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      Approaches, Progress, and Challenges to Hepatitis C Vaccine Development

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          Abstract

          Risk factors for hepatitis C virus (HCV) infection vary, and there were an estimated 1.75 million new cases worldwide in 2015. The World Health Organization aims for a 90% reduction in new HCV infections by 2030. An HCV vaccine would prevent transmission, regardless of risk factors, and significantly reduce the global burden of HCV-associated disease. Barriers to development include virus diversity, limited models for testing vaccines, and our incomplete understanding of protective immune responses. Although highly effective vaccines could prevent infection altogether, immune responses that increase the rate of HCV clearance and prevent chronic infection may be sufficient to reduce disease burden. Adjuvant envelope or core protein and virus-vectored nonstructural antigen vaccines have been tested in healthy volunteers who are not at risk for HCV infection; viral vectors encoding nonstructural proteins are the only vaccine strategy to be tested in at-risk individuals. Despite development challenges, a prophylactic vaccine is necessary for global control of HCV.

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          Most cited references130

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          Infectious Hepatitis C Virus Pseudo-particles Containing Functional E1–E2 Envelope Protein Complexes

          The study of hepatitis C virus (HCV), a major cause of chronic liver disease, has been hampered by the lack of a cell culture system supporting its replication. Here, we have successfully generated infectious pseudo-particles that were assembled by displaying unmodified and functional HCV glycoproteins onto retroviral and lentiviral core particles. The presence of a green fluorescent protein marker gene packaged within these HCV pseudo-particles allowed reliable and fast determination of infectivity mediated by the HCV glycoproteins. Primary hepatocytes as well as hepato-carcinoma cells were found to be the major targets of infection in vitro. High infectivity of the pseudo-particles required both E1 and E2 HCV glycoproteins, and was neutralized by sera from HCV-infected patients and by some anti-E2 monoclonal antibodies. In addition, these pseudo-particles allowed investigation of the role of putative HCV receptors. Although our results tend to confirm their involvement, they provide evidence that neither LDLr nor CD81 is sufficient to mediate HCV cell entry. Altogether, these studies indicate that these pseudo-particles may mimic the early infection steps of parental HCV and will be suitable for the development of much needed new antiviral therapies.
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            Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge.

            A major problem in hepatitis C virus (HCV) immunotherapy or vaccine design is the extreme variability of the virus. We identified human monoclonal antibodies (mAbs) that neutralize genetically diverse HCV isolates and protect against heterologous HCV quasispecies challenge in a human liver-chimeric mouse model. The results provide evidence that broadly neutralizing antibodies to HCV protect against heterologous viral infection and suggest that a prophylactic vaccine against HCV may be achievable.
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              HCV persistence and immune evasion in the absence of memory T cell help.

              Spontaneous resolution of hepatitis C virus (HCV) infection in humans usually affords long-term immunity to persistent viremia and associated liver diseases. Here, we report that memory CD4+ Tcells are essential for this protection. Antibody-mediated depletion of CD4+ Tcells before reinfection of two immune chimpanzees resulted in persistent, low-level viremia despite functional intra-hepatic memory CD8+ Tcell responses. Incomplete control of HCV replication by memory CD8+ Tcells in the absence of adequate CD4+ Tcell help was associated with emergence of viral escape mutations in class I major histocompatibility complex-restricted epitopes and failure to resolve HCV infection.
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                Author and article information

                Contributors
                Journal
                Gastroenterology
                Gastroenterology
                Gastroenterology
                W.B. Saunders
                0016-5085
                1528-0012
                1 January 2019
                January 2019
                : 156
                : 2
                : 418-430
                Affiliations
                [1 ]Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland
                [2 ]Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine and the Oxford NIHR Biomedical Research Centre, Oxford University, UK
                Author notes
                [] Reprint requests Address requests for reprints to: Andrea L. Cox, MD, PhD, Division of Infectious Diseases, Johns Hopkins University School of Medicine, 551 Rangos Building, 855 N Wolfe Street, Baltimore, Maryland 21205. fax: (443)769-1221. acox@ 123456jhmi.edu
                Article
                S0016-5085(18)35035-2
                10.1053/j.gastro.2018.08.060
                6340767
                30268785
                f2025f0d-0ead-4466-a25d-e865a3928575
                © 2019 The AGA Institute All rights reserved.

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 15 May 2018
                : 14 August 2018
                Categories
                Article

                Gastroenterology & Hepatology
                hcv,viral hepatitis,vaccines,prophylactic vaccination,ad5, adenovirus serotype 5,bnab, broadly neutralizing antibodies,cd81bs, cd81 receptor binding site,chad, chimpanzee adenovirus,daa, direct-acting antiviral,hcv, hepatitis c virus,hcvcc, hcv derived from cell culture,hcvpp, hcv pseudoparticles,hvr1, hypervariable region 1,mabs, monoclonal antibodies,mva, modified vaccinia ankara,nabs, neutralizing antibodies,ns, nonstructural,pd-1, programmed cell death 1,pwid, people who inject drugs,vlp, virus-like particle

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