JPWO2020102717A5 - - Google Patents
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- JPWO2020102717A5 JPWO2020102717A5 JP2021527120A JP2021527120A JPWO2020102717A5 JP WO2020102717 A5 JPWO2020102717 A5 JP WO2020102717A5 JP 2021527120 A JP2021527120 A JP 2021527120A JP 2021527120 A JP2021527120 A JP 2021527120A JP WO2020102717 A5 JPWO2020102717 A5 JP WO2020102717A5
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- clostridium difficile
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- 230000002163 immunogen Effects 0.000 claims description 64
- 239000000203 mixture Substances 0.000 claims description 61
- 241000193163 Clostridioides difficile Species 0.000 claims description 58
- 229920001184 polypeptide Polymers 0.000 claims description 31
- 101700023105 3L21 Proteins 0.000 claims description 30
- 210000004027 cells Anatomy 0.000 claims description 27
- 101700012833 3S11 Proteins 0.000 claims description 18
- 101700057439 TOXA Proteins 0.000 claims description 18
- 101700041767 ctxA Proteins 0.000 claims description 18
- 230000003000 nontoxic Effects 0.000 claims description 16
- 231100000252 nontoxic Toxicity 0.000 claims description 16
- 101710037563 alpha-delta-Bgt-2 Proteins 0.000 claims description 12
- 101700080113 toxB Proteins 0.000 claims description 12
- 108090001123 antibodies Proteins 0.000 claims description 8
- 102000004965 antibodies Human genes 0.000 claims description 8
- 108010032074 Clostridium difficile toxB protein Proteins 0.000 claims description 7
- 230000000240 adjuvant Effects 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 7
- 206010054236 Clostridium difficile infection Diseases 0.000 claims description 6
- 239000000284 extract Substances 0.000 claims description 6
- 239000003242 anti bacterial agent Substances 0.000 claims description 5
- 230000003115 biocidal Effects 0.000 claims description 5
- 201000009910 diseases by infectious agent Diseases 0.000 claims description 5
- 230000028993 immune response Effects 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 231100000765 Toxin Toxicity 0.000 claims description 4
- 229940037003 alum Drugs 0.000 claims description 4
- 239000003053 toxin Substances 0.000 claims description 4
- WNROFYMDJYEPJX-UHFFFAOYSA-K Aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 2
- 229940064005 Antibiotic throat preparations Drugs 0.000 claims description 2
- 229940083879 Antibiotics FOR TREATMENT OF HEMORRHOIDS AND ANAL FISSURES FOR TOPICAL USE Drugs 0.000 claims description 2
- 229940042052 Antibiotics for systemic use Drugs 0.000 claims description 2
- 229940042786 Antitubercular Antibiotics Drugs 0.000 claims description 2
- 229940093922 Gynecological Antibiotics Drugs 0.000 claims description 2
- 229940024982 Topical Antifungal Antibiotics Drugs 0.000 claims description 2
- 239000011324 bead Substances 0.000 claims description 2
- 229940079866 intestinal antibiotics Drugs 0.000 claims description 2
- 239000011159 matrix material Substances 0.000 claims description 2
- 239000011859 microparticle Substances 0.000 claims description 2
- 239000002480 mineral oil Substances 0.000 claims description 2
- 235000010446 mineral oil Nutrition 0.000 claims description 2
- 229940005935 ophthalmologic Antibiotics Drugs 0.000 claims description 2
- 230000001717 pathogenic Effects 0.000 claims description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 2
- 239000008158 vegetable oil Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 16
- 150000004676 glycans Polymers 0.000 claims 3
- 229920001282 polysaccharide Polymers 0.000 claims 3
- 239000005017 polysaccharide Substances 0.000 claims 3
- 150000004804 polysaccharides Polymers 0.000 claims 3
- 239000003814 drug Substances 0.000 claims 1
- 239000010452 phosphate Substances 0.000 claims 1
- 125000002467 phosphate group Chemical group [H]OP(=O)(O[H])O[*] 0.000 claims 1
- 229920000642 polymer Polymers 0.000 claims 1
- WCKIYBQZPOLJLE-DIAAKEKRSA-N β-D-Glcp-(1->3)-[β-D-Glcp-(1->3)-β-D-GalpNAc-(1->4)-α-D-Glcp-(1->4)]-β-D-GalpNAc-(1->3)-α-D-Manp Chemical group O([C@@H]1O[C@H](CO)[C@@H]([C@@H]([C@H]1NC(C)=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)O[C@@H]1[C@H](O)[C@@H](O)[C@@H]([C@H](O1)CO)O[C@H]1[C@@H]([C@H]([C@@H](O)[C@@H](CO)O1)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)NC(=O)C)[C@@H]1[C@H](O)[C@@H](O)O[C@H](CO)[C@H]1O WCKIYBQZPOLJLE-DIAAKEKRSA-N 0.000 claims 1
- 102100005577 NAP1L1 Human genes 0.000 description 4
- 108010018157 nucleic acid probe 1 Proteins 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 3
- 108020003112 toxins Proteins 0.000 description 3
- 102100003681 HSPD1 Human genes 0.000 description 2
- 101710013836 HSPD1 Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 229950004283 Actoxumab Drugs 0.000 description 1
- 229950008086 Bezlotoxumab Drugs 0.000 description 1
- 241000193403 Clostridium Species 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N Deoxycholic acid Chemical compound C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- IWDCLRJOBJJRNH-UHFFFAOYSA-N P-Cresol Chemical compound CC1=CC=C(O)C=C1 IWDCLRJOBJJRNH-UHFFFAOYSA-N 0.000 description 1
- 229960000380 Propiolactone Drugs 0.000 description 1
- 108010080226 actoxumab Proteins 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 108010067114 bezlotoxumab Proteins 0.000 description 1
- 229960003964 deoxycholic acid Drugs 0.000 description 1
- 230000003053 immunization Effects 0.000 description 1
- 238000002649 immunization Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- VEZXCJBBBCKRPI-UHFFFAOYSA-N β-Propiolactone Chemical compound O=C1CCO1 VEZXCJBBBCKRPI-UHFFFAOYSA-N 0.000 description 1
Description
[00170] 以上の記載は例示的であって、本発明を制限するものではないと理解された
い。本開示の全範囲と添付の特許請求の範囲に規定の発明について考慮すれば、当業者には追加の態様が可能であって、提起されよう。
本願は以下の発明を包含する。
［項目１］ （ａ）クロストリジウム・ディフィシル菌の１種以上の株の不活化した全細胞、又はクロストリジウム・ディフィシル菌の１種以上の菌株由来の細胞表面抽出物（ＣＳＥ）、及び
（ｂ）クロストリジウム・ディフィシルのトキシンＡ又はトキシンＢのトキソイド又は非毒性の免疫原性ポリペプチド断片を含んでなる少なくとも１つのポリペプチド、
を含んでなる免疫原性組成物であって、哺乳動物の被験体へ投与される場合、クロストリジウム・ディフィシル感染及び／又は再感染（再発）に対する防御を付与する、野生型クロストリジウム・ディフィシルを認識する抗体の産生と少なくとも１種のクロストリジウム・ディフィシル毒素を認識する抗体の産生とを誘発するのに有効である、前記組成物。
［項目２］ １種以上のクロストリジウム・ディフィシル株由来の全細胞を含む、項目１の免疫原性組成物。
［項目３］ １種以上のクロストリジウム・ディフィシル株由来のＣＳＥを含む、項目１の免疫原性組成物。
［項目４］ ＣＳＥが表１に明記される１種以上のタンパク質を含む、項目３の免疫原性組成物。
［項目５］ ＣＳＥが、ＣｂｐＡ、ＧｒｏＥＬ、ＣＤ３２４６、ＣＤ２３８１、ＣＤ０８７３、Ｄｉｆ５１、Ｄｉｆ１３０、Ｄｉｆ１９２、Ｄｉｆ２０８、Ｄｉｆ２０８Ａ、Ｄｉｆ２３２、及びＣＤＴの１以上を含む、項目３の免疫原性組成物。
［項目６］ ＣＳＥが、クロストリジウム・ディフィシル細胞のデオキシコール酸ナトリウム懸濁液より調製される、項目３の免疫原性組成物。
［項目７］ クロストリジウム・ディフィシル細胞が、高毒性クロストリジウム・ディフィシル株を含む、項目６の免疫原性組成物。
［項目８］ クロストリジウム・ディフィシル細胞が、クロストリジウム・ディフィシルＢＩ／ＮＡＰ１／０２７を含む、項目６の免疫原性組成物。
［項目９］ ＣＳＥ調製物に、ＣｂｐＡ、ＧｒｏＥＬ、ＣＤ３２４６、ＣＤ２３８１、ＣＤ０８７３、Ｄｉｆ５１、Ｄｉｆ１３０、Ｄｉｆ１９２、Ｄｉｆ２０８、Ｄｉｆ２０８Ａ、Ｄｉｆ２３２、ＣＤＴ、及び表１に明記されるタンパク質の１以上が添加されている、項目６の免疫原性組成物。
［項目１０］ 組換え的に発現される１以上の細胞表面成分を含む、項目３の免疫原性組成物。
［項目１１］ １種以上のクロストリジウム・ディフィシル株が、クロストリジウム・ディフィシルのリボタイプ００１、００３、０２７、１０６、０１２、０１４、及び０３６を含む、項目１の免疫原性組成物。
［項目１２］ ２種のクロストリジウム・ディフィシル株由来の全細胞又はＣＳＥを含む、項目１の免疫原性組成物。
［項目１３］ 熱処理、ＵＶ又はγ線照射、ホルムアルデヒド処理、抗生物質での処理、又はアルコール類での処理によって全細胞が不活化される、項目１の免疫原性組成物。
［項目１４］ エタノール、イソプロピルアルコール、フェノール、トリクレゾール、又はこれらの組合せでの処理によって全細胞が不活化される、項目１３の免疫原性組成物。
［項目１５］ β－プロピオラクトン（ＢＰＬ）での処理によって全細胞が不活化される、項目１３の免疫原性組成物。
［項目１６］ クロストリジウム・ディフィシルの培養物を６５℃～８０℃で少なくとも２０分間加熱することによって全細胞が不活化される、項目１３の免疫原性組成物。
［項目１７］ クロストリジウム・ディフィシル細胞をホルマリンに懸濁させることによって全細胞が不活化される、項目１３の免疫原性組成物。
［項目１８］ 成分（ｂ）が、クロストリジウム・ディフィシルのトキシンＡのトキソイド及び／又はクロストリジウム・ディフィシルのトキシンＢのトキソイドを含む、項目１の免疫原性組成物。
［項目１９］ 成分（ｂ）が、クロストリジウム・ディフィシルのトキシンＡの非毒性ポリペプチド断片及び／又はクロストリジウム・ディフィシルのトキシンＢの非毒性ポリペプチド断片を含む、項目１の免疫原性組成物。
［項目２０］ 配列番号７、８、９、１０、１１、１２、１３、１４、１５、１６、１７、１８、１９、２０、２１、２２、２３、２４、２５、２６、２７、２８、２９、３０、３１、３２、３３、３４、３５、３６、３７、３８、３９、又は４０に対して少なくとも５０％の同一性を有する非毒性ポリペプチド断片を含む、項目１９の免疫原性組成物。
［項目２１］ アクトクスマブへ結合する、クロストリジウム・ディフィシルのトキシンＡの非毒性ポリペプチド断片を含む、項目１９の免疫原性組成物。
［項目２２］ ベズロトクスマブへ結合する、クロストリジウム・ディフィシルのトキシンＢの非毒性ポリペプチド断片を含む、項目１９の免疫原性組成物。
［項目２３］ 成分（ｂ）が、クロストリジウム・ディフィシルのトキシンＡの少なくとも１つのＣＲＯＰ領域、クロストリジウム・ディフィシルのトキシンＢの少なくとも１つのＣＲＯＰ領域、又はこれらの組合せを含む、項目１の免疫原性組成物。
［項目２４］ 成分（ｂ）が、クロストリジウム・ディフィシルのトキシンＢのポリペプチドＣ末端の７１６アミノ酸又はその免疫原性断片を含む、項目２３の免疫原性組成物。
［項目２５］ トキシンＡ及び／又はトキシンＢが、１種より多いクロストリジウム・ディフィシル株由来の毒素を含む、項目１８の免疫原性組成物。
［項目２６］ トキシンＡポリペプチド断片及び／又はトキシンＢポリペプチド断片が、１種より多いクロストリジウム・ディフィシル株由来の断片を含む、項目１９の免疫原性組成物。
［項目２７］ 成分（ｂ）が、クロストリジウム・ディフィシルのリボタイプ００３、０２７、１０６、００１、０１２、０１４、０３６、及び０７８から成る群より選択される１種以上の株由来のポリペプチドを含む、項目１の免疫原性組成物。
［項目２８］ 成分（ｂ）が、クロストリジウム・ディフィシルＢＩ／ＮＡＰ１／０２７株由来のポリペプチドを含む、項目２７の免疫原性組成物。
［項目２９］ 成分（ｂ）が、配列番号３のアミノ酸配列を有するポリペプチドを含む、項目２８の免疫原性組成物。
［項目３０］ 成分（ａ）が、クロストリジウム・ディフィシルＢＩ／ＮＡＰ１／０２７株の不活化した全細胞を含み、成分（ｂ）が、クロストリジウム・ディフィシルＢＩ／ＮＡＰ１／０２７株由来のトキシンＡ及び／又はトキシンＢの非毒性の免疫原性ポリペプチド断片を含む、項目１の免疫原性組成物。
［項目３１］ （ｃ）アジュバント、
をさらに含んでなる、項目１～３０のいずれか１項の免疫原性組成物。
［項目３２］ アジュバントが、アラム、ミネラルオイル、植物油、水酸化アルミニウム、フロイント不完全アジュバント、又は生体適合性マトリックス材料の微粒子若しくはビーズより選択される、項目３１の免疫原性組成物。
［項目３３］ 成分（ｃ）がアラムである、項目３１の免疫原性組成物。
［項目３４］ クロストリジウム・ディフィシルの１種以上の株と反応する抗体を産生し、そして１種以上のクロストリジウム・ディフィシル毒素と反応する抗体を産生する免疫応答の誘発に有効な免疫原性組成物を作製する方法であって：
（１）第１成分（ａ）を第２成分（ｂ）と混合し、前記第１成分は、クロストリジウム・ディフィシルの少なくとも１種の株の不活化した細胞を、前記第１成分で免疫された哺乳動物の被験体において免疫応答を誘発してクロストリジウム・ディフィシルの少なくとも１種の株と反応する抗体を産生させるのに有効な量で含んでなり、前記第２成分は、クロストリジウム・ディフィシルのトキシンＡ又はトキシンＢのトキソイド又は非毒性の免疫原性ポリペプチド断片を含んでなる少なくとも１つのポリペプチドを、前記第２成分で免疫された哺乳動物の被験体において免疫応答を誘発して前記トキシンＡ又はトキシンＢの少なくとも１つと反応する抗体を産生させるのに有効な量で含んでなり；そして
（２）工程（１）の前記混合物を、クロストリジウム・ディフィシルに感染し易い哺乳動物の被験体へ投与するために製剤化する、
ことを含んでなる、前記方法。
［項目３５］ 被験体においてクロストリジウム・ディフィシルに対する免疫応答を誘発する方法であって、（ａ）クロストリジウム・ディフィシル菌の少なくとも１種の株の不活化した細胞又は細胞表面抽出物、及び（ｂ）クロストリジウム・ディフィシルのトキシンＡ又はトキシンＢのトキソイド又は非毒性の免疫原性ポリペプチド断片を含んでなる少なくとも１つのポリペプチドを含んでなる免疫原性組成物のある量を前記被験体へ投与することを含んでなる、前記方法。
［項目３６］ 抗生物質を投与することをさらに含む、項目３５の方法。
［項目３７］ 抗生物質で治療される被験体においてクロストリジウム・ディフィシル感染を妨げるための予防方法であって、（ａ）クロストリジウム・ディフィシル菌の少なくとも１種の株の不活化した細胞又は細胞表面抽出物、及び（ｂ）クロストリジウム・ディフィシルのトキシンＡ又はトキシンＢのトキソイド又は非毒性の免疫原性ポリペプチド断片を含んでなる少なくとも１つのポリペプチドを含んでなる免疫原性組成物を該被験体へ投与することを含む、前記方法。
［項目３８］ 被験体において感染を治療する方法であって、該感染を治療するのに有効な抗生物質の量と、（ａ）クロストリジウム・ディフィシル菌の少なくとも１種の株の不活化した細胞又は細胞表面抽出物、及び（ｂ）クロストリジウム・ディフィシルのトキシンＡ又はトキシンＢのトキソイド又は非毒性の免疫原性ポリペプチド断片を含んでなる少なくとも１つのポリペプチドを含んでなる免疫原性組成物の再感染を予防するための量とを該被験体へ投与することを含む、前記方法。
［項目３９］ クロストリジウム・ディフィシル感染に関連した病原性症状を予防的に軽減させる方法であって、（ａ）クロストリジウム・ディフィシル菌の少なくとも１種の株の不活化した細胞又は細胞表面抽出物、及び（ｂ）クロストリジウム・ディフィシルのトキシンＡ又はトキシンＢの少なくとも１つの非毒性の免疫原性ポリペプチド断片を含んでなる組成物を前記被験体へ投与することを含む、前記方法。
［項目４０］ 受動免疫法をさらに含む、項目３９の方法。
[00170] It is to be understood that the above description is illustrative and not restrictive of the invention. Additional aspects are possible and will be suggested to those skilled in the art given the full scope of this disclosure and the invention as defined in the appended claims.
The present application includes the following inventions.
[Item 1] (a) inactivated whole cells of one or more strains of Clostridium difficile, or cell surface extracts (CSE) from one or more strains of Clostridium difficile, and
(b) at least one polypeptide comprising a Clostridium difficile toxin A or toxin B toxoid or a non-toxic immunogenic polypeptide fragment;
which, when administered to a mammalian subject, confers protection against Clostridium difficile infection and/or reinfection (relapse), which recognizes wild-type Clostridium difficile Said composition effective to induce the production of antibodies and the production of antibodies that recognize at least one Clostridium difficile toxin.
[Item 2] The immunogenic composition of item 1, comprising whole cells from one or more Clostridium difficile strains.
[Item 3] The immunogenic composition of item 1, comprising CSE from one or more Clostridium difficile strains.
[Item 4] The immunogenic composition of item 3, wherein the CSE comprises one or more proteins specified in Table 1.
[Item 5] The immunogenic composition of item 3, wherein the CSE comprises one or more of CbpA, GroEL, CD3246, CD2381, CD0873, Dif51, Dif130, Dif192, Dif208, Dif208A, Dif232, and CDT.
[Item 6] The immunogenic composition of item 3, wherein the CSE is prepared from a sodium deoxycholate suspension of Clostridium difficile cells.
[Item 7] The immunogenic composition of item 6, wherein the Clostridium difficile cells comprise a highly virulent Clostridium difficile strain.
[Item 8] The immunogenic composition of item 6, wherein the Clostridium difficile cells comprise Clostridium difficile BI/NAP1/027.
[Item 9] The CSE preparation is supplemented with CbpA, GroEL, CD3246, CD2381, CD0873, Dif51, Dif130, Dif192, Dif208, Dif208A, Dif232, CDT, and one or more of the proteins specified in Table 1. The immunogenic composition of item 6.
[Item 10] The immunogenic composition of item 3, comprising one or more recombinantly expressed cell surface components.
[Item 11] The immunogenic composition of item 1, wherein the one or more Clostridium difficile strains comprises Clostridium difficile ribotypes 001, 003, 027, 106, 012, 014, and 036.
[Item 12] The immunogenic composition of item 1, comprising whole cells or CSE from two Clostridium difficile strains.
[Item 13] The immunogenic composition of item 1, wherein all cells are inactivated by heat treatment, UV or gamma irradiation, formaldehyde treatment, treatment with antibiotics, or treatment with alcohols.
[Item 14] The immunogenic composition of item 13, wherein all cells are inactivated by treatment with ethanol, isopropyl alcohol, phenol, tricresol, or a combination thereof.
[Item 15] The immunogenic composition of item 13, wherein all cells are inactivated by treatment with β-propiolactone (BPL).
[Item 16] The immunogenic composition of item 13, wherein all cells are inactivated by heating the culture of Clostridium difficile to 65°C to 80°C for at least 20 minutes.
[Item 17] The immunogenic composition of item 13, wherein all cells are inactivated by suspending Clostridium difficile cells in formalin.
[Item 18] The immunogenic composition of item 1, wherein component (b) comprises Clostridium difficile toxin A toxoid and/or Clostridium difficile toxin B toxoid.
[Item 19] The immunogenic composition of item 1, wherein component (b) comprises a non-toxic polypeptide fragment of Clostridium difficile toxin A and/or a non-toxic polypeptide fragment of Clostridium difficile toxin B.
[Item 20] SEQ. 29. The immunogenic composition of item 19 comprising a non-toxic polypeptide fragment having at least 50% identity to 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40. thing.
[Item 21] The immunogenic composition of item 19, comprising a non-toxic polypeptide fragment of Clostridium difficile toxin A that binds to actoxumab.
[Item 22] The immunogenic composition of item 19, comprising a non-toxic polypeptide fragment of Clostridium difficile toxin B that binds to bezlotoxumab.
[Item 23] The immunogenic composition of item 1, wherein component (b) comprises at least one CROP region of Clostridium difficile toxin A, at least one CROP region of Clostridium difficile toxin B, or a combination thereof. thing.
[Item 24] The immunogenic composition of item 23, wherein component (b) comprises the C-terminal 716 amino acids of a Clostridium difficile toxin B polypeptide or an immunogenic fragment thereof.
[Item 25] The immunogenic composition of item 18, wherein toxin A and/or toxin B comprises toxins from more than one Clostridium difficile strain.
[Item 26] The immunogenic composition of item 19, wherein the toxin A polypeptide fragment and/or the toxin B polypeptide fragment comprises fragments from more than one Clostridium difficile strain.
[Item 27] component (b) comprises a polypeptide from one or more strains selected from the group consisting of Clostridium difficile ribotypes 003, 027, 106, 001, 012, 014, 036, and 078; The immunogenic composition of item 1.
[Item 28] The immunogenic composition of item 27, wherein component (b) comprises a polypeptide derived from Clostridium difficile strain BI/NAP1/027.
[Item 29] The immunogenic composition of item 28, wherein component (b) comprises a polypeptide having the amino acid sequence of SEQ ID NO:3.
[Item 30] Component (a) contains inactivated whole cells of Clostridium difficile strain BI/NAP1/027, and component (b) contains toxin A derived from Clostridium difficile strain BI/NAP1/027 and/or The immunogenic composition of item 1, comprising a non-toxic, immunogenic polypeptide fragment of toxin B.
[Item 31] (c) an adjuvant,
31. The immunogenic composition of any one of items 1-30, further comprising:
[Item 32] The immunogenic composition of item 31, wherein the adjuvant is selected from alum, mineral oil, vegetable oil, aluminum hydroxide, incomplete Freund's adjuvant, or microparticles or beads of biocompatible matrix material.
[Item 33] The immunogenic composition of item 31, wherein component (c) is alum.
[Item 34] An immunogenic composition that produces antibodies that react with one or more strains of Clostridium difficile and is effective in eliciting an immune response that produces antibodies that react with one or more Clostridium difficile toxins. A method of making, comprising:
(1) mixing a first component (a) with a second component (b), said first component comprising inactivated cells of at least one strain of Clostridium difficile immunized with said first component; said second component comprising Clostridium difficile toxin A in an amount effective to induce an immune response in a mammalian subject to produce antibodies reactive with at least one strain of Clostridium difficile or at least one polypeptide comprising a toxoid of toxin B or a non-toxic immunogenic polypeptide fragment to elicit an immune response in a mammalian subject immunized with said second component to induce said toxin A or in an amount effective to produce antibodies reactive with at least one of toxin B; and
(2) formulating the mixture of step (1) for administration to a mammalian subject susceptible to infection with Clostridium difficile;
The method above, comprising:
[Item 35] A method of inducing an immune response to Clostridium difficile in a subject, comprising (a) an inactivated cell or cell surface extract of at least one strain of Clostridium difficile, and (b) Clostridium - administering to said subject an amount of an immunogenic composition comprising at least one polypeptide comprising a toxoid of toxin A or toxin B of difficile or a non-toxic immunogenic polypeptide fragment; said method comprising:
[Item 36] The method of item 35, further comprising administering an antibiotic.
[Item 37] A prophylactic method for preventing Clostridium difficile infection in a subject treated with an antibiotic, comprising: (a) an inactivated cell or cell surface extract of at least one strain of Clostridium difficile bacterium; and (b) administering to the subject an immunogenic composition comprising at least one polypeptide comprising a Clostridium difficile toxin A or toxin B toxoid or a non-toxic immunogenic polypeptide fragment. The above method, comprising:
[Item 38] A method of treating an infection in a subject, comprising an amount of an antibiotic effective to treat the infection and (a) inactivated cells of at least one strain of Clostridium difficile, or Reproduction of an immunogenic composition comprising a cell surface extract and (b) at least one polypeptide comprising a Clostridium difficile toxin A or toxin B toxoid or a non-toxic immunogenic polypeptide fragment. administering to said subject an amount to prevent infection.
[Item 39] A method for prophylactic relief of pathogenic symptoms associated with Clostridium difficile infection comprising (a) an inactivated cell or cell surface extract of at least one strain of Clostridium difficile bacterium; (b) administering to said subject a composition comprising at least one non-toxic, immunogenic polypeptide fragment of Toxin A or Toxin B of Clostridium difficile.
[Item 40] The method of item 39, further comprising passive immunization.
Claims (20)
（ｂ）クロストリジウム・ディフィシルのトキシンＡ又はトキシンＢのトキソイド又は非毒性の免疫原性ポリペプチド断片を含んでなる少なくとも１つのポリペプチド、
を含んでなる免疫原性組成物であって、哺乳動物の被験体へ投与される場合、クロストリジウム・ディフィシル感染及び／又は再感染（再発）に対する防御を付与する、野生型クロストリジウム・ディフィシルを認識する抗体の産生と少なくとも１種のクロストリジウム・ディフィシル毒素を認識する抗体の産生とを誘発するのに有効である、前記組成物。 (a) inactivated whole cells of one or more strains of Clostridium difficile, cell surface extracts (CSE) of one or more strains of Clostridium difficile, or one or more strains of Clostridium difficile and (b) at least one polypeptide comprising a Clostridium difficile toxin A or toxin B toxoid or non-toxic immunogenic polypeptide fragment;
which, when administered to a mammalian subject, confers protection against Clostridium difficile infection and/or reinfection (relapse), which recognizes wild-type Clostridium difficile Said composition effective to induce the production of antibodies and the production of antibodies that recognize at least one Clostridium difficile toxin.
をさらに含んでなる、請求項１～１２のいずれか１項の免疫原性組成物。 (c) an adjuvant;
13. The immunogenic composition of any one of claims 1-12 , further comprising:
16. A pharmaceutical composition or formulation for use in a method of prophylactically reducing pathogenic symptoms associated with Clostridium difficile infection in a subject, wherein the immunogenic composition of any one of claims 1-15. The pharmaceutical composition or formulation comprising
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| Application Number | Priority Date | Filing Date | Title |
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| US201862768220P | 2018-11-16 | 2018-11-16 | |
| US62/768,220 | 2018-11-16 | ||
| PCT/US2019/061793 WO2020102717A2 (en) | 2018-11-16 | 2019-11-15 | Clostridium difficile multi-component vaccine |
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| JP2022513077A JP2022513077A (en) | 2022-02-07 |
| JPWO2020102717A5 true JPWO2020102717A5 (en) | 2022-11-21 |
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| US (1) | US20210369831A1 (en) |
| EP (1) | EP3880240A4 (en) |
| JP (1) | JP2022513077A (en) |
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| TW202325338A (en) * | 2021-08-06 | 2023-07-01 | 美商碩騰服務有限責任公司 | Clostridium chauvoei vaccine and method of making |
| CN114507746B (en) * | 2022-03-25 | 2023-02-14 | 河北医科大学第二医院 | Probe, primer set and method for rapid identification and typing of high-yield-toxin clostridium difficile |
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| US8431361B2 (en) * | 2010-09-17 | 2013-04-30 | Board Of Regents Of The University Of Oklahoma | Bacterial cells, optimized nucleotide sequences and methods for improved expression of recombinant Clostridium difficile toxin B |
| GB201206070D0 (en) * | 2012-04-04 | 2012-05-16 | Health Prot Agency | Clostridium difficile antigens |
| CN102743746A (en) * | 2012-06-13 | 2012-10-24 | 广州医学院第一附属医院 | Live bacterial vaccine for controlling intestinal infection caused by clostridium difficile, preparation method thereof and application thereof |
| US10144775B2 (en) * | 2013-04-19 | 2018-12-04 | Immuron Limited | Methods and compositions for the treatment and/or prophylaxis of Clostridium difficile associated disease |
| KR20180011784A (en) * | 2015-05-15 | 2018-02-02 | 사노피 파스퇴르 인코포레이티드 | Methods for immunization against clostridium difficile |
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