JP2015535259A - 新規粘膜アジュバントおよびデリバリーシステム - Google Patents
新規粘膜アジュバントおよびデリバリーシステム Download PDFInfo
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- JP2015535259A JP2015535259A JP2015539892A JP2015539892A JP2015535259A JP 2015535259 A JP2015535259 A JP 2015535259A JP 2015539892 A JP2015539892 A JP 2015539892A JP 2015539892 A JP2015539892 A JP 2015539892A JP 2015535259 A JP2015535259 A JP 2015535259A
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Abstract
Description
本特許出願は、2012年10月29日出願の米国仮特許出願第61/719,713号の利益を主張するものであり、参照によりその全体が本願に組み込まれる。
本明細書において、キトサンを含むアジュバント、前記アジュバントを含むワクチン配合物、前記アジュバントの製造方法ならびに前記アジュバントおよびワクチン配合物の使用方法が提供される。要約すれば、非経口剤(注射剤)などに用いられる他のアジュバントと同様な方法に用いることができる新規アジュバント系が本明細書に記載される。基本分子はキトサンを含む。キトサンは、多くの無脊椎動物(シュリンプ、カニ、昆虫など)の外骨格であるキチンの脱アセチル化体である。キトサンは一般に安全と考えられる(GRAS)化合物とみなされ、体重減少、コレステロール低下、不眠症および腎機能改善に用いられている。キトサンはまた、種々の粘膜ワクチンにアジュバントとして用いられているが(Jabbal-Gill et al., 2012)、本明細書に記載のキトサンは新規であり、実施例に示すように、従来のキトサンよりも機能が優れている。
ホルムアルデヒドで架橋されたキトサン-タンパク質ワクチンを試験するための我々の最初の実験には、モデルタンパク質として古典的タンパク質であるβ-ガラクトシダーゼ(β-Gal)を用いた。以下の表1の記載に従って、処置群6匹および対照1匹を用いて、シチメンチョウのひなにβ-Galでワクチン接種した。孵化日に、非経口皮下(sq)注射で、ひなに、生理食塩水または、15%アラム、1%キトサン(ホルムアルデヒド(Form)で架橋)(3群)もしくは1.5%キトサン(ホルムアルデヒドで架橋されてない)のいずれかに含まれるβ-Gal100μg(0.25ml)でワクチン接種した。1%キトサン群の内の2匹を除くすべての群を14日目および25日目に同じ製剤でsqブーストした。両方の日に、1%キトサン群の内の2匹の内の1匹は、強制経口投与によって1%キトサン-β-Galでブーストし、もう1匹は、1%キトサン-β-Gal(2mL)でスプレーによってブーストした。
4X108cfu/mlクロストリジウム・セプチクム(Clostridium septicum)バクテリン(CS)を含むアラムまたはホルマリン架橋キトサンのいずれか単独で、あるいは12%アラムもしくは0.5%ホルマリン架橋キトサンと組み合わせて、鳥1匹あたりの最終用量が1X108cfu/鳥になるように、孵化日のシチメンチョウのひなの皮下(0.25mL)に投与することによって、上記の実験と同様な実験を行った。同じ経路を用い、同じワクチンですべての鳥を14日目にブーストした。得られた免疫応答のレベルを間接ELISAアッセイによって測定し、吸光度の試料対陽性対照(S/P)比で記録した。より大きなS/P比は、より高い抗CS抗体を示す。
鳥インフルエンザ(AI)は、重大な公衆衛生上の懸念であり、世界中に存在する商業家禽産業に対する重大な経済的脅威である。我々の以前のデータでは、CD154と関連するM2eを発現するサルモネラをベクターとするワクチンはAIに対して有効であるであることを示唆している。ベクターとしてのバチルス・ズブチリス(Bacillus subtilis)およびM2eエピトープを用いる新規構築物を免疫刺激分子と共に試験した。孵化後11日目、15日目および21日目にELISAによってM2e特異的血清IgGおよび粘膜IgA抗体レベルを測定した。孵化日に、強制経口投与または皮下注射のいずれかを用い、野生型バチルス(BSBB)、生ワクチンとしての、バチルスをベクターとする鳥インフルエンザワクチン(BSAI)、ホルマリン不活化後のBSAI、ホルマリン不活化、凍結乾燥および生理食塩水での再構成後のBSAI、またはホルマリン不活化および1%キトサンでの架橋後のBSAIのいずれかでひなをワクチン接種した。各ワクチンを、106cfu/ひなで、0.25mlまたは0.25ml生理食塩水に含ませて投与した。孵化10日目に、2つの群(BSAI生、BSAI不活化および凍結乾燥)のひなに、0日目に行ったものと同じ処置のブースターワクチン接種を行い、他の群はすべて、二次のワクチン用量を投与しなかった。
潜在的増強分子の添加または代替送達戦略による、キトサンベースのアジュバントを改善するために設計された一連の実験によって、本アジュバントはさらに増強された。免疫刺激化合物は、アジュバントと共に用いられるとき、応答を潜在的に改善することができ、以前、いくつかの研究がなされてきている。概説(Guy, 2007; Mutwiri et al., 2011)を参照のこと。潜在的アジュバントは、サポニン、細菌成分、自然免疫系と相互作用する化合物、例えばToll様受容体、核酸、例えばCpGモチーフ、ウイルス、リポソームを含むエマルションまたはこれらの成分の任意の組み合わせを含む。自然免疫系と相互作用するさらに有望な免疫刺激分子には、破傷風トキソイド(TT)、熱不安定性エンテロトキシンBサブユニット(LTB)およびコレラ毒素Bサブユニット(CTB)がある。固有の化学的特性によって、経験的に免疫系を増強することが示されている他の化合物は、サポニンおよびモノホスホリル脂質A(MPLA)を含む。マクロファージ受容体への結合を標的とするマンノースまたは他の糖を用いて、免疫機能を増強することができる。異なるアジュバントの組み合わせは、IL-12または他のサイトカインとの組み合わせと同様に、免疫応答を刺激するために相乗的に作用することができる。
ワクチン接種のための最良の経路およびアジュバントの組み合わせを研究した。孵化日に、ひなに、生理食塩水または、図8に示したそれぞれのアジュバント混合物を含むワクチンのいずれかを0.25mL投与した。比較したアジュバントは、ホルムアルデヒド架橋キトサン、還元型マンノシル化キトサン(Man CV1)、非還元型マンノシル化キトサン(Man CV2)を含む。各アジュバントは、抗原と混合し、孵化日に皮下にまたは飲料水で投与した。同じアジュバント-抗原組み合わせの第二投与で、皮下に、飲料水でまたは強制経口投与でのいずれかによって鳥にブーストした。飲料水(DW)でワクチン接種した群は、水に1:128に希釈した。強制経口投与によってブーストした群は、0.25mlを投与した。前述のように、競合的SEフラジェリンELISAアッセイ(IDEXX)を用いて粘膜IgA応答を測定した。図8における最後の5つの処置群は、大きくは異なっていないが、数字的に最も低い群は、一次ワクチン接種でsq送達し、ブーストでDWに1:128に希釈したマンノシル化キトサンV2であった。この群は、sqでの0.5%キトサン一次ワクチン接種およびsqまたはDWブーストのいずれかと比較して、回腸において有意に高いIgAレベルを有していた。マンノシル化キトサンの還元型と非還元型の間において、あるいは飲料水でまたは強制経口投与によってブーストが投与された場合において、有意差は認められなかった。
次いで、マンノシル化キトサンを、市販鉱油ベースアジュバントと比較し、市販鉱油ベースアジュバントと混合した。サルモネラ・エンテリティデス(SE)バクテリンを108cfu/mlに増殖させ、ホルムアルデヒドで不活化したものを抗原として用いた。サルモネラバクテリンを4X107cfu/mlでキトサン、マンノシル化キトサン、鉱油アジュバント、キトサンと鉱油アジュバント組み合わせまたはPBSと2:1比で混合し、最終用量を鳥1匹当たり1X107cfuとした。孵化日に、ブロイラーのひなを、上記のように、示された製剤0.25mlでプライミングした。12日齢で、強制経口投与でひなをブーストした。競合的ELISAキット(IDEXX)を用いて、22日目に、血清(IgG)および回腸粘膜(IgA)において抗体レベルを測定した。結果を、それぞれ図9および10に示す。試料対対照比の吸光度レベルの低下は、SEフラジェリンコーティングしたプレートを認識する抗体の高いレベルを示している。マンノシル化キトサンワクチン接種およびブーストプロトコルは、他の群のそれぞれと比較して、IgGおよびIgAレベルの有意の増加をもたらした。
単回非経口ワクチン接種後のIgG免疫応答を調べるために、孵化日のひなの皮下に、生理食塩水、通常のキトサンまたはマンノシル化キトサンと混合した2.5x108cfu/ひなのボルデテラ・アビウム(Bordetella avium)バクテリンでワクチン接種した。14日目に血清を採取し、ボルデテラ特異的IgGをELISAで測定した。結果を図11に示す。図は、示された処置に関する吸光度の試料対陽性対照比を示す。より高いレベルの吸光度は、特異的IgGの増加を示す。ボルデテラ抗原と混合されたマンノシル化キトサンは、最も高いレベルのIgGを生じた。
ボルデテラ・アビウムバクテリンを皮下に投与し、次いで14日目に飲料水ブーストを行った後にIgG免疫応答を調べた。孵化日のひなの皮下に、生理食塩水、通常のキトサンまたはマンノシル化キトサンと混合した2.5x108cfu/ひなのボルデテラ・アビウムバクテリンをワクチン接種した。14日目に、ワクチン接種のブーストとして、飲料水中に7.8x106cfu/mLのボルデテラ・アビウムバクテリンを含ませた。21日目、すなわちブースト7日目に血清を採取し、ELISAによって特異的IgG応答を測定した。結果を図12に示す。図は、示された処置に関する吸光度の試料対陽性対照比を示す。より高いレベルの吸光度は特異的IgGの増加を示す。ボルデテラ抗原と混合されたマンノシル化キトサンは、対照または未改変キトサンと比較して有意に高いレベルのIgGを生じた。
ホルムアルデヒドで架橋されたキトサン-タンパク質ワクチンの製造
マンノースを含まないキトサンの最終生成物は、ワクチン配合物中に、最小最終濃度0.5%キトサン〜最大最終濃度2%キトサンの範囲であることができる。適切な濃度(1.5%の酢酸水溶液)で、脱イオン水1L当たり氷酢酸15ml含む溶液にキトサンを溶解する。ブロス培養物に関しては、一般的に、2倍量の培養物を1倍量の1.5%キトサンと混合する(最終ワクチン配合物中に0.5%キトサン)。他の抗原は最小限に希釈し、最終濃度を1.5%までのキトサンを得る。次いで、抗原が溶解されたキトサン混合物に、ホルムアルデヒドを、ホルムアルデヒドが最終濃度0.2%、すなわち0.008Mになるように加える。上記の実施例において、ホルムアルデヒドの37%溶液を用いる。トリス-HClを最終濃度0.5g/Lまで加えることができる。
1倍量の0.1M酢酸ナトリウム(pH4.0)中でマンノース2モル当量を60℃で2時間加熱した。次いでこの溶液に、2倍量の1モル当量の2%キトサンの0.15%酢酸溶液を加え、室温で10分間反応させ、1.5%マンノシル化キトサン溶液を生成させた。次いで、これを、2倍量の培養物が1倍量の1.5%マンノシル化キトサンと混合されるようにブロス培養物と混合することができる。濃縮抗原は、出来るだけまたは必要に応じて最小限に希釈することができる。最終濃度0.5g/Lまでトリス-HClを加えることができる。
Claims (29)
- キトサンに結合してシッフ塩基を形成した炭水化物を含む、アジュバント組成物。
- 前記炭水化物がマンノース、マンノビオース、グルコース、ガラクトースまたはフルクトースから選択される、請求項1に記載の組成物。
- 前記炭水化物がマンノースである、請求項2に記載の組成物。
- 前記シッフ塩基が還元されていない、請求項1〜3のいずれか1項に記載の組成物。
- 前記シッフ塩基が還元されている、請求項1〜3のいずれか1項に記載の組成物。
- 0.5%〜2%のアルデヒド架橋キトサンを含む、アジュバント組成物。
- 前記キトサンがホルムアルデヒドで架橋されている、請求項6に記載の組成物。
- 遊離アルデヒドをクエンチするためのトリス-HClをさらに含む、請求項6または7に記載の組成物。
- 増強分子をさらに含む、請求項1〜8のいずれか1つに記載の組成物。
- 前記増強分子が、サポニン、Toll様受容体、細菌毒素Bサブユニット、細菌毒素、CpGモチーフ、リポソームまたはモノホスホリル脂質Aである、請求項9に記載の組成物。
- 前記増強分子が、破傷風トキソイド、コレラ毒素Bサブユニット、熱不安定性エンテロトキシンBサブユニットまたはトリポリホスフェートである、請求項9に記載の組成物。
- 請求項1〜11のいずれか1項に記載のアジュバント組成物と、抗原とを含む、ワクチン配合物。
- 前記抗原がタンパク質である、請求項12に記載のワクチン。
- 前記タンパク質が、インフルエンザM2e、ヘマグルチニン、ノイラミニダーゼまたは核タンパク質;アイメリアTRAPまたはMPP;クロストリジウムシアリダーゼ、SagA、α毒素、NetB毒素または鉄輸送タンパク質である、請求項13に記載のワクチン。
- 前記抗原が微生物を含む、請求項12に記載のワクチン。
- 前記微生物が、サルモネラ(Salmonella)、エシェリキア(Escherichia)、シゲラ(Shigella)、ボルデテラ(Bordetella)、クロストリジウム(Clostridium)、マイコプラズマ(Mycoplasma)、スタフィロコッカス(Staphylococcus)、ストレプトコッカス(Streptococcus)、バチルス(Bacillus)、インフルエンザ(Influenza)またはアイメリア(Eimeria)である、請求項15に記載のワクチン。
- 前記微生物が不活化されているか、または死滅されている、請求項15または16に記載のワクチン。
- 前記微生物が、ホルムアルデヒド、グルタルアルデヒドまたはホルマリンを用いて死滅されている、請求項17に記載のワクチン。
- キトサンを酢酸溶液中に溶解すること、溶解されたキトサンに抗原を添加すること、並びに、溶解されたキトサンおよび抗原にアルデヒドを混合し、前記アルデヒドの最終濃度を0.02%〜0.5%とすることを含む、請求項6〜8のいずれか1項に記載の組成物の製造方法。
- 前記抗原がタンパク質である、請求項19に記載の方法。
- 前記抗原が微生物ワクチンである、請求項19に記載の方法。
- トリス-HClを加えて遊離アルデヒドをクエンチすることをさらに含む、請求項19〜21のいずれか1項に記載の方法。
- 前記アルデヒドが最終濃度0.2%で添加される、請求項19〜22のいずれか1項に記載の方法。
- 抗原に対する被験者の免疫応答を増強する方法であって、請求項12〜18のいずれか1項に記載のワクチン配合物を被験者に投与することを含む、前記方法。
- 免疫応答が、アジュバントなしのワクチンの投与と比較して、増強された抗体応答を含む、請求項24に記載の方法。
- アジュバントなしのワクチンの投与と比較して、分泌IgA抗体応答が増強される、請求項25に記載の方法。
- ワクチン投与後のIgA応答が、対照ベクターを投与された被験者のIgA応答に対して少なくとも2倍増大される、請求項26に記載の方法。
- 前記被験者が哺乳動物または家禽である、請求項24〜27のいずれか1項に記載の方法。
- 投与経路が皮下または経口である、請求項24〜28のいずれか1項に記載の方法。
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