Live attenuated oral vaccine against shigellosis and typhoid fever
AssigneeSanaria Inc.
InventorsYun Wu, Dennis J. Kopecko, B. Kim Lee Sim, Stephen L. Hoffman
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Abstract
Disclosed is the attenuated Salmonella typhi vaccine Ty21a utilized as a vector for Shigella and/or enterotoxogenic E. coli genes stably integrated in the Ty21a chromosome. These genes include a heterologous Shigella sonnei O-antigen biosynthetic gene region that comprises the wzz gene and expresses Shigella sonnei form 1 O-antigen, as well as a heterologous acid resistance biosynthetic gene system comprising a YbaS gene, which enables increased stability of the Ty21a vector at pH 2.5 relative to Ty21a without the integrated acid resistance biosynthetic gene system.
Claims11
A method of treating or reducing the incidence of shigellosis in a human subject comprising oral administration of one or more doses of a vaccine, said vaccine comprising a transgenic Ty21a Salmonella typhi Ty21a, which comprises (i) a heterologous Shigella sonnei O-antigen biosynthetic gene region comprising a wzz gene, wherein the wzz gene comprises a DNA sequence that shares at least 95% sequence identity with the DNA sequence of nucleic acids 4,511,904 to 4,513,010 of SEQ ID NO:
- 4;
- and (ii) a heterologous acid resistance biosynthetic gene system comprising one or more YbaS genes;
- wherein said heterologous Shigella sonnei O-antigen biosynthetic gene region and said heterologous acid resistance biosynthetic gene system are both integrated into the Salmonella typhi Ty21a chromosome, and wherein:
- a. the heterologous Shigella sonnei O-antigen is stably expressed;
- b. the one or more YbaS genes are stably expressed;
- c. said transgenic Salmonella typhi Ty21a is more acid stable at pH 2.5 than Salmonella typhi Ty21a without the integrated acid resistance biosynthetic gene system;
- d. an immune response is elicited against virulent Shigella sonnei challenge;
- and,
- e. an immune response is elicited against virulent Salmonella typhi challenge.
A method of treating or reducing the incidence of enterotoxogenic E. coli (ETEC) in a human subject comprising oral administration of one or more doses of a vaccine, said vaccine comprising a transgenic Ty21a Salmonella typhi Ty21a comprising (i) a heterologous ETEC antigen biosynthetic gene region, and (ii) a heterologous acid resistance biosynthetic gene system comprising one or more YbaS genes;
- wherein said ETEC antigen biosynthetic gene region and said acid resistance biosynthetic gene system are both integrated into the Salmonella typhi Ty21a chromosome, and wherein:
- a. the ETEC antigen is stably expressed;
- b. the one or more YbaS genes are stably expressed;
- c. said transgenic Salmonella typhi Ty21a is more acid stable at pH 2.5 than Salmonella typhi Ty21a without the integrated acid resistance biosynthetic gene system;
- d. an immune response is elicited against virulent Enterotoxogenic E. coli challenge;
- and
- e. an immune response is elicited against virulent Salmonella typhi challenge.
Dependencies are inferred from the claim text.