臺灣博碩士論文加值系統

傳染性華氏囊病（infectious bursal disease; IBD）是由Birnaviridae科病毒所引起的幼齡雞隻B淋巴芽細胞壞死之免疫障礙性傳染病。本病在幼齡雞隻之預防控制主要依靠各種IBD活毒疫苗的免疫，但有關各種IBD活毒疫苗的安全性和免疫原性尚未有明確的資料可資參考，於是將23種IBD活毒疫苗分別免疫一組（每組20隻）之3週齡SPF小雞，於免疫後5、10、15和21日每組各抓取5隻採血檢測各組之IBDV ELISA抗體力價，稱取體重和華氏囊重供計算華氏囊體重比（bursa-body weight ratio; BBR）並剖檢華氏囊肉眼病變（BGL）和華氏囊組織學病變（BHL）以評估疫苗株之病原性。少部份（6組）免疫組在免疫後5日可測得100倍以上的ELISA抗體力價，大部份（13組）免疫組在免疫後21日達到最高（71—10748）之抗體力價，但其中分別有3和5組在免疫後10及15日時就可達到最高。各免疫組雞之BBR值計有3種（13.04％）、5種（21.74％）、6種（26.09％）和9種（39.13％）疫苗之病毒分別可分級成中間偏強毒（<1.5）、中間毒（1.51-2.0）、中間偏弱毒（2.01-3.0）和弱毒（>3.01）株級。免疫組之BGL值都很相近，除2組於免疫後10日有中等（1.13和1.30）數值外，其餘在免疫後各不同日期之數值均在0.78以下。各免疫組之BHL值計有3種（13.04％）、2種（8.70％）、5種（21.74％）和13種（56.52％）疫苗之病毒分別可分成中間偏強毒（>2.0）、中間毒（1.51-2.00）、中間偏弱毒（1.01-1.50）和弱毒（1.01-1.50）株級，若以上述BBR和BHL數值評判IBD活毒疫苗之毒性，有16種（69.57％）疫苗之兩種數值完全相同，其他7種（30.43％）疫苗的毒性評等也非常相近，因此BBR和BHL數值應可用為評判IBD活毒疫苗毒性的參考依據，但BGL數值則很難據以參考之。
以七種目前在台灣較為常用IBD活毒疫苗分別免疫七組（每組10隻）3週齡 SPF小雞，於免疫後3週以1995年台灣野外分離之1株（V97/TW95）強毒IBDV（vvIBDV）口服攻擊之，於攻擊直前和攻擊後7日均抓取5隻採血檢測IBD ELISA抗體，撲殺後稱取體重和華氏囊重量以計算BBR值，判讀BGL和BHL數值，結果全部免疫組均有良好（2261—4315）的ELISA抗體反應，僅有一種疫苗於免疫後21日之BBR和BHL達於上述中間偏強毒之標準，有3種疫苗免疫組於攻擊後見有明顯之BBR下降和BHL上升之免疫保護力不足。
收集經19種疫苗株各自免疫後和5株野外毒感染後4天含有大量IBDV增殖之華氏囊組織進行反轉錄聚合酶鏈鎖反應（RT-PCR）以增幅各IBDV VP2高度變異區（hvVP2）之643 bp核苷酸片段，該核苷酸片段選殖定序後，再以DNASTAR軟體進行其親源關係性等之比對。所有病毒株之胺基酸序列比對結果，如以V97/TW95株為比對標準時，野外分離株間和疫苗株間之相似度達97.2％以上者各有3種（60％）及4種（21.0％）；如以2002年台灣野外分離株（V263株）為比對標準時，野外分離株間和疫苗株間之相似度達97.2％以上者分別有4種（80％）和5種（26.3％），該5種疫苗亦是目前在臨床上被認為較具保護效力的疫苗，足見hvVP2胺基酸序列的比對頗可做為IBDV活毒保護力的參考應用。
以pET32a Escherichia coli系統將全長1492 bp之V97/TW95株IBDV VP2基因選殖後表現V97/TW95株全長約為70 kDa VP2蛋白，該蛋白經西方轉漬法及免疫墨點法檢測可與V97/TW95株免疫之SPF雞多株抗體血清呈陽性反應，此次單位蛋白之免疫原性尚須待日後進一步評估。

Infectious bursal disease (IBD) is a B lymphoblast necrotic immunosuppress disease in young chickens causing by a member of Birnaviridae, IBD virus (IBDV). Preventine and control of the disease has been mainly relayed on vaccinating young chicken with a variety of live IBD vaccine. Safety and the immunogenicity of the vaccine has not been clear indicated. An evaluation on the commercial available 23 live IBD vaccines was then designed and done orally in each of the 23 groups, 20 birds per proup, 3-week-old SPF chickens. A nonvaccinated control was also included. Five birds per group was removed for serological enzyme-linked immunosorbent assay (ELISA), body weighing and bursa weighing in calculating bursa/ body weight ratio (BBR), bursa gross lesion (BGL) grading and bursa histological lesion (BHL) grading. Only few (6) vaccinated group had ELISA antibody titer exceed 1:100 at 5 days post vaccination (DPV). Most (13) vaccinated groups had the highest titer (1:71-1:10748) at 21 DPV, but 3 and 7 groups were at 10 and 15 DPV. The BBR value of 3(13.04%), 5(21.74%), 6(26.09%), and 9 (39.13%) vaccinated groups was classified as intermediate plus (IM+; <1.5), intermediate (IM; 1.51-2.00), intermediate minus (IM-; 2.01-3.00) and low (>3.01) virulent level respectively. Only 2 vaccinated groups had moderate (1.13 and 1.30) BGL value at 10 DPV, the other BGL values in different DPV were all under 0.78 and most of the values are quite closed. The BHL value of 3 (13.04%), 2 (8.7%), 5 (21.74%) and 13 (56.52%) vaccinated groups was classified as IM+ (>2.0), IM (1.51-2.00), IM- (1.01-1.50) and low (<1.0) virulent level respectively. By using the above BBR and BHL virulence grading, 16 (69.57%) live IBD vaccines got the same virulent level. Also the BBR and BHL virulent level of the other 7 (30.43％) vaccines was all quite closed. Therefore the BBR and BHL value, but not the BGL value are good pathogenicity indice for live IBD vaccine.
Seven most popular use live IBD vaccines were individually taken to immunize a group of 10 3-week-old chickens then challenge at 21 DPV with a 1995 isolate (V97/TW95) of local very virulent IBDV (vvIBDV). A control group was also included. At 21 DPV and 7 day post challenge (DPC), 5 birds per group were removed for serological ELISA, body weighing and bursa weighing in calculating BBR, BGL grading and BHL grading. All the vaccinated groups had reasonable good titer (2261-4315) of ELISA antibody response. At 21 DPV, only 1 group had the BBR and BHL fall in the IM+ virulent level, the others were under IM virulent level. Three vaccinated groups were found not with good protection by showing much higher of BHL value and moderated lower of BBR value after challenge.
Each 24 groups 3-week-old SPF chickens, 10 birds per group, was individually given with one IBDV of the above 19 vaccines and 5 local vvIBDVs for virus propagation in the bursa. The bursa of each group was collected at 4 days post inoculation for reverse transcription-polymerase chain reaction (RT-PCR) amplifying a 643 bp nucleotide belong to the viral protein 2 hypervariable region (hvVP2) of IBDV. All the nucleotides were then cloned and sequenced. A computer DNASTAR software was used to figure out the relationship of the virus in the phylogenic tree, the identity of nucleotide and amino acid of the virus hvVP2. By using the amino acid sequence of V97/TW95 strain as standard, 3 (60%) local isolates and 4 (21.0%) vaccine strains had the amino acid over 97.2% identity as V97/TW95 stain. By using the amino acid sequence of a 2002 local isolate-V263 as standard, 4 (80%) local isolates and 5 (26.3%) vaccine strains had the amino acid over 97.2% identity as V263 stain. The 5 vaccines are the ones now most popular using in the local chicken industry. A comparison of the hvVP2 of IBD vaccine and local isolate strains comes to be a very valuable reference for practical protective evaluation of the live IBD vaccine.
A whole length of IBDV V97/TW95 strain VP2 gene, 1492 bp, was successfully cloned in pET32a Escherichia coli system and a expressied VP2 protein of 70kDa was verified by positive reaction in Western blotting and immuno-dot blotting assay with V97/TW95 strain immunized SPF chicken polyclonal antibody. The immunogenicity of the subunit vaccine need to be further studied.

中文摘要……………………………………………………... Ⅰ
英文摘要……………………………………………………... Ⅳ
中文、英文對照縮寫…….…………………………………… Ⅶ
誌謝…………………………………………………………... Ⅸ
目錄…………………………………………………………... ⅩⅠ
圖次索引....…………………………………………………... ⅩⅥ
表次索引……………………………………………………... ⅩⅩⅡ
第1章 前言…………………………………………………… 1
第2章 文獻回顧……………………………………………… 4
2. 1 IBDV的特性……………………………………………. 4
2. 1. 1 IBDV病毒株的病毒形態和發生學…………….... 5
2. 1. 2 IBDV之核苷酸及其蛋白質特性……………….... 6
2. 2 IBDV病毒株的歷史及急性型IBD的流行病學………. 9
2. 2. 1 IBDV之分子流行病學………………………….... 10
2. 2. 2 IBDV的野外保毒者與流行病學之關係………… 12
2. 3 IBDV病毒株之抗原性和致病性變異……………......... 12
2. 3. 1 IBDV病毒株的抗原性…………………………… 13
2. 3. 2 IBDV病毒株的致病性…………………………… 14
2. 3. 3 IBDV病毒株的毒力標誌………………………… 15
2. 3. 4 IBDV病毒株之減毒及適應於細胞之培養馴化… 16
2. 4 IBDV的致病機致和免疫缺陷性……………………..... 18
2. 4. 1 IBDV之致病機轉………………………………… 18
2. 4. 2 IBDV造成之免疫缺陷性………………………… 20
2. 5 IBD的診斷和vvIBDV的特性………………………… 22
2. 5. 1 IBD的感染症狀………………………………....... 22
2. 5. 2 IBDV診斷的分子應用工具……………………… 24
2. 5. 2. 1 反轉錄聚合酶鏈鎖反應（RT-PCR）………… 24
2. 5. 2. 2 反轉錄聚合酶鏈鎖反應-限制性片段長度多型性分析（reverse transcriptase-polymerase chain reaction-restriction fragment length polymorphism assay; RT-PCR-RFLP）應用….. 26
2. 5. 2. 3 單株抗體（monoclonal antibody; mAb）之偵測與分類……………………………………… 26
2. 5. 2. 4 原核表現系統之概述……………………….... 27
2. 6 vvIBDV之預防與控制…………………………………. 29
第3章 研究方法與步驟……………………………………… 32
3. 1 23種IBD活毒疫苗之效力評估……………………….. 32
3. 1. 1 試驗雞隻…………………………………………... 32
3. 1. 2 試驗用疫苗及野外病毒株………………………... 33
3. 1. 3 試驗用疫苗株之TCID50測定……………….......... 33
3. 1. 4 試驗用疫苗株之EID50測定………………………. 33
3. 1. 5 疫苗安全試驗……………………………………... 33
3. 1. 5. 1 血清酵素連結免疫吸附試驗（enzyme-linked immunosorbent assay; ELISA）抗體檢測…… 34
3. 1. 5. 2 華氏囊／體重比值（bursa／body-weight ratio; BBR）之測定…………………………………. 35
3. 1. 5. 3 華氏囊之肉眼及組織學病變分級………….. 35
3. 1. 6 疫苗效力試驗……………………………………... 35
3. 2 以hvVP2基因推定19種IBD活毒疫苗病毒株及5株新近台灣野外IBDV之親緣關係……………………… 36
3. 2. 1 華氏囊之收集…………………………………….. 36
3. 2. 2 病毒純化及核酸萃取……………………………... 36
3. 2. 3 病毒RNA抽取及純化…………………………… 37
3. 2. 4 PCR引子之設計…………………………………... 37
3. 2. 5 RT-PCR之增幅hvVP2 IBDV病毒cDNA……...… 38
3. 2. 6 RT-PCR產物之鑑定及純化………………………. 38
3. 2. 7 載體之製備……………………………………….. 39
3. 2. 8 勝任細胞（competent cell）E. coli（TOP10F’ strain）之製備…………………………………………….. 39
3. 2. 9 RT-PCR產物之分子選殖…………………………. 40
3. 2. 10 重組DNA之抽取及鑑定………………………… 41
3. 2. 11 IBDV hvVP2核酸定序及核酸與胺基酸序列比較分析………………………………………………... 42
3. 3 IBDV之全長VP2基因次單位蛋白製備………………. 42
3. 3. 1 IBDV之全長VP2基因選殖.................................... 42
3. 3. 2 表達用載體（vector）之製備…………………….. 43
3. 3. 3 勝任細胞（competent cells）E. coli BL21（DE3）之製備……………………………………………... 44
3. 3. 4 表達載體與IBDV VP2蛋白之分子重組與選殖…………………………………………………... 44
3. 3. 5 IBDV VP2 70 kDa蛋白質之表達………………… 44
3. 3. 6 免疫墨點反應（immuno-dot blotting assay）……… 45
3. 3. 7 西方免疫轉漬試驗（Western blotting assay）…… 45
第4章 結果…………………………………………………… 47
4. 1 23種IBD活毒疫苗之效力評估……………………… 47
4. 1. 1 23種IBD活毒疫苗之病毒力價測定……………. 47
4. 1. 2. 23種IBD活毒疫苗之安全試驗…………………. 47
4. 1. 2. 1 23種IBD活毒疫苗免疫後之ELISA抗體反應……………………………………………... 47
4. 1. 2. 2 23種IBD活毒疫苗免疫後之BBR值測定…. 49
4. 1. 2. 3 23種IBD活毒疫苗免疫後之華氏囊之肉眼及組織學分級………………………..........…….. 50
4. 1. 3 七種較常用之市售IBD活毒疫苗之效力試驗….. 51
4. 2 以hvVP2基因推定23種IBD活毒疫苗病毒株及5株新近台灣野外IBDV之親緣關係……………………… 52
4. 2. 1 反轉錄聚合酶鏈鎖反應（RT-PCR）……….......... 52
4. 2. 2 IBDV hvVP2核苷酸與胺基酸序列比較分析…… 52
4. 3 IBDV V97/TW95毒株之全長VP2基因次單位蛋白製備………………………………………………………… 54
4. 3. 1. IBDV V97/TW95毒株之全長VP2基因之RT-PCR……………………………………………. 54
4. 3. 2. IBDV V97/TW95毒株之全長VP2基因之重組確認…........................................................................... 54
4. 3. 3. IBDV V97/TW95毒株之VP2蛋白表現…………. 55
4. 3. 4. IBDV V97/TW95毒株之VP2融合蛋白之抗原性分析………………………………………………... 55
4. 3. 4. 1 免疫墨點法試驗（immuno-dot blotting assay） 55
4. 3. 4. 2 西方免疫轉漬法試驗（Western blotting assay） 55
第5章 討論…………………………………………………… 57
5. 1 23種IBD活毒疫苗之效力評估………………………. 57
5. 2 23種IBDV活毒疫苗株及5株新近台灣野外病毒株之親緣關係圖分析………………………………………… 62
5. 3 IBDV之全長VP2基因次單位蛋白製備………………. 66
第6章 參考文獻……………………………………………… 97
附錄……………………………………………………………... 133
附錄一 The pT-Adv vector for cloning ( from Clontech, http:// www.clontech.com. )…………………………..
133
附錄二 The pUC19 vector for cloning ( from Amersham Pharmacia Biotech, http://www.apbiotech.com )…….. 134
附錄三 The pET32a vector for expression ( from Novagen, http://www.novegen.com )…………………………… 135
附錄四 Phylogenetic tree based on nucleotide sequence located at the hypervariable region of the VP2 gene of various serologic standard and variant infectious bursal disease virus isolates ( Liu et al., 2001 )……… 136
附錄五 Comparison of nucleotide sequences ( 1-643 ) of at VP2 hypervariable region of vaccine strains and isolates of infectious bursal disease virus ( IBDV ). The sequence of isolate V97/TW95 is shown on top, and only differences are indicated.…………………… 137
作者簡介………………………………………………………... 144

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