# US 11,324,814 B2 · Live attenuated oral vaccine against ETEC and typhoid fever

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- Number: US 11,324,814 B2
- Document ID: US11324814B2
- Status: Granted
- Kind: B2
- Application number: 16/897,999
- Filed: 2020-06-10
- Published: 2020-12-03
- Granted: 2022-05-10
- Earliest claimed: 2015-07-06
- Assignees: Protein Potential, LLC
- Applicants: Protein Potential, LLC
- Inventors: Yun Wu; Dennis J. Kopecko; B. Kim Lee Sim; Stephen L. Hoffman
- Web page: https://patentgrep.com/patent/US11324814B2

## CPC

- A61K 39/0283: {Shigella}
- A61K 39/0275: {Salmonella}
- A61P 31/04: Antibacterial agents
- A61K 39/116: Polyvalent bacterial antigens
- A61K 2039/522: {avirulent or attenuated}
- A61K 2039/523: {expressing foreign proteins}
- A61K 2039/543: {intranasal}
- A61K 2039/70: {Multivalent vaccine}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## 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.

## Claims

### Claim 1

A transgenic Salmonella typhi Ty21a comprising a heterologous enterotoxogenic Escherichia coli (ETEC) antigen biosynthetic gene region and a heterologous acid resistance biosynthetic gene system comprising one or more heterologous Shigella acid resistance enzymes, wherein:
a. said heterologous ETEC antigen biosynthetic gene region and said heterologous acid resistance biosynthetic gene system are integrated into the Salmonella typhi Ty21a chromosome;
b. an ETEC antigen is stably expressed from said integrated heterologous ETEC antigen biosynthetic gene region;
c. said one or more heterologous Shigella acid resistance enzymes are stably expressed;
d. said one or more heterologous Shigella acid resistance enzymes of the heterologous acid resistance biosynthetic gene system comprises a YbaS gene; and
e. said transgenic Salmonella typhi Ty2a is more acid stable at pH 2.5 than Salmonella typhi Ty21a without the integrated heterologous acid resistance biosynthetic gene system.

### Claim 2 (depends on 1)

The transgenic Salmonella typhi Ty21a of claim 1, which is capable of eliciting an immune response against ETEC.

### Claim 3 (depends on 2)

The transgenic Salmonella typhi Ty21a of claim 2, which is further capable of eliciting an immune response against a Salmonella typhi challenge.

### Claim 4 (depends on 1)

A composition comprising the transgenic Salmonella typhi Ty21a of claim 1 in combination with a carrier suitable for pharmaceutical use.

### Claim 5 (depends on 4)

A vaccine comprising the composition of claim 4, which is suitable for oral administration.

### Claim 6 (depends on 1)

The transgenic Salmonella typhi Ty21a of claim 1, which is capable of eliciting an immune response against ETEC.

### Claim 7 (depends on 6)

The transgenic Salmonella typhi Ty21a of claim 6, which is further capable of eliciting an immune response against a Salmonella typhi challenge.

### Claim 8 (depends on 1)

The transgenic Salmonella typhi Ty21a of claim 1, wherein the YbaS gene comprises (i) a DNA sequence that shares at least 95% sequence identity with the DNA sequence of nucleic acids 4,503,240 to 4,504,172 of SEQ ID NO: 1 or (II) the DNA sequence of nucleic acids 4,503,240 to 4,504,172 of SEQ ID NO: 1.

### Claim 9 (depends on 1)

A composition comprising the transgenic Salmonella typhi Ty21a of claim 1 in combination with a carrier suitable for pharmaceutical use.

### Claim 10 (depends on 9)

A vaccine comprising the composition of claim 9, which is suitable for oral administration.

### Claim 11 (depends on 1)

The transgenic Salmonella typhi Ty21a of claim 1, wherein the heterologous acid resistance biosynthetic gene system further comprises GadA gene, GadB gene, GadC gene, or any combination thereof.