A novel strategy for the therapeutic vaccination of hepatitis C Virus using adenoviral vectors
Lead Research Organisation:
University of Oxford
Department Name: Clinical Medicine
Abstract
Hepatitis C virus currently infects 180 million people world-wide and 1% of the population in the United Kingdom. The majority of people that become infected do not clear the virus from the body and approximately 20% of people will develop severe liver scarring (cirrhosis) and may require liver transplantation. One of the main reasons why people do not get rid of hepatitis C is that the immune system does not see and attack the virus.
The current best treatment is called combination therapy. This treatment has many side effects, involves weakly injections and has to be given for a year in many patients. At the end of this treatment less than half of patients get rid of the virus. Our aim is to develop a vaccine that is given to patients before or during combination therapy so that more patients will get rid of the virus. To do this we have developed a vaccine that we hope will stimulate the immune system of patients.
This vaccine is made from a part of the common cold virus-called adenovirus-and we have put a part of the hepatitis C virus into the cold virus. The adenovirus acts like a carrier to deliver the part of the hepatitis C virus and hopefully turn on the immune system. Importantly, the cold virus and the part of the hepatitis C virus have been altered to that they cannot replicate and themselves cause an infection. However, many people have previously been infected with the cold virus and because of this their immune system may try to attack our vaccine. To get around this problem we are going to use two unusual types of carrier cold vaccines that will not have infected people before. One of these is a cold virus that usually infects only chimpanzees. We are going to test these vaccines in 2007-2008 in people without hepatitis C. In this project we want to give these vaccines to patients with hepatitis C to see if we can turn on the immune system to attack the virus.
The current best treatment is called combination therapy. This treatment has many side effects, involves weakly injections and has to be given for a year in many patients. At the end of this treatment less than half of patients get rid of the virus. Our aim is to develop a vaccine that is given to patients before or during combination therapy so that more patients will get rid of the virus. To do this we have developed a vaccine that we hope will stimulate the immune system of patients.
This vaccine is made from a part of the common cold virus-called adenovirus-and we have put a part of the hepatitis C virus into the cold virus. The adenovirus acts like a carrier to deliver the part of the hepatitis C virus and hopefully turn on the immune system. Importantly, the cold virus and the part of the hepatitis C virus have been altered to that they cannot replicate and themselves cause an infection. However, many people have previously been infected with the cold virus and because of this their immune system may try to attack our vaccine. To get around this problem we are going to use two unusual types of carrier cold vaccines that will not have infected people before. One of these is a cold virus that usually infects only chimpanzees. We are going to test these vaccines in 2007-2008 in people without hepatitis C. In this project we want to give these vaccines to patients with hepatitis C to see if we can turn on the immune system to attack the virus.
Technical Summary
Introduction/aims: Hepatitis C virus (HCV) infection is a world-wide epidemic. HCV genotype-1 is the commonest genotype in the UK and is resistant to therapy with current gold-standard treatment, pegylated-interferon and ribavirin, in the majority of patients. This treatment is prolonged, expensive and unpleasant. HCV protease and polymerase inhibitors are in development, however early viral resistance and side-effects appear problematic. In patients who spontaneously eradicate virus, effective cellular immunity plays a crucial role, whereas in persistent infection HCV specific T-cell responses are weak. Our aim is to develop a safe, effective, therapeutic T-cell vaccine for HCV that will prime or boost antiviral T-cell responses. These may contribute to control of viremia. We hypothesise that this strategy may be more effective in the setting of a reduced viral load and anticipate that in the future this would be given before or in conjunction with HCV antivirals to improve sustained virological response rates.
Methodology/outcomes: In this proof of concept study our primary outcomes will be safety, tolerability and immunogenicity using adenoviral vectors in HCV infected patients with high and low viral loads. Effect on HCV viral load will be a secondary end-point. Adenoviral vectors are highly immunogenic but immunogenicity against the vectors is an issue. To circumvent this problem, we will use a human adenoviral vector rarely encountered (Ad6) and a simian adenoviral vector (AdCh3) in a heterologous prime/boost regimen. The immunogen will be the non-structural HCV proteins NS3-NS5b, genetically mutated to inactivate the HCV polymerase, encoding multiple CD4+ and CD8+ T-cell epitopes. We are currently testing this regimen in healthy volunteers.
Experimental design/techniques: Vaccination will comprise 2 priming injections 4 weeks apart followed by a boost 8 weeks later. We will perform a sequential dose escalation study in 2 groups of patients (i) low viral load patients: These will be 12 weeks into combination therapy and have a 2 log decline in HCV load, or undetectable HCV-RNA and (ii) high viral load patients: these will have untreated chronic infection. State of the art immunological techniques will assess the quantity and quality of HCV specific T-cell responses before and after vaccination. These include IFN-? ELISpot, HLA class-I and class-II tetramer technology, and multiparametric assessment of cytokine secretion.
Application/Exploitation: These aims will be achieved together with an industrial partner (Okairos). If proof of concept is demonstrated we will be in an excellent position to take this technology into clinical trials of efficacy.
Methodology/outcomes: In this proof of concept study our primary outcomes will be safety, tolerability and immunogenicity using adenoviral vectors in HCV infected patients with high and low viral loads. Effect on HCV viral load will be a secondary end-point. Adenoviral vectors are highly immunogenic but immunogenicity against the vectors is an issue. To circumvent this problem, we will use a human adenoviral vector rarely encountered (Ad6) and a simian adenoviral vector (AdCh3) in a heterologous prime/boost regimen. The immunogen will be the non-structural HCV proteins NS3-NS5b, genetically mutated to inactivate the HCV polymerase, encoding multiple CD4+ and CD8+ T-cell epitopes. We are currently testing this regimen in healthy volunteers.
Experimental design/techniques: Vaccination will comprise 2 priming injections 4 weeks apart followed by a boost 8 weeks later. We will perform a sequential dose escalation study in 2 groups of patients (i) low viral load patients: These will be 12 weeks into combination therapy and have a 2 log decline in HCV load, or undetectable HCV-RNA and (ii) high viral load patients: these will have untreated chronic infection. State of the art immunological techniques will assess the quantity and quality of HCV specific T-cell responses before and after vaccination. These include IFN-? ELISpot, HLA class-I and class-II tetramer technology, and multiparametric assessment of cytokine secretion.
Application/Exploitation: These aims will be achieved together with an industrial partner (Okairos). If proof of concept is demonstrated we will be in an excellent position to take this technology into clinical trials of efficacy.