Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
2000-07-05
2002-06-18
Smith, Lynette R. F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S203100, C424S460000, C424S461000, C424S450000, C424S457000, C424S500000, C424S194100, C424S501000, C424S502000, C530S350000
Reexamination Certificate
active
06406703
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the treatment of gastroduodenal disease associated with
Helicobacter pylori
infection and in particular it relates to the use of active immunisation as a treatment for
H. pylori
—associated gastroduodenal disease.
BACKGROUND OF THE INVENTION
The bacterium,
Helicobacter pylori,
is now well established as a major gastroduodenal pathogen, and more than 50% of the world population is infected with this organism which causes gastritis of varying severity. While no symptoms are apparent in a great proportion of infected persons, in a significant number of
H. pylori
infected persons overt disease may result. The majority (95%) of duodenal ulcers are associated with
H. pylori
infection; a causal role is shown by treatment studies which indicate that if the organisms can be eradicated at the time of ulcer healing then the ulcers do not recur—in contrast to 80% recurrence rate at one year in those who remain infected with the organisms. Furthermore, up to 80% of gastric ulcers are thought to be
H. pylori
associated (Blaser, 1992).
There is now increasing evidence of the harmful consequence of long term
H. pylori
infection. In countries such as China, Colombia and Japan the bacterium is picked up very early in life, and in these persons the gastritis slowly progresses until after 30-40 years of continual infection, severe gastric atrophy appears. Gastric atrophy is well documented as being the precursor lesion for gastric cancer, although the actual cancer that develops in an atrophied stomach is dependent on a myriad of other factors including diet. However, all the evidence to date would suggest that the cancer would not develop if it was possible to remove the
H. pylori
infection at an early age before the atrophy had developed (Parsonnet et al., 1991).
There is no laboratory animal model of
H. pylori
infection that can be used for large scale assessment of new anti-
H. pylori
therapies. However, a
Helicobacter felis
mouse model of gastric Helicobacter infection has been developed that has proved extremely useful in the screening of the potential of new antimicrobial therapeutic regimens.
H. felis
is a spiral shaped bacterium that is very closely related to
H. pylori.
This bacterium colonises the stomach of mice in a very similar way to
H. pylori
in the human, i.e. the main ecological niche is gastric mucus and the localisation of colonisation is antral dominant. In germfree mice,
H. felis
infection induces a gastritis that is very similar to the human
H. pylori
infection with a chronic inflammation accompanied by polymorphonuclear leucocyte infiltration. Infection with each organism results in the induction of a similar raised immune response against
H. pylori
and
H. felis
respectively (Lee et al., 1990).
The
H. felis
mouse model has proved to be very predictive of the efficacy of anti-
H. pylori
agents in humans. Thus, monotherapy with agents with high in vitro activity such as erythromycin show no significant in vivo effect against
H. felis
in mice, just as erythromycin has no anti-
H. pylori
effect in humans despite high antimicrobial effects in vitro. In contrast, the triple therapy regimens of a bismuth compound, metronidazole, and tetracycline or amoxycillin lead to a very high eradication rate in
H. felis
infected mice (Dick-Hegedus and Lee, 1991). Such triple therapies are the most successful human anti-
H. pylori
regimens, and at the present time are recommended as the first choice for anti-
H. pylori
therapy. However, established Helicobacter infections are difficult to treat, and current chemotherapeutic regimens remain suboptimal due to problems with efficacy, toxicity, drug resistance and reinfection (O'Connor, 1992).
Active immunisation of already infected patients has not been proven efficacious for any clinically manifest human infectious disease (Burke, 1992). Given that
H. pylori
infections persist for long periods, if not the life of the infected individual, despite the presence of a vigorous immune response that includes a high level of circulating IgG antibody in the serum and the demonstration of local specific IgA antibody in the gastric mucosa, it has been considered that active immunisation was unlikely to be effective in therapy (Goodwin, 1993). Indeed, Czinn et al. (1993) in proposing that oral vaccination may be a feasible approach for the prevention of
H. pylori
infection in humans (based on an evaluation of an oral immunisation protocol in the
H. felis
mouse model), suggested that once infection is established neither antibody nor antibiotics are very effective at eradication.
Varga et al. (1992) have reported that a
H. pylori
vaccine prepared from organisms derived from a patient, and injected parenterally into that patient, resulted in an allergic reaction and failure to eradicate the organism.
Surprisingly, it has now been discovered for the first time that there is indeed a therapeutic potential for active immunisation against gastric Helicobacter infection. Furthermore, it has been discovered that oral administration of
H. pylori
antigen, with a suitable mucosal adjuvant, does not result in allergic or hypersensitivity symptoms, but results in suppression or eradication of the infecting organisms from the gastric mucosa.
SUMMARY OF THE INVENTION
According to one aspect of the present invention, there is provided a method for the treatment of Helicobacter infection in a mammalian host, which comprises the oral administration to said infected host of an immunologically effective amount of one or more Helicobacter antigen(s), optionally in association with a mucosal adjuvant.
In another aspect, there is provided a vaccine composition for the treatment of Helicobacter infection in a mammalian host, which comprises an immunologically effective amount of one or more Helicobacter antigen(s), optionally in association with a mucosal adjuvant.
In yet another aspect, the present invention provides the use of a vaccine composition comprising an immunologically effective amount of one or more Helicobacter antigen(s), optionally in association with a mucosal adjuvant. in the treatment of Helicobacter infection in a mammalian host.
Throughout this specification and the claims which follow, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.
By use of the term “immunologically effective amount” herein, it is meant that the administration of that amount to an individual infected host, either in a single dose or as part of a series, is effective for treatment of Helicobacter infection. This amount varies depending upon the health and physical condition of the individual to be treated, the taxonomic group of individual to be treated, the capacity of the individual's immune system to synthesise antibodies, the degree of protection desired, the formulation of the vaccine, the assessment of the medical situation, and other relevant factors. It is expected that the amount will all in a relatively broad range that can be determined through routine trials.
DETAILED DESCRIPTION OF THE INVENTION
The Helicobacter antigen(s) used in accordance with the present invention may be
H. felis
antigen(s), or more preferably
H. pylori
antigen(s). In a particularly preferred aspect of the present invention, a vaccine composition comprising
H. pylori
antigen(s) in association with a mucosal adjuvant is used the treatment of
H. pylori
infection in a human patient.
Preferably, the Helicobacter antigen(s) comprise a bacterial sonicate, and in particular a
H. pylori
sonicate. More preferably, the Helicobacter antigen(s) used in accordance with the present invention comprise inactivated whole bacterial cells of
H. pylori.
Alternatively, the Helicobacter antigen(s) used in accordance with the present invention may comprise one or more individual antigens, particularl
Doidge Christopher Vincent
Lee Adrian
CSL Limited
Foley & Lardner
Smith Lynette R. F.
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