JP5457340B2 - 水相中に抗原およびアジュバントを含むエマルジョンワクチン組成物 - Google Patents
水相中に抗原およびアジュバントを含むエマルジョンワクチン組成物 Download PDFInfo
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Description
(発明の分野)
本発明は、油中水型ワクチン処方物、上記処方物を作製するためのプロセスおよび動物のワクチン接種のためのこのような処方物の使用に関する。
多くの感染性疾患制御プログラムの基礎は、生の微生物もしくは不活性化微生物またはそれらの生成物のいずれかでのワクチン接種による、特異的免疫の誘導である。有効なワクチン接種手順は、ある抗原についての動物における免疫記憶の状態の発生を可能にし、上記抗原とのその後に接触した際に、上記動物における急激かつ強い免疫学的応答がもたらされる。しかし、いくつかの抗原は、ごくわずかに免疫原性である。このような抗原は、その後のチャレンジの際に上記動物に有効な防御を提供するに十分な免疫応答を誘導することができない可能性があるか、または免疫原性を増大させて、有効な防御を提供するさらなる因子との投与を要し得る。
本発明は、油ベースのエマルジョンワクチン組成物を水相中のアクリルポリマー(例えば、カルボポル)と処方することは、アクリルポリマーを含まない油ベースのエマルジョンワクチン組成物と比較して、ワクチン組成物によって生成される免疫応答を顕著に増大させるという驚くべき発見に一部基づいている。さらに、油中水型エマルジョンの上記水相中のアクリルポリマーを処方することによって、上記動物におけるアクリルポリマーの予測される有害な反応性が回避された。
本発明は、エマルジョンを含むワクチン組成物を提供する。上記エマルジョンは、油成分および水性成分を含む。上記水性成分は、少なくとも1種の抗原および少なくとも1種のアジュバントを含む。上記アジュバントは、アクリルポリマーおよび/もしくはDDAを含み得る。
種々のタイプの、ワクチン調製物において使用されるエマルジョンとしては、油中水型エマルジョン、水中油型エマルジョン、および水中油中水型エマルジョンが挙げられる。本発明の状況において使用するための異なるタイプのエマルジョンは、油中水型エマルジョンである。油中水型エマルジョンは、1種以上の油溶性界面活性剤、1種硫黄の水溶性界面活性剤、さらなるアジュバント、さらなる水相成分、エマルジョン安定化剤、もしくはこれらの組み合わせをさらに含み得る。油中水型エマルジョンを作製するための方法は、当該分野で公知であり、本明細書中の他の箇所で記載されている。
本明細書で使用される場合、「ワクチン組成物」とは、レシピエントにおける防御免疫を誘発するために使用され得る組成物である。従って、被験体に抗原をワクチン接種した後に、ワクチンは、非ワクチン接種被験体に対して、同じもしくは関連する抗原に曝された被験体における疾患を予防するか、遅延させるか、または上記疾患の発症の重篤度を軽減する。ワクチンによって提供される防御免疫は、液性(抗体媒介性)免疫もしくは細胞性免疫、またはその両方であり得る。ワクチン接種は、例えば、病原体もしくは感染細胞の負担を排除もしくは低下させ得るか、または任意の他の測定可能な感染の軽減を生じ得る。ワクチン接種はまた、免疫した(ワクチン接種した)被験体における腫瘍負荷を低下させ得る。
用語「アジュバント」とは、本明細書で使用される場合、抗原と共同して投与される場合に、その抗原に対する被験体の免疫応答を増強する化合物をいう。
用語「抗原」とは、本明細書において使用される場合、被験体に導入される場合に、宿主の免疫系によって認識され、免疫応答を誘発することができかつ防御免疫を生成することができる薬剤をいう。抗原としては、病原体の表面もしくは感染細胞の表面、または腫瘍細胞の表面に天然に発現されている「表面抗原」が挙げられるが、これらに限定されない。
本発明のワクチン組成物はまた、油成分を含む。上記油成分に含まれ得る油の例としては、テルペン油(例えば、スクアランおよびスクアレン);植物性油(例えば、ダイズ油、オリーブ油、コーン油、ホホバ油、ラッカセイ油、綿実油、ひまわり油、サフラワー油、ごま油、アプリコット油、アボカド油、小麦胚芽油、キャノーラ油、亜麻仁油、およびアーモンド油);魚油(例えば、鮫油、ヒウチ鯛油(orange roughy oil)、ニシン油(Menhaden oil)、および鱈肝油);動物性油(例えば、ミンク油、ラード油、および鶏脂油(chicken fat oil);ならびに合成油(例えば、オレイン酸エチル、ミリスチン酸イソプロピル、Miglyol(登録商標) 840(Sasol North America Inc.,Houston,TX)、およびCaptex(登録商標) 300(Abitec Corp.,Columbus,Ohio)ならびにミネラルオイル(Sigma−Aldrich,St.Louis,MOから市販される)、トリグリセリド油、プロピレングリコール誘導体、およびプリスタンが挙げられるが、これらに限定されない。上記油相の好ましい油は、ミネラルオイルである。これら油の組み合わせはまた、使用され得る。
本発明の特定の実施形態において、上記ワクチン組成物は、1種以上のさらなる成分(例えば、界面活性剤、緩衝化剤および安定化化合物)を含み得る。
本発明はまた、ワクチン組成物を作製するための方法を包含する。一実施形態において、本発明の方法は、油成分を水性成分と乳化する工程を包含する。上記でより詳細に記載されるように、上記ワクチン組成物の水性成分は、少なくとも1種の抗原、ならびにアクリルポリマーおよびDDAからなる群より選択される少なくとも1種のアジュバントを含む。上記油成分、抗原、アジュバントおよび本明細書の他の箇所で記載されるこれらのバリエーションのうちのいずれかは、本発明の方法において使用され得る。
本発明はまた、動物をワクチン接種するための方法を包含する。本発明の方法は、動物に、本明細書中の他の箇所で記載されるワクチン組成物のうちのいずれかを投与する工程を包含する。
特定の実施形態において、本発明は、免疫原性処方物の1種以上の成分を充填した1つ以上の容器を含む薬学的パックもしくはキットを提供する。好ましい実施形態において、薬学的組成物もしくはワクチン組成物の調製のためのキットは、少なくとも1種の抗原、アジュバント(例えば、カルボポル(登録商標)もしくはカルボポル(登録商標)+DDA)、油相、および水相を含み、上記キットは、異なる容器に上記成分を含み、そして必要に応じて、上記成分を混合するために、および/もしくは上記組成物の投与のために説明書を含む。上記キットの各容器はまた、必要に応じて、1種以上の生理学的に受容可能なキャリアおよび/もしくは賦形剤および/もしくは補助物質を含み得る。製造、製薬製品もしくは生物製品の使用もしくは販売を規制する政府当局によって規定された形態の注意書きは、このような容器と関連づけられ得、この注意書きは、製造、ヒト投与のための使用もしくは販売の当局による承認を示す。
本発明によれば、当該分野の技術班以内の従来の分子生物学、微生物学、および組換えDNA技術が使用され得る。このような技術は周知であり、参考文献中に十分に説明されている。例えば、Sambrook,Fritsch and Maniatis,Molecular Cloning: A Laboratory Manual,Second Edition(1989)Cold Spring Harbor Laboratory Press,Cold Spring Harbor,New York;DNA Cloning: A Practical Approach,Volumes I and II(D.N.Glover ed.1985);Oligonucleotide Synthesis(M.J.Gait ed.1984);Nucleic Acid Hybridization[B.D.Hames & S.J.Higgins eds.(1985)];Transcription And Translation [B.D. Hames & S.J. Higgins, eds. (1984)];Animal Cell Culture[R.I.Freshney,ed.(1986)];Immobilized Cells And Enzymes[IRL Press,(1986)];B.Perbal, A Practical Guide To Molecular Cloning (1984);およびF.M. Ausubelら(eds.),Current Protocols in Molecular Biology,John Wiley & Sons,Inc.(1994)を参照のこと。
不活性化逆遺伝学H5N3トリインフルエンザ(Liuら,Virology 314:580−590(2003))を、滅菌生理食塩水に添加した。上記混合物を攪拌して、均質な混合物を形成した。Tween(登録商標) 80(7.2mL)を上記混合物に添加して、続いて、混合して、均質な水性混合物を形成した。
水相にアジュバントを含む油中水型エマルジョンを、本質的に実施例1に記載されるように調製した。不活性化H5N3トリインフルエンザおよび表2の5種のアジュバントのうちの1種を、滅菌生理食塩水に添加して、全容積197mLにした。上記混合物を攪拌して、均質な混合物を形成した。Tween(登録商標) 80(3.0mL)を上記混合物に添加して、続いて、混合して、均質な水性混合物を形成した。
シチメンチョウを、128HAU、256HAU、もしくは512HAU(赤血球阻害単位)/0.5mLのアジュバントなしのワクチン(実施例1に記載されるとおり)を接種した。上記接種したシチメンチョウに由来する血液のHI(赤血球凝集阻害)力価を、接種の3週間後、6週間後、および9週間後に測定した。上記サンプルを、赤血球凝集阻害(HI)アッセイ(動物インフルエンザの診断およびサーベイランスに関する世界保健機関マニュアル、WHO/CDS/CSR/NCS/2002.5)で試験した。結果を図2に示す。各投与量は、合理的に良好な血清学的応答を最初に与えるが、上記HI力価は、その後すぐに劇的に低下した。
シチメンチョウに、水相中にアジュバントを含むワクチン(実施例2に記載されるとおり)を接種した。10羽の1週齡のシチメンチョウに、0.5mLの上記ワクチン(256HAU/用量)をワクチン接種した。コントロールとして、10羽のシチメンチョウに、実施例1に記載される処方物を接種し、10羽のシチメンチョウには、接種しなかった。接種したシチメンチョウを、最初のワクチン接種の3週間後に、0.5mLのワクチン(256HAU/用量)の第2のワクチンブースターを与えた。上記シチメンチョウ由来の血清サンプルを、4週齡、7週齡、および10週齡で採取し、実施例4に使用される同じ赤血球凝集阻害アッセイを使用して試験した。表3は、上記に記載されるような実験プロトコルの表の記載を提供する。
本実施例において、カルボポルもしくはカルボポル+DDAありもしくはなしの油中水型エマルジョン中にトリインフルエンザ抗原を含むワクチン組成物を使用して、シチメンチョウにワクチン接種し、上記インフルエンザ抗原に対する免疫応答を評価した。
本実施例において、水相中にカルボポルありまたはなしで、トリインフルエンザ抗原を油中水型エマルジョン中に含むワクチン組成物を使用して、異なる4品種のアヒルにワクチン接種し、上記インフルエンザ抗原に対する免疫応答を評価した。
Claims (24)
- 油中水型エマルジョンを含むワクチン組成物であって、
ここで該エマルジョンは、油成分および水性成分を含み;そして
ここで該水性成分は、少なくとも1種の抗原、ならびにアクリルポリマーおよびジメチルジオクタデシルアンモニウムブロミド(DDA)を含むアジュバントを含む、
ワクチン組成物。 - 前記アクリルポリマーは、ポリアリルスクロースで架橋されたアクリル酸のポリマーである、請求項1に記載のワクチン組成物。
- 前記アクリルポリマーは、アルキル−ポリアクリル酸(「アルキル−PAA」)アジュバントである、請求項1に記載のワクチン組成物。
- 前記アルキル−PAAアジュバントは、デシル−PAA、オクチル−PAA、ブチル−PAAおよびメチル−PAAからなる群より選択される、請求項3に記載のワクチン組成物。
- 前記アルキル−PAAアジュバントは、オクチル−PAAである、請求項4に記載のワクチン組成物。
- 前記少なくとも1種の抗原は、感染性因子である、請求項1に記載のワクチン組成物。
- 前記感染性因子は、生の感染性因子である、請求項6に記載のワクチン組成物。
- 前記感染性因子は、死滅感染性因子もしくは不活性化感染性因子である、請求項6に記載のワクチン組成物。
- 前記感染性因子は、ウイルス、細菌、真菌、もしくは寄生体である、請求項6に記載のワクチン組成物。
- 前記少なくとも1種の抗原は、ペプチド、ポリペプチド、もしくは核酸である、請求項1に記載のワクチン組成物。
- 前記感染性因子はウイルスである、請求項6に記載のワクチン組成物。
- 前記感染性因子は、トリ、イヌ、ネコ、ウシ、ブタ、もしくはウマ動物に感染することができる因子である、請求項6に記載のワクチン組成物。
- 前記感染性因子は、トリ動物に感染することができる因子である、請求項12に記載のワクチン組成物。
- 前記ウイルスは、インフルエンザウイルスである、請求項11に記載のワクチン組成物。
- 前記油成分は、ミネラルオイルを含む、請求項1に記載のワクチン組成物。
- 前記組成物は、1種以上の乳化剤をさらに含む、請求項1に記載のワクチン組成物。
- 前記水性成分はレシチンをさらに含む、請求項1に記載のワクチン組成物。
- ヒトを除く動物にワクチン接種するための方法であって、該方法は、該動物に、請求項1に記載のワクチン組成物を投与する工程を包含する、方法。
- 前記動物は、トリ、イヌ、ネコ、ウシ、ブタ、もしくはウマ動物である、請求項18に記載の方法。
- ワクチン組成物を作製するための方法であって、該方法は、油成分と、水性成分とを乳化する工程を包含し、
ここで該水性成分は、少なくとも1種の抗原、ならびにアクリルポリマーおよびジメチルジオクタデシルアンモニウムブロミド(DDA)を含むアジュバントを含む、
方法。 - 前記アクリルポリマーは、ポリアリルスクロースで架橋されたアクリル酸のポリマーである、請求項20に記載の方法。
- ワクチン組成物を作製するための方法であって、該方法は、
(a)抗原の水溶液と、アクリルポリマーおよびジメチルジオクタデシルアンモニウムブロミド(DDA)を含むアジュバントとを合わせて、抗原/アジュバント混合物を形成する工程;
(b)(a)の抗原/アジュバント混合物と、油成分および乳化剤とを合わせて、抗原/アジュバント/油成分混合物を形成する工程;ならびに
(c)(b)の抗原/アジュバント/油成分混合物を
乳化して、油中水型エマルジョンを形成し、それによって、ワクチン組成物を形成する工程、
を包含する、方法。 - 前記アクリルポリマーは、ポリアリルスクロースで架橋されたアクリル酸のポリマーである、請求項22に記載の方法。
- 前記油成分はミネラルオイルを含む、請求項22に記載の方法。
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CA2932681C (en) * | 2013-12-06 | 2022-08-30 | Moti Harel | Composition for oral delivery of bioactive agents |
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