Protection Against Helicobacter pylori Infection in BALB/c Mouse Model by Oral Administration of Multivalent Epitope-Based Vaccine of Cholera Toxin B Subunit-HUUC.

Xing Pan,Hong Ke,Xiaojuan Niu,Shan Li,Longrui Pan,Jun Lv

doi:10.3389/fimmu.2018.01003

Xing Pan, Hong Ke + Show 4 more

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https://doi.org/10.3389/fimmu.2018.01003

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Abstract

Vaccination is an increasingly important alternative approach to control Helicobacter pylori infection, since H. pylori resistance to previously efficacious antibiotic regimens is increased, and H. pylori eradication treatment for upper gastrointestinal diseases is becoming less successful. Fortunately, an efficient oral monovalent H. pylori vaccine has been developed. However, compared with monovalent vaccines, multivalent vaccines have the potential to induce more effective and comprehensive protection against H. pylori infection. In this study, we designed and produced a multivalent epitope-based vaccine cholera toxin B subunit (CTB)-HUUC with the intramucosal adjuvant CTB and tandem copies of B-cell epitopes (HpaA132-141, UreA183-203, and UreB321-339) and T-cell epitopes (HpaA88-100, UreA27-53, UreB229-251, UreB317-329, UreB373-385, UreB438-452, UreB546-561, CagA149-164, and CagA196-217) from H. pylori adhesion A subunit (HpaA), urease A subunit (UreA), urease B subunit (UreB), and cytotoxin-associated antigen (CagA). Serum IgG, stomach, and intestine mucosal sIgA from mice after CTB-HUUC vaccination neutralized H. pylori urease activity in vitro. CTB-HUUC vaccination promoted H. pylori-specific lymphocyte responses and a mixed CD4+ T cell immune response as indicated by IFN-γ, interleukin-4, and interleukin-17 production in mice. Both oral prophylactic and therapeutic CTB-HUUC vaccinations reduced gastric urease activity and H. pylori infection and protected stomachs in mice. Taken together, CTB-HUUC is a promising potent and safe multivalent vaccine in controlling H. pylori infection in BALB/c mouse model.

Highlights

Helicobacter pylori is the most important etiologic factor for upper gastrointestinal diseases including gastritis, peptic ulcer disease, gastric mucosa-associated lymphoid tissue lymphoma, and gastric carcinoma [1, 2]
The results showed that oral immunization with cholera toxin B subunit (CTB)-HUUC significantly increased levels of specific serum IgG, stomach mucosal secretory IgA and intestine mucosal sIgA antibodies compared with the PBS group (P < 0.001) (Figures 2A,B)
We examined the specificity of serum from mice immunized with CTB-HUUC using purified CTB, H. pylori adhesion A subunit (HpaA), urease A subunit (UreA), urease B subunit (UreB), and CagA peptides and Western blotting (Figures 2C–F) and ELISA (Figure 2G)

Summary

Introduction

Helicobacter pylori is the most important etiologic factor for upper gastrointestinal diseases including gastritis, peptic ulcer disease, gastric mucosa-associated lymphoid tissue lymphoma, and gastric carcinoma [1, 2]. UreA and UreB have been widely used as potential antigens for the development of vaccines against H. pylori infection in mice, Mongolian gerbils, nonhuman primates, and humans [15,16,17]. CagA+ H. pylori use a type IV secretion system to transfer CagA into host intestinal epithelial cells, leading to severe gastritis and gastric carcinoma, and CagA was selected as a good vaccine candidate in many studies [19,20,21]. Another study reported that the attenuated Salmonella vector vaccine, which expressed the fused protein CagA–VacA–UreB can significantly decrease H. pylori colonization in mice; and the protection was related to serum IgG and mucosal sIgA antibody responses and specific CD4+ T cell T-helper 1 (Th1) type responses [20]

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