Hepatitis C vaccines: Development of in vitro and in vivo Systems for HCV Replication and Evaluation of Vaccine Efficacy

Principal Investigator: Stephen Feinstone, MD
Office / Division / Lab: OVRR / DVP / LHV

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Overview

Public Health Issue: Two of the five human hepatitis viruses, hepatitis A and hepatitis B, can presently be prevented by licensed vaccines, which have had a major impact on public health worldwide. However, although approximately 3% of the world's population, including about 4 million Americans, has been infected with the hepatitis C virus (HCV), which causes persistent infections in the majority of people exposed, we have no licensed vaccines for HCV. Persistent HCV may result in chronic hepatitis, cirrhosis and liver cancer, a growing problem in the United States. Chronic HCV infections are the leading cause of chronic liver disease resulting in liver transplantation. Treatment of HCV infection is expensive, requires one year of therapy, is effective in only half the patients and carries significant side effects that often limits its utility.

Regulatory Contribution: There is a need for both preventive and therapeutic vaccines for HCV, but the path to an effective vaccine is not yet clear. Research is still required to understand both the nature of an effective vaccine and to develop tools to accurately measure vaccine induced immune responses, i.e., biomarkers of vaccine efficacy.

Research Approach: This research program seeks to evaluate new methods and models for evaluating the immune responses to HCV in systems that may be predictive of outcomes in people. Although currently the only available infection/disease model is the chimpanzee, chimeric transgenic rodent models (i.e., chimeric mouse/human liver) have been developed which support the replication of HCV. These models are presently extremely difficult to work with and suffer from the fact that the mice are immunodeficient. We have improved the immunodeficient mouse system and are working on a new system in immunocompetent mice. We are also studying the use of mesenchymal and embryonic stem cells to repopulate the liver in these mouse models. There have been recent advances in cell culture of HCV. We have established these systems at present and will adapt them to our specific needs. Such systems will be extremely useful for evaluation of neutralizing antibodies and for viral infectivity studies that previously could only be done in chimpanzees. Taken together, both the in vitro and in vivo models of HCV replication will have wide application for preclinical evaluation of vaccine candidates and vaccine safety. Further, models will be used to identify biomarkers of vaccine efficacy, i.e., immune correlates of protection from HCV infection or prevention of chronicity, since the current markers are poorly understood. While the mouse model offers hope that this small animal model will be useful, we continue to use the chimpanzee to answer questions on pathogenesis, vaccine efficay and to aid in the development of correlates of vaccine induced immune protection.

Mission Relevance & Outcomes: Evaluating immune correlates of protection will be invaluable in the assessment of candidate HCV vaccines and to support development of new HCV vaccines. In vitro assays for all types of immune response parameters have been established in this lab or are under development. We have studied the effects of both neutralizing antibody separate from T cell immunity and T cell immunity without the contribution of antibody. By measuring the relative contributions to these two arms of the adaptive immune system, we will understand which components of a vaccine are necessary for it to be effective.

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Publications

J Interferon Cytokine Res 2007 Dec;27(12):985-90
Proteasome activator and antigen-processing aminopeptidases are regulated by virus-induced type I interferon in the hepatitis C virus-infected liver.
Shin EC, Seifert U, Urban S, Truong KT, Feinstone SM, Rice CM, Kloetzel PM, Rehermann B

Proc Natl Acad Sci U S A 2007 May 15;104(20):8449-54
Hepatitis C virus epitope-specific neutralizing antibodies in Igs prepared from human plasma.
Zhang P, Wu CG, Mihalik K, Virata-Theimer ML, Yu MY, Alter HJ, Feinstone SM

Proc Natl Acad Sci U S A 2007 Feb 20;104(8):2879-84
Evidence for a functional RNA element in the hepatitis C virus core gene.
McMullan LK, Grakoui A, Evans MJ, Mihalik K, Puig M, Branch AD, Feinstone SM, Rice CM

Hepatology 2006 Dec;44(6):1478-86
Hepatic precursors derived from murine embryonic stem cells contribute to regeneration of injured liver.
Heo J, Factor VM, Uren T, Takahama Y, Lee JS, Major M, Feinstone SM, Thorgeirsson SS

J Clin Invest 2006 Nov;116(11):3006-14
Virus-induced type I IFN stimulates generation of immunoproteasomes at the site of infection.
Shin EC, Seifert U, Kato T, Rice CM, Feinstone SM, Kloetzel PM, Rehermann B

Hepatology 2006 Aug 29;44(3):736-745
CD4+ immune escape and subsequent T-cell failure following chimpanzee immunization against hepatitis C virus.
Puig M, Mihalik K, Tilton JC, Williams O, Merchlinsky M, Connors M, Feinstone SM, Major ME

Blood 2006 Jun 1;107(11):4424-32
Foxp3+CD4+CD25+ T cells control virus-specific memory T cells in chimpanzees that recovered from hepatitis C.
Manigold T, Shin EC, Mizukoshi E, Mihalik K, Murthy KK, Rice CM, Piccirillo CA, Rehermann B

J Virol 2005 Nov;79(21):13412-20
Liver-directed gamma interferon gene delivery in chronic hepatitis C.
Shin EC, Protzer U, Untergasser A, Feinstone SM, Rice CM, Hasselschwert D, Rehermann B

Hepatology 2005 Oct;42(4):962-73
Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes.
Simmonds P, Bukh J, Combet C, Deleage G, Enomoto N, Feinstone S, Halfon P, Inchauspe G, Kuiken C, Maertens G, Mizokami M, Murphy DG, Okamoto H, Pawlotsky JM, Penin F, Sablon E, Shin-I T, Stuyver LJ, Thiel HJ, Viazov S, Weiner AJ, Widell A

J Virol 2005 May;79(10):6291-8
New Antiviral Pathway That Mediates Hepatitis C Virus Replicon Interferon Sensitivity through ADAR1.
Taylor DR, Puig M, Darnell ME, Mihalik K, Feinstone SM

Gastroenterology 2005 Apr;128(4):1056-66
Mathematical modeling of primary hepatitis C infection: noncytolytic clearance and early blockage of virion production.
Dahari H, Major M, Zhang X, Mihalik K, Rice CM, Perelson AS, Feinstone SM, Neumann AU

J Virol Methods 2004 Oct;121(1):85-91
Inactivation of the coronavirus that induces severe acute respiratory syndrome, SARS-CoV.
Darnell ME, Subbarao K, Feinstone SM, Taylor DR

Proc Natl Acad Sci U S A 2004 Jul 6;101(27):10149-54
Neutralizing antibody response during acute and chronic hepatitis C virus infection.
Logvinoff C, Major ME, Oldach D, Heyward S, Talal A, Balfe P, Feinstone SM, Alter H, Rice CM, McKeating JA

Hepatology 2004 Jun;39(6):1709-20
Hepatitis C virus kinetics and host responses associated with disease and outcome of infection in chimpanzees.
Major ME, Dahari H, Mihalik K, Puig M, Rice CM, Neumann AU, Feinstone SM

Proc Natl Acad Sci U S A. 2004 May 18;101(20):7705-10.
Neutralizing antibodies to hepatitis C virus (HCV) in immune globulins derived from anti-HCV-positive plasma.
Yu MY, Bartosch B, Zhang P, Guo ZP, Renzi PM, Shen LM, Granier C, Feinstone SM, Cosset FL, Purcell RH

Vaccine 2004 Feb 25;22(8):991-1000
Immunization of chimpanzees with an envelope protein-based vaccine enhances specific humoral and cellular immune responses that delay hepatitis C virus infection.
Puig M, Major ME, Mihalik K, Feinstone SM