MICA: Developmental Clinical Studies-a novel vaccine candidate MVA-NS for use in a prime boost schedule in HCV infection.
Lead Research Organisation:
University of Oxford
Department Name: Clinical Medicine
Abstract
Hepatitis C virus currently infects 180 million people world-wide and 0.5-1% 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 will prevent infection or that is given to patients during combination therapy so that more patients will get rid of the virus.
To date we have developed a vaccine that very successfully stimulates the immune system of healthy people against the HCV virus. This vaccine is made from a part of the common cold virus-an 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.
We have tried to increase the immune response further, by giving a second different but related adenoviral vaccine to the volunteers. However, we were unable to achieve this as antibodies to the first injection developed after vaccination and so prevented the second one from working (cross-reactive antibodies). We now wish to develop a vaccine vector (MVA) that is quite different from adenoviral vectors so that the problem of the cross reactivity will not occur. We wish to test this in a small number of healthy and HCV infected patients. In doing so, we believe we will successfully boost the immune response further, and so significantly increase the chances of preventing or curing HCV infection.
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 will prevent infection or that is given to patients during combination therapy so that more patients will get rid of the virus.
To date we have developed a vaccine that very successfully stimulates the immune system of healthy people against the HCV virus. This vaccine is made from a part of the common cold virus-an 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.
We have tried to increase the immune response further, by giving a second different but related adenoviral vaccine to the volunteers. However, we were unable to achieve this as antibodies to the first injection developed after vaccination and so prevented the second one from working (cross-reactive antibodies). We now wish to develop a vaccine vector (MVA) that is quite different from adenoviral vectors so that the problem of the cross reactivity will not occur. We wish to test this in a small number of healthy and HCV infected patients. In doing so, we believe we will successfully boost the immune response further, and so significantly increase the chances of preventing or curing HCV infection.
Technical Summary
The global burden of hepatitis C virus (HCV) infection is immense with 180 million people infected world-wide leading to liver fibrosis, cirrhosis, liver failure and hepatocellular cancer. There is currently no vaccine for either the prevention or the treatment of HCV, and the best available current treatments are expensive, unpleasant and frequently ineffective. HCV infection is particularly susceptible to a T-cell vaccination strategy since it has been clearly shown by our group and others that spontaneous viral clearance occurs following primary infection in 20% of individuals and is crucially dependent on the induction of a robust and durable CD4 and CD8+ T-cell response. This forms the scientific rationale for our overarching aim-the development of a prophylactic and therapeutic T-cell vaccine for HCV.
Since pre-existing anti-vector immunity may limit vaccine efficacy we have conducted a phase-I clinical trial in healthy human subjects using human (AdHu6) and simian (AdCh3) adenoviral vectors found at low sero-prevalence in human populations, in a heterologous prime/boost regimen. These encode the HCV non-structural proteins with a genetically inactivated polymerase gene (NS). We show that both vectors are safe and highly immunogenic following a single priming injection. In preclinical primate studies using identical vectors, heterologous boosting increased peak responses and long-term immunity. However, in humans it appears that although HCV specific T-cell responses increase following boosting, the magnitude of this response is significantly reduced compared to that observed during vaccine priming. This is due to the induction of cross-reactive immunity between the two vectors. In contrast, it has recently been shown that Modified Vaccinia Ankara (MVA) encoding the malaria antigen ME-TRAP very successfully boosts T-cell responses primed with a simian Adenovirus vector, inducing the highest level of CD4+ and CD8+ T-cell responses ever observed using a vectored vaccine and affording protection from malaria infection.
For these reasons we now wish to develop an MVA construct encoding NS. This will be combined with AdCh3NS in a heterologous prime/boost vaccination regimen and used to assess the safety and immunogenicity of this strategy in healthy and HCV infected patients. We believe that the development of an MVA-NS vector and Phase I testing of the Adeno/MVA regimen will allow a comparison of the two most promising vectored vaccine approaches to date and so enable a comprehensive and rational approach toward development of an effective vaccine for HCV prevention and cure.
Since pre-existing anti-vector immunity may limit vaccine efficacy we have conducted a phase-I clinical trial in healthy human subjects using human (AdHu6) and simian (AdCh3) adenoviral vectors found at low sero-prevalence in human populations, in a heterologous prime/boost regimen. These encode the HCV non-structural proteins with a genetically inactivated polymerase gene (NS). We show that both vectors are safe and highly immunogenic following a single priming injection. In preclinical primate studies using identical vectors, heterologous boosting increased peak responses and long-term immunity. However, in humans it appears that although HCV specific T-cell responses increase following boosting, the magnitude of this response is significantly reduced compared to that observed during vaccine priming. This is due to the induction of cross-reactive immunity between the two vectors. In contrast, it has recently been shown that Modified Vaccinia Ankara (MVA) encoding the malaria antigen ME-TRAP very successfully boosts T-cell responses primed with a simian Adenovirus vector, inducing the highest level of CD4+ and CD8+ T-cell responses ever observed using a vectored vaccine and affording protection from malaria infection.
For these reasons we now wish to develop an MVA construct encoding NS. This will be combined with AdCh3NS in a heterologous prime/boost vaccination regimen and used to assess the safety and immunogenicity of this strategy in healthy and HCV infected patients. We believe that the development of an MVA-NS vector and Phase I testing of the Adeno/MVA regimen will allow a comparison of the two most promising vectored vaccine approaches to date and so enable a comprehensive and rational approach toward development of an effective vaccine for HCV prevention and cure.