JP6963018B2 - 免疫調節剤及びこれを含むワクチン組成物 - Google Patents
免疫調節剤及びこれを含むワクチン組成物 Download PDFInfo
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- JP6963018B2 JP6963018B2 JP2019545215A JP2019545215A JP6963018B2 JP 6963018 B2 JP6963018 B2 JP 6963018B2 JP 2019545215 A JP2019545215 A JP 2019545215A JP 2019545215 A JP2019545215 A JP 2019545215A JP 6963018 B2 JP6963018 B2 JP 6963018B2
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Description
本発明によれば、ヘキソサミンはグルコサミン、ガラクトサミンまたはマンノサミンであり、そして特定の例では、ヘキソサミンはグルコサミンである。
1.乾燥菌体の製造
大腸菌(E.coli)を37℃ TSB(Triptic soy broth,Difco)30g/L培地で20時間80rpm以下で振盪培養し、遠心分離機を用いて菌体を回収した。回収した菌体にエタノールを混ぜて遠心分離し、沈殿物を得た。その後、得られた沈殿物にアセトンを添加して十分に混ぜた後、遠心分離し、沈殿物を得た。得られた沈殿物にエチルエーテルを添加してよく混ぜた後、遠心分離し、沈殿物を得た。得られた沈殿物を60℃乾燥オーブンで乾燥させ、乾燥菌体を製造した。
乾燥菌体の重量を測定した後、重量1g当たり7.5mLのPCP(フェノール、クロロホルム、ペトロリウムエーテル)抽出混合液を添加し、菌体菌からLOSを分離した。この方法で分離して得たLOS抽出物は、回転蒸発器を用いて高温で有機溶媒を除去した。残っている抽出液は高温で遠心分離して沈殿物を得、沈殿物にエチルエーテルを添加して沈殿物を洗浄した。次に、精製水を入れて沈殿物を生成した。生成された沈殿物は遠心分離して上清液と分離し、沈殿物はエタノールで洗浄して回収した。高温乾燥オーブンで沈殿物を十分に乾燥させ、精製水で沈殿物を溶解させてLOSを抽出した。
LOS抽出物の含有量を確認した後、3mg/mL濃度にし、0.2N NaOHと1:1ボリュームで混ぜる。60℃恒温水槽で120分間反応させながら、10分ごとに5秒間vortexを用いて混ぜた。その後、初期0.2N NaOH量の約1/5程度の1N酢酸を添加した。その後、エタノール沈殿法を用いて免疫調節剤であるEG−IMを得た。
LOS及びEG−IMの含有量は、2−チオバルビツール酸(2−Thiobarbituric acid)を用いたKDO(2−ケト−3−デオキシオクトン酸)定量法で測定し、濃度を測定した後、SDS−PAGEで大きさによって分離し、シルバー染色によって確認し、図1に示した。図1のAは、抽出されたLOSを電気泳動及びシルバー染色によって確認した結果であり、図1のBは、LOSをアルカリ処理した時、脂質Aが分解されることによって抽出されたLOSを基準に、EG−IMの大きさが小さくなることを確認した結果である。Mはマーカー(SeeBlue(R) Plus2 Prestained standard,Invitrogen,LC5952)を表し、レーン1は、脱アシル化前の抽出されたLOS(脱アシル化前LOS)、レーン2は、脱アシル化されたLOSであるEG−IMを表す。
精製した試料は、精製水で適度に希釈した。C18逆相カラム(ACQUITY BEH300 C18 1.7um 2.1×150mm)を機器(Water社のUPLC)に装着した後、移動相A(50mMぎ酸アンモニウムpH4.5)と移動相B(100%アセトニトリル)を用いて35〜95%濃度勾配を与えて試料を分離した。MS分析及びMS/MS分析は、質量分析機(VELOS PRO、Thermo社)を利用した。100〜3000m/z範囲の分子を分析し、MS分析の後、確認された50〜2000m/z範囲の分子を再び分析した。2372m/z分子量を持つ分子が主として(majorly)確認され、それぞれのピーク(peak)を分析した構造模式図は、図2に示した。
1.免疫化及び血液サンプリング
5週齢で搬入し、1週間馴化した6週齢のマウス(BALB/c、female、中央実験動物/SLC Japan)の後足大腿部の三角筋に、本発明に係るEG−IM又はMPLを各3μgずつ投与した(n=3)。対照群マウスには食塩水を投与した。投与して1時間及び4時間後、キシラジン(Rompun)/ケタミン麻酔液を腹腔投与してマウスを麻酔し、心臓採血して血液を採取した。冷蔵条件に血液を約4時間静置した後、4℃、3000rpm、10分間遠心分離して血清を分離し、新しいチューブに移して−70℃に保管した。
マルチプレクスサイトカイン分析(Milliplex MAP assay kit,Millipore,Billerica,MA,USA)を行い、サイトカイン及びケモカインのレベルを測定した。標的サイトカインは、TNF−α、IL−5、IL−6、IL−10、IL−12p40、MCP−1、RANTESにし、分析装備[Luminex200(Millipore)]及び分析プログラム[MILLIPLEX Analyst(Millipore)]を用いて実験結果を分析し、図3〜図5に示した。図3はIL−6、IL−12p40、TNF−αの分析結果を、図4はIL−5、IL−10の分析結果を、図5はMCP−1、RANTESの分析結果を示している。
1.日本脳炎ワクチンの免疫
死ワクチンからEG−IM/Alumの免疫原性増強効果を確認するために、日本脳炎ウイルス(Japanese encephalitis virus;JEV)抗原を使用した。6週齢BALB/cマウス(コアテック、大韓民国)に、不活性化(inactivated)日本脳炎ワクチン、又は日本脳炎ワクチン及びミョウバン(アルミニウムヒドロキシ;Brenntag,Germany)の組合せを、不活性化日本脳炎ワクチン各0.5μg/マウス又は1μg/マウスを使用し、ミョウバン25μg/マウス、EG−IM0.5μg/マウスを組み合わせて最終体積100μlにし、2週間隔で2回投与した。陰性対照群は、PBS(Phosphate−Buffered Saline,pH7.3)を投与した。
最終投与日から2週後にマウスを麻酔して心臓採血し、血液サンプルを収集した。免疫後の血清内JEV抗原の特異−抗体力価を測定するために、エンド−ポイント希釈ELSIA(end−point dilution Enzyme−Linked Immunosorbent Assay)方法を利用した。JEVを1μg/mlの濃度で希釈し、100μl/wellずつ96−ウェルプレートにコーティング(4℃、一晩)した後、1% BSA(Bovine Serum Albumin)300μlでブロッキングをした(室温、1時間)。ブロッキング後、0.05% Tween−20が含まれたPBSで3回洗浄し、免疫後に得た血清を10倍系列希釈し、各希釈血清100μlを反応させた(37℃、2時間)。JEV抗原−特異抗体を確認するために、ホースラディッシュペルオキシダーゼ−コンジュゲート抗−マウスIgG抗体(Jackson,115−035−003)、IgG1抗体(Serotec,STAR132P)、IgG2a抗体(Serotec,STAR133P)を反応させた後、TMB(tetramethylbenzidine,BD Bio science,55555214)を添加し、1N H2SO4で反応を中止させた。実験結果は、450nmで吸光度を測定し、免疫後に回収した血中IgG、IgG1、IgG2a抗体力価を測定した。その結果、EG−IM/ミョウバンを用いた試験群では、EG−IM単独又はミョウバン単独を用いた試験群に比べて、JEVウイルス抗原−特異IgG抗体生成がそれぞれ、13倍、3倍程度増加した。また、EG−IM/ミョウバンを用いた試験群では、EG−IM単独又はミョウバン単独を用いた試験群に比べてそれぞれ、JEVウイルス抗原−特異IgG1抗体生成が12倍、3倍程度増加し、JEVウイルス抗原−特異IgG2a抗体生成も、EG−IM/ミョウバンを用いた試験群で増加した(図6)。
最終投与日から2週後にマウスを麻酔して脾臓組織を摘出した後、単一細胞として分離して不活性化JEV抗原又は組換えJEV gE蛋白質5μg/mlで刺激し、72時間細胞培養した後、細胞培養液中のIFN−γ、IL−5サイトカイン分泌量をサンドイッチELISA(R&D systems,DY485;DY405)で分析した。
1.B型ヘモフィルスインフルエンザワクチンの免疫
コンジュゲートワクチンからEG−IM/ミョウバンの免疫原性増強効果を確認するために、HIB(Haemophilus b)抗原を使用した。6週齢BALB/cマウス(SLC,Japan)に、ActHIB(Haemophilus b conjugate Vaccine,Tetanus Toxoid Conjugate,Sanofi Pasteur SA)とEG−IM/ミョウバンを混合して筋肉投与経路で2週間隔で3回投与した。投与容量は、ActHIB 2μg/マウス、ミョウバン25μg/マウス又はEG−IM 0.5μg/マウスを混合した。
最終投与日から2週後にマウスを麻酔して心臓採血し、血液サンプルを収集し、HIB抗原の特異−抗体力価を測定するために、mouse anti−Haemophilus influenza type b IgG ELISA kit(XpressBio,US)を用いて血中IgG抗体力価を測定した。
<MERSワクチン>
I.組換えMERS−CoVスパイクS1蛋白質を使用した場合
1.MERSワクチンの免疫
組換えワクチンからEG−IM/ミョウバンの免疫原性増強効果を確認するために、組換えMERS−CoVスパイクS1蛋白質(eEnzyme,MERS−S1−005P)を使用した。6週齢BALB/cマウス(SLC,Japan)に、組換えMERS−CoVスパイクS1蛋白質とミョウバン及び/又はEG−IMを混合して筋肉投与経路で2週間隔で3回投与した。投与容量は、S1蛋白質0.5μg/マウス又は1μg/マウス、ミョウバン25μg/マウス又はEG−IM 0.5μg/マウスを混合した。
最終投与日から4週後にマウスを麻酔して心臓採血し、血液サンプルを収集し、MERSウイルス抗原特異−抗体力価を測定するために、ELISAキットを用いて血中IgG1、IgG2a抗体力価を測定した。
最終投与日から4週後にマウスを麻酔して脾臓組織を摘出した後、単一細胞として分離してs1蛋白質で刺激し、72時間細胞培養した後、細胞培養液中のIFN−γ、IL−4、IL−5サイトカイン分泌量をサンドイッチELISA(R&D systems,DY485;DY404;DY405)で分析した。
1.MERSワクチンの免疫
組換えワクチンからEG−IM/ミョウバンの免疫原性増強効果を確認するために、組換えMERS−CoVS1RBD蛋白質を使用した。6週齢BALB/cマウス(SLC,Japan)に、組換えMERS−CoVS1RBD蛋白質とミョウバン及び/又はEG−IMを混合して筋肉投与経路で2週間隔で3回投与した。投与容量は、RBD蛋白質1μg/マウスとミョウバン25μg/マウス、Addavax 12.5μg/マウス又はEG−IM 0.5μg/マウスを混合した。
最終投与日から2週後にマウスを麻酔して脾臓組織を摘出した後、単一細胞として分離してRBG蛋白質で刺激し、72時間細胞培養した。IFN−γサイトカイン分泌に寄与するT細胞サブタイプを分析するために、各試験群を抗原で刺激する時にCD4ブロキング抗体又はCD8ブロキング抗体を処理した。72時間後に細胞培養液を回数し、細胞培養液中のIFN−γサイトカイン分泌量をサンドイッチELISA(R&D systems,DY485)で分析した。AddaVax(Invivogen)は対照免疫補助剤として使用された。
1.ジカワクチンの免疫
組換えワクチンからEG−IM/ミョウバンの免疫原性増強効果を確認するために、組換えジカウイルスエンベロープ蛋白質を使用した。6週齢BALB/cマウス(SLC,Japan)に、組換えジカウイルスエンベロープ蛋白質とミョウバン及び/又はEG−IMを混合して筋肉投与経路で2週間隔で2回投与した。投与容量は、組換えジカウイルスエンベロープ蛋白質2μg/マウスとミョウバン25μg/マウス又はEG−IM 0.5μg/マウスを混合した。
最終投与日から2週後にマウスを麻酔して心臓採血し、血液サンプルを収集し、組換えジカウイルスエンベロープ蛋白質特異−抗体力価を測定するために、ELISAキットを用いて血中IgG1、IgG2a抗体力価を測定した。
最終投与日から2週後にマウスを麻酔して脾臓組織を摘出した後、単一細胞として分離してs1蛋白質で刺激し、72時間細胞培養した後、細胞培養液中のIFN−γ、IL−5サイトカイン分泌量をサンドイッチELISA(R&D systems,DY485;DY405)で分析した。
1.緑膿菌ワクチンの免疫
抽出蛋白質ワクチンからEG−IM/ミョウバンの免疫原性増強効果を確認するために、P.aeruginosa FT2抗原又はFT1抗原を使用した。6週齢BALB/cマウスに、FT2抗原又はFT1抗原、ミョウバン及び/又はEG−IMを混合し、抗原は1週間隔で5μg又は6.5μgずつ2回投与した。PBSを投与した群を陰性対照群とした。
最終投与日から2週後にマウスを麻酔して心臓採血し、血液サンプルを収集し、緑膿菌特異−抗体力価を測定するために、ELISAキットを用いて血中(total)IgG、IgG1、IgG2a抗体力価を測定した。
緑膿菌ワクチン免疫化によって形成されたマウス血清のオプソニン貪食活性を測定するために、P.aeruginosa FT2抗原6.5μgを抗原単独、又はミョウバン及び/又はEG−IMを混合して2週間隔で2回投与した。最終免疫化2週後に心臓採血して血清を収集し、P.aeruginosa PA103(FT2 strain)に対してオプソニン貪食活性を測定した。具体的には、P.aeruginosa FT2を対数期まで育てて回収し、56℃で30分間熱不活性化(heat−inactivation)させ、100μg/ml FITC−Isomer Iと4℃で1時間反応させて菌株に蛍光を標示した。標示済み菌株はPBSで数回洗浄し、オプソニン貪食活性試験用バッファ溶液(5% defined FBS and 0.1% gelatin in HBSS)を用いてOD600 0.9となるように希釈した。蛍光標示された菌株をカウントし、5×106CFUを免疫化血清と混合し、不活性化ウサギ補体と混合して30分間暗所で振盪培養した。その後、HL−60細胞に菌株混合物を20:1(菌株:HL−60細胞)の比率で混合し、30分間培養した。培養を終了した後、0.1% BSAが含まれたPBSで細胞を洗浄し、細胞を回収してflow cytometry(FACSCanto IITM system,BD Biosciences)とFlowJo software(Treestar,USA)を用いて分析した。オプソニン貪食活性は、HL−60細胞に標示された平均蛍光強度(mean fluorescence intensity,MFI)で示した。
緑膿菌抗原に対するEG−IM/ミョウバンの感染防御能(Protective efficacy)を確認するために、6週齢BALB/cマウスに、FT2抗原、ミョウバン及び/又はEG−IMを混合し、抗原は1週間隔で5μgずつ2回投与した。PBSを投与した群を陰性対照群とした。最終投与日から2週後に血液サンプルを収集し、1週後に、マウスは、P.aeruginosa FT2strain PA103を10 LD50で致死チャレンジ(lethal challenge)して8日間生存を観察した。
Claims (10)
- 前記ホスフェートは、2〜6個であることを特徴とする、請求項1に記載の免疫調節剤。
- 前記各ホスフェートは、化学式1のAB、AC、AD、AE、AF、BC、BD、BE、BF、CD、CE、CF、DE、DF、EF、ABC、ABD、ABE、ABF、ACD、ACE、ACF、ADE、ADF、AEF、BCD、BCE、BCF、BDE、BDF、BEF、CDE、CDF、CEF、DEF、ABCD、ABCE、ABCF、ABDE、ABDF、ABEF、ACDE、ACDF、ADEF、BCDE、BCDF、BCEF、BDEF、CDEF、ABCDE、ABCEF及びABCDEFから構成される群から選ばれる位置に結合することを特徴とする、請求項1に記載の免疫調節剤。
- 前記免疫調節剤は、O−連結された(O−linked)脂肪酸を有しないことを特徴とする、請求項1に記載の免疫調節剤。
- 請求項1の免疫調節剤を有効成分として含む免疫補助剤(adjuvant)組成物。
- 前記組成物は、Mg、Ca、Sr、Ba及びRaから構成される群から選ばれる第2族元素又はその塩;Ti、Zr、Hf及びRfから構成される群から選ばれる第4族元素;アルミニウムの塩とその水和物;及び、ジメチルオクタデシルアンモニウムブロミドから構成される群から選ばれる免疫補助成分をさらに含むことを特徴とする、請求項5に記載の組成物。
- (a)抗原;(b)請求項1の免疫調節剤;及び、(c)ミョウバン(alum)を含む、ワクチン組成物。
- 前記抗原は、ペプチド、蛋白質、核酸、糖(sugar)、病原体、弱毒化された病原体、不活性化された病原体、ウイルス、ウイルス様粒子(VLP)、細胞及び細胞断片から構成される群から選ばれることを特徴とする、請求項7に記載のワクチン組成物。
- 前記抗原は、日本脳炎ウイルス(Japanese encephalitis virus)の抗原、HIB(Heamophilus influenzae type B)の抗原、MERSウイルスの抗原、ジカウイルスの抗原、緑膿菌(Pseudomonas aeruginosa)の抗原、百日咳の抗原、結核菌の抗原、炭疽菌抗原、HAV(Hepatitis A virus)の抗原、HBV(Hepatitis B
virus)の抗原、HCV(Hepatitis C virus)の抗原、HIV(human immunodeficiency virus)の抗原、HSV(Herpes simplex virus)の抗原、髄膜炎菌(Neisseria meningitidis)の抗原、コリネバクテリウムジフテリア(Corynebacterium diphtheria)の抗原、ボルデテラパーツシス(Bordetella pertussis)の抗原、破傷風菌(Clostridium tetani)の抗原、HPV(human papilloma virus)の抗原、水痘ウイルス(Varicella virus)の抗原、腸球菌(Enterococci)の抗原、黄色ブドウ球菌(Staphylococcus aureus)の抗原、肺炎桿菌(Klebsiella pneumonia)の抗原、アシネトバクターバウマニ(Acinetobacter baumannii)の抗原、エンテロバクター(Enterobacter)の抗原、ヘリコバクターピロリ(Helicobacter pylori)の抗原、マラリア(プラスモジウム菌)の抗原、デングウイルスの抗原、ツツガムシ(Orientia tsutsugamushi)の抗原、重症熱性血小板減少症候群(severe fever with thrombocytopenia syndrome Bunyavirus;SFTS Bunyavirus)の抗原、サーズコロナウイルス(severe acute respiratory syndrome−corona virus;SARS−CoV)の抗原、インフルエンザウイルスの抗原、エボラウイルスの抗原及び肺炎球菌の抗原から構成される群から選ばれることを特徴とする、請求項7に記載のワクチン組成物。 - 前記ワクチンは、死菌ワクチン、弱毒化ワクチン、サブユニットワクチン、組換えワクチン、蛋白接合ワクチン、単価ワクチン、多価ワクチン又は混合ワクチン形態であることを特徴とする、請求項7に記載のワクチン組成物。
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