CN109082415B - 一种鹅星状病毒病毒株及其应用 - Google Patents
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Abstract
本发明提供一种引起雏鹅痛风的鹅星状病毒，为GD 0122株，于2018年5月13日保藏在武汉大学中国典型培养物保藏中心，保藏编号为CCTCC No：V201820。本发明所提供的鹅星状病毒可用于制备用于预防雏鹅痛风的疫苗或抗体。本发明所筛选的病毒，其制备的雏鹅痛风疫苗安全性良好，未出现由疫苗引起的任何局部和全身不良反应。保存期试验中经过性状、安全性试验、效力试验数据的分析，各项指标均稳定有效；利用血清学方法和免疫攻毒法评估疫苗的免疫效果，结果显示，本发明中制备的灭活疫苗对鹅群能够提供有效的免疫保护，具有很好的商品化开发前景。
Description
技术领域
本发明属于兽用生物制品技术领域，具体涉及一种鹅星状病毒病毒株及其应用。
技术背景
痛风亦称尿酸盐沉积，肾病综合征，是由于体内尿酸产生过多或排泄障碍，造成体内大量尿酸蓄积，并以尿酸盐的形式沉积在关节、内脏器官浆膜面及其他组织间质，从而引起患禽运动迟缓、排白色稀粪、厌食、衰竭，甚至死亡，是特殊种类的蛋白质代谢紊乱性疾病。
当前鹅痛风主要发生在雏鹅，5～15日龄多发，有时可见1日龄雏鹅发病，多种品种鹅均可发病，死亡率在30％～70％，发病前2～3天病鹅排石灰样稀便，脱水变瘦，然后大群出现精神沉郁、减料、干脚、脱水、呼吸困难等症状。剖检可见心包由白色尿酸盐包被，俗称“绒毛心”，肝脏、气囊浆膜面及关节处均有白色尿酸盐沉积，肾脏肿大、斑驳，输尿管扩张并有尿酸盐沉积。
引起雏鹅痛风的诱因很多，通常认为与饲料蛋白含量过高、肾功能不全、引种、饲养管理不当等有关，但最近研究发现排除这些因素后，还是会发生痛风，将病死鹅剖检脏器进行触片染色，经革兰氏染色和瑞氏染色后镜下观察未发现细菌。刮取肠内容物，生理盐水涂片，置低倍镜下观察，未见球虫卵囊。取气囊及关节处石灰样物做涂片，置低倍镜下观察，可见大量针尖大小的尿酸盐结晶物。根据养殖户描述、临床症状、剖检病变，初步诊断为疑似鹅病毒性感染引发破坏肝肾功能，导致尿酸盐沉积。
通过对雏鹅痛风的流行病学调查，发现该病在我国鹅群中发病率呈日益上升趋势。基于目前，国内外没有预防和治疗该病的商品化疫苗(或抗体)，该病还在不断蔓延。研制安全有效的疫苗及预防和治疗用卵黄抗体迫在眉睫，必须通过创新技术克服这一问题。
发明内容
本发明的目的是提供一种引起雏鹅痛风症状的新型鹅星状病毒，并将其毒株制备成灭活疫苗免疫种鹅，使子代获得较高的母源抗体或是免疫蛋鸡，收集高免蛋，提取高免蛋中IgY抗体，用于预防雏鹅痛风，从而弥补现有技术的不足。
本发明所提供的引起雏鹅痛风症状的新型鹅星状病毒，为GD 0122株，于2018年5月13日保藏在武汉大学中国典型培养物保藏中心，保藏编号为CCTCC No：V201820。
本发明所提供的新型鹅星状病毒可用于制备用于预防雏鹅痛风的疫苗或抗体；
所述的疫苗为灭活疫苗。
本发明所筛选的病毒，其制备的雏鹅痛风疫苗安全性良好，未出现由疫苗免疫引起的任何局部和全身不良反应。保存期试验中经过性状、安全性试验、效力试验数据的分析，各项指标均稳定有效；利用血清学方法和免疫攻毒法评估疫苗的免疫效果，结果显示，本发明中制备的灭活疫苗对鹅群能够提供有效的免疫保护，具有很好的商品化开发前景。
具体实施方式
下面结合实施例对本发明进行详细的描述。
实施例1 GD 0122株的分离与鉴定
1、流行病学调查自2017年10月份以来，广东、四川、湖北等地区的雏鹅出现了一种死亡率较高、痛风症状明显的传染性疾病。该病多发于5～15日龄雏鹅，各种品种鹅均易感，对病死的雏鹅进行剖检，主要的病理变化如下：心包增厚，有白色结晶物附着或包被，俗称“绒毛心”，肝脏被尿酸盐覆盖，输尿管变粗、代谢受阻，肾脏红肿或苍白肿大、花斑肾，直肠末端内容物白色稀粪积聚，胆囊和脾脏肿大，肠壁变薄，严重的病例可见关节红肿、关节腔内有尿酸盐沉积。个别病例会出现严重的肠道栓塞，类似于小鹅瘟的典型发病症状。经临床调查和实验室检测，初步诊断为新型鹅星状病毒。发明人成功从广东某鹅场的10日龄发病鹅群中分离出一株病毒。
2、病毒分离选取发病症状典型的病死鹅肝脏、脾脏、肾脏，胰腺等组织50～100g，用研钵研磨组织，按1∶5(w/v)比例加含双抗(含1000U青霉素/ml+1000ug链霉素/ml)的无菌PBS(0.1mol/L，pH值7.2)匀浆，反复冻融3次后6000r/min离心10分钟，取上清液经0.22um滤器过滤除菌，无菌检验合格后保存备用。将病毒过滤液接种12～13日龄鹅胚，每胚0.2ml，36～37℃孵育，每日照胚2次，弃去24小时内死亡的鹅胚，收获24～168小时死亡鹅胚和168小时存活鹅胚尿囊液，置2～8℃冷却12～24小时，收获鹅胚尿囊液。
3、病毒的鉴定
3.1血凝性鉴定分别无菌采集SPF鸡和鹅血液5ml，按照2015版《中国兽药典》方法分别制备成0.8％、1％和2％浓度的红细胞悬液，4℃保存备用。将收获的鹅胚病毒液进行HA效价测定，检测分离毒株是否具有凝集这些红细胞的特性。结果：分离毒不能凝集SPF鸡和鹅红细胞，即使改变红细胞悬液的浓度，也不能使之凝集，红细胞对照成立。
3.2理化特性检验病毒液分别经氯仿、乙醚、盐酸(pH3)、温度(50℃、1小时)处理后，接种12日龄鹅胚(0.2ml/胚)，另设生理盐水处理组作为对照。37℃培养7日。结果：分离毒经乙醚、氯仿和盐酸(pH3)处理的毒株，不影响病毒鹅胚中的增殖，鹅胚出现死亡，PCR检测结果阳性，表明病毒没有脂质囊膜，对乙醚和氯仿有抵抗力，耐酸。病毒对热处理稳定，能抵抗50℃、1小时。分离毒株的核酸类型为RNA。
3.3PCR鉴定取分离株病毒200ul，利用RNA提取试剂盒提取病毒RNA，DNA提取试剂盒提取病毒DNA，RNA反转录成cDNA后，PCR检测鹅副粘、H5、H7、H9亚型禽流感、呼肠孤病毒及星状病毒，DNA PCR检测圆环病毒、禽腺病毒、小鹅瘟、番鸭细小病毒。PCR结束后1％琼脂糖凝胶电泳观察结果。
PCR反应体系：总体积25ul
在0.5m1 PCR管中依次加入
10×Ex Taq Mix-----------------12.5u1
上游引物(20pmol)---------------1u1
下游引物(20pmol)---------------1u1
DNA----------------------------2ul
用灭菌去离子水8.5ul补足至总体积25u1，PCR反应在PTC-100基因扩增仪内进行。PCR反应参数：预变性条件为94℃，3分钟，变性条件为94℃，30秒，退火温度和时间为50℃，30秒，延伸温度为72℃延伸45秒，35个循环，最后72℃延伸10分钟。
经扩增，分离毒株仅扩增出了星状病毒相应的目的片段，与预期目的片段大小相符。鹅副粘、H5、H7、H9亚型禽流感、呼肠孤病毒、圆环病毒、腺病毒、小鹅瘟病毒、番鸭细小病毒等检测均为阴性。对扩增的目的片段进行测序后，通过NCBI BLAST比对分析，分离毒与NCBI公布的星状病毒序列同源性最接近，但也存在较大的差异，同源性仅有60％左右，表明所筛选的病毒为一种新型的病毒。
3.4病毒致病性
3.4.1对鸡的致病性将GD 0122株分别以静脉注射和胸部肌肉途径接种7日龄SPF鸡各5只，1.0ml/只，观察14日，SPF鸡均健活，无任何临床表现，攻毒后14日剖检，未见任何病变。
3.4.2对鸭的致病性将GD 0122株分别以静脉注射和胸部肌肉途径接种2日龄雏鸭，1.0ml/只，观察14日，雏鸭均健活，无任何临床表现，攻毒后14日剖检，未见任何病变。
3.4.3对雏鹅的致病性将GD 0122株以肌肉注射途径接种2日龄雏鹅10只，1.0ml/只，雏鹅在攻毒后第4日开始出现死亡，死亡高峰集中在攻毒后7～9日，死亡率可达到8/10，发病雏鹅排白色稀粪，剖检病死雏鹅，可见肾脏发白或斑驳，输尿管肿大，肝脏遍布白点，严重者可见心包外尿酸盐沉积，在关节处出现干酪样尿酸盐沉积。
3.5病毒免疫原性检验将继代后的病毒液经纯化进行了免疫原性试验。该毒株制成灭活疫苗免疫成年雌性种鹅，免疫后2月龄所产子代均能够产生完全的攻毒保护，说明该毒株是一株理想的抗原。
3.6病毒特异性与中和效果检验该毒株和同期分离的其他流行毒株经继代和纯化制成灭活疫苗，分别免疫30日龄SPF鸡，首免剂量0.5ml/只，加强免疫剂量为1.0ml/只，每隔2周免疫一次，共免疫3次，3免后10天进行采血，分离血清，经56℃灭活1小时进行特异性试验。
将GD 0122株病毒液10倍稀释，分别与该毒株和流行株的阳性血清等体积混合，37℃中和1小时后，接种12日龄鹅胚，0.2ml/枚，接种后观察168小时。结果发现该病毒的阳性血清中和组鹅胚全部健活，其他流行株的阳性血清中和组仅70％～80％健活，未加血清中和的病毒组鹅胚全部死亡，说明本发明筛选的毒株作为抗原制备的阳性血清对本发明筛选的病毒的中和能力明显好于流行毒株制备的阳性血清。
实施例2
GD 0122株毒种的制备
将GD 0122株毒种10倍稀释，接种12～13日龄健康鹅胚，0.2ml/胚，置60％湿度、37℃温箱内培养168小时，24小时内死亡的鹅胚弃去，24～168小时死亡的鹅胚随即取出，置4℃保存，至168小时，将活胚全部取出，4℃存放12～24小时后，收取鹅胚尿囊液。依此方法将上述收获的鹅胚尿囊液继续在12～13日龄鹅胚中继代5代，分别标记为D2～D6代。测定每代次病毒含量。将检验无菌且病毒含量≥105.0TCID50病毒液混合，定量分装，冻干保存。
实施例3
GD 0122株抗原的制备
1、接种取GD 0122株毒种，用灭菌PBS(0.1mol/L，pH值7.2)作10倍稀释，接种12～13日龄健康鹅胚，0.2ml/胚，接种后密封针孔，置36～37℃继续孵育，不必翻胚。
2、孵育和观察鹅胚接种后，每日照胚2次，将24小时前死亡的鹅胚弃去。直至168小时，无论死亡与否，全部取出，气室向上直立，置于2～8℃冷却12～24小时。
3、收获将冷却的鹅胚取出，用碘酊消毒气室部位，然后以无菌方法剥除气室部卵壳，揭去卵膜，剪破绒毛尿囊膜及羊膜(谨防卵黄破裂)，吸取胚液。在吸取胚液前对每个鹅胚仔细检查，凡胎儿腐败、胚液混浊及有任何污染可疑者，应弃去。死胚和活胚分别收获，每若干个鹅胚分为一组，吸取胚液放入同一灭菌的容器内，置-20℃保存。
实施例4
GD 0122株病毒液的灭活及半成品检验与疫苗的制备
1灭活将GD 0122株病毒液导入灭活瓶内，计量加入10％甲醛溶液，开启搅拌机搅拌，使其充分混合，甲醛的最终浓度为0.1％。加甲醛溶液后导入另一灭活瓶中，以避免瓶口附近粘附的病毒未能接触灭活剂。4℃灭活36小时，如有剩余放2～8℃保存，应不超过1个月。
2半成品检验
2.1无菌检验取灭活的病毒液，按2015年版《中国兽药典》附录进行检验，无菌生长。
2.2灭活检验将灭活后的病毒液，接种12～13日龄鹅胚5枚，0.2ml/胚，每日照胚2次，观察7日，收获鹅胚尿囊液，PCR检测阴性，然后将胚液再盲传一次，观察7日，PCR检测仍未阴性时，认为灭活完全。
2.3病毒含量测定将毒种用灭菌PBS(0.1mol/L，pH值7.2)进行10倍系列稀释，取10－3、10－4、10－5、10－6 4个稀释度，分别接种于12～13日龄鹅胚，每个稀释度接种5枚，每胚0.2ml。同时设病毒阳性对照和PBS阴性对照，置60％湿度、37℃培养箱培养和观察168小时，鹅胚死亡或活胚PCR检测阳性者判为感染，计算EID50。
3灭活疫苗的制备
取灭活的抗原液与SEPPIC ISA71油佐剂按适当比例进行乳化，先开动电机低速搅拌ISA71佐剂2分钟，同时徐徐加入抗原液，10000r/min，乳化15分钟，即成油乳剂灭活疫苗。
4分装定量分装，加盖密封，并粘贴标签，置2～8℃保存。
实施例5
疫苗成品检验
1性状
外观乳白色乳剂。
剂型油包水型。取一清洁吸管，吸取少量疫苗滴入冷水中，除第1滴外，应不扩散。
稳定性吸取疫苗10ml加入离心管中，以3000r/min离心15分钟，管底析出的水相应不超过0.5ml。
黏度按现行《中国兽药典》附录进行，应符合规定。
2装量检查按现行《中国兽药典》附录进行检查，应符合规定。
3无菌检验按现行《中国兽药典》附录进行检验，应无菌生长。
4安全检验皮下免疫1日龄雏鹅10只，每只颈部皮下分点注射疫苗1.0ml，观察21日，生长发育均正常，精神状态良好，剖检注射部位疫苗吸收良好，无红肿、组织坏死等炎症反应。
5疫苗免疫效果检测
5.1血清学方法将疫苗以2.0ml/只的剂量颈部皮下或肌肉注射种鹅10只，另设不免疫对照10只。免疫后28日，免疫鹅和对照鹅分别采血，分离血清，用琼脂免疫扩散试验法测定血清抗体效价，记录抗体结果。
5.2免疫攻毒法将疫苗以2.0ml/只的剂量颈部皮下或肌肉注射种鹅，另设不免疫作对照。免疫后1～2月，收集种蛋，孵化出雏鹅，对1日龄雏鹅10只进行攻毒，同时设不免疫对照子代1日龄雏鹅10只作为对照。所有免疫鹅和对照鹅子代，肌肉注射病毒液0.5ml/只(病毒含量105.2EID50/0.2ml)。观察并详细记录免疫鹅和对照鹅子代的发病情况。
结果显示：3批疫苗免疫种鹅后，免后28天，琼扩抗体效价均能达到8/10以上阳性，而对照未免疫鹅，琼扩抗体效价均为阴性；子代1日龄雏鹅母源抗体高，攻毒后3批疫苗免疫鹅子代观察14日，保护数均不少于8只；对照鹅攻毒全部发病，死亡6只，死亡鹅进行剖检，均可见肾脏肿大，发白或斑驳，严重的出现“绒毛心”及关节处干酪样尿酸盐沉积等典型病变。详见下表1。
表1 3批疫苗效力检验结果
综上，本发明使用筛选的GD 0122株制备的疫苗是一种免疫效果比较理想的灭活苗，免疫种鹅后，使子代的母源抗体提升，能够有效的预防子代雏鹅痛风的发生。
Claims (6)
1.一种鹅星状病毒，其特征在于，所述的鹅星状病毒的保藏编号为CCTCC No：V201820。
2.权利要求1所述的鹅星状病毒在制备疫苗中的应用。
3.如权利要求2所述的应用，其特征在于，所述的疫苗为灭活疫苗。
4.如权利要求3所述的应用，其特征在于，所述的疫苗用于预防雏鹅痛风。
5.权利要求1所述的鹅星状病毒在制备抗体中的应用。
6.如权利要求5所述的应用，其特征在于，所述的抗体用于预防雏鹅痛风。
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| Novel Goose Astrovirus Associated Gout in Gosling, China;Xiaoyu Niu;《Veterinary Microbiology》;20180516;第53-56页 * |
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| 导致雏鹅痛风新型鹅星状病毒的分离鉴定;姜晓宁;《中国兽医学报》;20180531;第38卷(第5期);摘要，第877页右栏第2段 * |
| 鹅肾致病型星状病毒的分离与鉴定;张清水;《中国畜牧兽医学会兽医公共卫生学分会第六次学术研讨会论文集》;20180731;第13-14页 * |
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