PROPHYLACTIC AND THERAPEUTIC IMMUNIZATION AGAINST H PYLORI IN RHESUS MACAQUES

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Helicobacter pylori commonly infects the human stomach, where it causes inflammation (gastritis) in all individuals and peptic ulcer disease or gastric cancer in some. Although the infection can be treated with antibiotics, this approach is limited by the requirement for multiple drugs administered over a prolonged period of time, by antimicrobial resistance, and by recurrence of infection after treatment. Numerous H. pylori vaccines have been studied in the mouse model, but sterilizing immunity has typically not been achieved, and the results have rarely been extended to primates. The goal of this proposal is to perform a translational, preclinical study to determine the feasibility of using immunization with the outer membrane proteins, BabA and BabB, together with a novel adjuvant, to prevent and treat experimental H. pylori infection in non-human primates. The project brings together the expertise of the Born lab, which discovered and characterized BabA in a series of elegant studies, and the Solnick lab, which has developed and exploited the specific pathogen free (SPF) rhesus macaque model of H. pylori. Preliminary experiments suggest that immunization with BabA and a novel, non-toxic derivative of cholera toxin (CTA1-DD) is highly effective for prophylactic and therapeutic immunization in mice. Experiment 1 will examine protection from H. pylori challenge in specific pathogen free (SPF) rhesus macaques after immunization with purified BabA and BabB plus CTA1-DD, CTA1-DD alone, or control. Experiment 2 will examine the efficacy of immunization with BabA and BabB plus CTA1-DD for primary therapy of experimental H. pylori infection in macaques, and as an adjunct to antibiotic therapy to prevent reinfection upon secondary challenge. The primary endpoint will be quantitative cultures of gastric biopsies performed two and eight weeks after challenge. We will also examine BabA- and BabB-specific antibodies in serum, gastric juice, and feces, as well as histopathology to evaluate inflammation and the topography of infection. If the encouraging results from mouse studies can be replicated in non-human primates, they would serve as the basis for PhaseI/II clinical trials in humans. Helicobacter pylori is a common infection that causes peptic ulcer disease and gastric cancer. Although infection can be treated with antibiotics, this approach is limited by antibiotic resistance and recurrence of infection after treatment. The goal of this proposal is to determine the effectiveness of an Helicobacter pylori vaccine in non-human primates. These experiments could lead to development of a vaccine to prevent and treat Helicobacter pylori infection, which would likely reduce the frequency of peptic ulcer disease and gastric cancer.