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

本研究的目的是开发新的丙型肝炎病毒（HCV）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，因为丙型肝炎病毒感染的全球负担是巨大的，全世界有1.8亿人感染。在联合王国，有30万人受到感染。这可能会导致肝脏疤痕，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最常见的肝移植原因。目前还没有预防或治疗丙肝病毒的疫苗，现有的最佳药物治疗价格昂贵，充满副作用，治疗时间长，而且往往无效。新的药物疗法即将出现，但这些疗法只对某些毒株有效，可能与病毒耐药性有关，而且不能防止再次感染。几个世纪以来，丙型肝炎病毒已经进化，现在有7种不同的主要病毒株（基因型）分布在世界的特定区域。然而，即使在一个人体内，丙型肝炎病毒也以一群密切相关但不同的病毒的形式存在。在英国，两种主要的菌株是基因1型和基因3型。在一个国家内两种基因型的同等流行是HCV在英国流行的一个独特和特殊的特征。然而，病毒的某些部分在毒株之间是相同的——这些被称为保守区域。这些区域可能是病毒的“阿喀琉斯之踵”，因为有效地针对保守区域的疫苗可以保护免受多种毒株的侵害。到目前为止，我们已经开发出一种疫苗，我们相信它可以防止基因1型感染。这种疫苗通过刺激免疫系统产生大量的T细胞来攻击病毒的多个部位。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HCV至关重要。我们的疫苗也能够刺激已经感染的人的免疫反应，尽管这种情况下的反应较弱。通过这种方式，我们希望使用疫苗来预防和根除既定感染。现在我们计划改进我们的T细胞疫苗，使其能够对抗不同的毒株，尤其是在英国对抗基因1型和基因3型。我们将设计疫苗，使疫苗产生的T细胞靶向在病毒区域之间保守的区域。一旦我们开发出这种疫苗，我们就可以在基因型1和基因型3都流行的英国测试和使用这种新疫苗。我们还想了解为什么有些人对疫苗的反应比其他人好。此外，虽然我们对免疫系统以及它如何清除基因1型病毒了解很多，但我们对它如何清除基因3型病毒知之甚少。了解这些情况将使我们能够制定新的战略来改进丙肝病毒疫苗。我们在设计一种对多种病毒株有效的T细胞疫苗的过程中吸取的经验教训，也可能被证明对对抗艾滋病毒和乙型肝炎病毒等其他可变病毒有用。这项研究由埃莉·巴恩斯博士（牛津大学）进行。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研究人员密切合作。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，并使用新技术详细描述T细胞的特征。我们计划使用从接种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好。我们将利用过去十年中开发的数千种HCV序列数据库，针对多种HCV毒株的保守区域设计新的疫苗。通过这种方式，我们将开发出一种针对丙肝病毒的T细胞疫苗，可以在全世界范围内使用，并预防肝脏疾病的主要原因之一。

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.