Live attenuated oral vaccine against shigellosis and typhoid fever
Inventors
Wu, Yun • Kopecko, Dennis J. • Sim, B. Kim Lee • Hoffman, Stephen L.
Assignees
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Publication Number
US-12409213-B2
Publication Date
2025-09-09
Expiration Date
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.
Core Innovation
The invention provides a bivalent live attenuated oral vaccine using a transgenic Salmonella typhi Ty21a that comprises heterologous Shigella sonnei O-antigen biosynthetic gene region and a heterologous acid resistance biosynthetic gene system. The Shigella sonnei O-antigen biosynthetic gene region comprises a wzz gene and is stably expressed in the Ty21a background. The heterologous acid resistance biosynthetic gene system comprises one or more YbaS genes that are stably expressed in the Ty21a chromosome.
Both the heterologous Shigella sonnei O-antigen biosynthetic gene region and the heterologous acid resistance biosynthetic gene system are integrated into the Ty21a chromosome. The resulting transgenic Ty21a is more acid stable at pH 2.5 than Salmonella typhi Ty21a without the integrated acid resistance biosynthetic gene system. The enhanced acid stability is used to support that oral administration elicits immune responses.
The invention further provides a method that elicits an immune response against virulent Shigella sonnei challenge and an immune response against virulent Salmonella typhi challenge following oral administration of one or more doses of the vaccine to a human subject. In addition, the invention extends the platform to an enterotoxogenic E. coli (ETEC) application by using a transgenic Ty21a vaccine comprising a heterologous ETEC antigen biosynthetic gene region integrated with the YbaS-based acid resistance biosynthetic gene system. In that ETEC embodiment, the transgenic Ty21a is also more acid stable at pH 2.5 than Ty21a without the integrated acid resistance biosynthetic gene system and elicits immune responses against virulent ETEC challenge and virulent Salmonella typhi challenge.
Claims Coverage
The partial claims include two independent claims, each centered on oral administration of a transgenic Ty21a vaccine integrating a heterologous antigen biosynthetic gene region and a YbaS-based heterologous acid resistance biosynthetic gene system into the Ty21a chromosome. Across the independent claims, the coverage requires stable expression of the integrated gene regions, increased acid stability at pH 2.5, and elicitation of immune responses against the specified virulent challenge and against virulent Salmonella typhi challenge.
Transgenic Ty21a with Shigella sonnei O-antigen and YbaS acid resistance for oral shigellosis reduction
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, wherein the vaccine comprises a transgenic Ty21a Salmonella typhi Ty21a integrated into the Ty21a chromosome with a heterologous Shigella sonnei O-antigen biosynthetic gene region comprising a wzz gene and a heterologous acid resistance biosynthetic gene system comprising one or more YbaS genes, wherein the heterologous gene regions are stably expressed, the transgenic Ty21a is more acid stable at pH 2.5 than non-engineered Ty21a, and an immune response is elicited against virulent Shigella sonnei challenge and against virulent Salmonella typhi challenge.
Transgenic Ty21a with ETEC antigen and YbaS acid resistance for oral ETEC reduction
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, wherein the vaccine comprises a transgenic Ty21a Salmonella typhi Ty21a integrated into the Ty21a chromosome with a heterologous ETEC antigen biosynthetic gene region and a heterologous acid resistance biosynthetic gene system comprising one or more YbaS genes, wherein the heterologous gene regions are stably expressed, the transgenic Ty21a is more acid stable at pH 2.5 than non-engineered Ty21a, and an immune response is elicited against virulent Enterotoxogenic E. coli challenge and against virulent Salmonella typhi challenge.
Overall, the claim coverage requires a transgenic Ty21a vaccine with integrated, stably expressed heterologous antigen gene regions together with a stably expressed YbaS-based acid resistance system to produce increased acid stability at pH 2.5 and to elicit immune responses against the specified virulent challenge and against virulent Salmonella typhi challenge.
Stated Advantages
More acid stable at pH 2.5 than Salmonella typhi Ty21a without the integrated acid resistance biosynthetic gene system.
Elicits immune response against virulent Shigella sonnei challenge.
Elicits immune response against virulent Salmonella typhi challenge.
Elicits immune response against virulent Enterotoxogenic E. coli challenge.
Documented Applications
Treating or reducing the incidence of shigellosis in a human subject via oral administration of the transgenic Ty21a vaccine.
Treating or reducing the incidence of enterotoxogenic E. coli (ETEC) in a human subject via oral administration of the transgenic Ty21a vaccine.
Treatment/incidence reduction extending to typhoid fever is described as an additional target in dependent claim coverage.
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