JP7023248B2 - 過剰ブレブ形成Shigella株 - Google Patents
過剰ブレブ形成Shigella株 Download PDFInfo
- Publication number
- JP7023248B2 JP7023248B2 JP2019021756A JP2019021756A JP7023248B2 JP 7023248 B2 JP7023248 B2 JP 7023248B2 JP 2019021756 A JP2019021756 A JP 2019021756A JP 2019021756 A JP2019021756 A JP 2019021756A JP 7023248 B2 JP7023248 B2 JP 7023248B2
- Authority
- JP
- Japan
- Prior art keywords
- bacterium
- shigella
- bleb
- medium
- strain
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 208000002352 blister Diseases 0.000 title claims description 124
- 241000607768 Shigella Species 0.000 title claims description 96
- 230000015572 biosynthetic process Effects 0.000 title description 8
- 108090000623 proteins and genes Proteins 0.000 claims description 95
- 241000894006 Bacteria Species 0.000 claims description 93
- 102000004169 proteins and genes Human genes 0.000 claims description 73
- 239000002158 endotoxin Substances 0.000 claims description 38
- 229920006008 lipopolysaccharide Polymers 0.000 claims description 37
- 238000000034 method Methods 0.000 claims description 36
- 239000000427 antigen Substances 0.000 claims description 26
- 108091007433 antigens Proteins 0.000 claims description 25
- 102000036639 antigens Human genes 0.000 claims description 25
- 239000012528 membrane Substances 0.000 claims description 18
- RHTNTTODYGNRSP-UHFFFAOYSA-N Tolazoline hydrochloride Chemical compound Cl.C=1C=CC=CC=1CC1=NCCN1 RHTNTTODYGNRSP-UHFFFAOYSA-N 0.000 claims description 16
- 230000004048 modification Effects 0.000 claims description 16
- 238000012986 modification Methods 0.000 claims description 16
- 101150077062 pal gene Proteins 0.000 claims description 15
- 101100203377 Bacillus subtilis (strain 168) slp gene Proteins 0.000 claims description 14
- 101100242529 Drosophila melanogaster Pal2 gene Proteins 0.000 claims description 14
- 101150012565 LRIT1 gene Proteins 0.000 claims description 14
- 101100477497 Mus musculus Shcbp1 gene Proteins 0.000 claims description 14
- 241000350158 Prioria balsamifera Species 0.000 claims description 13
- 230000035772 mutation Effects 0.000 claims description 12
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 10
- GZQKNULLWNGMCW-PWQABINMSA-N lipid A (E. coli) Chemical group O1[C@H](CO)[C@@H](OP(O)(O)=O)[C@H](OC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCCCC)[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H]1OC[C@@H]1[C@@H](O)[C@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OP(O)(O)=O)O1 GZQKNULLWNGMCW-PWQABINMSA-N 0.000 claims description 10
- 229910052742 iron Inorganic materials 0.000 claims description 5
- 101100451792 Bacillus subtilis (strain 168) htrB gene Proteins 0.000 claims description 3
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical group N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 claims description 3
- 230000000415 inactivating effect Effects 0.000 claims description 3
- 230000000977 initiatory effect Effects 0.000 claims description 3
- 101150011311 lpxL gene Proteins 0.000 claims description 3
- 101150081449 stxA gene Proteins 0.000 claims description 3
- 101150017169 stxB gene Proteins 0.000 claims description 3
- 239000005725 8-Hydroxyquinoline Substances 0.000 claims description 2
- 108090000790 Enzymes Proteins 0.000 claims description 2
- 102000004190 Enzymes Human genes 0.000 claims description 2
- UBQYURCVBFRUQT-UHFFFAOYSA-N N-benzoyl-Ferrioxamine B Chemical compound CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN UBQYURCVBFRUQT-UHFFFAOYSA-N 0.000 claims description 2
- 229960003540 oxyquinoline Drugs 0.000 claims description 2
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 claims description 2
- 241000305071 Enterobacterales Species 0.000 claims 1
- 239000000203 mixture Substances 0.000 description 80
- 239000002671 adjuvant Substances 0.000 description 51
- 239000000839 emulsion Substances 0.000 description 39
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 24
- 229920000053 polysorbate 80 Polymers 0.000 description 24
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N dodecahydrosqualene Natural products CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 description 23
- 239000012634 fragment Substances 0.000 description 23
- 230000002163 immunogen Effects 0.000 description 22
- 229960005486 vaccine Drugs 0.000 description 22
- 229940024606 amino acid Drugs 0.000 description 21
- 150000001413 amino acids Chemical class 0.000 description 21
- 108090000765 processed proteins & peptides Proteins 0.000 description 21
- 125000003275 alpha amino acid group Chemical group 0.000 description 20
- 239000003921 oil Substances 0.000 description 20
- 235000019198 oils Nutrition 0.000 description 20
- 102000004196 processed proteins & peptides Human genes 0.000 description 20
- 229920001184 polypeptide Polymers 0.000 description 19
- 229930182490 saponin Natural products 0.000 description 19
- 150000007949 saponins Chemical class 0.000 description 19
- 235000017709 saponins Nutrition 0.000 description 19
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 description 18
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 description 18
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 description 17
- 239000013612 plasmid Substances 0.000 description 17
- 229940031439 squalene Drugs 0.000 description 17
- 239000004094 surface-active agent Substances 0.000 description 16
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 15
- -1 for example Chemical class 0.000 description 14
- 230000002588 toxic effect Effects 0.000 description 14
- 208000004429 Bacillary Dysentery Diseases 0.000 description 13
- 230000002779 inactivation Effects 0.000 description 13
- 239000001397 quillaja saponaria molina bark Substances 0.000 description 13
- 231100000331 toxic Toxicity 0.000 description 13
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
- 238000004519 manufacturing process Methods 0.000 description 12
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 11
- 239000002245 particle Substances 0.000 description 11
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 11
- 230000001580 bacterial effect Effects 0.000 description 10
- 230000037430 deletion Effects 0.000 description 10
- 238000012217 deletion Methods 0.000 description 10
- 108091034117 Oligonucleotide Proteins 0.000 description 9
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 9
- 238000001914 filtration Methods 0.000 description 9
- 229940035032 monophosphoryl lipid a Drugs 0.000 description 9
- 229940068968 polysorbate 80 Drugs 0.000 description 9
- 206010040550 Shigella infections Diseases 0.000 description 8
- 239000000147 enterotoxin Substances 0.000 description 8
- 231100000655 enterotoxin Toxicity 0.000 description 8
- 101710146739 Enterotoxin Proteins 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 7
- PRXRUNOAOLTIEF-ADSICKODSA-N Sorbitan trioleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC[C@H](O)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC PRXRUNOAOLTIEF-ADSICKODSA-N 0.000 description 7
- 238000013459 approach Methods 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 229910052500 inorganic mineral Inorganic materials 0.000 description 7
- 239000011707 mineral Substances 0.000 description 7
- 231100000252 nontoxic Toxicity 0.000 description 7
- 230000003000 nontoxic effect Effects 0.000 description 7
- 150000003839 salts Chemical class 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 7
- 241000607762 Shigella flexneri Species 0.000 description 6
- 239000013504 Triton X-100 Substances 0.000 description 6
- 229920004890 Triton X-100 Polymers 0.000 description 6
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 6
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- 101150041954 galU gene Proteins 0.000 description 6
- 229920000136 polysorbate Polymers 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 6
- 238000006467 substitution reaction Methods 0.000 description 6
- 239000011732 tocopherol Substances 0.000 description 6
- 229930003799 tocopherol Natural products 0.000 description 6
- 239000003053 toxin Substances 0.000 description 6
- 231100000765 toxin Toxicity 0.000 description 6
- 108700012359 toxins Proteins 0.000 description 6
- HNLXNOZHXNSSPN-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[4-(2,4,4-trimethylpentan-2-yl)phenoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CC(C)(C)CC(C)(C)C1=CC=C(OCCOCCOCCOCCOCCOCCOCCO)C=C1 HNLXNOZHXNSSPN-UHFFFAOYSA-N 0.000 description 5
- 241000588724 Escherichia coli Species 0.000 description 5
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 210000004027 cell Anatomy 0.000 description 5
- 235000012000 cholesterol Nutrition 0.000 description 5
- GVJHHUAWPYXKBD-UHFFFAOYSA-N d-alpha-tocopherol Natural products OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 5
- 239000003937 drug carrier Substances 0.000 description 5
- 230000003053 immunization Effects 0.000 description 5
- 238000002649 immunization Methods 0.000 description 5
- 230000003308 immunostimulating effect Effects 0.000 description 5
- 235000021317 phosphate Nutrition 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 235000015112 vegetable and seed oil Nutrition 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- NYHBQMYGNKIUIF-UUOKFMHZSA-N Guanosine Chemical group C1=NC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O NYHBQMYGNKIUIF-UUOKFMHZSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- 108010076504 Protein Sorting Signals Proteins 0.000 description 4
- 101100021843 Shigella flexneri lpxM1 gene Proteins 0.000 description 4
- 101100021844 Shigella flexneri lpxM2 gene Proteins 0.000 description 4
- 241000607760 Shigella sonnei Species 0.000 description 4
- 229930182558 Sterol Natural products 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 238000009295 crossflow filtration Methods 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002191 fatty alcohols Chemical class 0.000 description 4
- 238000000855 fermentation Methods 0.000 description 4
- 230000004151 fermentation Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000499 gel Substances 0.000 description 4
- 101150096208 gtaB gene Proteins 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000003550 marker Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000007764 o/w emulsion Substances 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 4
- 239000010452 phosphate Substances 0.000 description 4
- 150000003904 phospholipids Chemical class 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 108020001580 protein domains Proteins 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 101150066981 rfbF gene Proteins 0.000 description 4
- 101150010276 rfbG gene Proteins 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 201000005113 shigellosis Diseases 0.000 description 4
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 235000003702 sterols Nutrition 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 235000010384 tocopherol Nutrition 0.000 description 4
- 229960001295 tocopherol Drugs 0.000 description 4
- 108010039939 Cell Wall Skeleton Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 208000032759 Hemolytic-Uremic Syndrome Diseases 0.000 description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 3
- 108700020354 N-acetylmuramyl-threonyl-isoglutamine Proteins 0.000 description 3
- 241001644525 Nastus productus Species 0.000 description 3
- 101710116435 Outer membrane protein Proteins 0.000 description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 3
- 208000033464 Reiter syndrome Diseases 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 3
- HSCJRCZFDFQWRP-RDKQLNKOSA-N UDP-D-glucose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1OP(O)(=O)OP(O)(=O)OC[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 HSCJRCZFDFQWRP-RDKQLNKOSA-N 0.000 description 3
- 229910052782 aluminium Inorganic materials 0.000 description 3
- 229940047712 aluminum hydroxyphosphate Drugs 0.000 description 3
- 239000003242 anti bacterial agent Substances 0.000 description 3
- 239000000227 bioadhesive Substances 0.000 description 3
- 210000004520 cell wall skeleton Anatomy 0.000 description 3
- 235000013339 cereals Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 150000001875 compounds Chemical class 0.000 description 3
- 210000002808 connective tissue Anatomy 0.000 description 3
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical class NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 230000002950 deficient Effects 0.000 description 3
- 239000003599 detergent Substances 0.000 description 3
- 230000029087 digestion Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000010419 fine particle Substances 0.000 description 3
- 230000036039 immunity Effects 0.000 description 3
- 239000002955 immunomodulating agent Substances 0.000 description 3
- 229940121354 immunomodulator Drugs 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000002736 nonionic surfactant Substances 0.000 description 3
- 229950004053 octoxinol Drugs 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 239000002953 phosphate buffered saline Substances 0.000 description 3
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 3
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 3
- 229920001983 poloxamer Polymers 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 208000002574 reactive arthritis Diseases 0.000 description 3
- 238000001179 sorption measurement Methods 0.000 description 3
- 229940032094 squalane Drugs 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 150000003432 sterols Chemical class 0.000 description 3
- 101150088820 tolR gene Proteins 0.000 description 3
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 3
- 239000003981 vehicle Substances 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 2
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 239000002028 Biomass Substances 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 101710099025 Colicin I receptor Proteins 0.000 description 2
- MIKUYHXYGGJMLM-GIMIYPNGSA-N Crotonoside Natural products C1=NC2=C(N)NC(=O)N=C2N1[C@H]1O[C@@H](CO)[C@H](O)[C@@H]1O MIKUYHXYGGJMLM-GIMIYPNGSA-N 0.000 description 2
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 2
- NYHBQMYGNKIUIF-UHFFFAOYSA-N D-guanosine Natural products C1=2NC(N)=NC(=O)C=2N=CN1C1OC(CO)C(O)C1O NYHBQMYGNKIUIF-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 2
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 2
- CKLJMWTZIZZHCS-UWTATZPHSA-N L-Aspartic acid Natural products OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- GOWLTLODGKPXMN-MEKRSRHXSA-N OM-174 Chemical compound O1[C@H](OP(O)(O)=O)[C@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](O)[C@H](O)[C@H]1CO[C@H]1[C@H](NC(=O)C[C@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](CO)O1 GOWLTLODGKPXMN-MEKRSRHXSA-N 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 2
- 239000004365 Protease Substances 0.000 description 2
- 241000147000 Shigella flexneri 2a Species 0.000 description 2
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 2
- 241001053296 Sternostoma boydi Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- 238000003917 TEM image Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000010933 acylation Effects 0.000 description 2
- 238000005917 acylation reaction Methods 0.000 description 2
- 238000007792 addition Methods 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 229960005261 aspartic acid Drugs 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- 230000027455 binding Effects 0.000 description 2
- 238000009739 binding Methods 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000002759 chromosomal effect Effects 0.000 description 2
- 230000001086 cytosolic effect Effects 0.000 description 2
- 238000011026 diafiltration Methods 0.000 description 2
- 229930182470 glycoside Natural products 0.000 description 2
- 229940029575 guanosine Drugs 0.000 description 2
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 2
- 101150028517 hlb gene Proteins 0.000 description 2
- 230000006801 homologous recombination Effects 0.000 description 2
- 238000002744 homologous recombination Methods 0.000 description 2
- HOPZBJPSUKPLDT-UHFFFAOYSA-N imidazo[4,5-h]quinolin-2-one Chemical class C1=CN=C2C3=NC(=O)N=C3C=CC2=C1 HOPZBJPSUKPLDT-UHFFFAOYSA-N 0.000 description 2
- 230000028993 immune response Effects 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 230000005847 immunogenicity Effects 0.000 description 2
- 230000001965 increasing effect Effects 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 238000011081 inoculation Methods 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 102000006240 membrane receptors Human genes 0.000 description 2
- 108020004084 membrane receptors Proteins 0.000 description 2
- 230000002503 metabolic effect Effects 0.000 description 2
- 238000001471 micro-filtration Methods 0.000 description 2
- 230000000813 microbial effect Effects 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 230000003232 mucoadhesive effect Effects 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 235000014571 nuts Nutrition 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 2
- 229920002851 polycationic polymer Polymers 0.000 description 2
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 239000002510 pyrogen Substances 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 101150012103 rfc gene Proteins 0.000 description 2
- 238000010845 search algorithm Methods 0.000 description 2
- 239000010686 shark liver oil Substances 0.000 description 2
- 229940069764 shark liver oil Drugs 0.000 description 2
- 108010089727 siderophore receptors Proteins 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 150000003505 terpenes Chemical class 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229960000984 tocofersolan Drugs 0.000 description 2
- 125000002640 tocopherol group Chemical class 0.000 description 2
- 235000019149 tocopherols Nutrition 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- XETCRXVKJHBPMK-MJSODCSWSA-N trehalose 6,6'-dimycolate Chemical compound C([C@@H]1[C@H]([C@H](O)[C@@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](COC(=O)C(CCCCCCCCCCC3C(C3)CCCCCCCCCCCCCCCCCC)C(O)CCCCCCCCCCCCCCCCCCCCCCCCC)O2)O)O1)O)OC(=O)C(C(O)CCCCCCCCCCCCCCCCCCCCCCCCC)CCCCCCCCCCC1CC1CCCCCCCCCCCCCCCCCC XETCRXVKJHBPMK-MJSODCSWSA-N 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 1
- JNYAEWCLZODPBN-JGWLITMVSA-N (2r,3r,4s)-2-[(1r)-1,2-dihydroxyethyl]oxolane-3,4-diol Chemical class OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O JNYAEWCLZODPBN-JGWLITMVSA-N 0.000 description 1
- UGXDVELKRYZPDM-XLXQKPBQSA-N (4r)-4-[[(2s,3r)-2-[[(2r)-2-[(2r,3r,4r,5r)-2-acetamido-4,5,6-trihydroxy-1-oxohexan-3-yl]oxypropanoyl]amino]-3-hydroxybutanoyl]amino]-5-amino-5-oxopentanoic acid Chemical compound OC(=O)CC[C@H](C(N)=O)NC(=O)[C@H]([C@H](O)C)NC(=O)[C@@H](C)O[C@@H]([C@H](O)[C@H](O)CO)[C@@H](NC(C)=O)C=O UGXDVELKRYZPDM-XLXQKPBQSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- PORPENFLTBBHSG-MGBGTMOVSA-N 1,2-dihexadecanoyl-sn-glycerol-3-phosphate Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(O)=O)OC(=O)CCCCCCCCCCCCCCC PORPENFLTBBHSG-MGBGTMOVSA-N 0.000 description 1
- TZCPCKNHXULUIY-RGULYWFUSA-N 1,2-distearoyl-sn-glycero-3-phosphoserine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP(O)(=O)OC[C@H](N)C(O)=O)OC(=O)CCCCCCCCCCCCCCCCC TZCPCKNHXULUIY-RGULYWFUSA-N 0.000 description 1
- PXFBZOLANLWPMH-UHFFFAOYSA-N 16-Epiaffinine Natural products C1C(C2=CC=CC=C2N2)=C2C(=O)CC2C(=CC)CN(C)C1C2CO PXFBZOLANLWPMH-UHFFFAOYSA-N 0.000 description 1
- FKMHSNTVILORFA-UHFFFAOYSA-N 2-[2-(2-dodecoxyethoxy)ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCO FKMHSNTVILORFA-UHFFFAOYSA-N 0.000 description 1
- IEQAICDLOKRSRL-UHFFFAOYSA-N 2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-dodecoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO IEQAICDLOKRSRL-UHFFFAOYSA-N 0.000 description 1
- PFCLMNDDPTZJHQ-XLPZGREQSA-N 2-amino-7-[(2r,4s,5r)-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-1h-pyrrolo[2,3-d]pyrimidin-4-one Chemical compound C1=CC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PFCLMNDDPTZJHQ-XLPZGREQSA-N 0.000 description 1
- LYFYWXLKKQIOKO-UHFFFAOYSA-N 3,3-diaminopentan-1-ol Chemical compound CCC(N)(N)CCO LYFYWXLKKQIOKO-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- 108010042708 Acetylmuramyl-Alanyl-Isoglutamine Proteins 0.000 description 1
- 229910017119 AlPO Inorganic materials 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 235000007319 Avena orientalis Nutrition 0.000 description 1
- 244000075850 Avena orientalis Species 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- IELOKBJPULMYRW-NJQVLOCASA-N D-alpha-Tocopheryl Acid Succinate Chemical compound OC(=O)CCC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C IELOKBJPULMYRW-NJQVLOCASA-N 0.000 description 1
- YVGGHNCTFXOJCH-UHFFFAOYSA-N DDT Chemical compound C1=CC(Cl)=CC=C1C(C(Cl)(Cl)Cl)C1=CC=C(Cl)C=C1 YVGGHNCTFXOJCH-UHFFFAOYSA-N 0.000 description 1
- 235000001815 DL-alpha-tocopherol Nutrition 0.000 description 1
- 239000011627 DL-alpha-tocopherol Substances 0.000 description 1
- 208000005156 Dehydration Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010012741 Diarrhoea haemorrhagic Diseases 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 229920005682 EO-PO block copolymer Polymers 0.000 description 1
- 241000588921 Enterobacteriaceae Species 0.000 description 1
- 244000140063 Eragrostis abyssinica Species 0.000 description 1
- 235000014966 Eragrostis abyssinica Nutrition 0.000 description 1
- IAJILQKETJEXLJ-UHFFFAOYSA-N Galacturonsaeure Natural products O=CC(O)C(O)C(O)C(O)C(O)=O IAJILQKETJEXLJ-UHFFFAOYSA-N 0.000 description 1
- 101150102398 Galt gene Proteins 0.000 description 1
- 206010017915 Gastroenteritis shigella Diseases 0.000 description 1
- ZWZWYGMENQVNFU-UHFFFAOYSA-N Glycerophosphorylserin Natural products OC(=O)C(N)COP(O)(=O)OCC(O)CO ZWZWYGMENQVNFU-UHFFFAOYSA-N 0.000 description 1
- 108700005492 His(29)- cholera holotoxin Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000957351 Homo sapiens Myc-associated zinc finger protein Proteins 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 108090000978 Interleukin-4 Proteins 0.000 description 1
- 108010002616 Interleukin-5 Proteins 0.000 description 1
- 108090001005 Interleukin-6 Proteins 0.000 description 1
- 108010002586 Interleukin-7 Proteins 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 1
- 229920002884 Laureth 4 Polymers 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- SJNZALDHDUYDBU-IHRRRGAJSA-N Lys-Arg-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(O)=O SJNZALDHDUYDBU-IHRRRGAJSA-N 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 241001092142 Molina Species 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 102100038750 Myc-associated zinc finger protein Human genes 0.000 description 1
- 229910004616 Na2MoO4.2H2 O Inorganic materials 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 241000588650 Neisseria meningitidis Species 0.000 description 1
- 108091028043 Nucleic acid sequence Proteins 0.000 description 1
- 108020003540 O-antigen polymerase Proteins 0.000 description 1
- 241000040340 Oat mosaic virus Species 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 108700026244 Open Reading Frames Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 201000005702 Pertussis Diseases 0.000 description 1
- 244000046052 Phaseolus vulgaris Species 0.000 description 1
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 1
- 102000006335 Phosphate-Binding Proteins Human genes 0.000 description 1
- 108010058514 Phosphate-Binding Proteins Proteins 0.000 description 1
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 1
- 229920001710 Polyorthoester Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241001454523 Quillaja saponaria Species 0.000 description 1
- 235000009001 Quillaja saponaria Nutrition 0.000 description 1
- 206010057071 Rectal tenesmus Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 241000219287 Saponaria Species 0.000 description 1
- 241000209056 Secale Species 0.000 description 1
- 235000007238 Secale cereale Nutrition 0.000 description 1
- 244000000231 Sesamum indicum Species 0.000 description 1
- 235000003434 Sesamum indicum Nutrition 0.000 description 1
- 108010079723 Shiga Toxin Proteins 0.000 description 1
- 108010017898 Shiga Toxins Proteins 0.000 description 1
- 101100018379 Shigella flexneri icsA gene Proteins 0.000 description 1
- 244000044822 Simmondsia californica Species 0.000 description 1
- 235000004433 Simmondsia californica Nutrition 0.000 description 1
- 240000002493 Smilax officinalis Species 0.000 description 1
- 235000008981 Smilax officinalis Nutrition 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 239000004147 Sorbitan trioleate Substances 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 108091008874 T cell receptors Proteins 0.000 description 1
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 description 1
- 230000029662 T-helper 1 type immune response Effects 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 102000008235 Toll-Like Receptor 9 Human genes 0.000 description 1
- 108010060818 Toll-Like Receptor 9 Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 235000019714 Triticale Nutrition 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 101100476911 Yersinia enterocolitica yscW gene Proteins 0.000 description 1
- 101100398736 Yersinia pestis lcrF gene Proteins 0.000 description 1
- ZBNRGEMZNWHCGA-PDKVEDEMSA-N [(2r)-2-[(2r,3r,4s)-3,4-bis[[(z)-octadec-9-enoyl]oxy]oxolan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)[C@H]1OC(=O)CCCCCCC\C=C/CCCCCCCC ZBNRGEMZNWHCGA-PDKVEDEMSA-N 0.000 description 1
- FWXAUDSWDBGCMN-DNQXCXABSA-N [(2r,3r)-3-diphenylphosphanylbutan-2-yl]-diphenylphosphane Chemical compound C=1C=CC=CC=1P([C@H](C)[C@@H](C)P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 FWXAUDSWDBGCMN-DNQXCXABSA-N 0.000 description 1
- NKVLDFAVEWLOCX-GUSKIFEASA-N [(2s,3r,4s,5r,6r)-3-[(2s,3r,4s,5r,6s)-5-[(2s,3r,4s,5r)-4-[(2s,3r,4r)-3,4-dihydroxy-4-(hydroxymethyl)oxolan-2-yl]oxy-3,5-dihydroxyoxan-2-yl]oxy-3,4-dihydroxy-6-methyloxan-2-yl]oxy-4,5-dihydroxy-6-methyloxan-2-yl] (4ar,5r,6as,6br,9s,10s,12ar)-10-[(2r,3r,4s, Chemical compound O([C@H]1[C@H](O)CO[C@H]([C@@H]1O)O[C@H]1[C@H](C)O[C@H]([C@@H]([C@@H]1O)O)O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](C)O[C@H]1OC(=O)[C@]12CCC(C)(C)CC1C1=CCC3[C@@]([C@@]1(C[C@H]2O)C)(C)CCC1[C@]3(C)CC[C@@H]([C@@]1(C)C=O)O[C@@H]1O[C@@H]([C@H]([C@H](O[C@H]2[C@@H]([C@@H](O)[C@H](O)CO2)O)[C@H]1O[C@H]1[C@@H]([C@@H](O)[C@@H](O)[C@@H](CO)O1)O)O)C(=O)NCCCCCCCCCCCC)[C@@H]1OC[C@](O)(CO)[C@H]1O NKVLDFAVEWLOCX-GUSKIFEASA-N 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000021736 acetylation Effects 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 230000000240 adjuvant effect Effects 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- IAJILQKETJEXLJ-QTBDOELSSA-N aldehydo-D-glucuronic acid Chemical compound O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)=O IAJILQKETJEXLJ-QTBDOELSSA-N 0.000 description 1
- 150000005215 alkyl ethers Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229940061720 alpha hydroxy acid Drugs 0.000 description 1
- 150000001280 alpha hydroxy acids Chemical class 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 238000010913 antigen-directed enzyme pro-drug therapy Methods 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000001851 biosynthetic effect Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 238000006664 bond formation reaction Methods 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 230000036755 cellular response Effects 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 235000012716 cod liver oil Nutrition 0.000 description 1
- 239000003026 cod liver oil Substances 0.000 description 1
- 206010009887 colitis Diseases 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 238000012937 correction Methods 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000002577 cryoprotective agent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 229940099418 d- alpha-tocopherol succinate Drugs 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003795 desorption Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- PSLWZOIUBRXAQW-UHFFFAOYSA-M dimethyl(dioctadecyl)azanium;bromide Chemical compound [Br-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC PSLWZOIUBRXAQW-UHFFFAOYSA-M 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- ZGSPNIOCEDOHGS-UHFFFAOYSA-L disodium [3-[2,3-di(octadeca-9,12-dienoyloxy)propoxy-oxidophosphoryl]oxy-2-hydroxypropyl] 2,3-di(octadeca-9,12-dienoyloxy)propyl phosphate Chemical compound [Na+].[Na+].CCCCCC=CCC=CCCCCCCCC(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COP([O-])(=O)OCC(O)COP([O-])(=O)OCC(OC(=O)CCCCCCCC=CCC=CCCCCC)COC(=O)CCCCCCCC=CCC=CCCCCC ZGSPNIOCEDOHGS-UHFFFAOYSA-L 0.000 description 1
- NLEBIOOXCVAHBD-QKMCSOCLSA-N dodecyl beta-D-maltoside Chemical compound O[C@@H]1[C@@H](O)[C@H](OCCCCCCCCCCCC)O[C@H](CO)[C@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 NLEBIOOXCVAHBD-QKMCSOCLSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 238000000635 electron micrograph Methods 0.000 description 1
- 238000001493 electron microscopy Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000002357 endometrial effect Effects 0.000 description 1
- 230000007893 endotoxin activity Effects 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000002195 fatty ethers Chemical class 0.000 description 1
- 229960002413 ferric citrate Drugs 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 229940013317 fish oils Drugs 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 238000001943 fluorescence-activated cell sorting Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 101150002054 galE gene Proteins 0.000 description 1
- 101150045500 galK gene Proteins 0.000 description 1
- 101150054547 galM gene Proteins 0.000 description 1
- 238000001502 gel electrophoresis Methods 0.000 description 1
- 229940097043 glucuronic acid Drugs 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 244000005709 gut microbiome Species 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 208000027909 hemorrhagic diarrhea Diseases 0.000 description 1
- 108010037896 heparin-binding hemagglutinin Proteins 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930186900 holotoxin Natural products 0.000 description 1
- 229920002674 hyaluronan Polymers 0.000 description 1
- 229960003160 hyaluronic acid Drugs 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- FAHBNUUHRFUEAI-UHFFFAOYSA-M hydroxidooxidoaluminium Chemical compound O[Al]=O FAHBNUUHRFUEAI-UHFFFAOYSA-M 0.000 description 1
- 229960002751 imiquimod Drugs 0.000 description 1
- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 230000002584 immunomodulator Effects 0.000 description 1
- 230000001976 improved effect Effects 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229960003130 interferon gamma Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- NPFOYSMITVOQOS-UHFFFAOYSA-K iron(III) citrate Chemical compound [Fe+3].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NPFOYSMITVOQOS-UHFFFAOYSA-K 0.000 description 1
- 229940119170 jojoba wax Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 229940062711 laureth-9 Drugs 0.000 description 1
- 239000006193 liquid solution Substances 0.000 description 1
- 230000004807 localization Effects 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 101150060640 lpxM gene Proteins 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 230000003278 mimic effect Effects 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- BSOQXXWZTUDTEL-ZUYCGGNHSA-N muramyl dipeptide Chemical compound OC(=O)CC[C@H](C(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)O[C@@H](O)[C@@H]1NC(C)=O BSOQXXWZTUDTEL-ZUYCGGNHSA-N 0.000 description 1
- 238000002703 mutagenesis Methods 0.000 description 1
- 231100000350 mutagenesis Toxicity 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000019488 nut oil Nutrition 0.000 description 1
- 239000010466 nut oil Substances 0.000 description 1
- 229920002114 octoxynol-9 Polymers 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000002482 oligosaccharides Polymers 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 125000001477 organic nitrogen group Chemical group 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 101150003241 ospD3 gene Proteins 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 210000001322 periplasm Anatomy 0.000 description 1
- 150000003905 phosphatidylinositols Chemical class 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 1
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 239000004632 polycaprolactone Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229940051841 polyoxyethylene ether Drugs 0.000 description 1
- 229920000056 polyoxyethylene ether Polymers 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229920005606 polypropylene copolymer Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002028 premature Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 238000003259 recombinant expression Methods 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- BXNMTOQRYBFHNZ-UHFFFAOYSA-N resiquimod Chemical compound C1=CC=CC2=C(N(C(COCC)=N3)CC(C)(C)O)C3=C(N)N=C21 BXNMTOQRYBFHNZ-UHFFFAOYSA-N 0.000 description 1
- 229950010550 resiquimod Drugs 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 101150057996 rfaL gene Proteins 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 102200024899 rs121918123 Human genes 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 238000007127 saponification reaction Methods 0.000 description 1
- 230000000405 serological effect Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 101150039843 solR gene Proteins 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 235000019337 sorbitan trioleate Nutrition 0.000 description 1
- 229960000391 sorbitan trioleate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000012177 spermaceti Substances 0.000 description 1
- 229940084106 spermaceti Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 101150109379 srkA gene Proteins 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 235000020238 sunflower seed Nutrition 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 208000012271 tenesmus Diseases 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940101641 thiamine 50 mg Drugs 0.000 description 1
- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical compound [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000563 toxic property Toxicity 0.000 description 1
- 102000035160 transmembrane proteins Human genes 0.000 description 1
- 108091005703 transmembrane proteins Proteins 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 102000003390 tumor necrosis factor Human genes 0.000 description 1
- 230000005074 turgor pressure Effects 0.000 description 1
- 210000000689 upper leg Anatomy 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 101150103224 virF gene Proteins 0.000 description 1
- 101150033532 virG gene Proteins 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000010698 whale oil Substances 0.000 description 1
- 241000228158 x Triticosecale Species 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/025—Enterobacteriales, e.g. Enterobacter
- A61K39/0283—Shigella
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
- A61P37/04—Immunostimulants
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
- C07K14/25—Shigella (G)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/10—Transferases (2.)
- C12N9/1025—Acyltransferases (2.3)
- C12N9/1029—Acyltransferases (2.3) transferring groups other than amino-acyl groups (2.3.1)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y203/00—Acyltransferases (2.3)
- C12Y203/01—Acyltransferases (2.3) transferring groups other than amino-acyl groups (2.3.1)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K2035/122—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells for inducing tolerance or supression of immune responses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Wood Science & Technology (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Biomedical Technology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Tropical Medicine & Parasitology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biophysics (AREA)
- Virology (AREA)
- Immunology (AREA)
- Communicable Diseases (AREA)
- Mycology (AREA)
- Epidemiology (AREA)
- Nutrition Science (AREA)
- Oncology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Peptides Or Proteins (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本発明は、Shigella種に対する免疫の分野内にある。
Shigellaは、グラム陰性非運動性通性嫌気性バチルスであり、4つの血清群:S.dysenteriae、S.flexneri、S.boydii、およびS.sonneiに分類される。それらは細菌性赤痢(shigellosis)(細菌性赤痢(bacillary dysentery))を引き起こす。
Shigellaは、細胞エンベロープの膨圧(turgour pressure)のために、増殖の間、外膜ブレブを自然に放出する。参考文献2において開示されるように、ブレブの放出は、細菌のエンベロープ構造に高度に依存する。本発明者らは、エンベロープ構造を乱すために、Tol-Palシステムが破壊されたShigellaの変異株を用いた。正常な増殖の間に、これらの変異株は、大量のブレブ(これは、免疫原性の外膜タンパク質が豊富である)をその培地に放出する。従ってこれらのブレブを免疫原として使用し得る。本発明は以下をも提供する。
(1)TolAタンパク質、TolBタンパク質、TolQタンパク質、TolRタンパク質、およびPalタンパク質のうちの4つ以下を発現する、Shigella細菌。
(2)前記タンパク質のうちの4つを発現し、TolRを発現しない、項1に記載の細菌。
(3)TolRタンパク質を発現しない、Shigella細菌。
(4)ShigellaのΔtolR株である、細菌。
(5)天然のShigellaリポ多糖を発現しない、前述の項のいずれかに記載の細菌。
(6)天然のShigella O抗原を発現しない、項5に記載の細菌。
(7)前記株が、ΔtolRΔgalU株である、項4に記載の細菌。
(8)stxA遺伝子および/またはstxB遺伝子が、不活性化されている、前述の項のいずれかに記載の細菌。
(9)TolAタンパク質、TolBタンパク質、TolQタンパク質、TolRタンパク質およびPalタンパク質を発現するShigella細菌であって、該TolAタンパク質、該TolQタンパク質、該TolRタンパク質および/または該Palタンパク質は、(a)該細菌の内膜または外膜に位置し、かつ(b)1つまたはそれ以上のアミノ酸配列変異を含み、ここで、該細菌は、培地中で増殖する場合に、該変異を含まない同じ細菌と比較して、より多量の外膜ブレブを放出する、Shigella細菌。
(10)Shigella細菌であって、該Shigella細菌のTol-Palシステムの1つまたはそれ以上の成分が修飾を有し、ここで、該細菌は、培地中で増殖する間に、該修飾を欠いている同じ細菌よりも、該培地中に多量の外膜ブレブを放出し、かつ該細菌は、(i)天然のShigellaリポ多糖および/または(ii)Shigella腸毒素を発現しない、Shigella細菌。
(11)Shigellaブレブを調製するためのプロセスであって、項1から10のいずれか一項に記載の細菌を含む培地から該ブレブを分離する工程を含み、該細菌が、該細菌による該培地へのブレブの放出を可能にする条件下で増殖させられた、プロセス。
(12)前記細菌が、鉄制限条件下で増殖させられた、項11に記載のプロセス。
(13)過剰ブレブ形成Shigella細菌を調製する方法であって、培地中で増殖させられた場合に、修飾によって該細菌が開始細菌より多量の外膜ブレブを該培地中へ放出するように、該開始細菌のTol-Palシステムの1つまたはそれ以上の成分をコードする遺伝子を修飾する工程を含み、該修飾は、該開始細菌のtolA遺伝子、tolB遺伝子、tolQ遺伝子、tolR遺伝子、および/またはpal遺伝子の1つまたはそれ以上を変異させることを含む、方法。
(14)項1から10のいずれか一項に記載の細菌もしくは項13に記載の方法によって得ることができる細菌から単離されたかもしくは得ることができるか、または項11もしくは項12に記載のプロセスによって単離されたかもしくは得ることができる、ブレブ。(15)ブレブを含む組成物であって、該ブレブは、項1から10のいずれか一項に記載の細菌または項13に記載の方法によって得ることができる細菌の培養の間に培地に放出される、組成物。
(16)任意の生の細菌および/または細菌全体を含まない、項15に記載の組成物。
(17)ブレブを含む組成物であって、該ブレブが、培地の0.22μmのフィルターを通したろ過後に得ることができるろ液に存在し、項1から10のいずれか一項に記載の細菌または項13に記載の方法によって得ることができる細菌が、該培地中で増殖させられた、組成物。
(18)項1から10に記載の細菌または項13に記載の方法によって得ることができる細菌を含む培地であって、該細菌が、該細菌による該培地へのブレブの放出を可能にする条件下で増殖させられた、培地。
(19)機能的HtrB酵素を発現しない、Shigella株。
(20)htrBがノックアウトされている、項19に記載のShigella株。
(21)以下:
(a)配列番号8から67から選択されるアミノ酸配列からなるタンパク質;
(b)配列番号8から67のうちの1つと少なくとも85%の同一性を有するアミノ酸配列を含み、かつ/または配列番号8から67のいずれか1つの少なくとも7個の連続的なアミノ酸の断片であって、エピトープを含む、断片を含む、タンパク質
のうちの1つまたはそれ以上を含む、Shigellaブレブ。
(22)ブレブを含まない免疫原性組成物であって、該組成物は、
(a)アミノ酸配列配列番号8から136;
(b)配列番号8から136のうちの1つと少なくとも85%の同一性を有し、かつ/または配列番号8から136のいずれか1つの少なくとも7個の連続的なアミノ酸の断片を含み、かつ配列番号8から136のうちの1つに由来するエピトープを含む、アミノ酸配列
を含むタンパク質を含む、組成物。
(23)鉄利用可能性を制限している、Shigellaを培養するためのプロセス。
多くのグラム陰性細菌と同様、Shigellaは、天然でTol-Palシステムを有し、それはTolA、TolB、TolQ、TolR、およびPalタンパク質からなる。本発明によって、天然のTol-Palシステムを破壊し、それによって細菌の複製の間に、細菌がより多量の外膜ブレブを培地へ放出することを引き起こす。様々な破壊を行い得る。
本発明を、血清群S.dysenteriae、S.flexneri、S.boydiiおよびS.sonneiのいずれかと使用し得る。
本発明のShigella細菌は、その対応する野生型株と比較して、過剰にブレブを形成する。すなわち、それらは野生型株より多量のブレブを培地へ放出する。これらのブレブは、Shigellaワクチンの成分として有用である。
表1は、本発明のShigellaブレブにおいて検出された129個のタンパク質のGenBank名およびGI番号を列挙する。これらの127個のタンパク質を、ブレブから分離した精製形態で、免疫原性の成分として使用し得る。129個のうちの好ましいサブセットは、リストの最初の60個である(「サブセット3」)。
本発明は、(a)本発明のブレブ、および(b)薬学的に許容可能なキャリアを含む薬学的組成物を提供する。本発明はまた、本発明のブレブを薬学的に許容可能なキャリアと混合する工程を含む、そのような組成物を調製するためのプロセスを提供する。
本発明においてアジュバントとして使用するために適当な、ミネラルを含む組成物は、アルミニウム塩およびカルシウム塩のようなミネラル塩を含む。本発明は、水酸化物(例えばオキシ水酸化物)、リン酸塩(例えばヒドロキシリン酸塩、オルトリン酸塩)、硫酸塩等のようなミネラル塩[例えば参考文献19の第8および9章を参照のこと]、または異なるミネラル化合物の混合物を含み、その化合物はあらゆる適当な形態(例えばゲル、結晶性、非晶質等)を取り、および吸着が好ましい。そのミネラルを含む組成物はまた、ミネラル塩の粒子として処方され得る。
本発明においてアジュバントとして使用するために適当な油エマルジョン組成物は、MF59のようなスクアレン-水エマルジョンを含む[参考文献19の第10章;参考文献16も参照のこと](5%のスクアレン、0.5%のTween80、および0.5%のSpan85、マイクロフルイダイザーを用いてサブミクロンの粒子に処方する)。完全フロイントアジュバント(CFA)および不完全フロイントアジュバント(IFA)も使用し得る。
本発明において、サポニン処方物もアジュバントとして使用し得る。サポニンは、広い範囲の植物種の、樹皮、葉、茎、根、さらには花において見出される、ステロールグリコシドおよびトリテルペノイドグリコシドの異種群である。Quillaia saponaria Molinaの木の樹皮由来のサポニンは、アジュバントとして広く研究されている。サポニンをまた、Smilax ornata(サルサパリラ(sarsaprilla))、Gypsophilla paniculata(ブライズベール(brides veil))、およびSaponaria officianalis(ソープルート(soap root))から、市販で得ることができる。サポニンアジュバント処方は、QS21のような精製した処方物、およびISCOMのような脂質処方物を含む。QS21は、StimulonTMとして販売されている。
本発明において使用するために適当なアジュバントは、腸内細菌リポ多糖(LPS)の無毒性誘導体、リピドA誘導体、免疫刺激性オリゴヌクレオチドならびにADP-リボシル化毒素およびその無毒化誘導体のような、細菌または微生物誘導体を含む。
本発明においてアジュバントとして使用するために適当なヒト免疫調節物質は、インターロイキン(例えばIL-1、IL-2、IL-4、IL-5、IL-6、IL-7、IL-12[71]等)[72]、インターフェロン(例えばインターフェロン-γ)、マクロファージコロニー刺激因子、および腫瘍壊死因子のようなサイトカインを含む。好ましい免疫調節物質はIL-12である。
生体付着性物質および粘膜付着性物質も、本発明においてアジュバントとして使用し得る。適当な生体付着性物質は、エステル化ヒアルロン酸ミクロスフェア[73]またはポリ(アクリル酸)、ポリビニルアルコール、ポリビニルピロリドン、多糖類およびカルボキシメチルセルロースの架橋誘導体のような粘膜付着性物質を含む。キトサンおよびその誘導体も、本発明においてアジュバントとして使用し得る[74]。
微粒子も、本発明においてアジュバントとして使用し得る。生物分解性および無毒性である材料(例えばポリ(α-ヒドロキシ酸)、ポリヒドロキシ酪酸、ポリオルトエステル、ポリ酸無水物、ポリカプロラクトン等、(ポリ(ラクチド-コ-グリコリド)が好ましい))から形成された、微粒子(すなわち、直径約100nmから約150μm、より好ましくは直径約200nmから約30μm、そして最も好ましくは直径約500nmから約10μmの粒子)が好ましく、任意で負に荷電した表面(例えばSDSによって)または正に荷電した表面(例えばCTABのような陽イオン性界面活性剤によって)を有するように処理する。
アジュバントとして使用するために適当なリポソーム処方物の例が、参考文献75-77において記載されている。
本発明においてアジュバントとして使用するために適当なイミダゾキノロン化合物の例は、参考文献78および79においてさらに記載される、イミキモド(Imiquamod)およびそのホモログ(例えば「Resiquimod3M」)を含む。
上記で記載したような免疫原性組成物を提供することに加えて、本発明はまた、本発明の免疫原性組成物を哺乳動物に投与することを含む、哺乳動物において抗体反応を起こす方法を提供する。その抗体反応は、好ましくは保護的抗体反応である。本発明はまた、そのような方法において使用するための本発明の組成物を提供する。
「含む(comprising)」という用語は、「含む(including)」および「からなる(consisting)」を包含し、例えばXを「含む(comprising)」組成物は、Xのみからなり得、またはさらなる何かを含み得る(例えばX+Y)。
S.sonneiの変異体の調製
野生型S.sonnei53GのtolR遺伝子を、λ Redシステムを用いて欠失させた[11、102]。λ Redプラスミドで形質転換したコンピテント細胞を調製し、そして次いで相同的組換えによってtolR遺伝子を抗生物質耐性遺伝子と交換するようデザインされた直鎖状断片で形質転換する。その断片が染色体に組み込まれたクローンを、抗生物質に対する耐性によって選択し、そしてtolRの欠失を、PCRまたは他の技術によって確認する。次いで、37℃で新しいクローンを増殖させることによって、温度感受性λRedプラスミドを除去し得る。
S.flexneriのtolR遺伝子を、上記でS.sonneiに関して記載したように、λRedシステムを用いて欠失させた。S.flexneriのO抗原生合成を、完全なrfbG遺伝子ならびにrfbFおよびrfcの一部を含む染色体断片の欠失によって破壊し、このことは、3つの遺伝子全ての活性化を引き起こす。その欠失を、λRedシステムを用いて産生し、そしてΔrfbGと省略される。
二重変異体ΔtolRΔgalU株の発酵を、以下の条件下で行った:pH7.1、37℃、撹拌を調節し、そして通気を最大に設定することによって溶存酸素を30%飽和に維持。pHを、4Mの水酸化アンモニウムを加えることによって調節した。泡を、実施の間に10%のPPGを加えることによって調節した。培地は以下の成分からなっていた:KH2PO4 5g/l、K2HPO4 20g/l、および酵母抽出物30g/l。オートクレーブによって培地を滅菌した後、グリセロール 15g/lおよびMgSO4 2mMを、接種の前に加えた。培養接種材料は、発酵槽容量の5%であった。その発酵プロセスは約13時間かかり、そして細胞濃度を600nmにおける光学密度として測定した。
プロテオミクスアプローチは、そのブレブが本質的に純粋な外膜であることを確認した。外膜の破壊によって得られる従来の外膜小胞(OMV)と異なり、そのブレブは親油性タンパク質を保存し、そして本質的に細胞質および内膜成分を含まない。
ΔtolRΔgalU株由来のブレブで免疫化したマウスは、図4で示すように、ブレブの2Dゲルと反応する血清を産生する。従ってそのブレブは免疫原性である。
ブレブを、吸着のために水酸化アルミニウム(2mg/ml)と組み合わせた。吸着した物質を、4℃で1日、1週間、または1ヶ月間保存した。ブレブは1日後完全に吸着され、そして1ヶ月後でも脱着の証拠は存在しなかった(図6)。
図5は、様々な条件下で増殖したShigellaによって発現されるタンパク質を示す。レーン4において、細菌を200μMのFeSO4の存在下で増殖させ、一方レーン5においてその培養は200μMのジピリジルを有していた。挿入図は、鉄制限条件下で3つのタンパク質がアップレギュレートされることを示す。これらの3つのタンパク質は、FepA外膜受容体(GI74311118)、コリシンI受容体(GI74312677)、および推定鉄シデロホア受容体(GI74313972)と同定された。これらのタンパク質は、Shigella spp.およびenterobacteriaceae内でよく保存されており、そして潜在的に高度に免疫原性である。従って鉄制限条件下でShigellaを増殖させることは、通常の増殖条件と比較して、これらのタンパク質が濃縮されたブレブの放出を引き起こし得る。
サブセット2:配列番号8-15、17-58、60-67、70、71、73、74、76、111、112、114-129および131-135
サブセット3:配列番号1-60
NB:配列番号18は、配列番号5と同一である;配列番号33は、配列番号2と同一である;配列番号9および16は関連している(約97%の同一性);配列番号23および59は関連している(約98%の同一性)。
Claims (16)
- TolR不活性化変異を含むShigella細菌であって、前記Shigella細菌は、前記TolR不活性化変異を有しない同じ細菌と比較して、培地中により多量の外膜ブレブを放出し、TolAタンパク質、TolBタンパク質、TolQタンパク質、およびPalタンパク質を発現し、TolRを発現しない、前記Shigella細菌。
- ShigellaのΔtolR株である、請求項1に記載の細菌。
- 天然のShigellaリポ多糖を発現しない、請求項1又は2に記載の細菌。
- 天然のShigella O抗原を発現しない、請求項1又は2のいずれか一項に記載の細菌。
- 天然のリピドA構造が破壊されている、請求項1から3のいずれか一項に記載の細菌。
- 前記株が、ΔtolRΔgalU株である、請求項2から4のいずれか一項に記載の細菌。
- ΔtolRΔmsbB株またはΔtolRΔhtrB株である、請求項1から5のいずれか一項に記載の細菌。
- stxA遺伝子および/またはstxB遺伝子が不活性化されている、請求項1から6のいずれか一項に記載の細菌。
- 請求項1から7のいずれか一項に記載のShigella細菌であって、該Shigella細菌のTol-Palシステムの1つまたはそれ以上の成分が修飾を有し、ここで、該細菌は、培地中で増殖する間に、該修飾を欠いている同じ細菌よりも、該培地中に多量の外膜ブレブを放出し、かつ該細菌は、(i)天然のShigellaリポ多糖および/または(ii)Shigella腸毒素を発現しない、請求項1から7のいずれか一項に記載の細菌。
- Shigellaブレブを調製する方法であって、請求項1から9のいずれか一項に記載の細菌を含む培地から該ブレブを分離する工程を含み、該細菌は、該細菌による該培地へのブレブの放出を可能にする条件下で増殖させられたものである、前記方法。
- 前記細菌が、鉄制限条件下で増殖させられたものである、請求項10に記載の方法。
- 前記鉄制限条件が、デスフェラール、2,2'-ジピリジルまたは8-ヒドロキシキノリンの存在下での培養である、請求項11に記載の方法。
- 請求項1から9のいずれか一項に記載の過剰ブレブ形成Shigella細菌を調製する方法であって、培地中で増殖させられた場合に、修飾によって該細菌が開始細菌よりも多量の外膜ブレブを該培地中へ放出するように、該開始細菌のTol-PalシステムのTolRをコードする遺伝子を修飾する工程を含む、方法。
- 請求項1から9のいずれか一項に記載の細菌または請求項13に記載の方法によって得ることができる細菌を含む培地であって、該細菌が、該細菌による該培地へのブレブの放出を可能にする条件下で増殖させられたものである、前記培地。
- 機能的HtrB酵素を発現しない、請求項1から4および6から9のいずれか一項に記載のShigella細菌。
- htrBがノックアウトされている、請求項15に記載のShigella細菌。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0917002.8A GB0917002D0 (en) | 2009-09-28 | 2009-09-28 | Improved shigella blebs |
GB0917002.8 | 2009-09-28 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2016050789A Division JP2016105736A (ja) | 2009-09-28 | 2016-03-15 | 過剰ブレブ形成Shigella株 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2019068864A JP2019068864A (ja) | 2019-05-09 |
JP7023248B2 true JP7023248B2 (ja) | 2022-02-21 |
Family
ID=41350492
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012530359A Pending JP2013505716A (ja) | 2009-09-28 | 2010-09-28 | 過剰ブレブ形成Shigella株 |
JP2016050789A Pending JP2016105736A (ja) | 2009-09-28 | 2016-03-15 | 過剰ブレブ形成Shigella株 |
JP2019021756A Active JP7023248B2 (ja) | 2009-09-28 | 2019-02-08 | 過剰ブレブ形成Shigella株 |
Family Applications Before (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012530359A Pending JP2013505716A (ja) | 2009-09-28 | 2010-09-28 | 過剰ブレブ形成Shigella株 |
JP2016050789A Pending JP2016105736A (ja) | 2009-09-28 | 2016-03-15 | 過剰ブレブ形成Shigella株 |
Country Status (21)
Country | Link |
---|---|
US (2) | US20130052227A1 (ja) |
EP (2) | EP3279313B1 (ja) |
JP (3) | JP2013505716A (ja) |
KR (1) | KR101786025B1 (ja) |
CN (2) | CN107475168A (ja) |
AU (1) | AU2010299577B2 (ja) |
BR (1) | BR112012006912A8 (ja) |
CA (1) | CA2775642C (ja) |
CY (2) | CY1118970T1 (ja) |
DK (2) | DK3279313T3 (ja) |
ES (2) | ES2632747T3 (ja) |
GB (1) | GB0917002D0 (ja) |
HR (2) | HRP20170845T1 (ja) |
HU (1) | HUE053188T2 (ja) |
LT (2) | LT2483389T (ja) |
NZ (1) | NZ599598A (ja) |
PL (2) | PL3279313T3 (ja) |
PT (2) | PT2483389T (ja) |
SI (2) | SI2483389T1 (ja) |
WO (1) | WO2011036564A2 (ja) |
ZA (1) | ZA201202934B (ja) |
Families Citing this family (24)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8647642B2 (en) | 2008-09-18 | 2014-02-11 | Aviex Technologies, Llc | Live bacterial vaccines resistant to carbon dioxide (CO2), acidic PH and/or osmolarity for viral infection prophylaxis or treatment |
GB201017519D0 (en) | 2010-10-15 | 2010-12-01 | Novartis Vaccines Inst For Global Health S R L | Vaccines |
WO2014076714A2 (en) * | 2012-11-19 | 2014-05-22 | Indian Council Of Medical Research | Novel immunogenic antigens of shigella |
US9636390B2 (en) | 2012-11-19 | 2017-05-02 | Indian Council Of Medical Research | Immunogenic antigens of shigella |
US10376571B2 (en) | 2013-03-15 | 2019-08-13 | The Board Of Trustees Of The University Of Arkansas | Compositions and methods of enhancing immune responses to enteric pathogens |
EP2870974A1 (en) | 2013-11-08 | 2015-05-13 | Novartis AG | Salmonella conjugate vaccines |
CN104974946B (zh) * | 2014-04-08 | 2019-01-11 | 中国科学院天津工业生物技术研究所 | 耐高渗透压的重组大肠杆菌及其应用 |
CL2014001126A1 (es) * | 2014-04-29 | 2014-08-29 | Univ Chile | Composición farmacéutica útil como vacuna contra bacterias escherichia coli productoras de shigatoxinas (stec), que comprende al menos un antígeno o una proteína de membrana externa inmunogénica o proteína inmunogénica asociada y conservada en cepas stec. |
CA2989242A1 (en) | 2015-06-16 | 2016-12-22 | Glaxosmithkline Biologicals Sa | Immunogenic compositions |
CN105647893A (zh) * | 2016-03-04 | 2016-06-08 | 江南大学 | 一种D-丙氨酰-D-丙氨酸羧肽酶dacD基因及应用 |
CN105647892A (zh) * | 2016-03-04 | 2016-06-08 | 江南大学 | 一种D-丙氨酰-D-丙氨酸羧肽酶dacA基因及应用 |
EP3452069A4 (en) | 2016-05-03 | 2020-02-12 | The Board of Trustees of the University of Arkansas | Yeast vaccine vector with immunostimulating and antigenic polypeptides and method for using them |
WO2017218949A2 (en) * | 2016-06-17 | 2017-12-21 | Aileron Therapeutics, Inc. | Peptidomimetic macrocycles and uses thereof |
EP3263695A1 (en) | 2016-06-29 | 2018-01-03 | GlaxoSmithKline Biologicals SA | Immunogenic compositions |
US11180535B1 (en) | 2016-12-07 | 2021-11-23 | David Gordon Bermudes | Saccharide binding, tumor penetration, and cytotoxic antitumor chimeric peptides from therapeutic bacteria |
US11129906B1 (en) | 2016-12-07 | 2021-09-28 | David Gordon Bermudes | Chimeric protein toxins for expression by therapeutic bacteria |
WO2019163785A1 (ja) * | 2018-02-20 | 2019-08-29 | 株式会社山田養蜂場本社 | 膜小胞組成物の製造方法 |
KR102546461B1 (ko) * | 2018-07-24 | 2023-06-21 | 와커 헤미 아게 | 신규한 박테리아 lpp 돌연변이체 및 재조합 단백질의 분비 생산을 위한 그의 용도 |
CN111363018B (zh) * | 2020-03-26 | 2021-10-01 | 廊坊梅花生物技术开发有限公司 | 重组菌株及其在l-色氨酸制备中的应用 |
US11898174B2 (en) * | 2020-12-18 | 2024-02-13 | Codexis, Inc. | Engineered uridine phosphorylase variant enzymes |
GB202112149D0 (en) | 2021-08-24 | 2021-10-06 | Glaxosmithkline Biologicals Sa | Shigellla vaccine |
CN113897324B (zh) * | 2021-10-13 | 2023-07-28 | 云南师范大学 | 一种用作抗锰剂的JcVIPP1重组大肠杆菌及其构建方法 |
GB202118913D0 (en) | 2021-12-23 | 2022-02-09 | Glaxosmithkline Biologicals Sa | Method for preparing outer membrane vesicles |
CN116855471B (zh) * | 2023-09-04 | 2023-11-28 | 江苏申基生物科技有限公司 | 一种嘌呤核苷磷酸化酶突变体及其应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001500363A (ja) | 1995-12-01 | 2001-01-16 | ユニバーシティ オブ アイオワ リサーチ ファウンデーション | 病原性グラム陰性細菌の非毒性変異体 |
JP2004527235A (ja) | 2001-02-08 | 2004-09-09 | グラクソスミスクライン バイオロジカルズ ソシエテ アノニム | ハイパーブレビングな細菌株及びそのワクチン製造のための使用 |
JP2006505628A (ja) | 2002-08-02 | 2006-02-16 | グラクソスミスクライン バイオロジカルズ ソシエテ アノニム | グラム陰性細菌由来のトランスフェリン結合タンパク質およびHsfを含んでなるワクチン組成物 |
Family Cites Families (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
SE8205892D0 (sv) | 1982-10-18 | 1982-10-18 | Bror Morein | Immunogent membranproteinkomplex, sett for framstellning och anvendning derav som immunstimulerande medel och sasom vaccin |
US5916588A (en) | 1984-04-12 | 1999-06-29 | The Liposome Company, Inc. | Peptide-containing liposomes, immunogenic liposomes and methods of preparation and use |
US6090406A (en) | 1984-04-12 | 2000-07-18 | The Liposome Company, Inc. | Potentiation of immune responses with liposomal adjuvants |
US5057540A (en) | 1987-05-29 | 1991-10-15 | Cambridge Biotech Corporation | Saponin adjuvant |
AU631377B2 (en) | 1988-08-25 | 1992-11-26 | Liposome Company, Inc., The | Affinity associated vaccine |
JPH0832638B2 (ja) | 1989-05-25 | 1996-03-29 | カイロン コーポレイション | サブミクロン油滴乳剤を含んで成るアジュバント製剤 |
ES2108278T3 (es) | 1992-06-25 | 1997-12-16 | Smithkline Beecham Biolog | Composicion de vacuna con coadyuvantes. |
WO1994021292A1 (en) | 1993-03-23 | 1994-09-29 | Smithkline Beecham Biologicals (S.A.) | Vaccine compositions containing 3-o deacylated monophosphoryl lipid a |
AU5543294A (en) | 1993-10-29 | 1995-05-22 | Pharmos Corp. | Submicron emulsions as vaccine adjuvants |
GB9326174D0 (en) | 1993-12-22 | 1994-02-23 | Biocine Sclavo | Mucosal adjuvant |
GB9326253D0 (en) | 1993-12-23 | 1994-02-23 | Smithkline Beecham Biolog | Vaccines |
US6429199B1 (en) | 1994-07-15 | 2002-08-06 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules for activating dendritic cells |
US6239116B1 (en) | 1994-07-15 | 2001-05-29 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US6207646B1 (en) | 1994-07-15 | 2001-03-27 | University Of Iowa Research Foundation | Immunostimulatory nucleic acid molecules |
US5897475A (en) | 1994-10-05 | 1999-04-27 | Antex Biologics, Inc. | Vaccines comprising enhanced antigenic helicobacter spp. |
AUPM873294A0 (en) | 1994-10-12 | 1994-11-03 | Csl Limited | Saponin preparations and use thereof in iscoms |
UA56132C2 (uk) | 1995-04-25 | 2003-05-15 | Смітклайн Бічем Байолоджікалс С.А. | Композиція вакцини (варіанти), спосіб стабілізації qs21 відносно гідролізу (варіанти), спосіб приготування композиції вакцини |
GB9513261D0 (en) | 1995-06-29 | 1995-09-06 | Smithkline Beecham Biolog | Vaccines |
EP1005368B1 (en) | 1997-03-10 | 2009-09-02 | Ottawa Hospital Research Institute | Use of nucleic acids containing unmethylated CpG dinucleotide in combination with alum as adjuvants |
US6818222B1 (en) | 1997-03-21 | 2004-11-16 | Chiron Corporation | Detoxified mutants of bacterial ADP-ribosylating toxins as parenteral adjuvants |
US6080725A (en) | 1997-05-20 | 2000-06-27 | Galenica Pharmaceuticals, Inc. | Immunostimulating and vaccine compositions employing saponin analog adjuvants and uses thereof |
GB9712347D0 (en) | 1997-06-14 | 1997-08-13 | Smithkline Beecham Biolog | Vaccine |
EP1009382B1 (en) | 1997-09-05 | 2003-06-18 | GlaxoSmithKline Biologicals S.A. | Oil in water emulsions containing saponins |
GB9725084D0 (en) | 1997-11-28 | 1998-01-28 | Medeva Europ Ltd | Vaccine compositions |
CN1200730C (zh) | 1998-02-12 | 2005-05-11 | 惠氏控股有限公司 | 用白细胞介素-12配制的肺炎球菌和脑膜炎球菌疫苗 |
US6303114B1 (en) | 1998-03-05 | 2001-10-16 | The Medical College Of Ohio | IL-12 enhancement of immune responses to T-independent antigens |
US6562798B1 (en) | 1998-06-05 | 2003-05-13 | Dynavax Technologies Corp. | Immunostimulatory oligonucleotides with modified bases and methods of use thereof |
GB9817052D0 (en) | 1998-08-05 | 1998-09-30 | Smithkline Beecham Biolog | Vaccine |
WO2001025254A2 (en) * | 1999-10-04 | 2001-04-12 | University Of Maryland Biotechnology Institute | Novel adjuvant comprising a lipopolysaccharide antagonist |
EP1311288A1 (en) | 2000-01-20 | 2003-05-21 | Ottawa Health Research Institute | Immunostimulatory nucleic acids for inducing a th2 immune response |
ATE384072T1 (de) | 2000-09-26 | 2008-02-15 | Idera Pharmaceuticals Inc | Modulation der immunostimulatorischen aktivität von immunostimulierenden oligonukleotidanaloga durch positionelle chemische veränderungen |
WO2003035836A2 (en) | 2001-10-24 | 2003-05-01 | Hybridon Inc. | Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5' ends |
AU2004224746B2 (en) | 2003-03-24 | 2009-04-23 | Valneva Austria Gmbh | Improved vaccines |
EP1742659B1 (en) | 2004-04-05 | 2013-03-13 | Pah Usa 15 Llc | Microfluidized oil-in-water emulsions and vaccine compositions |
CN101180312A (zh) | 2005-02-18 | 2008-05-14 | 诺华疫苗和诊断公司 | 来自尿路病原性大肠杆菌的免疫原 |
AU2012207041A1 (en) | 2005-02-18 | 2012-08-16 | J. Craig Venter Institute, Inc. | Proteins and nucleic acids from meningitis/sepsis-associated Escherichia Coli |
US7691368B2 (en) | 2005-04-15 | 2010-04-06 | Merial Limited | Vaccine formulations |
US8703095B2 (en) | 2005-07-07 | 2014-04-22 | Sanofi Pasteur S.A. | Immuno-adjuvant emulsion |
-
2009
- 2009-09-28 GB GBGB0917002.8A patent/GB0917002D0/en not_active Ceased
-
2010
- 2010-09-28 US US13/498,723 patent/US20130052227A1/en not_active Abandoned
- 2010-09-28 CN CN201710653787.5A patent/CN107475168A/zh active Pending
- 2010-09-28 PL PL17168855T patent/PL3279313T3/pl unknown
- 2010-09-28 CA CA2775642A patent/CA2775642C/en active Active
- 2010-09-28 PT PT107685596T patent/PT2483389T/pt unknown
- 2010-09-28 BR BR112012006912A patent/BR112012006912A8/pt not_active Application Discontinuation
- 2010-09-28 SI SI201031507T patent/SI2483389T1/sl unknown
- 2010-09-28 ES ES10768559.6T patent/ES2632747T3/es active Active
- 2010-09-28 WO PCT/IB2010/002582 patent/WO2011036564A2/en active Application Filing
- 2010-09-28 KR KR1020127011091A patent/KR101786025B1/ko active IP Right Grant
- 2010-09-28 LT LTEP10768559.6T patent/LT2483389T/lt unknown
- 2010-09-28 EP EP17168855.9A patent/EP3279313B1/en active Active
- 2010-09-28 DK DK17168855.9T patent/DK3279313T3/da active
- 2010-09-28 PL PL10768559T patent/PL2483389T3/pl unknown
- 2010-09-28 PT PT171688559T patent/PT3279313T/pt unknown
- 2010-09-28 LT LTEP17168855.9T patent/LT3279313T/lt unknown
- 2010-09-28 JP JP2012530359A patent/JP2013505716A/ja active Pending
- 2010-09-28 CN CN201080052643.0A patent/CN102906245B/zh active Active
- 2010-09-28 SI SI201032053T patent/SI3279313T1/sl unknown
- 2010-09-28 EP EP10768559.6A patent/EP2483389B1/en active Active
- 2010-09-28 HU HUE17168855A patent/HUE053188T2/hu unknown
- 2010-09-28 NZ NZ599598A patent/NZ599598A/xx not_active IP Right Cessation
- 2010-09-28 ES ES17168855T patent/ES2846901T3/es active Active
- 2010-09-28 AU AU2010299577A patent/AU2010299577B2/en active Active
- 2010-09-28 DK DK10768559.6T patent/DK2483389T3/en active
-
2012
- 2012-04-20 ZA ZA2012/02934A patent/ZA201202934B/en unknown
-
2016
- 2016-03-15 JP JP2016050789A patent/JP2016105736A/ja active Pending
- 2016-04-08 US US15/094,077 patent/US11339367B2/en active Active
-
2017
- 2017-06-02 HR HRP20170845TT patent/HRP20170845T1/hr unknown
- 2017-06-16 CY CY20171100637T patent/CY1118970T1/el unknown
-
2019
- 2019-02-08 JP JP2019021756A patent/JP7023248B2/ja active Active
-
2021
- 2021-02-04 CY CY20211100093T patent/CY1123774T1/el unknown
- 2021-02-11 HR HRP20210243TT patent/HRP20210243T1/hr unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001500363A (ja) | 1995-12-01 | 2001-01-16 | ユニバーシティ オブ アイオワ リサーチ ファウンデーション | 病原性グラム陰性細菌の非毒性変異体 |
JP2004527235A (ja) | 2001-02-08 | 2004-09-09 | グラクソスミスクライン バイオロジカルズ ソシエテ アノニム | ハイパーブレビングな細菌株及びそのワクチン製造のための使用 |
JP2006505628A (ja) | 2002-08-02 | 2006-02-16 | グラクソスミスクライン バイオロジカルズ ソシエテ アノニム | グラム陰性細菌由来のトランスフェリン結合タンパク質およびHsfを含んでなるワクチン組成物 |
Non-Patent Citations (7)
Title |
---|
INFECTION AND IMMUNITY,1995年,Vol. 63, No. 1,pp. 229-237 |
INFECTION AND IMMUNITY,2002年,Vol. 70, No. 3,pp. 1150-1158 |
JOURNAL OF BACTERIOLOGY,1992年,Vol. 174, No. 20,pp. 6498-6507 |
JOURNAL OF BACTERIOLOGY,Vol. 177, No. 11,1995年,pp. 3128-3132 |
RESEARCH IN MICROBIOLOGY,2004年05月,Vol. 155, No. 6,pp. 437-446 |
The Journal of Immunology,2002年,Vol. 168,pp. 5240-5251 |
日本細菌学雑誌,1996年,Vol. 51, No. 2,pp. 523-547 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP7023248B2 (ja) | 過剰ブレブ形成Shigella株 | |
JP5960055B2 (ja) | 改変髄膜炎菌fHBPポリペプチド | |
RU2475496C2 (ru) | МЕНИНГОКОККОВЫЕ ПОЛИПЕПТИДЫ fHBP | |
JP2015110653A (ja) | 髄膜炎菌fHBP配列を含むハイブリッドポリペプチド | |
PT2279747E (pt) | Vesículas bacterianas imunogénicas dotadas de proteínas de membrana externa | |
ITMI20081249A1 (it) | Immunogeni di escherichia coli con solubilità migliorata. | |
US20130022639A1 (en) | Expression of meningococcal fhbp polypeptides | |
EP2988779B1 (en) | Mutant bacteria for production of generalized modules for membrane antigens | |
JP2017522319A (ja) | 髄膜炎菌ワクチン | |
BR112019019117A2 (pt) | métodos e composições para induzir respostas imunes contra clostridium difficile | |
CN112521464A (zh) | 突变型葡萄球菌抗原 | |
JP2012532626A (ja) | 無毒化されたEscherichiacoli免疫原 | |
US20220339277A1 (en) | Immunogenic compositions | |
RU2781057C9 (ru) | Способы и композиции для индукции иммунного ответа против clostridium difficile |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20190214 |
|
RD01 | Notification of change of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7426 Effective date: 20190416 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20190416 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200204 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200501 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20201013 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20210706 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20211105 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20211105 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20211115 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20211116 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20220111 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20220208 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7023248 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |