JP5257939B2 - 豚丹毒・豚マイコプラズマ肺炎経口投与型多価ワクチン - Google Patents
豚丹毒・豚マイコプラズマ肺炎経口投与型多価ワクチン Download PDFInfo
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- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/36—Adaptation or attenuation of cells
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- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/0241—Mollicutes, e.g. Mycoplasma, Erysipelothrix
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- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/30—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Mycoplasmatales, e.g. Pleuropneumonia-like organisms [PPLO]
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- A61K2039/52—Bacterial cells; Fungal cells; Protozoal cells
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Description
通常、グラム陽性菌の形質転換には、大腸菌とその菌とで複製が可能なシャトルプラスミドにクローニング後、その目的の菌株に導入して形質転換を行う。しかしながら、形質転換法が確立されていない豚丹毒菌を遺伝学的に改変することは極めて困難である。
宿主になる豚丹毒菌には我が国で長年注射用の生ワクチン株として実績のある豚丹毒菌小金井株の経口投与によるワクチン効果を確認し、これを経口投与型マ イコプラズマワクチンのベクターとしての弱毒豚丹毒菌として選択した。本菌に前述した相同組換えによりマイコプラズマ・ハイオニューモニエのP97アドへ ジン遺伝子の一部を導入し、マイコプラズマ・ハイオニューモニエP97アドへジンの一部を発現する豚丹毒小金井株を作出した。本株のワクチン効果を豚における感染及び発症防御試験で確認したところ、強毒豚丹毒菌、強毒マイコプラズマ・ハイオニューモニエに対し良好なワクチン効果を認めた。
SpaA.1の両端をクローニングした方法:<BR> SpaA.1は免疫原性が強い。そのため、豚丹毒菌の遺伝子ライブラリーの中から豚丹毒感染耐過豚の血清と反応するファージクローンを選択し、さらに、それらの中からspaA.1遺伝子及び、spaA.1遺伝子の上下流領域を含むファージミドクローンpER3を選択した。これはpBK-CMVベク ター(Stratagene)に約4300bpのインサートが挿入されたクローンである。この遺伝子の中央にあるEcoRIサイト断片と、EcoRIサイ トが付加するようにPCRで増幅したマイコプラズマP97蛋白遺伝子の断片とを置換する予定であったが、ベクターのマルチクローニングサイト(MCS)の 3'側にEcoRI切断サイトがあるため、その操作ができないことが分った。そこで、ベクター側のEcoRI、及びHindIII切断サイトを含む AAGAATTCAAAAAGCTTの配列を除去する形で変異を入れ、そのプラスミドにEcoRIサイトが付加するようにPCRで増幅したマイコプラズマ P97蛋白遺伝子の断片を挿入した。全体のシークエンスは図1及び図2に示した。
上記の配列を持つインサートを、グラム陽性菌と大腸菌とのシャトルベクターであるpGA14を以下に示す制限酵素サイトで切断し、spaA.1遺伝子に挟 まれた形のp97遺伝子を挿入した。これをエレクトロポーレーションにより豚丹毒菌に導入し、spaA.1遺伝子上下流領域が、導入した遺伝子とダブルク ロスオーバーにより置き換わった株を選択した。
構造を図3に示す。
得られた形質転換体の菌体表面へのマイコプラズマ抗原の発現を確認する目的で、培養菌体をナイロンメンブランにドットブロットし、抗SpaA抗体と抗 P97抗体を感作し、陽性を示したクローンを選択した。その結果、約90クローンの形質転換体より4個の陽性クローンErMh-KoA、B、C及びDを選択した。
ErMhKo-A、B、C及びDそれぞれの培養菌液(108CFU/ml)を0.1ml宛て4週齢ddyマウスの内股部皮下に接種し、マウスの生死と関節炎の有無を観察した。豚丹毒菌強毒株のマウスのLD100は103であり、毒性が復帰すればマウスが死亡する。毒性が復帰せず、免疫原性を保持しているクローンの指標として、マウス関節炎の発症率を採用した。
1)豚マイコプラズマ肺炎に対する効果
約10日齢のSPF豚11頭をワクチン群6頭、対照群5頭の2群にわけ、ワクチン群にはErMhKo-D株を対照群には豚丹毒菌小金井株をそれぞれ1頭当たり1010個、 抗生物質不含の代用乳と混合し、5日間投与した。最終投与より2週後、マイコプラズマ・ハイオニューモニエ培養液と感染肺乳剤の混合液を鼻腔内に3日間連 続で投与した。投与より4週後剖検し、肺病変形成率を比較した。その結果、攻撃後の飼育期間中、両群において発咳、くしゃみ等の呼吸器症状や発熱は認めな かった。しかし、剖検時に両群の肺病変を比較すると、表2に示すように、ワクチン群の肺病変形成率は対照群と比較して有意に低く、ErMh-D株を経口投 与された豚はマイコプラズマ・ハイオニューモニエ強毒株の攻撃に対し、良好な肺病変形成抑制効果を示すことが確認された。
約10日齢のSPF豚11頭をワクチン群5頭、対照群2頭の2群にわけ、ワクチン群にはErMhKo-D株を対照群には豚丹毒菌小金井株をそれぞれ1頭当たり1010個、抗生物質不含の代用乳と混合し、5日間投与した。最終投与より2週後、強毒藤沢株5.0×104を 皮内投与した。攻撃後、臨床症状及び菱形疹の発現の状態を観察した。表3に示すように、対照群は攻撃翌日より元気消失し、体温の上昇を認めた。また、菱形 疹は全身に転移し、豚No.26は6日目に死亡、豚No.27は6日目に横臥し、回復傾向を認めなかったため、安楽死させた。一方、ワクチン群は発熱、元 気消失などの臨床症状を認めず、菱形疹も接種部位のみで転移せず、良好なワクチン効果を認めた。
EnMhKo−D FERM−BP−11170
1235460550531_3.htm
Claims (7)
- 経口投与でワクチン効果を付与できる能力をもつ弱毒豚丹毒菌である豚丹毒菌小金井株の菌体表面にマイコプラズマ・ハイオニューモニエのP97アドヘジン蛋白の一部を発現させた豚丹毒菌。
- 二重交差により宿主DNAに外来遺伝子が挿入された請求項1記載の豚丹毒菌。
- 請求項1または2記載の菌株を用いたワクチン。
- 生きた菌体を用いる請求項3に記載のワクチン。
- 安定剤及び/又はアジュバントを含む請求項3または4に記載のワクチン。
- 請求項3〜5のいずれかに記載のワクチンを豚に経口投与し、豚において免疫を誘導する方法。
- 請求項3〜5のいずれかに記載のワクチンを飲水もしくは飼料に混ぜて投与し、豚を免疫化する方法。
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WO2020130224A1 (ko) * | 2018-12-19 | 2020-06-25 | 주식회사 이노백 | 마이코플라즈마 폐렴 및 흉막폐렴 예방용 백신 조성물 |
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CN108623663B (zh) * | 2018-05-14 | 2021-09-21 | 中国农业科学院哈尔滨兽医研究所(中国动物卫生与流行病学中心哈尔滨分中心) | 猪肺炎支原体p97蛋白的免疫原性功能多肽及其编码基因和应用 |
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JP2992980B2 (ja) * | 1997-11-19 | 1999-12-20 | 農林水産省家畜衛生試験場長 | 豚丹毒菌の莢膜欠損変異株 ys−1株 |
MY128159A (en) * | 2000-06-30 | 2007-01-31 | Wyeth Corp | Methods and composition for oral vaccination |
JP3793889B2 (ja) * | 2000-10-13 | 2006-07-05 | 独立行政法人農業・食品産業技術総合研究機構 | マイコプラズマ・ハイオニューモニエ抗原を発現する豚丹毒菌および該菌による免疫化方法 |
JP2006311824A (ja) * | 2005-05-09 | 2006-11-16 | National Agriculture & Food Research Organization | 豚マイコプラズマ肺炎ワクチン |
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WO2020130224A1 (ko) * | 2018-12-19 | 2020-06-25 | 주식회사 이노백 | 마이코플라즈마 폐렴 및 흉막폐렴 예방용 백신 조성물 |
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