JP6087041B2 - 血球凝集素およびマトリックスタンパク質を含むインフルエンザウイルスワクチン - Google Patents
血球凝集素およびマトリックスタンパク質を含むインフルエンザウイルスワクチン Download PDFInfo
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- JP6087041B2 JP6087041B2 JP2008551906A JP2008551906A JP6087041B2 JP 6087041 B2 JP6087041 B2 JP 6087041B2 JP 2008551906 A JP2008551906 A JP 2008551906A JP 2008551906 A JP2008551906 A JP 2008551906A JP 6087041 B2 JP6087041 B2 JP 6087041B2
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Description
Chaloupkaら、Eur J Clin Microbiol Infect Dis(1996)15:121−7
本発明は全ビリオン(WV)抗原を使用せず、すなわち生ウイルスまたは不活性化全ビリオンを使用するワクチンを含まない。その代りに、本発明の抗原は、スプリットビリオンのような非WV抗原または精製表面抗原である。本発明の組成物は、少なくとも2つのインフルエンザウイルス抗原、すなわち血球凝集素およびマトリックスを含む。それらは、ノイラミニダーゼのような他のインフルエンザウイルス抗原も含んでもよい。抗原は典型的には、インフルエンザビリオン(好ましくは細胞培養において増殖させた)から調製されるだろうが、いくつかの実施形態において、抗原は組換え宿主において(例えばパキュロウイルスベクターを使用する昆虫株化細胞において)発現させることができ、精製された形式で使用することができる[3、4]。しかしながら一般に、抗原はビリオンからであるだろう。
血球凝集素を含むことに加えて、本発明の組成物はマトリックスタンパク質を含む。インフルエンザA型ウイルスのセグメント7はM1ポリペプチドおよびM2ポリペプチドをコードする。M1はウイルス脂質二重層の下にあるが、M2はアマンタジンにより阻害されるイオンチャネルを呈する膜内在型タンパク質である。M2はスプライシングされたmRNAから発現される。インフルエンザB型ウイルスのセグメント7は、M1およびBM2のポリペプチドをコードする。
ウイルスを株化細胞で増殖させた場合には、DNAの任意の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の株化細胞DNAの残余量を最小限にすることが標準的技法である。マトリックスタンパク質は核酸(RNAおよび二本鎖DNAを含む)へ結合することができ[77]、したがって既存のHAに基づくワクチンよりも容易にDNAを保持するので、ワクチン中にインフルエンザウイルスのマトリックスタンパク質を含んでいる場合、この安全対策は特に重要である。
本発明の組成物は、都合よくアジュバントを含んでもよく、それは組成物を投与される患者に誘発される免疫反応(液性および/または細胞性)を促進するために機能することができる。インフルエンザワクチンとのアジュバントの使用は以前に記述されている。参考文献87および88において、水酸化アルミニウムが使用され、参考文献89において、水酸化アルミニウムおよびリン酸アルミニウムの混合物が使用された。参考文献90は、アルミニウム塩アジュバントの使用についても記述した。カイロン・ワクチン(Chiron Vaccines)社からのフルアド(FLUAD)(商標)製品は、水中油滴型エマルジョンを含む。
・メチルイノシン5’−1リン酸(「MIMP」)[114]。
・アルガムリンのような、γイヌリン[124]またはその誘導体。
水中油滴型エマルジョンはインフルエンザウイルスワクチンにアジュバント効果を与えるための使用のために特に適切であることが分かった。そのような様々なエマルジョンが公知であり、それらは典型的には少なくとも1つの油脂および少なくとも1つの界面活性剤を、生物分解性(代謝可能)、生体適合性のある油脂(複数可)および界面活性剤(複数可)の状態で含む。エマルジョン中の油滴は、一般に直径で5μm未満であり、安定したエマルジョンを提供するために微流動化装置により達成されている小さなサイズで、サブミクロン直径でさえあってもよい。濾過滅菌可能なように、220nm未満のサイズの液滴が好ましい。
インターフェロンおよびインターロイキンを含む放出サイトカインに対する免疫系を誘発するために患者に投与される場合、本発明の組成物への含有のためのサイトカイン誘導剤は可能である。サイトカイン反応はインフルエンザ感染に対する宿主防御の初期段階および決定的な段階に関与することが公知である[137]。好ましい薬剤は、インターフェロン−γ;インターロイキン−1;インターロイキン−2;インターロイキン−12;TNF−α;TNF−β;およびGM−CSFのうちの1つまたは複数の放出を誘発できる。好ましい薬剤は、Th1型免疫反応に関連したサイトカイン(例えばインターフェロン−γ、TNF−α、インターロイキン−2)の放出を誘発する。インターフェロン−γおよびインターロイキン−2の両方の刺激が好ましい。
R3は、水素、C1−6アルキル、置換されたC1−6アルキル、C6−10アリール、置換されたC6−10アリール、ヘテロシクリル、または置換されたヘテロシクリルでなく;
R4およびR5は、それぞれ独立して水素、ハロ、ヘテロシクリル、置換されたヘテロシクリル、−C(O)−Rd、C1−6アルキル、置換されたC1−6アルキルであるか、またはR4−5におけるような五員環をともに形成するように結合し、
R8は、水素、ハロ、−OH、C1−6アルキル、C2−6アルケニル、C2−6アルキニル、−OH、−NRaRb、−(CH2)n−O−Rc、−O−(C1−6アルキル)、−S(O)pRe、または−C(O)−Rdであり;
R9は、水素、C1−6、アルキル、置換されたC1−6アルキル、ヘテロシクリル、置換されたヘテロシクリルまたはR9aであり、
ここで、R9aは次式であり、
R10およびR11は、それぞれ独立して水素、ハロ、C1−6アルコキシ、置換されたC1−6アルコキシ、−NRaRb、または−OHであり;
それぞれRaおよびRbは、独立して水素、C1−6アルキル、置換されたC1−6アルキル、−C(O)Rd、C6−10アリールであり;
それぞれのRcは、独立して水素、リン酸、二リン酸、三リン酸、C1−6アルキル、または置換されたC1−6アルキルであり;
それぞれのRdは、独立して水素、ハロ、C1−6アルキル、置換されたC1−6アルキル、C1−6アルコキシ、置換されたC1−6アルコキシ、−NH2、−NH(C1−6アルキル)、−NH(置換されたC1−6アルキル)、−N(C1−6アルキル)2、−N(置換されたC1−6アルキル)2、C6−10アリール、またはヘテロシクリルであり;
それぞれのReは、独立して水素、C1−6アルキル、置換されたC1−6アルキル、C6−10アリール、置換されたC6−10アリール、ヘテロシクリル、または置換されたヘテロシクリルであり;
それぞれのRfは、独立して水素、C1−6アルキル、置換されたC1−6アルキル、−C(O)Rd、リン酸、二リン酸、または三リン酸であり;それぞれのnは、独立して0、1、2、または3であり;それぞれのpは、独立して0、1、または2であり;あるいは、
または(g)(a)〜(f)のいずれかの薬学的に許容される塩、(a)〜(f)のいずれかの互変異性体、または互変異性体の薬学的に許容される塩。
N2−メチル−1−(2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
N2,N2−ジメチル−1−(2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
N2−エチル−N2−メチル−1−(2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
N2−メチル−1−(2−メチルプロピル)−N2−プロピル−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
1−(2−メチルプロピル)−N2−プロピル−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
N2−ブチル−1−(2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
N2−ブチル−N2−メチル−1−(2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
N2−メチル−1−(2−メチルプロピル)−N2−ペンチル−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
N2−メチル−1−(2−メチルプロピル)−N2−プロプ−2−エニル−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
1−(2−メチルプロピル)−2−[(フェニルメチル)チオ]−1H−イミダゾ[4,5−c]キノリン−4−アミン
1−(2−メチルプロピル)−2−(プロピルチオ)−1H−イミダゾ[4,5−c]キノリン−4−アミン
2−[[4−アミノ−1−(2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−2−イル](メチル)アミノ]エタノール
2−[[4−アミノ−1−(2−メチルプロピル)−1H−イミダゾ[4,5−c]キノリン−2−イル](メチル)アミノ]エチルアセテート
4−アミノ−1−(2−メチルプロピル)−1,3−ジヒドロー−2H−イミダゾ[4,5−c]キノリン−2−オン
N2−ブチル−1−(2−メチルプロピル)−N4,N4−ビス(フェニルメチル)−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
N2−ブチル−N2−メチル−1−(2−メチルプロピル)−N4,N4−ビス(フェニルメチル)−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
N2−メチル−1−(2−メチルプロピル)−N4,N4−ビス(フェニルメチル)−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
N2,N2−ジメチル−1−(2−メチルプロピル)−N4,N4−ビス(フェニルメチル)−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン
1−{4−アミノ−2−[メチル(プロピル)アミノ]−1H−イミダゾ[4,5−c]キノリン−1−イル}−2−メチルプロパン−2−オール
1−[4−アミノ−2−(プロピルアミノ)−1H−イミダゾ[4,5−c]キノリン−1−イル]−2−メチルプロパン−2−オールN4,N4−ジベンジル−1−(2−メトキシ−2−メチルプロピル)−N2−プロピル−1H−イミダゾ[4,5−c]キノリン−2,4−ジアミン。
水酸化アルミニウムおよびリン酸アルミニウムとして公知のアジュバントが使用されてもよい。これらの名称は、どちらも存在する実際の化学化合物の正確な記述でないので、慣習的であるが、便宜的にのみ使用される(例えば、参考文献128の9章を参照)。本発明は、アジュバントとしての一般使用において「水酸化物」アジュバントまたは「リン酸」アジュバントのうちのいずれかを使用できる。
本発明の組成物は薬学的に許容できる。この組成物は、通常抗原に加えて成分を含んでおり、例えばこの組成物は典型的には1つまたは複数の薬学的担体(複数可)および/または賦形剤(複数可)を含む。そのような成分の詳細な考察は、参考文献198において利用可能である。
特にアジュバントが用いられている場合、本発明の組成物は送達時にその場で調製されていてもよい。したがって、本発明は、混合のために準備済みの様々な成分を含むキットを提供する。キットは、アジュバントおよび抗原が使用時まで別々に保たれることを可能にする。水中油滴型エマルジョンアジュバントを用いる場合、このアレンジは特に有益である。
本発明の組成物(またはキット成分)に適切な容器は、バイアル、シリンジ(例えば使い捨てシリンジ)および鼻内噴霧器などを含む。これらの容器は、無菌であるべきである。
本発明の組成物はヒト患者に対する投与に適切であり、本発明は患者に対して本発明の組成物を投与する工程を含む、患者における免疫反応を誘導する方法を提供する。
インフルエンザワクチンの特性を明らかにするために、存在するマトリックスタンパク質の量を決定することは有益であってもよい。したがって、マトリックスタンパク質の存在を決定するためにワクチンのサンプルが解析される場合には、本発明はインフルエンザワクチンを解析するための分析を提供する。この分析は、M1タンパク質の断片のための検査に特に有用である。
本発明は、(i)インフルエンザウイルス血球凝集素およびマトリックスタンパク質と、(ii)アジュバントとを含む免疫原性組成物を提供する。インフルエンザウイルスタンパク質は、細胞培養において増殖させるか、または卵において増殖させたウイルスから調製されていてもよい。上で記述されるように、組成物はさらなる成分(例えばインフルエンザウイルスノイラミニダーゼタンパク質、薬学的担体/賦形剤など)もまた含んでもよい。
用語「含む(comprising)」は、「なる(consisting)」とともに「含む(including)」も包含する。例えば組成物が、Xを「含む(comprising)」ことは、もっぱらXからなって(consist)もよいし、または付加的なもの、例えばX+Yを含ん(include)でもよい。
インフルエンザウイルスのための精製された表面抗原ワクチンについて調べている間に、ビリオンをMDCK細胞で増殖させた場合、CTABでインフルエンザA型ウイルスのスプリッティング後のSDS PAGEによって、比較的大量の低分子量ポリペプチドを検出することができることが観察された。この低分子量ポリペプチドはさらなる抗原精製間にも存在し、表面抗原の最終的な調製品中に存在した。このポリペプチドを調べるために、2kDaという小さなポリペプチドの識別を可能にする緩衝系を使用した(インビトロゲンからのニューページ(NuPAGE)(商標)ノベックス(Novex)ビス−トリスゲル)。この系を使用して、〜5kDaの明瞭な分子量のポリペプチドバンドが同定された。このポリペプチドバンドは、現行ワクチンのインフレキシアルV(商標)、インフルスプリット(INFLUSPLIT)(商標)、ミュータグリップ(MUTAGRIP)(商標)、バキシグリップ(VAXIGRIP)(商標)、ベグリバック(商標)、フルアリックス(商標)、インフルバック(商標)またはフルビリン(商標)中に見られず、それらのすべては卵で増殖させたビリオンから調製されている。意外にも、このポリペプチドバンドは、アグリッパル(商標)のいくつかのバッチで検出されたが、その実在または存在は今までに認識されなかった。
Claims (27)
- トリプシン存在下で細胞培養中で増殖したインフルエンザビリオンから調製した、精製された表面抗原インフルエンザワクチンであって、該ワクチンは、複合体として共精製されるインフルエンザウイルス血球凝集素および内在的M1マトリックスタンパク質の10kDa以下の分子量のフラグメントを含み、ここで、該ワクチンは、オボアルブミンを含まず、ここで、該M1マトリックスタンパク質フラグメントは、配列YSXGAL(配列番号27)を含む、ワクチン。
- 請求項1に記載のワクチンであって、ここで、前記M1マトリックスタンパク質フラグメントの分子量が2〜8kDaの範囲内である、ワクチン。
- 請求項2に記載のワクチンであって、ここで、前記M1マトリックスタンパク質フラグメントの分子量が5kDaである、ワクチン。
- 請求項1〜3のいずれか一項に記載のワクチンであって、ここで、前記M1マトリックスタンパク質フラグメントがインフルエンザウイルスM1タンパク質由来のT細胞エピトープを含む、ワクチン。
- 請求項1〜4のいずれか一項に記載のワクチンであって、前記M1マトリックスタンパク質フラグメントが、天然のM1配列のN末端メチオニンを欠く、ワクチン。
- 請求項1〜5のいずれか一項に記載のワクチンであって、前記M1マトリックスタンパク質フラグメントが、N末端配列EISLSYSAGALA(配列番号18)を有する、ワクチン。
- 前記M1マトリックスタンパク質フラグメントが、1μg/ml〜15μg/mlの濃度で存在する、請求項1〜6のいずれか一項に記載のワクチン。
- 前記血球凝集素が、H1、H2、H3、H5、H7またはH9インフルエンザA型ウイルスサブタイプ由来である、請求項1〜7のいずれか一項に記載のワクチン。
- 前記ワクチンが、1ウイルス株あたり0.1〜20μgの血球凝集素を含む、請求項1〜8のいずれか一項に記載のワクチン。
- アジュバントを含む、請求項1〜9のいずれか一項に記載のワクチン。
- 前記アジュバントが水中油滴型エマルジョンを含む、請求項10に記載のワクチン。
- 複合体として共精製されるインフルエンザウイルス血球凝集素および内在的M1マトリックスタンパク質の10kDa以下の分子量のフラグメントを含む免疫学的組成物の調製方法であって、ここで、該M1マトリックスタンパク質フラグメントは、配列YSXGAL(配列番号27)を含み、該方法は、以下の工程:
(i)トリプシン存在下において細胞培養中のインフルエンザウイルスを増殖させる工程;
(ii)工程(i)において増殖させたウイルスから抗原組成物を調製する工程であって、ここで、該抗原組成物は、血球凝集素、および、全ビリオンではないマトリックスタンパク質を含む、工程;ならびに、
(iii)該抗原組成物を薬学的担体と組み合わせて、免疫学的組成物を生成する工程;を包含する方法。 - 前記インフルエンザウイルスが、MDCK細胞において増殖する、請求項12に記載の方法。
- 前記MDCK細胞が、MDCK 33016(DSM ACC 2219)である、請求項13に記載の方法。
- 前記インフルエンザウイルスが、懸濁培養での増殖に適合した細胞株において増殖する、請求項12〜14のいずれか一項に記載の方法。
- 前記工程(ii)における抗原組成物は、臭化セチルトリメチルアンモニウムを用いてインフルエンザウイルスをスプリットすることによって調製される、請求項12〜15のいずれか一項に記載の方法。
- 請求項12〜16のいずれか一項に記載の方法であって、ここで、前記M1マトリックスタンパク質フラグメントがインフルエンザウイルスM1タンパク質由来のT細胞エピトープを含む、方法。
- 前記M1マトリックスタンパク質フラグメントが、1つまたは複数の配列番号1;配列番号21;配列番号22;配列番号23;配列番号24;配列番号25;配列番号26のアミノ酸配列を含む、請求項12〜17のいずれか一項に記載の方法。
- 前記M1マトリックスタンパク質フラグメントが、(a)全長M1マトリックスタンパク質アミノ酸配列の断片であるアミノ酸配列を有する、および/または、(b)前記マトリックスタンパク質が、天然のM1配列のN末端メチオニンを欠く、請求項12〜18のいずれか一項に記載の方法。
- 請求項12〜19のいずれか一項に記載の方法であって、前記M1マトリックスタンパク質フラグメントが、N末端配列EISLSYSAGALA(配列番号18)を有する、方法。
- 前記M1マトリックスタンパク質フラグメントが、1μg/ml〜15μg/mlの濃度で存在する、請求項12〜20のいずれか一項に記載の方法。
- スプリットインフルエンザウイルスまたは精製されたインフルエンザ表面抗原を含む、請求項12〜21のいずれか一項に記載の方法。
- 前記血球凝集素が、H1、H2、H3、H5、H7またはH9インフルエンザA型ウイルスサブタイプ由来である、請求項12〜22のいずれか一項に記載の方法。
- 複合体として共精製される前記血球凝集素および前記内在的M1マトリックスタンパク質フラグメントが宿主細胞の培養で増殖させたインフルエンザウイルスから調製されており、前記組成物が該宿主細胞由来の10ng未満の細胞性DNAを含む、請求項12〜23のいずれか一項に記載の方法。
- 前記組成物が、1ウイルス株あたり0.1〜20μgの血球凝集素を含む、請求項12〜24のいずれか一項に記載の方法。
- 前記組成物がアジュバント、または、1つ以上のアルミニウム塩を含む、請求項12〜25のいずれか一項に記載の方法。
- 前記アジュバントが、水中油滴型エマルジョンである、請求項26に記載の方法。
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