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

这项研究的目的是开发新的丙型肝炎病毒感染疫苗。重要的是，我们的新疫苗将对不同的病毒株有效。这是迫切需要的，因为全球丙型肝炎病毒感染的负担是巨大的，全世界有1.8亿人感染。在英国(UK)，有30万人感染。这可能会导致肝脏结疤，进而发展为肝硬化、肝功能衰竭和肝癌。丙型肝炎病毒现在是英国肝移植最常见的原因。目前，无论是预防还是治疗丙型肝炎都没有疫苗，最好的药物治疗都很昂贵，充满副作用，持续时间长，而且往往无效。新的药物疗法即将问世，但这些疗法只对某些毒株有效，可能与病毒耐药性有关，并不能预防再次感染。几个世纪以来，丙型肝炎病毒已经进化成现在世界上特定地区有7种不同的主要病毒株(基因类型)。然而，即使在一个人体内，丙型肝炎病毒也是以一群密切相关但不同的病毒存在的。在英国，两种主要的毒株是基因1型和基因3型。在一个国家内，两种基因型的平等流行是英国丙型肝炎疫情的一个独特和特殊的特征。然而，病毒的某些部分在不同毒株之间是相同的--这些部分被称为保守区。这些区域可能是病毒的“阿喀琉斯之踵”，因为一种有效针对保守区域的疫苗可能会预防多种毒株。到目前为止，我们已经开发出一种疫苗，我们相信这种疫苗将保护人们免受1型基因感染。疫苗的工作原理是刺激免疫系统产生非常高数量的T细胞，这些T细胞可以攻击病毒的多个部分。我们知道T细胞很重要，因为我们早期的工作表明，这些细胞在感染后自然清除丙型肝炎病毒方面至关重要。我们的疫苗还能够刺激已经感染的人的免疫反应--尽管在这种情况下反应较弱。通过这种方式，我们希望使用疫苗来预防和根除既定的感染。现在，我们计划改进我们的T细胞疫苗，使其对不同的菌株起作用--特别是对英国的1号和3号基因。我们将设计疫苗，使疫苗产生的T细胞针对病毒区域之间保守的区域。一旦我们开发出这种疫苗，我们就可以在英国测试和使用这种新疫苗，因为英国同时存在-1和-3两种基因。我们还想了解为什么有些人对疫苗的反应比其他人更好。此外，虽然我们知道很多关于免疫系统以及它如何清除1型病毒的知识，但我们对免疫系统清除3型病毒知之甚少。了解这些情况将使我们能够开发新的策略来改进针对丙型肝炎病毒的疫苗。我们在设计一种对多种病毒株有效的T细胞疫苗方面所学到的教训，也可能被证明对对抗其他可变病毒，如艾滋病毒和乙肝病毒有用。这项研究是由牛津大学的Ellie Barnes博士进行的。她正在与总部位于意大利的生物技术公司Okairos以及来自世界各地的几名调查人员密切合作。这些合作汇集了T细胞生物学、疫苗学和病毒序列分析方面的专家，并使用新技术来非常详细地描述T细胞的特征。我们计划使用从接种了我们疫苗的人身上收集的血液样本来了解为什么有些人的反应比其他人更好。我们将利用过去十年开发的数千个丙型肝炎病毒序列的数据库，针对多种丙型肝炎病毒株的保守区设计新的疫苗。通过这种方式，我们将开发一种针对丙型肝炎病毒的T细胞疫苗，这种疫苗可以在世界各地使用，并预防肝病的主要原因之一。

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.