Urease-based vaccine and treatment for helicobacter infection

Details Urease-based vaccine and treatment for helicobacter infection Urease-based vaccine and treatment for helicobacter infection

1994-02-23

2001-09-18

Mannfield, Nita (Department: 1645)

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Amino acid sequence disclosed in whole or in part; or...

C424S234100, C424S184100, C424S192100, C424S193100, C424S197110, C424S261100, C424S280100, C424S278100, C424S094600, C424S282100, C424S203100, C514S041000, C514S234500

Reexamination Certificate

active

06290962

ABSTRACT:

The present invention relates to the prevention and treatment of gastric infection in mammals, including humans. More particularly, the present invention relates to a vaccine suitable for use in the prevention and treatment of Helicobacter infection in mammals, including humans, and to a method of treatment of humans suffering from gastric infection, its consequences such as chronic gastritis or peptic ulcer, and prevention of gastric cancer.4
BACKGROUND OF THE INVENTION
Helicobacter infections of human gastric epithelium cause gastritis, are a major factor in the development of peptic ulcers and gastric lymphoma, and may be a risk factor for the development of gastric cancer. (Blaser, M. J. “Gastric Campylobacter-like Organisms, Gastritis and Peptic Ulcer Disease” Gastroenterology, vol. 93, 371-383 (1987); Graham, D. Y. “
Campylobacter pylori
and Peptic Ulcer Disease” Gastroenterology, vol. 196, 615-625 (1989); Parsonnet, J. et al. “
Helicobacter pylori
Infection in Intestinal and Diffuse-Type Gastric Adenocarcinomas” J. Natl. Cancer Inst., vol. 93, 640-643 (1991); Wotherspoon, A. C., et al., “Regression of Primary Low-Grade B-Cell Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue Type After Eradication of
Helicobacter pylori
,” Lancet, vol. 342, 575-577 (1993)). The most frequent infection agent is
Helicobacter pylori
, followed at a much lower frequency by
Helicobacter heilmanii. Helicobacter pylori
is a slender S-shaped gram negative microorganism, which is routinely recovered from gastric biopsies of adults and children with histologic evidence of gastritis or peptic ulceration. Evidence for a causal elationship between
Helicobacter pylori
and gastroduodenal disease comes from studies in human volunteers, patients with ulcers and gastric cancer, gnotobiotic pigs, and germ-free rodents. Regarding etiology, Koch's postulates were satisfied by creating histologically confirmed gastritis in previously uninfected individuals following consumption of viable microorganisms. (Marshall, B. J. et al. “Attempt to Fulfill Koch's Postulate for pyloric Campylobacter” Med. J. Aust., vol. 142, 436-439 (1985); Morris, A. et al. “Ingestion of
Campylobacter pyloritis
Causes Gastritis and Raised Fasting Gastric pH” Am. J. Gastroenterol., vol. 82, 192-199 (1987); Engstrand, L. et al. “Inoculation of Barrier-Born Pigs With
Helicobacter pylori
: A Useful Animal Model for Gastritis Type B” Infect. Immun., vol. 53, 1763-1768 (1990); Fox, J. G. et al. “Gastric Colonization by
Campylobacter pylori
Subsp. mustelae in Ferrets” Infect. Immun., vol. 56, 2994-2996 (1988); Fox, J. G. et al. “
Helicobacter mustelae
-Associated Gastritis in Ferrets: An Animal Model of
Helicobacter pylori
Gastritis in Humans” Gastroenterology, vol. 99, 352-361 (1990); Lee, A. et al. “A Small Animal Model of Human
Helicobacter pylori
Active Chronic Gastritis” Gastroenterology, vol. 99, 1315-1323 (1990); Fox, J. G. et al. “
Helicobacter Felis
Gastritis in Gnotobiotic Rats: An Animal Model of
Helicobacter pylori
Gastritis” Infect. Immun., vol. 59, 785-791 (1991); Eaton, K. A. et al. “
Campylobacter pylori
Virulence Factors in Gnotobiotic Piglets” Infect. Immun., vol. 57, 1119-1125 (1989)), and by treatment to eradicate
Helicobacter pylori
, with resolution of the gastritis and, in patients with peptic ulcer disease, a decrease in the recurrence rate. (Peterson, W. L. “
Helicobacter pylori
and Peptic Ulcer Disease” N. Engl. J. Med., vol. 324, 1043-1048 (1991)).
Gastroduodenal diseases thought to be associated with Helicobacter infection include acute, chronic, and atrophic gastritis, peptic ulcer disease including both gastric and duodenal ulcers, gastric cancer, chronic dyspepsia with severe erosive gastroduodenitis, refractory non-ulcer dyspepsia, intestinal metaplasia, and low grade MALT lymphoma. Helicobacter infection is also the principle cause of asymptomatic chronic gastritis.
In spite of in vitro susceptibility to many antimicrobial agents, in vivo eradication of established
Helicobacter pylori
infections with antimicrobial agents is often difficult to achieve. (Czinn, S. J. and Nedrud, J. G. “Oral Immunization Against
Helicobacter pylori
” Infect. Immun., vol. 59, 2359-2363 (1991)). The microorganism is found within the mucous coat overlying the gastric epithelium and in gastric pits. These are locations which do not appear to allow for adequate antimicrobial levels to be achieved even when antibiotics are given orally at high doses. At the present time, most authorities recommend a “triple therapy”, namely a bismuth salt in combination with drugs such as tetracycline and metronidazole for 2-4 weeks. However, the effectiveness of this or other chemotherapeutic regimens remains suboptimal. Recently, a National Institutes of Health panel of medical experts recommended a triple therapy with bismuth, tetracycline and metronidazole, administered for two weeks for treatment of peptic ulcers (Cimons, M., “Drug Combination Found Effective on Peptic Ulcers,”
L.A. Times
at A14 (Feb. 10, 1994)). However, this treatment is commonly associated with diarrhea and it may produce serious adverse drug reactions. (See, Dick-Hegedus, E. and Lee, A., “Use of a Mouse Model to Examine
Anti-Helicobacter pylori
Agents,” Scand. J. Gastroenterol., vol. 26, 909-915 (1991)). Treatment with antibiotics also may not solve the problem of reinfection and there is evidence for a high incidence of reinfection in some studies (Coelho, L. G., et al., “Duodenal Ulcer and Eradication of
H. pylori
in a Developing Country: An 18-Month Follow-Up Study,” Scand. J. Gastroenterol. vol. 27, 362-66 (1992)). Therefore there is a great need for a vaccine that can be used to treat infection and to prevent future infections.
At the present time little is known regarding the role of the mucosal immune systems in the stomach. The distribution of immunoglobulin (Ig) producing cells in the normal gastric antrum indicates that IgA plasma cells make up 80% of the total plasma cell population. In addition, the number of plasma IgA cells present in the gastric antrum is comparable to other mucus membranes. (Brandtzaeg, P. “Role of J Chain and Secretory Component in Receptor-Mediated Glandular and Hepatic Transport of Immunoglobulins in Man” Scand. J. Immunol., vol. 22, 111-146 (1985); Brandtzaeg, P. et al. “Production and Secretion of Immunoglobulins in the Gastrointestinal Tract” Ann. Allergy, vol. 59, 21-39 (November, 1987)). A number of studies in humans (Wyatt, J. I. et al. “Local Immune Response to Gastritis Campylobacter in Non-ulcer Dyspepsia” J. Clin. Path., vol. 39, 863-870 (1986)), and in animal models (Fox, J. G. et al. “
Helicobacter mustelae
-Associated Gastritis in Ferrets: An Animal Model of
Helicobacter pylori
Gastritis in Humans” Gastroenterology, vol. 99, 352-361 (1990); Fox, J. G. et al. “
Helicobacter felis
Gastritis in Gnotobiotic Rats: An Animal Model of
Helicobacter pylori
Gastritis” Infect. Immun., vol. 59, 785-791 (1991); Fox, J. G. et al. “Local and Systemic Immune Responses in Murine
Helicobacter felis
Active Chronic Gastritis,” Infect. & Immun., vol. 61, 2309-15 (1993)), have demonstrated specific IgG and IgA responses in serum and in gastric secretions in response to
Helicobacter infection
. However, the observation that
Helicobacter pylori
infection persists as a chronic infection for years, despite inducing a local and systemic immune response, is not encouraging the development of immunization strategies.
Lee et al. have reported the ability to infect germ-free rodents with Helicobacter felis, a bacterium closely related to
Helicobacter pylori
, and reproducibly document histologic gastritis. (Lee, A. et al. “A Small Animal Model of Human
Helicobacter pylori
Active Chronic Gastritis” Gastroenterology, vol. 99, 1315-1323 (1990); Fox, J. G. et al. “
Helicobacter felis
Gastritis in Gnotobiotic Rats: An Animal Model of
Helicobacter pylori
Gastritis” Infect. Immun., vol. 59, 785-791 (1991)). Since then, this bacterium-host pairing has been accepted as a good model to study Helicobacter-m

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