Abstract

Trichuriasis is one of the most common neglected tropical diseases of the world’s poorest people. A recombinant vaccine composed of Tm-WAP49, an immunodominant antigen secreted by adult Trichuris stichocytes into the mucosa of the cecum to which the parasite attaches, is under development. The prototype is being evaluated in a mouse model of Trichuris muris infection, with the ultimate goal of producing a mucosal vaccine through intranasal delivery. Intranasal immunization of mice with Tm-WAP49 formulated with the adjuvant OCH, a truncated analog of alpha-GalCer with adjuvanticity to stimulate natural killer T cells (NKT) and mucosal immunity, induced significantly high levels of IgG and its subclasses (IgG1 and IgG2a) in immunized mice. This also resulted in a significant reduction of worm burden after challenge with T. muris-infective eggs. The addition of QS-21 adjuvant to this vaccine formulation further reduced worm counts. The improved protection from the dual-adjuvanted vaccine correlated with higher serum antibody responses (IgG, IgG1, IgG2a, IgA) as well as with the induction of antigen-specific IgA in the nasal mucosa. It was also associated with the robust cellular responses including functional subsets of CD4 T cells producing IL-4, and cytotoxic CD8 T cells expressing granzyme B. The worm reduction achieved by mucosal immunization was higher than that induced by subcutaneous immunization. Intranasal immunization also induced a significantly higher nasal mucosa-secreted antigen-specific IgA response, as well as higher functional cellular responses including CD4+IL4+ (Th1) and CD8+GnzB+ (Th2) T cells, and antigen-specific INFγ-producing T cells in both spleen and MLNs and antibody-producing B cells (CD19+B220+/B220+GL7+). Mucosal immunization further induced long-term T lymphocyte memory with increased central (CD62L+CD44+) and effector (CD62L-CD44+) memory subsets of both CD4 and CD8 T cells at 60 days after the last immunization. In summary, intranasal immunization with recombinant Tm-WAP49 protein induced strong protection versus murine trichuriasis. It represents a promising vaccination approach against intestinal nematodes.

Highlights

  • Trichuriasis, caused by the infection with the gastrointestinal nematode Trichuris trichiura, is one of the most common neglected tropical diseases

  • To determine the protective immunity induced by intranasal immunization with rTm-WAP49, in the first trial, mice were immunized intranasally with rTm-WAP49 formulated with OCH, or with OCH and QS-21

  • The results showed that mice immunized intranasally with rTm-WAP49 formulated with OCH produced 30.9% worm reduction compared to control mice that had received OCH only (p < 0.05), while mice immunized with rTm-WAP49 formulated with OCH/QS-21 produced a significantly higher worm reduction rate (35.6%) over the dual-adjuvanted control group (p < 0.05, Figure 1)

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Summary

Introduction

Trichuriasis, caused by the infection with the gastrointestinal nematode Trichuris trichiura (human whipworm), is one of the most common neglected tropical diseases. The highest prevalence rates of infection occur in resource-poor regions of Southeast Asia, Sub-Saharan Africa, and the tropical regions of the Americas, where children carry the largest burden of T. trichiura infections [4, 7, 8]. Most of these parasitized children are coinfected with other soiltransmitted helminths (STHs), further negatively impacting growth and cognitive development [9, 10]

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