Prospects for a vaccine against the hepatitis C virus
Michael Houghton1 & Sergio Abrignani2 The recent discovery of natural immunity to the hepatitis C virus and vaccine efficacy in the chimpanzee challenge model has allowed optimism about the development of at least a partly effective vaccine against this heterogeneouspathogen that is responsible for much of the chronic liver disease around the world. The immune systems of some infected individuals can spontaneously clear the virus, whereas other people need treatment with antivirals that work partly by stimulating humoral and cellular immune responses. Therefore, therapeutic vaccine strategies are also being pursued to improve treatment outcome.
A decadeago, an effective vaccination against the hepatitis C virus (HCV) was considered only a remote possibility. Three factors contributed to this: the high propensity of HCV to promote chronic persistent infections1; evidence that convalescent humans and chimpanzees could be readily reinfected following re-exposure2; and the considerable genetic heterogeneity of this positive-stranded RNA virus3 . Thesituation today is more positive for two reasons. First, we now know that spontaneous eradication of the virus occurs in up to 50% of acute infections4 and that this viral clearance is associated with specific immune responses to the virus. Recapitulation of such immune responses by appropriate vaccination is therefore a realistic option. Second, clear evidence for at least some natural immunity hasemerged recently in both humans5 and chimpanzees6–8. (Chimpanzees are the only animal model available and develop only mild clinical sequelae.) Convalescent humans and chimpanzees are protected against re-exposure to the virus in the majority of cases, even against very divergent viral strains. Importantly, protection is usually at the level of prevention of progression to chronic, persistentinfection following re-exposure rather than prevention of acute reinfection but this could translate to effective prophylaxis because, in humans, it is the chronic, persistent nature of HCV infection that is mainly associated with viral pathogenicity1,4. Although some re-exposed individuals develop chronic infection9, most do not5–8. This suggests that the generation of at least a partly effectivevaccine against HCV is feasible. Indeed, emerging vaccine efficacy data from the chimpanzee challenge model indicate that it is possible to impede the progression to chronic infection in vaccinees.Until very recently10–12, it was not possible to grow HCV efficiently in cell culture, and so the use of inactivated or live, attenuated viral vaccines has not yet been evaluated. Vaccine approaches havetherefore included the use of adjuvanted recombinant polypeptide subunits of the virus in attempts to prime viralneutralizing antibodies to the envelope glycoproteins 1 and 2 (gpE1 and gpE2), as well as priming MHC class-II-restricted CD4+ T helper (TH) and MHC class-I-restricted CD8+ cytotoxic lymphocyte (CTL) responses to these and other viral proteins. Both types of T cell can secrete antiviralcytokines such as interferon- (IFN- ), and CD8+ CTLs have the potential to kill infected cells.
108 HCV viral load (IU ml–1) 107 106 105 104 103 102 101 0 ALT HCV RNA Controlpp neutralization 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 Weeks post infection HCVpp neutralization
100 90 80 70 60 50 40 30 20 10 0 Neutralization (%)
Figure 1 | Putative control of acute HCV viraemia byviral neutralizing antibodies. Association between circulating viral RNA load (blue) and antibodies that neutralize infectivity of HCV pseudoparticles (HCVpp; purple, expressed as percentage of neutralization). The percentage of neutralization of control pseudoparticles (Controlpp) is shown in red. Serum alanine aminotransferase (ALT) levels indicative of hepatitis are shown in green. Adapted from...