Infections with hepatitis C virus (HCV) are persistent and will severely damage and ultimately destroy the liver without treatment. HCV infections are spread through unsterilized needles; in the UK and other developed countries, HCV typically targets injecting drug users, but it is also widely distributed worldwide with an estimated 160 million people infected with the virus and at risk of developing life-threatening complications of infection. While effective treatments for HCV have been recently developed, they are expensive and their 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 way as HIV therapy. HCV-related deaths worldwide exceed 350,000 per year, of the same order to those attributed to AIDS, TB and malaria.
An effective vaccine for HCV would induce life-long immunity to HCV and prevent further spread of the virus to those currently at risk for infection. There is a further tantalising possibility that therapeutic immunisation with such a vaccine may be able to control and clear infection in those already infected with HCV. 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, adenovirus (AdV) that act as a live vaccine vector. Infections with AdV containing inserted HCV genes, once established, would therefore immunise the body against HCV, much more so than infection with HCV itself.
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 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 other adenovirus vaccine candidates in macaques, we believe this strategy will also prove effective for HCV and if confirmed, could translate through very rapidly into safety and efficacy clinical trials in humans.
The DPhil will provide experience and training in a wide range of laboratory molecular virology methods, in vivo studies and in immunology. These include:
The project will take place alongside groups of scientist working the supervisors’ groups investigating other aspects of vaccine design and HCV biology / immunology.
Project reference number: 838
|Professor Peter Simmonds||Experimental Medicine Division||Oxford University, Peter Medawar Building||GBRfirstname.lastname@example.org|
|Professor Ellie (Eleanor) Barnes||Experimental Medicine Division||Oxford University, Peter Medawar Building||GBRemail@example.com|
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. Hide abstract
A protective vaccine against hepatitis C virus (HCV) remains an unmet clinical need. HCV infects millions of people worldwide and is a leading cause of liver cirrhosis and hepatocellular cancer. Animal challenge experiments, immunogenetics studies, and assessment of host immunity during acute infection highlight the critical role that effective T cell immunity plays in viral control. In this first-in-man study, we have induced antiviral immunity with functional characteristics analogous to those associated with viral control in natural infection, and improved upon a vaccine based on adenoviral vectors alone. We assessed a heterologous prime-boost vaccination strategy based on a replicative defective simian adenoviral vector (ChAd3) and modified vaccinia Ankara (MVA) vector encoding the NS3, NS4, NS5A, and NS5B proteins of HCV genotype 1b. Analysis used single-cell mass cytometry and human leukocyte antigen class I peptide tetramer technology in healthy human volunteers. We show that HCV-specific T cells induced by ChAd3 are optimally boosted with MVA, and generate very high levels of both CD8(+) and CD4(+) HCV-specific T cells targeting multiple HCV antigens. Sustained memory and effector T cell populations are generated, and T cell memory evolved over time with improvement of quality (proliferation and polyfunctionality) after heterologous MVA boost. We have developed an HCV vaccine strategy, with durable, broad, sustained, and balanced T cell responses, characteristic of those associated with viral control, paving the way for the first efficacy studies of a prophylactic HCV vaccine. Hide abstract
Recent advances in sequencing technologies have greatly enhanced our abilities to identify novel microbial sequences. Thus, our understanding of the global virome and the virome of specific host species in particular is rapidly expanding. Identification of animal viruses is important for understanding animal disease, the origin and evolution of human viruses, as well as zoonotic reservoirs for emerging infections. Although the human hepacivirus, hepatitis C virus (HCV), was identified 25years ago, its origin has remained elusive. In 2011, the first HCV homolog was reported in dogs but subsequent studies showed the virus to be widely distributed in horses. This indicated a wider hepacivirus host range and paved the way for identification of rodent, bat and non-human primate hepaciviruses. The equine non-primate hepacivirus (NPHV) remains the closest relative of HCV and is so far the best characterized. Identification and characterization of novel hepaciviruses may in addition lead to development of tractable animal models to study HCV persistence, immune responses and pathogenesis. This could be particular important, given the current shortage of immunocompetent models for robust HCV infection. Much remains to be learned on the novel hepaciviruses, including their association with disease, and thereby how relevant they will become as HCV model systems and for studies of animal disease. This review discusses how virome analysis led to identification of novel hepaci- and pegiviruses, their genetic relationship and characterization and the potential use of animal hepaciviruses as models to study hepaciviral infection, immunity and pathogenesis. This article forms part of a symposium in Antiviral Research on "Hepatitis C: Next steps toward global eradication." Hide abstract