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

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. Infection by Helicobacter pylori is highly prevalent in humans and can lead to chronic inflammation and gastric cancer, but to date no effective vaccine has been approved for clinical use owing to the lack of appropriate antigens and of safe mucosal adjuvants that can produce protective and durable immunity to the bacterium. Sukanya Raghavan, Ed Lavelle and colleagues now show that prophylactic intragastric administration of an inactivated whole-cell H. pylori preparation, together with the oral adjuvant α-galactosylceramide, reduced H. pylori infection in mice by eliciting a protective mucosal and systemic TH1 response. The immunisation triggered antigen-specific antibodies and interferon-γ that prevented effective colonisation of H. pylori after challenge in a process dependent on the CD1d, IL-1 receptor and IL-17 receptor pathways. The reported enhanced immune response to this orally adjuvanted vaccine formulation paves the way for further studies of its safety and efficacy.