: 02/03/2012] [Indexed: 01/28/2023]
Abstract
Hepatitis C is one of the foremost challenging diseases all over the world. No vaccine has been developed, yet against Hepatitis C virus (HCV). This is partly due to the high mutation rate in the HCV genome, which generates new genotypes and sub genotypes. A mass of efforts have been devoted for the development of an efficient vaccine against HCV. DNA Vaccines, an emerging field of Vaccinology, grasp strong potential to be the most reliable and efficient mode of vaccination in the future. This technology is under investigation currently. Incredibly diverse approaches have been applied as an endeavor to develop a potent DNA vaccine against HCV. The HCV structural genes and the virus like particles have been attempted and so far the results are quite promising in the Lab animals. As there is no proper animal model for HCV infection except chimpanzees, it is very difficult to articulate whether these vaccines will also be pertinent in humans or not. This review will focus on different approaches being used for the development of DNA vaccines, the major tribulations in designing a DNA vaccine against HCV as well as the future prospects for the improvement of under trials DNA vaccines developed against HCV.
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Affiliation(s)
- Sami Ullah
- NUST Center of Virology and Immunology, National University of Science and Technology, Islamabad, Pakistan
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Gonzalez-Aseguinolaza G, Prieto J. Gene therapy of liver diseases: a 2011 perspective. Clin Res Hepatol Gastroenterol 2011; 35:699-708. [PMID: 21778133 DOI: 10.1016/j.clinre.2011.05.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2011] [Accepted: 05/20/2011] [Indexed: 02/04/2023]
Abstract
Liver diseases including inherited metabolic disorders, chronic viral hepatitis, liver cirrhosis and primary and metastatic liver cancer constitute a formidable health problem because of their high prevalence and the important limitations of current therapies. Gene therapy, a procedure based on the transfer of therapeutic genes to tissues, has been used since the 1990s as a new approach to treating a number of incurable conditions. After a period of lights and shades recent success in treating several devastating diseases like inherited immune deficiency disorders, beta-thalassemia, or inherited blindness appear to herald a new era where gene therapy can be listed among standard therapy options for a wide variety of human conditions. In this review, we provide information illustrating the potentiality of gene therapy in the management of liver diseases lacking other effective therapies.
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Affiliation(s)
- Gloria Gonzalez-Aseguinolaza
- Division of Hepatology and Gene Therapy, Centro de Investigación Medica Aplicada and Clinica Universitaria, University of Navarra, Pamplona, Spain
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Houghton M. Prospects for prophylactic and therapeutic vaccines against the hepatitis C viruses. Immunol Rev 2011; 239:99-108. [PMID: 21198667 DOI: 10.1111/j.1600-065x.2010.00977.x] [Citation(s) in RCA: 123] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Encouraging efficacy data have been obtained in the hepatitis C virus (HCV) chimpanzee model using prophylactic vaccines comprising adjuvanted recombinant envelope gpE1/gpE2 glycoproteins or prime/boost immunization regimens using defective adenoviruses and plasmid DNA expressing non-structural genes. While usually not resulting in sterilizing immunity after experimental challenge, the progression to chronic, persistent infection (which is responsible for HCV-associated pathogenicity in human) is inhibited. These and other vaccine candidates are in clinical development for both prophylactic as well as possible therapeutic applications. Given that other vaccines tested in the chimpanzee model may be possibly increasing the rate of chronicity, it is very important that this model continues to be available and used prior to initiation of clinical development. Several vaccine monotherapy trials in chronically infected HCV patients are resulting in small declines in viral load, suggesting that in future, combining vaccination with antiviral drug treatment may be beneficial.
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Affiliation(s)
- Michael Houghton
- Department of Medical Microbiology and Immunology, Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta, Canada.
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Dorner M, Horwitz JA, Robbins JB, Barry WT, Feng Q, Mu K, Jones CT, Schoggins JW, Catanese MT, Burton DR, Law M, Rice CM, Ploss A. A genetically humanized mouse model for hepatitis C virus infection. Nature 2011; 474:208-11. [PMID: 21654804 PMCID: PMC3159410 DOI: 10.1038/nature10168] [Citation(s) in RCA: 287] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2011] [Accepted: 04/28/2011] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) remains a major medical problem. Antiviral treatment is only partially effective and a vaccine does not exist. Development of more effective therapies has been hampered by the lack of a suitable small animal model. Although xenotransplantation of immunodeficient mice with human hepatocytes has shown promise, these models are subject to important challenges. Building on the previous observation that CD81 and occludin comprise the minimal human factors required to render mouse cells permissive to HCV entry in vitro, we attempted murine humanization via a genetic approach. Here we show that expression of two human genes is sufficient to allow HCV infection of fully immunocompetent inbred mice. We establish a precedent for applying mouse genetics to dissect viral entry and validate the role of scavenger receptor type B class I for HCV uptake. We demonstrate that HCV can be blocked by passive immunization, as well as showing that a recombinant vaccinia virus vector induces humoral immunity and confers partial protection against heterologous challenge. This system recapitulates a portion of the HCV life cycle in an immunocompetent rodent for the first time, opening opportunities for studying viral pathogenesis and immunity and comprising an effective platform for testing HCV entry inhibitors in vivo.
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Affiliation(s)
- Marcus Dorner
- Center for the Study of Hepatitis C, The Rockefeller University, New York, New York 10065, USA
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Deletion of major nonessential genomic regions in the vaccinia virus Lister strain enhances attenuation without altering vaccine efficacy in mice. J Virol 2011; 85:5016-26. [PMID: 21367889 DOI: 10.1128/jvi.02359-10] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
The vaccinia virus (VACV) Lister strain was one of the vaccine strains that enabled smallpox eradication. Although the strain is most often harmless, there have been numerous incidents of mild to life-threatening accidents with this strain and others. In an attempt to further attenuate the Lister strain, we investigated the role of 5 genomic regions known to be deleted in the modified VACV Ankara (MVA) genome in virulence in immunodeficient mice, immunogenicity in immunocompetent mice, and vaccine efficacy in a cowpox virus challenge model. Lister mutants were constructed so as to delete each of the 5 regions or various combinations of these regions. All of the mutants replicated efficiently in tissue culture except region I mutants, which multiplied more poorly in human cells than the parental strain. Mutants with single deletions were not attenuated or only moderately so in athymic nude mice. Mutants with multiple deletions were more highly attenuated than those with single deletions. Deleting regions II, III, and V together resulted in total attenuation for nude mice and partial attenuation for SCID mice. In immunocompetent mice, the Lister deletion mutants induced VACV specific humoral responses equivalent to those of the parental strain but in some cases lower cell-mediated immune responses. All of the highly attenuated mutants protected mice from a severe cowpox virus challenge at low vaccine doses. The data suggest that several of the Lister mutants combining multiple deletions could be used in smallpox vaccination or as live virus vectors at doses equivalent to those used for the traditional vaccine while displaying increased safety.
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Bailey J. An assessment of the use of chimpanzees in hepatitis C research past, present and future: 1. Validity of the chimpanzee model. Altern Lab Anim 2011; 38:387-418. [PMID: 21105756 DOI: 10.1177/026119291003800501] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The USA is the only significant user of chimpanzees in biomedical research in the world, since many countries have banned or limited the practice due to substantial ethical, economic and scientific concerns. Advocates of chimpanzee use cite hepatitis C research as a major reason for its necessity and continuation, in spite of supporting evidence that is scant and often anecdotal. This paper examines the scientific and ethical issues surrounding chimpanzee hepatitis C research, and concludes that claims of the necessity of chimpanzees in historical and future hepatitis C research are exaggerated and unjustifiable, respectively. The chimpanzee model has several major scientific, ethical, economic and practical caveats. It has made a relatively negligible contribution to knowledge of, and tangible progress against, the hepatitis C virus compared to non-chimpanzee research, and must be considered scientifically redundant, given the array of alternative methods of inquiry now available. The continuation of chimpanzee use in hepatitis C research adversely affects scientific progress, as well as chimpanzees and humans in need of treatment. Unfounded claims of its necessity should not discourage changes in public policy regarding the use of chimpanzees in US laboratories.
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Affiliation(s)
- Jarrod Bailey
- New England Anti-Vivisection Society, Boston, MA 02108-5100, USA.
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Dahari H, Feinstone SM, Major ME. Meta-analysis of hepatitis C virus vaccine efficacy in chimpanzees indicates an importance for structural proteins. Gastroenterology 2010; 139:965-74. [PMID: 20621699 PMCID: PMC3075980 DOI: 10.1053/j.gastro.2010.05.077] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2010] [Revised: 05/06/2010] [Accepted: 05/26/2010] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Studies in patients and chimpanzees that spontaneously cleared hepatitis C virus (HCV) infections demonstrated that natural immunity to the virus is induced during primary infections and that this immunity can be cross protective. These discoveries led to optimism about prophylactic HCV vaccines, and several studies were performed in chimpanzees, although most included fewer than 6 animals. To draw meaningful conclusions about the efficacy of HCV vaccines in chimpanzees, we performed statistical analyses of data from previously published studies from different groups. METHODS We performed a meta-analysis that compared parameters among naïve (n = 63), vaccinated (n = 53), and rechallenged (n = 36) animals, including peak RNA titer postchallenge, time points of peak RNA titer, duration of viremia, and proportion of persistent infections. RESULTS Each vaccination study induced immune responses that were effective in rapidly controlling HCV replication. Levels of induced T-cell responses did not indicate vaccine success. There was no reduction in the rate of HCV persistence in vaccinated animals, compared with naïve animals, when nonstructural proteins were included in the vaccine. Vaccines that contained only structural proteins had clearance rates that were significantly higher than vaccines that contained nonstructural components (P = .015). CONCLUSIONS The inclusion of nonstructural proteins in HCV vaccines might be detrimental to protective immune responses, and/or structural proteins might activate T-cell responses that mediate viral clearance.
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Affiliation(s)
- Harel Dahari
- Department of Medicine, The University of Illinois at Chicago, Chicago, IL 60612 USA
| | - Stephen M. Feinstone
- Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892 USA
| | - Marian E. Major
- Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892 USA
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Duan H, Struble E, Zhong L, Mihalik K, Major M, Zhang P, Feinstone S, Feigelstock D. Hepatitis C virus with a naturally occurring single amino-acid substitution in the E2 envelope protein escapes neutralization by naturally-induced and vaccine-induced antibodies. Vaccine 2010; 28:4138-44. [PMID: 20433800 DOI: 10.1016/j.vaccine.2010.04.024] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2009] [Revised: 03/08/2010] [Accepted: 04/13/2010] [Indexed: 11/24/2022]
Abstract
Mutations arising in neutralizing epitopes of hepatitis C virus may play a role in the ability of the virus to escape control by neutralizing antibodies and in the establishment of chronic infections. An amino-acid substitution, Q412H, within a major conserved neutralization epitope EP I (aa 412-426) in the E2 glycoprotein is observed in chronic HCV carriers. We found that naturally acquired polyclonal EP I-specific antibodies have an equivalent binding capacity toward either the wild type or the Q412H mutant peptide encompassing the EP I epitope. While EP I-specific antibodies neutralized J6/JFH1 virus in vitro, they did not neutralize J6/JFH1 virus containing the Q412H mutation. Furthermore, we found that plasma obtained from a chimpanzee that had anti-E1/E2 antibodies following experimental immunization, neutralized the wild type J6/JFH1 virus but failed to neutralize the mutant virus. Thus, mutation Q412H found in naturally occurring variants could represent an antibody escape mutation. These data may have important implications for vaccine design.
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Affiliation(s)
- Hongying Duan
- Division of Viral Products, Center for Biologics Evaluation and Research, FDA, 29 Lincoln Drive, Bethesda, MD 20892, USA
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Biassoni R, Ugolotti E, De Maria A. Comparative analysis of NK-cell receptor expression and function across primate species: Perspective on antiviral defenses. SELF NONSELF 2010; 1:103-113. [PMID: 21487512 DOI: 10.4161/self.1.2.11717] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/29/2010] [Accepted: 03/06/2010] [Indexed: 01/06/2023]
Abstract
Natural killer (NK) cells are lymphoid effectors that are involved in the innate immune surveillance against infected and/or tumor cells. Their function is under the fine-tuning control of cell surface receptors that display either inhibitory or activating function and in healthy condition, mediate self-tolerance. It is known that inhibitory receptors are characterized by clonal and stochastic distribution and are extremely sensible to any modification, downregulation or loss of MHC class I surface expression that are induced in autologous cells upon viral infection or cancer transformation. This alteration of the MHC class I expression weakens the strength of the inhibitory receptor-induced interaction, thus resulting in a prompt triggering of NK cell function, which ends up in the inhibition of tumor progression and proliferation of pathogen-infected cells. Thus, the inhibitory function of NK cells is only one face of the coin, since NK-cell activation is controlled by different arrays of activating receptors that finally are involved in the induction of cytolysis and/or cytokine release. Interestingly, the inhibitory NK-cell receptors that are involved in dampening NK cell-mediated responses evolved during speciation in different, often structurally unrelated surface-expressed molecules, all using a conserved signaling pathway. In detail, during evolution, the inhibitory receptors that assure the recognition of MHC class I molecules, originate in, at least, three different ways. This ended up in multigene families showing marked structural divergences that coevolved in a convergent way with the availability of appropriate MHC ligand molecules.
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Affiliation(s)
- Roberto Biassoni
- Molecular Medicine-Istituto Scientifico Giannina Gaslini; Genova, Italy
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40
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Giugliano S, Oezkan F, Bedrejowski M, Kudla M, Reiser M, Viazov S, Scherbaum N, Roggendorf M, Timm J. Degree of cross-genotype reactivity of hepatitis C virus-specific CD8+ T cells directed against NS3. Hepatology 2009; 50:707-16. [PMID: 19637188 DOI: 10.1002/hep.23096] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
UNLABELLED The inherent sequence diversity of the hepatitis C virus (HCV) with the existence of multiple genotypes that differ up to 20% at the amino acid level represents one of the major obstacles for immune control. Accordingly, immune control of a heterologous virus challenge, particularly across genotypes, is difficult to achieve; however, the overall role of genotype-specific sequence differences has not yet been defined at the epitope level. The aim of this study was to determine the role of genotype-specific sequence differences for the CD8+ T cell response against HCV. We analyzed a cohort of anti-HCV-positive injection drug users infected with HCV genotype 1 (n = 17) or genotype 3 (n = 22) or undetectable HCV-RNA (n = 14) with overlapping peptides covering consensus sequences of NS3 from both genotypes. Importantly, the majority of HCV-specific CD8 T cells were specific for one genotype only indicating that sequence differences between genotypes are relevant at the epitope level. Interestingly, T cells active against both genotypes were significantly more frequent in HCV-RNA-negative subjects. Of note, we identified five subjects with undetectable viremia and coexistence of two T cell populations-one for each genotype-suggesting immune control of two different genotypes. CONCLUSION We systematically analyzed the degree of cross-genotype reactivity of HCV-specific T cells and have shown that CD8 responses targeting different HCV genotypes can be primed in the same individual and that such responses potentially characterize a subgroup among injection drug users being protected from chronic HCV infection.
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Major ME. Prophylactic and Therapeutic Vaccination against Hepatitis C Virus (HCV): Developments and Future Perspectives. Viruses 2009; 1:144-65. [PMID: 21994543 PMCID: PMC3185488 DOI: 10.3390/v1020144] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2009] [Revised: 07/25/2009] [Accepted: 08/11/2009] [Indexed: 12/15/2022] Open
Abstract
Studies in patients and chimpanzees that spontaneously clear Hepatitis C Virus (HCV) have demonstrated that natural immunity to the virus is induced during primary infections and that this immunity can be cross protective. These discoveries led to optimism regarding prophylactic HCV vaccines and a number of studies in the chimpanzee model have been performed, all of which resulted in modified infections after challenge but did not always prevent persistence of the virus. Therapeutic vaccine strategies have also been pursued in an effort to reduce the costs and side effects associated with anti-viral drug treatment. This review summarizes the studies performed thus far in both patients and chimpanzees for prophylactic and therapeutic vaccination, assesses the progress made and future perspectives.
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Affiliation(s)
- Marian E Major
- Division of Viral Products, Center for Biologics, Food and Drug Administration, Bldg29A/Rm1D10, 8800 Rockville Pike, Bethesda, MD 20892, USA; E-mail: ; Tel.: +1-301-827-1881
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42
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Stoll-Keller F, Barth H, Fafi-Kremer S, Zeisel MB, Baumert TF. Development of hepatitis C virus vaccines: challenges and progress. Expert Rev Vaccines 2009; 8:333-45. [PMID: 19249975 DOI: 10.1586/14760584.8.3.333] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Development of an effective vaccine against the hepatitis C virus (HCV) has long been defined as a difficult challenge due to the considerable variability of this RNA virus and the observation that convalescent humans and chimpanzees could be re-infected after re-exposure. On the other hand, progress in the understanding of antiviral immune responses in patients with viral clearance has elucidated key mechanisms playing a role in the control of viral infection. Studies investigating prophylactic vaccine approaches in chimpanzees have confirmed that the induction and maintenance of strong helper and cytotoxic T-cell immune responses against multiple viral epitopes is necessary for protection against viral clearance and chronic infection. A multispecific B-cell response, resulting in rapid induction of cross-neutralizing antibodies may assist cellular responses. Therapeutic vaccine formulations currently being evaluated in clinical trials are facing the fact that the immune system of chronic carriers is impaired and needs the restoration of T-cell functions to enhance their efficacy.
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Affiliation(s)
- Françoise Stoll-Keller
- Inserm, U748 et Laboratoire de Virologie des Hôpitaux Universitaires de Strasbourg, 3 rue Koeberlé 67000 Strasbourg, France.
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