Vaccination for Hepatitis C Virus

Closing in on an Evasive Target

John Halliday; Paul Klenerman; Eleanor Barnes

Disclosures

Expert Rev Vaccines. 2011;10(5):659-672. 

In This Article

The Ideal Vaccine

The Requirements…

Based on the viral–host interactions of HCV infection, as delineated in the previous sections, there are three characteristic properties that are likely to be shared by successful preventive and therapeutic vaccine approaches alike:

  • These vaccines will need to deal with high levels of viral genetic diversity both between and within hosts – as such, vaccines that target relatively conserved viral regions will be required;

  • The 'magnitude' of antiviral immunity associated with viral control is not precisely defined. Nevertheless, it is likely that a robust, broad and functional T cell, and possibly also a humoral, immune response will be required;

  • Clearly, to be safe, a successful vaccine will need to eradicate HCV from the liver without inducing liver immunopathology. Human studies to date suggest that this is a realistic goal.

…and the Challenges

In addition to overcoming the diverse mechanisms by which HCV evades immune clearance, there are practical obstacles that have hindered the development of both a preventive and therapeutic HCV vaccine. HCV is highly fastidious and there is no readily accessible animal model of infection. In 2003, study of viral entry and antibody-mediated neutralization was enabled for the first time through the development of retroviral particles pseudotyped with HCV envelope glycoproteins.[59] It was not until 2005 that a successful tissue model of HCV infection was developed.[60] This model uses the human hepatoma cell line Huh-7 and a unique viral variant capable of ongoing viral replication. This discovery allowed researchers to characterize the viral life cycle and viral–host interactions during infection for the first time. Transgenic mice expressing human MHC class I molecules have been used for specific HCV epitope analysis. Severe combined immunodeficieny (SCID) mouse models with chimeric human livers have been used to evaluate in vivo effects of antibodies to envelope glycoproteins.[61]

To date, the only immunocompetent animal model for the pathogenesis or immune control of viral infection is the chimpanzee. This model has proved very useful in the preclinical phases of vaccine development since the immune mechanisms associated with viral control are broadly similar. For example, a study by Folgori was clearly able to demonstrate a reduction in HCV viremia, associated with the induction of robust immunity, using a small number of animals.[62] This study subsequently facilitated the use of adenoviral vector technology in human trials. However, there are practical, financial and, for some, ethical limitations in using these animals for research.[63] As a result, the small number of chimpanzees that can be used in HCV studies may limit the power of any conclusions that can be drawn.

Designing clinical studies in humans to evaluate a prophylactic vaccine is also challenging since the incidence of HCV infection in developed countries is relatively low other than in intravenous drug-using populations – targeting this patient group raises its own set of ethical and practical difficulties.[64] Large studies in developing countries where the incidence may be higher raises logistical difficulties. Assessing the efficacy of a prophylactic HCV vaccine will require large numbers of patients and careful follow-up, since acute infection is often asymptomatic. Furthermore, it is possible that a prophylactic vaccine may be unable to achieve sterilizing immunity. However, a vaccine that led to an attenuated course of acute infection associated with viral clearance may be sufficient to ultimately prevent chronic infection, as has been suggested by studies in the chimpanzee model.[62] In addition, this has study design implications; careful consideration must be given to the timing of IFN therapy during primary infection, in the context of a clinical study that is assessing vaccine efficacy. In theory, the vaccine may facilitate viral clearance weeks after current guidelines suggest IFN treatment should be given.

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