Attenuated microorganisms for the treatment of infection
The present invention pertains to a Salmonella microorganism having an attenuating mutation which disrupts the expression of a 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. The present invention also pertains to vaccine compositions and methods for treating and preventing a Salmonella infection in a patient.
1. A method of preventing or treating a Salmonella infection comprising administering to a patient a composition comprising Salmonella microorganisms, each microorganism comprising an attenuating mutation which disrupts expression of an ssaV gene and an attenuating mutation which disrupts expression of an aro gene.
2. The method of claim 1 , wherein said aro gene is aroC.
3. The method of claim 1 , wherein said aro gene is aroA.
4. The method of claim 1 , wherein said aro gene is aroD.
5. The method of claim 1 , wherein said aro gene is aroE.
6. The method of claim 1 , wherein said composition further comprises an adjuvant and/or a physiologically acceptable diluent.
7. The method of claim 1 , wherein administering the composition prevents salmonellosis.
8. The method of claim 1 , wherein administering the composition prevents typhoid fever.
9. The method of claim 1 , wherein said Salmonella microorganisms are S. typhi or S. typhimurium microorganisms.
10. The method of claim 1 , wherein said composition further comprises a buffering solution to neutralize stomach acid.
11. A method for treating an infection comprising administering to a patient a composition comprising Salmonella microorganisms, each microorganism comprising:
(i) an attenuating mutation which disrupts expression of an ssaV gene;
(ii) an attenuating mutation which disrupts expression of an aro gene; and
(iii) a gene encoding a heterologous antigen.
12. The method of claim 11 , wherein said aro gene is aroC.
13. The method of claim 11 , wherein said aro gene is aroA.
14. The method of claim 11 , wherein said aro gene is aroD.
15. The method of claim 11 , wherein said aro gene is aroE.
16. The method of claim 11 , wherein said composition further comprises an adjuvant and/or a physiologically acceptable diluent.
17. The method of claim 11 , wherein said heterologous antigen is from a pathogenic organism selected from the group consisting of pathogenic E. coli , ETEC, Shigella , Hepatitis A, B or C Virus, Lime disease producing Borrelia sp., Vibrio cholera, Helicobacter , Herpes Simplex Virus and Human Papilloma Virus.
18. The method of claim 11 , wherein said heterologous antigen is an E. coli heat-labile enterotoxin B subunit.
19. The method of claim 11 , wherein administering the composition elicits a Th1-type immune response in the patient.
20. The method of claim 11 , wherein the infection is a bacterial or viral infection.
21. The method of claim 11 , wherein said Salmonella microorganisms are S. typhi or S. typhimurium microorganisms.
22. The method of claim 11 , wherein said composition further comprises a buffering solution to neutralize stomach acid.
23. A method of inducing an immune response in a patient comprising administering to the patient a composition comprising Salmonella microorganisms, each microorganism comprising an attenuating mutation which disrupts expression of an ssaV gene and an attenuating mutation which disrupts expression of an aro gene.
24. The method of claim 23 , wherein said each microorganism further comprises a gene encoding a heterologous antigen.
25. The method of claim 23 , wherein said aro gene is aroC.
26. The method of claim 23 , wherein said aro gene is aroA.
27. The method of claim 23 , wherein said aro gene is aroD.
28. The method of claim 23 , wherein said aro gene is aroE.
29. The method of claim 23 , wherein said composition further comprises an adjuvant and/or a physiologically acceptable diluent.
30. The method of claim 24 , wherein said heterologous antigen is from a pathogenic organism selected from the group consisting of pathogenic E. coli , ETEC, Shigella , Hepatitis A, B or C Virus, Lime disease producing Borrelia sp., Vibrio cholera, Helicobacter , Herpes Simplex Virus and Human Papilloma Virus.
31. The method of claim 24 , wherein said heterologous antigen is an E. coli heat-labile enterotoxin B subunit.
32. The method of claim of claim 23 or 24 , wherein said immune response is a Th1-type response.
33. The method of claim 23 , wherein said Salmonella microorganisms are S. typhi or S. typhimurium microorganisms.
34. The method of claim 23 , wherein said composition further comprises a buffering solution to neutralize stomach acid.
35. The method of claim 1 , wherein said composition comprises about 10 7 to about 10 10 CFUs Salmonella CFUs.
36. The method of claim 23 , wherein said composition comprises about 10 7 to about 10 10 CFUs Salmonella CFUs.
37. The method of claim 30 , wherein said composition comprises about 10 7 to about 10 10 Salmonella CFUs.