JP2012527228A - 非内因性polIプロモーターを使用した逆遺伝学 - Google Patents
非内因性polIプロモーターを使用した逆遺伝学 Download PDFInfo
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Abstract
Description
本発明は逆遺伝学の分野にある。さらに、それは、様々なウイルスから保護するためのワクチンを製造することに関する。
逆遺伝学は、細胞培養中でのRNAウイルスの組換え発現および操作を可能にする。それは、(リアソータント(reassortant)を含む)組換えウイルスの迅速な産生および/またはその変異を可能とするため、ウイルス学およびワクチン製造における強力なツールである。その方法では、宿主細胞にウイルスゲノムをコードする1つまたは複数の発現構築物をトランスフェクトし、その細胞からウイルスを単離することを伴なう。例えば、特許文献1および2は、イヌpolIプロモーターを使用してイヌ細胞中でインフルエンザゲノムRNAを発現させる方法を記載している。他の出典は、ヒトpolIプロモーターを使用した、ヒト細胞中でのインフルエンザゲノムRNAの発現を報告している。
本発明者らは、現時点で驚くべきことに、宿主細胞が由来するのと同じ分類学上の目の生物にとって内因性ではないpolIプロモーターを使用して、宿主細胞中での導入遺伝子の発現を促進(drive)することが可能であることを発見した。
本発明者らは、驚くべきことに、細胞中で、その細胞と異なる分類学上の目に入る生物由来のpolIプロモーターを使用してRNA発現を促進することが可能であることを発見した。したがって、polIプロモーターは、その細胞が由来するのと同じ分類学上の目の生物にとって内因性ではない。「目」という用語は慣用的な分類学上の順位付けを指し、目の例は、霊長目、齧歯目、食肉目、有袋目、クジラ目などである。ヒトおよびチンパンジーは同じ分類学上の目に入る(霊長目)が、ヒトとイヌは異なる目に入る(霊長目に対して食肉目)。
上記に記載の発現構築物および宿主細胞は、逆遺伝学技術により組換えウイルス株を産生するのに特に適している。その技術を、プラス鎖RNAウイルス[6、7]、マイナス鎖RNAウイルス[8,9]および二本鎖RNAウイルス[10]を含めた幅広いRNAウイルスの産生に使用することができる。したがって、さらなる態様では、本発明は、組換えウイルスを産生する方法を提供し、そのウイルスは、上記に記載の発現系を使用して産生される。
目的のウイルスを産生することができる任意の真核または原核細胞を用いて、本発明を実施することができる。本発明は典型的には細胞系統を使用するが、例えば、代替として初代細胞を使用することができる。細胞は典型的には哺乳動物のものである。適切な哺乳動物細胞には、それだけに限らないが、ハムスター、ウシ、(ヒトおよびサルを含む)霊長目およびイヌ細胞が含まれる。腎臓細胞、線維芽細胞、網膜細胞、肺細胞など様々な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またはHKCCという名称を有する細胞系統である。適切なサル細胞は、例えば、Vero細胞系統のような腎臓細胞などのアフリカミドリザル細胞である[12〜14]。適切なイヌ細胞は、例えば、CLDKおよびMDCK細胞系統のような腎臓細胞である。
本発明に従って使用するのに適した細胞は広く入手可能である。さらに、当技術分野で一般に公知である技術を使用して、さらなる細胞をスクリーニングすることが可能である。適切な細胞のスクリーニングは、例えば、新たなpolIプロモーターが同定され、その新たなプロモーターによる発現を支援する細胞系統を見つけることが望ましい場合に必要となる可能性がある。同様に、新たな細胞が単離された場合、どのpolIプロモーターがその中で発現を促進できるかを確認することが必要となる可能性がある。
ほとんどの逆遺伝学の方法は、ウイルスゲノムRNAの転写を促進するRNAポリメラーゼI(RNApolI)プロモーターを含む発現ベクターを使用する。polIプロモーターは、多くのウイルス、例えばインフルエンザの完全な感染性に必要である、修飾されていない5’および3’末端を有する転写物をもたらす。
さらなる態様では、本発明は、(i)本明細書に記載の組換えウイルスを産生するステップと、(ii)培養宿主にステップ(i)で得られたウイルスを感染させるステップと、(iii)ウイルスを産生させるためにステップ(iii)の宿主を培養するステップと、(iv)ステップ(iii)で得られたウイルスを精製するステップと、(任意選択で)(v)ウイルスをワクチンへと処方するステップとを含む、ワクチン製造用のウイルスを調製する方法を提供する。
細胞中で逆遺伝学によって発現させることができる任意のウイルスを用いて、本発明の方法を実施することができる。そのようなウイルスは、分節型ウイルスでもよく、または非分節型ウイルスでもよい。さらに、ウイルスはプラス鎖RNAウイルスでもよく、またはマイナス鎖ウイルスでもよい。さらなる実施形態では、ウイルスは二本鎖RNAウイルスでもあり得る。
インフルエンザウイルス、特にインフルエンザA型ウイルスおよびインフルエンザB型ウイルスは、このウイルスの逆遺伝学が十分に特徴付けられているため、本発明の方法での使用に特に適している。インフルエンザウイルスは、分節型マイナス鎖RNAウイルスである。インフルエンザAおよびB型ウイルスは分節を8個有するが、インフルエンザC型ウイルスは7個有する。上記ウイルスは、複製および転写を開始するのに少なくとも4個のウイルスタンパク質(PB1、PB2、PAおよび核タンパク質)を必要とする。
本発明の第3の態様の方法は、ワクチンを産生する方法に従って産生されたウイルスを利用する。
本発明に従って製造されるワクチン組成物は薬学的に許容される。それは通常、抗原に加えて構成成分を含み、例えば典型的には1つまたは複数の薬学的キャリアおよび/または賦形剤を含む。下記に記載するように、アジュバントを含めることもできる。そのような構成成分の完全な論述は、参考文献39において入手可能である。
細胞系統でウイルスを単離および/または増殖させている場合、DNAのあらゆる腫瘍形成活性を最小限にするために、最終的なワクチン中に残存する細胞系統DNAの量を最小限にすることが標準的には実施される。
本発明の組成物は、有利には、組成物を受容した被験体中で惹起される(体液性および/または細胞性)免疫応答を増強するように機能することができるアジュバントを含んでよい。好ましいアジュバントは水中油型エマルジョンを含む。種々のそのような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つの油および少なくとも1つの界面活性剤を含み、油(複数可)および界面活性剤(複数可)は生分解性(代謝可能)であり生体適合性である。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、この小さいサイズは、安定なエマルジョンを提供するマイクロフルイダイザーを用いて実現される。フィルター滅菌に供することができるため、220nm未満のサイズを有する液滴が好ましい。
本発明の組成物(またはキット構成成分)に適した容器には、バイアル、シリンジ、(例えば、ディスポーザブルシリンジ)、鼻スプレーなどが含まれる。これらの容器は無菌であるべきである。
本発明は、本発明に従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、ヒトまたはブタなどの非ヒト動物被験体への投与に適しており、本発明は、本発明の組成物を被験体に投与するステップを含む、被験体中で免疫応答を起こす方法を提供する。本発明は、医薬として使用するための本発明の組成物も提供し、被験体中で免疫応答を起こす医薬を製造するための、本発明の組成物の使用も提供する。
「含む(comprising)」という用語は、「含む(including)」ならびに「からなる(consisting)」を包含し、例えば、Xを「含む(comprising)」組成物は、もっぱらXのみからなるものでもよく、または追加の何か、例えばX+Yを含んでもよい。
配列番号1は、完全長(FL)ヒトpolIプロモーター配列である。
配列番号2は、pHW2000ヒトPolIプロモーター配列である。
配列番号3は、完全長(FL)イヌpolIプロモーター配列である。
配列番号4は、MIDイヌpolIプロモーター配列である。
配列番号5は、SHORTイヌpolIプロモーター配列である。
配列番号6は、A/カリフォルニア/04/09由来のHA配列である。
配列番号7は、A/チリ/1/1983由来のHA配列である。
配列番号8は、A/カリフォルニア/04/09由来のNA配列である。
配列番号9は、A/チリ/1/1983由来のNA配列である。
(ヒトpolIプロモーターはヒトならびにイヌ細胞中で活性である)
非内因性宿主細胞中でのpolIプロモーターの活性を評価するために、ヒトpolIプロモーターの487bp断片またはイヌpolIプロモーターの様々な断片の調節下で(図3に示されている)、アンチセンスの方向でルシフェラーゼ(luc)RNAの発現を可能とする発現構築物をMDCK細胞にトランスフェクトした。発現したRNAをウイルスポリメラーゼによりmRNAに転写し、その後lucタンパク質に翻訳することができる。したがって、ルシフェラーゼ活性についてアッセイを行うことにより、導入遺伝子を発現している細胞を容易に同定することができる。このアッセイが働くには、ウイルスポリメラーゼを提供することが必要である。これは、細胞にウイルスポリメラーゼをコードする発現構築物を共トランスフェクト(co−transfect)するか、あるいはトランスフェクトした細胞にヘルパーウイルスを感染させることによって実現することができる。このアッセイは図1に図示されている。
標準的なプロトコールに従って、293TおよびMDCK細胞を溶解しそれをウェスタンブロット分析に供した。MおよびNPタンパク質に対する抗体を使用して、膜上のこれらのタンパク質を検出した。S6に対する抗体をローディング対照として使用した。「WSN」とラベルを付けたレーンに、レスキューされたウイルス由来のタンパク質をロードした。「M」および「NP」のラベルを付けたレーンは、対照として組換えMおよびNPタンパク質を含有する。これらの組換えタンパク質は異なる遺伝子から発現したので、ゲル中でわずかにゆっくりと移動する。
10%FCSを入れたDMEM500μlの入った48ウェルプレート中の1ウェル当たり細胞6.25×104個の密度に、感染していないMDCK細胞を入れた。次の日に、細胞に100〜150μlの容積のウイルスを37℃で2時間感染させた。それによって細胞は様々な希釈のウイルスに感染した。感染から2時間後、培地を吸引し10%FCSを入れたDMEM500μlを各ウェルに添加した。細胞を37℃で次の日までインキュベートした。
したがって、本発明は以下の項目を提供する:
(項目1) ウイルスRNA分子をコードする少なくとも1つの発現構築物を含む宿主細胞であって、該構築物からの該ウイルスRNA分子の発現は、該宿主細胞の分類学上の目にとって内因性ではないpolIプロモーターによって調節される、宿主細胞。
(項目2) 内因性rRNAの発現を調節する少なくとも1つの内因性polIプロモーター、および、ウイルスRNAまたはその相補体の発現を調節する少なくとも1つの非内因性polIプロモーターを有する細胞。
(項目3) ウイルスを産生させるためにウイルスRNA分子が発現される条件下で項目1または項目2に記載の細胞を増殖させるステップを含む、組換えウイルスを産生するための方法。
(項目4) (i)項目3に記載の方法によって組換えウイルスを産生するステップと、(ii)培養宿主にステップ(i)で得られたウイルスを感染させるステップと、(iii)さらなるウイルスを産生させるためにステップ(ii)の宿主を培養するステップと、(iv)ステップ(iii)で得られたウイルスを精製するステップとを含む、ウイルスを調製する方法。
(項目5) (a)項目4に記載の方法によってウイルスを調製するステップと、(b)該ウイルスからワクチンを調製するステップとを含む、ワクチンを調製するための方法。
(項目6) 前述の項目のいずれかに記載の細胞または方法であって、上記polIプロモーターが霊長目polIプロモーターであり、該細胞が非霊長目細胞である、細胞または方法。
(項目7) 項目1から5のいずれか一項に記載の細胞または方法であって、上記polIプロモーターが非イヌpolIプロモーターであり、該細胞がイヌ細胞である、細胞または方法。
(項目8) 項目7に記載の細胞または方法であって、上記polIプロモーターがヒトpolIプロモーターであり、該細胞がイヌ細胞である、細胞または方法。
(項目9) 項目8に記載の細胞または方法であって、該細胞がMDCK細胞である、細胞または方法。
(項目10) 項目9に記載の細胞または方法であって、上記MDCK細胞が細胞系統MDCK33016(DSM ACC2219)である、細胞または方法。
(項目11) 前述の項目のいずれかに記載の細胞または方法であって、該細胞が少なくとも1つの両方向性発現構築物を含む、細胞または方法。
(項目12) 上記発現構築物が発現ベクターまたは直鎖発現構築物である、前述の項目のいずれかに記載の細胞または方法。
(項目13) 上記ウイルスが分節型ウイルスである、前述の項目のいずれかに記載の細胞または方法。
(項目14) 上記ウイルスが非分節型ウイルスである、前述の項目のいずれかに記載の細胞または方法。
(項目15) 上記ウイルスがマイナス鎖RNAウイルスである、前述の項目のいずれかに記載の細胞または方法。
(項目16) 上記ウイルスがインフルエンザウイルスである、項目15に記載の細胞または方法。
Claims (16)
- ウイルスRNA分子をコードする少なくとも1つの発現構築物を含む宿主細胞であって、該構築物からの該ウイルスRNA分子の発現は、該宿主細胞の分類学上の目にとって内因性ではないpolIプロモーターによって調節される、宿主細胞。
- 内因性rRNAの発現を調節する少なくとも1つの内因性polIプロモーター、および、ウイルスRNAまたはその相補体の発現を調節する少なくとも1つの非内因性polIプロモーターを有する細胞。
- ウイルスを産生させるためにウイルスRNA分子が発現される条件下で請求項1または請求項2に記載の細胞を増殖させるステップを含む、組換えウイルスを産生するための方法。
- (i)請求項3に記載の方法によって組換えウイルスを産生するステップと、(ii)培養宿主にステップ(i)で得られたウイルスを感染させるステップと、(iii)さらなるウイルスを産生させるためにステップ(ii)の宿主を培養するステップと、(iv)ステップ(iii)で得られたウイルスを精製するステップとを含む、ウイルスを調製する方法。
- (a)請求項4に記載の方法によってウイルスを調製するステップと、(b)該ウイルスからワクチンを調製するステップとを含む、ワクチンを調製するための方法。
- 前述の請求項のいずれかに記載の細胞または方法であって、前記polIプロモーターが霊長目polIプロモーターであり、該細胞が非霊長目細胞である、細胞または方法。
- 請求項1から5のいずれか一項に記載の細胞または方法であって、前記polIプロモーターが非イヌpolIプロモーターであり、該細胞がイヌ細胞である、細胞または方法。
- 請求項7に記載の細胞または方法であって、前記polIプロモーターがヒトpolIプロモーターであり、該細胞がイヌ細胞である、細胞または方法。
- 請求項8に記載の細胞または方法であって、該細胞がMDCK細胞である、細胞または方法。
- 請求項9に記載の細胞または方法であって、前記MDCK細胞が細胞系統MDCK33016(DSM ACC2219)である、細胞または方法。
- 前述の請求項のいずれかに記載の細胞または方法であって、該細胞が少なくとも1つの両方向性発現構築物を含む、細胞または方法。
- 前記発現構築物が発現ベクターまたは直鎖発現構築物である、前述の請求項のいずれかに記載の細胞または方法。
- 前記ウイルスが分節型ウイルスである、前述の請求項のいずれかに記載の細胞または方法。
- 前記ウイルスが非分節型ウイルスである、前述の請求項のいずれかに記載の細胞または方法。
- 前記ウイルスがマイナス鎖RNAウイルスである、前述の請求項のいずれかに記載の細胞または方法。
- 前記ウイルスがインフルエンザウイルスである、請求項15に記載の細胞または方法。
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KR101323582B1 (ko) * | 2011-03-17 | 2013-10-30 | 충북대학교 산학협력단 | Vero 세포 유래의 polⅠ 프로모터 및 이를 포함하는 재조합 벡터 |
CN105120893B (zh) | 2012-12-03 | 2018-11-13 | 诺华股份有限公司 | 流感病毒重配 |
EP2968512A2 (en) | 2013-03-13 | 2016-01-20 | Novartis AG | Influenza b virus reassortment |
WO2014195920A2 (en) | 2013-06-06 | 2014-12-11 | Novartis Ag | Influenza virus reassortment |
WO2016148195A1 (ja) * | 2015-03-17 | 2016-09-22 | 一般財団法人阪大微生物病研究会 | インフルエンザウイルス作出用細胞 |
EP3472327B1 (en) | 2016-06-20 | 2020-08-19 | Janssen Vaccines & Prevention B.V. | Potent and balanced bidirectional promoter |
US20230000971A1 (en) | 2019-11-18 | 2023-01-05 | Seqirus Pty Ltd. | Method for producing reassortant influenza viruses |
BR102020010208A2 (pt) | 2020-05-21 | 2022-04-12 | Fundação Oswaldo Cruz | Construção de ácido nucleico, virus influenza recombinante, método para preparar um virus influenza recombinante, composição, e, uso. |
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EA021009B1 (ru) | 2015-03-31 |
KR20120028328A (ko) | 2012-03-22 |
HK1165827A1 (en) | 2012-10-12 |
AU2010250832B2 (en) | 2013-10-03 |
AU2010250832A1 (en) | 2011-12-08 |
CN102597246B (zh) | 2014-02-26 |
EP2401384B1 (en) | 2012-10-03 |
DK2401384T3 (da) | 2013-01-14 |
US20190284575A1 (en) | 2019-09-19 |
WO2010133964A1 (en) | 2010-11-25 |
JP5836266B2 (ja) | 2015-12-24 |
EP2401384A1 (en) | 2012-01-04 |
KR101800245B1 (ko) | 2017-11-22 |
JP2015204843A (ja) | 2015-11-19 |
EP2573184A1 (en) | 2013-03-27 |
US20120189656A1 (en) | 2012-07-26 |
SMT201300034B (it) | 2013-05-06 |
NZ596432A (en) | 2013-05-31 |
CA2762802A1 (en) | 2010-11-25 |
US20160024525A1 (en) | 2016-01-28 |
EA201171449A1 (ru) | 2012-05-30 |
PT2401384E (pt) | 2012-12-19 |
PL2401384T3 (pl) | 2013-03-29 |
US9072702B2 (en) | 2015-07-07 |
BRPI1011171A2 (pt) | 2015-08-25 |
SI2401384T1 (sl) | 2013-01-31 |
CN102597246A (zh) | 2012-07-18 |
HRP20121048T1 (hr) | 2013-02-28 |
ES2394797T3 (es) | 2013-02-05 |
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