Claims for Patent: 6,440,423

Summary for Patent: 6,440,423

Title:	Mutant enterotoxin effective as a non-toxic oral adjuvant
Abstract:	Methods and compositions are provided herein for the se of a novel mutant form of E. coli heat-labile enterotoxin which has lost its toxicity but has retained its immunologic activity. This enterotoxin is used in combination with an unrelated antigen to achieve an increased immune response to said antigen when administered as part of an oral vaccine preparation.
Inventor(s):	Clements; John D. (New Orleans, LA), Dickinson; Bonny L. (New Orleans, LA)
Assignee:	The Administrators of the Tulane Educational Fund (New Orleans, LA)
Application Number:	09/365,530
Patent Claims:	1. A vaccine preparation comprising an antigen in combination with a composition comprising a mutant E. coli heat-labile enterotoxin holotoxin, in which arginine at amino acid position 192 is replaced with glycine, which holotoxin is substantially less toxic than native E. coli heat-labile enterotoxin holotoxin as measured in the Y-1 adrenal cell assay and which has immunologic adjuvant activity but lacks ADP-ribosylating enzymatic activity as measured by the NAD-Agmatine ADP-ribosyltransferase assay. 2. The vaccine preparation of claim 1, in which the antigen is an antigen of a bacterium selected from the group consisting of Streptococcus pyogenes, Streptococcus pneumoniae, Neisseria gonorrheae, Neisseria meningitidis, Corynebacterium diphtheriae, Clostridium botulinum, Clostridium perfringens, Clostridium tetani, Hemophilus influenzae, Klebsiella pheumoniae, Klebsiella ozaenae, Klebsiella rhinoscleromatis, Staphylococcus aureus, Vibrio cholerae, Escherichia coli, Pseudomonas aeruginosa, Campylobacter (Vibrio) fetus, Aeromonas hydrophila, Bacillus cereus, Edwardsiella tarda, Yersinia enterocolitica, Yersinia pestis, Yersinia pseudotuberculosis, Shigella dysenteriae, Shigella flexneri, Shigella sonnei, Salmonella typhimurium, Treponema pallidum, Treponema pertenue, Treponema carateneum, Borrelia vincentii, Borrelia burgdorferi, Leptospira icterohemorrhagiae, Mycobacterium tuberculosis, Francisella tularensis, Brucella abortus, Brucella suis, Brucella melitensis, Mycoplasma spp., Rickettsia prowazeki, Rickettsia tsutsugamushi, and Chlamydia spp. 3. The vaccine preparation of claim 1, in which the antigen is an antigen of a fungus selected from the group consisting of Coccidioides immitis, Aspergillus fumigatus, Candida albicans, Blastomyces dermatitidis, Cryptococcus neoformans, and Histoplasma capsulatum. 4. The vaccine preparation of claim 1, in which the antigen is an antigen of a protozoan selected from the group consisting of Entomoeba histolytica, Trichomonas tenas, Trichomonas hominis, Trichomonas vaginalis, Trypanosoma gambiense, Trypanosoma rhodesiense, Trypanosoma gambiense, Trypanosoma rhodesiense, Trypanosoma cruzi, Leishania donovani, Leishamania tropica, Leishmania braziliensis, Pneumocystis pneumonia, Plasmodium vivax, Plasmodium falciparum, and Plasmodium malaria. 5. The vaccine preparation of claim 1, in which the antigen is an antigen of a Helminth selected from the group consisting of Enterobius vermicularis, Trichuris trichiura, Ascaris lumbricoides, Trichinella spiralis, Strongyloides stercoralis, Schistosoma japonicum, Schistosoma mansoni, Schistosoma haematobium, and hookworm. 6. The vaccine preparationof claim 1, in which the antigen is an antigen of a virus selected from the group consisting of Poxviridae, Herpesviridae, Herpes Simplex virus 1, Herpes Simples virus 2, Adenoviridae, Papovaviridae, Enteroviridae, Picornaviridae, Parvoviridae, Reoviridae, retroviridae, influenza viruses, parainfluenza viruses, mumps, measles, respiratory syncytial virus, rubella, Arboviridae, Rhabdoviridae, Arenaviridae, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis E virus, Non-A/Non-B Hepatitis virus, Rhinoviridae, Coronaviridae, and Rotaviridae. 7. A composition comprising (a) a vaccine selected from the group consisting of influenza vaccine, pertussis vaccine, diphtheria and tetanus toxoid combined with pertussis vaccine, hepatitis A vaccine, hepatitis B vaccine, hepatitis C vaccine, hepatitis E vaccine, Japanese encephalitis vaccine, herpes vaccine, measles vaccine, rubella vaccine, mumps vaccine, mixed vaccine of measles, mumps and rubella, papillomavirus vaccine, parvovirus vaccine, respiratory syncytial virus vaccine, Lyme disease vaccine, polio vaccine, malaria vaccine, varicella vaccine, gonorrhea vaccine, schistosomiasis vaccine, rota vaccine, Campylobacter vaccine, cholera vaccine, enteropathogenic E. coli vaccine, enterotoxic E. coli vaccine, mycoplasma vaccine, pneumococcal vaccine, and meningococcal vaccine, and (b) a composition comprising a mutant E. coli heat-labile enterotoxin holotoxin, in which arginine at amino acid position 192 is replaced with glycine, which holotoxin is substantially less toxic than native E. coli heat-labile enterotoxin holotoxin as measured in the Y-1 adrenal cell assay and which has immunologic adjuvant activity but lacks ADP-ribosylating enzymatic activity as measured by the NAD-Agmatine ADP-ribosyltransferase assay. 8. A kit useful in producing a protective immune response in a host to a pathogen comprising two components: (a) an effective amount of a protective antigen of a bacterial, viral or fungal pathogen, and (b) an adjuvant effective amount of a mutant E. coli heat-labile enterotoxin holotoxin, in which arginine at amino acid position 192 is replaced with glycine, and which has immunologic adjuvant activity but lacks ADP-ribosylating enzymatic activity as measured by the NAD-Agmatine ADP-ribosyltransferase assay, wherein both said components are in an orally acceptable carrier and said components may be administered either after having been mixed together or separately.

Details for Patent 6,440,423

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Glaxosmithkline Biologicals	HAVRIX	hepatitis a vaccine inactivated	Injection	103475	02/22/1995		2014-08-26