JP6110317B2 - 組換え流行性耳下腺炎ワクチン - Google Patents
組換え流行性耳下腺炎ワクチン Download PDFInfo
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Description
本出願は、2011年2月25日に出願された米国仮特許出願第61/446,619号明細書及び2011年9月1日に出願された米国仮特許出願第61/529,981号明細書の利益を主張するものであり、これらはそれぞれ、参照により本明細書に組み込まれるものとする。
本発明は、国立衛生研究所からの助成金第K02AI065795号の下で、政府の支援によりなされた。政府は本発明において一定の権利を有する。
最近の集団発生に関連した株に由来する野生型ムンプスウイルスのレスキューは、ムンプスウイルスの病変形成におけるSH ORFの役割を明らかにする。
本実施例により、流行に由来する代表的な株(MuV−IA)の完全なゲノムを配列決定した。MuV−IAは、遺伝子型Gのメンバーであり、2004〜2005年における英国での集団発生に関連したMuVと同じ遺伝子型である。逆遺伝学システムを、MuV−IA(rMuV−IA)のために構築し、SH遺伝子の翻訳領域(ORF)を欠くウイルス(rMuVΔSH)をレスキューするために使用した。L929細胞のrMuVΔSH感染は、rMuV−IAと比較して、NF−κB活性化、TNF−α産生、及びアポトーシスの増加を誘導した。rMuVΔSHは、動物モデルにおいて弱毒化していた。これらの結果から、ウイルス感染の間における、TNF−αシグナル伝達の妨害及びウイルス病変形成に、MuVのSH ORFが重要な役割を果たすことが示された。
MuV−IAの完全なゲノム配列。米国での最近の集団発生に関連したウイルスの遺伝子特性をよりよく理解するために、アイオワ州の集団発生に由来する代表的な分離株の完全なゲノム配列を決定した。これは、GENBANK受託番号JN012242として入手可能である。Jeryl Lynn、Urabe、88.1961、及びPetroNovのゲノム配列の比較から得られたコンセンサス配列に基づいて、一連のプライマーを設計した。これらのプライマーを表1に示す。ランダムヘキサマーを使用してMuV−IAのウイルスRNAをcDNAに逆転写し、次いで、プライマーのセットを使用してPCR反応を行い、対応するプライマーを使用してその産物を配列決定した。次いで、配列決定の結果に基づいた第2セットのプライマーを使用して、RT−PCRを実施し、第1回の配列決定断片の産物と重複する産物をこのプライマーを使用して配列決定した。この第2セットのプライマーを表2に示す。リーダー配列及びトレーラー配列は、5’/3’RACEを実施することにより決定した。
MuVに対する免疫は、米国で1歳及び5歳の小児に投与される、2回接種のMMR(流行性耳下腺炎、麻疹、及び風疹)ワクチンレジメンの一部である。2回のワクチン接種スケジュールでも、大規模な集団発生がワクチン接種を受けた集団に起こった。本実施例では、米国及び欧州での最近の集団発生に関連した株を代表する野生型ムンプスウイルスのレスキューについて記載されている。本実施例では、TNF−αの調節における、SHタンパク質の潜在的な役割が同定され、SH ORFの欠失がインビボでの弱毒化をもたらすことが実証され、SHがウイルスの病変形成にある役割を果たすことが示された。インビボでのrMuVΔSHの弱毒化は、SH ORFを欠失させることが、弱毒化されたムンプス株を開発するための可能な戦略となりうることを示唆する。GFP及びRLなどの外来遺伝子を発現する組換えMuVが得られており、興味深いことには、Vero細胞におけるrMuV−RLのRL発現レベルは、20継代後にも比較的高いままであり、おそらくMuVをベクターとして使用することができることを示している。
プラスミド、ウイルス、及び細胞。分子クローニングはすべて、以前に記載された標準手順に従って行った(He et al.,1997年,Virology;237:249−260)。MuV−IA NP、P、及びL遺伝子は、pCAGGS発現ベクターにクローン化した(Niwa et al.,1991年,Gene;108:193−200)。MuV−IA SH遺伝子は、pCAGGS発現ベクターにクローン化した。MuV−IA SH(停止コドン)は、3つの連続した停止コドン配列を、SH ORFの開始コドンの6ヌクレオチド下流に導入することにより構築した。pUC19におけるMuV−IAの完全長cDNAの構築は、PIV5の逆遺伝学システムと類似していた(He et al.,1997年,Virology;237:249−260)。pMuVΔSHを構築するために、4番目〜57番目のアミノ酸のSH ORF領域(156nt)を、サブクローニングを容易にし、ゲノムの長さを6の倍数に維持するように(「6の規則」として知られている)設計された短い6ヌクレオチド配列と置き換えた。pMuV−EGFP及びpMuV−RLは、F遺伝子開始とSH遺伝子終結に挟まれたEGFPまたはウミシイタケルシフェラーゼ遺伝子の何れかをFとSHの遺伝子間に挿入することにより構築した。
ムンプスウイルスのVタンパク質は病変形成に重要な役割を果たす。
ムンプスウイルス(MuV)は、耳下腺炎などの比較的軽度の症状から髄膜炎及び脳炎などの重症度の高い合併症に及ぶ多岐にわたる徴候を特徴とするヒトの急性感染症を引き起こす。広く普及したムンプスワクチン接種がムンプス発生率を劇的に低下させた;しかしながら、集団発生は依然としてワクチン接種を受けた集団に起こる。MuVのVタンパク質は、細胞培養で発現されると、インターフェロン(IFN)の発現及びシグナル伝達並びにインターロイキン6(IL−6)のシグナル伝達を遮断する。本実施例では、Vタンパク質を発現することができない組換えMuV(rMuVΔV)を生成した。レスキューされたMuVは、米国における最近の集団発生から取り出された臨床野生型分離株に由来する(MuVIowa/US/06、G遺伝子型)。このウイルスの分析により、IFNの発現及びシグナル伝達並びにIL−6のシグナル伝達の遮断における、Vタンパク質の役割が確認された。rMuVIowa/US/06ΔVウイルスがインビトロで高レベルのIL−6発現を誘導することも見出され、VがIL−6発現の低下にある役割を果たすことが示唆された。インビボでは、rMuVIowa/US/06ΔVウイルスは高度に弱毒化しており、Vタンパク質がウイルスの病原性に不可欠な役割を果たしていることが示された。
プラスミド、ウイルス、及び細胞。MuV株のMuVIowa/US/06は、米国における2006年の中西部ムンプス集団発生期間中の患者から得られた。ウイルス(pMuVIowa/US/06)の完全長cDNAクローンを、実施例1に記載のように構築した(Xu et al.,2011年,Virology;417:126−136も参照のこと)。このプラスミドは、P/V遺伝子の編集部位(GGGGGG;配列番号14のヌクレオチド1〜6)をGAGGAGGG(配列番号15のヌクレオチド1〜8)に変化させ、「6の規則」に従うように、更に4つの塩基対(CTAG;配列番号16のヌクレオチド3〜6)を遺伝子の3’非翻訳領域(3’UTR;配列番号16)に付加することにより、Vタンパク質を発現しないように改変した(Kolakofsky et al.,1998年,J Virol;72:891−899)。
Vタンパク質の発現を欠く組換えMuV(rMuVΔV)の回収。ウイルス感染の文脈の中でウイルスの病変形成におけるVタンパク質の役割を検討するために、我々は、Vタンパク質発現を消失させる変異を含有するMuVIowa/US/06ゲノムのcDNAを構築した(pMuVIowa/US/06ΔV)(MuVIowa/US/06ゲノムの受託番号はJN012242である)(Xu et al.,2011,Virology;417:126−136)。ゲノム由来のVタンパク質発現の消失は、P/V遺伝子中の編集部位(GGGGGG;配列番号14のヌクレオチド1〜6)をGAGGAGGG(配列番号15のヌクレオチド1〜8)に変化させることにより達成した。従って、Pタンパク質をコードする転写物のみが、P/V遺伝子転写から生成する(図9A)。Vタンパク質の発現を消失した感染性ウイルス(rMuVIowa/US/06ΔV)を、BSRT−7細胞へのpMuVIowa/US/06ΔVの形質移入を介するクローン化DNAからレスキューした。レスキューされたウイルスは、更にプラーク精製してVero細胞中で増幅した。レスキューされたウイルスゲノムの中にVタンパク質発現を遮断する遺伝子変化の存在を確認するために、ウイルスRNAをウイルスストックから抽出し、cDNAに逆転写して配列決定した(図9B及び9C)。
本実施例の結果により、インビトロ感染の文脈において、Vタンパク質の発現を消失した、臨床分離株(遺伝子型G)に由来する組換えウイルスに関する研究を通してこれらの発見が確認される。
マウスにおけるMuVΔSH及びMuVΔVの免疫原性
マウスにおけるrMuVΔSH及びrMuVΔVの免疫原性を判定し、MuV特異的免疫応答を測定した。一群10匹のマウスに、PBS、または106pfuのMuV、rMuVΔV、若しくはrMuVΔSHを鼻腔内に接種した。接種後21日目に、マウスから血液試料を採取した。ELISAを使用して血清中の抗MuV抗体の力価を測定した。ELISA用の96ウェルプレートを精製されたMuVビリオンでコーティングした。血清の最大希釈度及び最小希釈度における、MuVとrMuVΔSHに対するP値並びにMuVとMuVΔVに対するP値は、0.05未満であった。この結果を図18に示す。
rMuVΔSHΔVの生成及び分析
MuVワクチンは、1歳の幼児に使用されるので、新しいワクチンの開発において安全性は最重要の検討課題である。rMuVΔSH及びrMuVΔVは両方とも、ラットの脳ベースの神経毒性試験において弱毒化を示すが、更に、いかなる潜在的リスクも軽減するために、逆遺伝学システムを使用してSH及びVの両方を欠く組換えウイルス(rMuVΔSHΔV)を生成した。
ワクチン候補としての組換えMuVの改良
本実施例では、所望の位置に変異を導入するために、逆遺伝学システムを使用してrMuVコンストラクトを更に変異させる。得られるMuV変異体を組織培養細胞で分析する。神経毒性をラットモデルで評価し、ウイルスの免疫原性をマウス、フェレット、及び霊長類で調べる。V及びSHを欠く上に更なる点変異があるrMuVは、最も弱毒化されることになり、かつ復帰する可能性が最も低いように思われる。
フェレットにおける組換えムンプスウイルスの免疫原性
本明細書に記載の任意のMuVについてワクチン候補としての免疫原性及び有効性をフェレットで試験する。フェレットは、MuV感染の病変形成に関する研究にとっては小型の動物モデル系である。フェレットとヒトの間で肺の生理及び形態について顕著な類似性がある。フェレットは、呼吸系ウイルスによる感染に極めて罹りやすい。フェレットは、他のいくつかの呼吸器系病原体のための動物モデルとして確立されている。最も重要なことには、MuVが感染したフェレットから分離されており、感染動物の肺の中に病理変化が観察された(Gordon et al.,1956年,J Immunol;76(4):328−33)。研究には、rMuVコンストラクトによるフェレットの感染、フェレットにおけるrMuVコンストラクトの免疫原性の判定、及び暴露後の肺におけるウイルス負荷及び病理変化の軽減におけるそのようなワクチン候補の有効性の検討が含まれる。以前に記載されたように(Gordon et al.,1956年,J Immunol;76(4):328−33)、一群5匹のフェレットに、107pfuの野生型MuVまたはrMuVコンストラクトを1ml容量で感染させる。動物は、感染後の最初の1週間は毎日、次の週は1日置きに熱をモニターする。接種後3、4、5、7、9、及び11日目に、鼻洗浄液及び血液試料を回収し、プラークアッセイを使用してそれらの中のウイルス力価を測定する。接種後3、4、7、11、及び14日目に、フェレットを屠殺し、肺及び鼻甲介を回収して、ウイルス力価を測定する。肺及び鼻甲介における病理変化をH&E染色を使用して検査する。フェレットにおけるMuV変異体の免疫原性を、前の実施例に記載のように調べる。MuVに対する体液性免疫及び細胞性免疫を、ワクチン候補並びにJLワクチン及び野生型MuVによる接種後調べる。2回のIN接種及び3回接種(JLによる2回IM接種及びその後のワクチン候補の1回IN接種)を使用することができる。免疫学的検査に加えて、ワクチン接種を受けた動物を、野生型MuVに曝露する。細胞性免疫応答のアッセイ用の試薬を含む、フェレットにおける免疫学的アッセイ用の試薬を作製する。そのような試薬としては、CD3、CD4、CD8、IFN−β、IFN−γ、IL−6、及びIL−8に対するモノクローナル抗体を挙げることができる。
呼吸器合胞体ウイルスワクチン開発のためのベクターとしてのムンプスウイルス
呼吸器合胞体ウイルス(respiratory syncytial virus:RSV)は、小児のウイルス呼吸器感染症の最も重要な原因であり、幼児並びに免疫無防備状態の被験体及び高齢者の間の罹患率及び死亡率の主要な原因である(Collins,P.L.,R.M.Chanock,and B.R.Murphy,Respiratory syncytial virus,in Fields Virology,D.M.Knipe and P.M.Howley,Editors.2001年,Lippincott,Williams and Wilkins:Philadelphia.p.1443−1485)。加えて、重篤なRSV感染は、将来、喘鳴及び喘息をもたらすことがある。他の呼吸系ウイルスによる感染と異なり、RSVは、その後の感染に対する持続的な防御免疫を誘導しない。従って、ほとんどの個体は、一生を通して複数回感染する。現在、エアゾル化されたリバビリン及び予防的免疫グロブリン療法が臨床環境の中で使用されているが、RSVに対するワクチンも、重篤なRSV疾患に対する効果的な根治的治療も存在しない。しかしながら、高コストのパリビズマブによる予防処置には、RSVの季節の間、毎月注入する必要があるため、健康上の利益に対する費用対効果に疑問が提起されている。従って、RSVに対する安全で効果的なワクチンに対する差し迫った必要性がある。
配列番号1 Vタンパク質をコードするV/P遺伝子及び低分子疎水性タンパク質をコードするSH遺伝子を含むムンプスウイルスゲノム
配列番号2 ムンプスウイルスVタンパク質
配列番号3 ムンプスウイルス低分子疎水性タンパク質
配列番号4 ムンプスウイルス株Glouc1/UK96のSHタンパク質配列
配列番号5 ムンプスウイルス株UK01−22のSHタンパク質配列
配列番号6 ムンプスウイルス株MuV−IAのSHタンパク質配列
配列番号7 SH遺伝子の上流の核酸配列
配列番号8 SH遺伝子の欠失から得られる組換え核酸配列
配列番号9 SHタンパク質の欠失を確認するために配列決定されたPCR産物
配列番号10 抗体を生成するために使用されたMuV−IA SH N末端ペプチド配列
配列番号11 抗体を生成するために使用されたMuV−IA SH C末端ペプチド配列
配列番号12〜13 抗体を生成するために使用されたMuV−IA Vタンパク質ペプチド配列
配列番号14 P/V遺伝子内の核酸編集配列
配列番号15 Vタンパク質発現を消失させる組換え核酸配列
配列番号16 P/V遺伝子の改変から得られる組換え核酸配列
配列番号17 Vタンパク質の欠失を確認するために配列決定されたPCR産物
配列番号18 Vタンパク質欠失があるムンプスウイルスのNP遺伝子の終結からP/V遺伝子の開始までの核酸配列
配列番号19〜25 Vタンパク質欠失があるムンプスウイルスのNP遺伝子の終結からP/V遺伝子の開始までのレスキューされた核酸配列
配列番号:26〜81 合成オリゴヌクレオチドプライマー
Claims (26)
- ムンプスウイルスの完全長RNAゲノムをコードするcDNA配列を含む単離ポリヌクレオチドであって、前記ムンプスウイルスは、V/I/P遺伝子に対する1又は複数の変異を含み、前記変異は、Vタンパク質の発現を抑止するが、P遺伝子の発現を抑止しない、単離ポリヌクレオチド。
- 前記Vタンパク質の発現を抑止する、V/I/P遺伝子に対する前記1つまたは複数の変異が、P/V遺伝子内の編集部位にヌクレオチド配列GAGGAGGGを含む、請求項1に記載の単離ポリヌクレオチド。
- 低分子疎水性(SH)タンパク質を発現することができないムンプスウイルスを更にコードする、請求項1又は2に記載の単離ポリヌクレオチド。
- 前記SHタンパク質をコードする翻訳領域(ORF)の欠失、開始コドンを停止コドンに変換する変異、または前記SH遺伝子の転写を破壊する、FポリペプチドをコードするORFとSHポリペプチドをコードするORFとの間の領域にある変異を含む、請求項3に記載の単離ポリヌクレオチド。
- 前記SHタンパク質をコードするORFの欠失を含む、請求項4に記載の単離ポリヌクレオチド。
- 前記SHタンパク質をコードするORFの156ヌクレオチドの欠失を含む、請求項5に記載の単離ポリヌクレオチド。
- 変異及び/または欠失をさらに含む、請求項1〜6の何れか一項に記載の単離ポリヌクレオチド。
- Pタンパク質のリン酸化を抑制する変異または欠失を含む、請求項7に記載のムンプスウイルスの完全長RNAゲノムをコードするcDNA配列を含む単離ポリヌクレオチド。
- Pタンパク質のT147及び/またはS307における変異を含む、請求項7に記載の単離ポリヌクレオチド。
- L遺伝子の変異を更に含む、請求項1〜9の何れか一項に記載の単離ポリヌクレオチド。
- Iタンパク質の発現を更に含む、請求項1〜10の何れか一項に記載の単離ポリヌクレオチド。
- 前記ゲノムが異種のポリペプチドを更にコードする、請求項1〜11の何れか一項に記載の単離ポリヌクレオチド。
- 前記ムンプスウイルスが遺伝子型Gに属する、請求項1〜12の何れか一項に記載の単離ポリヌクレオチド。
- 前記ムンプスウイルスがMuV/IowaUS/2006(MuV−IA)である、請求項1〜13の何れか一項に記載の単離ポリヌクレオチド。
- 前記ムンプスウイルスの全長RNAゲノムが配列番号1の配列を含む、請求項14に記載の単離ポリヌクレオチド。
- 請求項1〜15の何れか一項に記載の単離ポリヌクレオチドを含む、組換えムンプスウイルス(rMuV)。
- 請求項1〜15の何れか一項に記載の単離ポリヌクレオチドを含むプラスミド。
- 請求項1〜15の何れか一項に記載の単離ポリヌクレオチドを含むムンプスウイルスゲノムをコードするプラスミド(pMuV)。
- 請求項1〜15の何れか一項に記載の単離ポリヌクレオチドを含むウイルス発現ベクター。
- 請求項1〜15の何れか一項に記載の単離ポリヌクレオチド、請求項16に記載の組換えムンプスウイルス、請求項17または18に記載のプラスミド、または請求項19に記載のウイルス発現ベクターを含む感染性ウイルス粒子。
- 請求項1〜15の何れか一項に記載の単離ポリヌクレオチド、請求項16に記載の組換えムンプスウイルス、請求項17または18に記載のプラスミド、請求項19に記載のウイルス発現ベクター、または請求項20に記載の感染性ウイルス粒子を含む組成物。
- 風疹及び/または麻疹の抗原決定基を更に含む、請求項21に記載の組成物。
- 鼻腔内、経口、皮内、または筋肉内投与のために製剤化された、請求項21または22に記載の組成物。
- 前記組成物が、被験体におけるムンプスウイルスに対する免疫応答を誘導する方法に使用され、前記方法が、請求項1〜15の何れか一項に記載の単離ポリヌクレオチド、請求項16に記載の組換えムンプスウイルス、請求項17または18に記載のプラスミド、請求項19に記載のウイルス発現ベクター、または請求項20に記載の感染性ウイルス粒子の有効量を、前記被験体に投与することを含む、請求項21〜23の何れか一項に記載の組成物。
- 鼻腔内、経口、皮内、または筋肉内投与を含む、請求項24に記載の組成物。
- 異種のRNAまたはポリペプチドをインビトロで発現させる方法であって、前記方法が請求項12に記載の単離ポリヌクレオチドをインビトロで発現させることを含む方法。
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JP2014512804A (ja) | 2014-05-29 |
EP2678043A4 (en) | 2016-09-07 |
CA2828229A1 (en) | 2012-08-30 |
EP2678043B1 (en) | 2018-04-25 |
WO2012116253A3 (en) | 2013-02-28 |
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EP2678043A2 (en) | 2014-01-01 |
US11027008B2 (en) | 2021-06-08 |
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