JP4676426B2 - 改良型ワクチン - Google Patents
改良型ワクチン Download PDFInfo
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- JP4676426B2 JP4676426B2 JP2006504798A JP2006504798A JP4676426B2 JP 4676426 B2 JP4676426 B2 JP 4676426B2 JP 2006504798 A JP2006504798 A JP 2006504798A JP 2006504798 A JP2006504798 A JP 2006504798A JP 4676426 B2 JP4676426 B2 JP 4676426B2
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- antigen
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- peptide
- influenza
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- 150000003212 purines Chemical class 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
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- RYYWUUFWQRZTIU-UHFFFAOYSA-K thiophosphate Chemical group [O-]P([O-])([O-])=S RYYWUUFWQRZTIU-UHFFFAOYSA-K 0.000 description 1
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Images
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Description
−配列R1-XZXZNXZX-R2を含むペプチド(ここで、Nは3〜7の自然数(好ましくは5)であり、Xは正に荷電した天然および/または非天然のアミノ酸残基であり、ZはL、V、I、Fおよび/またはWからなる群から選択されるアミノ酸残基であり、R1およびR2は-H、-NH2、-COCH3、-COH、20個までのアミノ酸残基のペプチドまたはペプチドを有するもしくは有さないペプチド反応性基またはペプチドリンカーからなる群から選択され、X-R2は該ペプチド(以下、「ペプチドA」と称する)のC末端アミノ酸残基のアミド、エステルまたはチオエステルであり得る)
−以下の式(I)の構造を有する免疫賦活性オリゴデオキシ核酸分子(ODN):
R1はヒポキサンチンおよびウラシルから選択され、
XはいずれもOまたはSであり、
NMPはいずれも、デオキシアデノシン−、デオキシグアノシン−、デオキシイノシン−、デオキシシトシン−、デオキシチミジン、2-メチル-デオキシイノシン-、5-メチル-デオキシシトシン-、デオキシシュードウリジン-、デオキシリボースプリン-、2-アミノ-デオキシリボースプリン-、6-S-デオキシグアニン-、2-ジメチル-デオキシグアノシン-またはN-イソペンテニル-デオキシアデノシン-モノホスフェートまたは-モノチオホスフェートからなる群から選択される2'-デオキシヌクレオシドモノフォスフェートまたはモノチオホスフェートであり
NUCは、デオキシアデノシン-、デオキシグアノシン-、デオキシイノシン-、デオキシシトシン-、デオキシイノシン-、デオキシチミジン-、2-メチル-デオキシウリジン-、5-メチル-デオキシシトシン-、デオキシシュードウリジン-、デオキシリボースプリン-、2-アミノ-デオキシリボースプリン-、6-S-デオキシグアニン-、2-ジメチル-デオキシグアノシン-またはN-イソペンテニル-デオキシアデノシンから選択される2'-デオキシヌクレオシドであり、
aおよびbは0〜100の整数であるが、ただし、a+bは4〜150であり、
BおよびEは核酸分子(以下、「I-/U-ODN」とも称する)の一般的な5'または3'末端基である]を含有する。
異なるオリゴデオキシヌクレオチド(ODN)(CpI、ntCpI、o-d(IC)13)とカチオン性ペプチド(pRまたはKLK)との同時注射は、市販のインフルエンザワクチン (Fluvirin)に対する1型体液性反応(IgG2b)を相乗的に強く誘発する。
1.未投薬
2.Fluワクチン
3.Fluワクチン+pR
4.Fluワクチン+KLK
5.Fluワクチン+Al(OH)3
6.Fluワクチン+o-d(IC)13
7.Fluワクチン+I-ODN2
8.Fluワクチン+I-ODN2b
9.Fluワクチン+pR+I-ODN 2
10.Fluワクチン+KLK+o-d(IC)13
11.Fluワクチン+KLK+I-ODN 2
12.Fluワクチン+KLK+I-ODN 2b
1.未接種
2.Fluワクチン
3.Fluワクチン+Al(OH)3
4.Fluワクチン+KLK+o-d (IC)13
カチオン性抗菌ペプチドKLKと合成オリゴデオキシヌクレオチド o-d (IC)13の組合せの単回注射は、市販のインフルエンザワクチン (Agrippal S1)に対する強い細胞性1型および体液性1型/2型免疫反応を相乗的に誘発する。
1.未接種
2.Agrippal S1
3.Fluad
4.Agrippal S1+KLK+o-d(IC)13
0日目に、BALB/cマウスの両後肢大腿筋に、上記化合物を含有する総体積100μlワクチン/マウス(50μl/筋肉)を筋肉内注射した。21日目に血清を回収し、インフルエンザワクチン特異的IgG1およびIgG2a抗体についてELISAで分析した。力価はOD405nmの最大半量を得た血清希釈に対応する。さらに、各実験群の脾臓を回収し、単一細胞懸濁液を調製した。脾細胞のアリコートを、磁性ソーティング(magnetic sorting)(CD4 MACSソート, Miltenyi)によりCD4+ T細胞に分けた。未分離の脾細胞および分離したCD4+ T細胞を非照射抗原提示細胞(APC;未接種マウス由来)と組み合わせて96ウェルELIspotプレート中で刺激して、各実験群についてAgrippal S1抗原特異的サイトカイン産生細胞の数を数えた。以下のサイトカイン産生を分析した:
IFN-γ(細胞性1型反応についての指標として)、
IL-4およびIL-5(細胞性2型反応についての指標として)。
少量のインフルエンザワクチンAgrippal S1 (非アジュバント加)およびFluad (MF59 アジュバント加(adjuvanted))のみを少量注射した場合、CD4+ T細胞によるワクチン (Agrippal S1)特異的IFN-γ産生は誘発することはできなかったが、KLK/o-d (IC)13と組み合わせてAgrippal S1を注射すると、CD4+ T細胞による強力なワクチン(Agrippal S1)特異的IFN-γ産生が観察された。未接種のマウスと比較すると、Agrippal S1単独ではCD4+ T細胞によるIL-4の産生はわずかに誘発するのみであり、KLK/o-d (IC)13のワクチンへの添加によるさらなる上昇は示されなかった。しかしながら、FluadはCD4+ T細胞によるIL-4産生および未分離の脾細胞によるIL-5産生の強力な誘導因子である。IL-5はAgrippal Slの単独注射の際に非常に低レベルでのみ検出可能であるが、KLK/o-d (IC)13と組合せた場合は検出可能ではない。未分離の脾細胞の再刺激の際に、同様の結果が得られた。
図3bは、アジュバント加インフルエンザワクチンFluadの単独注射は強力なワクチン(Agrippal Sl)特異的体液性2型反応(IgG1)を誘発するが、1型反応(IgG2a)は弱い反応のみであった。しかしながら、アジュバント加インフルエンザワクチンのKLK/o-d (IC)13との併用注射により、非常に強力なワクチン(Agrippal S1)特異的IgG2a (体液性1型免疫反応)およびAgrippal S1単独の場合よりも高レベルのIgG1を誘発する。インフルエンザに対する防御はワクチン抗原特異的IgG2a抗体の存在と相関するので、得られた結果はインフルエンザワクチンに対する強力なアジュバントとして非常に強力なKLK/o-d (IC)13を示す。
KLK/o-d (IC)13の組み合わせは、市販のインフルエンザワクチン (Agrippal S1)の有効性を単回注射で非常によく改善する。
1.未接種
2.Agrippal S1
3.Fluad
4.Agrippal S1+KLK+o-d(IC)13
Agrippal S1の単独注射とは反対に、インフルエンザワクチンを少量のKLK/o-d (IC)13と同時注射すると、試験したインフルエンザA株2種(A/ニューカレドニア/20/99; A/パナマ/2007/99)に対する中和抗体レベルの強い上昇が誘発される。しかしながら、Fluadでの免疫感作により、Agrippal S1と少量のKLK/o-d (IC)13との同時注射の場合と同レベルの中和抗体が誘発される。インフルエンザワクチンの有効性は抗血球凝集素抗体の血清力価と相関することが示されているので、本発明の結果は、KLK/o-d (IC) 13がインフルエンザに対する防御を誘発するためのアジュバントである可能性が高いことを示す。
KLK/o-d (IC)13と組み合わせてのインフルエンザAウィルス由来のncORF由来ペプチドを用いたワクチン接種。特異的T細胞反応をワクチン接種の7日後に測定し、続けて動物にマウス順化インフルエンザAウィルス(x31)を致死用量で接種した。15日間に生存をモニターする。
1.p1574+KLK+o-d(IC)13
2.p1569+KLK+o-d(IC)13
3.p1600+KLK+o-d(IC)13
4.p1664+KLK+o-d(IC)13
5.p1600+p1569+KLK+o-d(IC)13
第1群および第3群(ペプチドsp1574およびp1600) 由来の脾細胞は個々のペプチドでの再刺激の後では何ら特異的なスポットは示さなかった。第2群および第4群(p1569およびp1664) は、再刺激後に特にIFN-γを遊離する。第5群には2種のペプチドを個別にワクチン接種した(p1600およびp1569の混合物としてではない)。両方のペプチドの混合物またはp1569のいずれかを用いて再刺激すると、特異的なサイトカイン放出が検出される。反対に、p1600単独での再刺激の際には、IFN-γスポットは検出されない。これは第3群(p1600単独)と一致する。
図5bは、マウス順化インフルエンザAウィルスx31を致死用量で抗原投与したマウスの生存率を示す。第1群(p1574、H2-Dbに対する防御エピトープと報告されている)は、抗原投与した全マウスの30%を防御する。ペプチドp1569は全く防御しなかった(0%)。反対に、ペプチドsp1600およびp1664は抗原投与した動物をそれぞれ50%および62%で防御した。動物に2種の異なるペプチド(第5群、ペプチドsp1600および1569)をワクチン接種すると、最大70%の動物が防御される。
1.HCVペプチド
2.HCVペプチド+KLK+o-d (IC)13
異なるオリゴデオキシヌクレオチド(ODN)(CpI、ntCpI、o-d (IC)13)と同時注射したカチオン性ペプチド(pRまたはKLK)はB型肝炎表面抗原に対する強い1型細胞性反応(IFN-γ)を相乗的に誘発する。
1.HBsAg
2.HBsAg+Alum
3.HBsAg+I-ODN 2
4.HBsAg+I-ODN 2b
5.HBsAg+o-d(IC)13
6.HBsAg+pR
7.HBsAg+KLK
8.HBsAg+pR+I-ODN 2
9.HBsAg+pR+I-ODN 2b
10.HBsAg+pR+o-d(IC)13
11.HBsAg+KLK+I-ODN 2
12.HBsAg+KLK+I-ODN 2b
13.HBsAg+KLK+o-d(IC)13
単独またはAlumと組み合わせてのHBsAg注射はIFN-γを誘発しないか、または非常に低いレベルでのみ誘発する。他方、pR/ODNまたはKLK/ODNと組み合わせてHBsAgを注射すると、HBsAg特異的IFN-γ産生が誘発され、これは追加免疫感作によりさらに増加させることができる。追加免疫の後のAlum、pRおよびKLKの同時注射、ならびにKLK/ODN組合せの同時注射の際に、HBsAg単独注射の場合と比較してわずかにIL-4産生の増加を観察することができる。
カチオン性抗菌ペプチドKLKと合成オリゴデオキシヌクレオチド o-d (IC) 13 (ODN1a)、および少量の市販インフルエンザワクチン (Agrippal S1) の組合せは、単回注射により相乗的に、強いワクチン特異的細胞性1型免疫反応を誘発する。
材料
1.未接種
2.9μg Agrippal S1
3.0.1μg Agrippal S1
4.0.1μg Agrippal S1+100nmol KLK+4nmol ODN1a
5.0.1μg Agrippal S1+35nmol KLK+1.4nmol ODN1a
6.0.1μg Agrippal S1+10nmol KLK+0.4nmol ODN1a
IFN-γ(細胞性1型反応についての指標として)、
IL-4およびIL-5(細胞性2型反応についての指標として)。
Agrippal S1を単独で9μgおよび0.1μgで用いてマウスにワクチン接種した場合、CD4+脾細胞によるワクチン特異的IFN-γを誘導することができなかったが、他方、Agrippal S1を異なる濃度のKLK/o-d (IC)13と組み合わせて注射した場合は、CD4+脾細胞によるIFN-γの強い産生を観察した。しかしながら、CD8+脾細胞はIFN-γを誘導することはできなかった。未接種のマウスと比較して、Agrippal S1単独では非分離の脾細胞およびCD4+脾細胞によるIL-4の産生をわずかに誘導するのみであり、KLK/o-d (IC)13のワクチンへの添加によるさらなる増加は示されなかった。しかし、Agrippal S1が誘導したIL-5はKLK/o-d (IC)13との同時注射の際に完全には停止しなかった。非分離の脾細胞の再刺激の際に、同様の結果が得られる。
図8bに示すように、少量の非アジュバント加インフルエンザワクチンと異なる濃度のKLK/o-d (IC)13との混合注射は、非常に強力なワクチン (Agrippal S1)特異的IgG2a (体液性1型免疫反応)を誘導し、少量のAgrippal S1単独の場合よりも高レベルでIgG1を誘導した。しかし、高用量のAgrippal S1の場合に、最も高い力価のワクチン特異的IgG1抗体が示された。インフルエンザに対する防御はワクチン抗原特異的IgG2a抗体の存在と関連しているので、得られた結果はKLK/o-d (IC)13がインフルエンザワクチンに対する強力なアジュバントである可能性が高いことを示す。
低用量のカチオン性抗菌ペプチドKLKと合成オリゴデオキシヌクレオチド o-d (IC)13 (ODN1a)との単回注射により、市販のインフルエンザワクチン (Agrippal S1)に対する強力なワクチン特異的細胞性I型免疫反応を相乗的に誘発する。
1.未接種
2.9pg Agrippal S1
3.1μg Agrippal S1
4.1μg Agrippal S1+10nmol KLK+0.4nmol ODN1a
5.1μg Agrippal S1+5nmol KLK+0.2nmol ODN1a
6.1μg Agrippal S1+1nmol KLK+0.04nmol ODN1a
IFN-γ(細胞性1型反応についての指標として)、
IL-4およびIL-5(細胞性2型反応についての指標として)。
Agrippal S1(9μgおよび1μg)単独でマウスにワクチン接種するとやはりマウス脾細胞によるワクチン特異的IFN-γの誘導は可能ではなかったが(図8aをも参照のこと)、他方、異なる濃度(低用量)のKLK/o-d (IC)13と併用してAgrippal S1を注射すると、強力なIFN-γ産生が観察された。未接種のマウスと比較すると、Agrippal S1単独のみがマウス脾細胞によるIL-4の産生をほんのわずか増加させ、KLK/o-d(IC)13のワクチンへの添加は効果がなかった。Agrippal S1が誘発したIL-5は、KLK/o-d(IC)13との同時注射の際に濃度依存的に停止した。非常に低い投与量の場合でさえ、KLK/o-d(IC)13の組合せは強い細胞性I型免疫反応を誘発する。
少量の非アジュバント加インフルエンザワクチンを異なる濃度のKLK/o-d (IC)13と混合注射することにより、非常に強力なワクチン (Agrippal S1)特異的IgG2a (体液性1型免疫反応) および少量のAgrippal S1単独の場合とほぼ匹敵するレベルのIgG1を誘発した。しかしながら、高用量のAgrippal S1単独ではワクチン特異的IgG1抗体の力価はわずかな上昇を示し、Agrippal S1および最低濃度のKLK/o-d (IC)13を同時注射した場合と同等レベルのIgG2a抗体が示された。インフルエンザに対する防御はワクチン抗原特異的IgG2a抗体の存在と相関関係があり、得られた結果は、非常に低い用量でさえ、KLK/o-d (IC)13のインフルエンザワクチン用の強力なアジュバントとしての高い可能性を示す。
カチオン性抗菌ペプチドKLKおよび合成オリゴデオキシヌクレオチド o-d (IC)13(ODN1a)と組み合わせた場合の市販のインフルエンザワクチン (Agrippal S1)単回注射の、他のアジュバントとの比較
1.未接種
2.9μg Fluad
3.9μg Agrippal S1
4.1μg Agrippal S1
5.1μg Agrippal S1+10nmol KLK+0.4nmol ODN1a
6.1μg Agrippal S1+5nmol CpG1668
7.1μg Agrippal S1+100μg pR43
8.1μg Agrippal S1+100nmol KLK
9.1μg Agrippal S1+Alum
10.1μg Agrippal S1+CFA
11.1μg Agrippal S1+IFA
IFN-γ(細胞性1型反応についての指標として)、
IL-4およびIL-5(細胞性2型反応についての指標として)。
少量の非アジュバント加インフルエンザワクチンを低用量のKLK/o-d (IC)13と混合注射すると、Agrippal S1およびFluad単独で免疫感作させた場合と比較して、マウス脾細胞によるワクチン (Agrippal S1)-特異的IFN-γが高レベルで誘導された。
Claims (7)
- インフルエンザウイルス感染を予防するためのワクチンであって、
−インフルエンザ抗原、
−アミノ酸配列KLKL5KLKを含むペプチド、ならびに
−オリゴデオキシヌクレオチドd(IC)13 である免疫刺激オリゴデオキシ核酸分子(ODN)を含有するワクチン。 - Al(OH)3アジュバントをさらに含有する、請求項1に記載のワクチン。
- 該抗原が血球凝集素抗原またはノイラミニダーゼ抗原である請求項1または2に記載のワクチン。
- インフルエンザウイルス感染に対する防御効果を改善するインフルエンザウイルスに対するワクチンを製造するための、インフルエンザ抗原、アミノ酸配列KLKL5KLKを含むペプチド、ならびにオリゴデオキシヌクレオチドd(IC)13 である免疫刺激オリゴデオキシ核酸分子(ODN)の組合せの使用。
- インフルエンザウイルス感染に対するワクチンの抗原特異的1型反応を改善し、同時に該ワクチンの2型反応を維持するか、または増加させる、インフルエンザウイルスに対するワクチンを製造するための、インフルエンザ抗原、アミノ酸配列KLKL5KLKを含むペプチド、ならびにオリゴデオキシヌクレオチドd(IC)13 である免疫刺激オリゴデオキシ核酸分子(ODN)の組合せの使用。
- 該抗原特異的1型反応がIgG2抗体反応またはIFN-γ反応であり、および/または該2型反応がIgG1抗体反応またはインターロイキン-4(IL-4)である請求項5記載の使用。
- 該ワクチンが血球凝集素抗原またはノイラミニダーゼ抗原を含む請求項4〜6のいずれかに記載の使用。
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CN115120713A (zh) * | 2021-03-25 | 2022-09-30 | 四川大学 | 氢氧化铝-CpG寡核苷酸-多肽复合佐剂、疫苗及制备方法和用途 |
WO2022214678A2 (en) | 2021-04-09 | 2022-10-13 | Valneva Se | Human metapneumo virus vaccine |
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AU2009202420B2 (en) | 2012-04-26 |
US8784837B2 (en) | 2014-07-22 |
EP1608402A1 (en) | 2005-12-28 |
AU2004224746B2 (en) | 2009-04-23 |
CA2517673C (en) | 2013-08-13 |
US20100297170A1 (en) | 2010-11-25 |
ATE485056T1 (de) | 2010-11-15 |
AU2004224746A1 (en) | 2004-10-07 |
EP1608402B1 (en) | 2010-10-20 |
AU2009202420A1 (en) | 2009-07-09 |
JP2013121975A (ja) | 2013-06-20 |
JP5586717B2 (ja) | 2014-09-10 |
CA2517673A1 (en) | 2004-10-07 |
JP2011042678A (ja) | 2011-03-03 |
US20150010595A1 (en) | 2015-01-08 |
US20060263386A1 (en) | 2006-11-23 |
JP2006521320A (ja) | 2006-09-21 |
WO2004084938A1 (en) | 2004-10-07 |
EP2345420A1 (en) | 2011-07-20 |
DE602004029657D1 (de) | 2010-12-02 |
ES2562456T3 (es) | 2016-03-04 |
EP2345420B1 (en) | 2016-01-06 |
US7704514B2 (en) | 2010-04-27 |
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