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US 8,465,755 B2Granted
Recombinant bacterium capable of eliciting an immune response against enteric pathogens
AssigneeArizona Board of Regents for and on behalf of Arizona State University
InventorsRoy Curtiss, III, Melha Mellata, Bereket Zekarias, Zhaoxing Shi, Christine Branger, Kenneth Roland
Life of this patent
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Abstract
The present invention relates to a recombinant bacterium that is capable of eliciting an immune response against at least two enteric pathogens, without substantially inducing an immune response specific to the serotype of the bacterium. The invention also relates to methods of making such a bacterium and vaccines and methods of using such a bacterium.
Claims28
A recombinant Salmonella bacterium, wherein
- (a) the recombinant bacterium is selected from the group consisting of S. Typhimurium, S. Paratyphi, or S. Typhi, and comprises one or more mutations that reduce serotype-specific immune responses caused by at least one serotype-specific antigen selected from LPS O-antigen, a component of a flagellum, or the Vi capsular antigen, wherein the one or more mutations are selected from the group consisting of:
- (i) a pmi mutation that results in lack of function of the pmi gene product,
- (ii) a rfc mutation, such that LPS O-antigen synthesis is greater during in vitro growth compared to in vivo growth of the recombinant bacterium,
- (iii) a galE mutation that results in lack of function of the galE gene product,
- (iv) a fliB mutation that reduces expression of the structural gene for Phase II flagellar antigen,
- (v) a fliC mutation that reduces expression of the antigenically variable serotype-specific domain of the Phase I FliC flagellar antigen, and
- (vi) or a Vi capsular antigen mutation that reduces synthesis of the Vi capsular antigen;
- (b) the recombinant bacterium expresses at least one nucleic acid encoding at least two enteric antigens, wherein the enteric antigens are selected from the groups consisting of:
- (i) Salmonella enterica iron regulated outer membrane protein (IROMP) or manganese regulated outer membrane protein (MnROMP),
- (ii) Yersinia entercolitica V antigen or psn nucleic acid product,
- (iii) Shigella species IpaD or aerobactin,
- (iv) E. coli salmochelin, aerobactin, sit operon nucleic acid product, vaqZ nucleic acid product, a fimbrial operon nucleic acid product, tsh nucleic acid product, iss nucleic acid product, or LTB,
- (v) C. jejuni PilA or CjaA, and
- (vi) C. perfringens alpha-toxin or NetB,
- such that the recombinant bacterium, when administered to a host, is capable of eliciting an immune response against at least two enteric pathogens;
- and
- (c) the recombinant bacterium comprises at least one mutation in a nucleic acid regulating the expression of a nucleic acid encoding an IROMP or MnROMP, such that expression of IROMP or MnROMP is greater during in vivo growth of the bacterium compared to in vitro growth of the bacterium.
14 more elements
A recombinant Salmonella bacterium, wherein
- (a) the recombinant bacterium is from the group consisting of S. Typhimurium, S. Paratyphi, and S. Typhi, and comprises one or more mutations that reduce serotype-specific immune responses caused by at least one serotype-specific antigen selected from LPS O-antigen, a component of a flagellum, or the Vi capsular antigen, wherein the one or more mutations are selected from the group consisting of:
- (i) a pmi mutation that results in lack of function of the pmi gene product,
- (ii) a rfc mutation, such that LPS O-antigen synthesis is greater during in vitro growth compared to in vivo growth of the recombinant bacterium,
- (iii) a galE mutation that results in lack of function of the galE gene product,
- (iv) a fliB mutation that reduces expression of the structural gene for Phase II flagellar antigen,
- (v) a fliC mutation that reduces expression of the antigenically variable serotype-specific domain of the Phase I FliC flagellar antigen, and
- (vi) or a Vi capsular antigen mutation that reduces synthesis of the Vi capsular antigen;
- (b) the recombinant bacterium comprises the mutation ΔPcrp::TT araC PBAD crp;
- and
- (c) the recombinant bacterium comprises at least one mutation in fur or mntR.
7 more elements
A recombinant Salmonella bacterium, wherein
- (a) the recombinant bacterium is derived-selected from the group consisting of S. Typhimurium, S. Paratyphi, or S. Typhi, and comprises one or more mutations that reduce serotype-specific immune responses caused by at least one serotype-specific antigen selected from LPS O-antigen, a component of a flagellum, or the Vi capsular antigen, wherein the one or more mutations are selected from the group consisting of:
- (i) a pmi mutation that results in lack of function of the pmi gene product,
- (ii) a rfc mutation, such that LPS O-antigen synthesis is greater during in vitro growth compared to in vivo growth of the recombinant bacterium,
- (iii) a galE mutation that results in lack of function of the galE gene product,
- (iv) a fliB mutation that reduces expression of the structural gene for Phase II flagellar antigen,
- (v) a fliC mutation that reduces expression of the antigenically variable serotype-specific domain of the Phase I FliC flagellar antigen, and
- (vi) or a Vi capsular antigen mutation that reduces synthesis of the Vi capsular antigen;
- (b) the recombinant bacterium comprises the mutation ΔPcrp::TT araC PBAD Crp;
- (c) the recombinant bacterium comprises at least one mutation in fur or mntR;
- and
- (d) the recombinant bacterium expresses at least one enteric antigen selected from the group consisting of (i) Salmonella enterica IROMP or MnROMP, (ii) Yersinia entercolitica V antigen nucleic acid product or psn nucleic acid product, (iii) Shigella species IpaD or aerobactin, (iv) E. coli salmochelin, aerobactin, sit operon nucleic acid product, yagZ nucleic acid product, a fimbrial operon nucleic acid product, tsh nucleic acid product, iss nucleic acid product, or LTB, (v) C. jejuni PilA or CjaA, and (vi) C. perfringens alpha-toxin or NetB.
8 more elements
Dependencies are inferred from the claim text.