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Title: Towards the development of a novel vaccine for Trichuris trichiura
Author: Zawawi, Ayat
ISNI:       0000 0004 9354 0582
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2019
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Trichuris trichiura (whipworm) is a soil-transmitted helminth parasite that affects around 500 million people worldwide, resulting in disability and poor child development, especially in areas of poor hygiene and sanitation. The ideal vaccine to protect against T. trichiura in humans would include protein epitopes that elicit a protective T helper cell type 2 immune response. Herein, we used bioinformatics tools to identify candidate histocompatibility complex class II (MHC-II) molecule T-cell epitopes from known Trichuris muris proteins selected using inclusion and exclusion criteria. T. muris is the murine whipworm that is closely related to the human pathogen making it a relevant model parasite. A number of prediction tools are available for the identification of peptides that bind to MHC-II molecules. The lack of standardised methodology and the difficulty of MHC-II epitope prediction make the selection of an appropriate prediction tool difficult. This study reports a systematic review to choose the most appropriate tools to predict MHC-II epitopes. Subsequently, up to fifteen epitopes were predicted, from the selected T. muris proteins and expressed on Hepatitis B core antigen virus-like particles VLP (HBc-Ag). VLPs expressing Trichuris MHC-II T-cell epitopes were tested in vitro to address whether they could activate and be taken up by antigen-presenting cells (APCs). VLPs expressing T-cell epitopes efficiently stimulated both antigen-presenting cells (dendritic cells and macrophages) to produce a broad range of pro-inflammatory and anti-inflammatory cytokines and were internalised and well co-localized in the lysosomes of both APCs. I also immunised mice with VLPs+ T-cell epitopes prior to infection with T. muris to test the protective immune response in vivo. Notably, upon challenge infection, mice vaccinated with the VLPs+ T-cell epitopes showed a significantly reduced worm burden in the caecum and colon. Immunisation of mice with VLPs+ T-cell epitopes followed by infection induced T. muris-specific IgM and IgG2c antibody responses. High levels of VLPs+ T-cell epitopes-specific IgM and IgG2c, were also induced after challenge infections. The protection of mice by VLPs+ T-cell epitopes was also characterised by the production of mesenteric lymph node (MLN)-derived Th2 cytokines. The predicted epitopes identified using the right combination of immunoinformatics and immunogenicity screening tools have the potential to bring T. trichiura to a vaccine trial.
Supervisor: Derrick, Jeremy ; Brass, Andrew ; Else, Kathryn Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: VLP-based vaccine ; Trichuris trichiura