Possible Hepatitis C Vaccine
Hepatitis C Virus (HCV) infects up to 500,000 people in the UK alone, many of the infections going undiagnosed. It is the single biggest cause of people requiring a liver transplant in Britain. Now scientists have found monoclonal antibodies which may make a successful vaccine a reality.
Hepatitis treatment is expensive and only successful in half of patients. Untreated or unresponsive patients can go on to develop cirrhosis of the liver, with life affecting consequences or the need for a transplant.
In a collaborative effort with groups across Europe and the USA, scientists from Nottingham University have recently identified antibodies that can successfully prevent infection with many diverse strains of Hepatitis C virus in laboratory models.
“The clinical potential of this work cannot be overstated. Historically, successful vaccines against viruses have required the production of antibodies, and this is likely to be the case for Hepatitis C virus”, says Dr Alexander Tarr from the Virus Research Group at the University of Nottingham. “Identifying regions of the virus that are able to induce broadly reactive neutralising antibodies is a significant milestone in the development of a HCV vaccine, which will have distinct healthcare benefits for hepatitis sufferers, and could also help us design vaccines for other chronic viral diseases such as HIV.”
Hepatitis C virus infects 180 million people worldwide. Infection with the virus can lead to liver cancer, and is the most common reason for liver transplantation in both the UK and the USA.
“We are also currently exploring the possibility of improving liver transplantation success rates by passively infusing people with these antibodies” says Dr Tarr. “We are also using the information gained by identifying and characterising the antibody responses to Hepatitis C virus to design new ways of making vaccine candidates. If the antibodies we have discovered can be reproduced by vaccination, control of the disease might be possible.”
‘Human antibodies to Hepatitis C virus – potential for vaccine design’ presented at 1615 on Tuesday 04 September 2007 in the Young Microbiologist of the Year Competition of the 161st Meeting of the Society for General Microbiology at the University of Edinburgh, 03 – 06 September 2007 – no abstract available yet on the site of the Society for General Microbiology.
J Gen Virol. 2007 Feb;88(Pt 2):458-69.
Cross-genotype characterization of genetic diversity and molecular adaptation in hepatitis C virus envelope glycoprotein genes.
Brown RJ, Tarr AW, McClure CP, Juttla VS, Tagiuri N, Irving WL, Ball JK.
The University of Nottingham, Institute of Infection, Immunity and Inflammation, School of Molecular Medical Sciences, Division of Microbiology and Infectious Diseases, Queens Medical Centre, West Block, Nottingham, UK. firstname.lastname@example.org
Investigation of the mechanisms underlying hepatitis C virus (HCV) envelope glycoprotein gene evolution will greatly assist rational development of broadly neutralizing antibody-based vaccines or vaccine components. Previously, comprehensive cross-genotype evolutionary studies of E1E2 have not been possible due to the paucity of full-length envelope gene sequences representative of all major HCV genotypes (1-6) deposited in international sequence databases. To address this shortfall, a full-length E1E2 clone panel, corresponding to genotypes of HCV that were previously under-represented, was generated. This panel, coupled with divergent isolates available via international sequence databases, was subjected to high-resolution methods for determining codon-substitution patterns, enabling a fine-scale dissection of the selective pressures operating on HCV E1E2. Whilst no evidence for positive selection was observed in E1, the E2 protein contained a number of sites under strong positive selection. A high proportion of these sites were located within the first hypervariable region (HVR1), and statistical analysis revealed that cross-genotype adaptive mutations were restricted to a subset of homologous positions within this region. Importantly, downstream of HVR1, a differential genotype-specific distribution of adaptive mutations was observed, suggesting that subtly different evolutionary pressures shape present-day genotype diversity in E2 outside HVR1. Despite these observations, it is demonstrated that purifying selection due to functional constraint is the major evolutionary force acting on HCV E1E2. These findings are important in the context of neutralizing-antibody vaccine targeting, as well as in contributing to our understanding of E1E2 function.
Methods Mol Biol. 2007;379:177-97.
Cloning, expression, and functional analysis of patient-derived hepatitis C virus glycoproteins.
Tarr AW, Owsianka AM, Szwejk A, Ball JK, Patel AH.
The Institute of Infection, Immunity, and Inflammation, School of Molecular Medical Sciences, The University of Nottingham, Queen’s Medical Centre, UK.
Hepatitis C virus (HCV) infection is a major cause of severe chronic liver disease including cirrhosis and hepatocellular carcinoma. HCV has been classified into six major genotypes that exhibit extensive genetic variability, particularly in the envelope glycoproteins E1 and E2. Knowledge of genotypic and quasispecies variation on viral glycoprotein properties is important in understanding the structure-function relationship of the proteins. Through their perceived role as components of the virion and mediators of virus attachment and entry, HCV glycoproteins are primary targets for the development of antiviral agents. In this chapter, we describe methods optimized to extract E1E2-encoding sequences of all the major genotypes from HCV-infected patient sera, and their amplification, cloning, expression, and biochemical characterization. Furthermore, we describe a method to generate retroviral nucleocapsid pseudotyped with HCV E1E2 of diverse genotypes (HCVpp) whereby infectivity of the retroviral particle is conferred by HCV glycoproteins. Finally, we show how the HCVpp can be used in an infection assay to determine the viral glycoprotein function at the level of the host-pathogen interface and subsequent events leading to virus infection.