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

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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.