JP2021536228A - ヘマグルチニン(ha)タンパク質内の非ドミナントエピトープに対する免疫応答を誘起するためのベクター - Google Patents
ヘマグルチニン(ha)タンパク質内の非ドミナントエピトープに対する免疫応答を誘起するためのベクター Download PDFInfo
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Abstract
Description
本出願は、2018年8月20日に出願されたアメリカ合衆国出願第62/719,952号の出願日の恩恵を主張するものであり、その開示内容が参照によって本明細書に組み込まれている。
本発明は、政府の援助を得て国立衛生研究所から資金提供されたHHSN272201400008Cのもとでなされた。政府は本発明において所定の権利を有する。
VLPは、インフルエンザHAを単一のウイルスマトリックスタンパク質とともに発現させることによって生成させることができる。したがってインフルエンザウイルスの他のタンパク質(M1、NAなど)に対する免疫応答が結果の解釈に影響することはなかろう。エボラウイルスVP40マトリックスタンパク質に基づくVLPを使用する。なぜならヒトはVP40に対する抗体を持たないため、エボラVP40に基づいていてHAを発現するVLPが効率的に形成されるからである。
免疫ドミナントエピトープに多数の変異を有するHA(ID-EpiMut HA)の生成とインビトロでの特徴づけ
ID-EpiMutワクチンの免疫原性と保護効果。この方法によって作製したバリアントのそれぞれは、免疫系にとって新奇な抗原を持っている可能性が大きい。これらバリアントを混合することにより、ワクチンは、非天然のヘッド内免疫ドミナント抗原エピトープのそれぞれを少量含有するが、(すべてのID-EpiMut HAにおいて同じである)免疫サブドミナントエピトープの量は多い。このようなワクチンは、(インフルエンザワクチンの現在の慣行である)1種類の野生型HAだけを提示するワクチンと比べて保存された免疫サブドミナントエピトープに向かうより多くの抗体を誘起する。保存された免疫サブドミナントエピトープに対する抗体のレベルがより高いことで交差防御が得られる。実験的アプローチ。個々のID-EpiMut HAバリアントに対するマウス抗血清と、混合されたID-EpiMut HAバリアントに対するマウス抗血清を生成させ、反応性を調べる。ワクチン接種とチャレンジの研究をマウスとフェレットで実施し、非天然の免疫ドミナントエピトープの混合物がこれらエピトープに対する反応を減弱させるとともに免疫サブドミナントエピトープに対する抗体のレベルを上昇させて、より広い保護免疫が得られるかどうかを評価する。
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Claims (56)
少なくとも2つの免疫ドミナントエピトープを有するインフルエンザウイルスヘマグルチニンをコードする単離された親インフルエンザ核酸分子の1つ以上の免疫ドミナントエピトープの複数のコドンにランダムな変異を導入することにより、変異インフルエンザウイルスヘマグルチニンをコードするインフルエンザ核酸分子のライブラリを提供すること;
このライブラリを細胞に導入して、該変異ヘマグルチニンを発現する細胞のライブラリを提供すること;および
該1つ以上の免疫ドミナントエピトープを形成する残基に1つ以上の置換および/または欠失がある結果として該親ヘマグルチニンと比べて免疫ドミナントエピトープの数が減少したライブラリによってコードされる変異ヘマグルチニンを同定すること
を含む、方法。
親H3 HA核酸分子において、121位、131位、135位、138位、140位、142位、144位、145位、155位、156位、157位、158位、171位、189位、193位、212位、または225位の残基についての2つ以上のコドンに、この親H3 HA内の免疫ドミナントエピトープの残基ではない残基をコードする変異を導入すること;および
この変異したH3 HAを持つ1種類以上のインフルエンザウイルスを単離または作製すること、
を含む方法。
親H5 HA核酸分子において、119位、123位、125位、126位、127位、129位、138位、140位、141位、151位、152位、153位、154位、155位、156位、185位、または189位の残基についての2つ以上のコドンに、この親H5 HA内の免疫ドミナントエピトープの残基ではない残基をコードする変異を導入すること;および
この変異したH5 HAを持つインフルエンザウイルスを単離または作製すること、
を含む方法。
該複数のインフルエンザウイルスのそれぞれが、H3内に、121位、131位、135位、138位、140位、142位、144位、145位、155位、156位、157位、158位、171位、189位、193位、212位、もしくは225位のうちの2つ以上に置換を含むか、または121位、131位、135位、138位、140位、142位、144位、145位、155位、156位、157位、158位、171位、189位、193位、212位、もしくは225位のうちの1つ以上に欠失を含むか、またはこれらの任意の組み合わせを含む、
組成物。
該複数のインフルエンザウイルスのそれぞれが、H5内に、119位、123位、125位、126位、127位、129位、138位、140位、141位、151位、152位、153位、154位、155位、156位、185位、もしくは189位のうちの2つ以上に置換を含むか、または119位、123位、125位、126位、127位、129位、138位、140位、141位、151位、152位、153位、154位、155位、156位、185位、もしくは189位のうちの1つ以上に欠失を含むか、またはこれらの任意の組み合わせを含む、
組成物。
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US11802273B2 (en) | 2014-06-20 | 2023-10-31 | Wisconsin Alumni Research Foundation (Warf) | Mutations that confer genetic stability to additional genes in influenza viruses |
US11807872B2 (en) | 2019-08-27 | 2023-11-07 | Wisconsin Alumni Research Foundation (Warf) | Recombinant influenza viruses with stabilized HA for replication in eggs |
US11851648B2 (en) | 2019-02-08 | 2023-12-26 | Wisconsin Alumni Research Foundation (Warf) | Humanized cell line |
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US9534042B2 (en) | 2010-09-03 | 2017-01-03 | Fujita Health University | Influenza virus-neutralizing antibody and screening method therefor |
US10063211B2 (en) | 2016-02-03 | 2018-08-28 | Qualcomm Incorporated | Compact bypass and decoupling structure for millimeter-wave circuits |
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US11802273B2 (en) | 2014-06-20 | 2023-10-31 | Wisconsin Alumni Research Foundation (Warf) | Mutations that confer genetic stability to additional genes in influenza viruses |
US11851648B2 (en) | 2019-02-08 | 2023-12-26 | Wisconsin Alumni Research Foundation (Warf) | Humanized cell line |
US11807872B2 (en) | 2019-08-27 | 2023-11-07 | Wisconsin Alumni Research Foundation (Warf) | Recombinant influenza viruses with stabilized HA for replication in eggs |
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