Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/02—Bacterial antigens
  • A61K39/025—Enterobacteriales, e.g. Enterobacter
  • A61K39/0258—Escherichia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/12—Antidiarrhoeals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/04—Antibacterial agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P37/00—Drugs for immunological or allergic disorders
  • A61P37/02—Immunomodulators
  • A61P37/04—Immunostimulants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
  • A61K2039/541—Mucosal route
  • A61K2039/542—Mucosal route oral/gastrointestinal
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
  • A61K2039/55511—Organic adjuvants
  • A61K2039/55544—Bacterial toxins
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
  • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
  • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

• the present invention relates to an oral vaccine against diarrhea. More precisely, it relates to an oral vaccine composition against enterotoxigenic E.coli caused diarrhea in humans.
• CFA colonization factor antigens
• a number of bacteria which are of medical interest have been shown to produce CFAs associated with their membrane.
• the ones which are most important for humans are organisms which colonize the human gastrointestinal tract and the respiratory airways.
• organisms which colonize the gastrointestinal tract are enterotoxigenic Escherichia coli, Vibrio cholerae, Helicobacter pylori, Campylobacter, Shigellae, Salmonellae and Yersinia.
• ETEC enterotoxigenic Escherichia coli
• Enterotoxigenic E. coli are characterized in that they produce heat labile enterotoxin (LT) and/or heat stable enterotoxin (ST).
• LT heat labile enterotoxin
• ST heat stable enterotoxin
• CS-antigens heat stable enterotoxin
• the present invention provides a new vaccine composition which is based on LT- negative killed enterotoxigenic E. coli bacteria comprising defined amounts of at least three different types of colonization factor antigens, and the B-subunit of cholera toxin (CTB) which is antigenically similar to the heat labile enterotoxin of ETEC. Further, the vaccine composition is purified from possible heat stable enterotoxin (ST).
• ST heat stable enterotoxin
• the LT- negative ETEC bacteria are either laboratory selected from naturally genetically modified strains or produced by recombinant techniques.
• enterotoxin which is a comparatively small protein of 19 amino acid residues, is washed away during the down stream processing of the vaccine composition.
• the present invention provides an oral vaccine composition against enterotoxigenic E.coli caused diarrhea in humans, which comprises a defined amount of at least three different types of colonization factor antigens (CFAs) selected from the group consisting of CFA I, CFA II (CS 1, CS2 and CS3) and CFA IV (CS4, CS5 and CS6), on killed E.
• CFAs colonization factor antigens
• coli bacteria lacking the gene encoding the heat labile (LT " ) enterotoxin, together with a defined amount of the B-subunit of cholera toxin (CTB), and an vehicle, which vaccine composition is purified from possible heat stable enterotoxin (ST).
• LT heat labile enterotoxin
• the defined amount of different types of CFAs is for each type of CFA at least 100 ⁇ g, and the defined amount of CTB is at least 0.5 mg, and the vehicle is a physiologically acceptable buffer solution. In a preferred embodiment the defined amount of different types of CFAs is for each type of CFA 100 to 300 ⁇ g, and the defined amount of CTB is 0.5 to 2.0 mg.
• the defined amount of different types of CFAs are 200 ⁇ g of CFA/I, 200 ⁇ g of CSl, 150 ⁇ g of CS2, 200 ⁇ g of CS4 and 150 ⁇ g of CS5, and 1.0 mg of CTB, and the physiologically acceptable buffer solution is phosphate buffered saline solution.
• a dose of the vaccine composition will contain approximately 10 bacteria.
• the vaccine composition is administered to person as a drink in a glas of water containing carbonate buffer, such as sodium hydrogen carbonate.
• E. coli fimbriae antigens are detected by using an inhibition ELISA substantially as described by Lopez- Vidal Y., et al in the Journal of Clinical Microbiology, vol 26, 1967- 1972 (1988). Briefly, the bacterial sample to be analyzed is incubated together with a fixed amount of monoclonal antibody directed against the CFA. After incubation the mixture is transferred to a plate previously coated with CFA, where residual monoclonal antibody can bind to the CFA. Bound antibody is visualized by adding horseradish peroxidase conjugated anti-mouse immunoglobulin. As substrate, o-phenylenediaminedihydrochloride in a citrate buffer is used. The optical density is measured at 450 nm in a spectrophotometer connected to a computer equipped with a data reduction software. The optical density observed is inversely proportional to the concentration of antibody in the sample. Formulation of the vaccine composition
• strains SBL- 104 and SBL-105 also produced CS 6, but the amount thereof was not established.
• the strain SBL- 107 also produced CS3, but the amount thereof was not established.
• ETEC vaccine containing 1 mg of recombinant B-subunit of cholera toxin plus 10 11 formalin killed ETEC bacteria of five ETEC strains expressing the most common colonization factor antigens (CFA's) such as CFA I, CFA II (CS 1, CS2 and CS3) and CFA IN (CS4, CS5 and CS6); a B-subunit cholera whole cell vaccine (registered in Sweden since 1992), containing 1 mg recombinant subunit B cholera toxin and 10 u killed whole cells (Inaba, Ogawa, classical and El Tor); placebo containing 10 n killed E.coli K12.
• CFA's colonization factor antigens
• the formulations were suspended in 4 ml buffer and each dose of vaccine or placebo was given as a drink in 150 cc of a sodium hydrogen carbonate solution. Isolation and characterization of ETEC bacteria and the anti-CTB IgA ELISA were performed as described (Jertborn M., et al ibid).
• Reactogenicity results are as follows: In total 43 volunteers (17%) had mild to moderate gastrointestinal or general symptoms after the first, dose; 13 (16%) in the placebo, 13 (16%) in the cholera vaccine group and 17 (20%) in the ETEC vaccine group. After the second dose 20 (8%o) had symptoms; 6 (7%) in the placebo, 7 (9%) in the cholera vaccine group and 7 (8%) in the ETEC vaccine group. Statistically, there were no differences in the proportion of volunteers reporting symptoms between the study groups.
• ETEC diarrhea was defined as having three or more liquid stools, and ETEC, but no other pathogens, detected in pretreatment stools.
• ETEC ETEC
• Comparison of ETEC diarrhea rates was done by one-sided Fisher's exact test. All ETEC isolates in the Per Protocol population expressed colonization factors included in the vaccine.
• the cholera vaccine gave no detectable protection against ETEC as compared with the placebo group, but it is noteworthy that only two of the ETEC cases in the cholera vaccine group were caused by bacteria producing solely the heat-labile enterotoxin (LT) against which the cholera vaccine (through its B-subunit) can theoretically work.
• LT heat-labile enterotoxin
• the cholera vaccine is not supposed to have any effect.

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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
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