Regulated attenuation of live vaccines to enhance cross-protective immunogenicity
AssigneeWashington University
InventorRoy Curtiss
Life of this patent
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Abstract
A live attenuated derivative of a pathogenic bacterium intended for use as a vaccine
Claims40
A live attenuated derivative of a pathogenic Salmonella species consisting essentially of
- (a) a means for regulatable expression of a gene that encodes a regulatory protein, wherein non-expression of said regulatory protein in vivo causes synthesis of a first antigen that is conserved among Salmonella species and E. coli strains;
- and
- (b) a means for regulatable synthesis of a first carbohydrate antigen, wherein said first carbohydrate antigen ceases to be synthesized in vivo, exposing a second carbohydrate antigen that is conserved among Salmonella species and E. coli strains;
- wherein said attenuated derivative has enhanced ability to induce cross-protective immunity against Salmonella species and E. coli strains.
A live attenuated derivative of a pathogenic Salmonella species, consisting essentially of
- (a) a means for regulatable expression of a fur gene;
- and
- (b) a mutation that renders a pmi gene inoperable,
- wherein said attenuated derivative has enhanced ability to induce cross-protective immunity against Salmonella species and E. coli.
A live attenuated derivative of a pathogenic Salmonella species consisting essentially of
- (a) a means for regulatable expression of a first surface antigen, wherein said first surface antigen is conserved among Salmonella species and E. coli strains;
- and
- (b) a means for regulatable expression of a second surface antigen, wherein said second surface antigen is not conserved among Salmonella species and E. coli strains,
- wherein up regulation of said first surface antigen and down regulation of said second surface antigen results in enhanced ability of said attenuated derivative to produce immunity against Salmonella species and E. coli strains.
A vaccine comprising a live attenuated strain of Salmonella, wherein said live attenuated strain consists essentially of
- (a) a mutation in a pmi gene that renders said pmi gene non functional;
- and;
- (b) a genetic construction that allows for regulatable expression of a fur gene,
- wherein said vaccine has enhanced ability to stimulate cross protective immunity against Salmonella species and E. coli strains.
A method for inducing an immune response to Salmonella species and E. coli strains comprising administering to an individual a live attenuated derivative of a pathogenic Salmonella species that is capable of colonizing the intestinal tract and reaching and persisting in the Gut Associated Lymphoid Tissue, and wherein expression of at least one conserved surface antigen is up regulated and at least one non-conserved surface antigen is down regulated in said attenuated derivative when said attenuated derivative is in the lymphoid tissue of the individual, wherein said live attenuated derivative has enhanced ability to stimulate cross protective immunity against infection by Salmonella species and E. coli strains.
A vaccine comprising a live attenuated strain of Salmonella, wherein said live attenuated strain consists essentially of
- (a) a mutation that renders a pmi gene non functional;
- and
- (b) a regulatable promotor operably linked to a fur gene wherein said fur gene is expressed when said attenuated strain is in the intestinal tract of an individual and said fur gene is not expressed when said attenuated strain is within internal tissues of an individual.
A live attenuated derivative of a Salmonella species consisting essentially of
- (a) a means for regulatable synthesis of LPS O-antigen side chains, wherein said O-antigen side chains are synthesized when said attenuated derivative is in the intestinal tract of an individual and are not synthesized when said attenuated derivative is within internal tissues of an individual;
- and
- (b) a means for regulatable expression of a fur gene, wherein said fur gene is expressed when said attenuated derivative is in the intestinal tract of an individual and wherein said fur gene is not expressed when said attenuated derivative within internal tissues of an individual
- wherein said attenuated derivative has increased ability to induce cross-protective immunity against infection by Salmonella species and E. coli strains.
A live attenuated derivative of a Salmonella typhimurium comprising
- (a) a ΔPfur::TTaraCPBADfur deletion-insertion mutation;
- and
- (b) a Δpmi mutation
A recombinant bacterial strain consisting essentially of a means of regulatable expression of a virulence gene, wherein said regulatable expression of a virulence gene renders said bacterial strain attenuated while maintaining immunogenicity.
A live attenuated derivative of a pathogenic Enterobacteriaceae species consisting essentially of a ΔPfur::araCPBADfur genetic construction.
A live attenuated derivative of a pathogenic Salmonella species consisting essentially of
- (a) a means for regulatable expression of a gene that encodes a regulatory protein, wherein non-expression of said regulatory protein in vivo causes synthesis of a first antigen that is conserved among Salmonella species and E. coli strains;
- and
- (b) a means for regulatable synthesis of a first carbohydrate antigen, wherein said first carbohydrate antigen ceases to be synthesized in vivo, exposing a second carbohydrate antigen that is conserved among Salmonella species and E. coli strains;
- and
- (c) a mutation of fliC or fljB, wherein said mutation results in deletion of the variable domain while retaining the N-terminal and C-terminal constant domains of flagellar proteins;
- wherein said attenuated derivative has enhanced ability to induce cross-protective immunity against Salmonella species and E. coli strains.
Dependencies are inferred from the claim text.