Expert Commentary
Progress in our understanding of HCV pathogenesis and the treatment of infected patients is remarkable given that HCV was discovered only 21 years ago. Nevertheless, current gold-standard therapy (IFN/ribavirin) is ineffective in 30–50% of patients depending on viral genotype. Direct antivirals (protease inhibitors) will be available in the clinic in the next 2 years. These will increase viral clearance rates in genotype-1 patients in particular. However, these novel agents will be given in combination with IFN/ribavirin, costs will be prohibitive in many countries, and treatment will remain ineffective in approximately 30% of patients overall. So, while the authors welcome the addition of these drugs to the anti-HCV therapeutic armory, a HCV vaccine that prevented or increased the cure rates when treating infected patients remains an attractive goal.
The challenges in developing a prophylactic and a therapeutic vaccine overlap but are not identical. The diversity of the HCV genome is a significant challenge to vaccine development and may be greater once chronic infection is established. Similarly, the ability of HCV to subvert and evade antiviral immunity increases over time. Indeed, a hallmark of chronic HCV infection is a weak and narrowly focused HCV-specific T-cell response. The challenge to developing a successful therapeutic vaccination strategy will be to safely recover these responses and to broadly target circulating viral strains.
The fact that a significant proportion of acutely infected patients spontaneously eradicate infection in association with robust antiviral immunity suggests that the development of a prophylactic vaccine is an attainable goal. The ability to compare hosts who spontaneously clear HCV infection with those who develop persistent disease has allowed characterization of many important innate and adaptive immune processes that determine outcome. Although a broad CD4+ and CD8+ T-cell response is clearly important in clearing infection, humoral and innate immune responses also play an important part in this complex and dynamic process, and a single 'correlate of protection' has not been defined. It is, however, clear that a successful prophylactic HCV vaccine will need to exploit and enhance these natural immune defense mechanisms. Some of the challenges to prophylactic HCV vaccine development are the assessment of efficacy in clinical studies. In Western countries with the infrastructure and finance needed to support large clinical trials, the 'HCV at-risk population' are those who abuse intravenous drugs, and assessment of this cohort is not easy.
Significant advances in genomics and proteomics in recent years have enabled a variety of new HCV vaccine approaches to reach clinical trials. Peptide, recombinant protein, DNA and vector-based vaccines have all been explored with varying degrees of success. Recombinant protein vaccines that induce anti-envelope antibody responses are unlikely to provide sterilizing immunity owing to the genetic variability of the HCV envelope region – but may yet play a role in attenuating the course of primary infection or serve as an adjunct to a T-cell-based vaccine. Peptide and protein-based T-cell vaccines have induced weak T-cell responses only – this approach is likely to only progress with the development of novel adjuvants. DNA vaccines with additional techniques to enhance delivery and immunogenicity show some promise and have been shown to decrease viral load in some chronically infected patients. Adenoviral vectors appear to be highly immunogenic in healthy volunteers and Phase II studies in at-risk populations are required to assess efficacy. The effects of these vectors in HCV-infected patients is not yet known.
Ultimately, since HCV infection can be cleared by an appropriate immune response – vaccination remains a realistic goal.
Expert Rev Vaccines. 2011;10(5):659-672. © 2011 Expert Reviews Ltd.
Cite this: Vaccination for Hepatitis C Virus - Medscape - May 01, 2011.
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