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Durability of protection is another critical issue, and results to date show very durable immunity after oral immunization with recombinant urease. Animals challenged at various intervals show up to 94 percent protection when challenged 1-year after immunization. Significantly, these animals also have very high concentrations of salivary IgA antibodies one year after immunization. This distinguishes artificial immunization from natural immunity, which in this model is primarily serum IgG. Based on this finding, researchers now theorize that HP may avoid the natural host immune response (at least in part) through an antigen-specific suppression of a Th-2 response (other possible explanations include antigenic variation, molecular mimicry, privileged site of sequestration, and polyclonal stimulation).

Other studies have confirmed that immunized mice produce IgA-class antibodies not only in their saliva but also directly in their stomachs following challenge. Immunocytochemistry reveals a marked increase in the number of IgA-secreting cells in immunized animals and a much lower response in infected controls. In fact, up to 20 percent of the IgA-secreting cells in the gastric mucosa of immunized mice were urease-specific. It was this vigorous local immune response that first suggested the possibility of developing a therapeutic vaccine.

The same results were achieved when these experiments were repeated in the mouse model using H. pylori instead of H. pilus, and similar studies are now being conducted with H. pylori in cats, which may be a better model of the human infection. Domestic cats immunized with urease and LT adjuvant developed salivary IgA responses to urease that peaked at 2 weeks and declined somewhat by 5 weeks. When challenged 8 weeks after immunization and sacrificed 8 weeks after challenge, immunized cats had significantly lower mean numbers of bacteria in the stomach compared with controls, and significant recruitment of urease-specific antibody-secreting cells in the gastric mucosa.

Therapeutic Vaccine. After discovering that immunized animals could become transiently colonized and then clear the infection, researchers designed an experiment to see if they could eradicate an infection by active immunization. Mice were infected, given the typical vaccine course, and then sacrificed after 2 or 8 weeks to determine outcome. Controls were 100-percent infected, but there was a significant decrease in the infection rate in immunized mice. When immunized mice were challenged a second time 4 weeks later, there was significant protection to rechallenge among animals that had cleared their infection.

The next question was how best to use the vaccine therapeutically. Current therapeutic regimes achieve cure rates of up to 90 percent using a combination of antacids and various antibiotics, and vaccine can transiently suppress the infection as well. But neither antibiotics nor vaccine by itself can achieve 100-percent clearance, and bacteria populations tend to drift upward again over time. Working with the mouse model, however, researchers found that the combination of amoxicillin, Pepto Bismol, and vaccine was able to achieve 100-percent clearance of the infection and to protect against recrudescence or reinfection.

Current Status of Vaccine. Researchers filed an Investigational New Drug application in 1995. A Phase I safety study indicated that the vaccine was



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