Elsevier

Journal of Hepatology

Volume 37, Issue 5, November 2002, Pages 684-695
Journal of Hepatology

Review
The challenge of developing a vaccine against hepatitis C virus

https://doi.org/10.1016/S0168-8278(02)00308-2Get rights and content

Introduction

Hepatitis C virus (HCV) is a single stranded positive-sense RNA virus belonging to the Flaviviridae family [1]. Members of this family are small enveloped viruses that have been classified into three different genera: Pestivirus, which contains animal pathogens such as bovine viral diarrhea virus and hog cholera virus; Flavirirus, which contains mostly arthropod-transmitted human pathogens such as dengue fever and yellow fever viruses; and Hepacivirus, whose only member is HCV [1]. The recently discovered GB virus-B (GBV-B), which causes hepatitis in experimentally infected tamarins, will probably be classified with HCV [2], [3].

HCV is an important human pathogen, but the scope of its impact on human health has only recently been truly appreciated. The prevalence of HCV infection in the general population varies depending on the geographical area and ranges from less than 1% in Northern Europe to as high as 20% in some developing countries such as Egypt. It has been estimated that approximately 170 million people are chronically infected with HCV worldwide [4]. However, despite effective screening of blood and blood products, and use of sterile techniques, acute HCV is still a problem in industrialized countries. For example, around 40 000 new HCV infections occur each year in the US [5] and the majority of individuals with acute infection become persistently infected [6]. The source of these infections is principally the illicit use of parenteral drugs. Exposure to contaminated blood, especially via contaminated needles, syringes and surgical instruments, also accounts for the spread of HCV in developing countries. Chronic HCV infection is an important cause of liver cirrhosis and hepatocellular carcinoma in the Western World and Japan and, furthermore, represents the most frequent indication for liver transplantation in developed countries.

Treatment of chronic HCV infection has improved considerably during the last few years: the combination of interferon and the nucleoside analogue ribavirin achieves a sustained virological response in approximately 40% of patients with chronic hepatitis C [7], [8], [9]. It is possible that during the next few years, new antiviral agents such as inhibitors of the viral protease, helicase or polymerase will further improve the response rate of the current therapeutic agents. However, antiviral therapy is not affordable in most developing countries, where the prevalence of HCV is generally the highest. Thus, given the huge reservoir of HCV worldwide, the development of an effective vaccine will be the only way to control disease associated with HCV infection.

Section snippets

The prospect of success for the development of HCV vaccines

Prophylactic vaccines against some other members of the Flaviviridae family already exist or are under development [1]. For example, a live-attenuated vaccine against yellow fever virus is available and has proven to be highly effective. Efforts have been made since the 1940s to produce dengue vaccines. Immunity acquired from natural infection is specific for each dengue serotype and infection of an individual with three different serotypes has been reported. For this reason, tetravalent

Approaches to HCV vaccine development

The classical approaches to vaccine development, live attenuated or whole inactivated virus, are not feasible for HCV because there is no cell culture system to produce viral particles. In addition, a live attenuated approach is not realistic because of the high tendency of the virus to persist in the host. Even recombinant viruses, such as those with deletions of the 3′ untranslated region or HVR1, which appear to cause attenuated acute disease in chimpanzees, readily persist in the host [31],

Summary

It is apparent that the development of an HCV vaccine poses a great challenge to the scientific community. Some difficulties are inherent to the virus, such as its high genetic heterogeneity and the ability to establish persistent infections, perhaps by escaping the host immune responses. Other limitations are technical, such as the lack of a cell culture system or a small animal model for HCV. Several studies have demonstrated that neutralizing antibodies to HCV exist, but that they appear to

First page preview

First page preview
Click to open first page preview

References (115)

  • M.J Gale et al.

    Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the non-structural 5A protein

    Virology

    (1997)
  • S Abrignani et al.

    Perspectives for a vaccine against hepatitis C virus

    J Hepatol

    (1999)
  • P Botarelli et al.

    T-lymphocyte response to hepatitis C virus in different clinical courses of infection

    Gastroenterology

    (1993)
  • M Lechmann et al.

    T- and B-cell responses to different hepatitis C virus antigens in patients with chronic hepatitis C infection and in healthy anti-hepatitis C virus – positive blood donors without viremia

    Hepatology

    (1996)
  • H.M Diepolder et al.

    Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection

    Lancet

    (1995)
  • S Cooper et al.

    Analysis of a successful immune response against hepatitis C virus

    Immunity

    (1999)
  • S.E Bassett et al.

    Protective immune response to hepatitis C virus in chimpanzees rechallenged following clearance of primary infection

    Hepatology

    (2001)
  • R Bartenschlager et al.

    Novel cell culture systems for the hepatitis C virus

    Antiviral Res

    (2001)
  • T.F Baumert et al.

    Hepatitis C virus-like particles synthesized in insect cells as a potential vaccine candidate

    Gastroenterology

    (1999)
  • M Lechmann et al.

    Hepatitis C virus-like particles induce virus-specific humoral and cellular immune responses in mice

    Hepatology

    (2001)
  • H Tighe et al.

    Gene vaccination: plasmid DNA is more than just a blueprint

    Immunol Today

    (1998)
  • X Forns et al.

    DNA immunization of mice and macaques with plasmids encoding hepatitis C virus envelope E2 protein expressed intracellularly and on the cell surface

    Vaccine

    (1999)
  • T Saito et al.

    Plasmid DNA-based immunization for hepatitis C virus structural proteins: immune responses in mice

    Gastroenterology

    (1997)
  • S.W Lee et al.

    Hepatitis C virus envelope DNA-based immunization elicits humoral and cellular immune responses

    Mol Cells

    (1998)
  • X Forns et al.

    Characterization of modified hepatitis C virus E2 proteins expressed on the cell surface

    Virology

    (2000)
  • G Inchauspe

    DNA vaccine strategies for hepatitis C

    J Hepatol

    (1999)
  • X Forns et al.

    Vaccination of chimpanzees with plasmid DNA encoding the hepatitis C virus (HCV) envelope E2 protein modified the infection after challenge with homologous monoclonal HCV

    Hepatology

    (2000)
  • M.M Lai

    Hepatitis viruses and signal transduction: true to the core?

    Hepatology

    (2000)
  • J.H Cho et al.

    Enhanced cellular immunity to hepatitis C virus non-structural proteins by codelivery of granulocyte macrophage-colony stimulating factor gene in intramuscular DNA immunization

    Vaccine

    (1999)
  • X Ma et al.

    DNA-based vaccination against hepatitis C virus (HCV): effect of expressing different forms of HCV E2 protein and use of CpG-optimzed vectors in mice

    Vaccine

    (2002)
  • C.M Rice
  • J.N Simons et al.

    Isolation of novel virus-like sequences associated with human hepatitis

    Nat Med

    (1995)
  • Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium

    J Viral Hepat

    (1999)
  • I Williams

    Epidemiology of hepatitis C in the United States

    Am J Med

    (1999)
  • M Houghton

    The hepatitis C viruses

  • J.G McHutchison et al.

    Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group

    N Engl J Med

    (1998)
  • J Bukh et al.

    Acute resolving monoclonal hepatitis C virus (HCV) infection in a chimpanzee modifies subsequent infections with the homologous monoclonal virus

    Hepatology (Abstract)

    (1999)
  • P Farci et al.

    Lack of protective immunity against reinfection with hepatitis C virus

    Science

    (1992)
  • A.M Prince et al.

    Immunity in hepatitis C infection

    J Infect Dis

    (1992)
  • J Bukh et al.

    Genetic heterogeneity of hepatitis C virus: quasispecies and genotypes

    Semin Liver Dis

    (1995)
  • M Martell et al.

    Hepatitis C virus (HCV) circulates as a population of different but closely related genomes: quasispecies nature of HCV genome distribution

    J Virol

    (1992)
  • A.J Weiner et al.

    Evidence for immune selection of hepatitis C virus (HCV) putative envelope glycoprotein variants: potential role in chronic HCV infections

    Proc Natl Acad Sci USA

    (1992)
  • A Weiner et al.

    Persistent hepatitis C virus infection in a chimpanzee is associated with emergence of a cytotoxic T lymphocyte escape variant

    Proc Natl Acad Sci

    (1995)
  • G Sitia et al.

    Evolution of the E2 region of hepatitis C virus in an infant infected by mother-to-infant transmission

    J Med Virol

    (2001)
  • P Farci et al.

    Prevention of hepatitis C virus infection in chimpanzees by hyperimmune serum against the hypervariable region 1 of the envelope 2 protein

    Proc Natl Acad Sci USA

    (1996)
  • J Bukh et al.

    Sterilizing immunity against hepatitis C virus is subtype specific, is apparently not mediated by neutralization antibodies, but is correlated with anamnestic cellular immune responses

    Hepatology (Abstract)

    (2001)
  • D.H Barouch et al.

    Eventual AIDS vaccine failurein a rhesus monkey by viral escape from cytotoxic T lymphocytes

    Nature

    (2002)
  • M.E Major et al.

    Long-term follow-up of chimpanzees inoculated with the first infectious clone for hepatitis C virus

    J Virol

    (1999)
  • A.A Kolykhalov et al.

    Transmission of hepatitis C by intrahepatic inoculation with transcribed RNA

    Science

    (1997)
  • M Yanagi et al.

    Transcripts from a single full-length cDNA clone of hepatitis C virus are infectious when directly transfected into the liver of a chimpanzee

    Proc Natl Acad Sci USA

    (1997)
  • Cited by (0)

    View full text