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-10695415-B2
Publication Date
2020-06-30
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 describes a transgenic Salmonella typhi Ty21a in which a heterologous Shigella sonnei O-antigen biosynthetic gene region and a heterologous acid resistance biosynthetic gene system are integrated into the Salmonella typhi Ty21a chromosome. The heterologous Shigella sonnei O-antigen biosynthetic gene region comprises a wzz gene, and the heterologous Shigella sonnei O-antigen is stably expressed.
The transgenic Ty21a further comprises heterologous Shigella acid resistance enzymes including a YbaS gene, integrated as part of the heterologous acid resistance biosynthetic gene system. The heterologous acid resistance enzymes are stably expressed and make the transgenic Salmonella typhi Ty21a more acid stable at pH 2.5 than Salmonella typhi Ty21a without the integrated acid resistance biosynthetic gene system.
The invention further relates to eliciting immune responses against virulent Shigella sonnei challenge and virulent Salmonella typhi challenge using the transgenic Salmonella typhi Ty21a. The described constructs include Ty21a derivatives with different O-antigen and acid resistance configurations, and the described examples evaluate stable expression, acid stability at pH 2.5, and challenge-protection and immunogenicity outcomes.
Claims Coverage
The document contains one independent claim. The independent claim covers an engineered transgenic Salmonella typhi Ty21a with chromosomal integration of a heterologous Shigella sonnei O-antigen biosynthetic gene region and a heterologous Shigella acid resistance biosynthetic gene system, where stable O-antigen expression and stable acid-resistance enzyme expression together provide improved acid stability at pH 2.5 and elicit immune responses against virulent Shigella sonnei challenge and virulent Salmonella typhi challenge.
Chromosomal integration of heterologous Shigella sonnei O-antigen and heterologous acid resistance systems
A transgenic Salmonella typhi Ty21a comprising a heterologous Shigella sonnei O-antigen biosynthetic gene region and a heterologous acid resistance biosynthetic gene system comprising one or more heterologous Shigella acid resistance enzymes, wherein both are integrated into the Salmonella typhi Ty21a chromosome.
Defined wzz gene enabling stable Shigella sonnei O-antigen expression
The heterologous Shigella sonnei O-antigen biosynthetic gene region comprises a wzz gene defined by a DNA sequence sharing at least 95% sequence identity with the specified sequence or being that specified sequence, wherein a heterologous Shigella sonnei O-antigen is stably expressed.
Heterologous YbaS-based acid resistance system enabling improved acid stability at pH 2.5
One or more heterologous Shigella acid resistance enzymes comprising a YbaS gene are stably expressed, wherein the transgenic Salmonella typhi Ty21a is more acid stable at pH 2.5 than Salmonella typhi Ty21a without the integrated acid resistance biosynthetic gene system.
Immune responses against virulent Shigella sonnei and virulent Salmonella typhi
An immune response is elicited against virulent Shigella sonnei challenge and an immune response is elicited against virulent Salmonella typhi challenge.
Overall, the claim set centers on a chromosomally integrated Ty21a that stably expresses a heterologous Shigella sonnei O-antigen gene region containing a defined wzz gene, together with a stably expressed heterologous Shigella acid resistance gene system comprising YbaS. The combination is claimed to produce improved acid stability at pH 2.5 while eliciting immune responses against both virulent Shigella sonnei challenge and virulent Salmonella typhi challenge.
Stated Advantages
The transgenic Salmonella typhi Ty21a is more acid stable at pH 2.5 than Salmonella typhi Ty21a without the integrated acid resistance biosynthetic gene system.
An immune response is elicited against virulent Shigella sonnei challenge.
An immune response is elicited against virulent Salmonella typhi challenge.
Documented Applications
An immune-response-eliciting vaccine use against virulent Shigella sonnei challenge and virulent Salmonella typhi challenge, including a dependent narrowing to an oral administration vaccine formulation.
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