Combined TLR7/8 and TLR9 Ligands Potentiate the Activity of a Schistosoma japonicum DNA Vaccine

Xuefeng Wang,Xiaojun Chen,Zhipeng Xu,Feng Liu,Liyang Dong,Qiaoyun Chen,Jason Shih Hoellwarth,Jun Wang,Hongchang Ni,Sha Zhou,Rongbo Zhang,Chuan Su,Malcolm K Jones

doi:10.1371/journal.pntd.0002164

Abstract

BackgroundToll-like receptor (TLR) ligands have been explored as vaccine adjuvants for tumor and virus immunotherapy, but few TLR ligands affecting schistosoma vaccines have been characterized. Previously, we developed a partially protective DNA vaccine encoding the 26-kDa glutathione S-transferase of Schistosoma japonicum (pVAX1-Sj26GST).Methodology/Principal FindingsIn this study, we evaluated a TLR7/8 ligand (R848) and a TLR9 ligand (CpG oligodeoxynucleotides, or CpG) as adjuvants for pVAX1-Sj26GST and assessed their effects on the immune system and protection against S. japonicum. We show that combining CpG and R848 with pVAX1-Sj26GST immunization significantly increases splenocyte proliferation and IgG and IgG2a levels, decreases CD4+CD25+Foxp3+ regulatory T cells (Treg) frequency in vivo, and enhances protection against S. japonicum. CpG and R848 inhibited Treg-mediated immunosuppression, upregulated the production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-4, IL-10, IL-2, and IL-6, and decreased Foxp3 expression in vitro, which may contribute to prevent Treg suppression and conversion during vaccination and allow expansion of antigen-specific T cells against pathogens.ConclusionsOur data shows that selective TLR ligands can increase the protective efficacy of DNA vaccines against schistosomiasis, potentially through combined antagonism of Treg-mediated immunosuppression and conversion.

Highlights

Schistosomiasis is regarded as one of the most neglected tropical diseases (NTDs) of high importance, and remains a major problem in public health in endemic countries [1,2]
Our data shows that selective Toll-like receptor (TLR) ligands can increase the protective efficacy of DNA vaccines against schistosomiasis, potentially through combined antagonism of Treg-mediated immunosuppression and conversion
Single CpG or R848 induced an increase in the CD4+CD25+ Treg population after vaccination (Figure 4). These results suggest that the combination of CpG and R848 might prevent the expansion of CD4+CD25+ Tregs and thereby improve the immune response and protection of pVAX1-Sj26GST vaccination

Summary

Introduction

Schistosomiasis is regarded as one of the most neglected tropical diseases (NTDs) of high importance, and remains a major problem in public health in endemic countries [1,2]. Schistosomiasis can be treated with the drug praziquantel [3], high reinfection rates limit its overall success, where repeated administering is often necessary multiple times during the first two decades [4,5]. Despite decades of effort developing vaccines against schistosoma, including Schistosoma japonicum (S. japonicum), the current schistosoma vaccine induces only limited protection for reasons that remain unclear. A potential issue limiting the immune response to vaccination is the presence of regulatory T cells (Tregs) that suppress T cell activation [8,9]. Multiple studies in mice have shown that Tregs dampen the immune response against pathogens, including S. japonicum [10,11]. We developed a partially protective DNA vaccine encoding the 26-kDa glutathione S-transferase of Schistosoma japonicum (pVAX1-Sj26GST)

Methods

Results

Discussion

Conclusion