Genetic and molecular technologies to optimise novel vaccines for Hepatitis C virus infection

Analysis of the immune response during spontaneous clearance and protection upon reinfection with hepatitis C (HCV) has highlighted the importance of T-cells in the control of HCV infection. An effective T-cell vaccine for HCV would have a significant effective on the global burden of disease associated with HCV. No clear immune correlates of protection exists for HCV and we lack immunological competent animal models in which to assess candidate HCV vaccines. I have performed in-depth characterisation of the T-cell response to candidate virally vectored HCV vaccines with regard to the T-cell parameters most likely to impact on their efficacy in a prophylactic and therapeutic setting. I describe here a heterologous prime/boost vaccine regimen of a simian adenoviral vector (ChAd3), boosted with a modified vaccinia Ankara (MVA) encoding the non-structural (NS) proteins of HCV. This regimen elicits an unprecedented magnitude of HCV-specific CD8+ and CD4+ T-cells; which are broadly targeted, durable, and highly functional. ChAd3-NS/MVA-NS vaccination induces a population of persistent effector memory CD8+ T-cells (Tem) similar in phenotype to those induced by infection with CMV. I show that in these diverse settings the functional and phenotypic characteristics of the CD8+ T-cells are highly conserved and are controlled at the level of gene expression. Vaccination of HCV+ patients induced T-cell response that were significantly lower in magnitude, and viral sequencing at key epitopes demonstrates that the T-cells induced by vaccination show weak cross-recognition of the patients circulating virus. While working with an industrial collaborator, I have developed our understanding of the mechanism of action of the enhancer element, MHC class II invariant chain. I show that tethering antigen to Ii within virally vectored vaccines targets it for rapid degradation by the proteasome, enhancing its presentation on MHC class I molecules and the concomitant CD8+ T-cell response to vaccination. The work described here is relevant to T-cell vaccine development, in particular for Ad and MVA constructs, and to our understanding of antigen processing and heterogeneity within the CD8+ T-cell compartment.