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

面对多样性的免疫和新型强效丙型肝炎疫苗的开发

• 批准号: MR/K010239/1
• 负责人: Eleanor Barnes
• 金额: $ 175.17万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FK010239%2F1
• 关键词: Immunity; face; diversity; development; novel

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.

本研究的目的是开发针对丙型肝炎病毒（HCV）感染的新疫苗。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HCV感染的全球负担是巨大的，全世界有1.8亿人感染。在英国，有30万人受到感染。这可能会导致肝瘢痕形成，进而发展为肝硬化、肝衰竭和肝癌。HCV现在是英国肝移植最常见的原因。目前还没有预防或治疗HCV的疫苗，并且最好的药物治疗昂贵，充满副作用，长期且经常无效。新的药物疗法即将出现，但这些药物仅对某些毒株有效，可能与病毒耐药性有关，并且不能防止再次感染。几个世纪以来，HCV已经进化到现在有7种不同的主要病毒株（基因型）位于世界特定地区。然而，即使在一个人体内，HCV也是作为一群密切相关但不同的病毒存在的。在英国，两种主要的菌株是基因型-1和基因型-3。一个国家内两种基因型的平均患病率是英国HCV流行的独特和特殊特征。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。这些区域可能是病毒的“阿喀琉斯之踵”，因为有效靶向保守区域的疫苗可能会保护多个毒株。到目前为止，我们已经开发出一种疫苗，我们相信它会保护免受基因型1感染。该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HCV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。我们希望通过这种方式使用疫苗来预防和根除已建立的感染。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菌株，特别是英国的基因型1和3。我们将设计疫苗，使疫苗产生的T细胞靶向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，在英国，基因型1和基因型3都在流行。我们还想了解为什么有些人对疫苗接种的反应比其他人好。此外，虽然我们对免疫系统以及它如何清除基因型1病毒了解很多，但我们对它清除基因型3病毒知之甚少。了解这些事情将使我们能够开发新的策略来改进针对HCV的疫苗。我们在设计一种有效对抗多种病毒株的T细胞疫苗时学到的经验教训也可能被证明对对抗其他可变病毒如HIV和HBV有用。这项研究是由埃莉巴恩斯博士（牛津大学）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位调查人员密切合作。这些合作将T细胞生物学、疫苗学和病毒序列分析方面的专家聚集在一起，并使用新技术来详细研究T细胞。我们计划使用我们从接种过我们疫苗的人那里收集的血液样本来了解为什么有些人的反应比其他人好。我们将使用过去十年开发的数千个HCV序列的数据库，针对多种HCV毒株的保守区域设计新疫苗。通过这种方式，我们将开发出一种抗HCV的T细胞疫苗，可以在世界各地使用，并预防肝脏疾病的主要原因之一。

项目成果

Hepatitis virus (HCV) diagnosis and access to treatment in a UK cohort.

• DOI: 10.1186/s12879-018-3367-3
• 发表时间: 2018-09-14
• 期刊: BMC infectious diseases
• 影响因子: 3.7
• 作者: Adland E;Jesuthasan G;Downs L;Wharton V;Wilde G;McNaughton AL;Collier J;Barnes E;Klenerman P;Andersson M;Jeffery K;Matthews PC
• 通讯作者: Matthews PC

Multiparametric magnetic resonance for the non-invasive diagnosis of liver disease.

• DOI: 10.1016/j.jhep.2013.09.002
• 发表时间: 2014-01
• 期刊: JOURNAL OF HEPATOLOGY
• 影响因子: 25.7
• 作者: Banerjee, Rajarshi;Pavlides, Michael;Tunnicliffe, Elizabeth M.;Piechnik, Stefan K.;Sarania, Nikita;Philips, Rachel;Collier, Jane D.;Booth, Jonathan C.;Schneider, Jurgen E.;Wang, Lai Mun;Delaney, David W.;Fleming, Ken A.;Robson, Matthew D.;Barnes, Eleanor;Neubauer, Stefan
• 通讯作者: Neubauer, Stefan

A modified RNA-Seq approach for whole genome sequencing of RNA viruses from faecal and blood samples.

• DOI: 10.1371/journal.pone.0066129
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Batty EM;Wong TH;Trebes A;Argoud K;Attar M;Buck D;Ip CL;Golubchik T;Cule M;Bowden R;Manganis C;Klenerman P;Barnes E;Walker AS;Wyllie DH;Wilson DJ;Dingle KE;Peto TE;Crook DW;Piazza P
• 通讯作者: Piazza P

Adenoviral Vector Vaccination Induces a Conserved Program of CD8(+) T Cell Memory Differentiation in Mouse and Man.

• DOI: 10.1016/j.celrep.2015.10.034
• 发表时间: 2015-11-24
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Bolinger B;Sims S;Swadling L;O'Hara G;de Lara C;Baban D;Saghal N;Lee LN;Marchi E;Davis M;Newell E;Capone S;Folgori A;Barnes E;Klenerman P
• 通讯作者: Klenerman P

Therapeutic vaccines in HBV: lessons from HCV.

• DOI: 10.1007/s00430-014-0376-8
• 发表时间: 2015-02
• 期刊: Medical microbiology and immunology
• 影响因子: 5.4
• 作者: Barnes E