VACCINE: Development and evaluation of vectored vaccines for HCV using an enhanced gene expression technology in a novel rodent hepacivirus model Hepatitis C virus (HCV) is a major pathogen worldwide, causing progressive and often severe liver disease in the estimated 160 million people infected with the virus. In the UK, a substantial proportion of the estimated 350,000 individuals chronically infected with HCV will eventually develop cirrhosis and liver cancer (hepatocellular carcinoma; HCC) if left untreated. While there is treatment available, conventional therapies based on interferon are effective in only a proportion of those treated while more recently developed antiviral therapy that directly targets the virus is expensive and its use will remain cost-limited for many years. Importantly, such treatments will not stem the spread of HCV and the large numbers of new infections recorded every year; even those who have been effectively treated remain prone to re-infection. HCV also poses a much greater medical problem worldwide where access to treatment will remain limited in much the same as HIV therapy. HCV-related deaths worldwide exceed 350,000 per year, of the same order to those attributed to AIDS, TB and malaria.   Large scale immunisation with a safe and effective HCV vaccine would induce life-long immunity to HCV and prevent further spread of the virus to those currently at risk for infection. Secondly, the therapeutic use of a vaccine in which immunisation would control and clear infection in those already infected with HCV would prevent and in many cases reverse development of liver disease complications, such as cirrhosis and HCC associated with long term chronic infection. The development of such vaccines would therefore have profound effects on global health.   The development of HCV vaccine has been hampered by a lack of animal models with which to test different type of vaccine. It has also proven exceptionally difficult to develop vaccines that induce long-lived protective immunity - even clearance of natural infections does not protect from subsequent re-infection, quite unlike the situation of poliovirus, measles and hepatitis A virus (as examples) for which effective vaccines have been developed.   We believe the solution to the problems is to generate novel vaccines in which viral proteins, such as those from HCV, are inserted into another virus, cytomegalovirus (CMV) or adenovirus (AdV). A feature of CMV infections is that although harmless, infection leads invariably to persistent infections. Infections with CMV containing inserted HCV genes, once established, would therefore continuously immunise the body against HCV, much more so than infection with HCV itself. The most compelling evidence for the effectiveness of this method of immunisation arises from HIV vaccine research, where CMV vectors were effective at preventing infection of macaques with SIV, a monkey version of HIV. Furthermore, the CMV/SIV vaccine was able to clear infection from macaques already infected with SIV. A human version of this CMV vaccine, containing HIV genes, is currently entering human clinical trial. AdV-vectored vaccines for HCV have proven efficacy in animal models and are currently in human phase I/II clinical trial.   The other development that will enable us to develop an effective HCV vaccine is the very recent discovery of a virus called rodent hepacivirus (RHV), closely related to HCV, that infects rats and causes the same pattern of liver disease and frequency of persistence as HCV in humans. In our planned project, we will develop CMV and AdV vectors containing genes from RHV to directly evaluate whether this approach can generate protective immunity and can clear RHV infection in rats that are chronically infected with the virus. Based on previous experience with CMV/SIV vaccine candidates in macaques, we believe this strategy will also prove effective for HCV and if confirmed, could translate through very rapidly into human clinical trials. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.