JP2017214357A - 非経口ノロウイルスワクチン製剤 - Google Patents
非経口ノロウイルスワクチン製剤 Download PDFInfo
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- JP2017214357A JP2017214357A JP2017091755A JP2017091755A JP2017214357A JP 2017214357 A JP2017214357 A JP 2017214357A JP 2017091755 A JP2017091755 A JP 2017091755A JP 2017091755 A JP2017091755 A JP 2017091755A JP 2017214357 A JP2017214357 A JP 2017214357A
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Abstract
【解決手段】ジェノグループI型ノロウイルスウイルス様粒子の混合物を含む単回投与の非経口ワクチン組成物。組成物を投与することによって、ヒト対象にノロウイルス感染に対する防御免疫を与える方法。
【選択図】なし
Description
[0001] 本出願は、2011年7月11日出願の米国仮特許出願第61/506,447号に対する優先権を主張し、その全内容は参照により本明細書に組み込むものとする。
ャム、GenBankアクセッション番号X81879;ヒトカリシウイルス株MX、GenBankアクセッション番号U22498;ミニレオウイルスTV24、GenBankアクセッション番号U02030;及びノーウォーク様ウイルスNLV/グウィネズ/273/1994/米国、GenBankアクセッション番号AF414409があり、これらの配列はすべて(本出願の出願日に登録した状態で)参照により本明細書に組み込むものとする。追加のノロウイルス配列は、以下の特許公報、すなわち、WO2005/030806号、WO2000/79280号、JP2002020399号、US2003129588号、米国特許第6,572,862号、WO1994/05700号、及びWO 05/032457号に開示され、これはすべて参照により全体を本明細書に組み込むものとする。また、配列の比較、及びノロウイルスの遺伝子の多様性及び系統学的分析の検討については、Green他(2000)のJ. Infect. Dis., Vol. 181 (Suppl. 2): S322-330;Wang他(1994)のJ. Virol., Vol. 68: 5982-5990;Chen他(2004)のJ. Virol., Vol. 78: 6469-6479;Chakravarty他(2005)のJ. Virol., Vol. 79: 554-568;Hansman他(2006)のJ. Gen. Virol., Vol. 87: 909-919;Bull他(2006)のJ. Clin. Micro., Vol. 44(2): 327-333;Siebenga他(2007)のJ. Virol., Vol. 81(18): 9932-9941;及びFankhauser他(1998)のJ. Infect. Dis., Vol. 178: 1571-1578を参照されたい。それぞれの核酸及び対応するアミノ酸の配列はすべて、参照により全体を本明細書に組み込むものとする。幾つかの実施形態では、識別目的に暗号を使用することができ、系統立てられている。すなわち、ウイルスを分離した元の宿主の種/属の略語/科の略語/株名/発生年/発生国である(Green他、Human Caliciviruses, in Fields Virology Vol. 1 841-874(Knipe及びHowley、主任編集者、第4版、Lippincott Williams & Wilkins 2001))。幾つかの実施形態では、ジェノグループII、遺伝子型4(GII.4)ウイルス株(例えばヒューストン、ミネルバ(デンハーグとしても知られる)、及びローレンス(イェルセケとしても知られる)株)が好ましい。新しい株が識別され、その遺伝子配列が使用可能になるにつれ、当業者は、組成物のこれら最近の株、及び本発明の方法を使用し、通常の技術でVLPを採用することができる。したがって、本発明は本明細書で述べる組成物及び方法で使用するために適切な抗原として、このような株から作成したVLPを想定する。
実施例1.ヒトにおける筋肉内ノロウイルス二価ウイルス様粒子(VLP)ワクチンの用量増大、安全性及び免疫原性の検討(LV03−104試験)、コホートA
[0072] この実施例は、モノホスホリルリピドA(MPL)及び水酸化アルミニウム(AlOH)のアジュバントを追加した筋肉内(IM)ノロウイルス二価VLPワクチンの4用量レベルの安全性及び免疫原性を成人対象でプラセボと比較した、ランダム化多部位用量増大試験のコホートAについて説明する。18歳〜49歳の対象ほぼ48名がコホートに登録した。対象には、28日間隔で1.5インチ(38mm)の針を使用し、筋肉内(IM)注射によって2用量のワクチン又はプラセボを投与した。
[0080] コード化した試料をスクリーニングする標的抗原として精製した組み換えノロウイルスVLP(別個にGI.1及びGII.4)を使用して、ある対象でELISAによるノロウイルスの抗体の測定を実施した。簡潔に言うと、炭水化物コーティング緩衝液pH9.6中のノロウイルスVLPを使用して、マイクロタイタプレートをコーティングした。コーティングしたプレートを洗浄し、ブロッキングして、試験血清の段階的2倍希釈液でインキュベートし、その後に洗浄し、ヒト全IgG、IgG1、IgG2、IgG3、IgG4、IgA及びIgMに特異的な酵素結合2次抗体試薬でインキュベートした。適切な基質溶液を添加し、色を発現させ、プレートを読み取り、各抗体クラスの基準標準曲線と比較して、IgG、IgA及びIgMエンドポイントタイタを判定した。各群の幾何平均抗体価(GMT)、幾何平均上昇倍数(GMFR)及び血清応答割合を判定した。抗体応答は、免疫前の抗体価と比較して抗体価が4倍増加すると定義した。
[0081] 上述したように、血清抗体がH1型又はH3型合成炭水化物に対するNV VLPの結合を阻止する能力を測定するために阻害アッセイを実施した(Reeck他(2010)、J Infect Dis, Vol. 202(8): 1212-1218)。簡潔に言うと、阻害アッセイのNV VLPを同等量の血清でインキュベートし、1:25の開始希釈液から段階的に2倍希釈した。ニュートラアビジンでコーティングした96ウェルのマイクロタイタプレートを洗浄し、2.5μg/mLの合成多価H型1−PAAビオチン又は多価H型3−PAAビオチンでコーティングした。血清VLP溶液を添加した。プレートを洗浄し、NV VLPに特異的なウサギの多クローン血清を添加し、洗浄して、その後にホースラディッシュペルオキシダーゼ共役ヒツジ抗ウサギIgGでインキュベートした。色は、テトラメチルベンジジンペルオキシダーゼ液体基質で発現させ、1Mリン酸で停止させた。光学密度は450で測定した。プラス及びマイナスの制御を実施した。50%阻害価(BT50)を判定し、これは(空白を除いた後の)OD読み取り値がプラスの対照標準の50%である力価と定義される。BT50が25未満のサンプルに12.5の値を割り当てた。各群の幾何平均抗体価(GMT)、幾何平均上昇倍数(GMFR)及び血清応答割合を判定した。抗体応答は、免疫前の抗体価と比較して抗体価が増加したことと定義した。阻害対照標準血清サンプルを内部対照標準として使用した。以下を除いては阻害アッセイと同じプロトコルを使用して、阻害の特異性を確認するアッセイを実施した。すなわち、炭水化物でコーティングした後、血清は、最初にVLPで事前にインキュベートせずに、プレート上で直接インキュベートした。洗浄後、VLPをプレート上でインキュベートし、阻害アッセイと同様に検出した。
[0082] 上述したように(El Kamary他(2010)、J Infect Dis, Vol. 202(11): 1649-58)、ワクチン誘導の抗体がノロウイルスVLPによるヒトのO型RBCの赤血球凝集を阻止する能力があるか検査した。HAI抗体価を、赤血球凝集を阻止した最高希釈の逆数としてコンパクトなマイナスRBCパターンで計算し、GMT、GMRF、及び4倍上昇以上として提示する。
[0084] IMノロウイルス二価VLPワクチン又はプラセボを投与した後0、7+3、28+3、及び35+3日目に約60mLの抗凝固処理した血液からPBMCを分離した。新しいPBMCアッセイ用に約25mLの血液、PBMCの凍結保存用に35mLの血液を入手した。ASCアッセイは、ノロウイルスVLPに対する抗体を分泌する細胞を検出する(Tacket他(2000)、J. Infect. Dis., Vol. 182: 302-305;Tacket他(2003)、Clin. Immunol., Vol. 108: 241-247;El Kamary他(2010)、J. Infect Dis, Vol. 202(11): 1649-58)。対象のサブセットからのASC頻度について新しいPBMCを評価し、回復マーカーを判定した。コホートAに参加した対象からの凍結保存したPBMCのASC頻度を評価した。群ごとに各時点におけるPBMC106個当たりのASCの平均数及び応答割合を既述した。プラスの応答は、全対象、及び少なくとも8つのASCスポットで、でPBMC106個当たりワクチン接種後のASCカウントが、(ログ計量で)ワクチン接種前の平均カウントより少なくとも3標準偏差(SD)高いことと定義され、これは同様のアッセイで判定された中程度刺激のマイナスの対照標準ウェル(2スポット)の平均に3SDを加えた値に対応する。
[0085] 抗凝固血をコホートAの対象からのみ(0、28、56及び180日目に約25mL)採取し、in vitro抗原刺激が先行するELISpotアッセイを使用して、ワクチン接種後0、28、56及び180日目にメモリB細胞を測定した(Crotty他(2004)、J. Immunol. Methods, Vol. 286: 111-122.;Li 他(2006)、J. Immunol. Methods, Vol. 313: 110-118)。末梢血単核細胞(細胞5×106個/mL、1mL/24ウェルプレートのウェル)を、ノロウイルスGI.1及びGII.4のVLP抗原で4日間別個にインキュベートし、抗原特異的メモリB細胞がクローン増殖して、抗体分泌細胞に分化できるようにした。対照標準には、抗原及び/又は無関係の抗原でインキュベートした細胞を使用せずに同じ状態でインキュベートした細胞が含まれた。刺激後、細胞を洗浄し、カウントして、ノーウォークVLPでコーティングしたELISpotプレートに移した。全Ig分泌Bリンパ球当たりのウイルス特異的メモリB細胞の頻度を判定するために、抗ヒトIgG及び抗ヒトIgA抗体でコーティングしたウェルにも、増殖したB細胞を加えた。適切な基質後のHRPで標識された抗ヒトIgG又は抗ヒトIgAで、結合抗体が明らかになった。顕著なエフェクタのメカニズム及び免疫初回刺激の位置と関連しているような抗原特異的サブクラス応答を判定するために、IgA及びIgGサブクラス(IgA1、IgA2及びIgG1〜4)との共役も使用した。ELISpot読み取り装置でスポットをカウントした。各対象の増殖細胞集団をフローサイトメトリで検査し、特にそのメモリB細胞のフェノタイプ、すなわちCD19+、CD27+、IgG+、IgM+、CD38+、IgDを確認した(Crotty他(2004)、J. Immunol. Methods, Vol. 286: 111-122.;Li他(2006)、J. Immunol. Methods, Vol. 313: 110-118)。
[0086] ノロウイルスGI.1及びGII.4のVLP抗原に対するCMI応答を将来評価する可能性があるので、そのためにコホートAの対象からコード化した試料として抗凝固血を(0、28、56及び180日目に約25mL)採取し、PBMCを分離して、液体窒素中で凍結保存した。実施するアッセイには、確立された技術により特にインタフェロン(IFN)−γ及びインタロイキン(IL)−4のレベルを測定することによる、ノロウイルスGI.1及びGII.4のVLP抗原に対するPBMC増殖及びサイトカイン応答が含まれる(Samandari他(2000)、J. Immunol., Vol. 164: 2221-2232;Tacket他(2003)、Clin. Immunol., Vol. 108: 241-247)。T細胞応答も評価した。
[0087] 安全性評価には、各投与後、7日間の聴き取り局所及び全身症状、及び28日間の非聴き取り症状が含まれた。12ヶ月間、重篤な有害事象をモニタする。panELISA抗体(IgG、IgA及びIgM混合)、及びIgG及びIgA抗体分泌細胞(ASC)の末梢血単核細胞(PBMC)についてElispotを介してワクチン接種する度に、その前後で取得した血清で免疫原性を評価した。
[0097] 以下の実施例は、実施例1で述べた臨床試験の残りの計画部分を提供し、ここでは18歳以上の成人で、モノホスホリルリピドA(MPL)及び水酸化アルミニウム(AlOH)のアジュバントを加えた筋肉内(IM)ノロウイルス二価VLPワクチンの4用量レベルの安全性及び免疫原性をプラセボと比較して実施した。対象には、28日間隔で1.5インチ(38mm)の針を使用し、筋肉内(IM)注射によって2用量のワクチン又はプラセボを投与した。この実施例は、本発明の原理を更に例証するためのものである。
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Claims (38)
- ヒトにノロウイルスに対する防御免疫を誘発する方法であって、
ワクチン組成物をヒトに非経口で単回投与することを含み、前記組成物がジェノグループIノロウイルスのウイルス様粒子(VLP)を含み、前記組成物が、前記組成物の投与前の前記ヒトにおけるノロウイルス特異的血清抗体価と比較して少なくとも3倍増加した前記抗体価を誘導し、前記ジェノグループIノロウイルスVLPが、ジェノグループIウイルス株由来のカプシドタンパク質を含む、方法。 - 前記組成物が、150μg以下の前記ジェノグループIノロウイルスVLPを含む、請求項1に記載の方法。
- 前記組成物が、50μg以下の前記ジェノグループIノロウイルスVLPを含む、請求項1に記載の方法。
- 前記組成物が、25μg以下の前記ジェノグループIノロウイルスVLPを含む、請求項1に記載の方法。
- 前記組成物が、15μg以下の前記ジェノグループIノロウイルスVLPを含む、請求項1に記載の方法。
- 前記組成物が、前記組成物の投与前の前記ヒトにおけるノロウイルス特異的血清抗体価と比較して、少なくとも6倍増加した前記抗体価を誘導する、請求項1に記載の方法。
- 前記ノロウイルスVLPが、一価VLP又は多価VLPである、請求項1に記載の方法。
- 前記組成物が、ジェノグループIIノロウイルスVLPを更に含み、前記ジェノグループIIノロウイルスVLPがジェノグループIIウイルス株由来のカプシドタンパク質を含む、請求項1に記載の方法。
- 前記組成物が、150μg以下のジェノグループIIノロウイルスVLPを含む、請求項8に記載の方法。
- 前記組成物が、50μg以下のジェノグループIIノロウイルスVLPを含む、請求項8に記載の方法。
- 前記組成物が、25μg以下のジェノグループIIノロウイルスVLPを含む、請求項8に記載の方法。
- 前記組成物が、15μg以下のジェノグループIIノロウイルスVLPを含む、請求項8に記載の方法。
- 前記ジェノグループIノロウイルスVLPが、ノーウォークウイルスVLPであり、前記ジェノグループIIノロウイルスVLPが、ジェノグループIIノロウイルスのコンセンサス配列の発現により生成されたVLPである、請求項8に記載の方法。
- ヒトにノロウイルスに対する防御免疫を誘発する方法であって、
ワクチン組成物をヒトに非経口で単回投与することを含み、前記組成物がジェノグループIIノロウイルスのウイルス様粒子(VLP)を含み、前記組成物が、前記組成物の投与前の前記ヒトにおけるノロウイルス特異的血清抗体価と比較して少なくとも3倍増加した前記抗体価を誘導し、前記ジェノグループIIノロウイルスVLPが、ジェノグループIIウイルス株由来のカプシドタンパク質を含む、方法。 - 前記組成物が、150μg以下の前記ジェノグループIIノロウイルスVLPを含む、請求項14に記載の方法。
- 前記組成物が、50μg以下の前記ジェノグループIIノロウイルスVLPを含む、請求項14に記載の方法。
- 前記組成物が、25μg以下の前記ジェノグループIIノロウイルスVLPを含む、請求項14に記載の方法。
- 前記組成物が、15μg以下の前記ジェノグループIIノロウイルスVLPを含む、請求項14に記載の方法。
- 前記ジェノグループIIノロウイルスVLPが、ジェノグループII遺伝子型4ウイルス株由来のカプシドタンパク質を含む、請求項14に記載の方法。
- 前記組成物が、前記組成物の投与前の前記ヒトにおけるノロウイルス特異的血清抗体価と比較して、少なくとも6倍増加した前記抗体価を誘導する、請求項14に記載の方法。
- 前記ノロウイルスVLPが、一価VLP又は多価VLPである、請求項14に記載の方法。
- 前記組成物が、ジェノグループIノロウイルスVLPを更に含み、前記ジェノグループIノロウイルスVLPがジェノグループIウイルス株由来のカプシドタンパク質を含む、請求項14に記載の方法。
- 前記組成物が、150μg以下の前記ジェノグループIノロウイルスVLPを含む、請求項22に記載の方法。
- 前記組成物が、50μg以下の前記ジェノグループIノロウイルスVLPを含む、請求項22に記載の方法。
- 前記組成物が、25μg以下の前記ジェノグループIノロウイルスVLPを含む、請求項22に記載の方法。
- 前記組成物が、15μg以下の前記ジェノグループIノロウイルスVLPを含む、請求項22に記載の方法。
- 前記ジェノグループIIノロウイルスVLPが、ジェノグループIIノロウイルスのコンセンサス配列の発現から生成されるVLPである、請求項14に記載の方法。
- 前記組成物が、少なくとも1つのアジュバントを更に含む、請求項1〜27のいずれか1項に記載の方法。
- 前記少なくとも1つのアジュバントが、toll様受容体アゴニストである、請求項28に記載の方法。
- 前記組成物が、2つのアジュバントを更に含む、請求項1〜27のいずれか1項に記載の方法。
- 前記2つのアジュバントが、モノホスホリルリピドA及び水酸化アルミニウムである、請求項30に記載の方法。
- 前記組成物が、緩衝剤を更に含む、請求項1〜31のいずれか1項に記載の方法。
- 前記緩衝剤が、L−ヒスチジン、イミダゾール、コハク酸、トリス、及びクエン酸からなる群から選択される、請求項32に記載の方法。
- 前記ワクチン組成物が、静脈内、皮下、皮内、又は筋肉内投与経路によって前記ヒトに投与される、請求項1〜33のいずれか1項に記載の方法。
- 前記ワクチン組成物が、筋肉内投与経路によって前記ヒトに投与される、請求項34に記載の方法。
- 前記ワクチン組成物が、液体として配合される、請求項1〜35のいずれか1項に記載の方法。
- 前記ノロウイルス特異的抗体価の増加が、前記単回投与の前記組成物の投与から7日以内に誘導される、請求項1〜35のいずれか1項に記載の方法。
- 前記ワクチン組成物が、ノロウイルス感染の1つ又は複数の症状からの防御を与える、請求項1〜35のいずれか1項に記載の方法。
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