朱漢守-PRRSV感染的疫苗接種和免疫.pdf

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1、PRRS virus vaccination&control in pigs 豬藍耳病毒免疫和控制HanSoo Joo,DVM,PhD 朱漢守，DVM，博士Professor Emeritus 榮譽退休教授University of Minnesota 明尼蘇達大學4/26/2024一帶一路國際生豬產業大會History of PRRS 藍耳病歷史z 1987 1991:Mystery swine disease(unknown),SIRS,PEARS,Blue ear,PRRS 豬神秘?。ㄎ粗?，豬繁殖障礙綜合征，豬流行性流產和呼吸綜合征，藍耳，豬繁殖與呼吸綜合征z 1991:Etiolog

2、ic agent(Lelystad virus,VR-2332)was identified using primary PAM cells 病原體（萊利斯塔德病毒，VR-2332）的鑒定使用了原代豬肺泡巨噬細胞z 1993:MARC-145 cell was cloned from MA-104 line cells 從MA-104細胞系克隆出MARC-145細胞z 1994:First MLV vaccine(VR-2332)第一個弱毒疫苗（VR-2332）z Homologous inactivated vaccine 同源性滅活疫苗yBEI inactivated vaccine 二乙

3、烯亞胺滅活苗yMJ vaccine(Envelope proteins enriched vaccine)MJ疫苗（囊膜蛋白富集疫苗）Efficacy of PRRS MLV or inactivated vaccine:藍耳弱毒苗或滅活苗的功效：May be effective or ineffective 可能有效或無效一帶一路國際生豬產業大會PRRSV causes two different diseases藍耳病毒導致兩種不同疾病Late-term abortion,Premature farrowing,stillborn&mummified fetuses In pregnant

4、 sows 懷懷孕孕母母豬豬妊妊娠娠晚晚期期流流產產，早早產產，死死胎胎和和木木乃乃伊伊Respiratory diseases with interstitial pneumonia in growing pigs 生長長豬間間質質性肺炎呼吸道疾病一帶一路國際生豬產業大會Pathogenesis of PRRSV infection in pregnant sows 妊娠母豬感染藍耳的病理機制 z Transplacental infection is caused by viremia and may occur in any stage of pregnancy z 任何妊娠階段都可能發

5、生病毒血癥導致的經胎盤感染z Fetal infection and tissue damage occur around 70 days of gestation when susceptible alveolar macrophages are formed in the fetus 胎兒感染和組織損失發生在妊娠期70天左右，這時胎兒體內形成易感肺泡巨噬細胞z Abortion and pre-mature farrowing are caused by high fever,and no evidence was found placental lesion.流產和早產是由發燒引起，沒有

6、證據證明胎盤損傷。z Stillbirth and mummification are caused by viral infection z 死胎和木乃伊胎是由病毒感染引起Viremia can be prevented by humoral immunity alone 單獨的體液免疫就可以阻止病毒血癥Following on-farm outbreak,normal litter can be expected when mummies length show 17cm(70 days of gestation).農場暴發后，當木乃伊胎長度17厘米時預期窩產仔正常（妊娠70天）No mu

7、mmies from sows 70 days of gestation at outbreak.暴發時妊娠期不足70天時不會導致木乃伊胎。Anti-fever drugs may be useful for reducing abortion 退燒藥可能對減少流產有用PRRSV can be isolated from fresh stillborn 從新鮮死胎可以分離出藍耳病毒一帶一路國際生豬產業大會PRRSV is the primary cause for PRDC in growing pigs 藍耳病毒是生長豬呼吸道疾病綜合征的首要原因 z PRRSV alone usually

8、causes mild pneumonia but severe clinical disease in PRDC(porcine respiratory disease complex)with mixed infections.z 單獨的藍耳病毒感染常導致慢性肺炎，但混合感染時可引起嚴重的臨床疾?。ㄘi呼吸道疾病綜合征）z PRDC has been observed commonly in commercial farms,and PRRSV has been most common triggering factors for PRDC.z 豬呼吸道疾病綜合征在商品豬場常見，藍耳病毒是最

9、常見的誘發因素。z PRDC has been experienced in two different stages 豬呼吸道綜合征經歷兩個不同階段y Stage 1:Late nursery 階段1：保育晚期-No PRRSV infection during sucking 哺乳階段沒有藍耳病毒感染-PRRSV infection starts 3-6 weeks of age 藍耳病毒感染從3-6周開始y Stage 2:Early to mid grower phase 階段2：生長階段的早期到中期-No PRRSV infection during suckling&nursery

10、 periods 哺乳階段和保育階段沒有藍耳病毒感染-PRRSV infection starts 10-16 weeks of age 藍耳病毒感染從10-16周齡開始一帶一路國際生豬產業大會PRRSV variants 藍耳病毒變異株z Genetic variants 基因變異株yORF5/whole genome sequence:Epidemiologic analysis ORF5/全基因測序：流行病學分析yRFLP patterns:Indicate better for clinical virulence 限制性內切酶片段長度多態性分型：更好顯示臨床毒力z Serologic

11、 variants 血清學變異株yIdentical,partial or no relationship by cross serum neutralization test y通過交叉血清中和試驗，可全部、部分或不能鑒別yFew research on serologic variants was performed 對血清學變異體的研究很少z Immunologic variants 免疫學變異株yCross protection test by challenge in host animal 通過在宿主動物體內攻毒提供交叉保護yNo research report are avail

12、able 沒有研究報道一帶一路國際生豬產業大會Virus sequence similarity between PRRSV at acclimation and during outbreak 在暴發和馴化期間的病毒序列相似性PRRSV used at acclimation(A)and isolated during outbreak(O)in 4 different farms with severe reproductive clinical signs 4個暴發藍耳均有嚴重繁殖臨床癥狀的不同農場使用的馴化毒株（A）和暴發時分離到的毒株（O）SequenceFarmcomparison

13、ORF 5 Whole genome1A:O98.297.62A:O98.899.03A:O98.096.84A:O99.299.3PRRSV with high sequence similarity can cause mild or very severe clinical signs 有較高相似性的藍耳病毒可以導致慢性或很嚴重的臨床癥狀PRRSV sequence similarity does not predict ability of the protection 藍耳病毒序列相似性不能預測保護能力Murtaugh 2007農農場場 序序列列對對比比 ORF5 全全基基因因組組

14、一帶一路國際生豬產業大會PRRSV grouping 藍耳病毒分組 Genetic group vs Serologic or immunologic group-Sequence analysis-RFLP pattern -Bioassay cross challenge test in nave pigs -Potentially by cross SN test using farm specific PRRSV基基因因分分組組 血血清清或或免免疫疫學學分分組組 序序列列分分析析 在在陰陰性性豬豬中中進進行行生生物物測測定定交交叉叉攻攻毒毒試試驗驗限制性內切酶片段長度多態性分型使用農場

15、專有藍耳病毒可潛在進行交叉血清中和試驗一帶一路國際生豬產業大會Identification of PRRSV serologic relationship鑒定藍耳病毒血清學關系 An example of serologic relationship by cross serum neutralization(SN)test 使用交叉血清中和實驗鑒定血清學關系的例子_PRRSVPRRSV strain specific hyperimmune serum toin SN testMLV1ABCMLV2MLV11286432168A64B64C64MLV264Three serologic gr

16、oups 3個血清學分組1.Identical or related:Same titer or 2 fold different e.g.MLV1 and A or A and B 可鑒定或相關：同等滴度或2倍差異，如MLV1和A或者A和B2.Partially related:4 or 8 fold different e.g.MLV1&B or A&B 部分相關：4或8倍差異，如MLV1&B或者A&B3.Unrelated:16 or more fold different e.g.MLV1&MLV2 or A MLV2 不相關：16倍或更多倍差異，如MLV1&MLV2或A MLV2血清

17、中和試驗的藍耳病毒藍耳病毒毒株特異性高免血清一帶一路國際生豬產業大會V Vi ir re emmi ia a i in n P PR RR RS S MML LV V v va ac cc ci in na at te ed d p pi ig gs s f fo ol ll lo owwi in ng g a a h ho ommo ol lo og go ou us s o or r h he et te er ro ol lo og go ou us s c ch ha al ll le en ng ge e 免免疫疫藍藍耳耳弱弱毒毒苗苗的的豬豬在在同同源源或或疫疫苗苗毒毒株株攻攻毒毒后

18、后的的病病毒毒血血癥癥Two groups of pigs vaccinated with VR2332,and another 2 groups without vaccination.2組豬免疫了VR2332，另外2組沒有免疫。Challenge with VR2332 or heterologous PRRSV of KS-06 使用VR2332或者異源的KS-06的PRRSV毒株攻毒Li et al 2014MLV VR 2332 or KS064個實驗組4 exp groups最初用VR2332弱毒苗免疫Origin of MLV was VR2332 VR2332 or KS06一

19、帶一路國際生豬產業大會Homologous vs heterologous PRRSV challenge 同源VS異源藍耳病毒攻毒ViremiaChallenge ViremiaGroup71421282835(13)421.VR 2332+VR2332-2.VR 2332+KS-06-+-3.None-VR2332-+4.None-KS06-+*Complete protection against homologous strain but no protection against heterologous virus KS-06 對同源毒株有完全保護但是對異源病毒KS-06無保護*V

20、R2332 and KS-06 are immunologically unrelated VR2332和KS-06無免疫學相關性病毒血癥 攻毒 病毒血癥分組 無無一帶一路國際生豬產業大會HHo oww l lo on ng g p pr ro ot te ec ct ti iv ve e i immmmu un ni it ty y l la as st t a ag ga ai in ns st t h ho ommo ol lo og go ou us s P PR RR RS SV V s st tr ra ai in n?對對同同源源藍藍耳耳毒毒株株的的保保護護性性免免疫疫能能持持續

21、續多多久久？Lager&Mengeling 1997 Vet Microbiol 58:127 Group A A組1.11 gilts were infected with a field virus via oral at the same time and bred each gilts between 143 514 days after infection.同時對11頭后備母豬經口感染野毒，并在感染后143-514天進行配種。2.Homologous challenge to all gilts was made in 90-days of pregnancy對所有后備母豬在妊娠90

22、天時進行同源病毒攻毒 562 and 604 days post-exposure 暴露后的562天和604天*All gilts were housed in strictly isolated rooms before challenge 所有后備母豬在攻毒前飼養在嚴格分離的房間Group B B組 At the time of challenge,10 age matched PRRS free pregnant sows were purchased and challenged as control without previous infection history 攻毒時，購買1

23、0頭日齡相當的無感染病史的藍耳陰性懷孕母豬進行攻毒作為對照。一帶一路國際生豬產業大會D Du ur ra at ti io on n o of f P PR RR RS S v vi ir ru us s p pr ro ot te ec ct ti iv ve e i immmmu un ni it ty y i in n p pr re eg gn na an nt t s so owws s:E Ex xp pe er ri imme en nt ta al l r re es su ul lt ts s 懷懷孕孕母母豬豬的的藍藍耳耳病病毒毒保保護護性性免免疫疫力力的的持持續續時時間間：

24、試試驗驗結結果果Demonstration of transplacental infection 胎胎盤盤感感染染的的展展示示0/9(11)previously infected sows;0%infection 0/9（11）之前感染的母豬；0%感染8/10 PRRS free sows;80%infection 8/10 藍耳陰性母豬；80%感染Conclusion 結結論論1.Homologous protection persist for 604 days post infection 同源保護力能在感染后持續604天(may persist for life-time 也可能持續

25、終生）2.No need to vaccinate repeatedly with same vaccine for up to 604 days 在長達604天的時間里沒有必要重復免疫相同疫苗3.Instead of using same vaccine repeatedly,vaccinate different vaccine 使用不同疫苗免疫來取代重復用相同疫苗免疫 to get broader protection 來獲得保保護護的的范范圍圍更更廣廣Lager&Mengeling 1997 Vet Microbiol 58:127一帶一路國際生豬產業大會How to choose a

26、 commercial MLV for your farm 如何給你的農場選擇一個商品化弱毒苗Cross-sectional SN titer distribution in a sow farm一個母豬場的血清中和抗體滴度的隊列分布Sow No.ofMean SN titers to PRRS MLV A,B or CSerumserumABCParity 15Parity 35Parity 55Parity 75Total2083264*Use of vaccine A the choice(Lowest mean SN titers)母豬血清 血清編號 對藍耳弱毒苗A,B,C的平均血清中

27、和抗體滴度1胎3胎5胎7胎總總計計選擇使用疫苗A（最低的平均血清中和抗體滴度）一帶一路國際生豬產業大會Vaccination strategy:MLV免疫策略：弱毒苗3 times repeated vaccination3 times repeated vaccination with the same vaccine with 3 different vaccinesWider range of coverageNarrow range of coverageGenetic/Antigenic variation range up to 25%基基因因/抗抗原原變變異異高高達達25%Whi

28、ch one is better to vaccinate between one vaccine 3 times ad 3 different vaccines 3 times?Protection line*At least 2 months interval in case of using different MLV vaccines 若使用不同弱毒疫苗，至少要有2個月時間間隔使用1個疫苗免疫3次好，還還是3次免疫使用3種不同疫苗更好？覆蓋范圍圍較較窄覆蓋范圍圍更寬寬保護護線線3次用相同疫苗重復免疫3次用3種不同疫苗重復免疫一帶一路國際生豬產業大會On-farm PRRSV contr

29、ol program農場上的藍耳控制z Following an acute outbreak in a nave farm,no additional vaccination may be necessary except for nave incoming gilts with home farm virus(serum)先天陰性場急性暴發藍耳后，可能不需要額外的免疫，除非是入群的陰性后備母豬可以用農場毒株（血清）免疫z Inoculation with serum containing farm specific PRRSV will be helpful for all incomin

30、g gilts in most commercial farms z 在大部分商品場對入群的后備母豬使用農場專有藍耳病毒血清接種是有幫助的。一帶一路國際生豬產業大會Serum inoculation接種血清Artificial infection/immunization of PRRS virus PRRS 病毒的人工感染/免疫Goal ELISA positive in 100%of the nave pigs after 2 weeks of the serum inoculation 目標-血清接種2周后100%陰性豬ELISA陽性。Preparation of PRRSV inocu

31、lum 制備藍耳病毒接種液1.Pool of serum from PRRS suspected pigs 對藍耳可疑豬的血清進行合樣PRRSV from stillborn or weak-born vs nursery pigs 從死胎或弱仔VS保育豬中準備藍耳病毒PRRSV from nursery pigs may not be effective for reproductive form 保育豬中的藍耳病毒可能對繁殖問題無效2.Pool of serum from PRRSV infected pigs 用藍耳感染豬的血清進行合樣On-farm virus culture usin

32、g PRRS nave pigs 使用藍耳先天陰性豬培養農場自身病毒3.In-clinic virus culture using PAM cells in large companies 大型公司可用豬肺泡巨噬細胞進行臨床病毒培養Problems:問題-Insufficient amount of virus 病毒量不足-Contamination of unwanted pathogen 污染了其他病原-Incorrect immunotype of PRRSV in the serum 血清中藍耳病毒的免疫型不對-Incorrect measurement of virus 病毒測量不對

33、一帶一路國際生豬產業大會No PRRSV infection in gene edited pigs with lack of CD163 receptor缺乏CD163受體的基因編輯豬不感染藍耳病毒PRRSV infection to alveolar macrophages require CD 163 receptor藍耳病毒感染巨噬細胞需要CD163受體一帶一路國際生豬產業大會Future research on PRRS control藍耳控制的未來研究z Development of PRRSV vaccines to have broaden cross-protective e

34、fficacy -Universal vaccine 開發有廣譜交叉保護力的藍耳疫苗-通用疫苗z Development of antiviral substance for PRRSV replication z 開發對藍耳病毒復制有抗病毒作用的物質yCompounds targeting CD163 靶向CD163的復合物yFeed additive to inhibit viral replication -Medium chain fatty acidsy抑制病毒復制的飼料添加劑-中鏈脂肪酸Li L,Wang H,Dong S,Ma Y.Supplementation with alp

35、ha-glycerol monolaurate during late gestation and lactation enhances sow performance,ameliorates milk composition,and improves growth of suckling piglets.Journal of Animal Science and Biotechnology.2023;14(1):1-12.https:/doi.org/10.1186/s40104-023-00848-x一帶一路國際生豬產業大會A An nt ti iv vi ir ra al l e ef

36、ff fe ec ct t o of f MMC CF FA A t to o P PE ED DV V中鏈脂肪酸對流行性腹瀉病毒的抗病毒作用Sal CURB,1%MCFA,0.66%caproic,0.66%caprylic and 0.66%capric acids enhance the RNA degradation of PEDV in swine feed.Sal-CURB、1%中鏈脂肪酸、0.66%己酸、0.66%辛酸和0.66%癸酸促進豬飼料中PEDV的RNA降解。Negative bioassay in the pigs showing that the treatments

37、 prevented infection.在豬上進行的陰性生物測定表明，這些處理可以預防感染。Medium chain fatty acids 中鏈脂肪酸-Feed additive fatty acids with 6,8,10 or 12 carbon atoms飼料添加劑脂肪酸含有6、8、10、12個碳原子-Ability to make weak certain types of bacteria or viruses 對某些細菌或病毒有致弱能力一帶一路國際生豬產業大會Inhibition of viral growth in vitro following treatment wit

38、h MCFA 使用中鏈脂肪酸處理在體外抑制了病毒生長No PRRSV was detected with C10MG,C12 or GML使用C0MG,C12或月桂酸甘油酯處理檢測不到藍耳病毒Significant reduction of ASFV with GML月桂酸甘油酯能顯著減少非瘟病毒一帶一路國際生豬產業大會Summary 總結z History,clinical signs,pathogenesis 歷史，臨床癥狀，發病機制yReproductive vs respiratory forms 繁殖型VS呼吸型z PRRSV variants&grouping 藍耳病毒變異體&分組

39、yGenetic vs serologic groups 基因分類VS血清分類z Homologous vs heterologous challenge 同源性攻毒VS異源性攻毒yProtection up to 604 days for reproductive form against homologous challenge y繁殖型的病毒保護力對抗同源攻毒的時間長達604天z Vaccination strategy 免疫策略yMLV:Repeated vaccination with different MLV y弱毒苗：使用不同弱毒苗重復免疫yInactivated vaccine:Repeated vaccination with farm-specific virusy滅活疫苗：使用農場專有病毒重復免疫 一帶一路國際生豬產業大會