Abstract
Trichuris trichiura is a parasite that infects 500 million people worldwide, leading to colitis, growth retardation and Trichuris dysentery syndrome. There are no licensed vaccines available to prevent Trichuris infection and current treatments are of limited efficacy. Trichuris infections are linked to poverty, reducing children’s educational performance and the economic productivity of adults. We employed a systematic, multi-stage process to identify a candidate vaccine against trichuriasis based on the incorporation of selected T-cell epitopes into virus-like particles. We conducted a systematic review to identify the most appropriate in silico prediction tools to predict histocompatibility complex class II (MHC-II) molecule T-cell epitopes. These tools were used to identify candidate MHC-II epitopes from predicted ORFs in the Trichuris genome, selected using inclusion and exclusion criteria. Selected epitopes were incorporated into Hepatitis B core antigen virus-like particles (VLPs). Bone marrow-derived dendritic cells and bone marrow-derived macrophages responded in vitro to VLPs irrespective of whether the VLP also included T-cell epitopes. The VLPs were internalized and co-localized in the antigen presenting cell lysosomes. Upon challenge infection, mice vaccinated with the VLPs+T-cell epitopes showed a significantly reduced worm burden, and mounted Trichuris-specific IgM and IgG2c antibody responses. The protection of mice by VLPs+T-cell epitopes was characterised by the production of mesenteric lymph node (MLN)-derived Th2 cytokines and goblet cell hyperplasia. Collectively our data establishes that a combination of in silico genome-based CD4+ T-cell epitope prediction, combined with VLP delivery, offers a promising pipeline for the development of an effective, safe and affordable helminth vaccine.
Highlights
Trichuriasis, caused by the whipworm Trichuris trichiura, is one of the most widespread soiltransmitted helminths (STH) in the world [1]
The results suggest that a pipeline based on in silico prediction of potent MHC-II T-cell epitopes, followed by incorporation into virus-like particles (VLPs), could be a strategy which enables rapid translation into a vaccine against Trichuris trichiura
Based on a list of search terms (S1 Table) used on Google and other websites (S2 Table), 88 servers that predict T-cell epitopes based on MHC class I and II binding were identified (S3 Table)
Summary
Trichuriasis, caused by the whipworm Trichuris trichiura, is one of the most widespread soiltransmitted helminths (STH) in the world [1]. Using the mouse model of human trichuriasis, Trichuris muris excretory/secretory (ES) products [5], ES fractions [6], extracellular vesicles (EVs) [7], and, more recently, T. muris whey acidic protein [8] in the context of the adjuvant alum, have shown considerable potential in a number of pre-clinical protection trials. Despite these successes, developing a vaccine based on native antigens is associated with many manufacturing challenges, including cost, time consumption, difficulties in purifying large quantities of worm antigens and control over differences between batches [9, 10]. The reverse vaccinology (RV) approach combines genome information with immunological and bioinformatics tools to overcome some of the limitations of conventional methods of screening vaccine candidates [12,13,14]
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