TWI221774B - Porcine circovirus and parvovirus vaccine - Google Patents
Porcine circovirus and parvovirus vaccine Download PDFInfo
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- TWI221774B TWI221774B TW088111464A TW88111464A TWI221774B TW I221774 B TWI221774 B TW I221774B TW 088111464 A TW088111464 A TW 088111464A TW 88111464 A TW88111464 A TW 88111464A TW I221774 B TWI221774 B TW I221774B
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Description
1221774 五、弩明說明（3)
Portprl Down, Salisbury, Wiltshire SP4 OJG, United Kingdom) ° 於1997年10月2日星期四寄存的有： -寄存號V 97100219(在本文稱為Imp. 1 008PCV) -寄存號V97 002 1 8 (在本文稱為Imp.lOlOPCV) -寄存號V97 1 00 21 7(在本文稱為Imp.999PCV) 於1 998年1月16日星期五寄存的有： -寄存號 V98011608(在本文稱為 Imp .1011-48285) -寄存號V98 0 1 1 60 9 (在本文稱為Imp· 101卜48121) 申請人於一豬多重系統耗弱症候群之實驗性複製之試驗 結果中，察覺合併豬細小病毒及環病毒可導致其病症更加 惡化。 因此本發明係關於使用豬環病毒（特別是第一型及第二 型’最佳者為第一型）疫苗進行豬隻之疫苗接種，合併使 用豬細小病毒進行疫苗接種。頃瞭解，對豬隻施打二價疫 苗’或同時施打豬細小病毒疫苗友豬環病毒疫苗，以達到 有效之接種。 該參考細小病毒菌株係為NADL-2菌株，其可得自ATCC收 集中心，參考號為VR-742。諳此藝者熟知拮抗豬細小病毒 之疫苗接種，而且豬細小病毒疫苗在市面上亦有售。例如 有Parvovax (拮抗豬細小病毒之去活性疫苗，由MERIal販 售）。同時請參閱（例如）p. Vannier et A. Laval·，
Point. Vet· 1 9 93，25(151)，5 3-6 0; G· Florent et al·, Proceedings of the Ninth Congress of Pig
1221774 五、發明說明（7) 組合’例如將乳液與Avridine®或DDA合用。 此類抗原製劑及免疫組合物或疫苗，較佳包含1 05至1 08 TCID50之去活性全病毒。 上述活疫苗所需之佐劑可選自用於去活性疫苗之佐劑。 以採用乳液為較佳。如同去活性疫苗，可添加在 WOU 4 1 6 68 1中所述之佐劑。 至於冷滚乾燥安定劑，可提及之例子有S P G A (請參閱
Bovarnik et a 1 J· Bacteriology 59， 509， 950) ’ 碳
水化合物如山梨糖醇、甘露糖醇、澱粉、蔗糖葡聚糖或葡 萄糖’蛋白質如白蛋白或酪蛋白，該等化合物之衍生物， 或缓衝液如驗金屬鱗酸鹽。 根據本發明之抗原製劑，免疫組合物及疫苗可包含一種 或多種根據本發明之環病毒及/或細小病毒之一種或多種 活性成份（抗原）。 除此之外，申請人頃獲得四株第二型豬環病毒單離株之 基因組’其被命名為SEQ ID NO: 1至4。PK-15菌株之序列 命名為SEQ I D N0 : 5。當然，本發明自動涵蓋其同等序
列，即不改變上述序列或其編碼之多胜肽的功能或菌株專 一性的序列。當然亦包括因密碼簡併而不同之序列。 本發明亦涵蓋可在嚴苛條件下與上述序列雜合及/或盘 本發明之菌株具高類似性之同等序列。 在合適的載體幫助之下，該等序列及其片段可被用在 行活體外或活體内多胜肽之表現。 特別是形成本發明之DNA片段之開放譯碼區構（〇rf^13)
第11頁 1221774 五、释明說明（11)
Imp· 1 0 1 1 -48285皆株之基因組之DNA序列 Imp. 999菌株之基因組之DNA序列 I mp · 1 0 1 0菌株之基因組之DNA序列 PK/15菌株之基因組之DNA序列
SEQ ID NO SEQ ID NO SEQ ID NO SEQ ID NO 實例 病毒之培卷及輩龅： 組織樣本係收集自法國，加拿大，美國小豬之肺及淋巴 結。該等小豬呈現斷奶後多重系統耗弱症候群之典型臨床 病薇。為加速該病毒之單離，該組織樣本在屍體 即冷凍於-70。(：之下。 在病毒單離方面，使用無菌之研钵及杵在含鄂氏鹽 (Earle’s Salt)(EMEM ，BioWhittaker公司英國，现
Wokingham，英國），盤尼西林俊1〇〇IU/毫升，及 (^00微克/毫升）（MEM-SA培養基）之最簡培養基中研磨 織和無菌砂，接著將此研磨之製劑置入mem_sa中，磨，、且 300 0g ’4。(：之下離心30分鐘後回收其上清液以 1 5%組織樣本之懸浮液。 表爾3約 在細胞培養接種之前，於每管2毫升之主 微升之氣仿，並在室溫下持續混合10分鐘/ °入 物轉移至微離心管，在3 000g之下離心1〇分鐘者將此^合 收其上清液I此上清液可充作病毒單離實驗之接者回 所有病毒單離之研究均在已知未被豬環病。 病毒（Pestiviruses)，豬腺病毒及豬細小= )，疫 PK/15細胞培養中進行（請參閱AUan ^毒感乐之 n、et al.，不給初
第15頁 1221774 五、声明說明（12) 乳弋小豬環病毒實驗性感染之病·理學及豬胎物質之檢定，
Vet· Microbiol· 1995， 44， 49-64)。 根據下列技藝進行豬環病毒之單離： 生長至群集之單層Ρκ/15細胞藉胰蛋白酶（胰蛋白酶一乙 二胺四乙酸混合物）分解而分離，並收集至含15%未被疫病 毒感染之牛胎血清的MEM —SA培養基（=MEM —G培養基）中，其 最終濃度為每毫升含約4 〇 〇，〇 〇 〇個細胞。接著將丨〇毫升份 ϊ之細胞懸浮液分離物與2毫升份量之上述接種物分離物 混合’最終混合物均分至兩個2 5平方公分之fa 1 con培養瓶
中’每瓶6毫升。該等培養物接著在37 °c及含1 〇% c〇2的環 境之下培養1 8小時。 在培養後’該半群集單層之培養基以3〇〇mM2D-葡萄糖 月女（Cat#G48175，英國波耳市Sigma-Aldrich有限公 司）（Tischr I· et al·，Arch，Virol。·，1 987 96 39 - 57)
處理’接著在37 °C再培養48-72小時。在此最終培養之 後，取兩瓶接種物之一進行三回成功之冷凍/解凍循環。 剩餘培養瓶之PK-1 5細胞以胰蛋白酶—乙二胺四乙酸水溶 液處理，再懸浮於20毫升之MEM-G培養基中，接著以 400, 0 0 0細胞/毫升之濃度接種至75平方公分之培養瓶。再 添加5毫升得自冷凍/解凍循環之相對應溶胞產物以，，超感 染n(superinfected)該初接種之培養瓶。 fAL;以免疫縈光或就地雜合泽j貞測含豬環病舂之細昀埤 i樣本之製備 口 收集5毫升體積之"超感染，，懸浮液並接種至直徑55公厘
1221774 五、發明說明（13) 4 且含無菌去脂蓋玻片之培養孤。·該’语養瓶中及蓋玻片上的 培養物在3 7 °C下培養並依實例1所述之方法以葡萄糖胺處 理。以葡萄糖胺處理2 4至4 8小時之後’採集蓋玻片上的培 養物並以丙酮在室溫之下固定分鐘或以10%曱酸緩衝液 固定4小時。在固定之後及使用於就地雜合研究和免疫細 胞化學標記研究之前，將所有蓋玻片放置在矽膠之上並保 存在-70 °C之下。 f例3 : 以就地雜合法偵測PVC庠列之技術 在收集自病豬並經甲醛固定之組織上，及在供病毒單離 而接種（見實例2 )並固定於蓋玻片之細胞培養製劑上進行 就地雜合。 使用對應於PK/1 5豬環病毒（PVC)及傳染性雞貧血病毒 (CAV)之完全基因組探針。使用質體pPVC1做為pvc之特異 性病毒DNA來源，其中該質體ppvci含有PCV基因組之可複 製形式且以單個1.7千鹼基對（kbp)插子之形式被選殖 (Meehan B· et al ·豬環病毒DNA之序列：與植物環病毒之 親和性，J· Gen· Virol· 1 997， 78，22 1 -227)。用包含 2· 3 kbp鳥環病毒複製形式之質體類似物（pCAAl )作為陰性 對照組。該二質體之個別甘油貯存品被用於按照鹼性&胞 技術（Sambrook J· et al· M〇lecuia]r Cloning: a
Laboratory Manual. 2nd Edition, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, 1 98 9 )製造及純化質體，然後將該質體作為製備探針之模 板。PCV及CAV完全基因組之環病毒探針代表，係根據供應
1221774
五、發明說明（14) 4 商之建議，使用市售無放射性之·標1己套組（英國路易士市 之Boehringer Mannheim公司），從上述純化質體（每探針 使用1微克）及從六核苷酸隨機引子製作。 在使用於就地雜合之前’用50-1〇〇微升之無菌水溶解以 洋地黃毒甘（(1丨8〇义丨8611丨11)標記之探針。 製備以石蠟包覆及甲醛固定之病豬組織樣本和以曱醛固 定之已感染的細胞培養製劑以供按照下述技術偵測pCV核 酸：
自包覆於石臘中的組織塊切出5微米厚之切片，除去石 鐵’接者以漸次降低》辰度之酒精再水合（r e h y d r a t e )該組 織切片。該組織切片及以甲醛固定之細胞培養物在37 t下 與含0.5%蛋白酶之溶液在Tris-HC1緩衝液（含5mM EDTA， ρΗ7· 6)中分別炎養1 5分鐘及5分鐘。將該等玻片置於溶在 滅菌蒸餾水之1 %甘胺酸水溶液中3 0秒，以〇 . 〇 1 Μ PB S緩衝 液（磷酸鹽緩衝液，pH7· 2 )清洗兩次。最後以無菌蒸餾水 清洗5分鐘，在風乾之後與探針進行觸合。 每一份組織/探針製劑物皆以潔淨無脂之蓋玻片覆蓋， 並置入90 °C烤箱中1 〇分鐘，之後放在冰塊上冷卻1分鐘， 最後在37 °C下培養18小時。該等製劑短暫的泡入2X檸檬酸 | 鈉鹽（SSC)緩衝液（ρΗ7·0)中以移去保護用之蓋玻片，之後丨% 以2X SSC清洗兩次，每次5分鐘，最後以PBS緩衝液清洗兩 次，每次5分鐘。 在此等清洗之後，將該等製劑物泡入順丁烯二酸緩衝液 (0.1M，順丁烯二酸，〇.15MNaCl，ρΗ7·5) 10 分鐘，之後
第18頁 1221774 五、發明說明（15) * 與含'1 % 的封阻劑（Cat #1096176，Boehringer Mannheim UK，Lewis，East Sussex，UK)水溶液之順丁烯二酸緩衝 液在3 7 °C下培養2 0分鐘。 接著將該製備與以封阻緩衝液稀釋而得之抗—洋地黃毒 管單株抗體（Boehringer Mannheim)之1/250溶液在37 °C下 培養1小時，以P BS清洗，最後在3 7 °C之下與以生物素標記 之抗-小鼠免疫球蛋白培養30分鐘。該等製劑物以pBs清 洗’接著以含0.5%過氧化氫之pbs水溶液，在室溫下處理 2 0分鐘以阻絕其内因性過氧化酶活性。該等製劑物以p B s 再清洗一次並以在使用之前才配製之3_胺基—9二乙基咔唑 (AEC)受質（央國劍橋之劍橋生物科學公司提供）處理。 以自來水做最後清洗之後，該等製劑物以蘇木素反染 色’並以自來水顯色（藍色），並以置放液（m〇unt ing fluid)(GVA Mount，由英國劍橋之劍橋生物科學公司提供） 置放在顯微鏡蓋玻片之上。該實驗對照組包括在得自病豬 及非病豬樣本上使用無關之陰性探針（CAV)及陽性探針 (PCV)。 實例4丄偵測P V C之免疫螢光祜何
以丙酮固定之所有細胞培養製劑物之初始篩選係使用成 豬血清匯集物之1 : 1 00倍稀釋液藉間接免疫螢光技術（丨IF) 進行。此血清匯集物包含來自北愛爾蘭的25隻成豬並已知 含拮抗多種野生種豬病毒（包含Pvc :豬細小病毒，豬腺病 毒及PRRS病毒）之抗體。I iF技術藉著將該細胞培養物與血 清在（已用PBS稀釋37 °C下培養1小時，接著以pBS清洗兩次
1221774 五、牙明說明〇6) ”'行：·然後將該細胞培養物用與‘異硫化氰螢光素結人 免抗豬免疫球蛋白之1/80倍稀釋液（用PBS稀釋）染:之 後用PBS清洗，在紫外線下以顯微鏡、」 於甘油緩衝液中。 〜別置 复組織就地雜奋之鈷罢
准心多重系統耗弱症候群之法國、加拿 集而得且以甲藤固定之組織用PCV基因探針所進行1 之小緒收 ：示在數個被研究之損害處中存在與損害心之地 c核酸。當PCV基因組探針用在收集自健康豬隻的 或當CAV探針用在收集自病豬的組織時皆未觀察到任何^時 ，、’二t疋發現p c v核酸存在於加州小豬經病害浸潤^肺 部之細胞質和許多單核細胞之細胞核中。pcv核酸亦被證 明存在於肺細胞，枝氣管和細枝氣管的表皮細胞以及小動 脈，靜脈和淋巴管的内皮細胞之中。 經偵測發現PCV核酸存在於法國病豬之許多毛囊淋巴細 胞及淋巴結的匕打“丨叫的丨心丨單，核細胞之中。在少數融 合細胞中亦可測得PCV核酸。根據該等偵測結果，選擇加
州豬之肺’法國豬腸系膜淋巴結，加拿大豬之器官等樣本 以供單離豬環病毒新株之用。 例6 ··~~瘦之細胞培養及免疫螢光俏則之結果 在以自顯示多重系統耗弱症候群之臨床徵候之法國小豬 (I mp· 1 0 0 8菌株）加州小豬（I mp· 9 9 9菌株）及加拿大小豬 (Imp .1010菌株）收集得之樣本接種的細胞培養物中，未觀 察到細胞病變。然而，得自該接種之細胞培養物之製劑經
第20頁 1221774 五、發明說明（17) 4 丙嗣.固|定及以豬血清多株抗體進行，，免疫標記後，顯示以加 州小豬之肺（I mp · 9 9 9菌株），法國小豬之腸系膜淋巴結 (1111口.1008菌株），加拿大小豬之器官（11111)1〇1()菌株）接種 之細胞培養物中許多細胞呈現核螢光染色。 复例7 :~~組DNA之抽取 如CAV之複製型式之選殖乙節所述（T〇dd· D· et ai·，用 經選殖之DNA探針對雞貧血病毒進行點吸潰雜合測定，豬 環病毒新株之複製形式藉著使用培育72_76小時後收取且 用葡糖胺處理之被感染Ρκ/1 5細胞培養物（見實例丨）（1 〇個 75cm2之培養瓶）而製備。豬細小病毒DN^二病毒單離株之 基因組複製形式之特徵，Vir〇1〇gy， 1 984，1 37, 24 1 一254) 之描述抽取該等複製型式之雙股DNA藉修改過之Hirt技術 萃取（HirtB ’來自被感染細胞培養物之多廇病毒DNA之選 擇性萃取，J· Mol· Biol· 1967，36，365-369)。 t例8 :豬環病毒Imp· 9 99菌妷之基因組之複製形式之限劁 圖譜 · 將使用Hirt技術萃取之DNa(卜5 " g)，依據提供廠商之 建議以S1核酸酶（Amersham)處理，接著將此DNA以不同之 限制酶（Boehringer Mannhein，Lewis，East Sussex，
UK)消化’之後如Todd等人所述（雞貧血病毒之純化及生化 特徵，J· Gen· Virol· 1 99 0，7 1, 81 9-823 )，該消化之 產物在含溴化乙錠之1 · 5 %瓊脂糠凝膠上以電泳分離。萃取 自ImP· 999菌株培養物之DNA具有一獨特的ElcoRI位置，2個 SacI位置，但不含任何pst I位置。然而，此限制圖譜pc V
第21頁 1221774 五、發明說明（18) 4 PK/ip菌株所表現之限制圖譜不同（Meehan Β· et al.豬 環病毒之序列，及與植物環病毒之親和性，1 9 9 7 7 8， 221 -22 7) ’後者具有PstI位置並且不含Ec〇fn位置。 f例9 :豬環病卷I m p · 9 9 9菌株之基因組之選殖 以EcoRI限制酶消化該pcv imp. 99 9菌株之複製形式所產 生之約1· 8kbP長限制片段，藉著使用Qiagen販售之套組 (QIAEXII 凝膠萃取套組Cat# 2〇〇21，QIAGEN Ltd·， Crawley’West Sussex，UK)，在1.5%瓊脂糖凝膠上以電泳 而被單離（見實例3 )。接著此EcoRI-EcoRI限制片段與事先 根據標準選殖技藝（Sambrook J. et al Molecular Cloning: A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York，1 98 9 )以相同的限制酶消化並脫磷酸之pGEM — 7載體愛 爾蘭都柏林之（Promega醫藥供應公司出品）連接。將所得 到之質體依據標準技藝轉化至大腸桿菌jM1〇9宿主菌株 (81^七3忌6116，1^】〇113，113八）中’。該？(：¥111^.999 菌株之
EcoRI-EcoRI限制片段亦選殖入pBiuescript SK +載體之 EcoRI 位置（Stratagene Inc· La Jolla, USA)。在得自各 別宿主菌株之單株之中，選出包含預期大小片段之單株至 少兩株。所得到之單株經過培養，依據標準質體製備及純 化技術’小量（2毫升）或大量（ 25 0毫升）地純化其含完整 Imp.999菌株基因組之質體。 實倒LQj上CV Imp· 9 99菌抶之基因組DNA(雙股葙事型式、夕 定序
第22頁 1221774 五、野明說明〇9) 依·，據Sanger之雙脫氧核苷酸技術，並根據提供廠商之建議 使用定序套組’’AmpliTaq DNA polymeerase FS,! (Cat#402 079 PE Applied BioSystems , Warrington, UK)及生物應用系統公司之ABi 373A自動定序儀定序之 EcoRI lmp· 9 99 單株（單株pGEM-7/2 和pGEM-7/8)之核苷酸 序列。採用Μ 1 3之”順向”及"反向"通用引子進行起始定序 反應。其後之定序反應則依據"DNA步行（DNA walking)1’技 術製作。其後定序所需之多核甘酸係由生命科技 (Inchinnan Busines Park, Parsley, UK)合成。 組合所產生之序列並依MeDNAS IS 第3. 2版軟體（Cat #22020101，Appligene, Durham, UK)之方法分析之。採用 來自生技資訊國家中心（NCB I， Bethesda, Maryland, USA)伺服器之BLAST規則系統方法分析該等不同之開放譯 碼區。 該完全序列（EcoRI - EcoRI片段）呈現在SEQ ID Νο··3(圖 3 )。頃提供此菌株之完整序列，該序列經改造而任意地 以EcoRI開頭位置為起點，即其第一個核苷酸為G。 採用類似方法以取得根據本發明之其他三單離株之序列 (見SEQ ID No· 1，2 及4 及圖 1，2 及4)。 此四菌株之基因組之大小如下：
Imp, 1 0 1 1 -48 1 21 1767 核哲酸
Imp. 1 0 1 1 -48 285 1 76 7 核甘酸
Imp. 9 99 1768 核哲酸
Imp. 1 0 1 0 1 76 8 核苷酸
1221774 五、發明說明（20) 實例1 1 : PCV I mp· 9 9 9菌株之序列之分析 當產自Imp· 99 9菌株之序列被用於測試與基因銀行資料 庫所含序列之類似性時’所偵測到唯一明顯的類似性為與 PK/15菌株（寄存號Y0992 1及U491 86)之序列（在核酸方面f 具約7 6 %之類似性（見圖5 )。 在胺基酸位階，序列之6相轉譯與資料庫（ΝΑβ I伺服器之 B L A S Τ X規則糸統）之類似性之測試證明其與對應於β β τ ν病 毒之其理論性複製品之開放譯碼區具有9 4 %類似性，其中 該BBTV病毒與基因銀行U49 1 86序列編碼之植物環病毒'(基 因銀行辨識碼1 8 41 5 1 5 )類似。 資料庫所含之其他序列中並無與PCV Imp. 999菌株所衍 生之序列展現明顯之類似性者。 以收集自具多重系統耗弱症候群之臨床病徵之加州小豬 病體所培養之Imp· 999菌株之序列分析，清楚顯示此病毒 單離株係新穎的豬環病毒。 實例1 2 :庠列之比鲛分析 將4株新穎PCV菌株之核苷酸序歹ij與pcv PK/1 5菌株之序 列對準比較（圖5 )。建立斟酌該四#穎菌株及前述之pK / j 5 菌株所得到之類似性矩陣。其結果如下： 1 : Imp· 1011-48121 2: Imp· 1011-48285 3: Imp· 999 4 ·· Imp· 1 01 〇 5: PK/15
第24頁 1221774 五、發明說明（21) 2_3 4 5 1 1.0000 0.9977 0.9615 0.9621 —0.7600 2 1.0000 0.9621 0.9632 0.7594 3 1.0000 0.9949 0.75600 4 1.0000 0.7566 5 1.0000 兩株法國菌株Imp· l〇11—48121 & Imp· 1〇 1 1 —48 285 間之類 似性大於99%(0.9977)。 兩株北美菌株lmp· 999及Imp· 1010間之類似性亦大於 99%(〇· 9949 )。法國菌株及北美菌株間之類似性略大於 96%。
所有該等菌株與PK/15間之類似性均落於75及76%之間。 由此可推論根據本發明之菌株係代表新穎類型之豬環病 毒，與PK/15菌株所代表之類型不同。此單離自呈現抑… 症候群之豬隻之新類型稱為第二型豬環病毒，ρκ/1 5則為 第一型之代表。屬於此第二型之菌株展現顯著的核苷酸序 列類似性，雖然該等菌株實際上單離自非常不同的地區。 -實·例1 3 :新穎PC V菌株之基因組所編碼之蛋白皙的合析
I mp · 1 0 1 0單離株之核苷酸序列可被視為其他與多重系統 耗弱症候群有關之環病毒菌株之代表。此序列在β L a S T X規 則系統（Altschul et al· J. Mol. Biol. 199〇φ 215· 403-410)及MacVector 6.0 版軟體（〇xford Molecular Group, Oxford 0X4 4GA，UK)之綜合程式的協 助下進行更詳細之分析。由此序列（圓形基因組）可能偵測 到1 3個長度大於2 0個胺基酸之開放譯碼區（或q r ρ s )。此 13 ORFs如下所示：
第25頁 1221774 五、發明說明（22) 名稱 起點 終點 股性 ORF大小 核甘酸㈣ 蛋白質大小 胺基酸⑽ ORF1 103 210 順式 108nt 35aa ORF2 1180 1317 順式 138nt 45 aa ORF3 1363 1524 順式 162nt 53aa ORF4 398 1342 順式 945nt 314aa ORF5 900 1079 順式 180nt 59aa ORF6 1254 1334 順式 81nt 26aa ORF7 1018 704 反式 315nt 104aa ORF8 439 311 反式 129nt 42aa ORF9 190 101 反式 90nt 29aa ORF10 912 733 反式 180nt 59aa ORF11 645 565 反式 81nt 26aa ORF12 1100 1035 反式 66nt 21aa ORF13 314 1381 反式 702nt 213aa 菌株1 0 1 0基因組的每個ORF的起點及終點位置請對照呈 現在圖4(SEQ ID Νο·4)之序列。菌株999之0RF1至13的限 制完全相同。除了 0RFs3及13之外，菌株1011-48121和 1011-48285的限制亦完全相同：， 0RF3 1 43 2-1 53 9，順式，108nt， 35aa 0RF13 314-1377 ，反式，705nt ， 234aa 在該等13 ORFs之中，有4個ORFs與座落在被選殖之病毒 PCV PK/15基因組之ORFs類似物具有明顯的類似性。分析 所有與多重系統耗弱症候群病症有關之環病毒單離株之基 因組的每一個開放譯碼區。該4 ORF s如下所列：
第26頁 1221774 五、舞明說明（23) 多稱， 起點 終點 股性 ORF之大小㈣ 蛋白質之大小 ⑽ 分子量 r mass ORF 4 389 1342 順式 945 nt 314 aa 37.7 kDa ORF 7 1018 704 反式 315 nt 104 aa IT8kDa ORF 10 912 733 式 Γΐ80ηί 59 aa 6.5 kDa ORF 13 314 1381 反式 702 nt 233 aa 57.8kDa
每一個ORF之起點及終點位置請對照呈現在圖4(SEQ ID
No· 4)之序列。該〇RF之大小（核哲酸=nt)包括其終止密碼 子。 ”、 ?0 11^.1010及？(^?1(/15單離株之基因組組織間之比 較使其可辨識存在於該二者病毒之4 〇RFs 。下表列出所 觀察到之類似性程度： ORF Imp.lOlO/ORF PCV PK-15 類似性百分比 ~ ORF4/ORF1 86% " ORF13/ORF2 66.4% ORF7/ORF3 61.5%重疊的部份104 aa ORF10/ORF4 83〇/0重疊的部份59 aa 在0RF4 Imp.1010及〇RFl PK/15之間觀察到最大的序列 相同性（86°/◦類似性）。既然此蛋白質可能參與病毒⑽八之複 製並為病毒複製所必需，因此可預見上述之結果（Meehan et al· J. Gen· Virol· 1 9 97· 78. 22 1 -227; Mankertz et al· J. Gen. Virlo. 1 9 98· 79· 381 -384)。 ORF 13 Imp· 10 10及ORF2 PK/15間之序列相同性較弱 (6 6 · 4%類似性），但此二〇RF s之各個呈現高度保守性之n -端鹼性區域，該區域與烏類環病毒C A V之主要架構蛋白質 之N-端區域相同，（Meehan et al· Arch· Virol. 1992.
1221774 五、發明說明（24) i 124·Α301-319)。在0RF7 Imp.lOlil·與0RF3 PK-15和ORF10 Imp.1010與ORF4 PK-15之間則可見大差異。當與PCV PK-15之ORF3和0RF4比較時，imp. 1〇1〇單離株之〇rf7和 ORF10皆呈現C-端區域缺失。在〇rf7/ORF3(重疊部份，有 61· 5%之類似性）和〇RF1〇/〇RF4(重疊部份有83%之類似性） 之N -端區域可見最大之序列類似性。 由於其基因組極緊密的結果，豬環病毒的基因組組織顯 得非常複雜。其主要之架構蛋白質可能衍生自位於同股豬 環病毒基因組之數個譯碼區間之接合處。因此依據上表所 陳述之任一開放譯碼區可以代表全部或部分第二類豬環病 毒所編碼之抗原性蛋白而且可能可做為專一性診斷及/或 疫苗接種之抗原。因此本發明係有關包含該等0RFs其中之 一的蛋白質。最佳者，本發明係關於本質上包含0RF4， ORF7· ORF10 或0RF13 者。 實例1 4 :選殖自新菌株之PCV基因組的感染性牯皙 依據Meehan 等人（Characterization of viral DNAs from cells infected with chicken anemia agent: sequence analysis of the cloned replicative form and transfection capabilities of cloned genome fragments· Arch· Virol· 1 992，124，301-319)所述之 技術將Imp ·999單離株之完全基因組（複製型）的質體 pGEM-7/8轉染至ΡΚ/15細胞中。在無污染之ΡΚ/1 5細胞轉染 後的第一繼代上所進行之免疫螢光分析（見實例4 )顯示單 株PGEM7/8質體可以誘發感染性PCV病毒之製造。包含感染
1221774 五、發明說明（25) " 性pcy基因物質之單株，其可利用性可使病毒基因組進行 任何有用之巧妙操作以製造修飾之pcv病毒（在豬隻中其毒 性減弱或變成缺陷），而此經修飾之PCv病毒可用^製&減 毒或重組之疫苗，或用來製造診斷用套組之抗原。 實例1 5 : PCV抗原經活體外培養之產製 採用與實例1相同的方法培養無污染之Ρκ/丨5細胞及複製 病毒。該等感染細胞在3 7 °c下培養4天後以胰蛋白酶處理 接著予以採集並計數。次繼代用4〇〇, 〇〇〇個感染細胞ml以 培養。 實例1 6 : 病毒抗原之去活柹 在病毒培養終了時，收集該感染細胞並使用超音波 (Branson Sonifier)或在 rotor-stator 型膠體磨子 (UltraTurrax， IKA)的幫助之下溶胞。接著將該懸浮 370 0 8之下離心3。分鐘。該病毒懸浮液在37。:下二= 乙亞胺處理1 8小時或在28 °c之下以〇· 5%Beta-丙内醋處理 24小時以去其活性。若在去活性之前該病毒之滴定濃度不 足，可使用3 00 kDa截斷膜（Millipore PTMK3〇〇)以超過 渡方式濃縮。該去活性之病毒懸浮液貯存於5 之下。 實例1 7 :以擴物油為_基礎之乳液劑塑疫苗之製備 該疫苗係依據下列配方製備： -去活性豬環是毒懸浮液 25〇毫升 -Montanide ISA 70( SEPP I C) ： 毫升 該水相及油相以過濾方式分別滅菌。在^卜61^〇11錐形 乳化儀的幫助之下授拌並均質該等成份以製備成乳液劑。
1221774 五、發明說明（26) 單一疫苗劑量包含大約1 07.5 TC I D 5 0。經由皮内注射途徑 施藥所需之單一疫苗劑量之體積為〇 . 5毫升，經由肌肉注 射途徑施藥所需之單一疫苗劑量之體積為2毫升。 此疫苗與Parvovax®疫苗合用在拮抗多重系統耗弱症候 群之疫苗接種計劃。 實例IA:可射之油性乳液劑型癌苗之製備 該疫苗係依據下列配方製備： -去活性豬環病毒懸浮液 2 0 0毫升 -Dehymuls HRE 7(Henkel)： 60 毫升
-Radia 7204 (Oleofina) 740 毫升 該水相及油相以過濾方式分別滅菌。在S i 1 v e r s 〇 η錐形 乳化儀的幫助之下攪拌並均質該等成份以製備成乳液劑。 單一疫苗劑量包含大約l〇7.5TCID50 ，經由肌肉注射途 徑施藥所需之單一疫苗劑量之體積為2毫升。 ' 此疫苗與Parvova#疫苗合用在拮抗多重系統耗弱症候 群之疫苗接種計劃上。 '
實例1 9 :有關使用過免疫血清（pcV-T)及<系列製備 自PK/15之F99單株抗體_二和製備自加拿_^菌株（PCV-C)少 過免〇清染ϋ國i ^JPCV病毒It-^pK/15 間接免疫螢光結果
第30頁 1221774 五、發明說明（27) 病毒 PK/15 美國 法國 PCV-T抗血淸 PCV-C抗血淸 F99 1H4 F99 4B10 F99 2B7 F99 2E12 F99 1C9 F99 2E1 F99 1H4 26400 200 g 10 000 210 000 g 10 000 ^10 000 $10 000 210 000 ^10 000 200 ^6.400 <100 <100 100 <100 <100 <100 100 800 >6.400 100 <100 <100 <100 100 <100 <100 *可以產生間接免疫螢光陽性反應的血清或單株抗體之最 終稀釋度之倒數 實例2 0 :豬多重系統耗弱症候群之實驗性製造-方法1 以剖腹生產法取得3天大的限菌小豬並保存在接種PC V病 毒溶液之隔離單位。所使用的第-二型PCV病毒為Imp. 1010 單離株，該病毒係得自病豬之淋巴結勻漿。 將小豬分成五組，依據下列圖表，所有的小豬在3天大 時均以1. 5毫升之病毒溶液經由口鼻途徑接種： 組別 _號碼 病毒 劑量 A 6 淋巴結勻漿 ND B 5 Imp. 1010(低繼代） 10(2) TCID50 C 4 Imp. 1010(高繼代） 10(2) TCID50 D 2 無PCV病毒之PK15細_溶胞產物 E 3 — — 實驗性激發之結果： 在五週的觀察期間，除了 B組的一隻小豬顯現實質上的
1221774 五、發明說明（28) 困頓不堪外，該蓉f灿' 時，A，B及C組的豬隹豬沒有發展出臨床症狀。屍體剖檢 組的動物大2到10^广呈現淋巴結增質現象（其大小比〇及£ 和股神經結的淋巴:尤其是頷下，$氣管，腸結膜，路 細旳、*列Η丨i 、、、° °此增質係與皮質區經白血球及巨嗤 , 、j ^的擴張有關。 A，B及C組的]、娃★ ^ A D ^ ^ z 猪亦呈現支氣管類淋巴組織增質現象。 A咄及0組各有—隻小豬得肺炎》 B組呈現實質上的困頓不堪的小豬和a組小豬得胃潰 瘍。
並且，所有Α，β及C組的豬隻均有胃腸肌肉被膜肌炎。 大部分A，B及C組的豬隻有心肌炎，由淋巴細胞，巨噬 細胞足噬伊紅血球浸潤引起之篆一病灶肝炎，和皮質及骨髓 的頂間腎炎。 C組一隻小豬的肝較正常者大並且在其表面散佈清楚的 病灶。 D組及E組的小豬不見任何病害。 從A ’ B及C組的豬隻器官中可單離出環病毒。
實例2 1 :豬多重系統耗矣群之實驗性複製—方法2及3 自出生後即與其母親隔離之一般小豬以PCV第二型病毒 溶液，豬細小病毒或此二者病毒混合物接種。 所使用的PCV第二型病毒有imp.i〇i〇及imp.i〇ii單離株 (菌種株48121)。 所使用的PPV病毒係加拿大來源之單離株，Imp. 1 0 0 5。 此病毒有一段序列（已定序基因組之1 / 3 )與其他已知之豬
第32頁 1221774 五、發明說明（29) 細小病毒菌株（PPV菌株NADL-2及Kresse菌株）完全相同。 以兩種實驗方法進行。 方法2 將三天大的小豬分成三組。依據下列圖表，所有的小豬 均以1毫升之病毒溶液經由口鼻途徑接種。 數量 病毒 劑量 Α~·~- 5 Imp. 1010 10(7) TCID50 Β - 5 Imp. 1010+Imp. 1005 5x10(6) TCED50 cmmm 2 --- 實驗性激發之結果： 隻小豬在接種後
A組··兩隻小豬在接種後2 1天玉亡， 24小時予以無痛宰殺。 B組：一隻小豬在接種後2 3天死亡，一隻小豬在接種後 24天予以無痛宰殺。 感染後死亡的小豬經屍體剖檢顯現存在實質上肉眼可^ 包括肋獏腔充水，肺水腫，腎臟出血，腎臟（上出
仞二Ϊ形式之）白色病害’肝壞死。該等病害與在原野案 例靦察到的病害相同。 無痛宰殺的小豬竣居辦划』 . ^ ^ 柯、a乾體剖檢不見病害之存在。 取自Α及Β組中缚咸仇他# 杆鈿她认级木後死亡及經無痛宰殺的小豬器官ϋ 多重系統耗弱症候；身上所觀察的典型及完整6 臟壞死，腎臟多病=;;式：肝壞死，淋巴結壞死，用 壞死和嚴重出血，肺細胞融合現象，
第33頁 1221774 五、發明說明（30) 因核内士3,導至之肝細胞嚴重壞死 該注意的是在所有病害（ PCV抗原。但在相 死亡或宰殺的豬隻）均發現大量 。 同的病害中不存在PPV抗原。 在對照組C纟且的t 方法3 、1 ^ 的小豬身上沒有偵測到任何病害。 將四週大的+紐 的1宏么4 諸分成四組。依據下列圖表，所有的小豬 构U 1宅升之病盖、+ 努〉谷液經由口鼻途徑接種。 組別 Λ PS \ ^：___ 病毒 劑量 A(對照組） Ty ---- — — D ----- Imp. 1005 (PPV) 10(5.3) TCID50 c Tv --- Imp. 1011 (PCV) 10(5) TCID50 D ~ - Imp.l005+Impl011 10(5)+5xl0(4) TCED50
實驗性激發之結果： 接種後2星期，^ ?隹 二 無痛宰殺1隻對照組小豬和每組實驗組的 。又小猪並進行屍體剖檢。觀察到D組（PCV + PPV共感染）的
:又小，具明顯的免疫組織病害。該注意的是在該等病害 不可肖b彳貞測到豬細小病毒之存在，雖然在β組小豬中可 見有關豬細小病毒之血清轉化。 對照組及其他組的小豬沒有觀察到肉眼可見或組織的病 害。 因此PCV + PPV之組合顯然能複製典型的豬多重系統耗弱 症候群組織病害。依照此二者實驗方法，像接種pC V + ppV 混合物一般，可觀察到當單獨接種p CV時可導致或輕或重
第34頁 1221774 五、發明說明（31)
的緒多重系統耗弱症候群複製。但在病害中僅能偵測到豬 環病毒。相反的，在一組單獨以PPV感染的實驗當中（方法 3B組）並沒有誘發肉眼可見或組織的病害。然而，當PCV存 在時，在4周大的豬隻身上可觀察到病害發生（方法3D 組）〇
第35頁 1221774 案號88111464 年月日 修正
O:\59\59261-930430.ptc 第36頁
Claims (1)
122^774 修正 年月曰 ΓΑ 口 索號 88111464
六、申請專利範圍 1. 一種針對豬多重系統耗弱症候群之抗原製劑，其包含 去活性豬環病毒抗原和去活性豬細小病毒抗原。 2 .根據專利申請範圍第1項之製劑，其包含第二型豬環 病毒抗原。 3 . —種針對豬多重系統耗弱症候群之疫苗，其包含有效 量之專利申請範圍第1或2項之抗原製劑，以及獸醫學上可 接受之溶媒或賦形劑。 4. 根據專利申請範圍第3項之疫苗，其包含獸醫學上可 接受之佐劑。 5. 根據專利申請範圍第3或4項之疫苗，其包含數種豬環 病毒抗原。
O:\59\59261-930430.ptc 第37頁
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1999
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- 1999-06-28 DE DE69941843T patent/DE69941843D1/de not_active Expired - Lifetime
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2000
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2001
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2010
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| TWI473813B (zh) * | 2011-12-06 | 2015-02-21 | Sbc Virbac Ltd | 豬第二型環狀病毒次單位疫苗 |
| US9657063B2 (en) | 2011-12-06 | 2017-05-23 | Sbc Virbac Limited | Porcine circovirus type-2 (PCV2) subunit vaccine |
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