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

Abstract

Trichuriasis is a disease that affects ~465 million people worldwide caused by the intestinal dwelling parasite T. trichiura, colloquially known as the human whipworm. The anthelmintic drugs currently employed as the primary treatment against T. trichiura have limited efficacy in the field and thus novel treatments are urgently required. No licensed vaccines against T. trichiura exist. However, an anti-Trichuris vaccine candidate developed by Zawawi et al., 2020 comprised of a cocktail of virus-like particles (VLPs) expressing MHC-II T cell epitopes derived from Trichuris displayed partial protection against Trichuris spp. using the T. muris mouse model of the parasitic disease, representing the most effective anti-Trichuris vaccine candidate to date. In the PhD project, two of the four VLP anti-Trichuris vaccine candidates created by Zawawi et al. 2020 were reproduced and modified to express the P2 Tetanus epitope. However, the reproduced and modified vaccine candidates did not impart any protection against T. muris in vivo. Although the vaccine candidates did elicit robust humoral immunity against the target T cell epitopes, this did not translate into protection against T. muris. Furthermore, incorporation of the P2 Tetanus epitope into the vaccine candidates enabled them to exploit immunological memory of the tetanus toxoid to boost immune responses against T cell epitope targets. This project also investigated potential obstacles to an anti-Trichuris vaccine in the field. Vaccination with T. muris ES, considered the gold standard for vaccination in the T. muris mouse model was incapable of clearing an already established low dose T. muris infection in C57BL/6 mice. If this finding is translatable to the human version of the disease it should inform the future vaccination policy of novel anti-Trichuris vaccine candidates applied to the field. Finally, the project examined the use of a peptide microarray to screen sera from a wide range of laboratory mice and wild mice, exposed to T. muris infection or T. muris ES vaccination, and baboons infected with T. trichiura. The peptide microarray was designed from Trichuris antigens currently being investigated as potential vaccine candidates, providing researchers with the ability to investigate humoral immune responses against Trichuris antigens of interest across host species in unprecedented detail. Interestingly, both laboratory and wild mice susceptible to T. muris infection exhibited greater IgG reactivity against the Trichuris antigens of interest than their resistant counterparts, suggesting that to create effective anti-Trichuris vaccines new Trichuris antigens may have to be discovered that are not currently being investigated.

Date of Award	3 Feb 2025
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Kathryn Else (Main Supervisor) & Jeremy Derrick (Co Supervisor)