Hepatitis C virus: why do we need a vaccine to prevent a curable persistent infection?

Abstract

Chronic hepatitis C virus infection is now curable by antiviral therapy but the global burden of liver disease is unlikely to diminish without a vaccine to prevent transmission. The objective of HCV vaccination is not to induce sterilizing immunity, but instead to prevent persistent infection. One vaccine that incorporates only non-structural HCV proteins is now in phase I/II efficacy trials to test the novel concept that T cell priming alone is sufficient for protection. Evidence also suggests that antibodies contribute to infection resolution. Vaccines comprised of recombinant envelope glycoproteins targeted by neutralizing antibodies have been assessed in humans for immunogenicity. Here, we discuss current concepts in protective immunity and divergent approaches to vaccination against a highly mutable RNA virus.

Figure 1

Bottlenecks in HCV vaccine development. HCV was discovered approximately 25 years ago when there was rapid progress in understanding pathways of antigen processing and presentation, as well as development of recombinant proteins and vectors as vaccines. These advances provided a rich pipeline of ideas for strategies to vaccinate against HCV. Many candidate vaccines were tested for immunogenicity in rodents or other species not susceptible to HCV infection. Very few vaccines were assessed for protection of chimpanzees, the only immunocompetent animal model for human HCV infection. Approximately half of chimpanzees infected with HCV resolve the infection spontaneously. Because chimpanzee vaccine studies necessarily involve very few individuals, it is difficult to detect an increased frequency of resolved infections compared to mock vaccinated controls. The lack of a more tractable animal model is a significant bottleneck in vaccine development. To date, only two vaccine approaches have been assessed for immunogenicity in humans. The difficulty in designing phase II and III human vaccine studies in populations who are at risk for infection, with protection from persistence rather than protection as an endpoint, is also a barrier to progress.

Figure 2

Summary of two HCV vaccines that advanced to human clinical trials. Very different approaches to vaccine antigen selection and delivery reflect uncertainty about mechanisms of protective immunity against HCV. The Chiron vaccine is comprised of adjuvanted recombinant envelope glycoproteins E1 and E2. The Okairos vaccine is comprised of recombinant viruses expressing the non-structural 3 to 5 genes as indicated in the figure.