Live attenuated oral vaccine against etec and typhoid fever

A method of treating, preventing, eliciting an immune response to, or reducing the incidence of shigellosis in a human subject comprising orally administering a composition comprising:

• a transgenic Salmonella typhi Ty21a comprising a heterologous Shigella sonnei O-antigen biosynthetic gene region and a heterologous acid resistance biosynthetic gene system, said heterologous Shigella sonnei O-antigen biosynthetic gene region and said heterologous acid resistance biosynthetic gene system both being integrated into the Salmonella typhi Ty21a chromosome, wherein the heterologous Shigella sonnei O-antigen biosynthetic gene region comprises a wzz gene comprising (i) 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;
• or (ii) the DNA sequence of nucleic acids 4,511,904 to 4,513,010 of SEQ ID NO:
• 4, and wherein:
• a. a heterologous Shigella sonnei O-antigen is stably expressed;
• b. one or more heterologous Shigella acid resistance enzymes of the heterologous acid resistance biosynthetic gene system, which comprises a YbaS gene, are stably expressed;
• c. said transgenic Salmonella typhi Ty21a is more acid stable at pH 2.5 than Salmonella typhi Ty21a without the integrated heterologous acid resistance biosynthetic gene system;
• and
• d. an immune response is elicited against a virulent Shigella sonnei challenge.

A method of treating, preventing, eliciting an immune response to, or reducing the incidence of typhoid fever in a human subject comprising orally administering a composition comprising:

• a transgenic Salmonella typhi Ty21a comprising a heterologous Shigella sonnei O-antigen biosynthetic gene region and a heterologous acid resistance biosynthetic gene system, said heterologous Shigella sonnei O-antigen biosynthetic gene region and said heterologous acid resistance biosynthetic gene system both being integrated into the Salmonella typhi Ty21a chromosome, wherein the heterologous Shigella sonnei O-antigen biosynthetic gene region comprises a wzz gene comprising (i) 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;
• or (ii) the DNA sequence of nucleic acids 4,511,904 to 4,513,010 of SEQ ID NO:
• 4, and wherein:
• a. a heterologous Shigella sonnei O-antigen is stably expressed;
• b. one or more heterologous Shigella acid resistance enzymes of the heterologous acid resistance biosynthetic gene system, which comprises a YbaS gene, are stably expressed;
• c. said transgenic Salmonella typhi Ty21a is more acid stable at pH 2.5 than Salmonella typhi Ty21a without the integrated heterologous acid resistance biosynthetic gene system;
• d. an immune response is elicited against a virulent Shigella sonnei challenge;
• and
• e. an immune response is elicited against a virulent Salmonella typhi challenge.