JP2022517322A - 組み換え単純ヘルペスウイルス2(hsv-2)ワクチンベクターを使用する免疫の受動伝達 - Google Patents
組み換え単純ヘルペスウイルス2(hsv-2)ワクチンベクターを使用する免疫の受動伝達 Download PDFInfo
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Abstract
Description
本PCT国際出願は、2019年1月3日出願の米国出願番号16/238,933に基づく優先権を主張しており、同出願は、2018年6月1日出願の米国出願番号15/995,471の一部継続出願であり、後者は、2016年2月4日出願の米国特許出願番号15/015,322であって、2018年6月19日登録の米国特許9,999,665の継続出願であり、同出願は、2015年3月2日出願のPCT国際出願PCT/US2015/018272の一部継続出願であり、後者は、2014年3月3日出願の米国仮出願番号61/946,965および2014年11月17日出願の米国仮出願番号62/080,663に基づく利益を主張しており、これらすべての出願の内容を、引用により本明細書に包含させる。
本発明は、アメリカ国立衛生研究所(NIH)により認定された認可番号AI061679、AI51519、AI097548、AI026170およびAI065309に基づく政府支援を受けてなされた。政府は本発明に一定の権利を有する。
本明細書をとおして、種々の刊行物が、角括弧内の番号によるものを含めて引用されている。これらの文献の完全な引用は、本明細書の最後にまとめられている。これら刊行物ならびにここに引用する全ての特許、特許出願公報および書籍の開示は、本発明が関与する技術をより完全に記載するために、全体として引用により本明細書に包含させる。
第一の対象においてHSV-2および/またはHSV-1感染に対する免疫応答を誘導する方法であって、ゲノムにHSV-2糖タンパク質Dコード遺伝子全体の欠失を有するHSV-2で免疫化した妊婦からの産物の一定量を第一の対象に受動伝達させることを含み、ここで、該HSV-2は、単純ヘルペスウイルス-1(HSV-1)糖タンパク質Dを発現する補完的細胞における該HSV-2の増殖により該HSV-1糖タンパク質Dで表現型的に補完され、ここで、該産物はそれにより誘導された抗体を含み、第一の対象におけるHSV-2および/またはHSV-1感染に対する免疫応答の誘導に有効であり、ここで、該第一の対象は胎児または新生児である、方法が提供される。
ゲノムにHSV-2糖タンパク質Dコード遺伝子の欠失を有する、単離された、組み換えHSV-2のビリオンもまた提供される。
第一の対象においてHSV-2および/またはHSV-1感染に対する免疫応答を誘導する方法であって、ゲノムにHSV-2糖タンパク質Dコード遺伝子全体の欠失を有するHSV-2で免疫化した妊婦からの産物の一定量を第一の対象に受動伝達させることを含み、ここで、該HSV-2は、単純ヘルペスウイルス-1(HSV-1)糖タンパク質Dを発現する補完的細胞における該HSV-2の増殖により該HSV-1糖タンパク質Dで表現型的に補完され、ここで、該産物はそれにより誘導された抗体を含み、第一の対象におけるHSV-2および/またはHSV-1感染に対する免疫応答の誘導に有効であり、ここで、該第一の対象は胎児または新生児である、方法が提供される。
MGRLTSGVGTAALLVVAVGLRVVCAKYALADPSLKMADPNRFRGKNLPVLDQLTDPPGVKRVYHIQPSLEDPFQPPSIPITVYYAVLERACRSVLLHAPSEAPQIVRGASDEARKHTYNLTIAWYRMGDNCAIPITVMEYTECPYNKSLGVCPIRTQPRWSYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLVKINDWTEITQFILEHRARASCKYALPLRIPPAACLTSKAYQQGVTVDSIGMLPRFIPENQRTVALYSLKIAGWHGPKPPYTSTLLPPELSDTTNATQPELVPEDPEDSALLEDPAGTVSSQIPPNWHIPSIQDVAPHHAPAAPSNPGLIIGALAGSTLAVLVIGGIAFWVRRRAQMAPKRLRLPHIRDDDAPPSHQPLFY(HSV-2対照株HG52)
MGGAAARLGAVILFVVIVGLHGVRGKYALADASLKMADPNRFRGKDLPVLDQLTDPPGVRRVYHIQAGLPDPFQPPSLPITVYYAVLERACRSVLLNAPSEAPQIVRGASEDVRKQPYNLTIAWFRMGGNCAIPITVMEYTECSYNKSLGACPIRTQPRWNYYDSFSAVSEDNLGFLMHAPAFETAGTYLRLVKINDWTEITQFILEHRAKGSCKYALPLRIPPSACLSPQAYQQGVTVDSIGMLPRFIPENQRTVAVYSLKIAGWHGPKAPYTSTLLPPELSETPNATQPELAPEDPEDSALLEDPVGTVAPQIPPNWHIPSIQDAATPYHPPATPNNMGLIAGAVGGSLLAALVICGIVYWMRRRTQKAPKRIRLPHIREDDQPSSHQPLFY(HSV-1対照株F)
実施例1
ここで、HSV-2のgD(US6)遺伝子の遺伝子操作した欠失変異体およびマウス感染モデルにおける腟内HSV-2曝露に対して評価したその安全性、免疫原性およびワクチン有効性を開示する。gD遺伝子を緑色蛍光タンパク質(gfp)をコードするDNAフラグメントで置き換え、HSV-1 gDを発現するVero細胞(VD60細胞)をこの構築物でトランスフェクトし、緑色プラークを形成する相同組み換えウイルスについてスクリーニングした。分子分析は、補完的VD60細胞において高力価まで複製するが、非補完的細胞で増殖させたとき、非感染性である、正確な組み換え体が構築されていることを確認した。野生型またはSCIDマウスの補完gD-ヌルウイルス(遺伝子型でgD欠失しているが、VD60細胞での増殖により表現型的に補完されているウイルスについて、ここで、HSV-2 ΔgD-/+と命名する)への107pfu/マウスでの腟内曝露により病原性がないことが確認され、一方、親野生型ウイルスは、104pfu/マウスの低用量でも100%致死性であった。さらにHSV-2 ΔgD-/+でのマウスの免疫化は、HSV-2の臨床単離株への腟内曝露に対する完全保護をもたらした。HSV-2 ΔgD-/+により誘導されたロバストな液性および細胞性免疫が測定され、gDがインビボでの増殖性感染に必要であり、この必須糖タンパク質を欠く弱毒化株は、HSV-2に対する保護免疫を誘導すると結論付けられる。故に、HSV-2 ΔgD-/+は、性器ヘルペスの予防または処置のための有望なワクチンである。
世界保健機関は、世界で5億を超える人々が単純ヘルペスウイルス2型(HSV-2)に感染し、年間約2000万の新規症例があると推定した[1]。感染リスクは年齢と共に増加し、ウイルスが頻繁な無症候性または臨床的再活性化を伴う潜伏感染を確立するため、感染の影響は一生である。注意が必要なことには、HSV-2はHIVを獲得および伝播するリスクを有意に増加させる[2-4]。HSV-2の有病率は世界の地域間で変わり、日本の8.4%から、HIV有病率が卓越しているサブサハラアフリカで70%まで変わる[5, 6]。米国で、HSV-2の有病率は約16%であり、HSV-1は約54%に減少している。米国(および他の欧州各国)におけるHSV-1の有病率の減少は、性器ヘルペス疾患の大部分の症例がHSV-1が原因であったとの糖タンパク質D(gD)サブユニットワクチン治験の最近の残念な結果により証明されるとおり、性器HSV-1の増加と関連する[7-9]。HSV-1は、HSV-2と比較して再発が少なく、生殖器ウイルス排出が少ないが、両血清型は周産期に伝達され、新生児疾患を引き起こす;新生児疾患は、アシクロビル処置をしても、高い罹病率および死亡率と関連する[10-12]。性器ヘルペスに関連する罹病率、HIV流行との相乗性および米国単独で5億ドルを超える直接医療費は、安全かつ有効なワクチンの開発が急務であることを強調する[13]。
ワクチンが臨床的HSV-1およびHSV-2単離株に対して保護する能力を、感染部位の局所免疫応答としてさらに確認した。古典的に、HSVは、ヒトにおける皮膚または皮膚粘膜層の裂け目のため、主として性器または口腔有核上皮細胞に感染するとされている(75)。ヒトHSV感染をより密接にモデル化するために、ヒトに類似するウイルス動態および病理組織を模倣する皮膚乱刺モデルを、これら試験に使用した(76)。
低用量のΔgD-2での免疫化は、致死的腟内および皮膚曝露に対して保護的である。先の試験は、ワクチン接種材料として、5×106PFU(補完的VD60細胞で決定された力価)のΔgD-2を用いて実施された。用量漸減試験を実施して、低用量のワクチン接種での保護を検討した。C57BL/6マウス(5マウス/群)に、5×106PFU、5×105PFUまたは5×104PFUのΔgD-2を皮下(sc)初回刺激し、21日後ブーストした。3週間後、マウスを、先に記載された臨床単離株のHSV-2(4674)のLD90(5×105PFU)に、腟内または皮膚乱刺により曝露させた(77)。全HSV-2 ΔgD-2免疫化マウスは生存し(5/5/群)、一方対照ワクチン接種マウス(VD60細胞ライセートで免疫化)は全て疾患に屈した(図8A、8B)。最低用量(5×104)をワクチン接種したマウスは軽度上皮疾患を示したが、神経疾患の徴候は観察されず、膣および皮膚曝露モデル両者で、全ての動物は14日目までに完全に回復した。HSV抗体(ELISAにより測定)は、ブースト1週間後、全ワクチン接種マウスの血清で検出されたが、初回刺激後はされず、抗体力価は、投与するワクチン用量が高いほど、増加した(図8C)。
注:*Balb/Cマウス皮膚曝露モデルで90%罹病率を引き起こすプラーク形成単位
この試験は、HSV-2 ΔgD-2でのワクチン接種が一団の遺伝的に多様なHSV-1およびHSV-2臨床単離株に対する完全保護を提供し、潜伏感染の確立を防止することをさらに確認する。ワクチン有効性は、ヒト一次疾患を反映する最適化皮膚モデルで確認された。ΔgD-2は高力価抗体を誘導し、これは迅速に皮膚に動員され、最も病原性の株であるSD90のLD90の100倍暴露後でさえ、5日目までのウイルスのクリアランスをもたらした。広範囲のHSV-1およびHSV-2臨床単離株に対するΔgD-2の保護効果により、臨床単離株D90に対する十分な保護に失敗したHSV-2 ΔUL5/ΔUL29などの他の候補ワクチンまたはgDサブユニットワクチンおよび1種または2種の実験室ウイルス株に対してしか試験されていないその他のものと区別される。
細胞およびウイルス:Vero(アフリカミドリザル腎臓細胞株;CCL-81;American Type Culture Collection (ATCC), Manassas, VA, USA)細胞、VD60細胞[内因性プロモーター下にgD-1をコードするVero細胞(85)]およびCaSki(ヒト子宮頸部上皮性細胞株;CRL-1550;ATCC)を、10%ウシ胎児血清(FBS、Gemini Bio-Products, West Sacramento, CA)添加DMEMで継代させた。THP-1(ヒト単球細胞株;TIB-202;ATCC)細胞を、10%FBS添加RPMI-1640(Life Technologies)で継代し、ATCCガイドラインに従い継代培養した。HSV-2(G)ΔgD-2の構築およびVD60細胞でのその増殖は、先に記載されている(95, 94)。5種の異なるウイルス調製物を比較して、ワクチン有効性の変動は観察されていない。HSV-2(4674)(86)をCaSki細胞で増殖させた。実験室株HSV-2(G)(87)、HSV-2(333-ZAG)(86)、HSV-1(17)(89)およびHSV-1(F)(87)をVero細胞で増殖させた。南アフリカ単離株HSV-2(SD90)(97)は、David Knipeにより恵与され、Vero細胞で増殖させた。非特定化した5種のHSV-1(B3x1.1~B3x1.5)および5種のHSV-2(B3x2.1~B3x2.5)臨床単離株はClinical Virology Lab at Montefioreにより提供され、低継代作業ストックのためにVero細胞で3回継代した。
新生児HSV感染は、世界中で、約14,000症例/年である。一次母体性器HSVが新生児症例の50~80%を占める。周産期伝播は、有効な治療があっても、深刻な死亡および罹病をもたらす。再発性母体HSV疾患では周産期HSV伝播のリスクが1~3%減少するため、母体に既に存在する抗体がある程度の保護を提供できることは明らかである。しかしながら、HSV1/2両者に血清陰性である妊婦が増えている。
ΔgD-2をワクチン接種した母体は、HSV-1またはHSV-2曝露から7~14日齢仔を保護する:母体ワクチン接種が出生後仔をHSVから保護できるかを決定するために、成熟雌性マウスに、2用量のΔgD-2、rgD-2/Alum-MPLまたは対照として、非感染VD60細胞ライセートを、交尾前にワクチン接種し、仔を、ほぼLD90用量で、HSV-1またはHSV-2の臨床単離株に鼻腔内曝露させた。仔は、正期産ヒト乳児と免疫学的に対応する、生後7日目に最初に曝露された。致死的HSV-1およびHSV-2疾患に対する有意な保護が、対照ワクチン接種した母体から生まれた仔と比較して、ΔgD-2免疫化母体から生まれた仔で観察された(p<0.001)(図15A)。対照的に、母体rgD-2/Alum-MPLは、7日齢仔において、HSV-1(1/5(20%)生存)またはHSV-2(3/18(16.7%生存)に対してほとんど保護を提供しなかった。仔が、生後14日目に曝露されたとき保護は持続したが(図15B、p<0.001)、仔が生後1日目に曝露されたとき、減少した(HSV-1でHSV-2よりも減少)(図15C)。
世界的に、HSVは、100,000名の新生児あたり10名に感染すると推定され、大部分の症例は、母体HSV-2の高発生率を暗影するアフリカで生じる。しかしながら、全体的有病率が最高であるのは、生殖可能年齢に達するHSV-1およびHSV-2血清陰性、故に、いずれかの血清型での一次性器感染を獲得するリスクがより大きい、女性の数が増えているアメリカであり得る。頻繁な再発の病歴のある女性の抑制的アシクロビル処置および/または出産時に活動性損傷が検出されるときの帝王切開は、HSVのリスクを減少し得るが、大部分の周産期伝播は、一次母体HSVの状況でかつ臨床的病変非存在下で生じる。故に、最適予防には、HSV-1およびHSV-2両者の臨床単離株に対し有効であり、胎盤を効率的に通過するIgG応答を産生するワクチンが必要とされる。
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Claims (25)
- 第一の対象においてHSV-2および/またはHSV-1感染に対する免疫応答を誘導する方法であって、ゲノムにHSV-2糖タンパク質Dコード遺伝子全体の欠失を有するHSV-2で免疫化した妊婦からの産物の一定量を第一の対象に受動伝達させることを含み、ここで、該HSV-2は、単純ヘルペスウイルス-1(HSV-1)糖タンパク質Dを発現する補完的細胞における該HSV-2の増殖により該HSV-1糖タンパク質Dで表現型的に補完され、ここで、該産物はそれにより誘導された抗体を含み、第一の対象におけるHSV-2および/またはHSV-1感染に対する免疫応答の誘導に有効であり、ここで、該第一の対象は胎児または新生児である、方法。
- 該産物が該妊婦の血清を含む、請求項1の方法。
- 該産物が該妊婦の母乳を含む、請求項1または請求項2の方法。
- 該第一の対象が胎児である、請求項1~3の何れかの方法。
- 該第一の対象が新生児である、請求項1~4の何れかの方法。
- (原文に記載なし)
- 該第一の対象が第二の対象から生まれる、請求項5の方法。
- 該妊婦が該胎児を妊娠している、請求項4の方法。
- 該第一の対象および妊婦がヒトである、請求項1~8の何れかの方法。
- 該産物が、妊婦を欠失を有するHSV-2で免疫化することにより誘導した抗体を含む、請求項1~9の何れかの方法。
- 該方法が、第一の対象におけるHSV-2に対する免疫応答を誘導する、請求項1~10の何れかの方法。
- 該方法が、第一の対象におけるHSV-1に対する免疫応答を誘導する、請求項1~11の何れかの方法。
- 該産物が、免疫アジュバントをさらに含む、請求項1~12の何れかの方法。
- 該産物が、ゲノムにHSV-2糖タンパク質Dコード遺伝子全体の欠失を有するHSV-2をさらに含み、ここで、該HSV-2が、単純ヘルペスウイルス-1(HSV-1)糖タンパク質Dを発現する補完的細胞における該HSV-2の増殖により該HSV-1糖タンパク質Dが表現型的に補完されている、請求項13の方法。
- 新生児における周産期HSV-1および/またはHSV-2感染を阻止する方法であって、該新生児になる胎児を妊娠している女性にゲノムにHSV-2糖タンパク質Dコード遺伝子全体の欠失を有するHSV-2の一定量を投与することを含み、ここで、該HSV-2が、単純ヘルペスウイルス-1(HSV-1)糖タンパク質Dを発現する補完的細胞における該HSV-2の増殖により該HSV-1糖タンパク質Dで表現型的に補完され、新生児における周産期HSV-1および/またはHSV-2感染の阻止に有効である、方法。
- 母体から新生児へのHSV-1および/またはHSV-2ウイルス伝播を阻止する方法であって、母体にゲノムにHSV-2糖タンパク質Dコード遺伝子全体の欠失を有するHSV-2の一定量を投与することを含み、ここで、該HSV-2が、単純ヘルペスウイルス-1(HSV-1)糖タンパク質Dを発現する補完的細胞における該HSV-2の増殖により該HSV-1糖タンパク質Dで表現型的に補完され、母体から新生児へのHSV-1および/またはHSV-2ウイルス伝播の阻止に有効である、方法。
- 該母親が、該新生児になる胎児を妊娠している、請求項16の方法。
- 該HSV-1感染またはHSV-1ウイルス伝播が阻止される、請求項15または請求項16の方法。
- 該HSV-2感染またはHSV-2ウイルス伝播が阻止される、請求項15または請求項16の方法。
- 免疫応答がHSV-1に対して誘導される、請求項1の方法。
- 免疫応答がHSV-2に対して誘導される、請求項1の方法。
- 該補完的細胞がVD60細胞である、請求項1、請求項15または請求項16の方法。
- 該妊婦、母親または第二の対象がHSV-1について血清陰性、HSV-2について血清陰性またはHSV-1およびHSV-2両者について血清陰性である、請求項1~22の何れかの方法。
- 該妊婦または母親が、ゲノムにHSV-2糖タンパク質Dコード遺伝子全体の欠失を有するHSV-2を皮下投与される、請求項1~23の何れかの方法。
- 該妊婦または母親が、HSV-2糖タンパク質Dコード遺伝子全体の欠失を有するHSV-2の初期皮下投与後、皮下ブースト用量のゲノムにHSV-2糖タンパク質Dコード遺伝子全体の欠失を有するHSV-2を投与される、請求項24の方法。
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