CN109111518A - 防治猫瘟热的特异性卵黄抗体及其制备方法 - Google Patents
防治猫瘟热的特异性卵黄抗体及其制备方法 Download PDFInfo
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- CN109111518A CN109111518A CN201811016402.5A CN201811016402A CN109111518A CN 109111518 A CN109111518 A CN 109111518A CN 201811016402 A CN201811016402 A CN 201811016402A CN 109111518 A CN109111518 A CN 109111518A
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Abstract
本发明公开了一种防治猫瘟热的特异性卵黄抗体,以FPV灭活苗和FPV亚单位疫苗为免疫原,通过免疫蛋鸡制得。据此建立了相应制备方法,该法创造性的以两种不同FPV免疫原接种蛋鸡,以FPV灭活苗为基础免疫原,以FPV亚单位疫苗为加强免疫原,并优化了免疫接种方法和接种剂量以产生高抗体效价;免疫蛋鸡后,收取高免蛋,分离蛋黄,提取卵黄抗体粗品,并对其进行纯化处理,制备获得抗猫瘟热病毒特异性卵黄抗体。试验表明,本发明的卵黄抗体安全性好、特异性强、抗体效价高,且成本低、产量高,可用于猫瘟热的治疗与紧急预防,增加患病猫的抵抗力,具有很好的推广应用前景。
Description
技术领域
本发明属于猫瘟热治疗技术领域,尤其涉及一种防治猫瘟热的特异性卵黄抗体及其制备方法。
背景技术
猫瘟热又名猫泛白细胞减少症、猫传染性肠炎等,是由猫细小病毒(FPV)引起的猫的一种急性、高度接触性和致死性传染病,临床上以突发高热、呕吐、腹泻及白细胞严重减少为主要特征,是家猫最常见的传染病。FPV只有一个血清型,自然条件下可感染猫科、浣熊科和鼬科等多种动物,其中以小体型猫科动物和水貂最易感。FPV可通过直接或间接接触感染,发病动物通过粪、尿、呕吐物、唾液等排泻物和分泌物排毒,污染环境、器具、饲料等,引起直接和间接传染,常呈地方性流行,其病死率一般为60%~70%,最高可达90%以上(幼兽死亡率可达100%),危害极为严重。
猫瘟热是猫科动物疾病预防的重点,目前,国内外均采用疫苗免疫注射来预防该病的发生。由于还没有针对病毒性疫病的特效药物,对于发病的动物,临床上主要采用对症治疗或用抗生素来预防并发症的发生,疗效并不显著。因此,开发一种针对猫瘟热特异性好,防治效果显著的预防治疗制剂,具有重要的现实意义。
发明内容
本发明要解决的技术问题是提供一种防治猫瘟热的特异性卵黄抗体及其制备方法,以缓解FPV缺乏特效药物、疗效不佳等现状。
为解决上述技术问题,本发明采用以下技术方案:
防治猫瘟热的特异性卵黄抗体,以FPV灭活苗和FPV亚单位疫苗为免疫原,通过免疫蛋鸡制得。
上述防治猫瘟热的特异性卵黄抗体,以FPV灭活苗为基础免疫原,以FPV亚单位疫苗为加强免疫原,通过先后免疫蛋鸡制得。
上述防治猫瘟热的特异性卵黄抗体的制备方法,包括以下步骤:
(1)免疫原制备
灭活FPV-GX01病毒(猫细小病毒GX01株),加入胸腺肽至终浓度为0.3mg/mL,然后将其与白油佐剂按照体积比1∶2(V/V)充分乳化制备FPV灭活苗;将FPV-VLPs(猫细小病毒样粒子)与ISA206佐剂按照体积比1∶1(V/V)充分乳化制备FPV亚单位疫苗;
(2)蛋鸡免疫
利用FPV灭活苗、FPV亚单位疫苗先后免疫注射蛋鸡,收集鸡蛋,测定卵黄液中FPV特异抗体效价,当卵黄液血凝抑制效价≥1∶32~64,大量收集高免蛋;
(3)卵黄抗体分离纯化
将获得的高免蛋用辛酸法分离和纯化FPV卵黄抗体。
步骤(1)中FPV-VLPs是经过昆虫细胞密码子偏好优化的FPV-VP2基因在杆状病毒/昆虫细胞表达系统中表达形成的,并且其血凝效价≥1∶29。
优化的FPV VP2基因具有序列表SEQ.ID.No.1的碱基序列,其编码的VP2蛋白具有序列表SEQ.ID.No.2的氨基酸序列
步骤(2)中免疫注射的程序为:先用FPV灭活苗进行基础免疫注射1次,免疫剂量为0.2-1mL/只,于免疫后14d、28d改用FPV亚单位疫苗进行2次加强免疫,免疫剂量分别为0.4-2mL/只、0.6-3mL/只;若卵黄液FPV血凝抑制效价低于1∶32时,进行再一次加强免疫。
步骤(3)按以下操作进行:
(A)将高免蛋放入自来水中冲洗浸泡5-10min后转移到1%的新洁尔灭溶液中再浸泡10-20min,晾干后再进行75%乙醇擦拭消毒备用;
(B)收集卵黄,搅拌成卵黄液后用无菌蒸馏水将其进行4-6倍稀释,调节pH至5.2后4℃放置6-10h后离心收集上清液;
(C)用pH值为5.2-5.4,0.1M的醋酸盐缓冲液进行2倍稀释,搅拌30-60min,加入终浓度为1%-3%的辛酸,静置分层后取水相进行离心,收集上清液,0.45um滤膜过滤,收集滤液,即为猫瘟热卵黄抗体。
针对目前防治猫瘟热特异性抗体缺乏的现状,发明人设计并制备了一种防治猫瘟热的特异性卵黄抗体,以FPV灭活苗和FPV亚单位疫苗为免疫原,通过免疫蛋鸡制得。据此建立了相应制备方法,该法创造性的以两种不同FPV免疫原接种蛋鸡,以FPV灭活苗为基础免疫原,以FPV亚单位疫苗为加强免疫原,并优化了免疫接种方法和接种剂量以产生高抗体效价,免疫蛋鸡后,收取高免蛋,分离蛋黄,提取卵黄抗体粗品,并对其进行纯化处理,制备获得抗猫瘟热病毒特异性卵黄抗体。试验表明,本发明的卵黄抗体安全性好、特异性强、抗体效价高,且成本低、产量高,可用于猫瘟热的治疗与紧急预防,增加患病猫的抵抗力,具有很好的推广应用前景。
具体实施方式
一、FPV灭活疫苗的制备
将FPV-GX01毒株按1/10的体积同步接种到猫肾传代细胞FK81细胞中,37℃CO2培养箱中静置24h后弃掉生长液并换成维持液继续培养,逐日观察细胞病变,待75%细胞出现病变时,收集细胞,反复冻融3次,然后4℃,12000rpm离心15min,去除细胞碎片,收集上清液,测定其TCID50/0.1mL值≥5.0,血凝效价≥1∶210后,加入胸腺肽至终浓度为0.3mg/mL后,加入甲醛至终浓度为0.1%,37℃灭活24h,每隔4h振荡1次,随后加入4%吐温-80作为水相;Span80与10号白油按3∶47的体积比(V/V)混合作为油相,水相与油相按体积比1∶2混合进行油包水搅拌乳化,制得FPV油乳剂灭活苗。
二、FPV亚单位疫苗的制备
人工合成经昆虫细胞密码子偏好优化的FPV VP2基因(SEQ.ID.No.1),将其定向克隆到杆状病毒转移载体pFastBacI上,构建重组质粒pFastBac-VP2。重组质粒转化大肠杆菌DH10Bac感受态细胞,进行100倍稀释后,涂布于含四环素(10μg/mL)、卡那霉素(50μg/mL)、庆大霉素(7μg/mL)、β-半乳糖苷(100μg/mL)和IPT6(40μg/mL)的SOB平板中,培养72小时后,挑取白色菌落重新接种于新的SOB平板中,37℃培养过夜,挑取白色单克隆接种于含(50μg/mL)卡那霉素,(7μg/mL)庆大霉素,(10μg/mL)四环素的LB培养液中,37℃培养8-12h后提取重组杆粒Bac-VP2,并用M13引物进行重组杆粒鉴定。用3000将鉴定正确的重组杆粒转染Sf9细胞27℃培养4-5天后收取重组杆状病毒。重组杆状病毒按10%接种量感染Sf9细胞,待细胞出现病变后以80%预冷丙酮固定,以FITC荧光标记的羊抗鼠IgG为一抗对重组杆状病毒表达产物进行IFA鉴定;同时收集重组杆状病毒培养物进行电镜观察;经IFA及电镜观察确定VP2蛋白(SEQ.ID.No.2)表达并形成VLPs子后,大量培养收集细胞及其培养物上清,-20~20℃反复冻融3次,4℃,12000rpm离心15min,收集上清液,用饱和(NH4)2SO4沉淀蛋白,TritonX-100和磷酸三丁酯(TBP)灭活杆状病毒,透析袋初步纯化VLPs,测定并调整其血凝效价为1∶29,最后按照抗原/佐剂体积比1∶1加入ISA 206佐剂完全乳化,制备成为重组FPV亚单位疫苗。
三、卵黄抗体的制备
(1)选择90日龄健康的蛋鸡,使用FPV灭活苗进行初次基础免疫(翼下肌肉注射0.5mL);间隔14d,使用FPV亚单位疫苗进行第一次加强免疫(翼下肌肉注射1mL);间隔28d,使用FPV亚单位疫苗进行第二次加强免疫(翼下肌肉注射1.5mL)。第三次免疫后测定卵黄液FPV抗体效价,血凝抑制效价达到1∶32时,大量收集高免蛋。
(2)将高免蛋放入自来水中冲洗浸泡10min后转移到1%的新洁尔灭溶液中再浸泡20min,晾干后进行75%乙醇擦拭消毒备用;
(3)收集卵黄,搅拌成卵黄液后用无菌蒸馏水将其进行4倍稀释,调节pH至5.2后4℃放置6h后离心收集上清液;
(4)用pH值为5.2,0.1M的醋酸盐缓冲液进行2倍稀释,搅拌30min,加入终浓度为1%的辛酸,静置分层后取水相进行离心,收集上清液,0.45um滤膜过滤,收集滤液,即为纯化的猫瘟热卵黄抗体。
四、卵黄抗体效价测定
取纯化后卵黄抗体进行血凝抑制试验,所制备的卵黄抗体血凝抑制效价不低于1∶256。五、卵黄抗体临床治疗效果试验
取4月龄感染FPV病猫12只,随机分3组,每组4只,第1组使用本发明制备的卵黄抗体,第2组使用市售猫瘟热单克隆抗体注射液,第3组使用生理盐水。其中第1组每只病猫每次肌肉注射卵黄抗体4mL,连续注射3天;第2组注射市售单克隆抗体2mL,连续注射3天;第3组同样方法注射4mL生理盐水;此外每组猫在注射抗体治疗的同时给予消炎、止吐、止血等辅助治疗。观察记录治疗情况。
结果显示(表1),在治疗前,病猫普遍精神沉郁、嗜睡、呕吐、腹泻等,经过治疗后,猫的精神状况得到明显改善,临床症状明显减轻,治疗7天后,75%的猫临床症状消失,而注射生理盐水的病猫,发病后7天均死亡。试验表明,所制备的卵黄抗体与单克隆抗体治疗猫瘟热的作用相似,具有良好的瘟热治疗效果。
表1卵黄抗体临床治疗效果
六、卵黄抗体临床预防效果试验
取健康4月龄猫12只,同时按上述分组方式进行分组开展预防试验,用相同方式对试验组和对照组分别肌肉注射3mL卵黄抗体、2mL单克隆抗体和3mL生理盐水,连续注射3天。第5天,所有试验猫皮下注射1mL FPV细胞培养液进行人工攻毒,观察其发病情况。以粪便检出FPV,体温升高、腹泻和呕吐为发病判断标准。结果显示,生理盐水注射组4只猫均发病,发病率为100%,卵黄抗体和单克隆抗体注射组的发病率均为50%,显著低于生理盐水对照组。结果表明,与单克隆抗体显示,所制备的卵黄抗体具有良好的预防猫瘟热的作用。
表2卵黄抗体临床预防效果试验
综上,本发明制备的卵黄抗体可用于猫瘟热的紧急预防和治疗,具体应用方法规定如下:
(1)紧急预防用量:按3mL/只进行皮下或肌肉注射,连续注射3天,每天1次,大流行时用量可加倍。
(2)治疗用量:按1-2mL/kg体重皮下或肌肉注射,连续注射3天,每天1次。
序列表
<110> 广西壮族自治区兽医研究所
<120> 防治猫瘟热的特异性卵黄抗体及其制备方法
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agcggtggtg tgggaatcag tactggtact tttaataacc agactgagtt taagttcctg 240
gagaacggat gggtggagat tactgctaac tcctccaggc tggtgcattt gaatatgcca 300
gagtctgaga attacaagcg cgtggtggtg aacaacatgg acaagaccgc cgttaaaggt 360
aacatggctt tggacgacac ccacgtgcag atcgtgaccc cttggtccct ggtggacgct 420
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gtggccctgg actccaacaa tacaatgcct ttcacccctg ctgctatgcg ctccgagaca 660
ctcggtttct atccctggaa gcctaccatc cccacccctt ggcgctacta cttccagtgg 720
gatcgcaccc tgatcccttc ccacaccggc acctccggca ctcccaccaa cgtgtaccac 780
ggcaccgacc ccgatgacgt ccaattctac accatcgaga attccgtccc cgtccacctt 840
ctgcgcactg gtgacgagtt cgcaaccggc accttcttct tcgactgcaa gccttgccgc 900
ctgacccaca cctggcaaac caaccgcgcc ctgggtctgc ctcctttcct taactccctc 960
cctcagtccg agggtgctac caactttggc gacatcggtg tgcagcagga caagagacgc 1020
ggcgtcaccc agatgggcaa caccgattac atcaccgagg ctaccatcat gcgccctgct 1080
gaggttggat actccgcccc ttactattcc ttcgaggctt ccacccaggg ccctttcaaa 1140
acccccatcg ctgctggtcg cggtggcgct caaaccgacg agaaccaggc tgctgacggt 1200
gatcctcgct acgctttcgg ccgccagcac ggacaaaaaa ccactaccac tggtgagacc 1260
cctgagcgct tcacctacat cgctcaccag gacactggtc gctaccctga gggtgactgg 1320
attcaaaaca tcaacttcaa cctgcctgtg accaacgaca acgtgctgct gcctactgac 1380
cctatcggtg gtaagactgg tatcaactac accaacatct tcaacaccta cggtcctctg 1440
accgctctga acaacgtgcc tcctgtgtac cctaacggtc agatctggga caaggagttc 1500
gacaccgacc tgaagcctcg cctgcacgtg aacgctcctt tcgtgtgcca gaacaactgc 1560
cctggtcagc tgttcgtgaa ggtggctcct aacctgacca acgagtacga ccctgacgct 1620
tccgctaaca tgtcccgcat cgtgacctac tccgacttct ggtggaaggg taagctggtg 1680
ttcaaggcta agctgcgcgc ttcccacacc tggaacccta tccagcagat gtccatcaac 1740
gtggacaacc agttcaacta cgtgcctaac aacatcggtg ctatgaagat cgtgtacgag 1800
aagtcccagc tggctcctcg caagctgtac accggtcacc accaccacca ccactaa 1857
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Met Lys Phe Leu Val Asn Val Ala Leu Val Phe Met Val Val Tyr Ile
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Ser Tyr Ile Tyr Ala Gly Leu Glu Ile Asp Met Ser Asp Gly Ala Val
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Gln Pro Asp Gly Gly Gln Pro Ala Val Arg Asn Glu Arg Ala Thr Gly
35 40 45
Ser Gly Asn Gly Ser Gly Gly Gly Gly Gly Gly Gly Ser Gly Gly Val
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Gly Ile Ser Thr Gly Thr Phe Asn Asn Gln Thr Glu Phe Lys Phe Leu
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Glu Asn Gly Trp Val Glu Ile Thr Ala Asn Ser Ser Arg Leu Val His
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Leu Asn Met Pro Glu Ser Glu Asn Tyr Lys Arg Val Val Val Asn Asn
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Met Asp Lys Thr Ala Val Lys Gly Asn Met Ala Leu Asp Asp Thr His
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Val Gln Ile Val Thr Pro Trp Ser Leu Val Asp Ala Asn Ala Trp Gly
130 135 140
Val Trp Phe Asn Pro Gly Asp Trp Gln Leu Ile Val Asn Thr Met Ser
145 150 155 160
Glu Leu His Leu Val Ser Phe Glu Gln Glu Ile Phe Asn Val Val Leu
165 170 175
Lys Thr Val Ser Glu Ser Ala Thr Gln Pro Pro Thr Lys Val Tyr Asn
180 185 190
Asn Asp Leu Thr Ala Ser Leu Met Val Ala Leu Asp Ser Asn Asn Thr
195 200 205
Met Pro Phe Thr Pro Ala Ala Met Arg Ser Glu Thr Leu Gly Phe Tyr
210 215 220
Pro Trp Lys Pro Thr Ile Pro Thr Pro Trp Arg Tyr Tyr Phe Gln Trp
225 230 235 240
Asp Arg Thr Leu Ile Pro Ser His Thr Gly Thr Ser Gly Thr Pro Thr
245 250 255
Asn Val Tyr His Gly Thr Asp Pro Asp Asp Val Gln Phe Tyr Thr Ile
260 265 270
Glu Asn Ser Val Pro Val His Leu Leu Arg Thr Gly Asp Glu Phe Ala
275 280 285
Thr Gly Thr Phe Phe Phe Asp Cys Lys Pro Cys Arg Leu Thr His Thr
290 295 300
Trp Gln Thr Asn Arg Ala Leu Gly Leu Pro Pro Phe Leu Asn Ser Leu
305 310 315 320
Pro Gln Ser Glu Gly Ala Thr Asn Phe Gly Asp Ile Gly Val Gln Gln
325 330 335
Asp Lys Arg Arg Gly Val Thr Gln Met Gly Asn Thr Asp Tyr Ile Thr
340 345 350
Glu Ala Thr Ile Met Arg Pro Ala Glu Val Gly Tyr Ser Ala Pro Tyr
355 360 365
Tyr Ser Phe Glu Ala Ser Thr Gln Gly Pro Phe Lys Thr Pro Ile Ala
370 375 380
Ala Gly Arg Gly Gly Ala Gln Thr Asp Glu Asn Gln Ala Ala Asp Gly
385 390 395 400
Asp Pro Arg Tyr Ala Phe Gly Arg Gln His Gly Gln Lys Thr Thr Thr
405 410 415
Thr Gly Glu Thr Pro Glu Arg Phe Thr Tyr Ile Ala His Gln Asp Thr
420 425 430
Gly Arg Tyr Pro Glu Gly Asp Trp Ile Gln Asn Ile Asn Phe Asn Leu
435 440 445
Pro Val Thr Asn Asp Asn Val Leu Leu Pro Thr Asp Pro Ile Gly Gly
450 455 460
Lys Thr Gly Ile Asn Tyr Thr Asn Ile Phe Asn Thr Tyr Gly Pro Leu
465 470 475 480
Thr Ala Leu Asn Asn Val Pro Pro Val Tyr Pro Asn Gly Gln Ile Trp
485 490 495
Asp Lys Glu Phe Asp Thr Asp Leu Lys Pro Arg Leu His Val Asn Ala
500 505 510
Pro Phe Val Cys Gln Asn Asn Cys Pro Gly Gln Leu Phe Val Lys Val
515 520 525
Ala Pro Asn Leu Thr Asn Glu Tyr Asp Pro Asp Ala Ser Ala Asn Met
530 535 540
Ser Arg Ile Val Thr Tyr Ser Asp Phe Trp Trp Lys Gly Lys Leu Val
545 550 555 560
Phe Lys Ala Lys Leu Arg Ala Ser His Thr Trp Asn Pro Ile Gln Gln
565 570 575
Met Ser Ile Asn Val Asp Asn Gln Phe Asn Tyr Val Pro Asn Asn Ile
580 585 590
Gly Ala Met Lys Ile Val Tyr Glu Lys Ser Gln Leu Ala Pro Arg Lys
595 600 605
Leu Tyr Thr Gly His His His His His His
610 615
Claims (7)
1.一种防治猫瘟热的特异性卵黄抗体,其特征在于以FPV灭活苗和FPV亚单位疫苗为免疫原,通过免疫蛋鸡制得。
2.根据权利要求1所述的防治猫瘟热的特异性卵黄抗体,其特征在于以FPV灭活苗为基础免疫原,以FPV亚单位疫苗为加强免疫原,通过先后免疫蛋鸡制得。
3.权利要求1所述防治猫瘟热的特异性卵黄抗体的制备方法,其特征在于包括以下步骤:
(1)免疫原制备
灭活FPV-GX01病毒,加入胸腺肽至终浓度为0.3mg/mL,然后将其与白油佐剂按照体积比1∶2充分乳化制备FPV灭活苗;将FPV-VLPs与ISA206佐剂按照体积比1∶1充分乳化制备FPV亚单位疫苗;
(2)蛋鸡免疫
利用FPV灭活苗、FPV亚单位疫苗先后免疫注射蛋鸡,收集鸡蛋,测定卵黄液中FPV特异抗体效价,当卵黄液血凝抑制效价≥1∶32~64,大量收集高免蛋;
(3)卵黄抗体分离纯化
将获得的高免蛋用辛酸法分离和纯化FPV卵黄抗体。
4.根据权利要求3所述的防治猫瘟热的特异性卵黄抗体的制备方法,其特征在于步骤(1)中FPV-VLPs是经过昆虫细胞密码子偏好优化的FPV-VP2基因在杆状病毒/昆虫细胞表达系统中表达形成的,并且其血凝效价≥1∶29。
5.根据权利要求3所述的防治猫瘟热的特异性卵黄抗体的制备方法,其特征在于:所述优化的FPV VP2基因具有序列表SEQ.ID.No.1的碱基序列,其编码的VP2蛋白具有序列表SEQ.ID.No.2的氨基酸序列。
6.根据权利要求3所述的防治猫瘟热的特异性卵黄抗体的制备方法,其特征在于步骤(2)中免疫注射的程序为:先用FPV灭活苗进行基础免疫注射1次,免疫剂量为0.2-1mL/只,于免疫后14d、28d改用FPV亚单位疫苗进行2次加强免疫,免疫剂量分别为0.4-2mL/只、0.6-3mL/只;若卵黄液FPV血凝抑制效价低于1:32时,进行再一次加强免疫。
7.根据权利要求3所述的防治猫瘟热的特异性卵黄抗体的制备方法,其特征在于步骤(3)按以下操作进行:
(A)将高免蛋放入自来水中冲洗浸泡5-10min后转移到1%的新洁尔灭溶液中再浸泡10-20min,晾干后再进行75%乙醇擦拭消毒备用;
(B)收集卵黄,搅拌成卵黄液后用无菌蒸馏水将其进行4-6倍稀释,调节pH至5.2后4℃放置6-10h后离心收集上清液;
(C)用pH值为5.2-5.4,0.1M的醋酸盐缓冲液进行2倍稀释,搅拌30-60min,加入终浓度为1%-3%的辛酸,静置分层后取水相进行离心,收集上清液,0.45um滤膜过滤,收集滤液,即为猫瘟热卵黄抗体。
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