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1. WO2020157203 - SOUCHE MODIFIÉE DE SALMONELLA ENTERICA TYPHI

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Claims

1. A live attenuated strain of Salmonella enterica serovar Typhi wherein said strain is modified to express the lipopolysaccharide 02 O-antigens and the flagella proteins of Salmonella enterica serovar Paratyphi A.

2. The live attenuated strain of claim 1 , wherein the modification of said strain includes where the native rfbE gene is inactivated.

3. The live attenuated strain of claim 1 or 2, wherein the modification of said strain includes where the native rfbE gene is deleted.

4. The live attenuated strain of claims 1 -3, wherein the native rfbE gene is inactivated by the insertion of a spacer region of DNA, preferably wherein the spacer region of DNA is the cistron of the Escherichia coli gene wbdR.

5. The live attenuated strain of claims 1-4, wherein the resulting lipopolysaccharide 02 O-antigens are at least equivalent in length to the lipopolysaccharide 09 O-antigens of Salmonella enterica serovar Typhi.

6. The live attenuated strain of claims 1 -5, wherein said strain has its native fliC gene substituted with the fliC gene of Salmonella enterica serovar Paratyphi A, or wherein the substituted fliC gene is expressed in trans, such that the conferred serotype is altered from an Hd serotype to a Ha serotype.

7. The live attenuated strain of claims 1 -6 , wherein said strain is modified to contain a functional fepE gene, such that long O-antigen chains are generated, preferably wherein the O-antigen chains are 100 repeated units of the trisaccharide backbone in length and/or wherein said strain is further modified to constitutively express gtrC, or wherein the gtrC gene is expressed in trans, and/or wherein said strain is further modified to contain an additional copy of the tviA gene under the control of a phagosomally induced promoter.

8. A vaccine comprising the live attenuated strain of claims 1 -7, for use in enhancing immunogenicity against Salmonella enterica serovar Paratyphi A and for use in the treatment or prevention of enteric fever and salmonellosis.

9. The vaccine according to claims 1-8, wherein said strain is ZH9 or ZH9PA.

10. The vaccine according to claim 9, wherein ZH9 or ZH9PA is a single component of said vaccine or wherein ZH9 and ZH9PA are present in combination.

11. A live attenuated strain of Salmonella enterica serovar Typhi wherein said strain is modified to express the lipopolysaccharide 04 O-antigens and the flagella proteins of Salmonella enterica serovar Paratyphi B and Salmonella enterica serovar Typhimurium.

12. The live attenuated strain of claim 11 , wherein the modification of said strain includes the replacement of the native rfbS gene with the rfbJ gene of Salmonella enterica serovar Paratyphi B and/or Salmonella enterica serovar Typhimurium, or wherein the modification of said strain includes the inactivation of the native rfbS gene with the concurrent trans expression of the rfbJ gene of Salmonella enterica serovar Paratyphi B and/or Salmonella enterica serovar Typhimurium.

13. The live attenuated strain of claims 1 1 or 12, wherein said strain has its native fliC gene replaced with the fliC gene of Salmonella enterica serovar Paratyphi B and/or Salmonella enterica serovar Typhimurium, or wherein the substituted fliC gene is expressed in trans, such that the conferred serotype is altered from an Hd serotype to a Hb and Hi serotype respectively.

14. The live attenuated strain of claims 1 1-13, wherein the fljBA locus of Salmonella enterica serovar Paratyphi B and Salmonella enterica serovar Typhimurium are inserted into the chromosome of Salmonella enterica serovar Typhi or expressed in trans.

15. The live attenuated strain of claims 1 1-13, wherein the hix sites flanking the native promoter of the fljBA operon, or the hin recombinase gene, are modified to achieve constitutive expression.

16. The live attenuated strain of claims 1 1 -15, wherein the strain is further modified according to claim 7.

17. A vaccine comprising the live attenuated strain of claims 11 -16, for use in enhancing immunogenicity against Salmonella enterica serovar Paratyphi B and/or Salmonella enterica serovar Typhimurium and for use in the treatment or prevention of enteric fever and salmonellosis.