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1
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Emmelot ME, Bodewes R, Maissan C, Vos M, de Swart RL, van Els CACM, Kaaijk P. Impact of genotypic variability of measles virus T-cell epitopes on vaccine-induced T-cell immunity. NPJ Vaccines 2025; 10:36. [PMID: 39979288 PMCID: PMC11842548 DOI: 10.1038/s41541-025-01088-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 02/11/2025] [Indexed: 02/22/2025] Open
Abstract
After the COVID-19 pandemic, significant increases in measles cases were observed globally. Community-wide vaccination remains the most effective strategy for preventing measles. However, it is crucial to understand whether prevalent genotypes, when circulating in populations with suboptimal vaccination coverage, may undergo adaptive mutations that allow them to escape vaccine-induced immunity. In this study, a bioinformatics-guided approach was used to predict universal helper T-cell epitopes specific to the measles vaccine virus (vaccine-MeV) presented by multiple HLA-DR, -DP, and -DQ alleles to achieve population-wide coverage. By using MeV-specific T-cell lines, we identified 37 functional epitopes out of 83 predicted candidates, including 25 novel ones. Strikingly, 73% of these epitope regions were associated with sequence variations in wild-type viruses. More importantly, we demonstrated that mutations disrupted the ability of vaccine-induced CD4+ T cells to respond to circulating viruses. Consequently, mutations in epitope regions of circulating viruses may affect the effectiveness of vaccine-induced T-cell immunity.
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Affiliation(s)
- Maarten E Emmelot
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Rogier Bodewes
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Cyril Maissan
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Martijn Vos
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
| | - Rik L de Swart
- Department of Viroscience, Erasmus MC, Rotterdam, The Netherlands
| | - Cécile A C M van Els
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands
- Division Infectious Diseases and Immunology, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Patricia Kaaijk
- Centre for Infectious Disease Control, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
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2
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Herron ICT, Laws TR, Nelson M. Marmosets as models of infectious diseases. Front Cell Infect Microbiol 2024; 14:1340017. [PMID: 38465237 PMCID: PMC10921895 DOI: 10.3389/fcimb.2024.1340017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2023] [Accepted: 01/29/2024] [Indexed: 03/12/2024] Open
Abstract
Animal models of infectious disease often serve a crucial purpose in obtaining licensure of therapeutics and medical countermeasures, particularly in situations where human trials are not feasible, i.e., for those diseases that occur infrequently in the human population. The common marmoset (Callithrix jacchus), a Neotropical new-world (platyrrhines) non-human primate, has gained increasing attention as an animal model for a number of diseases given its small size, availability and evolutionary proximity to humans. This review aims to (i) discuss the pros and cons of the common marmoset as an animal model by providing a brief snapshot of how marmosets are currently utilized in biomedical research, (ii) summarize and evaluate relevant aspects of the marmoset immune system to the study of infectious diseases, (iii) provide a historical backdrop, outlining the significance of infectious diseases and the importance of developing reliable animal models to test novel therapeutics, and (iv) provide a summary of infectious diseases for which a marmoset model exists, followed by an in-depth discussion of the marmoset models of two studied bacterial infectious diseases (tularemia and melioidosis) and one viral infectious disease (viral hepatitis C).
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Affiliation(s)
- Ian C. T. Herron
- CBR Division, Defence Science and Technology Laboratory (Dstl), Salisbury, United Kingdom
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3
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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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4
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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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5
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Smith S, Honegger JR, Walker C. T-Cell Immunity against the Hepatitis C Virus: A Persistent Research Priority in an Era of Highly Effective Therapy. Cold Spring Harb Perspect Med 2021; 11:cshperspect.a036954. [PMID: 32205413 PMCID: PMC7778213 DOI: 10.1101/cshperspect.a036954] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Approximately 70% of acute hepatitis C virus (HCV) infections become chronic, indicating that the virus is exceptionally well adapted to persist in humans with otherwise normal immune function. Robust, lifelong replication of this small RNA virus does not require a generalized failure of immunity. HCV effectively subverts innate and adaptive host defenses while leaving immunity against other viruses intact. Here, the role of CD4+ and CD8+ T-cell responses in control of HCV infection and their failure to prevent virus persistence in most individuals are reviewed. Two issues of practical importance remain priorities in an era of highly effective antiviral therapy for chronic hepatitis C. First, the characteristics of successful T-cell responses that promote resolution of HCV infection are considered, as they will underpin development of vaccines that prevent HCV persistence. Second, defects in T-cell immunity that facilitate HCV persistence and whether they are reversed after antiviral cure to provide protection from reinfection are also addressed.
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Affiliation(s)
- Stephanie Smith
- The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43004, USA
| | - Jonathan R. Honegger
- The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43004, USA
| | - Christopher Walker
- The Center for Vaccines and Immunity, The Abigail Wexner Research Institute at Nationwide Children's, Columbus, Ohio 43205, USA,Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, Ohio 43004, USA
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6
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Immune system control of hepatitis C virus infection. Curr Opin Virol 2020; 46:36-44. [PMID: 33137689 DOI: 10.1016/j.coviro.2020.10.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 10/11/2020] [Indexed: 12/20/2022]
Abstract
Hepatitis C virus (HCV) remains a global public health problem even though more than 95% of infections can be cured by treatment with direct-acting antiviral agents. Resolution of viremia post antiviral therapy does not lead to protective immunity and therefore reinfections can occur. Immune cell detection of HCV activates signaling pathways that produce interferons and trigger the innate immune response against the virus, preventing HCV replication and spread. Cells in the innate immune system, including natural killer, dendritic, and Kupffer cells, interact with infected hepatocytes and present viral antigens to T and B cells where their effector responses contribute to infection outcome. Despite the immune activation, HCV can evade the host response and establish persistent infection. Plans to understand the correlates of protection and strategies to activate proper innate and adaptive immune responses are needed for development of an effective prophylactic vaccine that stimulates protective immunity and limits HCV transmission.
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7
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Dawood RM, Moustafa RI, Abdelhafez TH, El-Shenawy R, El-Abd Y, Bader El Din NG, Dubuisson J, El Awady MK. A multiepitope peptide vaccine against HCV stimulates neutralizing humoral and persistent cellular responses in mice. BMC Infect Dis 2019; 19:932. [PMID: 31690267 PMCID: PMC6833294 DOI: 10.1186/s12879-019-4571-5] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 10/16/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Although DAAs hold promise to significantly reduce rates of chronic HCV infections, its eradication still requires development of an effective vaccine. Prolonged T cell responses and cross neutralizing antibodies are ideal for vaccination against the infection. We aimed to design and synthesize a 6 multi epitope peptide vaccine candidate and provide evidence for production of extended cellular and neutralizing Abs in mice. METHODS Six peptides derived from conserved epitopes in E1, E2 (n = 2),NS4B, NS5A and NS5B were designed, synthesized in a multiple antigenic peptide (MAP) form and administered w/o adjuvant to BALB/c mice as HCVp6-MAP at doses ranging from 800 ng to 16 μg. Humoral responses to structural epitopes were assayed by ELISA at different times after injection. ELISpot assay was used to evaluate IFN ɣ producing CD4+/ CD8+ T- lymphocytes at extended durations i.e. > 20 weeks. Viral neutralization by mice sera was tested for genotypes 2a (JFH1) and a chimeric 2a/4a virus (ED43/JFH1) in HCVcc culture. RESULTS HCVp6-MAP confers potent viral neutralization and specific cellular responses at > 1600 ng/ animal for at least 20 weeks. CONCLUSION We report on a promising anti HCV vaccine for future studies on permissive hosts and in clinical trials.
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Affiliation(s)
- Reham M Dawood
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt.
| | - Rehab I Moustafa
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL- Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France
| | - Tawfeek H Abdelhafez
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
| | - Reem El-Shenawy
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
| | - Yasmine El-Abd
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
| | - Noha G Bader El Din
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
| | - Jean Dubuisson
- Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 8204 - CIIL- Centre d'Infection et d'Immunité de Lille, F-59000, Lille, France
| | - Mostafa K El Awady
- Micrbial Biotechnology Department, National Research Center, 33 Tahrir street, Dokki, Cairo, 12622, Egypt
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8
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Abd Ellah NH, Tawfeek HM, John J, Hetta HF. Nanomedicine as a future therapeutic approach for Hepatitis C virus. Nanomedicine (Lond) 2019; 14:1471-1491. [PMID: 31166139 DOI: 10.2217/nnm-2018-0348] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Hepatitis C virus (HCV) is not easily cleared from the human body and in most cases turned into chronic infection. This chronicity is a major cause of liver damage, cirrhosis and hepatocellular carcinoma. Therefore, immediate detection and treatment of HCV guarantees eradication of the virus and prevention of chronicity complications. Since discovery of HCV in 1989, several emerging treatments were developed such as polyethylene glycol(PEG)-ylated interferon/ribavirin, direct acting antivirals and host targeting antivirals. Despite the progress in anti-HCV therapy, there is still a pressing need of new approaches for affordable and effective drug delivery systems using nanomedicine. In this review, the contribution of nanoparticles as a promising delivery system for HCV immunizing, diagnostic and therapeutic agents are discussed.
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Affiliation(s)
- Noura H Abd Ellah
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, Medical Sciences Building, University of Cincinnati, Cincinnati, OH 45267, USA.,Department of Pharmaceutics, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt
| | - Hesham M Tawfeek
- Department of Industrial Pharmacy, Faculty of Pharmacy, Assiut University, Assiut, 71526, Egypt.,Department of Pharmaceutics & Pharmaceutical Technology, Faculty of Pharmacy, Mutah University, Karak, Jordan
| | - James John
- Central Research Facilities, Sri Ramachandra institute of higher education & research, Sri Ramachandra University, Chennai, India
| | - Helal F Hetta
- Department of Medical Microbiology & Immunology, Faculty of Medicine, Assiut University, Assiut, 71526, Egypt.,Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0595, USA
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9
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Masavuli MG, Wijesundara DK, Underwood A, Christiansen D, Earnest-Silveira L, Bull R, Torresi J, Gowans EJ, Grubor-Bauk B. A Hepatitis C Virus DNA Vaccine Encoding a Secreted, Oligomerized Form of Envelope Proteins Is Highly Immunogenic and Elicits Neutralizing Antibodies in Vaccinated Mice. Front Immunol 2019; 10:1145. [PMID: 31178869 PMCID: PMC6543710 DOI: 10.3389/fimmu.2019.01145] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 05/07/2019] [Indexed: 12/24/2022] Open
Abstract
Hepatitis C virus (HCV) persistently infects approximately 71 million people globally. To prevent infection a vaccine which elicits neutralizing antibodies against the virus envelope proteins (E1/E2) which are required for entry into host cells is desirable. DNA vaccines are cost-effective to manufacture globally and despite recent landmark studies highlighting the therapeutic efficacy of DNA vaccines in humans against cervical cancer, DNA vaccines encoding E1/E2 developed thus far are poorly immunogenic. We now report a novel and highly immunogenic DNA vaccination strategy that incorporates secreted E1 and E2 (sE1 and sE2) into oligomers by fusion with the oligomerization domain of the C4b-binding protein, IMX313P. The FDA approved plasmid, pVax, was used to encode sE1, sE2, or sE1E2 with or without IMX313P, and intradermal prime-boost vaccination studies in BALB/c mice showed that vaccines encoding IMX313P were the most effective in eliciting humoral and cell-mediated immunity against the envelope proteins. Further boosting with recombinant E1E2 proteins but not DNA nor virus-like particles (VLPs) expressing E1E2 increased the immunogenicity of the DNA prime-boost regimen. Nevertheless, the antibodies generated by the homologous DNA prime-boost vaccinations more effectively inhibited the binding of VLPs to target cells and neutralized transduction with HCV pseudoparticles (HCVpp) derived from different genotypes including genotypes 1, 2, 3, 4, 5, and 6. This report provides the first evidence that IMX313P can be used as an adjuvant for E1/E2-based DNA vaccines and represents a translatable approach for the development of a HCV DNA vaccine.
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Affiliation(s)
- Makutiro Ghislain Masavuli
- Virology Laboratory, Basil Hetzel Institute for Translational Medicine, Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia
| | - Danushka K Wijesundara
- Virology Laboratory, Basil Hetzel Institute for Translational Medicine, Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia
| | - Alexander Underwood
- Faculty of Medicine, The Kirby Institute, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Dale Christiansen
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Linda Earnest-Silveira
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Rowena Bull
- Faculty of Medicine, The Kirby Institute, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia
| | - Joseph Torresi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
| | - Eric J Gowans
- Virology Laboratory, Basil Hetzel Institute for Translational Medicine, Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia
| | - Branka Grubor-Bauk
- Virology Laboratory, Basil Hetzel Institute for Translational Medicine, Discipline of Surgery, University of Adelaide, Adelaide, SA, Australia
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10
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Chigbu DI, Loonawat R, Sehgal M, Patel D, Jain P. Hepatitis C Virus Infection: Host⁻Virus Interaction and Mechanisms of Viral Persistence. Cells 2019; 8:cells8040376. [PMID: 31027278 PMCID: PMC6523734 DOI: 10.3390/cells8040376] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 03/25/2019] [Accepted: 04/17/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C (HCV) is a major cause of liver disease, in which a third of individuals with chronic HCV infections may develop liver cirrhosis. In a chronic HCV infection, host immune factors along with the actions of HCV proteins that promote viral persistence and dysregulation of the immune system have an impact on immunopathogenesis of HCV-induced hepatitis. The genome of HCV encodes a single polyprotein, which is translated and processed into structural and nonstructural proteins. These HCV proteins are the target of the innate and adaptive immune system of the host. Retinoic acid-inducible gene-I (RIG-I)-like receptors and Toll-like receptors are the main pattern recognition receptors that recognize HCV pathogen-associated molecular patterns. This interaction results in a downstream cascade that generates antiviral cytokines including interferons. The cytolysis of HCV-infected hepatocytes is mediated by perforin and granzyme B secreted by cytotoxic T lymphocyte (CTL) and natural killer (NK) cells, whereas noncytolytic HCV clearance is mediated by interferon gamma (IFN-γ) secreted by CTL and NK cells. A host-HCV interaction determines whether the acute phase of an HCV infection will undergo complete resolution or progress to the development of viral persistence with a consequential progression to chronic HCV infection. Furthermore, these host-HCV interactions could pose a challenge to developing an HCV vaccine. This review will focus on the role of the innate and adaptive immunity in HCV infection, the failure of the immune response to clear an HCV infection, and the factors that promote viral persistence.
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Affiliation(s)
- DeGaulle I Chigbu
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
- Pennsylvania College of Optometry at Salus University, Elkins Park, PA 19027, USA.
| | - Ronak Loonawat
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
| | - Mohit Sehgal
- Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA 19104, USA.
| | - Dip Patel
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
| | - Pooja Jain
- Department of Microbiology and Immunology, and the Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 2900 West Queen Lane, Philadelphia, PA 19129, USA.
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11
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Guo X, Zhong JY, Li JW. Hepatitis C Virus Infection and Vaccine Development. J Clin Exp Hepatol 2018; 8:195-204. [PMID: 29892184 PMCID: PMC5992307 DOI: 10.1016/j.jceh.2018.02.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Accepted: 02/08/2018] [Indexed: 12/12/2022] Open
Abstract
In the twenty-seven years since the discovery of hepatitis C virus (HCV) the majority of individuals exposed to HCV establish a persistent infection, which is a leading cause of chronic liver disease, cirrhosis and hepatocellular carcinoma. In developed nations, the cure rates of HCV infection could be over 90% with direct-acting antiviral (DAA) regimens, which has made the great progress in global eradication. However, the cost of these treatments is so expensive that the patients in developing nations, where the disease burden is the most severe, could not afford it, which highly restricted its access. Additionally, the largely asymptomatic nature of infection facilitates continued transmission in risk groups due to limited surveillance. Consequently a protective vaccine and likely emergence of drug-resistant viral variants call for further studies of HCV biology. In the current review, the development and the progress of preventive and therapeutic vaccines against the HCV have been reviewed in the context of peptide vaccines, recombinant protein vaccines, HCV-like particle, DNA vaccines and viral vectors expressing HCV genes.
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Affiliation(s)
- Xuan Guo
- Research Institute of Chemical Defense, No.1 Huaiyin Road, Beijing 102205, China
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, No.1 Dali Road, Tianjin 300050, China
| | - Jin-Yi Zhong
- Research Institute of Chemical Defense, No.1 Huaiyin Road, Beijing 102205, China
| | - Jun-Wen Li
- Department of Environment and Health, Tianjin Institute of Health and Environmental Medicine, No.1 Dali Road, Tianjin 300050, China
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12
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Immunological responses following administration of a genotype 1a/1b/2/3a quadrivalent HCV VLP vaccine. Sci Rep 2018; 8:6483. [PMID: 29691437 PMCID: PMC5915487 DOI: 10.1038/s41598-018-24762-9] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2017] [Accepted: 03/12/2018] [Indexed: 12/16/2022] Open
Abstract
The significant public health problem of Hepatitis C virus (HCV) has been partially addressed with the advent of directly acting antiviral agents (DAAs). However, the development of an effective preventative vaccine would have a significant impact on HCV incidence and would represent a major advance towards controlling and possibly eradicating HCV globally. We previously reported a genotype 1a HCV viral-like particle (VLP) vaccine that produced neutralizing antibodies (NAb) and T cell responses to HCV. To advance this approach, we produced a quadrivalent genotype 1a/1b/2a/3a HCV VLP vaccine to produce broader immune responses. We show that this quadrivalent vaccine produces antibody and NAb responses together with strong T and B cell responses in vaccinated mice. Moreover, selective neutralizing human monoclonal antibodies (HuMAbs) targeting conserved antigenic domain B and D epitopes of the E2 protein bound strongly to the HCV VLPs, suggesting that these critical epitopes are expressed on the surface of the particles. Our findings demonstrate that a quadrivalent HCV VLP based vaccine induces broad humoral and cellular immune responses that will be necessary for protection against HCV. Such a vaccine could provide a substantial addition to highly active antiviral drugs in eliminating HCV.
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13
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Muñoz de Rueda P, Jiménez-Ruiz SM, Quiles R, Pavón-Castillero EJ, Muñoz-Gámez JA, Casado J, Gila A, Ruiz-Extremera A, Salmerón J. The antigenic variability of HCV in viral HLA-Ag binding is related to the activation of the host immune response. Sci Rep 2017; 7:15513. [PMID: 29138492 PMCID: PMC5686107 DOI: 10.1038/s41598-017-15605-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2017] [Accepted: 10/23/2017] [Indexed: 01/17/2023] Open
Abstract
Our previous data show that hepatitis C virus (HCV) genotype 1 patients expressing the HLA-DQB1 * 0301 allele have a combined response probability of 69%, while the remaining 31% do not respond, probably because the HCV immunodominant epitope (IE) against the DQB1 * 0301 allele is mutated. HCV IE (region sequenced in NS3 is a region encoding aa 1253–1272) from 37 patients (21 Sustained Virological Response, SVR; 16 non-SVR) HLA-DQB1 * 0301+, were analysed by pyrosequencing. In vitro cultures were also determined by CD4+ proliferation, using non-mutated IE (wild-type synthetic peptide) and synthetic mutated peptide. The pyrosequencing study revealed 34 different haplotypes. The SVR patients had fewer haplotypes (P = 0.07), mutations/haplotypes (P = 0.01) and polymorphic sites (P = 0.02) than non-SVR. Three polymorphic sites were associated with the non-SVR patients: haplotype 7 (L5P); haplotype 11 (L7P); and haplotype 15, (L15S) (P = 0.02). The in vitro study (n = 7) showed that in 4/7 patients (Group 1) the CD4+ proliferation obtained with wild-type synthetic peptide was higher than that obtained with the negative control and with the synthetic mutated peptide (P = 0.039). However, in the remaining 3/7 patients (Group 2) this pattern was not observed (P = 0.7). Our findings suggest that HLA-DQB1 * 0301+ patients with high antigenic variability in HCV IE (NS31253-1272) have a lower SVR rate, due to reduced CD4+ proliferation as a result of incorrect viral HLA-Ag binding.
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Affiliation(s)
- P Muñoz de Rueda
- Clinical Management Unit of Digestive Diseases, Research Unit, San Cecilio University Hospital, Granada, 18012, Spain.,CIBER for Liver and Digestive Disease (CIBERehd), Instituto de Salud Carlos III, Madrid, 28029, Spain.,Instituto De Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, 18012, Spain
| | | | - R Quiles
- Clinical Management Unit of Digestive Diseases, Research Unit, San Cecilio University Hospital, Granada, 18012, Spain. .,CIBER for Liver and Digestive Disease (CIBERehd), Instituto de Salud Carlos III, Madrid, 28029, Spain. .,Instituto De Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, 18012, Spain.
| | - E J Pavón-Castillero
- Clinical Management Unit of Digestive Diseases, Research Unit, San Cecilio University Hospital, Granada, 18012, Spain.,Instituto De Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, 18012, Spain
| | - J A Muñoz-Gámez
- Clinical Management Unit of Digestive Diseases, Research Unit, San Cecilio University Hospital, Granada, 18012, Spain.,Instituto De Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, 18012, Spain
| | - J Casado
- Clinical Management Unit of Digestive Diseases, Research Unit, San Cecilio University Hospital, Granada, 18012, Spain.,Instituto De Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, 18012, Spain
| | - A Gila
- Clinical Management Unit of Digestive Diseases, Research Unit, San Cecilio University Hospital, Granada, 18012, Spain.,CIBER for Liver and Digestive Disease (CIBERehd), Instituto de Salud Carlos III, Madrid, 28029, Spain.,Instituto De Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, 18012, Spain
| | - A Ruiz-Extremera
- CIBER for Liver and Digestive Disease (CIBERehd), Instituto de Salud Carlos III, Madrid, 28029, Spain.,Instituto De Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, 18012, Spain.,Paediatric Unit, San Cecilio University Hospital and Virgen de las Nieves University Hospital, Granada, 18012, Spain.,Paediatric Department, Granada University, Granada, 18016, Spain
| | - J Salmerón
- Clinical Management Unit of Digestive Diseases, Research Unit, San Cecilio University Hospital, Granada, 18012, Spain.,CIBER for Liver and Digestive Disease (CIBERehd), Instituto de Salud Carlos III, Madrid, 28029, Spain.,Instituto De Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, 18012, Spain.,Medicine Departament, Granada University, Granada, 18016, Spain
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14
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Torresi J. The Rationale for a Preventative HCV Virus-Like Particle (VLP) Vaccine. Front Microbiol 2017; 8:2163. [PMID: 29163442 PMCID: PMC5674006 DOI: 10.3389/fmicb.2017.02163] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 10/20/2017] [Indexed: 12/16/2022] Open
Abstract
HCV represents a global health problem with ~200 million individuals currently infected, worldwide. With the high cost of antiviral therapies, the global burden of chronic hepatitis C infection (CHCV) infection will be substantially reduced by the development of an effective vaccine for HCV. The field of HCV vaccines is generally divided into proponents of strategies to induce neutralizing antibodies (NAb) and those who propose to elicit cell mediated immunity (CMI). However, for a hepatitis C virus (HCV) vaccine to be effective in preventing infection, it must be capable of generating cross-reactive CD4+, CD8+ T cell, and NAb responses that will cover the major viral genotypes. Simulation models of hepatitis C have predicted that a vaccine of even modest efficacy and coverage will significantly reduce the incidence of hepatitis C. A HCV virus like particle (VLP) based vaccine would fulfill the requirement of delivering critical conformational neutralizing epitopes in addition to providing HCV specific CD4+ and CD8+ epitopes. Several approaches have been reported including insect cell-derived genotype 1b HCV VLPs; a human liver-derived quadrivalent genotype 1a, 1b, 2, and 3a vaccine; a genotype 1a HCV E1 and E2 glycoprotein/MLV Gag pseudotype VLP vaccine; and chimeric HBs-HCV VLP vaccines. All to result in the production of cross-NAb and/or T cell responses against HCV. This paper summarizes the evidence supporting the development of a HCV VLP based vaccine.
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Affiliation(s)
- Joseph Torresi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, VIC, Australia
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15
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Tan WG, Zubkova I, Kachko A, Wells F, Adler H, Sutter G, Major ME. Qualitative differences in cellular immunogenicity elicited by hepatitis C virus T-Cell vaccines employing prime-boost regimens. PLoS One 2017; 12:e0181578. [PMID: 28732046 PMCID: PMC5521799 DOI: 10.1371/journal.pone.0181578] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 07/03/2017] [Indexed: 12/31/2022] Open
Abstract
T-cell based vaccines have been considered as attractive candidates for prevention of hepatitis C virus (HCV) infections. In this study we compared the magnitude and phenotypic characteristics of CD8+ T-cells induced by three commonly used viral vectors, Adenovirus-5 (Ad5), Vaccinia virus (VV) and Modified Vaccinia Ankara (MVA) expressing the HCV NS3/4A protein. C57/BL6 mice were primed with DNA expressing NS3/4A and boosted with each of the viral vectors in individual groups of mice. We then tracked the vaccine-induced CD8+ T-cell responses using pentamer binding and cytokine production analysis. Overall, our data indicate that the memory cells induced by Ad5 were inferior to those induced by VV or MVA. We found that Ad5 boosting resulted in rapid expansion and significantly higher frequencies of NS3-specific T-cells compared to VV and MVA boosting. However, the functional profiles, assessed through analysis of the memory cell marker CD127 and the anti-apoptotic molecule Bcl-2 in the blood, spleen, and liver; and measurements of interferon-gamma, tumor necrosis factor-alpha, and interleukin-2 production indicated significantly lower frequencies of long-lived memory T-cells following Ad5 boosting compared to VV and MVA. This same set of analyses suggested that the memory cells induced following boosting with MVA were superior to those induced by both Ad5 and VV. This superiority of the MVA-induced CD8+ T-cells was confirmed following surrogate challenge of mice with a recombinant mouse herpes virus expressing the HCV NS3 protein. Higher levels of NS3-specific CD8+ T-cells displaying the functional markers CD69, Ki67 and Granzyme B were found in the spleens of mice boosted with MVA compared to VV and Ad5, both alone and in combination. These data suggest that MVA may be a more successful viral vector for induction of effective CD8+ T-cell responses against hepatitis C virus.
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Affiliation(s)
- Wendy G. Tan
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD United States of America
| | - Iryna Zubkova
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD United States of America
| | - Alla Kachko
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD United States of America
| | - Frances Wells
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD United States of America
| | - Heiko Adler
- Comprehensive Pneumology Center, Research Unit Lung Repair and Regeneration, Helmholtz Zentrum München—German Research Center for Environmental Health (GmbH), Member of the German Center of Lung Research (DZL), Munich, Germany
| | - Gerd Sutter
- Institute for Infectious Diseases and Zoonoses, LMU University of Munich, Munich, Germany
| | - Marian E. Major
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD United States of America
- * E-mail:
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16
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Swadling L, Halliday J, Kelly C, Brown A, Capone S, Ansari MA, Bonsall D, Richardson R, Hartnell F, Collier J, Ammendola V, Del Sorbo M, Von Delft A, Traboni C, Hill AVS, Colloca S, Nicosia A, Cortese R, Klenerman P, Folgori A, Barnes E. Highly-Immunogenic Virally-Vectored T-cell Vaccines Cannot Overcome Subversion of the T-cell Response by HCV during Chronic Infection. Vaccines (Basel) 2016; 4:E27. [PMID: 27490575 PMCID: PMC5041021 DOI: 10.3390/vaccines4030027] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2016] [Revised: 07/19/2016] [Accepted: 07/19/2016] [Indexed: 02/06/2023] Open
Abstract
An effective therapeutic vaccine for the treatment of chronic hepatitis C virus (HCV) infection, as an adjunct to newly developed directly-acting antivirals (DAA), or for the prevention of reinfection, would significantly reduce the global burden of disease associated with chronic HCV infection. A recombinant chimpanzee adenoviral (ChAd3) vector and a modified vaccinia Ankara (MVA), encoding the non-structural proteins of HCV (NSmut), used in a heterologous prime/boost regimen induced multi-specific, high-magnitude, durable HCV-specific CD4+ and CD8+ T-cell responses in healthy volunteers, and was more immunogenic than a heterologous Ad regimen. We now assess the immunogenicity of this vaccine regimen in HCV infected patients (including patients with a low viral load suppressed with interferon/ribavirin therapy), determine T-cell cross-reactivity to endogenous virus, and compare immunogenicity with that observed previously in both healthy volunteers and in HCV infected patients vaccinated with the heterologous Ad regimen. Vaccination of HCV infected patients with ChAd3-NSmut/MVA-NSmut was well tolerated. Vaccine-induced HCV-specific T-cell responses were detected in 8/12 patients; however, CD4+ T-cell responses were rarely detected, and the overall magnitude of HCV-specific T-cell responses was markedly reduced when compared to vaccinated healthy volunteers. Furthermore, HCV-specific cells had a distinct partially-functional phenotype (lower expression of activation markers, granzyme B, and TNFα production, weaker in vitro proliferation, and higher Tim3 expression, with comparable Tbet and Eomes expression) compared to healthy volunteers. Robust anti-vector T-cells and antibodies were induced, showing that there is no global defect in immunity. The level of viremia at the time of vaccination did not correlate with the magnitude of the vaccine-induced T-cell response. Full-length, next-generation sequencing of the circulating virus demonstrated that T-cells were only induced by vaccination when there was a sequence mismatch between the autologous virus and the vaccine immunogen. However, these T-cells were not cross-reactive with the endogenous viral variant epitopes. Conversely, when there was complete homology between the immunogen and circulating virus at a given epitope T-cells were not induced. T-cell induction following vaccination had no significant impact on HCV viral load. In vitro T-cell culture experiments identified the presence of T-cells at baseline that could be expanded by vaccination; thus, HCV-specific T-cells may have been expanded from pre-existing low-level memory T-cell populations that had been exposed to HCV antigens during natural infection, explaining the partial T-cell dysfunction. In conclusion, vaccination with ChAd3-NSmut and MVA-NSmut prime/boost, a potent vaccine regimen previously optimized in healthy volunteers was unable to reconstitute HCV-specific T-cell immunity in HCV infected patients. This highlights the major challenge of overcoming T-cell exhaustion in the context of persistent antigen exposure.
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Affiliation(s)
- Leo Swadling
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
| | - John Halliday
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
- Oxford NIHR BRC, and Translational Gastroenterology Unit, Oxford OX3 9DU, UK.
- Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
| | - Christabel Kelly
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
- Oxford NIHR BRC, and Translational Gastroenterology Unit, Oxford OX3 9DU, UK.
| | - Anthony Brown
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
| | - Stefania Capone
- Reithera Srl (former Okairos Srl), Viale Città d'Europa, 679, Rome 00144, Italy.
| | - M Azim Ansari
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
| | - David Bonsall
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
| | - Rachel Richardson
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
| | - Felicity Hartnell
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
| | - Jane Collier
- Oxford NIHR BRC, and Translational Gastroenterology Unit, Oxford OX3 9DU, UK.
| | - Virginia Ammendola
- Reithera Srl (former Okairos Srl), Viale Città d'Europa, 679, Rome 00144, Italy.
| | | | - Annette Von Delft
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
| | - Cinzia Traboni
- Reithera Srl (former Okairos Srl), Viale Città d'Europa, 679, Rome 00144, Italy.
| | - Adrian V S Hill
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
- The Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
| | - Stefano Colloca
- Reithera Srl (former Okairos Srl), Viale Città d'Europa, 679, Rome 00144, Italy.
| | - Alfredo Nicosia
- Reithera Srl (former Okairos Srl), Viale Città d'Europa, 679, Rome 00144, Italy.
- CEINGE, via Gaetano Salvatore 486, Naples 80145, Italy.
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, Naples 80131, Italy.
| | | | - Paul Klenerman
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
- Oxford NIHR BRC, and Translational Gastroenterology Unit, Oxford OX3 9DU, UK.
- The Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
| | - Antonella Folgori
- Reithera Srl (former Okairos Srl), Viale Città d'Europa, 679, Rome 00144, Italy.
| | - Eleanor Barnes
- Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, UK.
- Oxford NIHR BRC, and Translational Gastroenterology Unit, Oxford OX3 9DU, UK.
- The Jenner Institute, University of Oxford, Oxford, OX3 7DQ, UK.
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17
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Large scale production of a mammalian cell derived quadrivalent hepatitis C virus like particle vaccine. J Virol Methods 2016; 236:87-92. [PMID: 27373602 DOI: 10.1016/j.jviromet.2016.06.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Revised: 06/24/2016] [Accepted: 06/27/2016] [Indexed: 12/14/2022]
Abstract
A method for the large-scale production of a quadrivalent mammalian cell derived hepatitis C virus-like particles (HCV VLPs) is described. The HCV core E1 and E2 coding sequences of genotype 1a, 1b, 2a or 3a were co-expressed in Huh7 cell factories using a recombinant adenoviral expression system. The structural proteins self-assembled into VLPs that were purified from Huh7 cell lysates by iodixanol ultracentrifugation and Stirred cell ultrafiltration. Electron microscopy, revealed VLPs of the different genotypes that are morphologically similar. Our results show that it is possible to produce large quantities of individual HCV genotype VLPs with relative ease thus making this approach an alternative for the manufacture of a quadrivalent mammalian cell derived HCV VLP vaccine.
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18
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Earnest-Silveira L, Chua B, Chin R, Christiansen D, Johnson D, Herrmann S, Ralph SA, Vercauteren K, Mesalam A, Meuleman P, Das S, Boo I, Drummer H, Bock CT, Gowans EJ, Jackson DC, Torresi J. Characterization of a hepatitis C virus-like particle vaccine produced in a human hepatocyte-derived cell line. J Gen Virol 2016; 97:1865-1876. [PMID: 27147296 DOI: 10.1099/jgv.0.000493] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
An effective immune response against hepatitis C virus (HCV) requires the early development of multi-specific class 1 CD8+ and class II CD4+ T-cells together with broad neutralizing antibody responses. We have produced mammalian-cell-derived HCV virus-like particles (VLPs) incorporating core, E1 and E2 of HCV genotype 1a to produce such immune responses. Here we describe the biochemical and morphological characterization of the HCV VLPs and study HCV core-specific T-cell responses to the particles. The E1 and E2 glycoproteins in HCV VLPs formed non-covalent heterodimers and together with core protein assembled into VLPs with a buoyant density of 1.22 to 1.28 g cm-3. The HCV VLPs could be immunoprecipited with anti-ApoE and anti-ApoC. On electron microscopy, the VLPs had a heterogeneous morphology and ranged in size from 40 to 80 nm. The HCV VLPs demonstrated dose-dependent binding to murine-derived dendritic cells and the entry of HCV VLPs into Huh7 cells was blocked by anti-CD81 antibody. Vaccination of BALB/c mice with HCV VLPs purified from iodixanol gradients resulted in the production of neutralizing antibody responses while vaccination of humanized MHC class I transgenic mice resulted in the prodution of HCV core-specific CD8+ T-cell responses. Furthermore, IgG purified from the sera of patients chronically infected with HCV genotypes 1a and 3a blocked the binding and entry of the HCV VLPs into Huh7 cells. These results show that our mammalian-cell-derived HCV VLPs induce humoral and HCV-specific CD8+ T-cell responses and will have important implications for the development of a preventative vaccine for HCV.
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Affiliation(s)
- L Earnest-Silveira
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia
| | - B Chua
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia
| | - R Chin
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia
| | - D Christiansen
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.,Department of Surgery, Austin Hospital, University of Melbourne, Australia
| | - D Johnson
- Department of Infectious Diseases, Austin Hospital, Heidelberg, Victoria 3084, Australia
| | - S Herrmann
- Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Australia
| | - S A Ralph
- Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Australia
| | - K Vercauteren
- Center for Vaccinology, Ghent University and Hospital, De Pintelaan 185 9000, Ghent, Belgium
| | - A Mesalam
- Center for Vaccinology, Ghent University and Hospital, De Pintelaan 185 9000, Ghent, Belgium
| | - P Meuleman
- Center for Vaccinology, Ghent University and Hospital, De Pintelaan 185 9000, Ghent, Belgium
| | - S Das
- Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India
| | - I Boo
- Centre for Biomedical Research, Burnet Institute, Melbourne, Australia
| | - H Drummer
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia.,Centre for Biomedical Research, Burnet Institute, Melbourne, Australia.,Department of Microbiology, Monash University, Clayton, Australia
| | - C-T Bock
- Department of Infectious Diseases, Robert Koch Institute, Berlin, Germany
| | - E J Gowans
- The Basil Hetzel Institute and Queen Elizabeth Hospital, University of Adelaide, Australia
| | - D C Jackson
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia
| | - Joseph Torresi
- Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Parkville, Victoria 3010, Australia
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19
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Abstract
Despite advances in therapy, hepatitis C virus infection remains a major global health issue with 3 to 4 million incident cases and 170 million prevalent chronic infections. Complex, partially understood, host-virus interactions determine whether an acute infection with hepatitis C resolves, as occurs in approximately 30% of cases, or generates a persistent hepatic infection, as occurs in the remainder. Once chronic infection is established, the velocity of hepatocyte injury and resultant fibrosis is significantly modulated by immunologic as well as environmental factors. Immunomodulation has been the backbone of antiviral therapy despite poor understanding of its mechanism of action.
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Affiliation(s)
- David E. Kaplan
- Medicine and Research Services, Philadelphia VA Medical Center, Philadelphia PA,Division of Gastroenterology, Department of Medicine, University of Pennsylvania
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20
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Walker CM, Grakoui A. Hepatitis C virus: why do we need a vaccine to prevent a curable persistent infection? Curr Opin Immunol 2015; 35:137-43. [PMID: 26241306 DOI: 10.1016/j.coi.2015.06.010] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2015] [Revised: 06/23/2015] [Accepted: 06/23/2015] [Indexed: 02/06/2023]
Abstract
Chronic hepatitis C virus infection is now curable by antiviral therapy but the global burden of liver disease is unlikely to diminish without a vaccine to prevent transmission. The objective of HCV vaccination is not to induce sterilizing immunity, but instead to prevent persistent infection. One vaccine that incorporates only non-structural HCV proteins is now in phase I/II efficacy trials to test the novel concept that T cell priming alone is sufficient for protection. Evidence also suggests that antibodies contribute to infection resolution. Vaccines comprised of recombinant envelope glycoproteins targeted by neutralizing antibodies have been assessed in humans for immunogenicity. Here, we discuss current concepts in protective immunity and divergent approaches to vaccination against a highly mutable RNA virus.
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Affiliation(s)
- Christopher M Walker
- Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University School of Medicine, 700 Children's Drive, Columbus, OH 43004, United States.
| | - Arash Grakoui
- Yerkes National Primate Research Center, Emory Vaccine Center, Emory University, Atlanta, GA 30329, United States; Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA 30322, United States.
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21
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Li D, Huang Z, Zhong J. Hepatitis C virus vaccine development: old challenges and new opportunities. Natl Sci Rev 2015. [DOI: 10.1093/nsr/nwv040] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Abstract
Hepatitis C virus (HCV), an enveloped positive-sense single-stranded RNA virus, can cause chronic and end-stage liver diseases. Approximately 185 million people worldwide are infected with HCV. Tremendous progress has been achieved in the therapeutics of chronic hepatitis C thanks to the development of direct-acting antiviral agents (DAAs), but the worldwide use of these highly effective DAAs is limited due to their high treatment cost. In addition, drug-resistance mutations remain a potential problem as DAAs are becoming a standard therapy for chronic hepatitis C. Unfortunately, no vaccine is available for preventing new HCV infection. Therefore, HCV still imposes a big threat to human public health, and the worldwide eradication of HCV is critically dependent on an effective HCV vaccine. In this review, we summarize recent progresses on HCV vaccine development and present our views on the rationale and strategy to develop an effective HCV vaccine.
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Affiliation(s)
- Dapeng Li
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhong Huang
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jin Zhong
- Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China
- Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
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22
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Rossi LMG, Escobar-Gutierrez A, Rahal P. Advanced molecular surveillance of hepatitis C virus. Viruses 2015; 7:1153-88. [PMID: 25781918 PMCID: PMC4379565 DOI: 10.3390/v7031153] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Revised: 02/05/2015] [Accepted: 02/20/2015] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C virus (HCV) infection is an important public health problem worldwide. HCV exploits complex molecular mechanisms, which result in a high degree of intrahost genetic heterogeneity. This high degree of variability represents a challenge for the accurate establishment of genetic relatedness between cases and complicates the identification of sources of infection. Tracking HCV infections is crucial for the elucidation of routes of transmission in a variety of settings. Therefore, implementation of HCV advanced molecular surveillance (AMS) is essential for disease control. Accounting for virulence is also important for HCV AMS and both viral and host factors contribute to the disease outcome. Therefore, HCV AMS requires the incorporation of host factors as an integral component of the algorithms used to monitor disease occurrence. Importantly, implementation of comprehensive global databases and data mining are also needed for the proper study of the mechanisms responsible for HCV transmission. Here, we review molecular aspects associated with HCV transmission, as well as the most recent technological advances used for virus and host characterization. Additionally, the cornerstone discoveries that have defined the pathway for viral characterization are presented and the importance of implementing advanced HCV molecular surveillance is highlighted.
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Affiliation(s)
- Livia Maria Gonçalves Rossi
- Department of Biology, Institute of Bioscience, Language and Exact Science, Sao Paulo State University, Sao Jose do Rio Preto, SP 15054-000, Brazil.
| | | | - Paula Rahal
- Department of Biology, Institute of Bioscience, Language and Exact Science, Sao Paulo State University, Sao Jose do Rio Preto, SP 15054-000, Brazil.
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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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24
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Abstract
Host immunity is a major driver of pathogen evolution and thus a major determinant of pathogen diversity. Explanations for pathogen diversity traditionally assume simple interactions between pathogens and the immune system, a view encapsulated by the susceptible-infected-recovered (SIR) model. However, there is growing evidence that the complexity of many host-pathogen interactions is dynamically important. This revised perspective requires broadening the definition of a pathogen's immunological phenotype, or what can be thought of as its immunological niche. After reviewing evidence that interactions between pathogens and host immunity drive much of pathogen evolution, I introduce the concept of a pathogen's immunological phenotype. Models that depart from the SIR paradigm demonstrate the utility of this perspective and show that it is particularly useful in understanding vaccine-induced evolution. This paper highlights questions in immunology, evolution, and ecology that must be answered to advance theories of pathogen diversity.
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Affiliation(s)
- Sarah Cobey
- Department of Ecology and Evolution, University of Chicago, Chicago, Illinois
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25
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Cubero M, Gregori J, Esteban JI, García-Cehic D, Bes M, Perales C, Domingo E, Rodríguez-Frías F, Sauleda S, Casillas R, Sanchez A, Ortega I, Esteban R, Guardia J, Quer J. Identification of host and viral factors involved in a dissimilar resolution of a hepatitis C virus infection. Liver Int 2014; 34:896-906. [PMID: 24134179 DOI: 10.1111/liv.12362] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Accepted: 10/13/2013] [Indexed: 02/05/2023]
Abstract
BACKGROUND & AIMS Hepatitis C virus (HCV) transmission from a chronic patient to a susceptible individual is a good opportunity to study viral and host factors that may influence the natural course of hepatitis C infection towards either spontaneous recovery or chronicity. To compare a documented case of a bottleneck event in the sexual transmission of HCV from a chronically infected patient to a recipient host that cleared infection. METHODS Host genetic components such as Class I and II HLA and IL28B polymorphism (rs12979860 SNPs) were identified by direct sequencing and LightMix analysis, respectively. Deep nucleotide sequence analysis of quasispecies complexity was performed using massive pyrosequencing platform (454 GS-FLX), and the CD4 specific immune response was characterized by ELISPOT. RESULTS AND CONCLUSIONS Sequencing analysis and CD4 response highlighted several NS3-helicase domains in which an interplay between amino acid variability and CD4 immune response might have contributed either to chronicity in the donor patient or to viral clearance in the receptor (newly infected) patient.
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MESH Headings
- Adult
- Antiviral Agents/therapeutic use
- Female
- Genotype
- Hepacivirus/drug effects
- Hepacivirus/genetics
- Hepacivirus/immunology
- Hepacivirus/pathogenicity
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/immunology
- Hepatitis C, Chronic/transmission
- Hepatitis C, Chronic/virology
- Host-Pathogen Interactions
- Humans
- Male
- Phenotype
- Remission Induction
- Sexual Partners
- Sexually Transmitted Diseases, Viral/diagnosis
- Sexually Transmitted Diseases, Viral/drug therapy
- Sexually Transmitted Diseases, Viral/immunology
- Sexually Transmitted Diseases, Viral/transmission
- Sexually Transmitted Diseases, Viral/virology
- Substance Abuse, Intravenous/complications
- Time Factors
- Treatment Outcome
- Viral Nonstructural Proteins/genetics
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Affiliation(s)
- Maria Cubero
- Liver Unit. Internal Medicine. Lab. Malalties Hepàtiques, Vall d'Hebron Institut Recerca-Hospital Universitari Vall d'Hebron (VHIR-HUVH), Barcelona, Spain; Roche Diagnostics SL, Sant Cugat del Vallès, Barcelona, Spain
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26
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Saeedi A, Ghaemi A, Tabarraei A, Moradi A, Gorji A, Semnani S, Soleimanjahi H, Adli AH, Hosseini SY, Vakili MA. Enhanced cell immune responses to hepatitis c virus core by novel heterologous DNA prime/lambda nanoparticles boost in mice. Virus Genes 2014; 49:11-21. [DOI: 10.1007/s11262-014-1070-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2013] [Accepted: 04/04/2014] [Indexed: 02/15/2023]
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27
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Zubkova I, Duan H, Wells F, Mostowski H, Chang E, Pirollo K, Krawczynski K, Lanford R, Major M. Hepatitis C virus clearance correlates with HLA-DR expression on proliferating CD8+ T cells in immune-primed chimpanzees. Hepatology 2014; 59:803-13. [PMID: 24123114 PMCID: PMC4079472 DOI: 10.1002/hep.26747] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Accepted: 09/11/2013] [Indexed: 12/18/2022]
Abstract
UNLABELLED Vaccination of chimpanzees against hepatitis C virus (HCV) using T-cell-based vaccines targeting nonstructural proteins has not resulted in the same levels of control and clearance as those seen in animals reexposed after HCV clearance. We hypothesized that the outcome of infection depends on the different subtypes of activated T cells. We used multicolor flow cytometry to evaluate activation (CD38+/HLA-DR+) and proliferation (Ki67+/Bcl-2-low) profiles of CD4+ and CD8+ T cells in peripheral blood before and after challenge in chimpanzees vaccinated using DNA/adenovirus, mock-vaccinated, and chimpanzees that had spontaneously cleared infection (rechallenged). The frequencies of activated or proliferating CD8+ T cells peaked at 2 weeks postchallenge in the vaccinated and rechallenged animals, coinciding with reductions in viral titers. However, the magnitude of the responses did not correlate with outcome or sustained control of viral replication. In contrast, proliferation of the CD8+ T cells coexpressing HLA-DR either with or without CD38 expression was significantly higher at challenge in animals that rapidly cleared HCV and remained so throughout the follow-up period. CONCLUSION Our data suggest that the appearance of proliferating HLA-DR+/CD8+ T cells can be used as a predictor of a successfully primed memory immune response against HCV and as a marker of effective vaccination in clinical trials.
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Affiliation(s)
- Iryna Zubkova
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
| | - Hongying Duan
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
| | - Frances Wells
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
| | - Howard Mostowski
- Office of Cellular and Gene Therapy, Center for Biologics evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
| | - Esther Chang
- Office of Cellular and Gene Therapy, Center for Biologics evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
| | - Kathleen Pirollo
- Office of Cellular and Gene Therapy, Center for Biologics evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
| | - Kris Krawczynski
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Robert Lanford
- Division of Viral Hepatitis, NCHHSTP, Centers for Disease Control and Prevention. Atlanta, GA
| | - Marian Major
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892,Corresponding author. Marian E. Major, Laboratory of Hepatitis Viruses, Division of Viral Products, Bldg 29A/Rm 1D10/HFM 448, 8800 Rockville Pike, Bethesda, MD 20892, Telephone number: 1-301 827 1881, Fax number: 301 402 5585,
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28
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Abstract
We present a rigorous mathematical analysis of a deterministic model, for the transmission dynamics of hepatitis C, using a standard incidence function. The infected population is divided into three distinct compartments featuring two distinct infection stages (acute and chronic) along with an isolation compartment. It is shown that for basic reproduction number R0≤1, the disease-free equilibrium is locally and globally asymptotically stable. The model also has an endemic equilibrium for R0>1. Uncertainty and sensitivity analyses are carried out to identify and study the impact of critical parameters on R0. In addition, we have presented the numerical simulations to investigate the influence of different important parameters on R0. Since we have a locally stable endemic equilibrium, optimal control is applied to the deterministic model to reduce the total infected population. Two different optimal control strategies (vaccination and isolation) are designed to control the disease and reduce the infected population. Pontryagin’s Maximum Principle is used to characterize the optimal controls in terms of an optimality system which is solved numerically. Numerical results for the optimal controls are compared against the constant controls and their effectiveness is discussed.
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29
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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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30
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Bellier B, Klatzmann D. Virus-like particle-based vaccines against hepatitis C virus infection. Expert Rev Vaccines 2014; 12:143-54. [DOI: 10.1586/erv.13.10] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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31
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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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32
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Hepatitis C virus adaptation to T-cell immune pressure. ScientificWorldJournal 2013; 2013:673240. [PMID: 23554569 PMCID: PMC3608127 DOI: 10.1155/2013/673240] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 02/17/2013] [Indexed: 01/07/2023] Open
Abstract
Replication of the hepatitis C virus (HCV) is an error-prone process. This high error rate results in the emergence of viral populations (quasispecies) within hosts and contributes to interhost variability. Numerous studies have demonstrated that both viral and host factors contribute to this viral diversity, which can ultimately affect disease outcome. As the host's immune response is an important correlate of infection outcome for HCV, many of these viral variations are strongly influenced by T-cell immune pressure and accordingly constitute an efficient strategy to subvert such pressures (viral adaptations). This paper will review the data on viral diversity observed between and within hosts infected with HCV from the acute to the chronic stage of infection and will focus on viral adaptation to the host's T-cell immune response.
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33
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WANG DONGSHENG, ZHOU DING, DU QIN, LIANG QI, WANG QIANG, FANG LI, WANG GUANGRONG, FAN QUMING, LIU BEIZHONG, ZHOU JINGGUO, TANG ZHONG, WU HAO, GUO XIAOLAN, JIAO YANMEI, ZHANG GUOYUAN. Aberrant production of soluble inducible T-cell co-stimulator (sICOS) and soluble programmed cell death protein 1 (sPD-1) in patients with chronic hepatitis C. Mol Med Rep 2013; 7:1197-202. [DOI: 10.3892/mmr.2013.1326] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2012] [Accepted: 01/16/2013] [Indexed: 11/06/2022] Open
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34
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Beaumont E, Roingeard P. Prospects for prophylactic hepatitis C vaccines based on virus-like particles. Hum Vaccin Immunother 2013; 9:1112-8. [PMID: 23406827 DOI: 10.4161/hv.23900] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Given the global prevalence and long-term complications of chronic hepatitis C virus (HCV) infection, HCV constitutes one of the greatest challenges to human health of this decade. Considerable efforts have focused on the development of new effective treatments, but about three to four million individuals become infected each year, adding to the world reservoir of HCV infection. The development of a prophylactic vaccine against hepatitis C virus has thus become an important medical priority. Only a few vaccine candidates have progressed to the clinical phase, and published data on both the efficacy and safety of these vaccines are limited, due to many scientific, logistic and bioethic challenges. Fortunately, new innovative vaccine formulations, modes of vaccination and delivery technologies have been developed in recent years. Several preclinical trials of virus-like particle (VLP)-based vaccination strategies are currently underway and have already generated very promising results. In this commentary, we consider the current state of prophylactic HCV vaccines, the hurdles to be overcome in the future and the various VLP-based vaccination approaches currently being developed.
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Affiliation(s)
- Elodie Beaumont
- 1 INSERM U966; Université François Rabelais and CHRU de Tours; Tours, France
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35
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Hepatitis C VLPs delivered to dendritic cells by a TLR2 targeting lipopeptide results in enhanced antibody and cell-mediated responses. PLoS One 2012; 7:e47492. [PMID: 23091628 PMCID: PMC3472981 DOI: 10.1371/journal.pone.0047492] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Accepted: 09/12/2012] [Indexed: 01/10/2023] Open
Abstract
Although many studies provide strong evidence supporting the development of HCV virus-like particle (VLP)-based vaccines, the fact that heterologous viral vectors and/or multiple dosing regimes are required to induce protective immunity indicates that it is necessary to improve their immunogenicity. In this study, we have evaluated the use of an anionic self-adjuvanting lipopeptide containing the TLR2 agonist Pam2Cys (E8Pam2Cys) to enhance the immunogenicity of VLPs containing the HCV structural proteins (core, E1 and E2) of genotype 1a. While co-formulation of this lipopeptide with VLPs only resulted in marginal improvements in dendritic cell (DC) uptake, its ability to concomitantly induce DC maturation at very small doses is a feature not observed using VLPs alone or in the presence of an aluminium hydroxide-based adjuvant (Alum). Dramatically improved VLP and E2-specific antibody responses were observed in VLP+E8Pam2Cys vaccinated mice where up to 3 doses of non-adjuvanted or traditionally alum-adjuvanted VLPs was required to match the antibody titres obtained with a single dose of VLPs formulated with this lipopeptide. This result also correlated with significantly higher numbers of specific antibody secreting cells that was detected in the spleens of VLP+E8Pam2Cys vaccinated mice and greater ability of sera from these mice to neutralise the binding and uptake of VLPs by Huh7 cells. Moreover, vaccination of HLA-A2 transgenic mice with this formulation also induced better VLP-specific IFN-γ-mediated responses compared to non-adjuvanted VLPs but comparable levels to that achieved when coadministered with complete freund’s adjuvant. These results suggest overall that the immunogenicity of HCV VLPs can be significantly improved by the addition of this novel adjuvant by targeting their delivery to DCs and could therefore constitute a viable vaccine strategy for the treatment of HCV.
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36
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Feinstone SM, Hu DJ, Major ME. Prospects for prophylactic and therapeutic vaccines against hepatitis C virus. Clin Infect Dis 2012; 55 Suppl 1:S25-32. [PMID: 22715210 DOI: 10.1093/cid/cis362] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Natural cross-protective immunity is induced after spontaneous clearance of primary hepatitis C virus (HCV) infection. Although this suggests that effective prophylactic vaccines against HCV are possible, there are still several areas that require further study. Current data indicate that, at best, vaccine-induced immunity may not completely prevent HCV infection but rather prevent persistence of the virus. However, this may be an acceptable goal, because chronic persistence of the virus is the main cause of pathogenesis and the development of serious liver conditions. Therapeutic vaccine development is also highly challenging; however, strategies have been pursued in combination with current or new treatments in an effort to reduce the costs and adverse effects associated with antiviral therapy. This review summarizes the current state of HCV vaccines and the challenges faced for future development and clinical trial design.
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Affiliation(s)
- Stephen M Feinstone
- Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA
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37
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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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38
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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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Callendret B, Walker CM. Will there be a vaccine to protect against the hepatitis C virus? Gastroenterology 2012; 142:1384-7. [PMID: 22537447 PMCID: PMC3862033 DOI: 10.1053/j.gastro.2012.02.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Revised: 01/26/2012] [Accepted: 02/01/2012] [Indexed: 01/27/2023]
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40
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Bes M, Sauleda S, Casamitjana N, Piron M, Campos-Varela I, Quer J, Cubero M, Puig L, Guardia J, Esteban JI. Reversal of nonstructural protein 3-specific CD4(+) T cell dysfunction in patients with persistent hepatitis C virus infection. J Viral Hepat 2012; 19:283-94. [PMID: 22404727 DOI: 10.1111/j.1365-2893.2011.01549.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Hepatitis C virus (HCV)-specific T cell responses are essential for HCV control, and chronic infection is characterized by functionally altered antigen-specific T cells. It has been proposed that the early inactivation of specific CD4(+) T cell responses may be involved in establishment of HCV persistence. We have investigated whether HCV-specific CD4(+) T cells dysfunction can be reversed in vitro. Nonstructural protein 3 (NS3) and core-specific CD4(+) T cells from eight chronically infected and eight spontaneously resolved HCV individuals were selected through transient CD154 (CD40 ligand) expression, and their functional profile (IFN-γ, IL-2, TNF-α, IL-10 and IL-4 production by enzyme-linked immunospot assay, cytometric bead array and intracellular cytokine staining, and proliferation by carboxy-fluorescein diacetate succinimidyl ester dilution assay) was determined both ex vivo and after in vitro expansion of sorted CD154-expressing cells in the absence of specific antigen in IL-7/IL-15-supplemented medium. Ex vivo bulk CD4(+) T cells from chronic patients expressed CD154 in most cases, albeit at lower frequencies than those of resolved patients (0.11%vs 0.41%; P = 0.01), when stimulated with NS3, but not core, although they had a markedly impaired capacity to produce IL-2 and IFN-γ. Antigen-free in vitro expansion of NS3-specific CD154(+) cells from chronic patients restored IFN-γ and IL-2 production and proliferation to levels similar to those of patients with spontaneously resolved infection. Hence, NS3-specific CD4(+) T cell response can be rescued in most chronic HCV patients by in vitro expansion in the absence of HCV-specific antigen. These results might provide a rationale for adoptive immunotherapy.
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Affiliation(s)
- M Bes
- Transfusion Safety Laboratory, Banc de Sang i Teixits, Servei Català de la Salut, Barcelona, Spain
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Gupte GM, Arankalle VA. Evaluation of the immunogenicity of liposome encapsulated HVR1 and NS3 regions of genotype 3 HCV, either singly or in combination. Virol J 2012; 9:74. [PMID: 22452828 PMCID: PMC3349533 DOI: 10.1186/1743-422x-9-74] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Accepted: 03/27/2012] [Indexed: 01/15/2023] Open
Abstract
Background Hepatitis C virus displays a high rate of mutation and exists as a quasispecies in infected patients. In the absence of an effective universal vaccine, genotype-specific vaccine development represents an alternative. We have attempted to develop a genotype 3 based, liposome encapsulated HCV vaccine with hypervariable region-1 (HVR1) and non-structural region-3 (NS3) components. Results HCV RNA extracted from serum samples of 49 chronically infected patients was PCR amplified to obtain HVR1 region. These amplified products were cloned to obtain 20 clones per sample in order to identify the quasispecies pattern. The HVR1 consensus sequence, along with three variants was reverse transcribed to obtain peptides. The peptides were checked for immunoreactivity individually, as a pool or as a single peptide tetramer interspersed with four glycine residues. Anti-HCV positivity varied from 42.6% (tetramer) to 92.2% (variant-4) when 115 anti-HCV positive sera representing genotypes 1, 3, 4 and 6 were screened. All the 95 anti-HCV negatives were scored negative by all antigens. Mice were immunized with different liposome encapsulated or Al(OH)3 adjuvanted formulations of HVR1 variants and recombinant NS3 protein, and monitored for anti-HVR1 and anti-NS3 antibody titres, IgG isotypes and antigen specific cytokine levels. A balanced Th1/Th2 isotyping response with high antibody titres was observed in most of the liposome encapsulated antigen groups. The effect of liposomes and aluminium hydroxide on the expression of immune response genes was studied using Taqman Low Density Array. Both Th1 (IFN-gamma, Il18) and Th2 (Il4) genes were up regulated in the liposome encapsulated HVR1 variant pool-NS3 combination group. In-vitro binding of the virus to anti-HVR1 antibodies was demonstrated. Conclusion The optimum immunogen was identified to be combination of peptides of HVR1 consensus sequence and its variants along with pNS3 encapsulated in liposomes, which could generate both cellular and humoral immune responses in mice deserving further evaluation in a suitable cell culture system/non-human primate model.
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Affiliation(s)
- Gouri M Gupte
- Hepatitis Division, National Institute of Virology, Microbial Containment Complex, Sus Road, Pashan, Pune, India 411021
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Zhou XL, Sullivan GJ, Sun P, Park IH. Humanized murine model for HBV and HCV using human induced pluripotent stem cells. Arch Pharm Res 2012; 35:261-9. [PMID: 22370780 DOI: 10.1007/s12272-012-0206-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2011] [Revised: 11/17/2011] [Accepted: 11/21/2011] [Indexed: 12/23/2022]
Abstract
Infection of hepatitis B virus (HBV) and hepatitis C virus (HCV) results in heterogeneous outcomes from acute asymptomatic infection to chronic infection leading to cirrhosis and hepatocellular carcinoma (HCC). In vitro models using animal hepatocytes, human HCC cell lines, or in vivo transgenic mouse models have contributed invaluably to understanding the pathogenesis of HBV and HCV. A humanized mouse model made by reconstitution of human primary hepatocytes in the liver of the immunodeficient mouse provides a novel experimental opportunity which mimics the in vivo growth of the human hepatocytes. The limited access to primary human hepatocytes necessitated the search for other cellular sources, such as pluripotent stem cells. Human embryonic stem cells (hESCs) have the features of self-renewal and pluripotency and differentiate into cells of all three germ layers, including hepatocytes. Humaninduced pluripotent stem cells (iPSCs) derived from the patient's or individual's own cells provide a novel opportunity to generate hepatocyte-like cells with the defined genetic composition. Here, we will review the current perspective of the models used for HBV and HCV study, and introduce the personalized mouse model using human iPSCs. This novel mouse model will facilitate the direct investigation of HBV and HCV in human hepatocytes as well as probing the genetic influence on the susceptibility of hepatocytes to HBV and HCV.
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Affiliation(s)
- Xiao-Ling Zhou
- Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, CT 06520, USA
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Different aspects of CD4 T cells that lead to viral clearance or persistence of HCV infection. Hepatol Int 2012. [PMID: 26201340 DOI: 10.1007/s12072-011-9321-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
More than 170 million people worldwide are infected with hepatitis C virus (HCV). A characteristic of this virus is a high tendency toward chronic infection. Several factors affect the viral outcome after infection. Among them, HCV-specific CD4 T cells are thought to play a crucial role in controlling viremia. Cumulative data showed that spontaneously resolved individuals have vigorous CD4 T-cell responses to a broad spectrum of HCV antigens and maintain these responses over a long period of time, whereas chronically infected patients lose their CD4 T-cell responses in the acute phase of infection. Although several possibilities of why CD4 T cells lose their function have been proposed, the mechanisms are not completely understood. Moreover, there is another subset of CD4 T cells called regulatory T cells (Tregs). These cells suppress immune reaction of T cells, B cells, and antigen-presenting cells, and are thought to protect organs from immune overreaction and autoimmunity. An increasing amount of data supports the possibility that Tregs participate in the mechanism of HCV persistence. It is obvious that CD4 T cells are the main effectors controlling HCV outcome. To achieve a better prognosis, we need to understand the mechanism of how HCV earns its chronicity by escaping from host cellular immune attacks. In this review, we will focus on the role of HCV-specific T cells in controlling viremia, particularly the aspects of these cells being either inhibitors or propellers of chronic infection.
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Torresi J, Johnson D, Wedemeyer H. Progress in the development of preventive and therapeutic vaccines for hepatitis C virus. J Hepatol 2011; 54:1273-85. [PMID: 21236312 DOI: 10.1016/j.jhep.2010.09.040] [Citation(s) in RCA: 104] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2010] [Revised: 08/27/2010] [Accepted: 09/07/2010] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) is a blood borne disease estimated to chronically infect 3% of the worlds' population causing significant morbidity and mortality. Current medical therapy is curative in approximately 50% of patients. While recent treatment advances of genotype 1 infection using directly acting antiviral agents (DAAs) are encouraging, there is still a need to develop vaccine strategies capable of preventing infection. Moreover, vaccines may also be used in future in combination with DAAs enabling interferon-free treatment regimens. Viral and host specific factors contribute to viral evasion and present important impediments to vaccine development. Both, innate and adaptive immune responses are of major importance for the control of HCV infection. However, HCV has evolved ways of evading the host's immune response in order to establish persistent infection. For example, HCV inhibits intracellular interferon signalling pathways, impairs the activation of dendritic cells, CD8(+) and CD4(+) T cell responses, induces a state of T-cell exhaustion and selects escape variants with mutations CD8(+) T cell epitopes. An effective vaccine will need to produce strong and broadly cross-reactive CD4(+), CD8(+) T cell and neutralising antibody (NAb) responses to be successful in preventing or clearing HCV. Vaccines in clinical trials now include recombinant proteins, synthetic peptides, virosome based vaccines, tarmogens, modified vaccinia Ankara based vaccines, and DNA based vaccines. Several preclinical vaccine strategies are also under development and include recombinant adenoviral vaccines, virus like particles, and synthetic peptide vaccines. This paper will review the vaccines strategies employed, their success to date and future directions of vaccine design.
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Affiliation(s)
- Joseph Torresi
- Austin Centre for Infection Research, Department of Infectious Diseases Austin Hospital, Heidelberg, Victoria 3084, Australia.
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Abstract
The hepatitis C virus (HCV) is a global public health problem affecting approximately 2% of the human population. The majority of HCV infections (more than 70%) result in life-long persistence of the virus that substantially increases the risk of serious liver diseases, including cirrhosis and hepatocellular carcinoma. The remainder (less than 30%) resolves spontaneously, often resulting in long-lived protection from persistence upon reexposure to the virus. To persist, the virus must replicate and this requires effective evasion of adaptive immune responses. In this review, the role of humoral and cellular immunity in preventing HCV persistence, and the mechanisms used by the virus to subvert protective host responses, are considered.
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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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Watanabe H, Wells F, Major ME. Clearance of hepatitis C in chimpanzees is associated with intrahepatic T-cell perforin expression during the late acute phase. J Viral Hepat 2010; 17:245-53. [PMID: 19709361 DOI: 10.1111/j.1365-2893.2009.01172.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The liver is the primary site of hepatitis C virus (HCV) replication. Therefore, we undertook detailed intrahepatic studies of T-cell dynamics, apoptosis, and gene expression during the acute phase of infection using liver biopsies from chimpanzees that developed persistent infection or spontaneously cleared the virus. We examined more than 40 liver biopsies histologically and quantitatively for T-cell infiltration, hepatocyte apoptosis and perforin expression. These data were correlated with outcome and viral kinetics. We observed intrahepatic T-cell infiltration in both groups of animals with CD8(+) T cells representing the major population. The appearance of T cells was always associated with apoptosis and mild alanine aminotransferase (ALT) elevations. Apoptosis (5-20% of hepatocytes) always occurred prior to serum ALT peak. Quantification of intrahepatic ALT mRNA revealed no upregulation of gene expression confirming that serum ALT increases were due to release of this enzyme from cells. During the late acute phase, cleared animals showed an increased frequency of hepatocyte apoptosis relative to persistently infected animals (P < 0.05). This correlated with a higher intrahepatic CD8(+) T-cell frequency in the cleared group (P < 0.01) with a greater proportion of lymphocytes expressing perforin compared with the persistent group (P < 0.001). All infected animals mounted intrahepatic immune responses during the acute phase, but these were not maintained in frequency or efficacy in persistent infections. There is a reduction in the numbers of intrahepatic T cells during the late acute phase in infections that become persistent with significantly fewer of these cells functional in clearing the virus by killing infected hepatocytes.
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Affiliation(s)
- H Watanabe
- Laboratory of Hepatitis Viruses, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA
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Fuller MJ, Shoukry NH, Gushima T, Bowen DG, Callendret B, Campbell KJ, Hasselschwert DL, Hughes AL, Walker CM. Selection-driven immune escape is not a significant factor in the failure of CD4 T cell responses in persistent hepatitis C virus infection. Hepatology 2010; 51:378-87. [PMID: 19918975 PMCID: PMC2821874 DOI: 10.1002/hep.23319] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
UNLABELLED Immune escape driven by selection pressure from virus-specific CD8 T cells has been demonstrated in both chimpanzees and humans infected with the hepatitis C virus (HCV). Although escape mutations have also been characterized in major histocompatibility complex (MHC) class II-restricted HCV epitopes, it is unknown whether selection-driven immune escape by CD4 T cell epitopes is a significant factor in the failure of these responses or contributes to persistent infection. To address this issue, evolution of MHC class I- and class II-restricted HCV epitopes was compared in four chimpanzees persistently infected with the virus for more than 10 years. We identified an amino acid change in a CD4 epitope of the HCV NS3 protein in one of the chimpanzees 3 years after infection. This mutation resulted in diminished activation, cytokine production (interferon-gamma and interleukin-2), and proliferation by an epitope-specific CD4 T cell line. We expanded our analysis to determine if mutations were common in multiple CD4 versus CD8 T cell epitopes in the four chronically infected animals. Whereas we observed mutations in over 75% of CD8 T cell epitopes analyzed in this study, only 18% of CD4 T cell epitopes analyzed showed amino acid changes. The frequency of changes in class II epitopes was not different from flanking regions, so CD4 T cells rarely exert selection pressure against the HCV genome. CONCLUSION Apparent mutational escape can occur in MHC class II-restricted epitopes, but this is uncommon when compared with class I-restricted epitopes in the same individual. This indicates that other mechanisms for silencing CD4 T cells are dominant in persistent HCV infections.
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Affiliation(s)
- Michael J. Fuller
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Naglaa H. Shoukry
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Toshifumi Gushima
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - David G. Bowen
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Benoit Callendret
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Katherine J. Campbell
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | | | - Austin L. Hughes
- Division of Biological Sciences, University of South Carolina, Columbia, SC
| | - Christopher M. Walker
- Center for Vaccines and Immunity, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, College of Medicine and Public Health, The Ohio State University, Columbus, OH
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Fleming VM, Harcourt G, Barnes E, Klenerman P. Virological footprint of CD4+ T-cell responses during chronic hepatitis C virus infection. J Gen Virol 2010; 91:1396-406. [PMID: 20107020 PMCID: PMC3052717 DOI: 10.1099/vir.0.017699-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Human and animal model evidence suggests that CD4+ T cells play a critical role in the control of chronic hepatitis C virus (HCV) infection. However, despite their importance, the mechanism behind the failure of such populations in chronic disease is not understood and the contribution of viral mutation is not known. To address this, this study defined the specificity and virological footprint of CD4+ T cells in chronic infection. CD8+ T-cell-depleted peripheral blood mononuclear cells from 61 HCV genotype 1-infected patients were analysed against a panel of peptides covering the HCV genotype 1 core – a region where CD4+ T-cell responses may be reproducibly obtained. In parallel, the core region and E2 protein were sequenced. Gamma interferon-secreting CD4+ T-cell responses directed against multiple epitopes were detected in 53 % of individuals, targeting between one and four peptides in the HCV core. Viral sequence evaluation revealed that these CD4+ T-cell responses were associated with mutants in 2/21 individuals. In these two cases, the circulating sequence variant was poorly recognized by host CD4+ T cells. Bioinformatics analyses revealed no overall evidence of selection in the target epitopes and no differences between the groups with and without detectable CD4+ T-cell responses. It was concluded that sustained core peptide-specific CD4+ T-cell responses may be reproducibly measured during chronic HCV infection and that immune escape may occur in specific instances. However, overall the virological impact of such responses is limited and other causes for CD4+ T-cell failure in HCV must be sought.
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Affiliation(s)
- Vicki M Fleming
- Peter Medawar Building for Pathogen Research, Nuffield Department of Clinical Medicine, University of Oxford, South Parks Road, Oxford, UK.
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Abstract
BACKGROUND Chimpanzees have been widely used in hepatitis C virus (HCV) research, but their endangered status and high financial and ethical costs have prompted a closer review. METHODS One hundred and nine articles published in 1998-2007 were analyzed for the number of chimpanzees involved, experimental procedures, objectives and other relevant issues. RESULTS The articles described the use of 852 chimpanzees, but accounting for likely multiple uses, the number of individual chimpanzees involved here is estimated to be approximately 500. Most articles addressed immunology and inoculation studies. A significant portion of studies lasted for several months or years. Approximately one half of the individual chimpanzees were each used in 2-10 studies. CONCLUSIONS Significant financial and scientific resources have been expended in these chimpanzee HCV studies. Discussion addresses troublesome questions presented by some of the reviewed articles, including statistical validity, repeatability, and biological relevance of this model. These concerns merit attention as future approaches to HCV research and research priorities are considered.
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