JP5654345B2 - 多量体マルチエピトープインフルエンザワクチン - Google Patents
多量体マルチエピトープインフルエンザワクチン Download PDFInfo
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- JP5654345B2 JP5654345B2 JP2010518815A JP2010518815A JP5654345B2 JP 5654345 B2 JP5654345 B2 JP 5654345B2 JP 2010518815 A JP2010518815 A JP 2010518815A JP 2010518815 A JP2010518815 A JP 2010518815A JP 5654345 B2 JP5654345 B2 JP 5654345B2
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Description
B細胞エピトープ、T−ヘルパー細胞エピトープ、および細胞毒性Tリンパ球エピトープはすべて、これらの2つの免疫応答において重要な役割を果たすことが知られている。明らかに、効果的なワクチン接種のためには、広域スペクトルかつ持続性の、液性および細胞性応答が誘導されるべきである。インフルエンザウイルスおよびヒト免疫不全ウイルスなどの突然変異率が高いウイルスに対する、広域スペクトルかつ効果的なワクチンはまだない。
インフルエンザは、それらの抗原決定基に従って分類される3つの主なサブタイプ、インフルエンザA、BおよびCのウイルスによって引き起こされる疾病である。インフルエンザビリオンは、核タンパク質(NP)と密に会合し、かつ基質タンパク質(M1)により裏打ちされ、ヘマグルチニン(HA)およびノイラミニダーゼ(NA)という2つの主要表面糖タンパク質抗原を保有するリポタンパク質エンベロープによって囲まれる、一本鎖RNAゲノムからなる。HAおよびNA糖タンパク質は最も変化を受けやすく、例えば、H1N1またはH3N2のような異なるインフルエンザウイルスサブタイプの基盤を提供する、HAの16の免疫クラスと9の異なるNAクラスとがある。インフルエンザAウイルスは、異なるHNサブタイプ間で高度に保存された、付加的な膜貫通糖タンパク質、M2を有する。M2遺伝子は、ビリオン細胞表面上で四量体として発現される、96〜97のアミノ酸を有するタンパク質をコード化する。これは、約24の細胞外アミノ酸、約19の膜貫通アミノ酸、および約54の細胞質残基で構成される(非特許文献3)。
インフルエンザウイルスのための免疫化は、ウイルスの抗原変異によって、また呼吸粘膜への感染の限定によって制限される。現在利用可能なインフルエンザワクチンは、不活性ウイルス全体、細菌細胞の表面上に提示されるウイルスタンパク質、またはウイルスの抗原決定基を保有するフラゲリンのいずれかに基づくものである。HAは、強い免疫原であり、かつ異なるウイルス株の血清学的特異性を規定するうえで最も重要な抗原である。
便宜のため、明細書、実施例および請求の範囲で使用する特定の用語を以下に説明する。
本発明の好ましい実施形態によれば、ペプチドエピトープは、HA、M1、M2、およびNPからなる群より選択されるインフルエンザタンパク質に由来するものである。エピトープはまた、それらの型(B細胞型、Th型、およびCTL型)に従って選択してもよい。
「キメラタンパク質」、「キメラポリペプチド」または「組換えタンパク質」は、互換的に使用され、ポリペプチドに作動可能に連結されたインフルエンザ多量体ポリペプチドをいい、このポリペプチドは、ペプチドエピトープ由来元のポリペプチド以外のものである。本発明の多量体マルチエピトープポリペプチドは、それ自体またはキメラタンパク質として、発現ベクター中での発現により調製することができる。1以上のインフルエンザペプチドエピトープを含むキメラまたは組換えタンパク質を生産する方法は、当業者に既知である。1以上のインフルエンザペプチドエピトープをコード化する核酸配列は、宿主細胞における増殖および発現用のポリヌクレオチド構築体の調製のための発現ベクターの中へ挿入することができる。多量体マルチエピトープポリペプチドなどの、いくつかのエピトープの多重リピートを含むポリペプチドをコード化する核酸構築体は、小ポリヌクレオチド構築体で、それらの3’および5’端に適正化制限部位をライゲーションにより調製できる。
ひとたび宿主細胞により発現されれば、前記多量体ポリペプチドは、数多くのタンパク質精製法によって望ましくない成分から分離することができる。このような方法の1つでは、組換えタンパク質にてポリヒスチジンタグを使用する。ポリヒスチジンタグは、組換えタンパク質に付加される(N末端またはC末端での付加が多い)、少なくとも6つのヒスチジン(His)残基に存する。ポリヒスチジンタグは、大腸菌または他の原核性発現系において発現される、ポリヒスチジンタグ化組換えタンパク質のアフィニティー精製のために使用されることが多い。細菌細胞は遠心によって収集し、得られる細胞ペレットは物理的手段により、または界面活性剤またはリゾチームなどの酵素を用いて溶解できる。この段階で未加工溶菌液は、細菌由来のいくつかの他のタンパク質のうち、組換えタンパク質を含み、NTA−アガロース、HisPur樹脂またはタロン(Talon)樹脂などの親和性媒体とインキュベートされる。これらの親和性媒体には、ミクロモルの親和性で前記ポリヒスチジンタグが結合する、ニッケルまたはコバルトのいずれかの金属イオンが結合している。この樹脂は次いでリン酸緩衝液で洗浄して、コバルトまたはニッケルイオンと特異的に相互作用しないタンパク質を除去する。洗浄効率は、20mMイミダゾールの添加によって高めることができ、タンパク質はその後、通常150〜300mMイミダゾールで溶出される。前記ポリヒスチジンタグはその後、制限酵素、エンドプロテアーゼまたはエキソプロテアーゼを用いて除去してもよい。ヒスチジンタグ付きタンパク質の精製用のキットは、例えばQiagenから購入できる。
本発明のワクチンは、マルチエピトープポリペプチド、またはマルチエピトープポリペプチドおよび任意にアジュバントを含む組換え融合タンパク質を含む。ワクチンは、多くの異なる形態の1つでの投与用に製剤化することができる。本発明の1つの実施形態によれば、ワクチンは鼻腔内に投与される。そのワクチン製剤は、任意の簡便な方法で鼻のリンパ組織に適用してもよい。しかし、これを液体流または液滴として鼻孔の壁に適用することが好ましい。鼻腔内組成物は、例えば、点鼻剤、噴霧剤のような液状形態に、または吸入に好適な粉末として、クリームとして、またはエマルションとして製剤化できる。組成物は、アジュバント、賦形剤、安定剤、緩衝剤、または保存剤などの種々の添加剤を含むことができる。
(多量体マルチエピトープポリペプチド)
表1に列挙するインフルエンザウイルスペプチドエピトープE1〜E9のいくつかのリピートを含む多量体マルチエピトープポリペプチドの例を示す。それらポリペプチドは、アミノ酸と、スペーサーとしての短いペプチドを含んでいる。これらポリペプチドは、交互連続重合構造またはブロック共重合体構造で配置される。それらポリペプチドは、当該ポリペプチドをさらに操作するための種々の制限部位を含むポリヌクレオチド構築体から、発現ベクターでの発現によって調製される。そのポリヌクレオチド構築体は、商業的供給源から供給される。
実施例1〜3に示す多量体マルチエピトープポリペプチドから調製したワクチンを、種々のマウス系統の免疫化研究に使用した。生産して試験した具体的なワクチンの例は、以下に示すとおりである。
マウスの3種の系:非近交系(ICR)、近交系(BALB/c)、およびヒトHLA A* 0201分子に対してトランスジェニックな系(HLA A*0201)を、免疫化研究用や、いくつかの実験でウサギに対して使用した。使用したウイルスは、以下のもの:A/Texas/1/77、A/Wisconsin/67/05(WISC)、A/WSN/33(WSN)、B/Malaysia/2506/04(MAL)、A/California/07−2007、A/New Caledonia20/99(NC)、その他を含んでいた。すべての研究は、100μL中150megの多量体マルチエピトープポリペプチドの筋肉内投与で、両後肢に同様に投与して行った。
本実施例は、交互連続重合構造[E1E2E3E4E5E6E7E8E9]5で配置される9つのインフルエンザペプチドエピトープの5つのリピートを含む多量体ポリペプチドの例である。推定分子量は、80kDである。
本実施例にて、ブロック共重合体構造[E1]3−[E2]3−[E3]3−[E4]3−[E5]3−[E6]3−[E7]3−[E8]3−[E9]3で配置される9つのインフルエンザペプチドエピトープの3つのリピートを含む多量体ペプチドを調製するのに用いるポリヌクレオチド構築体のDNA配列を図2Aに示し、対応するアミノ酸配列を図2Bに示す。推定分子量は、48kDである。
本実施例は、交互連続重合構造[E1E2E3E4E5E6E7E8E9]3で配置される9つのインフルエンザペプチドエピトープの3つのリピートを含む多量体ポリペプチドの例である。推定分子量は、48kDである。
A/Texas/1/77、A/WisxWisc/67/05、A/California/07−2007、およびB/Malaysia/2506/04の株の、異なる2種の濃度の刺激性インフルエンザウイルスに対する細胞性免疫応答を評価した。トランスジェニックマウス(HLA A*0201に対する遺伝子組換え(transgenesys))マウスに、IFA(フロイント不完全アジュバント)に乳化した2種の多量体ワクチン:#11および#14を1回、ワクチン接種した。免疫化後7〜10日に、それらの脾臓およびリンパ節(LN)を取り出して、さらに前記のウイルスとインキュベートした。増殖は、チミジン取り込みによって測定し、刺激性ウイルスとインキュベートしたリンパ球に対する増殖指数として図4に示す。増殖は、300〜1300pg/mlの範囲で、IFN−ガンマ分泌と相関していた。この応答は、ウイルス感染を攻撃するための、より確実な免疫を付与することのできる、ワクチンに対するTh1細胞媒介免疫応答を示唆している。
交互連続重合構造[E1E2E3E4E5E6E7E8E9]5で配置される9つのエピトープの5つのリピートを含む多量体マルチエピトープポリペプチド(多量体#11)で、またはブロック共重合体構造[E1]3−[E2]3−[E3]3−[E4]3−[E5]3−[E6]3−[E7]3−[E8]3−[E9]3で配置される9つのエピトープの3つのリピートを含む多量体マルチエピトープポリペプチド(多量体#14)で、50%グリセロールのPBSに懸濁させたもの、もしくはアジュバントとしてIFAに懸濁させたものを用いて、または溶媒対照として50%グリセロールのPBSを用いて、ICRマウスを免疫化した。抗原ポリペプチド(それぞれ#11および#14)で免疫化したマウスの血清による、既知の防御インフルエンザエピトープHA 91−108およびM2 2−12、ならびにいくつかのインフルエンザウイルス(WISC、WSN、NC、およびMAL)の認識をELISAによって調べ、その結果を表4aおよび4bにまとめる。免疫前血清と2〜3週間の間隔で3回IM(筋肉内)免疫化した後の血清との間の力価における少なくとも4倍の上昇として、有意な認識を定義する。
3週間の間隔で8匹のトランスジェニックマウスの群を3回、多量体#14ワクチンで、またはPBSで筋肉内に免疫化した。高度に致死的な用量(300LD50)のH3N2 A/Texas/1/77での攻撃感染は、最後の追加免疫の3週間後に与えた。マウスは、感染の5日後に屠殺した。感染に用いたウイルスが大量であったにも関わらず、図5に示されるように、マウス肺のウイルス力価の有意な低減が観察された。
2種のワクチン、すなわち50%グリセロールのPBSに、またはフロイント不完全アジュバントに懸濁した多量体ポリペプチドを、インビボで評価している。
ワクチンの有効性を、ICRおよびトランスジェニック(HLA A* 0201)マウスを用いた予備研究で立証した。マウスに3週間の間隔で3回、アジュバント(IFA)と共に、およびIFAなしで、ワクチン#11、#12および#14を150meg/マウスの用量にて筋肉内へワクチン接種した。最後の免疫化の3〜4週間後に、マウスを300LD50のマウス適応性インフルエンザウイルスH3N2株(A/Texas/1/77)で感染させた。感染の後5日、生存率をモニターした。処置群と、IFAと共に、およびIFAなしで50%グリセロールのPBSにて免疫化した対照群とを比較した。
反復投与毒性試験を、http://www3.niaid.nih.gov/daids/vaccine/Science/VRTT/06_SafetyTest.htm.に基づくプロトコルに従って、50%グリセロールのPBSに、またはフロイント不完全アジュバントに懸濁したワクチン#14(3つのブロックリピートでの多量体ワクチン)を用いて実施する。
この臨床研究の主な目的は、単回または二回の筋肉内投与後の予防的抗インフルエンザワクチンの安全性を調べることにある。この研究は、18歳から49歳までの年齢の健常なボランティアで、臨床背景制御下に行う。第2の目的は、多量体ワクチンの投与によって誘導される免疫原性を推定することにある。この第I/II相研究では、最も一般的な急性の有害作用を査定し、また副作用が高発生率で起こることなく患者が安全に取ることのできる用量の規模を調べる。
HLA A* 0201に対するトランスジェニックマウスを市販の不活化インフルエンザワクチン(スプリットビリオン(split virion))BP Vaxigrip(登録商標)で第0、60、81日に3回、またはVaxigrip(登録商標)で第0日に免疫化して、多量体ワクチン#11、#12および#14でさらに2回(第60および81日に)免疫化した。免疫化の前(免疫前)、および最後の免疫化後に採血を実施した。いくつかのインフルエンザ株に対する抗体:H3N2:A/Wisconsin/67/05、A/Texas/1/77、A/California/07/2007、A/Fujian/411/2002、A/Moscow/10/99およびA/Panama/2007/99;H1N1:A/New Caledonia/20/99、A/WSN/33、A/PR8/34 B:B/Malaysia/2506/04、B/Lee/40を、集めた血清にて定量した。
代表的な固相ペプチド合成を用い、以下の材料:保護アミノ酸、9−フルオレニルメチルオキシカルボニル−N−ヒドロキシスクシンイミド(Fmoc−OSu)、ブロモ−tris−ピロリドン−ホスホニウムヘキサフルオロホスフェート(PyBrop)、リンク(Rink)アミドメチルベンズヒドリルアミン(MBHA)ポリスチレン樹脂および多くの有機物(organic)でペプチドおよび多量体ペプチドを合成し、固相ペプチド合成(SPPS)用の支持体は、Nova Biochemicals(Laufelfingen,スイス)から購入した。Bis(トリクロロメチル)カーボネート(BTC)は、Lancaster(Lancashire,イギリス)から購入し、高速液体クロマトグラフィー(HPLC)用のトリフルオロ酢酸(TFA)および溶媒は、Bio−Lab(Jerusalem,イスラエル)から購入した。
Claims (9)
- 複数のインフルエンザウイルスペプチドエピトープの多重コピーを含む、合成または組換えインフルエンザマルチエピトープポリペプチドであって、その配置は、
交互連続重合構造(X1X2X3...Xm)n;および
ブロック共重合体構造(X1)n(X2)n(X3)n...(Xm)nからなる群より選択される構成であり、
ここで、nは各出現ごとに独立に3〜5の整数であり;mは9であり;X1、X2...Xmの各々は、HA 354−372(E1、配列番号82)、HA 91−108(E2、配列番号48)、M1 2−12(E3、配列番号25)、HA 150−159(E4、配列番号52)、HA 143−149(E5、配列番号51)、NP 206−229(E6、配列番号64)、HA 307−319(E7、配列番号59)、NP 335−350(E8、配列番号69)、およびNP 380−393(E9、配列番号70)からなる群より選択されるインフルエンザペプチドエピトープであり、
前記ポリペプチドは、
i.以下の交互連続重合構造[E1E2E3E4E5E6E7E8E9]nで配置される異なる9つのインフルエンザウイルスペプチドエピトープであって、ここで、nは3または5である、インフルエンザウイルスペプチドエピトープ、および
ii.以下のブロック共重合体構造[E1E1E1−E2E2E2−E3E3E3−E4E4E4−E5E5E5−E6E6E6−E7E7E7−E8E8E8−E9E9E9]で配置される異なる9つのインフルエンザウイルスペプチドエピトープの3つのリピート、
からなる群より選択される、ポリペプチド。 - 配列番号84、配列番号86および配列番号88からなる群より選択される配列に記載される、請求項1記載のポリペプチド。
- 請求項1または2に記載のインフルエンザマルチエピトープポリペプチドをコード化する、単離されたポリヌクレオチド。
- 配列番号84、配列番号86、および配列番号88からなる群より選択されるポリペプチド配列をコード化する、請求項3記載の単離されたポリヌクレオチド。
- 配列番号83、配列番号85、および配列番号87からなる群より選択される配列を含む、請求項4記載の単離されたポリヌクレオチド。
- 請求項1記載の少なくとも1つのポリペプチドを含む、インフルエンザに対して被検者を免疫化させるためのワクチン。
- さらにアジュバントを含む、請求項6記載のワクチン。
- 免疫応答を誘導し、インフルエンザに対する防御を付与するための薬剤の製造における、請求項6または7に記載のワクチンの使用。
- インフルエンザに対する免疫化用のワクチン組成物の調製のための、請求項1または2に記載のポリペプチドの使用。
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KR101580660B1 (ko) | 2015-12-28 |
WO2009016639A2 (en) | 2009-02-05 |
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PL2173376T3 (pl) | 2015-08-31 |
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HK1142809A1 (en) | 2010-12-17 |
CA2695399C (en) | 2017-10-17 |
DK2173376T3 (en) | 2015-06-29 |
EA017887B1 (ru) | 2013-03-29 |
ES2539818T3 (es) | 2015-07-06 |
JP2010535026A (ja) | 2010-11-18 |
CN101795709A (zh) | 2010-08-04 |
CA2695399A1 (en) | 2009-02-05 |
AU2008281384C1 (en) | 2012-08-16 |
EA201070219A1 (ru) | 2010-08-30 |
EP2173376B1 (en) | 2015-03-25 |
AU2008281384A1 (en) | 2009-02-05 |
HUE025149T2 (hu) | 2016-01-28 |
KR20100045473A (ko) | 2010-05-03 |
BRPI0815008B1 (pt) | 2019-11-19 |
BRPI0815008B8 (pt) | 2021-05-25 |
WO2009016639A3 (en) | 2009-04-30 |
PT2173376E (pt) | 2015-07-30 |
EP2173376A2 (en) | 2010-04-14 |
US8747861B2 (en) | 2014-06-10 |
US9353159B2 (en) | 2016-05-31 |
CN101795709B (zh) | 2013-07-17 |
HRP20150479T1 (hr) | 2015-07-17 |
AU2008281384B2 (en) | 2012-02-16 |
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