An oral alpha-galactosylceramide adjuvanted Helicobacter pylori vaccine induces protective IL-1R- and IL-17R-dependent Th1 responses

Stephanie Longet,Craig P Mcentee,Sukanya Raghavan,Aine Abautret-Daly,Ed C Lavelle,Christopher J H Davitt,Monica Rosa,Vincenzo Aversa,Ivan S Coulter,Jan Holmgren

doi:10.1038/s41541-019-0139-z

Abstract

Helicobacter pylori causes chronic gastric infection that can lead to peptic ulcers and is an identified risk factor for gastric cancer development. Although much effort has been put into the development of a Helicobacter pylori vaccine over the last three decades, none has yet reached clinical application. Specific challenges pertaining to effective H. pylori vaccine development include the lack of proven vaccine-effective antigens and safe mucosal adjuvants to enhance local immune responses as well as the lack of accepted correlates of protection. Herein, we demonstrate that prophylactic intragastric immunisation with a whole-cell killed H. pylori antigen administered together with the non-toxic oral adjuvant α-galactosylceramide (α-GalCer) induced effective immune protection against H. pylori infection in mice, which was of similar magnitude as when using the “gold standard” cholera toxin as adjuvant. We further describe that this α-GalCer-adjuvanted vaccine formulation elicited strong intestinal and systemic Th1 responses as well as significant antigen-specific mucosal and systemic antibody responses. Finally, we report that the protective intestinal Th1 responses induced by α-GalCer are dependent on CD1d, IL-1R as well as IL-17R signalling. In summary, our results show that α-GalCer is a promising adjuvant for inclusion in an oral vaccine against H. pylori infection.

Highlights

Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium that colonises the stomach of ~50% of the worlds population[1] and mostly causes asymptomatic chronic gastritis
The effect of immunisation on both acute and chronic infection was determined by measuring the bacterial load in the addition to enhancing Th1 responses, immunisation with WC H. pylori antigen and α-GalCer promoted an increase in antigenspecific spleen and mesenteric lymph nodes (MLN) cell proliferation after stimulation stomach 5 days or 3 weeks after challenge by quantitative culture (Supplementary Fig. 3a and 3b)
IFNγ is essential for protective immunity induced by oral vaccination with WC H. pylori antigen adjuvanted with α-GalCer Having shown that oral delivery of α-GalCer significantly enhanced immune protection induced by a WC H. pylori antigen and promoted both local (MLN) and systemic Th1 responses, we evaluated the importance of the IFNγ response for α-GalCer driven protection

Summary

Introduction

Helicobacter pylori (H. pylori) is a gram-negative, spiral-shaped bacterium that colonises the stomach of ~50% of the worlds population[1] and mostly causes asymptomatic chronic gastritis. The bacteria reside in the mucus of the stomach and in the duodenum. H. pylori-specific CD4+ T cells, mainly producing IFNγ and/or IL-17A were detected in the gastric mucosa and peripheral blood of infected individuals,[7,8] yet these responses while apparently preventing development of manifest disease in the majority of cases, are not sufficiently effective for interrupting colonisation in most individuals. Beside antigen-specific T cells, antigen-specific IgA- and IgM-antibody-secreting cells were detected in the stomach of H. pylori-infected subjects.[9] A birth cohort study in a high-endemicity area of Bangladesh demonstrated that infants fed with breast milk containing high levels of H. pylori-specific

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