JP2017189179A - 逆遺伝学系 - Google Patents
逆遺伝学系 Download PDFInfo
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- JP2017189179A JP2017189179A JP2017146473A JP2017146473A JP2017189179A JP 2017189179 A JP2017189179 A JP 2017189179A JP 2017146473 A JP2017146473 A JP 2017146473A JP 2017146473 A JP2017146473 A JP 2017146473A JP 2017189179 A JP2017189179 A JP 2017189179A
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Abstract
【解決手段】本発明は、分節RNAウイルスを生成する種々の逆遺伝学系を提供する。該系は、その発現構築物のすべての増殖のために細菌を必要としない。第1の態様においては、逆遺伝学系は、少なくとも2種のウイルスゲノムセグメントをコードする非細菌性発現構築物に基づく。この系は、完全なウイルスゲノムの生成のために宿主細胞に移入しなければならない構築物の数を削減する。例えば、単一の構築物を使用して8種のインフルエンザウイルスセグメントをコードし、それによって移入の複雑さを参考文献6の1/8にすることができる。したがって、本発明は、分節RNAウイルスの少なくとも2種の異なるゲノムセグメントを発現するコード配列を含む、非細菌性発現構築物を提供する。本発明は、この非細菌性発現構築物を含む真核宿主細胞も提供する。
【選択図】なし
Description
したがって、本発明は、以下の項目を提供する:
(項目1)
分節RNAウイルスの少なくとも2種の異なるゲノムセグメントを発現するコード配列を含む、非細菌性発現構築物。
(項目2)
上記構築物が細菌複製起点と細菌選択マーカーの両方を欠く、項目1に記載の構築物。
(項目3)
上記構築物が線状である、項目1又は項目2に記載の構築物。
(項目4)
A型又はB型インフルエンザウイルスの全8種のゲノムセグメントを発現するコード配列を含む、任意の先行する項目のいずれかに記載の構築物。
(項目5)
任意の先行する項目のいずれかに記載の非細菌性発現構築物を含む、真核宿主細胞。
(項目6)
(i)A型又はB型インフルエンザウイルスゲノムセグメントPB2、PB1、PA、NP及びNSのコード配列を含む第1の非細菌性発現構築物、及び(ii)A型又はB型インフルエンザウイルスゲノムセグメントHAのコード配列を含む第2の非細菌性構築物を含む、発現構築物のセット。
(項目7)
上記第1の非細菌性発現構築物又は上記第2の非細菌性発現構築物が、さらに、NAゲノムセグメント及びMゲノムセグメントを含む、項目6に記載のセット。
(項目8)
(i)分節RNAウイルスの1種以上のゲノムセグメントのコード配列(単数又は複数)を含む少なくとも1つのプラスミド、及び(ii)該RNAウイルスの1種以上のゲノムセグメントのコード配列(単数又は複数)を含む少なくとも1つの非細菌性発現構築物を含み、細菌性構築物と非細菌性構築物の組合せが該RNAウイルスの少なくとも2種の異なるゲノムセグメントを与える、発現構築物のセット。
(項目9)
項目8に記載の構築物のセットを含む、真核宿主細胞。
(項目10)
分節RNAウイルスの少なくとも2種の異なるゲノムセグメントのコード配列を含む線状発現構築物を含む、宿主細胞。
(項目11)
インフルエンザウイルスの8種の異なるゲノムセグメントのコード配列を含む細菌プラスミドであって、各セグメントの発現がほ乳動物pol−Iプロモーターによって制御される、細菌プラスミド。
(項目12)
項目11に記載のプラスミドを含む、真核宿主細胞。
(項目13)
項目5、項目7又は項目10に記載の宿主細胞を調製するための方法であって、項目1から4、項目6又は項目9に記載の構築物、セット又はプラスミドを上記細胞に挿入する工程を含む、方法。
(項目14)
分節RNAウイルスを生成するための方法であって、該RNAウイルスセグメントの発現が起きて該ウイルスを生成するように、項目5、項目8、項目10又は項目12に記載の宿主細胞を培養する工程を含む、方法。
(項目15)
分節RNAウイルスゲノムの少なくとも2種の異なるセグメントを発現するコード配列を含むDNA分子を調製するための方法であって、該方法が、(i)該DNA分子の複数の重複断片を合成する工程であって、該重複断片が完全な該DNA分子に広がっている工程、及び(ii)該断片を連結して該DNA分子を生成する工程を含む、方法。
(項目16)
上記細胞がMDCK細胞である、項目5、項目8、項目10又は項目12に記載の宿主細胞。
本発明の第1、第2及び第3の態様は、1種類以上の「非細菌性発現構築物」を利用する。この用語は、構築物が、その中にコードされたウイルスRNAセグメントを真核細胞中で発現させることができるが、細菌中での構築物の増殖に必要な成分は含まないことを意味する。したがって、構築物は、細菌複製起点(ori)を含まず、通常は細菌選択マーカー(例えば、抗生物質耐性マーカー)を含まない。これらの成分は、真核宿主細胞中での所望のウイルスRNAを発現させるのには不要であり、したがって細菌が構築物の増殖に使用されないときには無用である。これらの増殖成分の欠如は、構築物が細菌に導入された場合に、構築物が複製されないことを意味する。
上述したように、DNA発現構築物は、化学合成によって少なくとも部分的に調製することができる。構築物は、分節RNAウイルスゲノムの少なくとも2種の異なるセグメントを発現する(好ましくは、分節RNAウイルスの完全なゲノムを発現する)コード配列を含み、好都合には、参考文献8に開示された合成法を使用して調製することができる。
本発明の第2及び第4の態様は、プラスミドの使用を含む。これらのプラスミドは、好都合には、細菌中で増殖することができ、したがって細菌複製起点(ori)を含み、通常は細菌選択マーカー(例えば、抗生物質耐性マーカー)も含む。したがって、プラスミドは、上で考察した非細菌性発現構築物から(配列と機能の両方によって)容易に識別される。一般的には、プラスミドは、逆遺伝学の分野で既知であるプラスミドと同じであり得るが、従来技術は、それをウイルス回収のために非細菌性発現構築物と併用することを開示していない。
本発明で使用される非細菌性発現構築物及びプラスミド発現構築物は、ウイルスRNAセグメント(単数又は複数)をコードする。これらのコード配列は、適切な真核宿主細胞中で発現されて、ビリオンにパッケージされて組換え発現ウイルスを生成することができるウイルスRNAを提供することができる。
大部分の逆遺伝学方法は、ウイルスRNAセグメントの転写を駆動するためのRNAポリメラーゼI(RNA pol−I)プロモーターを含む発現ベクターを使用する。pol−Iプロモーターは、修飾していない5’及び3’末端を有する転写物を生成する。これは、多数のウイルス、例えばインフルエンザの完全な感染力に必要である。
本発明は、改変された又はリアソータントな系統を含めて、ウイルス系統の生成に有用である。この技術をDNA構築物のin vitro操作に使用して、ウイルスセグメントの組合せ物を作製することができ、ウイルスセグメント中のコード配列又は非コード配列の操作を容易にすることができ、変異を導入することなどができる。リアソータントなウイルス系統の生成は、流行に対抗するのにワクチンの迅速な製造が必要である状況において特に有益であるリアソータントな種ウイルスを得るのに必要な時間をかなり短縮することができるので、有用である。したがって、発現構築物を使用して、少なくとも2種類の野生型系統のウイルスセグメント又は該野生型系統由来のウイルスセグメントを発現させることが好ましい。
本発明の方法は、任意の分節RNAウイルスを使用して実施することができる。かかるウイルスは、プラス鎖、マイナス鎖又は二本鎖とすることができる。
ザウイルス、トゴトウイルス、感染性サケ貧血ウイルス、ブンヤムウェラウイルス、ハンターンウイルス、Dugbeウイルス、リフトバレー熱ウイルス、トマトスポッテットウイルトウイルス、リンパ球性脈絡髄膜炎ウイルス、柑橘類ソローシスウイルス、イネ縞葉枯ウイルス及びデルタ型肝炎ウイルスからなる群から選択される。好ましい実施形態においては、ウイルスはインフルエンザウイルスである(下記参照)。
本発明は、逆遺伝学が十分に特徴づけられたA型インフルエンザウイルス及びB型インフルエンザウイルスに用いるのに特に適切である。インフルエンザウイルスは、分節マイナス鎖RNAウイルスである。A及びB型インフルエンザウイルスは、8種のセグメント(PB2、PB1、PA、HA、NP、NA、M及びNS)を有し、一方C型インフルエンザウイルスは7種(NAセグメントなし)を有する。上記ウイルスは、通常、複製を開始するのに少なくとも4種類のウイルスタンパク質(PB1、PB2、PA及び核タンパク質)の存在を必要とする。したがって、少なくともこれら4種類のウイルスタンパク質は、タンパク質をコードする発現構築物によって提供されるべきである。
本発明は、発現構築物(単数又は複数)の移入後に対象ウイルスを発現することができる任意の細胞において実施することができる。本発明は、典型的には細胞系を使用するが、初代細胞を代替として使用することができる。細胞は、典型的にはほ乳動物のものであるが、トリ又は昆虫細胞を使用することもできる。適切なほ乳動物細胞としては、ハムスター、ウシ、(ヒト及びサルを含めた)霊長類及びイヌ細胞が挙げられるが、それだけに限定されない。腎細胞、線維芽細胞、網膜細胞、肺細胞などの種々の細胞型を使用することができる。適切なハムスター細胞の例は、BHK21又はHKCCという名称の細胞系である。適切なサル細胞は、例えば、Vero細胞系のような腎細胞などのアフリカミドリザル細胞である[19〜21]。適切なイヌ細胞は、例えば、CLDK及びMDCK細胞系のような腎細胞である。適切なトリの細胞としては、ニワトリ胚性幹細胞由来のEBx細胞系EB45、EB14及びEB14−074が挙げられる[22]。
PTA−6503)を含めた非腫瘍形成性MDCK細胞を開示している。参考文献31は、「MDCK.5F1」細胞(ATCC CRL12042)を含めて、感染に対する感受性の高いMDCK細胞を開示している。
本発明は、本発明の宿主細胞によって産生されるインフルエンザウイルスを提供する。このインフルエンザウイルスは、種々の方法で、例えばワクチン製造用種ウイルスとして、使用することができる。
ウイルスが細胞系において単離及び/又は増殖された場合、残留細胞系のDNAの発癌活性を最小化するために、最終ワクチン中の残留細胞系のDNAの量を最小化することが標準的慣行である。したがって、本発明によって調製されるワクチン組成物は、好ましくは、1回の投与量当たり10ng未満(好ましくは1ng未満、より好ましくは100pg未満)の残留宿主細胞DNAを含むが、痕跡量の宿主細胞DNAが存在してもよい。
本発明によって製造されたワクチン組成物は薬学的に許容される。それは、通常、抗原に加えて諸成分を含み、例えば、典型的には、1種類以上の薬学的キャリア(単数又は複数)及び/又は賦形剤(単数又は複数)を含む。以下に記載するように、アジュバントを含むこともできる。かかる成分の徹底した考察は参考文献49から得られる。
本発明のワクチン組成物は、有利には、アジュバントを含むことができる。上記アジュバントは、上記組成物を投与された被験体において誘発された(液性及び/又は細胞性)免疫応答を増強するように機能することができる。好ましいアジュバントは、水中油型エマルジョンを含む。種々のかかるアジュバントが公知であり、それらは、典型的には、少なくとも1種類のオイル及び少なくとも1種類の界面活性剤を含み、オイル(単数又は複数)及び界面活性剤(単数又は複数)は生分解性(代謝性)及び生体適合性である。エマルジョン中の油滴は、一般に直径5μm未満であり、理想的にはサブミクロンの直径を有し、これらの小さいサイズは、マイクロフルイダイザーを使用して得られ、安定なエマルジョンを生成する。220nm未満のサイズの滴は、フィルター滅菌にかけることができるので好ましい。
2.5%及びポリソルベート80 0.2%)。それは、「AF」アジュバントのようにThr−MDPなしで使用することもできる[59](スクアラン5%、Pluronic L121 1.25%及びポリソルベート80 0.2%)。マイクロ流体化が好ましい。
本発明は、本発明によって製造されたワクチンを提供する。これらのワクチン組成物は、ヒト又はブタなどの非ヒト動物被験体への投与に適している。本発明は、本発明の組成物を上記被験体に投与するステップを含む、被験体における免疫応答を引き起こす方法を提供する。本発明は、医薬品として使用するための本発明の組成物も提供し、被験体における免疫応答を引き起こす医薬品の製造のための本発明の組成物の使用を提供する。
「含む(comprising)」という用語は、「including」及び「consisting」を包含し、例えば、Xを「含む」組成物は、専らXから成ることができ、又は追加の何かを含むことができる(例えば、X+Y)。
インフルエンザウイルス源は、HA及びNAセグメントについてはS−OIV系統A/California/4/09であり、残りの6種の骨格セグメントについてはPR/8/34である。これら8種のセグメントをコードするDNA配列が調製され、各セグメントは、一端がヒトpol−Iプロモーターに、もう一端がpol−Iターミネーターに隣接する。これらのpol−I要素は、CMV由来のpol−IIプロモーター、pol−IIターミネーター配列及びpolAシグナルで囲まれている。pol−Iプロモーターは、忠実な野生型vRNA末端を有するマイナスセンスウイルスRNAセグメントの転写を駆動する。pol−IIプロモーターは、ウイルスタンパク質をコードするmRNAの転写を駆動する。各セグメントのDNAセグメントが連結されて、約24kbpの単一線状DNA分子となり、それは、リアソータントなインフルエンザウイルスゲノム全体をコードする。この分子の合成全体は、参考文献8のGibson等によって開示された一般的方法に従う。
Claims (1)
- 分節RNAウイルスの少なくとも2種の異なるゲノムセグメントを発現するコード配列を含む、非細菌性発現構築物。
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JOURNAL OF VIROLOGY, vol. 83, no. 18, JPN6014045806, 8 July 2009 (2009-07-08), pages 9296 - 9303 * |
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 100, no. 26, JPN6016007434, 2003, pages 15440 - 15445 * |
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CA2769673A1 (en) | 2011-02-03 |
US9821052B2 (en) | 2017-11-21 |
JP6666311B2 (ja) | 2020-03-13 |
AU2010277310A1 (en) | 2012-02-23 |
KR20120039047A (ko) | 2012-04-24 |
US20120270321A1 (en) | 2012-10-25 |
JP2016019547A (ja) | 2016-02-04 |
HK1175814A1 (en) | 2013-07-12 |
US10610584B2 (en) | 2020-04-07 |
AU2010277310B2 (en) | 2015-01-15 |
CN102666860B (zh) | 2015-06-17 |
EP2459722B1 (en) | 2017-09-06 |
JP2013500712A (ja) | 2013-01-10 |
CN102666860A (zh) | 2012-09-12 |
WO2011012999A1 (en) | 2011-02-03 |
CN104862335A (zh) | 2015-08-26 |
EP2459722A1 (en) | 2012-06-06 |
US20180236058A1 (en) | 2018-08-23 |
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