Title:
ATTENUATED MICROORGANISMS FOR THE TREATMENT OF INFECTION
Document Type and Number:
WIPO Patent Application WO/2000/068261
Kind Code:
A2
Abstract:
A Salmonella microorganism has an attenuating mutation which disrupts the expression of an apparatus gene located within the Spi2 pathogenicity island, and an auxotrophic mutation. The microorganism therefore has a double mutation which helps prevent reactivity of the microorganism while maintaining the effectiveness of the microorganism to elicit an immune response.
Inventors:
DOUGAN GORDON
SANTANGELO JOSEPH DAVID
HOLDEN DAVID WILLIAM
SHEA JACQUELINE ELIZABETH
HINDLE ZOE
SANTANGELO JOSEPH DAVID
HOLDEN DAVID WILLIAM
SHEA JACQUELINE ELIZABETH
HINDLE ZOE
Application Number:
PCT/GB2000/001749
Publication Date:
November 16, 2000
Filing Date:
May 09, 2000
Export Citation:
Assignee:
MICROSCIENCE LTD (GB)
International Classes:
A61K35/74; A61K39/112; A61K48/00; A61P31/04; A61P43/00; C12N15/09; C07K14/255; C12N1/21; C12N15/31; C12R1/42; (IPC1-7): C07K14/255; C12N1/21; C12R1/42; C12N15/31; A61K35/74
Domestic Patent References:
| WO2000014240A2 | 2000-03-16 |
Foreign References:
| US5876931A | 1999-03-02 |
Other References:
MEDINA E ET AL: "Pathogenicity island 2 mutants of S. typhimurium are efficient carriers for heterologous antigens and enable modulation of immune responses" INFECTION AND IMMUNITY,US,AMERICAN SOCIETY FOR MICROBIOLOGY. WASHINGTON, vol. 67, no. 3, March 1999 (1999-03), pages 1093-1099, XP002136715 ISSN: 0019-9567
SHEA JACQUELINE E ET AL: "Influence of the Salmonella typhimurium pathogenicity island 2 Type III secretion system on bacterial growth in the mouse." INFECTION AND IMMUNITY, vol. 67, no. 1, January 1999 (1999-01), pages 213-219, XP002151954 ISSN: 0019-9567
CHATFIELD ET AL: "CONSTRUCTION OF A GENETICALLY DEFINED SALMONELLA TYPHI TY2 AROA, AROC MUTANT FOR THE ENGINEERING OF A CANDIDATE ORAL TYPHOID - TETANUS VACCINE" VACCINE,GB,BUTTERWORTH SCIENTIFIC. GUILDFORD, vol. 10, no. 1, 1992, pages 53-60, XP002102621 ISSN: 0264-410X
LEVINE MYRON M ET AL: "Attenuated Salmonella as live oral vaccines against typhoid fever and as live vectors." JOURNAL OF BIOTECHNOLOGY, vol. 44, no. 1-3, 1996, pages 193-196, XP004036865 ISSN: 0168-1656
DOUGAN G ET AL: "LIVE BACTERIAL VACCINES AND THEIR APPLICATION AS CARRIERS FOR FOREIGN ANTIGENS" ADVANCES IN VETERINARY SCIENCE AND COMPARATIVE MEDICINE,US,ACADEMIC PRESS, NEW YORK, NY, vol. 33, 1989, pages 271-300, XP000607245 ISSN: 0065-3519
HOHMANN E L ET AL: "EVALUATION OF A PHOP/PHOQ-DELETED, AROA-DELETED LIVE ORAL SALMONELLA TYPHI VACCINE STRAIN IN HUMAN VOLUNTEERS" VACCINE,GB,BUTTERWORTH SCIENTIFIC. GUILDFORD, vol. 14, no. 1, 1996, pages 19-24, XP002068852 ISSN: 0264-410X
LOWE ET AL: "Characterization of candidate live oral Salmonella typhi vaccine strains harboring defined mutations in aroA, aroC, and htrA" INFECTION AND IMMUNITY,US,AMERICAN SOCIETY FOR MICROBIOLOGY. WASHINGTON, vol. 67, no. 2, February 1999 (1999-02), pages 700-707, XP002112176 ISSN: 0019-9567
SCHOEDEL F ET AL: "HEPATITIS B VIRUS NUCLEOCAPSID-PRE-S2 FUSION PROTEINS EXPRESSED IN ATTENUATED SALMONELLA FOR ORAL VACCINATION" JOURNAL OF IMMUNOLOGY, vol. 145, no. 12, 1990, pages 4317-4321, XP000960317 ISSN: 0022-1767
HENSEL MICHAEL ET AL: "Functional analysis of ssaJ and the ssaK/U operon, 13 genes encoding components of the type III secretion apparatus of Salmonella Pathogenicity Island 2." MOLECULAR MICROBIOLOGY, vol. 24, no. 1, 1997, pages 155-167, XP000906797 ISSN: 0950-382X
SHEA JACQUELINE E ET AL: "Influence of the Salmonella typhimurium pathogenicity island 2 Type III secretion system on bacterial growth in the mouse." INFECTION AND IMMUNITY, vol. 67, no. 1, January 1999 (1999-01), pages 213-219, XP002151954 ISSN: 0019-9567
CHATFIELD ET AL: "CONSTRUCTION OF A GENETICALLY DEFINED SALMONELLA TYPHI TY2 AROA, AROC MUTANT FOR THE ENGINEERING OF A CANDIDATE ORAL TYPHOID - TETANUS VACCINE" VACCINE,GB,BUTTERWORTH SCIENTIFIC. GUILDFORD, vol. 10, no. 1, 1992, pages 53-60, XP002102621 ISSN: 0264-410X
LEVINE MYRON M ET AL: "Attenuated Salmonella as live oral vaccines against typhoid fever and as live vectors." JOURNAL OF BIOTECHNOLOGY, vol. 44, no. 1-3, 1996, pages 193-196, XP004036865 ISSN: 0168-1656
DOUGAN G ET AL: "LIVE BACTERIAL VACCINES AND THEIR APPLICATION AS CARRIERS FOR FOREIGN ANTIGENS" ADVANCES IN VETERINARY SCIENCE AND COMPARATIVE MEDICINE,US,ACADEMIC PRESS, NEW YORK, NY, vol. 33, 1989, pages 271-300, XP000607245 ISSN: 0065-3519
HOHMANN E L ET AL: "EVALUATION OF A PHOP/PHOQ-DELETED, AROA-DELETED LIVE ORAL SALMONELLA TYPHI VACCINE STRAIN IN HUMAN VOLUNTEERS" VACCINE,GB,BUTTERWORTH SCIENTIFIC. GUILDFORD, vol. 14, no. 1, 1996, pages 19-24, XP002068852 ISSN: 0264-410X
LOWE ET AL: "Characterization of candidate live oral Salmonella typhi vaccine strains harboring defined mutations in aroA, aroC, and htrA" INFECTION AND IMMUNITY,US,AMERICAN SOCIETY FOR MICROBIOLOGY. WASHINGTON, vol. 67, no. 2, February 1999 (1999-02), pages 700-707, XP002112176 ISSN: 0019-9567
SCHOEDEL F ET AL: "HEPATITIS B VIRUS NUCLEOCAPSID-PRE-S2 FUSION PROTEINS EXPRESSED IN ATTENUATED SALMONELLA FOR ORAL VACCINATION" JOURNAL OF IMMUNOLOGY, vol. 145, no. 12, 1990, pages 4317-4321, XP000960317 ISSN: 0022-1767
HENSEL MICHAEL ET AL: "Functional analysis of ssaJ and the ssaK/U operon, 13 genes encoding components of the type III secretion apparatus of Salmonella Pathogenicity Island 2." MOLECULAR MICROBIOLOGY, vol. 24, no. 1, 1997, pages 155-167, XP000906797 ISSN: 0950-382X
Attorney, Agent or Firm:
GILL JENNINGS & EVERY (Broadgate House 7 Eldon Street London EC2M 7LH, GB)
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Claims:
Claims
| 1. | A Salmonella microorganism having an attenuating mutation which disrupts the expression of an apparatus gene located within the Spi2 pathogenicity island, and an auxotrophic mutation. |
| 2. | A microorganism according to claim 1, wherein the auxotrophic mutation disrupts the expression of an aro gene. |
| 3. | A microorganism according to daim 2, wherein the aro gene is aroC. |
| 4. | A microorganism according to any of claims 1 to 3, wherein the attenuating mutation disrupts the expression of any of the ssaV, ssaJ, ssaK or ssaH genes. |
| 5. | A microorganism according to any preceding claim, wherein the attenuating mutation disrupts ssa V and the auxotrophic mutation disrupts aroC. |
| 6. | A microorganism according to any of claims 1 to 4, wherein the attenuating mutation is within an intergenic region between ssaK and ssaJ. |
| 7. | A microorganism according to any preceding claim, wherein the microorganism further comprises a heterologous antigen or a therapeutic protein. |
| 8. | A microorganism according to claim 7, wherein the antigen is a hepatitis A, B or C antigen. |
| 9. | A microorganism according to any preceding claim, wherein the microorganism is Salmonella typhi Ty2. |
| 10. | A microorganism according to any of daims 1 to 8, wherein the microorganism is that disclosed herein as ZH9 or WT05. |
| 11. | A microorganism according to any preceding claim, for use in therapy. |
| 12. | A vaccine composition comprising a microorganism according to any of claims 1 to 10, and an adjuvant and a physiologically acceptable diluent. |
| 13. | A composition according to claim 12, comprising from 10710'° CFUs in a single dosage unit. |
| 14. | A composition according to claim 13, comprising 108109 CFUs. |
| 15. | Use of a microorganism as defined in any of claims 1 to 10, in the manufacture of a medicament for intravenous administration for the treatment of systemic bacterial infection. |
| 16. | Use of a microorganism as defined in any of claims 1 to 10, in the manufacture of a medicament for oral delivery for the treatment of systemic bacterial infection. |
| 17. | Use according to claim 15 or daim 16, for the treatment of typhoid. |
Description:
INTERNATIONALSEARCHREPORT j----------------. Inte. onalApplicationNo PCT/GB00/01749 C.(Continuation)DOCUMENTSCONSIDEREDTOBERELEVANT Categoryo Citationofdocument,withindication,whereappropriate,oftherele
vantpassagesRelevanttoclaimNo. YSHEAJACQUELINEEETAL:"Influenceof1-4,7,9, theSalmonellatyphimuriumpathogenicity11-17 island2TypeIIIsecretionsystemon bacterialgrowthinthemouse." INFECTIONANDIMMUNITY, vol.67,no.1,January1999(1999-01), pages213-219,XP002151954 ISSN:0019-9567 thewholedocument YCHATFIELDETAL:"CONSTRUCTIONOFA1-4,7,9, GENETICALLYDEFINEDSALMONELLATYPHITY211-17 AROA,AROCMUTANTFORTHEENGINEERINGOFA CANDIDATEORALTYPHOID-TETANUSVACCINE" VACCINE,GB,BUTTERWORTHSCIENTIFIC. GUILDFORD, vol.10,no.1,1992,pages53-60, XP002102621 ISSN:0264-410X thewholedocument YLEVINEMYRONMETAL:"Attenuated1-4,7,9, Salmonellaasliveoralvaccinesagainst11-16 typhoidfeverandaslivevectors." JOURNALOFBIOTECHNOLOGY, vol.44,no.1-3,1996,pages193-196, XP004036865 ISSN:0168-1656 thewholedocument YDOUGANGETAL:"LIVE BACTERIALVACCINES1-4,7,9, ANDTHEIRAPPLICATIONASCARRIERSFOR11-17 FOREIGNANTIGENS" AVANCESINVETERINARYSCIENCEAND COMPARATIVEMEDICINE,US,ACADEMICPRESS, NEWYORK,NY, vol.33,1989,pages271-300,XP000607245 ISSN:0065-3519 page280,paragraph2-page291,paragraph 1 YHOHMANNELETAL:"EVALUATION OFA1,2,4,9, PHOP/PHOQ-DELETED,AROA-DELETEDLIVEORAL11-17 SALMONELLATYPHIVACCINESTRAININHUMAN VOLUNTEERS" VACCINE,GB,BUTTERWORTHSCIENTIFIC. GUILDFORD, vol.14,no.1,1996,pages19-24, XP002068852 ISSN:0264-410X page21,left-handcolumn page21,right-handcolumn,lastparagraph -page22,right-handcolumn,paragraph1 3 INTERNATIONALSEARCHREPORT Inte.onalApplicationNo PCT/GB00/01749 C.(Continuation)DOCUMENTS CONSIDERED TO BE RELEVANT Category°Citationofdocument,withindication,whereappropriate
,oftherelevantpassagesRelevanttoclaim No. YLOWEETAL:"Characterizationof1-4,7,9, candidateliveoralSalmonellatyphi11-17 vaccinestrainsharboringdefined mutationsinaroA,aroC,andhtrA" INFECTIONANDIMMUNITY,US,AMERICANSOCIETY FORMICROBIOLOGY.WASHINGTON, vol.67,no.2,February1999(1999-02), pages700-707,XP002112176 ISSN:0019-9567 thewholedocument AUS5876931A(HOLDENDAVIDWILLIAM)1-17 2March1999(1999-03-02) column19-column35 ASCHOEDELFETAL:"HEPATITISBVIRUS8 NUCLEOCAPSID-PRE-S2FUSIONPROTEINS EXPRESSEDINATTENUATEDSALMONELLAFOR ORALVACCINATION" JOURNALOFIMMUNOLOGY, vol.145,no.12,1990,pages4317-4321, XP000960317 ISSN:0022-1767 thewholedocument AHENSELMICHAELETAL:"Functional1-11 analysisofssaJandthessaK/Uoperon,13 genesencodingcomponentsofthetypeIII secretionapparatusofSalmonella PathogenicityIsland2." MOLECULARMICROBIOLOGY, vol.24,no.1,1997,pages155-167, XP000906797 ISSN:0950-382X thewholedocument P,XWO0014240A(GUZMANCARLOSALBERTO1,2,7, ;APFELHEIKO(DE);HENSELMICHAEL(DE);11-17 HUEC)16March2000(2000-03-16) claims40,41,52,69,70 page52,line15-20 examples5,6 3 INTERNATIONALSEARCHREPORT Inte. onal ApplicationNo Information on patent family members PCT/GB 00/01749 PCT/GB00/01749 PatentdocumentPublication PatentPublication citedinsearchreportdate member(s)date US5876931A02-03-1999AT 171477 T 15-10-1998 AU 711524 B 14-10-1999 AU 4121996 A 26-06-1996 CA 2206515 A 13-06-1996 CN 1176662 A 18-03-1998 CZ 9701755 A 15-10-1997 DE 69505011 D 29-10-1998 DE 69505011 T 06-05-1999 DK 796341 T 14-06-1999 EP 0796341 A 24-09-1997 EP 0889120 A 07-01-1999 ES 2126332 T 16-03-1999 FI 972424 A 06-08-1997 WO 9617951 A 13-06-1996 HU 76975 A 28-01-1998 JP 10509872 T 29-09-1998 NO 972468 A 08-08-1997 US 6015669 A 18-01-2000 WO0014240A16-03-2000AU 5860599 A 27-03-2000