Broad spectrum vaccine against non-typhoidal
The present invention is drawn to attenuated Salmonella serovar strains S. Typhimurium and S. Enteritidis , conjugate vaccines derived from these attenuated strains of S. Typhimurium and S. Enteritidis , comprising an O polysaccharide covalently linked to a flagellin protein, and methods for inducing an immune response in a subject comprising administering the attenuated strains and/or the conjugate vaccines of the invention.
1. A method of inducing an immune response, comprising administering to a subject in need thereof an immunologically-effective amount of a Salmonella enterica serovar conjugate, wherein the conjugate consists essentially of an O polysaccharide (OPS) covalently linked to a flagellin protein, wherein the serovar is selected from the group consisting of S. Typhimurium and S. Enteritidis.
2. The method of claim 1 , wherein the flagellin protein is a Phase 1 flagella protein.
3. The method of claim 1 , wherein the conjugate is made from a serovar that has at least one attenuating mutation selected from group consisting of an attenuating mutation in the guaBA locus and the clpPX locus.
4. The method of claim 1 , wherein the conjugate is administered parenterally.
5. The method of claim 4 , wherein prior to administering the conjugate, the subject is administered an attenuated strain of the serovar.
6. The method of claim 5 , wherein said strain is orally administered to the subject.
7. The method of claim 6 , wherein said attenuated strain of the serovar has at least one attenuating mutation selected from group consisting of an attenuating mutation in the guaBA locus and the clpPX locus.
8. The method of claim 7 , wherein said subject is a human.
9. The method of claim 2 , wherein said effective amount is between about 0.01 μg and 10 μg.
10. The method of claim 9 , wherein said Phase 1 flagella protein is covalently linked to said OPS either directly or using a linker.
11. The method of claim 10 , wherein said linker is selected from the group consisting of 1-cyano-4-dimethylaminopyridinium tetrafluoroborate, adipic acid dihydrazide, ε-aminohexanoic acid, chlorohexanol dimethyl acetal, D-glucuronolactone and p-nitrophenylethyl amine.
12. The method of claim 11 , wherein said linker is 1-cyano-4-dimethylaminopyridinium tetrafluoroborate.
13. The method of claim 8 , wherein said conjugate is combined with a pharmaceutically acceptable carrier in a pharmaceutical composition.
14. A composition comprising a Salmonella enterica serovar conjugate, wherein the conjugate consists essentially of an O polysaccharide (OPS) covalently linked to a flagellin protein, wherein the serovar is selected from the group consisting of S. Typhimurium and S. Enteritidis.
15. The composition of claim 14 , wherein the flagellin protein is a Phase 1 flagella protein.
16. The composition of claim 15 , wherein the conjugate is made from a serovar that has at least one attenuating mutation selected from group consisting of an attenuating mutation in the guaBA locus and the clpPX locus.
17. A Salmonella enterica serovar strain, wherein said strain has attenuating mutations in the guaBA locus and the clpPX locus and said serovar is selected from the group consisting of S. Typhimurium (Group B) and S. Enteritidis (Group D).
18. The Salmonella serovar strain of claim 17 , wherein said serovar is S. Typhimurium (Group B).
19. The Salmonella serovar strain of claim 17 , wherein said serovar is S. Enteritidis (Group D).
20. The Salmonella serovar strain of claim 17 , wherein said attenuating mutation is an attenuating mutation that reduces the level of expression of said loci, or blocks expression of said loci.