JP7388636B2 - 結核の感染リスクがある人に対する予防剤として、又は感染した結核患者を治療するための二次薬として使用する組成物 - Google Patents
結核の感染リスクがある人に対する予防剤として、又は感染した結核患者を治療するための二次薬として使用する組成物 Download PDFInfo
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Description
「MTBVAC株」は、M.ツベルクローシスMT103臨床株のRv0757遺伝子を欠失し、更にRv2930(fadD26)遺伝子の欠失を備えるM.ツベルクローシス株の分離された微生物を指すために使用される。したがって、上記株は、M.ツベルクローシスに由来する2つの独立した変異を提示し、独立したphoP欠失は、上記遺伝子の不活性化に由来するワクチンの特性に影響を及ぼさない。したがって、「MTBVAC株」は、Rv2930(fadD26)遺伝子の欠失によりPDIM産生が不活性化されることを特徴とするため、この株はRv2930遺伝子及びRv0757遺伝子の欠失を備えることを特徴とする。
配列番号1
ATGCCGGTGACCGACCGTTCAGTGCCCTCTTTGCTGCAAGAGAGGGCCGACCAGCAGCCTGACAGCACTGCATATACGTACATCGACTACGGATCCgaccccaagggatttgctgacagcttgacttggtcgcaggtctacagtcgtgcatgcatcattgctgaagaactcaagttatgcgggttacccggagatcgagtggcggttttagcgccacaaggactggaatatgtccttgcattcctgggcgcacttcaggctggatttatcgcggttccgctgtcaactccacagtatggcattcacgatgaccgcgtttctgcggtgttgcaggattccaagccggtagccattctcacgacttcgtccgtggtaggcgatgtaacgaaatacgcagccagccacgacgggcagcctgccccggtcgtagttgaggttgatctgcttgatttggactcgccgcgacagatgccggctttctctcgtcagcacaccggggcggcttatctccaatacacgtccggatcgacgcgtacgccggccggagtcattgtgtcgcacacgaatgtcattgccaatgtgacacaaagtatgtacggctatttcggcgatcccgcaaagattccgaccgggactgtggtgtcgtggctgcctttgtatcacgatatgggcctgattctcggaatttgcgcaccgctggtggcccgacgccgcgcgatgttgatgagcccaatgtcatttttgcgccgtccggcccgctggatgcaactgcttgccaccagcggccggtgcttttctgcggcaccgaatttcgccttcgagctggccgtgcgcagaacatctgaccaggacatggcggggctcgacctgcgcgacgtggtcggcatcgtcagtggcagtgagcgaatccatgtggcaaccgtgcggcggttcatcgagcggttcgcgccgtacaatctcagccccaccgcgatacggccgtcgtacgggctcgcggaagcgaccttatatgtggcagctcccgaagccggcgccgcgcccaagacggtccgttttgactacgagcagctgaccgccgggcaggctcggccctgcggaaccgatgggtcggtcggcaccgaactgatcagctacggctcccccgacccatcgtctgtgcgaatcgtcaacccggagaccatggttgagaatccgcctggagtggtcggtgagatctgggtgcatggcgaccacgtgactatggggtattggcagaagccgaagcagaccgcgcaggtcttcgacgccaagctggtcgatcccgcgccggcagccccggaggggccgtggctgcgcaccggcgacctgggcgtcatttccgatggtgagctgttcatcatgggccgcatcaaagacctgctcatcgtggacgggcgcaaccactaccccgacgacatcgaggcaacgatccaggagatcaccggtggacgggccgcggcgatcgcagtgcccgacgacatcaccgaacaactggtggcgatcatcgaattcaagcgacgcggtagtaccgccgaagaggtcatgctcaagctccgctcggtgaagcgtgaggtcacctccgcGATATCGAAGTCACACAGCCTGCGGGTGGCCGATCTCGTTCTGGTGTCACCTGGTTCGATTCCCATCACCACCAGCGGCAAGATCCGGCGGTCAGCCTGCGTCGAACGCTATCGCAGCGACGGCTTCAAGCGGCTGGACGTAGCCGTATGA
配列番号2
ATGCCGGTGACCGACCGTTCAGTGCCCTCTTTGCTGCAAGAGAGGGCCGACCAGCAGCCTGACAGCACTGCATATACGTACATCGACTACGGATCCACTAGTTCTAGAGCAACCGTCCGAAATATTATAAATTATCGCACACATAAAAACAGTGCTGTTAATGTGTCTATTAAATCGATTTTTTGTTATAACAGACACTGCTTGTCCGATATTTGATTTAGGATACATTTTTATGAGATCCCCCGGGCTGCAGGAATTCGATATCGAAGTCACACAGCCTGCGGGTGGCCGATCTCGTTCTGGTGTCACCTGGTTCGATTCCCATCACCACCAGCGGCAAGATCCGGCGGTCAGCCTGCGTCGAACGCTATCGCAGCGACGGCTTCAAGCGGCTGGACGTAGCCGTATGA
配列番号3
ATGCGGAAAGGGGTTGATCTCGTGACGGCGGGAACCCCAGGCGAAAACACCACACCGGAGGCTCGTGTCCTCGTGGTCGATGATGAGGCCAACATCGTTGAACTGCTGTCGGTGAGCCTCAAGTTCCAGGGCTTTGAAGTCTACACCGCGACCAACGGGGCACAGGCGCTGGATCGGGCCCGGGAAACCCGGCCGGACGCGGTGATCCTCGATGTGATGATGCCCGGGATGGACGGCTTTGGGGTGCTGCGCCGGCTGCGCGCCGACGGCATCGATGCCCCGGCGTTGTTCCTGACGGCCCGTGACTCGCTACAGGACAAGATCGCGGGTCTGACCCTGGGTGGTGACGACTATGTGACAAAGCCCTTCAGTTTGGAGGAGGTCGTGGCCAGGCTGCGGGTCATCCTGCGACGCGCGGGCAAGGGCAACAAGGAACCACGTAATGTTCGACTGACGTTCGCCGATatcgagctcgacgaggagacccacgaagtgtggaaggcgggccaaccggtgtcgctgtcgcccaccgaattcaccctgctgcgctatttcgtGATCAACGCGGGCACCGTGCTGAGCAAGCCTAAGATTCTCGACCACGTTTGGCGCTACGACTTCGGTGGTGATGTCAACGTCGTCGAGTCCTACGTGTCGTATCTGCGCCGCAAGATCGACACTGGGGAGAAGCGGCTGCTGCACACGCTGCGCGGGGTGGGCTACGTACTGCGGGAGCCTCGATGA
配列番号4
ATGCGGAAAGGGGTTGATCTCGTGACGGCGGGAACCCCAGGCGAAAACACCACACCGGAGGCTCGTGTCCTCGTGGTCGATGATGAGGCCAACATCGTTGAACTGCTGTCGGTGAGCCTCAAGTTCCAGGGCTTTGAAGTCTACACCGCGACCAACGGGGCACAGGCGCTGGATCGGGCCCGGGAAACCCGGCCGGACGCGGTGATCCTCGATGTGATGATGCCCGGGATGGACGGCTTTGGGGTGCTGCGCCGGCTGCGCGCCGACGGCATCGATGCCCCGGCGTTGTTCCTGACGGCCCGTGACTCGCTACAGGACAAGATCGCGGGTCTGACCCTGGGTGGTGACGACTATGTGACAAAGCCCTTCAGTTTGGAGGAGGTCGTGGCCAGGCTGCGGGTCATCCTGCGACGCGCGGGCAAGGGCAACAAGGAACCACGTAATGTTCGACTGACGTTCGCCGATATCGAATTCCTGCAGCCCGGGGGATCTCATAAAAATGTATCCTAAATCAAATATCGGACAAGCAGTGTCTGTTATAACAAAAAATCGATTTAATAGACACATTAACAGCACTGTTTTTATGTGTGCGATAATTTATAATATTTCGGACGGTTGCTCTAGAACTAGTGGATCAACGCGGGCACCGTGCTGAGCAAGCCTAAGATTCTCGACCACGTTTGGCGCTACGACTTCGGTGGTGATGTCAACGTCGTCGAGTCCTACGTGTCGTATCTGCGCCGCAAGATCGACACTGGGGAGAAGCGGCTGCTGCACACGCTGCGCGGGGTGGGCTACGTACTGCGGGAGCCTCGATGA
ヒトにおいてTBを予防するためのワクチンの使用は、今でほぼ1世紀の間、大きな課題であることが証明されている。M.ボビス由来のBCGは、現在使用されている唯一の認可されたTBワクチンであり、世界で最も広く使用されているワクチンである。1920年代の初めからBCGワクチンの開発及び一般投与は、世界からTBを根絶することができるという見通しで、大きく発展してきた。しかしながら、これらの初期の見通しは達成されておらず、多数の有効性試験の結果から、現在の形態のBCGワクチンは、特に疾患が流行している第三世界の地域で成人の呼吸器型の疾患の制御への使用は制限されていることが明らかである。Fine, P.E. Variation in protection by BCG: implications of and for heterologous immunity. Lancet 1995, 346(8986), 1339-1345。M.ツベルクローシスの病原性及び防御免疫の生成につながる免疫応答モデルに関するより多くの知識により、BCGよりも良好なワクチンを開発することが可能である。宿主にBCGがワクチン接種される場合に、より高い防御レベルが達成されるという観察は、生存能及び持続性が結核ワクチンの成功に必要な基本特性であることを示唆している。この意味で、米国特許第8287886号では、不活性化されたRv0757(phoP)遺伝子と、PDIM合成を妨げるphoPの第2の独立した変異とを有し、プロトタイプの単回投与の生ワクチン用に提供されるM.ツベルクローシス株の使用が、免疫不全SCIDマウスにおいてBCGよりも弱毒化されており、マウスではBCGによって付与されるものに匹敵する防御レベル、またモルモットではBCGよりも高い防御をもたらすことを教示した。
健康なBCGナイーブのHIVに曝露されていない南アフリカの新生児において、BCGワクチンと比較して、MTBVACの用量レベルを段階的に増大させて安全性及び反応原性を評価する。
健康なBCGナイーブのHIVに曝露されていない南アフリカの新生児において、MTBVACの用量レベルを段階的に増大させて免疫原性を評価する。
段階的に用量レベルを増大させたMTBVACを受ける新生児においてQuantiFERON-TB Gold Plus(QFT)変換率を評価する。
MTBVAC及びBCGのワクチン接種によって誘導される主要組織適合性(MHC)拘束性T細胞応答の差異を評価する。
MTBVAC及びBCGのワクチン接種により誘導されるドナー非拘束性T細胞応答の差異を評価する。
Middlebrook 7H9及び変形(Media for Tubercle Bacilli, Dubos, R.J. and Middlebrook, G. American Review of Tuberculosis and Pulmonary Diseases, 1947 Vol. 56 No.4 pp. 334-45 ref.15)。
Sauton合成培地(Handbook of Microbiological Media, Fourth Edition, Ronald M. Atlas, CRC Press, 2010. Page 1540)及び変形。
前記微生物が、
i)Rv0757遺伝子の遺伝的欠失による不活性化によるPhoP-表現型と、
ii)PDIM産生を妨げる第2の遺伝子Rv2930(fadD26)の欠失(PDIM-表現型)とを有し、好ましくは前記M.ツベルクローシス株がMTBVAC株であり、
前記組成物がフリーズドライ組成物であり、
前記組成物が、安定剤としてスクロース及びグルタミン酸ナトリウムを添加することにより前記微生物を含む培養培地を凍結乾燥させることによって得られ、
前記培養培地がSDG培地である、ワクチン組成物を提供する。より好ましくは、第13の態様では、本発明は、弱毒生M.テューバキュローシスワクチン組成物であって、i)Rv0757遺伝子の遺伝的欠失による不活性化によるPhoP-表現型と、ii)PDIM産生を妨げる第2の遺伝子Rv2930(fadD26)の欠失(PDIM-表現型)とを有するM.ツベルクローシス株に属する分離された微生物を含み、好ましくは前記M.ツベルクローシス株がMTBVAC株であり、前記弱毒生M.ツベルクローシスワクチン組成物が本発明の第12の態様の方法によって得られる又は取得可能である、ワクチン組成物を提供する。
新生仔C3Hマウス(1日齢~3日齢)に、1回の臨床用量を含む25μlのBCG(およそ2.5×105)、又は指定のCFU投与量のMTBVACを用いて皮内にワクチン接種を行った。BCG群の場合、ロット111053F及びロット113033Cに対応する、BCGデンマーク株の市販バイアルを使用した。MTBVACの場合、MTBVAC株を増殖させたSDG培地の凍結乾燥によって生産されるMTBVACワクチンで動物を免疫し、上記凍結乾燥を行うため、グルタミン酸ナトリウム10g/L~40g/L及びスクロース100g/L~400g/Lの濃度のグルタミン酸ナトリウム及びスクロース(GSA)を加えた。凍結乾燥した製剤を再懸濁した。
ワクチン接種から8週間後、マウスに150CFUのM.ツベルクローシス株H37Rvで鼻腔内チャレンジを行った。4週間後、マウスを屠殺し、7H11S固体培地上の組織ホモジネートのプレーティングにより肺における細菌負荷を特定した。結果を図4に示す。
ワクチン接種から8週間後、マウスを屠殺し、免疫原性評価のため脾臓細胞を分離した。100万個の脾臓細胞を、精製タンパク質誘導体(PPD)10μg/ml、オーバーラップするESAT6ペプチド若しくはCFP10ペプチド2μg/ml、又は非抗原(陰性対照)の存在下で24時間インキュベートした。インターフェロンガンマ(IFNγ)産生細胞をELISPOTにより分析した。結果を図5に示す。
MTBVACによって誘発されるPPD、ESAT6又はCFP10に特異的な防御有効性も免疫原性も、新生仔マウスモデルにおいて用量依存性ではないことが示された。
目的:本発明者らは、本発明に記載されるMTBVACワクチンを用いた新生児のワクチン接種後の免疫原性を決定し、誘導免疫応答を特性評価するため探索を行った。
ヘパリン化した新鮮な全血を、BCG、MTBVAC、若しくはフィトヘマグルチニン(PHA)で直ちに刺激するか、又は37℃で12時間刺激せずにおいた(Nil)。刺激条件は、血液量の半分[250μL(0.25ml)]、並びにNilのみ、MTBVAC及びBCGを含む。7時間の刺激の後、上清(可溶性サイトカイン/ケモカイン分析用)を全ての条件から収集し、-BOCで凍結し、更なる分析用にSponsorに送るため保管した。上清除去後、ブレフェルジン(brefeldin)Aを、残りの全血及びチューブに加えて、プログラム可能な水浴で更に5時間インキュベートした。水浴は、合計12時間の刺激の後にスイッチがオフになる。翌朝、赤血球を溶解するため、また白血球を固定するためFACS溶解液を加えた。次いで、固定された白血球を、後の細胞内サイトカイン染色用及びフローサイトメトリー用に凍結した。フローサイトメトリーの染色及び取得は、後の時間点で、バッチで行われる。CD4 T細胞による特異的1型サイトカイン及びIL-17の頻度及びパターンの測定を評価した。免疫原性の時間点は、SATVIにより行われた最近の研究に基づいて選択されており、乳児におけるBCG誘発性T細胞応答のピークは生後6週~10週あたりであることを示している。
Claims (4)
- 使用準備の整ったフリーズドライ弱毒生M.ツベルクローシスワクチン組成物を製造する方法であって、
前記組成物が、
i)Rv0757遺伝子の遺伝的欠失による不活性化によるPhoP-表現型であって、PhoPのオープンリーディングフレーム(ORF)配列が配列番号4からなる表現型と、
ii)PDIM産生を妨げる第2の遺伝子Rv2930(fadD26)の欠失(PDIM-表現型)であって、fadD26のオープンリーディングフレーム(ORF)配列が配列番号2からなる欠失と、
を有する、M.ツベルクローシスMTBVAC株に属する分離された微生物を含み、
前記方法が、MTBVAC株の培養を開始することと、1つ以上の適切な細胞培地を用いて前記細菌を拡大又は増幅することとを含み、
前記方法が、凍結乾燥前の大量培養のため、以下:
前記方法が好気的条件下で行われる、方法。 - 前記方法が、凍結乾燥工程に先立って大量培養に使用されるSDG培地に安定剤としてスクロース及びグルタミン酸ナトリウムを添加することによるフリーズドライ工程を更に含む、請求項1又は2に記載の方法。
- MTBVAC株に属する分離された微生物を含む弱毒生M.ツベルクローシスワクチン組成物であって、
前記微生物が、
i)Rv0757遺伝子の遺伝的欠失による不活性化によるPhoP-表現型と、
ii)PDIM産生を妨げる第2の遺伝子Rv2930(fadD26)の欠失(PDIM-表現型)と、
を有し、
前記組成物がフリーズドライ組成物であり、
前記組成物が、安定剤としてスクロース及びグルタミン酸ナトリウムを添加することにより前記微生物を含む培養培地を凍結乾燥させることによって得られ、
前記培養培地がSDG培地である、ワクチン組成物。
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