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Salmonella vaccine materials and methods

a technology of salmonella and vaccine materials, applied in the field of genetically engineered salmonella, can solve the problems of large doses, poor to moderate protection of vaccines, and most economic damag

Inactive Publication Date: 2005-11-24
PHARMACIA & UPJOHN CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to safe and effective vaccines using attenuated mutant gram-negative bacteria, specifically Salmonella bacteria. The invention is based on the discovery that certain genes within the Salmonella pathogenicity island 2 (SPI2) are involved in the process of infection and can be inactivated to create a safer vaccine. The invention provides vaccine compositions comprising attenuated mutant Salmonella bacteria in which one or more genes within SPI2 have been inactivated. The vaccine can be administered to animals, including cattle, sheep, horses, pigs, and humans, to provide immunological protection against Salmonella infection. The invention also provides methods of immunizing and reducing transmission of infection by administering the vaccine. The invention further provides a method of delivering immunogenic polypeptide antigens to an animal by administering the mutant bacteria or a vaccine composition comprising the mutant bacteria.

Problems solved by technology

Salmonella infection is a widespread occurrence in animals, especially in poultry and swine, and is one of the most economically damaging of the enteric and septicemic diseases that affect food producing animals.
ecies. Although these serotypes primarily infect animals, S. dublin and S. choleraesuis also often cause human
Many of the vaccines provide only poor to moderate protection and require large doses to be completely efficacious.
Despite this, high doses of live vaccines are often required for efficacy and few live-attenuated Salmonella vaccines are commercially available.
Prior attempts to use attenuation methodologies to provide safe and efficacious live vaccines have encountered a number of problems.
First, an attenuated strain of Salmonella that exhibits partial or complete reduction in virulence may not retain the ability to induce a protective immune response when given as a vaccine.
Third, genetically engineered Salmonella strains that contain a mutation in only a single gene may spontaneously mutate and “revert” to the virulent state.
However, the use of double or multiple gene disruptions is unpredictable in its effect on virulence and immunogenicity; the introduction of multiple mutations may overattenuate a bacteria for a particular host [Linde et al., Vaccine 8:278-282 (1990); Zhang et al., Microb. Pathog., 26(3):121-130 (1999)].

Method used

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  • Salmonella vaccine materials and methods
  • Salmonella vaccine materials and methods
  • Salmonella vaccine materials and methods

Examples

Experimental program
Comparison scheme
Effect test

example 1

Construction of Salmonella Mutants Containing Single and Double Deletions of Selected Genes: ssaT, ssaJ, ssaC, rfaK and glnA

A. Construction of pCVD442::Δgene Plasmids

[0055] For each of the S. typhimurium and S. dublin ssaT, ssaJ, ssaC, rfaK and glnA genes, positive selection suicide vectors based on the plasmid pCVD442 [Donnenberg and Kaper, Infect Immun 59:4310-17 (1991)] were constricted that contained a portion of the 5′ and 3′ chromosomal regions flanking each gene but with substantial internal deletions (typically >95%) within the gene itself. Gene splicing by overlap extension (“gene SOEing” [Horton et al., Biotechniques 8:528-535 (1990)]) was used to generate DNA fragments which were complementary to the gene to be deleted, but which lacked the majority of the internal nucleotide sequence. The plasmids containing these internally deleted genes were designated pCVD442::ΔssaT, pCVD442::ΔssaJ, pCVD442::ΔssaC, pCVD442::ΔrfaK, and pCVD442::ΔglnA, respectively. These vectors we...

example 2

Safety and Efficacy of Single and Double Deletion SPI2 Mutants

A. Efficacy of a S. choleraesuis ΔssaC Mutant as a Vaccine in Swine

(Trial No. 704-7923-I-MJK-96-008)

[0074] The safety and efficacy of a live attenuated S. choleraesuis ΔssaC mutant as a vaccine was determined in swine (3-4 week old pigs). The pigs (8 pigs per group) were vaccinated either orally via the drinking water or intramuscularly (IM), at a dose of about ˜1×109 CFUs / pig. For oral vaccination, 10 ml of the lab grown culture of the vaccine (grown generally as described in Example 2.D. below) was diluted 1:4 in ddH2O. 40 ml of this mixture was further diluted by adding 960 ml of sterile ddH2O; 100 ml of this final mixture was given to pigs orally via a waterer (pigs drank approximately 50 ml of water, giving a final vaccine dose of ˜2.6×108 per pig). For the IM vaccination, 27 ml of the 1:4 diluted vaccine culture was added to 3 ml of sterile WFI; 2.5 ml of this mixture was administered intramuscularly to each a...

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Abstract

Attenuated mutant Salmonella bacteria containing inactivated virulence genes are provided for use in safe efficacious vaccines.

Description

[0001] The present invention claims priority of U.S. provisional application No. 60 / 190,178 filed Mar. 17, 2000, the entire disclosure of which is incorporated by reference herein.FIELD OF THE INVENTION [0002] The present invention relates generally to genetically engineered salmonellae, which are useful as live vaccines. BACKGROUND OF THE INVENTION [0003] Diseases caused by Salmonella bacteria range from a mild, self-limiting diarrhea to serious gastrointestinal and septicemic disease in humans and animals. Salmonella is a gram-negative, rod-shaped, motile bacterium (nonmotile exceptions include S. gallinarum and S. pullorum) that is non-spore forming. Environmental sources of the organism include water, soil, insects, factory surfaces, kitchen surfaces, animal feces, raw meats, raw poultry, and raw seafoods. [0004]Salmonella infection is a widespread occurrence in animals, especially in poultry and swine, and is one of the most economically damaging of the enteric and septicemic d...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/00C12N15/01A61K39/112A61K48/00A61P1/00A61P1/12A61P31/04A61P37/02C07K14/255C12N1/20
CPCA61K2039/522C07K14/255A61K2039/523A61P1/00A61P1/12A61P31/04A61P37/02
Inventor LOWERY, DAVIDKENNEDY, MICHAEL
Owner PHARMACIA & UPJOHN CO
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