Helicobacter pylori (H. pylori) is a gram-negative spiral organism which is found overlying the gastric epithelium in approximately 50% of adults in this country. We and others have confirmed a causal relationship between H. pylori infection and gastritis and peptic ulcer disease. Recently this infection has even been implicated in the pathogenesis of gastric cancer. Although in vitro studies indicate H. pylori is sensitive to most anti-microbial agents, numerous studies including our own have demonstrated the difficulty in consistent eradicating H. pylori from the gastric epithelium. Therefore, prevention of infection by oral immunization is an alternative approach for control of disease. Among several existing animal models for H. pylori-associated gastritis, a germ- free mouse model is the most amenable to experimental manipulation. We are using this model in our laboratory. Our preliminary results have shown that an oral vaccine containing Helicobacter antigens plus cholera toxin results in significantly elevated levels of anti-Helicobacter IgA antibodies in gastric secretions, thereby conferring protection from infection. We have also shown that passive administration of anti- Helicobacter antibody can also prevent acute Helicobacter infection. There are a number of unanswered questions, however, which are the focus of this proposal. We seek to optimize an oral vaccine protocol for induction of protection from Helicobacter infection. A series of mutant cholera toxin molecules with amino acid changes in the A subunit which possess reduced or no toxicity will be tested for their capacity to enhance oral immunization. In the present proposal we will also investigate live attenuated Salmonella bacteria expressing Helicobacter proteins such as urease as a vector for more efficient oral immunization. Salmonellae naturally colonize the intestinal Peyer's patches and thus are a good candidate to delivery antigens to the body's largest concentration of mucosal lymphoid tissue from where the immune response can be disseminated to the gastric mucosa. Finally, in passive immunization experiments will prepare and use well characterized anti-Helicobacter monoclonal antibodies to study the relative protective efficacies of different antibody isotypes, including IgA. These studies may ultimately allow us to develop a safe efficacious subunit vaccine to prevent the morbidity and potential long-term consequences of Helicobacter infection.
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