Live attenuated oral vaccine against shigellosis and typhoid fever

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 suitable for oral administration, 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, 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 suitable for oral administration, 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/or
• e. an immune response is elicited against virulent Salmonella typhi challenge.