Title:  Treatment and prevention of helicobacter infection

United States Patent:  6,468,545

Issued:  October 22, 2002

Inventors:  Doidge; Christopher V. (Vincent, AU); Lee; Adrian (Lane Cove, AU); Radcliff; Fona J. (Sydney, AU); Hazell; Stuart L. (Glenfield, AU)

Assignee:  The University of New South Wales (Kensington, AU); CSL Limited (Victoria, AU)

Appl. No.:  421238

Filed:  October 20, 1999

An antigenic preparation for use in the treatment of prevention of Helicobacter infection in a mammalian host, comprises the catalase enzyme of Helicobacter bacterial, particularly the catalase enzyme of H. pylori or H. felis, or an immunogenic fragment thereof.

DETAILED DESCRIPTION OF THE INVENTION

Preferably, the antigen preparation or isolated antigen of this invention comprises the catalase of H. pylori or H. felis, most preferably H. pylori catalase. Preferably also, this antigenic preparation or isolated antigen is used in a vaccine composition for oral administration which includes a mucosal adjuvant.

In a particularly preferred aspect of this invention, an oral vaccine composition comprising substantially pure H. pylori catalase, more preferably recombinant H. pylori catalase, in association with a mucosal adjuvant is used for the treatment or prevention of H. pylori infection in a human host.

The mucosal adjuvant which is optionally, and preferably, administered with the Helicobacter catalase preparation or antigen to the infected host is preferably cholera toxin. Mucosal adjuvants other than cholera toxin which may be used in accordance with the present invention include non-toxic derivates of cholera toxin, such as the B sub-unit (CTB), chemically modified cholera toxin, or related proteins produced by modification of the cholera toxin amino acid sequence. These may be added to, or conjugated with, the Helicobater catalase preparation or antigen. The same techniques can be applied to other molecules with mucosal adjuvant or delivery properties such as Escherichia coli heat labile toxin. Other compounds with mucosal adjuvant or delivery activity may be used such as bile; polycations such as DEAE-dextran dextran and polyomithine; detergents such as sodium dodecyl benzene sulphate; lipid-conjugated materials; antibiotics such as streptomycin; vitamin A; and other compounds that alter the structural or functional integrity of mucosal surfaces. Other mucosally active compounds include derivatives of microbial structures such as MDP; acridine and cimetidine.

The Helicobacter catalase preparation or antigen may be delivered in accordance with this invention in ISCOMS (immune stimulating complexes), ISCOMS containing CTB, liposomes or encapsulated in compounds such as acrylates or poly(DL-lactide-co-glycoside) to form microspheres of a size suited to adsorption by M cells. Alternatively, micro or nanoparticles may be covalently attached to molecules such as vitamin B12 which have specific gut receptors. The Helicobacter catalase preparation or antigen may also be incorporated into oily emulsions and delivered orally. An extensive though not exhaustive list of adjuvants can be found in Cox and Coulter⁷.

Other adjuvants, as well as conventional pharmaceutically acceptable carriers, excipients, buffers or diluents, may also be included in the prophylactic or therapeutic vaccine composition of this invention. The vaccine composition may, for example, be formulated in enteric coated gelatine capsules including sodium bicarbonate buffers together with the Helicobacter catalase preparation or antigen and cholera toxin mucosal adjuvant.

The formulation of such therapeutic compositions is well known to persons skilled in this field. Suitable pharmaceutically acceptable carriers and/or diluents include any and all conventional solvents, dispersion media, fillers, solid carriers, aqueous solutions, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art, and it is described, by way of example, in Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Company, Pennsylvania, USA. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the pharmaceutical compositions of the present invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

As an alternative to the delivery of the Helicobacter catalase preparation or antigen in the form of a therapeutic or prophylactic oral vaccine composition, the catalase or an immunogenic fragment thereof may be delivered to the host using a live vaccine vector, in particular using live recombinant bacteria, viruses or other live agents, containing the genetic material necessary for the expression of the catalase or immunogenic fragment as a foreign antigen. Particularly, bacteria that colonise the gastrointestinal tract, such as Salmonella, Yersinia, Vibrio, Escherichia and GCG have been developed as vaccine vectors, and these and other examples are discussed by Holmgren et al.⁸ and McGhee et al.⁹.

The Helicobacter catalase preparation or antigen of the present invention may be administered as the sole active immunogen in a vaccine composition or expressed by a live vector. Alternatively, however, the vaccine composition may include or the live vector may express other active immunogens, including other Helicobacter antigens such as urease or the lipopolysaccharide (LPS) of Helicobacter bacteria (see International Patent Application No. PCT/AU95/00077), as well as immunologically active antigens against other pathogenic species.

It is especially advantageous to formulate compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the human subjects to be treated; each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier and/or diluent. The specifications for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active ingredient and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active ingredient for the particular treatment.

Data obtained from Western blots mentioned above, show that H. pylori catalase is recognised by the serum of mice vaccinated with an H. felis antigen preparation (pulse cholera toxin adjuvant). These mice can be shown to be protected against H. felis infection. This data indicates the use of H. pylori catalase as a protective antigen in human H. pylori infection, and purified or recombinant catalase may be used as an antigenic component of a therapeutic or prophylactic vaccine, either on its own, or in combination with other antigens, carriers, adjuvants, delivery vehicles or excipients.

Claim 1 of 20 Claims

What is claimed is:

1. A composition for use in the treatment or prevention of Helicobacter infection in a mammalian host, which comprises an immunologically effective amount of a preparation of substantially pure, full-length Helicobacter catalase, wherein the catalase content is at least 80% of the total Helicobacter antigens in the preparation, together with a muscosal adjuvant and a pharmaceutically acceptable carrier or diluent.
 

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