JP2021502957A - ワクチン - Google Patents
ワクチン Download PDFInfo
- Publication number
- JP2021502957A JP2021502957A JP2020519095A JP2020519095A JP2021502957A JP 2021502957 A JP2021502957 A JP 2021502957A JP 2020519095 A JP2020519095 A JP 2020519095A JP 2020519095 A JP2020519095 A JP 2020519095A JP 2021502957 A JP2021502957 A JP 2021502957A
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- JP
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- Prior art keywords
- vaccine
- polysaccharide
- fever
- conjugated
- infection
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Abstract
Description
コクシエラ・バーネッティイ細胞の培養及び精製
[0069]血清学的に相IのC.バーネッティイ菌株ナインマイル、RSA 493(Davis及びCox、Public Health Rep.53巻:2259−2276頁、1938年)(本発明者らの実験室において卵黄嚢3継代)を6〜7日齢の発育鶏卵中で増殖させた。接種に関しては、リン酸緩衝生理食塩水(PBS)中のC.バーネッティイ感染した卵黄嚢(40%)の懸濁原液を使用した。接種物は、Laboratory for Diagnosis and Prevention of Rickettsial and Chlamydial Infections、Institute of Virology、Slovak Academy of Sciences、Bratislava、Slovakiaからのものである。ふ化卵を、感染懸濁原液(各0.25ml)で希釈して接種すると、接種してから7〜8日後に胚の死滅が最も多く生じた。接種された卵を、35.5℃及び50〜90%の相対湿度でインキュベートした。3日目から、インキュベートを、ovoscopeを用いて1日2回モニターし、顕微鏡下、ヒメネス染色されたスメアによって卵黄嚢を評価した。最初の72時間以内に死滅した胚を有する卵黄嚢を廃棄した。翌日、死滅した胚を卵黄嚢から分離し、胚を収集し、−20℃で貯蔵した。残りの胚の40〜60%が死滅した日に、培養を終了した。C.バーネッティイに感染した全ての卵黄嚢から胚を採取し、収集し、−20℃で貯蔵した。
C.バーネッティイリポ多糖の単離及び解毒
[0071]C.バーネッティイ細胞(1.5g)を50mMトリス−HCl緩衝液(150ml、pH7.5)中に懸濁し、両方ともウシ膵臓(Boehringer)から得たRNA分解酵素(EC3.1.27.5)及びDNase(EC3.1.27.1)を用いて、37℃で16時間、同時に治療した。次いで細胞をトリプシン1:250(EC232−650−8;Sigma)を用いて37℃で90分間、続いてTritirachium album(EC3.4.21.14;Sigma)から得たプロテイナーゼKによって、37℃で16時間、治療した。酵素治療後、細胞懸濁液を14,000×g、10℃で50分間遠心分離し、沈殿物をアセトンで洗浄した。細胞をクロロホルム−メタノール(2:1、v/v)を用いて20℃で3時間抽出し、リン脂質を除去した。抽出を、新鮮な溶媒混合物を用いて2時間繰り返した。細胞懸濁液を3,000×g、20℃で20分間遠心分離し、沈殿物を予熱した蒸留水(150ml、68℃)中に懸濁し、等体積の90%フェノール水溶液で前述のように抽出した(Westphal and Jann、1965年)。リポ多糖(LPS)を、大規模の透析(分子量カットオフ3,500、Serva)後に水性相から得、凍結乾燥した。粗製LPSの収量は、もとの細胞の重量に対して計算し、144mg(9.6%)であった。LPSを、RNA分解酵素、DNase、及びプロテイナーゼK(上記を参照のこと)で治療し、透析し、凍結乾燥することによって更に精製した。
脱脂O−特異的多糖の担体タンパク質へのコンジュゲート
[0074]毒性リピドA構成成分を除去することによる、そのリポ多糖(LPS)由来の解毒(脱脂)Q熱O−特異的多糖(dOSP)を、担体タンパク質としての破傷風トキソイドにコンジュゲートした。担体タンパク質の第1の目的は、動物に注射した場合にdOSPの免疫原性を改善し、T細胞依存性免疫応答を誘導することである。
C.バーネッティイワクチンのモルモットへの投与
[0077]モルモットに、多糖−担体タンパク質(dOSP−TT)コンジュゲートワクチン又は多糖(dOSP)単独ワクチンのいずれかを1相C.バーネッティイナインマイル菌株に感染させる前にワクチン接種した。C.バーネッティイに感染したモルモットは急性ヒト感染症を最も詳細に模倣するので、モルモットはQ熱研究のために選択される実験用小動物である。感染後、モルモットは数日間発熱し、次いで自然回復し、大部分のヒト感染症の進行を反映する。対照的に、実験室マウスの大部分の系統は、C.バーネッティイに感染した場合、感染症のいずれの症状も示さない。更に、いくつかのモルモットは、症状が消失するにもかかわらず感染症は完全に治癒せず、免疫抑制された場合、後日再発性感染症が再発する場合がある。これは、ヒトにおける慢性Q熱に類似しており、ヒトの場合、急性Q熱から明らかに回復した後に再発し、慢性Q熱を発症する。
1群 陽性対照;ワクチンなし;C.バーネッティイ感染;n=8
2群 陰性対照;ワクチンなし;未感染;n=4
3群 C.バーネッティイに感染する前にdOSP−TTコンジュゲートワクチン(単回用量)をワクチン接種した;n=8
4群 C.バーネッティイに感染する前にdOSP−TTコンジュゲートワクチン(×2用量)をワクチン接種した;n=8
5群 C.バーネッティイに感染する前にdOSP単独ワクチン(単回用量)をワクチン接種した;n=6
6群 C.バーネッティイに感染する前にdOSP単独ワクチン(×2用量)をワクチン接種した;n=6
Brade et al., Eur J Biochem, 131:195-200,1983
Hartree, Anal Biochem, 48:422-427, 1972
Konadu et al., Infect Immun, 64:2709-2715,1996
Lowry et al., J Biol Chem, 207:1-17, 1954
Swann and Balazs, Biochim Biophys Acta,130:112-129, 1966
Toman et al., Carbohyd Res, 306:291-296,1998
Westphal and Jann, Meth Carbohydr Chem,5:83-91, 1965
Claims (20)
- コクシエラ・バーネッティイ感染症に対する防御のためのワクチンであって、C.バーネッティイの細胞壁リポ多糖由来の脱脂C.バーネッティイ多糖を含むワクチン。
- C.バーネッティイ感染症と関連する発熱に対して対象を防御する、請求項1に記載のワクチン。
- Q熱の少なくとも1つの症状を治療するか又は予防するためのワクチンであって、C.バーネッティイの細胞壁リポ多糖由来の脱脂C.バーネッティイ多糖を含むワクチン。
- 前記少なくとも1つの症状が発熱である、請求項3に記載のワクチン。
- 脱脂多糖が、1相細胞壁リポ多糖のリピドA構成成分を除去することによって得られるO−特異的多糖である、請求項1〜4のいずれか一項に記載のワクチン。
- 前記脱脂多糖が誘導体化されている、請求項1〜5のいずれか一項に記載のワクチン。
- 前記脱脂多糖が、免疫原性担体にコンジュゲートしている、請求項1〜6のいずれか一項に記載のワクチン。
- 前記担体がタンパク質又はポリペプチドである、請求項7に記載のワクチン。
- 前記担体が破傷風トキソイドである、請求項8に記載のワクチン。
- 前記脱脂多糖が、架橋剤を使用して前記担体にコンジュゲートしている、請求項7〜9のいずれか一項に記載のワクチン。
- コクシエラ・バーネッティイ感染症に対する防御のためのコンジュゲートワクチンであって、免疫原性担体に連結した、C.バーネッティイの細胞壁リポ多糖由来の脱脂C.バーネッティイ多糖を含む、コンジュゲートワクチン。
- C.バーネッティイ感染症と関連する発熱に対して対象を防御する、請求項11に記載のコンジュゲートワクチン。
- Q熱の少なくとも1つの症状を治療するか又は予防するためのコンジュゲートワクチンであって、免疫原性担体に連結した、C.バーネッティイの細胞壁リポ多糖由来の脱脂C.バーネッティイ多糖を含む、コンジュゲートワクチン。
- 前記少なくとも1つの症状が発熱である、請求項13に記載のコンジュゲートワクチン。
- 前記脱脂多糖が、架橋剤を使用して前記担体にコンジュゲートしている、請求項11〜14のいずれか一項に記載のコンジュゲートワクチン。
- 前記担体が、タンパク質又はポリペプチドであり、任意選択で破傷風トキソイドである、請求項11〜15のいずれか一項に記載のコンジュゲートワクチン。
- 前記脱脂多糖が、1相細胞壁リポ多糖のリピドA構成成分を除去することによって得られるO−特異的多糖である、請求項11〜16のいずれか一項に記載のコンジュゲートワクチン。
- コクシエラ・バーネッティイ感染症に対する防御のための、及び/又はQ熱の少なくとも1つの症状を治療するか又は予防するための非毒性ワクチンを調製するための方法であって、C.バーネッティイの細胞壁リポ多糖由来の脱脂多糖を免疫原性担体に連結することを含む方法。
- コクシエラ・バーネッティイ感染症に対して対象を防御するための方法であって、免疫防御量の請求項1〜17のいずれか一項に記載のワクチンを前記対象に投与することを含む方法。
- 必要とする対象においてQ熱の少なくとも1つの症状を治療するか又は予防するための方法であって、免疫防御量の請求項1〜17のいずれか一項に記載のワクチンを前記対象に投与することを含む方法。
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PALKOVICOVA, K. ET AL.: "A monoclonal antibody specific for a unique biomarker, virenose, in a lipopolysaccharide of Coxiella", CLINICAL MICROBIOLOGY AND INFECTION, vol. Vol.15, Suppl. 2, JPN6022032556, 2009, pages 183 - 184, ISSN: 0004977525 * |
SLABA, K. ET AL.: "Studies on the immunological role of virenose and dihydrohydroxystreptose present in the Coxiella bu", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, vol. 990, JPN6022032559, 2003, pages 505 - 509, XP055608676, ISSN: 0004977524, DOI: 10.1111/j.1749-6632.2003.tb07419.x * |
VADOVIC, P. ET AL.: "Structural and functional characterization of the glycan antigens involved in immunobiology of Q fev", ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, vol. 1063, JPN6022032561, 2005, pages 149 - 153, XP055608659, ISSN: 0004977523, DOI: 10.1196/annals.1355.023 * |
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