Developing a whipworm vaccine composed of virus-like particles expressing Trichuris T cell epitopes.

开发由表达鞭虫 T 细胞表位的病毒样颗粒组成的鞭虫疫苗。

• 批准号: 2442380
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2442380
• 关键词: Developing; whipworm; vaccine; composed; virus

Vaccination is one of the greatest advances in global health; however most successful vaccines have been made empirically. In the context of basic bioscience, we still have little insight into how many vaccines work and the mechanisms by which they trigger protective immune responses. Antigen delivery to the right antigen presenting cell is critically important for the quality of the T cell response. However targeting of specific antigen presenting cell populations is often ignored in vaccine design. Trichuris trichiura (whipworm) is a soil transmitted helminth parasite that affects around 500 million people worldwide. Infection is common especially in areas of poor hygiene and sanitation and results in morbidity and poor child development. The ideal vaccine to protect against T. trichiura in humans would include protein epitopes that elicit a T helper 2 cell immune response. This multidisciplinary project will use a novel, module-based technology which combines specific antigens with monoclonal antibodies targeting specific receptors on DCs, on a modified Virus Like Particle (VLP) platform. These modified VLPs will provide an experimental system enabling vaccines to be targeted to the right antigen presenting cell population in order to stimulate effective T cell responses against this gut-dwelling nematode parasite. Using the mouse model of human trichuriasis, we will immunize mice with T cell epitopes expressed on the modified VLPs, or synthetic proteins generated from multiple T cell epitopes, and infect with T. muris, to test their ability to prime for a protective immune response in vivo. Adding a fluorescent tag to the VLPs will enable tracking in vivo which, in combination with multi-colour flow cytometry, will allow the identification of the type of antigen presenting cell targeted. OBJECTIVES:2. 1. To evaluate the cellular targeting of VLPs carrying CD4+ T cell epitopes in vivo. Fluorescently labelled VLPs will be injected subcutaneously and tracked in vivo. This will allow an assessment of the internalisation of antigen by different antigen presenting cells (dendritic cells, macrophages, B cells) in the draining lymph nodes. 2. To assess the ability of VLPs carrying CD4+ T cell epitopes to prime for protective immune responses against Trichuris muris in vivo. VLPs bearing CD4+ T cell epitopes or synthetic proteins derived from Trichuris antigens, will be delivered in vivo and the host challenged with Trichuris. Protection from infection will be monitored by a reduction in worms and the quality of the cellular immune response. High dose AKR infections and low dose C57BL6 infections will be used to model human trichuriasis. 3. To improve vaccine efficacy by modifying the novel antigen delivery system using a VLP - protein A fusion platform which allows targeting of antigen to dendritic cells. We will incorporate dendritic cell (DC)-targeting antibodies into the VLP platform and test DC-specific delivery both in vitro and in vivo. Collectively we present an innovative proposal that combines the use of modified VLPs to present multiple antigens, with the ability to induce potent immune responses and protection from infection in vivo, and one that thus aligns well with the BBSRC vision of world class underpinning bioscience.

疫苗接种是全球卫生领域最大的进步之一;然而，大多数成功的疫苗都是经验性的。在基础生物科学的背景下，我们仍然对有多少疫苗起作用以及它们触发保护性免疫反应的机制知之甚少。将抗原递送至正确的抗原呈递细胞对于T细胞应答的质量至关重要。然而，靶向特异性抗原呈递细胞群体在疫苗设计中经常被忽视。鞭虫（鞭虫）是一种土壤传播的蠕虫寄生虫，影响全球约5亿人。感染很常见，特别是在卫生条件差的地区，导致发病和儿童发育不良。预防T.人类中的鞭毛虫将包括引发T辅助2细胞免疫应答的蛋白质表位。这个多学科项目将使用一种新的基于模块的技术，该技术将特异性抗原与靶向DC上特异性受体的单克隆抗体结合在一个改良的病毒样颗粒（VLP）平台上。这些修饰的VLP将提供一种实验系统，使疫苗能够靶向正确的抗原呈递细胞群，以刺激针对这种肠道寄生线虫寄生虫的有效T细胞应答。使用人鞭毛虫的小鼠模型，我们将用修饰的VLP上表达的T细胞表位或由多个T细胞表位产生的合成蛋白免疫小鼠，并用T.小鼠，以测试它们在体内引发保护性免疫应答的能力。将荧光标签添加到VLP将使得能够在体内跟踪，其与多色流式细胞术组合将允许鉴定靶向的抗原呈递细胞的类型。第二章：1.评价携带CD 4 + T细胞表位的VLP的体内细胞靶向性。将皮下注射荧光标记的VLP并在体内追踪。这将允许评估引流淋巴结中不同抗原呈递细胞（树突细胞、巨噬细胞、B细胞）对抗原的内化。2.评估携带CD 4 + T细胞表位的VLP在体内引发针对鼠鞭虫的保护性免疫应答的能力。携带CD 4 + T细胞表位或衍生自鞭虫抗原的合成蛋白的VLP将在体内递送，并用鞭虫攻击宿主。保护免受感染将通过蠕虫的减少和细胞免疫反应的质量来监测。高剂量AKR感染和低剂量C57 BL 6感染将用于模拟人鞭毛虫病。3.通过使用VLP -蛋白A融合平台修饰新型抗原递送系统来提高疫苗效力，该平台允许抗原靶向树突细胞。我们将把树突状细胞（DC）靶向抗体纳入VLP平台，并在体外和体内测试DC特异性递送。总的来说，我们提出了一个创新的建议，结合使用修饰的VLP来呈现多种抗原，能够诱导有效的免疫反应和保护免受体内感染，因此与BBSRC世界级基础生物科学的愿景保持一致。