The development of novel therapeutic vaccines for chronic hepatitis B infection

Chronic infection with Hepatitis B virus (HBV) remains a significant health problem, infecting millions of people worldwide. Cirrhosis and hepatocellular carcinoma, the sequalae of longstanding HBV infection, have a high mortality. Current therapy controls HBV replication but does not eradicate the virus, and therefore most people require life-long treatment. A robust adaptive immune response is required to control acute HBV but is dysfunctional in individuals that go onto develop chronic infection. The immune response is an attractive target for novel HBV therapies, which aim to induce functional cure of HBV in finite treatment courses by restoring HBV specific immunity. Therapeutic vaccination, which describes the process of delivering non-infective HBV antigen into the body in order to induce or boost cellular immune responses to HBV, is one strategy under investigation for chronic HBV treatment. In this thesis I evaluate the novel vaccines ChAdOx1-HBV and MVA-HBV as candidates for HBV therapeutic vaccination. I investigate their immunogenicity in heterologous prime-boost strategies in healthy mice, describing in detail the fine specificity, functionality and phenotype of vaccine induced T cell responses in the blood and the liver. I also describe the safety and immunogenicity ChAdOx1-HBV in a phase-1 open label clinical trial in healthy volunteers and patients with chronic HBV infection. This work is important to inform the development of therapeutic strategies using ChAdOx1-HBV and MVA-HBV in patients with chronic HBV going forward.