Therapeutic Vaccination against Helicobacter pylori in the Beagle Dog Experimental Model: Safety, Immunogenicity, and Efficacy

Helicobacter pylori is a spiral-shaped, gram-negative bacterium that infects the stomach of >50% of the population worldwide, with higher prevalence in the developing countries. H. pylori induces chronic inflammation of the stomach mucosa, causing chronic gastritis and peptic ulcer (9, 33); moreover, H. pylori infection is related to gastric mucosa-associated lymphoid tissue lymphoma (4) and to an increased risk of gastric cancer (36), as also proved in animal models (13, 38). Current therapies, based on one antisecretory agent plus antibiotics, although effective in 80 to 90% of cases, face problems of patient compliance, increasing antibiotic resistance, and possible recurrence or reinfection; in spite of continuous effort to improve these treatments, no major breakthroughs have been achieved in the most recent years (30). To overcome the limits of antibiotic-based therapies, the vaccine approach has been undertaken since the last decade, leading us to identify some relevant bacterial antigens as candidates for vaccines (2). On the other hand, animal models of H. pylori infection have been developed to study the interaction between the bacterium and the host, the mechanisms of immune response to either infection or vaccination, and to determine the efficacy of both prophylactic and therapeutic vaccination (2, 17, 26, 34). Among these animal models, that of the beagle dog reproduces several aspects of the human infection with H. pylori. In fact, in the beagle dog model, intragastric administration of H. pylori results in a long-term chronic infection, characterized by gastritis, epithelial alterations, superficial erosions, and the appearance of macroscopic follicles in the gastric mucosa, mainly in the antral region of the stomach (28, 29). Most of the examples of vaccination against H. pylori in animal models reported in the literature concern the use of either whole-cell preparation or single purified antigens, administered mucosally. Previous work in our laboratories has shown the feasibility of both prophylactic and therapeutic vaccination in mice with a mixture of three H. pylori toxins—CagA, VacA, and NAP—relevant in the pathogenesis of infection (8, 22, 32). Moreover, parenteral vaccination of beagle dogs with these H. pylori antigens gave good rate of protection against subsequent H. pylori experimental challenge (unpublished data). We report here data from experiments aimed at evaluating the therapeutic approach of vaccination in beagle dogs experimentally infected with H. pylori, using recombinant CagA, VacA, and NAP, administered intramuscularly at different doses and vaccination schedules.