Immunity in the face of diversity and the development of novel potent HCV vaccines

The aim of this research is to develop new vaccines against hepatitis C virus (HCV) infection. Importantly, our new vaccines will be effective against different strains of the virus. This is urgently needed as the global burden of HCV infection is immense with 180 million people infected world wide. Within the United Kingdom (UK) 300,000 people are infected. This may lead to liver scarring that progresses to cirrhosis, liver failure and liver cancer. HCV is now the most common reason for liver transplantation in the UK. There is currently no vaccine for either the prevention or the treatment of HCV, and the best available drug treatments are expensive, fraught with side effects, prolonged and frequently ineffective. New drug therapies are on the horizon, but these are only effective against some strains, may be associated with viral resistance, and do not protect against re-infection.

Over centuries, HCV has evolved so that there are now 7 different major viral strains (genotypes) located in particular regions of the world. However, even within a single person, HCV exists as a swarm of closely related but different viruses. Within the UK the two major strains are genotype-1 and genotype-3. The equal prevalence of two genotypes within a country is a unique and special feature of the HCV epidemic in the UK. However, some parts of the virus are the same between strains -these are known as conserved regions. These regions may be the "Achilles heel" of the virus, since a vaccine that effectively targets conserved regions may protect against multiple strains.

So far, we have developed a vaccine that we believe will protect against genotype-1 infection. The vaccine works by stimulating the immune system to make very high number of T cells that attack multiple parts of the virus. We know that T cells are important, since our earlier work showed that these cells are crucial in clearing HCV naturally after infection. Our vaccine is also able to stimulate immune responses in people that are already infected -although responses are weaker in this situation. In this way we hope to use the vaccine to both prevent and eradicate established infection.

Now we plan to improve our T cell vaccine so that it works against different strains -and especially against both genotypes 1 and 3 in the UK. We will design the vaccine so that the T cells generated by the vaccine target regions that are conserved between viral regions. Once we have developed this, we can test and use the new vaccine in the UK where both genotypes-1 and -3 circulate. We also want to understand why some people respond better than others to vaccination. In addition, whilst we know a lot about the immune system and how it clears genotype-1 virus, we know very little about it clears genotype-3 virus. Understanding these things will allow us to develop new strategies to improve vaccines against HCV. The lessons that we learn in designing a T cell vaccine that is effective against multiple viral strains may also prove useful in combating other variable viruses like HIV and HBV.

The research is being carried out by Dr. Ellie Barnes (Oxford University). She is collaborating closely with Okairos, a biotechnology company based in Italy, and several investigators from around the world. These collaborations draw together experts in the biology of T cells, vaccinology, and viral sequence analysis and uses new technologies to characterise T cells in great detail. We plan to use blood samples that we have collected from people who have been vaccinated with our vaccines to understand why some people respond better than others. We will design new vaccines against the conserved regions of multiple HCV strains using a database of thousands of HCV sequences that has been developed over the last decade. In this way we will develop a T cell vaccine against HCV that can be used throughout the world and prevent one of the major causes of liver disease.

The long term goal is to develop effective T cell vaccines to tackle hepatitis C virus (HCV) diversity. HCV exists globally as seven major genotypes, multiple subtypes and swarms of variants within each host. Within the UK genotype-1 and subtype-3a are equally prevalent - a unique feature of the epidemic.

To date I have, in collaboration, developed a highly immunogenic HCV T cell vaccine in healthy volunteers. This consists of simian and human adenoviral (Ad) vectors derived from rare serotypes, in addition to Modified Vaccinia Ankara (MVA) vectors, used in heterologous prime/boost regimens. Both vectors encode the entire non-structural (NS) genotype-1b HCV proteins (1995 amino-acids) Significant immunogenicity is also induced in HCV infected patients, though the mean magnitude of the response is lower.

My aims are to identify the determinants of the relative immune non-responsiveness in HCV infected patients. This will be achieved through the detailed characterisation of innate RNA signatures and adaptive T cell immunity, at baseline and in response to vaccination, in association with viral sequence analysis. This will give insight into the mechanism of T cell non-responsiveness that is the hallmark of many persistent viral infections. I will assess the immune correlates of viral clearance in HCV subtype-3a infection through the assessment of T and B cell immunity in natural infection. This will aid the rational design of effective UK HCV vaccines. Finally I will design a prophylactic vaccine for "broad" HCV coverage based on conserved peptide fragments. This will be delivered through the generation of a global relative prevalence HCV subtype dataset, and the "virtual" design of novel immunogens through computer algorithms that interrogate the dataset. Vaccines encoding the novel immunogens will be assessed in pre-clinical models.

Delivering these aims will facilitate the rational development of novel HCV vaccines within the UK and globally.

Beneficiaries of the proposed research;
The ultimate aim is to develop a prophylactic and therapeutic HCV vaccine that is effective against multiple viral genotypes. This is highly relevant to the UK population that are infected with both subtype-3a and genotype-1, but potential beneficiaries include people globally at risk of HCV (health care workers, intravenous drug users, renal dialysis patients, those living in high HCV prevalence countries, people with HIV, and partners and children of people with HCV) and people with HCV. Major objectives are to understand why people with HCV infection have an attenuated response to potent T cell vaccines, and to develop an effective strategy to tackle viral variability. Achieving these objectives, may protect people from other persistent viruses (HIV and HBV), other variable pathogens (e.g. Dengue), and other diseases where T cells are attenuated in the face of prolonged antigen exposure-such as cancer.

The generation of the first effective T cell vaccine would drive the commercial and academic sectors that manufacture viral vectors (IDT Germany, CBF, Oxford UK), and who are striving to develop T cell vaccines against a range of pathogens (e.g. RDT-malaria; Okairos-HCV, HIV, malaria and RSV). A successful HCV vaccine would also significantly impact upon public health policy decisions both nationally and globally.
Societal impacts; The work could be enormously beneficial to health and quality of life globally. HCV currently infects 180 million people worldwide and 4 million people are newly infected annually. Within the UK 0.4% of the population are infected, whilst in other countries the prevalence increases to 10-30% (Egypt and parts of Asia). Many of the people susceptible to HCV exist within vulnerable sectors of society and developing countries, where treatment with current therapies is not an option.

HIV infected people in particular would benefit from an effective HCV vaccine. By the end of 2010, there were 2.3 million HIV+ people in Europe, of whom over half were co-infected with HCV (WHO data 2011). HCV infection in HIV+ people is associated with an increased risk of developing chronic HCV infection and rapidly progressive liver fibrosis, and is the commonest cause of death in HIV+ people on HAART. Furthermore, there are currently epidemic outbreaks of acute HCV infection in multiple major European cities in men who have sex with men highlighting the failure of preventative measures aimed at changing behaviour.

New protease inhibitors for HCV represent a major breakthrough in the field, increasing viral clearance rates to 70% for genotype-1. However, these will be ineffective in the 50% of the UK population with genotype-3 infection, and will inevitably be associated with the development of drug resistance. New oral agents currently in development should be available in the future to treat other viral genotypes-but the costs will be prohibitive for the majority. As an analogy, we have had effective treatments with HAART for HIV for over a decade, and yet millions of people around the world have no access to these drugs.

Enhancing economic prosperity;
T cell vaccine technologies are highly competitive at an international level within the UK. The development of the first effective T cell vaccine would place the UK at the forefront of the field. This would increase UK economic prosperity through the commercialisation and exploitation of novel vaccines, and would increase innovative research capacity within academic organisations that seek to develop T cells strategies to combat disease.

Direct economic savings can also be anticipated since the cost of protease inhibitors is £18,000-£32,000/treatment course. Treatment of only 1% of those currently infected within the UK with these therapies will cost the UK £75 million.

Realistic time-scales for the benefits to be realised are 5-10 years.