CN101605898A - 新型犬流感病毒及用于它的疫苗 - Google Patents
新型犬流感病毒及用于它的疫苗 Download PDFInfo
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- CN101605898A CN101605898A CNA2007800299717A CN200780029971A CN101605898A CN 101605898 A CN101605898 A CN 101605898A CN A2007800299717 A CNA2007800299717 A CN A2007800299717A CN 200780029971 A CN200780029971 A CN 200780029971A CN 101605898 A CN101605898 A CN 101605898A
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Abstract
本文公开了新型流感病毒A/Canine/Korea/01/07(H3N2)、A/Canine/Korea/02/07(H3N2)和A/Canine/Korea/03/07(H3N2)。还公开了一种包含至少一种所述病毒的疫苗组合物、一种通过给予所述疫苗组合物来预防或治疗由流感病毒感染引起的疾病的方法以及一种用于检测所述病毒的分析试剂盒。
Description
技术领域
本发明涉及新型流感病毒A/Canine/Korea/01/07(H3N2)、A/Canine/Korea/02/07(H3N2)和A/Canine/Korea/03/07(H3N2),还涉及包含至少一种所述病毒作为活性成分的疫苗组合物、用于预防或治疗由流感病毒感染引起的疾病的方法以及用于检测所述病毒的分析试剂盒。
背景技术
由正黏液病毒科(Orthomyxoviridae)家族的流感病毒A引起的流感,是人、猪、马和家禽最具有经济学重要性的疾病。
基于已知的红血球凝集素(H)和神经氨酸苷酶(N)这两种表面蛋白的特性,将流感病毒A进一步分类。将流感病毒A表示为H(红血球凝集素)亚型和一种类型N(神经氨酸苷酶)的组合(例如,H9N2)。有16种不同的H亚型和9种N亚型,导致流感病毒A的H和N亚型总计有144种不同的可能组合。
流感是一种人畜共患病。在3种流感类型中,A型病毒是最恶性的人病原体,引发最严重的疾病。此外,它们非常易于变异并且易于从一个物种传播到另一物种,引发流行病。因此,流行性流感的爆发已成为亟待解决的重大问题。此外,有几个报道认为流感病毒正在感染迄今已知能抵抗病毒感染的新物种。
犬流感指的是引起犬科动物流感的流感病毒A的新品种。因为之前没有暴露于这种病毒,所以犬类对这种病毒没有天然免疫力。因此,所有种类和各种年龄均易感染这种病毒。带有犬流感的犬类可能患有急性肺炎,表现出剧烈咳嗽、高烧和流鼻涕的症状。
高度传染性流感病毒经发现是造成2004年Florida赛犬跑道上Greyhound赛犬因呼吸性疾病死亡的原因。当时,因为在美国的Texas、Alabama、Arkansas和其他州均报导了犬流感的爆发,所以犬流感被视为犬类的新流行病。流行病学的调查显示出:从带有犬流感的犬分离出来的病毒几乎与马流感病毒H3N8相同,表明犬流感的产生是由马传播到犬的结果。有报道说马流感病毒H3N8引起赛犬出血性肺炎,并从犬类分离出人流感病毒H3N8。然而,必须找到犬流感的足够的血清学和病毒学证据。
此外,已有犬科动物爆发禽流感的报导病例。据推测,流感由禽类传播到犬类的流行病学机理有两种途径:一种途径是通过向犬类喂食未煮过的携带流感的禽类,如鸭、鸡等;流感病毒蔓延的另一种主要途径是以咳嗽和喷嚏的呼吸小滴从感染的犬类传播到正常犬类。另外,据推测,犬流感在感染的犬类暴露于新环境并与正常犬类接触后形成。重要的是预防犬流感,因为犬流感病毒可引起具有不同死亡率的继发性感染。这时没有可用于犬类的疫苗。
发明内容
技术问题
为实现本发明,本发明者在上述背景下对犬科动物流感病毒的产生进行了深入彻底的研究,结果发现来自韩国某些犬类的流感病毒是A血清型变体,与以前的流感病毒不同,并且,尽管属于禽群,但是通过病毒学、血清学、病理学和进化分析却显示出禽类和犬类之间的种间传播。此外,已经成功开发了抵抗这些病毒的高度稳定的疫苗。
技术方案
本发明的一个目的是,提供一种新型的H3N2血清型犬流感病毒。
本发明的另一个目的是,提供一种编码流感病毒蛋白组分的核苷酸序列。
本发明的另一个目的是,提供一种抵抗上述新型病毒的疫苗组合物。
本发明的另一个目的是,提供一种用于检测H3N2血清型流感病毒的分析试剂盒,所述分析试剂盒包括本发明的病毒或其抗原决定簇。
附图说明
图1显示与流感病毒A/Dove/Korea/S11/03(H3N2)、A/Duck/Korea/S7/03(H3N2)和A/Chicken/Korea/S6/03(H3N2)的那些相比较,用流感病毒A/Canine/Korea/01/07(H3N2)的NA基因编码的完全氨基酸序列。
图2显示与流感病毒A/Canine/Korea/01/07(H3N2)、A/Dove/Korea/S11/03(H3N2)、A/Duck/Korea/S7/03(H3N2)和A/Chicken/Korea/S6/03(H3N2)的那些相比较,用流感病毒A/Equine/Jilin/1/1989(H3N8)的HA基因编码的完全氨基酸序列。
图3显示与流感病毒A/Canine/Korea/01/07(H3N2)、A/Canine/Korea/02/07(H3N2)、A/Canine/Korea/03/07(H3N2)、A/Dove/Korea/S11/03(H3N2)、A/Duck/Korea/S7/03(H3N2)和A/Chicken/Korea/S6/03(H3N2)的那些相比较,用流感病毒A/Equine/Jilin/1/1989(H3N8)的HA基因编码的部分氨基酸序列。
图4显示HA基因的进化树,根自流感病毒A/Canine/Korea/01/07(H3N2)。
图5显示NA基因的进化树,根自流感病毒A/Canine/Korea/01/07(H3N2)。
图6是显示用流感病毒A/Canine/Korea/01/07(H3N2)进行免疫的动物和没有用其进行免疫的动物一周内体温、抗体滴度和病毒后代产生的变化的图。
图7显示用流感病毒A/Canine/Korea/01/07(H3N2)进行免疫的动物(免疫组B、D和F)和没有用其进行免疫的动物(对照组,A和C)的器官和肺的组织病理损伤:(A)侵袭性接种9天后对照组正常器官内的伪复层柱状上皮层(400倍放大);(B)侵袭性接种9天后免疫组内的坏死器官(n)、鳞状上皮化(s)和***上的上皮增生和慢性炎症(c)(400倍放大);(C)侵袭性接种3天后对照组的正常肺泡(200倍放大);(D)侵袭性接种3天后免疫组的支气管腔内严重扩散坏死性支气管炎和脓性细支气管炎(100倍放大);(E)侵袭性接种6天后免疫组内严重坏死性细支气管炎(充满分离的坏死性细胞和嗜中性粒细胞,并在细支气管周围观察到轻度或中度慢性炎症)(200倍放大);(F)侵袭性接种9天后免疫组内严重坏死性肺泡炎(H&E染色的肺泡管(ad)和肺泡(a)内的坏死性细胞浸润(200倍放大))。
具体实施方式
根据本发明的一个方面,本发明是关于新型的H3N2血清型犬流感病毒。
根据本发明的新型H3N2血清型犬流感病毒,它具有由SEQ ID NO.9的氨基酸序列或与其共有95%以上同源性的氨基酸序列表示的红血球凝集素(HA)蛋白。
当与以前已知的马流感病毒H3N8相比较时,根据对完全神经氨酸苷酶(NA)氨基酸序列(图1)和完全红血球凝集素(HA)氨基酸序列(图2)的分析,发现本发明的犬流感病毒的氨基酸序列具有极为特征性的变化。具体而言,A/Canine/Korea/01/07(H3N2)、A/Canine/Korea/02/07(H3N2)和A/Canine/Korea/03/07(H3N2)的HA氨基酸序列特征性地改变为在位置27具有N(天冬酰胺)、在位置127具有I(异亮氨酸)、在位置142具有T(苏氨酸)、在位置176具有T(苏氨酸)、在位置188具有N(天冬酰胺)、在位置209具有S(丝氨酸)、在位置212具有I(异亮氨酸)和在位置252具有I(异亮氨酸)(图3)。与SEQ ID NO.9的氨基酸序列共有至少95%同源性的氨基酸序列在位置97、127、142、176、188、209、212和252中的至少一个位置含有与SEQ ID NO.9的氨基酸序列相同的氨基酸残基。
此外,根据本发明的新型H3N2血清型犬流感病毒,它具有由SEQ IDNO.11的氨基酸序列或与其共有95%以上同源性的氨基酸序列表示的神经氨酸苷酶(NA)蛋白。
此外,根据本发明的新型犬流感病毒,其还可包含选自以下的蛋白:由SEQ ID NO.3的核苷酸序列编码的非结构性蛋白(NS)、由SEQ ID NO.4的核苷酸序列编码的基质蛋白(M)、由SEQ ID NO.5的核苷酸序列编码的核蛋白(NP)、由SEQ ID NO.6的核苷酸序列编码的聚合酶(PA)、由SEQID NO.7的核苷酸序列编码的聚合酶蛋白2(PB2)、由SEQ ID NO.8的核苷酸序列编码的聚合酶蛋白1(PB1)及其组合。
对于本文的红血球凝集素或神经氨酸苷酶,术语“同源性”用于指与野生型氨基酸序列的相似性。在本发明的流感病毒中表达的红血球凝集素和神经氨酸苷酶分别与SEQ ID NO.9和SEQ ID NO.11的氨基酸序列共有90%以上、优选95%以上、更优选98%以上和最优选99%以上的同源性。通常,蛋白同源物具有与其原型相同的活性位点。使用裸眼或使用软件可进行氨基酸序列之间的同源性比较。使用市售软件可计算两个或更多个氨基酸序列之间的同源性并表示成百分数。
本发明的犬流感病毒包含A/Canine/Korea/01/07(H3N2)、A/Canine/Korea/02/07(H3N2)和A/Canine/Korea/03/07(H3N2)。
流感病毒A/Canine/Korea/01/07(H3N2)的蛋白显示出与禽流感病毒的蛋白95.5-98.9%的同源性。例如,本发明的流感病毒A/Canine/Korea/01/07(H3N2)与A/Dove/Korea/S11/03(H3N2)对于HA(红血球凝集素)和NA(神经氨酸苷酶)基因以及与A/Chicken/Nanchang/7-010/2000(H3N6)对于NS(非结构性)基因共有最高的同源性。关于PB1(聚合酶碱性蛋白1)、PB2、PA(聚合酶)、NP(核蛋白)和M(基质)的基因,它们显示出与香港、日本和中国发现的禽流感病毒较高的同源性。流感病毒A/Canine/Korea/01/07(H3N2)于2007年9月19日保藏在位于Eoeun-dong,Yusung Gu,Daejeon City,South Korea的Korean Research Institute of Bioscience and Biotechnology(韩国生物科学与生物技术研究所),保藏编号为KCTC 11205BP。
流感病毒A/Canine/Korea/01/07(H3N2)具有包含SEQ ID NO.1的核苷酸序列的红血球凝集素(HA)基因和包含SEQ ID NO.2的核苷酸序列的神经氨酸苷酶(NA)基因。SEQ ID NO.9中给出了HA的完全核苷酸序列和其完全氨基酸序列,而SEQ ID NO.11中给出了NA的完全核苷酸序列和其完全氨基酸序列。此外,NS基因含有SEQ ID NO.3的核苷酸序列、M基因含有SEQ ID NO.4的核苷酸序列、NP基因含有SEQ ID NO.5的核苷酸序列、PA基因含有SEQ ID NO.6的核苷酸序列、PB2基因含有SEQ ID NO.7的核苷酸序列以及PB 1基因含有SEQ ID NO.8的核苷酸序列。
本发明的流感病毒A/Canine/Korea/02/07(H3N2)具有包含SEQ IDNO.13的核苷酸序列的HA基因和包含SEQ ID NO.14的核苷酸序列的NA基因。发现这种病毒与流感病毒A/Canine/Korea/01/07(H3N2)基本相同,因为两种病毒之间的HA和NA核苷酸序列以及氨基酸序列经分析共有98%的同源性。流感病毒A/Canine/Korea/02/07(H3N2)于2007年9月19日保藏在位于Eoeun-dong,Yusung Gu,Daejeon City,South Korea的Korean Collection for Type Cultures(KCTC)of Korea Research Institute ofBioscience and Biotechnology(韩国生物科学与生物技术研究所的韩国典型菌种保藏中心),保藏编号为KCTC 11206BP。
流感病毒A/Canine/Korea/03/07(H3N2)具有包含SEQ ID NO.1的核苷酸序列的HA基因和包含SEQ ID NO.16的核苷酸序列的NA基因。这种病毒经鉴定与流感病毒A/Canine/Korea/02/07(H3N2)和流感病毒A/Canine/Korea/03/07(H3N2)基本相同,因为流感病毒A/Canine/Korea/03/07(H3N2)和流感病毒A/Canine/Korea/01/07(H3N2)之间的HA和NA核苷酸序列和氨基酸序列经分析共有99%的同源性,并且流感病毒A/Canine/Korea/03/07(H3N2)和A/Canine/Korea/02/07(H3N2)之间的HA和NA核苷酸序列和氨基酸序列经分析共有98%的同源性。流感病毒A/Canine/Korea/03/07(H3N2)于2007年9月19日保藏在位于Eoeun-dong,Yusung Gu,Daejeon City,South Korea的Korean Collection forType Cultures(KCTC)of Korea Research Institute of B ioscience andBiotechnology(韩国生物科学与生物技术研究所的韩国典型菌种保藏中心),保藏编号为KCTC 11207BP。
从韩国犬类鼻腔分离出来的根据本发明的犬流感病毒具有图4和图5中的进化图表显示的进化关系。基于流感病毒A/Canine/Korea/01/07(H3N2),构建HA基因和NA基因的图4和图5的进化树。如在HA和NA基因的这些进化树中所看到的,本发明的流感病毒和禽流感病毒形成了与从马类和犬类分离出来的H3N8病毒所属群不同的群。
当用于感染犬类时,根据本发明的犬流感病毒显示出致病性,引起发烧和肺炎,因此是韩国犬类的流行性病毒。当给予抵抗本发明的犬流感病毒的疫苗时,发现犬类在极大程度上对病毒具有免疫性并由此抑制病毒的传播和产生。
根据本发明的另一个方面,本发明是关于一种基因,所述基因编码具有SEQ ID NO.9的氨基酸序列或与其共有95%以上同源性的氨基酸序列的红血球凝集素(HA)蛋白。优选地,所述基因具有SEQ ID NO.9的核苷酸序列。
此外,本发明是关于一种基因,所述基因编码具有SEQ ID NO.11的氨基酸序列或与其共有95%以上同源性的氨基酸序列的神经氨酸苷酶(NA)蛋白。优选地,所述基因具有SEQ ID NO.10的核苷酸序列。
根据本发明的另一个方面,本发明关于一种疫苗组合物,其可提供对犬流感病毒的免疫力。
优选地,本发明的疫苗组合物包含犬流感病毒或其抗原作为活性成分。用于疫苗组合物的犬流感病毒选自A/Canine/Korea/01/07(H3N2)、A/Canine/Korea/02/07(H3N2)、A/Canine/Korea/03/07(H3N2)及其组合。
用于本发明的抗原指的是病毒组分的抗原部分,它引起免疫应答,并可包含具有与SEQ ID NO.9的氨基酸序列或其片段共有90%以上同源性、优选95%以上同源性的氨基酸序列的红血球凝集素(HA)蛋白。与SEQID NO.9的氨基酸序列共有至少95%同源性的氨基酸序列在位置97、127、142、176、188、209、212和252中的至少一个位置含有与SEQ IDNO.9的氨基酸序列相同的氨基酸残基。
可选择地,抗原可包含具有与SEQ ID NO.11的氨基酸序列或其片段共有95%以上同源性的氨基酸序列的神经氨酸苷酶(NA)蛋白。
根据本发明的疫苗可包括减毒活疫苗或灭活疫苗、亚单位疫苗、合成疫苗和基因工程疫苗,优选活疫苗,因为其能诱发有效的免疫应答。
本文所用的术语“活疫苗”指的是从已经减毒但仍可复制宿主生物体的细胞的病毒制备的疫苗。本文所用的术语“减毒”用于指以使基因丧失致病性、但保持抗原性的方式对涉及病原体基本代谢的基因进行突变来人工降低病原体毒性。通常,通过UV辐射、化学处理或体外连续高阶继代培养实现减毒。外显的基因改变,如使已知序列中的特定核苷酸缺失以提供毒性或将核苷酸***病毒基因组中,也可能导致减毒。
本文所用的术语“灭活疫苗”,也称作失活疫苗,指的是用作抗原以产生免疫力的灭活病毒的混悬液。灭活疫苗的例子包括全病毒疫苗和裂解型疫苗。使用已知方法可以很容易地产生灭活疫苗。例如,通过用***处理病毒可获得全病毒疫苗。裂解型疫苗可在用醚处理后由病毒包膜制备得到。
术语“亚单位疫苗”指的是包含通过提取从病毒性生物体分离出来的纯化的抗原决定簇的疫苗。它比全病毒疫苗引起副反应的可能性小。例如,从犬流感病毒提取的HA蛋白和/或NA蛋白可用于制备亚单位疫苗。
术语“合成疫苗”指的是主要由化学合成抗原或基因工程抗原、抗原决定簇或肽组成的疫苗。例如,犬流感病毒的HA蛋白和/或NA蛋白可被合成用作疫苗。
基因工程疫苗可没有造成致病性的特定基因或可含有修饰的基因。
此外,本发明的流感疫苗可与其他失活生物体或抗原组合使用以制备抵抗包括流感的各种疾病的混合疫苗或复合疫苗。本文所用的术语“混合疫苗”用于指从本发明的犬流感病毒与至少一种不同病毒的病毒混合物制备的疫苗。术语“复合疫苗”指的是从病毒和细菌制备的疫苗。例如,本发明的犬流感病毒可与犬仙台病毒、犬瘟热病毒、犬腺病毒和/或支气管炎博德特菌(Bordetella bronchiseptica)混合或组合。
根据本发明的犬流感病毒疫苗可使用以下方法制备,该方法包括:(a)将本发明的犬流感病毒注射到胚胎卵中并使病毒在其中增殖;(b)用***、BPL(β-丙内酯)或BEI(二乙烯亚胺)处理来自胚胎卵的尿囊液;以及收集来自化学处理的尿囊液的失活病毒。
在步骤(a)中,将犬流感病毒注射到9-11天大的胚胎卵中并在30~40℃下孵育24~72小时。在步骤(b)中,使用常规方法从孵育的卵获得尿囊液,用0.005~0.2(v/w)%的***、BEI或BPL处理并在低温下孵育以使病毒失活。在步骤(c)中,通过离心或过滤收集来自用***、BEI或BPL处理的尿囊液的失活病毒。然后,病毒被吸附到氢氧化铝凝胶上。这种方法可包括众所周知的技术或可改变为更易于实施的形式。
此外,本发明的疫苗组合物还可包含介质、佐剂和/或赋形剂。生理盐水或蒸馏水可用作介质。用于疫苗组合物的佐剂的例子包括Freund的不完全佐剂或完全佐剂、氢氧化铝凝胶、植物油或矿物油等。赋形剂的例子包括磷酸铝、氢氧化铝和硫酸铝钾,但不限于此。在实践中,本领域技术人员已知的用于疫苗制备的所有物质均可适用于本发明的疫苗组合物。
优选地,本发明的疫苗组合物可包含25HAU(血凝(反应)单位)量的犬流感病毒。当犬流感病毒以少于25HAU的量使用时,疫苗不能有效诱发抗体产生。另一方面,超过25HAU的量可能是不经济的。
可将根据本发明的疫苗组合物制备成口服剂型或非口服剂型。优选的是可通过皮内、肌肉、腹膜内、静脉内、皮下、鼻内或硬脑膜外途径给予的非口服剂型。
根据本发明的疫苗组合物适用于易感染A/Canine/Korea/01/07(H3N2)、A/Canine/Korea/02/07(H3N2)或A/Canine/Korea/03/07(H3N2)并作为宿主的所有受试者,包括人类、宠物、家禽和禽类,如狗、猪、鸡、鸭、火鸡等。
根据本发明的另一个方面,本发明是关于一种用于预防和治疗流感病毒相关疾病的方法,所述方法包括将疫苗组合物给予有危险的个体。
本文所用的术语“流感病毒相关疾病”用于指由流感病毒感染引起的疾病。它的例子包括鼻窦炎、痉挛性孝喘、中耳炎、囊肿性纤维化、支气管炎、肺炎、痢疾等(Pitkaranta and Hayden,1998.Ann.Med.),但不限于此。
本文所用的术语“个体”用于指已经感染或可能感染流感病毒的所有脊椎动物(包括人类)。通过给予本发明的疫苗组合物,可有效地预防和治疗疾病。例如,可用本发明的疫苗组合物来治疗感染各种亚型或变型流感病毒的人。此外,为了预防流感,可用疫苗组合物使鸡或猪免疫。可将本发明的疫苗组合物与流感病毒相关疾病的常规治疗组合给予。
本文所用的术语“预防”指通过给予根据本发明的疫苗组合物抑制流感病毒感染或推迟流感发作的所有行为。术语“治疗”指通过给予根据本发明的疫苗组合物使流感病毒感染引起的症状减轻或转好的所有行为。
以药物有效量给予根据本发明的疫苗组合物。本文所用的术语“药物有效量”用于指以药物治疗的益处对危险的合理比率来用于治疗流感病毒相关疾病的量。本发明化合物的剂量取决于疾病的种类和严重性、药物活性、药物敏感性、给予次数和时间间隔、给予途径、***率和本领域熟知的因素(包括例如同时使用的药物等)。本发明的疫苗组合物可用作单一药物或与其他药物同时或顺序组合使用,可以单剂量或多剂量给予。考虑到上面提到的因素,重要的是确定能引起最大治疗作用而没有不需要的副作用的剂量,这对本领域技术人员来说很容易。
根据本发明的另一个方面,本发明是关于一种用于检测H3N2血清型流感病毒的分析试剂盒,所述分析试剂盒包括本发明的流感病毒或其抗原决定簇。
通过抗原-抗体复合反应,本发明的流感病毒或其抗原决定簇用于流感病毒的特定检测,同时消灭被感染的细胞内的流感病毒。
这种分析试剂盒包括通常用于免疫学领域的工具/试剂和本发明的流感病毒。工具/试剂的例子包括适合的载体、产生可检测信号的标记物、增溶剂、洗涤剂、缓冲剂、稳定剂等,但不限于此。当标记物是酶时,所述试剂盒还可包括用于分析酶活和反应终止物的底物。适合的载体例子包括但不限于可溶性的载体,如本领域熟知的生理上可接受的缓冲液(例如,PBS),不溶性的载体,如聚苯乙烯、聚乙烯、聚丙烯、聚酯、聚丙烯腈、氟树脂、交联葡聚糖、多糖等,磁性微粒,如金属被覆乳胶、纸、玻璃、金属、琼脂糖,以及它们的组合。
关于抗原-抗体复合物形成的分析,其例子包括免疫组织化学染色、放射免疫分析(RIA)、酶联免疫吸附测定(ELISA)、Western免疫印迹、免疫沉淀分析、免疫扩散分析、补体结合分析、FACS和蛋白芯片,但不限于此。
定性或定量分析抗原-抗体复合物的标记物的例子是酶、荧光剂、配体、发光剂、微粒、氧化还原分子和放射性同位素,但不受此限制。用作可检测的标记物的酶的例子包括β-葡萄糖苷酸酶、β-D-葡萄糖苷酶、β-D-半乳糖苷酶、脲酶、过氧化物酶、碱性磷酸酶、乙酰胆碱酯酶、葡萄糖氧化酶、己糖激酶和GDP酶的组合、核糖核酸酶、葡萄糖氧化酶和荧光素酶的组合、磷酸果糖激酶、磷酸烯醇式丙酮酸羧化酶、天门冬氨酸氨基转移酶、磷酸烯醇式丙酮酸脱羧酶和β-内酰胺酶,但不限于此。用于本发明的荧光剂的示例性的、非限制性的例子包括荧光素、异硫氰酸盐、若丹明、phycoerytherin、藻青蛋白、别藻蓝蛋白、邻苯二甲醛和荧光胺。生物素衍生物可用作配体,但不限制本发明范围。吖啶酯、虫荧光素和荧光素酶用作发光剂,但所列举的这些不用于限制本发明范围。示例性的、非限制性的微粒包括胶体金、被覆的乳胶等。作为用于本发明的氧化还原分子,有二茂铁、钌复合物、紫精、醌、钛离子、铯离子、二酰亚胺、1,4-苯醌、氢醌、K4W(CN)8、[Os(bpy)3]2+、[RU(bpy)3]2+和[MO(CN)8]4-,给出这些只用于示例性目的,但不用于限制本发明范围。用于本发明的放射性同位素的例子包括3H、14C、32P、35S、36Cl、51Cr、57Co、58Co、59Fe、90Y、125I、131I和186Re,但不限于此。
实施例
通过以下实施例可更好地理解本发明,所举的实施例用于说明、而不用于限制本发明。
实施例1:样本采集和病毒分离
从在位于Kyeonggi-Do,Korea的兽医院治疗的犬类采集样本:一只是遭受3天流鼻涕和2天打喷嚏然后从流感恢复的5岁小型髯狗(Miniature Schnauzer);一只是遭受发烧、咳嗽、流鼻涕和食欲不振并最终死亡的3岁英国可卡犬(Cocker Spaniel);遭受严重咳嗽、发烧和流鼻涕并住院治疗2天后死亡的一只约克郡犬(Yorkshire terrier)和两只金刀犬(Jindo)。
根据利用购自Anigen的快速试剂盒和RT-PCR的分析,所有这些动物被鉴定为均感染了A型流感病毒。未对这些犬类检测其他病原体。
将来自动物的样本(鼻分泌物)接种到11天大的卵中,之后从其采集尿囊液。发现尿囊液使鸡红血球聚集。从动物分离出来的病毒经血清鉴定为H3N2型血清。这些病毒被命名为A/Canine/Korea/01/07(H3N2)、A/Canine/Korea/02/07(H3N2)和A/Canine/Korea/03/07(H3N2),并于2007年9月19日保藏在位于Eoeun-dong,Yusung Gu,Daejeon City,SouthKorea的Korean Collection for Type Cultures(KCTC)of Korea ResearchInstitute of Bioscience and Biotechnology(韩国生物科学与生物技术研究所的韩国典型菌种保藏中心),保藏编号分别为KCTC 11205BP、KCTC11206BP和KCTC 11207BP。
实施例2:分离的病毒的遗传特性
通过基因分析来确定在实施例1中分离的病毒的遗传特性。将使用Trizol LS从尿囊液分离的流感病毒总RNA用作使用随机六聚体引物的RT-PCR的模板,接下来使用表1所示的引物进行PCR。使用改进的Primer3程序(Whitehead Institute/MT Center for Genome Research)来设计用于扩增H3、N2、PB 1、PB2、PA、NP、M和NS基因的引物序列。
将cDNA(2μl)与试剂混合物{2.5μl,10×Taq DNA聚合酶缓冲液、MgCl21.5mM、dNTPs(2.5mM/μl)2.0μl、每种引物(10pmol)1μl、Taq DNA聚合酶(Promega,USA)1μl)}混合,并用蒸馏水将终体积调节到25μl以制备PCR混合物。在94℃下变性10min开始PCR,进行在96℃下变性30sec、在53℃下退火30sec和在72℃下延伸2min的32个循环,接下来在72℃下延伸10min。在4℃下终止PCR。通过在含有溴化乙啶的1.5%琼脂糖凝胶上进行电泳分析所得的PCR产物。用Bioedit软件分析所得的序列数据。
表1 PCR引物序列
将来自A/Canine/Korea/01/07(H3N2)的8个基因片段进行碱基排序并与基因库的基因(SEQ ID NO.1~12)相比较。发现根据本发明的病毒与以前已知的禽流感病毒具有95.5~98.9%同源性(表2)。具体而言,根据本发明的病毒对于HA和NA基因与韩国分离的S 11共有最高的同源性,而对于NS基因与从中国鸡类分离的菌株共有最高的同源性。关于PB1、PB2、PA、NP和M基因,在本发明的病毒与香港、日本和中国分离的禽流感病毒之间检测出较高的同源性。在本发明的病毒A/Canine/Korea/01/07、A/Canine/Korea/02/07和A/Canine/Korea/03/07中,发现HA和NA基因具有98%~99%的同源性,这表明它们基本相同。
表2 犬流感病毒的基因同源性比较
实施例3:分离病毒的进化
使用群对齐算法和MEGALIGN软件(DNASTAR,Madison,WI)确定A/Canine/Korea/01/07在进化树中的位置。从HA和NA基因的观点来看,本发明的病毒经鉴定属于与以前从马类和犬类分离出来的H3N8病毒群不同的群,并且显示出与韩国分离的H3N2病毒非常近的遗传关系(图4和图5)。
实施例4:分离的病毒的致病性分析
为了检验其致病性,将A/Canine/Korea/01/07(H3N2)接种到犬类体内。
将10只10周龄的比格犬(beagle)分成7只的试验组和3只的对照组。将HA滴度为1∶64(106.9EID50/0.1ml)的分离病毒(2ml)鼻内和口服给予试验组的7只比格犬,而将没有病原体的PBS(磷酸盐缓冲盐水,2ml)鼻内和口服给予对照组的3只比格犬,接下来监控临床症状7天。从接种当天起,使用RT-PCR对通过***和流鼻涕进行的病毒排出监控10天。使用以重组NP(核蛋白)为抗原的竞争型ELISA(Animal Genetics Inc.Korea)进行血清研究。按照OIE的建议,为了检测重组NP的抗体,对血清样品也进行分析。为了观察病理损伤,在接种3、6和9天后各用1ml甲苯噻嗪使试验组的两只比格犬和对照组的1只比格犬经受安乐死并验尸。
在接种后的2~7天,观察比格犬遭受包括打喷嚏和流鼻涕的临床症状。整个实验过程中对照组比格犬的直肠温度保持在39℃,但接种24小时后,试验组比格犬平均上升到40.14℃(图6)。
接种前所有实验犬中病毒的血清试验均为阴性,试验组的比格犬在实验中仍保持阴性。ELISA显示接种6天后试验组比对照组的抑制百分数远远高出,表明产生了抗体。有趣的是,接种8天后,发现接种的比格犬HI滴度为1∶80。
在接种后6天内于接种的比格犬的鼻分泌物中均发现病毒,但在***物中没有检测到。通常,感染1天后,犬流感病毒开始从犬体内排出并且在感染4天后达到滴度为106.0EID50/0.1ml的峰值。
发现组织病理损伤限于肺部。大组织学上,在上呼吸道(支气管)和下呼吸道(细支气管和肺泡)发现严重的坏死损伤。尽管在程度上略有不同,但是在所有接种的比格犬中均发生细支气管炎和支气管炎(图7)。
因此,分离的病毒经鉴定在犬体内为致病性的,引起体温升高和肺炎。此外,发现病毒在6天内排出。
实施例5:疫苗制备
将新分离的犬流感病毒A/Canine/Korea/01/07(H3N2)接种到10天的胚胎卵的***中。3天后,采集尿囊液作为病毒堆。向该病毒堆加入0.2%***,接下来在室温下孵育24小时使其失活。将病毒堆重新接种到胚胎卵中后,当没有检测到病毒后代时,确定病毒堆失活。将失活的病毒堆浓缩到25HAU以上。通过在10,000rpm下搅拌10min,使该病毒堆与氢氧化铝凝胶以7∶3的比率混合。病毒阴性试验之后,将混合物用作疫苗。
实施例6:预防接种后的侵袭性接种
以0.5ml的剂量将制备的疫苗皮下注射到10周龄的10只比格犬体内,3周后以相同方式另外注射。第二次注射两周后,以2ml的剂量通过口服或鼻内途径将HA滴度为1∶64(106.9EID50/0.1ml)的分离的病毒A/Canine/Korea/01/07(H3N2)侵袭性接种到比格犬体内。作为对照,在侵袭性接种前,将PBS接种到3只比格犬体内。在实验中对实验动物进行体温、病毒产生、临床症状和抗体滴度的监控。
即使在接种后,预防接种的比格犬仍没有表现出体温变化、没有排出病毒后代并且没有显示出临床症状。相反,对照组在接种一周内体温升高(表3)。PCR显示病毒后代从对照组的全部3只比格犬体内排出,但没有从接种6天后的任何一只体内排出(表4)。此外,观察到对照组遭受包括流鼻涕和咳嗽(如犬窝咳(kennel cough)或湿排痰性咳(wet productivecough))的临床症状。关于抗体滴度,在以对预防接种的比格犬进行侵袭性接种7天后为开始的实验期间,对于核蛋白的ELISA抗体和红血球凝集素的HI抗体,抗体滴度开始增加(表5)。然而,对照组从侵袭性接种7天后开始,则是核蛋白和红血球凝集素的抗体的滴度开始增加。
因此,发现预防接种的比格犬能抵制侵袭性接种,表明本发明的疫苗组合物可用作抵抗流感病毒的疫苗。
表3侵袭性接种后预防接种和未预防接种的动物的体温
(在第21天进行加强接种,在第35天进行侵袭性接种)
预防接种后的天数 | 预防接种的组 | 对照组(未预防接种) |
0 | 37.8±0.1 | 38.2±0.2 |
7 | 37.6±0.2 | 37.8±0.1 |
14 | 38.4±0.1 | 38.0±0.2 |
21 | 38.2±0.1 | 37.6±0.1 |
28 | 38.1±0.2 | 38.3±0.1 |
35 | 38.3±0.2 | 37.6±0.1 |
36 | 40.2±0.3 | 38.3±0.2 |
37 | 40.6±0.1 | 38.0±0.3 |
38 | 39.84±0.2 | 38.0±0.2 |
39 | 39.3±0.1 | 37.6±0.1 |
40 | 38.9±0.2 | 38.3±0.1 |
41 | 38.7±0.1 | 37.6±0.1 |
42 | 38.6±0.1 | 38.0±0.1 |
49 | 38.0±0.1 | 38.0±0.1 |
*PCR阳性数/PCR试验数
表4 侵袭性接种后病毒从预防接种和未预防接种的动物的排出
(在第21天进行加强接种,在第35天进行侵袭性接种)
预防接种后的天数 | 预防接种的组 | 对照组(未预防接种) |
0 | 0/10* | 0/3 |
7 | 0/10 | 0/3 |
14 | 0/10 | 0/3 |
21 | 0/10 | 0/3 |
28 | 0/10 | 0/3 |
35 | 0/10 | 0/3 |
36 | 0/10 | 3/3 |
37 | 0/10 | 3/3 |
38 | 0/10 | 3/3 |
39 | 0/10 | 3/3 |
40 | 0/10 | 2/3 |
41 | 0/10 | 0/3 |
42 | 0/10 | 0/3 |
49 | 0/10 | 0/3 |
*PI值为正
表5侵袭性接种后预防接种和未预防接种的动物的抗体滴度
(在第21天进行加强接种,在第35天进行侵袭性接种)
工业实用性
如本文所述,本发明提供新型的犬流感病毒和抵抗它们的疫苗。因为能诱发对犬流感病毒的有效免疫,因此所述疫苗用于预防和治疗犬类和由犬类继发性感染的个体的流感病毒相关疾病。
尽管为了说明已经公开了本发明的优选实施方案,但是本领域技术人员将会理解在没有偏离所附权利要求公开的本发明范围和精神的条件下,可作出各种修改、添加和替代。
序列表
1 <110>Animal Genetics,Inc.(韩国安捷公司)
2
3 <120>新型犬流感病毒及用于它的疫苗
(A Novel Canine Influenza Virus and Vaccine Therefore)
4
5 <160>32
6
7 <170>KopatentIn 1.71
8
9 <210>1
10 <211>722
11 <212>DNA
12 <213>人工序列(Artificial Sequence)
13
14 <220>
15 <223>A/Canine/Korea/01/07(H3N2)的HA部分基因
(HA partial gene of A/Canine/Korea/01/07(H3N2))
16
17
18 <400>1
19 cagattgagg tgaccaatgc cactgagcta gtccaaaact cctcaacagg gaaaatatgc 60
20
21 aacaatcccc acaagattct tgatgggagg gactgcacac taatagatgc cctactaggg 120
22
23 gacccgcact gtgatgtctt ccaaaatgag acatgggacc tttttgtgga acgaagcaat 180
24
25 gcttttagca attgttaccc ttatgatgta ccagactatg catcccttcg atccatagtt 240
26
27 gcatcatcag gcacattgga gttcatcact gaaggtttca cttgggcagg agtaactcaa 300
28
29 aatagaggaa gcggtgcttg caaaagggga cctgctaatg gtttcttcag tagattgaat 360
30
31 tggttaacta agtcaggaaa tacatatcca gtgttgaatg tgactatgcc aaacaataac 420
32
33 aatttcgaca aattatacat ttggggagtt catcacccaa gcactaatca agaacaaacc 480
34
35 agcctgtata ttcaggcctc aggaagagtc acagtctcta ccaggagaag ccaacagacc 540
36
37 ataatcccaa acattggatc tagacccttg gtaaggggcc aatctggcag aataagcgta 600
38
39 tattggacaa tagtcaaacc tggagacgta ctggtaataa acagtaatgg aaacctaatc 660
40
41 gctcctcgag gctacttcaa aatgcgcatt gggaaaagct caataatgag atcagatgca 720
42
43 cc 722
44
45
46 <210>2
47 <211>477
48 <212>DNA
49 <213>人工序列(Artificial Sequence)
50
51 <220>
52 <223>A/Canine/Korea/01/07(H3N2)的NA部分基因
(NA partial gene ofA/Canine/Korea/01/07(H3N2))
53
54
55 <400>2
56 ccaacaagcc ctgaacacac ataactggaa tcgatgctat aatctgccat atttatatct 60
57
58 ataacgggcc tattagagcc cttccaattg tctctgcaaa cacatctaac atttggatat 120
59
60 cgaggataac aggaacattc ctctatatgt tgagcactcc ctgacaatgg gctaatatgg 180
61
62 acaattttcc cctctctgat gaatagtatt ctagtatcag cccttcctga tgcacttcca 240
63
64 tcagtcatta ctactgtaca agttccatta atgcaaacgc attctgactc ctgagttctg 300
65
66 aggatatttc gagaccatga accaatactg tcaacaagca ttccattata aacgaaacta 360
67
68 gcagtcgcat ttctatcatc cccagtgaca caaacatgta accatgcttt cccatcgtga 420
69
70 caacttgaac tggaccatgc tatgcacact tgtttggttc ccaaatgaaa cggaaca 477
71
72
73 <210>3
74 <211>240
75 <212>DNA
76 <213>人工序列(Artificial Sequence)
77
78 <220>
79 <223>A/Canine/Korea/01/07(H3N2)的NS部分基因
(NS partial gene ofA/Canine/Korea/01/07(H3N2))
80
81
82 <400>3
83 tggaccaggc aataatggat aaaaacatca cattgaaagc aaacttcagt gtgatttttg 60
84
85 agcgactgga aaccctaata ctacttagag ctttcacaaa cgaaggagca attgtgggag 120
86
87 aaatttcacc gttaccttct cttccaggac atactgataa ggatgtcaaa aatgcaattg 180
88
89 gggtcctcat cggaggactg gaatggaatg ataacacagt tcgagtctct gaaactctac 240
90
91 240
92
93
94 <210>4
95 <211>406
96 <212>DNA
97 <213>人工序列(Artificial Sequence)
98
99 <220>
100 <223>A/Canine/Korea/01/07(H3N2)的M部分基因
(M partial gene ofA/Canine/Korea/01/07(H3N2))
101
102
103 <400>4
104 gcacttgcca gttgtatggg tctcatatac aacaggatgg gaacagtgac cacagaagtg 60
105
106 gcttttggcc tagtgtgtgc cacctgtgag cagattgctg attcacagca tcggtcccac 120
107
108 aggcagatgg taactaccac caacccacta atcaggcatg aaaacaggat ggtgctagcc 180
109
110 agcaccacag ctaaggctat ggagcagatg gctgggtcga gtgagcaggc agcggaagcc 240
111
112 atggaggttg ccagtcaggc taggcagatg gtgcaagcaa tgaggacaat tggaactcac 300
113
114 cctagctcca gtgccggtct gaaagatgat cttcttgaaa acttgcaggc ctaccagaaa 360
115
116 cggatgggag tgcaaatgca gcgatttaag tgatcctccg tttatt 406
117
118
119 <210>5
120 <211>582
121 <212>DNA
122 <213>人工序列(Artificial Sequence)
123
124 <220>
125 <223>A/Canine/Korea/01/07(H3N2)的NP部分基因
(NP partial gene of A/Canine/Korea/01/07(H3N2))
126
127
128 <400>5
129 tcatcctgag aggatcagtg gcccataagt cctgcttgcc tgcttgtgtg tacggacttg 60
130
131 ccgtggccag tggatatgat tttgagagag aagggtactc tctggttgga atagatcctt 120
132
133 tccgtctgct tcaaaacagc caggtcttca gtctcattag accaaatgag aatccagcac 180
134
135 ataagagtca gttggtgtgg atggcatgcc attctgcagc atttgaggac ctaagagtct 240
136
137 caagtttcat cagaggaaca agagtaattc caagaggaca actatccacc agaggagttc 300
138
139 aaattgcttc aaatgagaac atggaaaaaa tagactccag tactcttgaa ctgagaagca 360
140
141 gatattgggc tataagaacc aggagtggag ggaacaccaa ccaacagaga gcatctgcag 420
142
143 gacaaatcag tgtacagcca actttctcgg tacagagaaa tattcccttc gagcgagcta 480
144
145 ccattatggc aacattcaca gggaatactg agggcagaac atctgacatg cggactgaaa 540
146
147 tcataagaat gatggaaagt gccaaaccag aagatgtgtc tt 582
148
149
150 <210>6
151 <211>438
152 <212>DNA
153 <213>人工序列(Artificial Sequence)
154
155 <220>
156 <223>A/Canine/Korea/01/07(H3N2)的PA部分基因
(PA partial gene of A/Canine/Korea/01/07(H3N2))
157
158
159 <400>6
160 cgccaaaatt gaaccatttt tgaagacaac accacgccct ctcagattac ctgatgggcc 60
161
162 tccctgcacc caacggtcaa aattcttgct gatggatgct ctgaacctaa gcattgaaga 120
163
164 cccgagtcat gagggggagg ggataccgct atacgatgcg atcaaatgca ctgaagacat 180
165
166 ttttcggctg gaaagagccc aacataacca aaccacatga gaaaggcata aaccccaatt 240
167
168 atctcttggc ttggaaacag gtgctagcag agctccagaa tattgaaaat gaggagaaaa 300
169
170 tcccaaagac aaagaatatg aagaaaacaa gccaattaaa atgggtagct tggtgaaaat 360
171
172 atggcaccag aaaaagtgga ctttgaggat tgcaaggatg ttagcgacct aaaacaatat 420
173
174 gacagcgatg agccagag 438
175
176
177 <210>7
178 <211>592
179 <212>DNA
180 <213>人工序列(Artificial Sequence)
181
182 <220>
183 <223>A/Canine/Korea/01/07(H3N2)的PB2部分基因
(PB2 partial gene of A/Canine/Korea/01/07(H3N2))
184
185
186 <400>7
187 aattgacaat aacaaaagag aagaaggaag agctccaaga ttgtaagatt gctcctttaa 60
188
189 tggtggcata catgttggaa agagaactgg tccgcaaaac caggttccta ccggtagcag 120
190
191 gcggaacaag cagtgtgtac attgaggtat tgcatttgac acaagggacc tgctgggaac 180
192
193 agatgtacac tccaggcgga gaagtgagaa atgacgatgt tgaccagagt ttgatcatcg 240
194
195 ccgceagaaa cattgttagg agagcaacgg tatcagcgga tccactggca tcactgctgg 300
196
197 agatgtgcca cagcacacaa attggtggga taaggatggt ggacatcctt aggcaaaatc 360
198
199 caactgagga acaagctgtg gatatatgca aagcagcaat gggtttgagg atcagttcat 420
200
201 cctttagctt tggaggcttc actttcaaaa gaacaagtgg gtcatccgtc aagaaggaag 480
202
203 aggaagtgct cacaggaaac ctccaaacat tgaaaataag agtacatgag gggtatgagg 540
204
205 aattcacaat agttgggcgg agagcaacag ctatcctaag gaaagcaacc ag 592
206
207
208 <210>8
209 <211>603
210 <212>DNA
211 <213>人工序列(Artificial Sequence)
212
213 <220>
214 <223>A/Canine/Korea/01/07(H3N2)的PB1部分基因
(PB1 partial gene of A/Canine/Korea/01/07(H3N2))
215
216
217 <400>8
218 ggacaacaaa cacagagact ggagcacccc aactcaatcc aattgatgga ccactacccg 60
219
220 aggataatga gccaagcgga tatgcacaaa cagattgtgt gttggaagca atggctttcc 120
221
222 ttgaagagtc ccacccaggg atctttgaaa actcatgtat tgaaacgatg gaagttgttc 180
223
224 agcaaacaag agtggacaaa ttgacccaag gtcgccagac ctatgactgg acattgaata 240
225
226 gaaaccagcc ggctgcaact gctttggcca atactataga ggtcttcaga tcgaacggtc 300
227
228 taacagccaa tgaatcggga agactaatag atttccttaa ggatgtaatg gaatcaatgg 360
229
230 acaaagaaga gatggagata acaacacatt tccagagaaa aagaagagta agggacaaca 420
231
232 tgaccaagaa aatggtcaca cagaggacaa tagggaagaa aaagcagagg ctgaacaaga 480
233
234 ggagctacgt aataagagca ctgacattga acacaatgac caaggatgca gaaagaggca 540
235
236 aattgaagag gcgggcaatt gcaacacccg ggatgcagat cagagggttc gtgtactttg 600
237
238 ttg 603
239
240
241 <210>9
242 <211>1701
243 <212>DNA
244 <213>人工序列(Artificial Sequence)
245
246 <220>
247 <223>A/Canine/Korea/01/07(H3N2)的HA完全基因
(HA full gene ofA/Canine/Korea/01/07(H3N2))
248
249
250 <220>
251 <221>CDS
252 <222>(1)..(1698)
253 <223>A/Canine/Korea/01/07(H3N2)的HA氨基酸
(HA amino acid ofA/Canine/Korea/01/07(H3N2))
254
255
256 <400>9
257 atg aag acc gtt att gct tta agc tac att ttc tgc ctg gct ttt ggt 48
258 Met Lys Thr Val Ile Ala Leu Ser Tyr Ile Phe Cys Leu Ala Phe Gly
259 1 5 10 15
260
261 cag aat ctt cca gga aat gaa aat aat gct gca aca cta tgc ctg gga 96
262 Gln Asn Leu Pro Gly Asa Glu Asn Asn Ala Ala Thr Leu Cys Leu Gly
263 20 25 30
264
265 cat cat gca gtg ccg aac ggg aca ata gtg aaa act atc aca gac gat 144
266 His His Ala Val Pro Asn Gly Thr Ile Val Lys Thr Ile Thr Asp Asp
267 35 40 45
268
269 caa att gag gtg acc aac gcc acc gag cta gtc caa aac tcc tca aca 192
270 Gln Ile Glu Val Thr Asn Ala Thr Glu Leu Val Gln Asn Ser Ser Thr
271 50 55 60
272
273 ggg aaa ata tgc aac aat ccc cac aag att ctt gat ggg agg gac tgc 240
274 Gly Lys Ile Cys Asn Asn Pro His Lys Ile Leu Asp Gly Arg Asp Cys
275 65 70 75 80
276
277 aca cta ata gat gcc cta cta ggg gac ccg cac tgt gat gtc ttc caa 288
278 Thr Leu Ile Asp Ala Leu Leu Gly Asp Pro His Cys Asp Val Phe Gln
279 85 90 95
280
281 aat gag aca tgg gac ctt ttt gtg gaa cga agc aat gct ttt agc aat 336
282 Asn Glu Thr Trp Asp Leu Phe Val Glu Arg Ser Asn Ala Phe Ser Asn
283 100 105 110
284
285 tgt tac cct tat gat gta cca gac tat gca tcc ctt cga tcc ata gtt 384
286 Cys Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Ser Leu Arg Ser Ile Val
287 115 120 125
288
289 gca tca tca ggc aca ttg gag ttc atc act gaa ggt ttc act tgg aca 432
290 Ala Ser Ser Gly Thr Leu Glu Phe Ile Thr Glu Gly Phe Thr Trp Thr
291 130 135 140
292
293 gga gta act cag aat gga gga agc ggt gct tgc aaa agg gga cct gct 480
294 Gly Val Thr Gln Asn Gly Gly Ser Gly Ala Cys Lys Arg Gly Pro Ala
295 145 150 155 160
296
297 aat ggt ttc ttc agt aga ttg aat tgg tta act aag tca gga aat aca 528
298 Asn Gly Phe Phe Ser Arg Leu Asn Trp Leu Thr Lys Ser Gly Asn Thr
299 165 170 175
300
301 tat cca gtg ttg aat gtg act atg cca aac aat aac aat ttc gac aaa 576
302 Tyr Pro Val Leu Asn Val Thr Met Pro Asn Asn Asn Asn Phe Asp Lys
303 180 185 190
304
305 tta tac att tgg gga gtt cat cac cca agc act aat caa gaa caa acc 624
306 Leu Tyr Ile Trp Gly Val His His Pro Ser Thr Asn Gln Glu Gln Thr
307 195 200 205
308
309 agc ctg tat att cag gcc tca gga aga gtc aca gtc tct acc agg aga 672
310 Ser Leu Tyr Ile Gln Ala Ser Gly Arg Val Thr Val Ser Thr Arg Arg
311 210 215 220
312
313 agc caa cag acc ata atc cca aac att gga tct aga ccc ttg gta agg 720
314 Ser Gln Gln Thr Ile Ile Pro Asn Ile Gly Ser Arg Pro Leu Val Arg
315 225 230 235 240
316
317 ggc caa tct ggc aga ata agc gta tat tgg aca ata gtc aaa cct gga 768
318 Gly Gln Ser Gly Arg Ile Ser Val Tyr Trp Thr Ile Val Lys Pro Gly
319 245 250 255
320
321 gac gta ctg gta ata aac agt aat gga aac cta atc gct cct cga ggc 816
322 Asp Val Leu Val Ile Asn Ser Asn Gly Asn Leu Ile Ala Pro Arg Gly
323 260 265 270
324
325 tac ttc aaa atg cgc att ggg aaa agc tca ata atg aga tca gat gca 864
326 Tyr Phe Lys Met Arg Ile Gly Lys Ser Ser Ile Met Arg Ser Asp Ala
327 275 280 285
328
329 cct att gac acc tgc att tcc gaa tgt atc act ccg aac ggg agc atc 912
330 Pro Ile Asp Thr Cys Ile Ser Glu Cys Ile Thr Pro Asn Gly Ser Ile
331 290 295 300
332
333 ccc aat gac aag ccc ttc caa aat gta aac aag atc aca tac gga gca 960
334 Pro Asn Asp Lys Pro Phe Gln Asn Val Asn Lys Ile Thr Tyr Gly Ala
335 305 310 315 320
336
337 tgt ccc aaa tat gtt aag caa aac acc ttg aaa ctg gca aca gga atg 1008
338 Cys Pro Lys Tyr Val Lys Gln Asn Thr Leu Lys Leu Ala Thr Gly Met
339 325 330 335
340
341 cgg aat gtc cct gag agg caa acc aga ggc ctg ttc ggc gca ata gca 1056
342 Arg Asn Val Pro Glu Arg Gln Thr Arg Gly Leu Phe Gly Ala Ile Ala
343 340 345 350
344
345 ggt ttc ata gaa aat gga tgg gaa ggg atg gta gac ggt tgg tat ggc 1104
346 Gly Phe Ile Glu Asn Gly Trp Glu Gly Met Val Asp Gly Trp Tyr Gly
347 355 360 365
348
349 ttc agg cac caa aat tcc gaa ggt aca gga caa gca gca gac ctt aaa 1152
350 Phe Arg His Gln Asn Ser Glu Gly Thr Gly Gln Ala Ala Asp Leu Lys
351 370 375 380
352
353 agc act cag gca gcc att gac cag att aat ggg aaa ttg aac aga gtg 1200
354 Ser Thr Gln Ala Ala Ile Asp Gln Ile Asn Gly Lys Leu Asn Arg Val
355 385 390 395 400
356
357 att gaa aaa acg aat gag aag ttc cat caa atc gaa aag gag ttt tcc 1248
358 Ile Glu Lys Thr Asn Glu Lys Phe His Gln Ile Glu Lys Glu Phe Ser
359 405 410 415
360
361 gaa gta gaa ggg agg att caa gac ctt gag aga tac gtt gaa gac aca 1296
362 Glu Val Glu Gly Arg Ile Gln Asp Leu Glu Arg Tyr Val Glu Asp Thr
363 420 425 430
364
365 aaa gta gat ctt tgg tct tac aat gcc gag ctt ctt gtt gct tta gaa 1344
366 Lys Val Asp Leu Trp Ser Tyr Asn Ala Glu Leu Leu Val Ala Leu Glu
367 435 440 445
368
369 aac cag aaa aca att gat tta act gat tca gaa atg aac aaa ttg ttt 1392
370 Asn Gln Lys Thr Ile Asp Leu Thr Asp Ser Glu Met Asn Lys Leu Phe
371 450 455 460
372
373 gaa aag act agg agg caa ttg agg gaa aat gct gaa gac atg ggc aat 1440
374 Glu Lys Thr Arg Arg Gln Leu Arg Glu Asn Ala Glu Asp Met Gly Asn
375 465 470 475 480
376
377 ggc tgc ttc aag ata tac cac aag tgt gac aat gct tgc ata gaa tcg 1488
378 Gly Cys Phe Lys Ile Tyr His Lys Cys Asp Asn Ala Cys Ile Glu Ser
379 485 490 495
380
381 att aga aac gga act tat gac cat aac ata tat aga gat gag gca gtg 1536
382 Ile Arg Asn Gly Thr Tyr Asp His Asn Ile Tyr Arg Asp Glu Ala Val
383 500 505 510
384
385 aac aat cgg ttc cag atc aaa ggt gtt gag cta aag tct gga tac aaa 1584
386 Asn Asn Arg Phe Gln Ile Lys Gly Val Glu Leu Lys Ser Gly Tyr Lys
387 515 520 525
388
389 gac tgg atc ttg tgg att tcc ttt gcc ata tca tgc ttt ttg ctt tgt 1632
390 Asp Trp Ile Leu Trp Ile Ser Phe Ala Ile Ser Cys Phe Leu Leu Cys
391 530 535 540
392
393 gtt gtc ttg ctg ggt ttc att atg tgg gcc tgc cag aga ggc aac att 1680
394 Val Val Leu Leu Gly Phe Ile Met Trp Ala Cys Gln Arg Gly Asn Ile
395 545 550 555 560
396
397 agg tgc aac att tgc att tg a 1701
398 Arg Cys Asn Ile Cys Ile
399 565
400
401
402 <210>10
403 <211>566
404 <212>PRT
405 <213>人工序列(Artificial Sequence)
406
407 <400>10
408 Met Lys Thr Val Ile Ala Leu Ser Tyr Ile Phe Cys Leu Ala Phe Gly
409 1 5 10 15
410
411 Gln Asn Leu Pro Gly Asn Glu Asn Asn Ala Ala Thr Leu Cys Leu Gly
412 20 25 30
413
414 His His Ala Val Pro Asn Gly Thr Ile Val Lys Thr Ile Thr Asp Asp
415 35 40 45
416
417 Gln Ile Glu Val Thr Asn Ala Thr Glu Leu Val Gln Asn Ser Ser Thr
418 50 55 60
419
420 Gly Lys Ile Cys Asn Asn Pro His Lys Ile Leu Asp Gly Arg Asp Cys
421 65 70 75 80
422
423 Thr Leu Ile Asp Ala Leu Leu Gly Asp Pro His Cys Asp Val Phe Gln
424 85 90 95
425
426 Asn Glu Thr Trp Asp Leu Phe Val Glu Arg Ser Asn Ala Phe Ser Asn
427 100 105 110
428
429 Cys Tyr Pro Tyr Asp Val Pro Asp Tyr Ala Ser Leu Arg Ser Ile Val
430 115 120 125
431
432 Ala Ser Ser Gly Thr Leu Glu Phe Ile Thr Glu Gly Phe Thr Trp Thr
433 130 135 140
434
435 Gly Val Thr Gln Asn Gly Gly Ser Gly Ala Cys Lys Arg Gly Pro Ala
436 145 150 155 160
437
438 Asn Gly Phe Phe Ser Arg Leu Asn Trp Leu Thr Lys Ser Gly Asn Thr
439 165 170 175
440
441 Tyr Pro Val Leu Asn Val Thr Met Pro Asn Asn Asn Asn Phe Asp Lys
442 180 185 190
443
444 Leu Tyr Ile Trp Gly Val His His Pro Ser Thr Asn Gln Glu Gln Thr
445 195 200 205
446
447 Ser Leu Tyr Ile Gln Ala Ser Gly Arg Val Thr Val Ser Thr Arg Arg
448 210 215 220
449
450 Ser Gln Gln Thr Ile Ile Pro Asn Ile Gly Ser Arg Pro Leu Val Arg
451 225 230 235 240
452
453 Gly Gln Ser Gly Arg Ile Ser Val Tyr Trp Thr Ile Val Lys Pro Gly
454 245 250 255
455
456 Asp Val Leu Val Ile Asn Ser Asn Gly Asn Leu Ile Ala Pro Arg Gly
457 260 265 270
458
459 Tyr Phe Lys Met Arg Ile Gly Lys Ser Ser Ile Met Arg Ser Asp Ala
460 275 280 285
461
462 Pro Ile Asp Thr Cys Ile Ser Glu Cys Ile Thr Pro Asn Gly Ser Ile
463 290 295 300
464
465 Pro Asn Asp Lys Pro Phe Gln Asn Val Asn Lys Ile Thr Tyr Gly Ala
466 305 310 315 320
467
468 Cys Pro Lys Tyr Val Lys Gln Asn Thr Leu Lys Leu Ala Thr Gly Met
469 325 330 335
470
471 Arg Asn Val Pro Glu Arg Gln Thr Arg Gly Leu Phe Gly Ala Ile Ala
472 340 345 350
473
474 Gly Phe Ile Glu Asn Gly Trp Glu Gly Met Val Asp Gly Trp Tyr Gly
475 355 360 365
476
477 Phe Arg His Gln Asn Ser Glu Gly Thr Gly Gln Ala Ala Asp Leu Lys
478 370 375 380
479
480 Ser Thr Gln Ala Ala Ile Asp Gln Ile Asn Gly Lys Leu Asn Arg Val
481 385 390 395 400
482
483 Ile Glu Lys Thr Asn Glu Lys Phe His Gln Ile Glu Lys Glu Phe Ser
484 405 410 415
485
486 Glu Val Glu Gly Arg Ile Gln Asp Leu Glu Arg Tyr Val Glu Asp Thr
487 420 425 430
488
489 Lys Val Asp Leu Trp Ser Tyr Asn Ala Glu Leu Leu Val Ala Leu Glu
490 435 440 445
491
492 Asn Gln Lys Thr Ile Asp Leu Thr Asp Ser Glu Met Asn Lys Leu Phe
493 450 455 460
494
495 Glu Lys Thr Arg Arg Gln Leu Arg Glu Asn Ala Glu Asp Met Gly Asn
496 465 470 475 480
497
498 Gly Cys Phe Lys Ile Tyr His Lys Cys Asp Asn Ala Cys Ile Glu Ser
499 485 490 495
500
501 Ile Arg Asn Gly Thr Tyr Asp His Asn Ile Tyr Arg Asp Glu Ala Val
502 500 505 510
503
504 Asn Asn Arg Phe Gln Ile Lys Gly Val Glu Leu Lys Ser Gly Tyr Lys
505 515 520 525
506
507 Asp Trp Ile Leu Trp Ile Ser Phe Ala Ile Ser Cys Phe Leu Leu Cys
508 530 535 540
509
510 Val Val Leu Leu Gly Phe Ile Met Trp Ala Cys Gln Arg Gly Asn Ile
511 545 550 555 560
512
513 Arg Cys Asn Ile Cys Ile
514 565
515
516
517 <210>11
518 <211>1410
519 <212>DNA
520 <213>人工序列(Artificial Sequence)
521
522 <220>
523 <223>A/Canine/Korea/01/07(H3N2)的NA完全基因
(NA full gene of A/Canine/Korea/01/07(H3N2))
524
525
526 <220>
527 <221>CDS
528 <222>(1)..(1407)
529 <223>A/Canine/Korea/01/07(H3N2)的NA氨基酸
(NA amino acid of A/Canine/Korea/01/07(H3N2))
530
531
532 <400>11
533 atg aac cca aat cag aag ata ata gca ata ggc tct gtc tct cta acc 48
534 Met Asn Pro Asn Gln Lys Ile Ile Ala Ile Gly Ser Val Ser Leu Thr
535 1 5 10 15
536
537 att gca aca gta tgt ttc ctc ttg cag att gcc atc cta gca aca act 96
538 Ile Ala Thr Val Cys Phe Leu Leu Gln Ile Ala Ile Leu Ala Thr Thr
539 20 25 30
540
541 gtg aca ctg cac ttc aag caa aat gaa tgc aac atc ccc tcg aac agt 144
542 Val Thr Leu His Phe Lys Gln Asn Glu Cys Asn Ile Pro Ser Asn Ser
543 35 40 45
544
545 caa gta gtg cca tgt aaa cca atc ata ata gaa agg aac ata aca gag 192
546 Gln Val Val Pro Cys Lys Pro Ile Ile Ile Glu Arg Asn Ile Thr Glu
547 50 55 60
548
549 gta gta tat ttg aat aat act acc ata gaa aaa gaa att tgt tcc ata 240
550 Val Val Tyr Leu Asn Asn Thr Thr Ile Glu Lys Glu Ile Cys Ser Ile
551 65 70 75 80
552
553 gtg cta gaa tac agg aac tgg tcg aag ccg cag tgt caa att aca gga 288
554 Val Leu Glu Tyr Arg Asn Trp Ser Lys Pro Gln Cys Gln Ile Thr Gly
555 85 90 95
556
557 ttt gct cct ttc tcc aag gac aac tca atc cga ctc tcc gct ggt ggg 336
558 Phe Ala Pro Phe Ser Lys Asp Asn Ser Ile Arg Leu Ser Ala Gly Gly
559 100 105 110
560
561 gac att tgg gta aca agg gaa cct tat gtg tca tgc gac ccc agc aaa 384
562 Asp Ile Trp Val Thr Arg Glu Pro Tyr Val Ser Cys Asp Pro Ser Lys
563 115 120 125
564
565 tgt tac cag ttt gca ctt ggg cag ggg acc acg ctg aac aat aaa cac 432
566 Cys Tyr Gln Phe Ala Leu Gly Gln Gly Thr Thr Leu Asn Asn Lys His
567 130 135 140
568
569 tca aac ggc aca ata cat gat agg atc tct cat cga act ctt tta atg 480
570 Ser Asn Gly Thr Ile His Asp Arg Ile Ser His Arg Thr Leu Leu Met
571 145 150 155 160
572
573 aat gag ttg ggt gtt ccg ttt cat ttg gga acc aaa caa gtg tgc ata 528
574 Asn Glu Leu Gly Val Pro Phe His Leu Gly Thr Lys Gln Val Cys Ile
575 165 170 175
576
577 gca tgg tcc agt tca agt tgt cac gat ggg aaa gca tgg tta cat gtt 576
578 Ala Trp Ser Ser Ser Ser Cys His Asp Gly Lys Ala Trp Leu His Val
579 180 185 190
580
581 tgt gtc act ggg gat gat aga aat gcg act gct agt ttc gtt tat aat 624
582 Cys Val Thr Gly Asp Asp Arg Asn Ala Thr Ala Ser Phe Val Tyr Asn
583 195 200 205
584
585 gga atg ctt gtt gac agt att ggt tca tgg tct cga aat atc ctc aga 672
586 Gly Met Leu Val Asp Ser Ile Gly Ser Trp Ser Arg Asn Ile Leu Arg
587 210 215 220
588
589 act cag gag tca gaa tgc gtt tgc atc aat gga act tgt aca gta gta 720
590 Thr Gln Glu Ser Glu Cys Val Cys Ile Asn Gly Thr Cys Thr Val Val
591 225 230 235 240
592
593 atg act gat gga agt gca tca gga agg gct gat act aga ata cta ttc 768
594 Met Thr Asp Gly Ser Ala Ser Gly Arg Ala Asp Thr Arg Ile Leu Phe
595 245 250 255
596
597 atc aga gag ggg aaa att gtc cat att agc cca ttg tca ggg agt gct 816
598 Ile Arg Glu Gly Lys Ile Val His Ile Ser Pro Leu Ser Gly Ser Ala
599 260 265 270
600
601 caa cat ata gag gaa tgt tcc tgt tat cct cga tat cca aat gtt aga 864
602 Gln His Ile Glu Glu Cys Ser Cys Tyr Pro Arg Tyr Pro Asn Val Arg
603 275 280 285
604
605 tgt gtt tgc aga gac aat tgg aag ggc tct aat agg ccc gtt ata gat 912
606 Cys Val Cys Arg Asp Asn Trp Lys Gly Ser Asn Arg Pro Val Ile Asp
607 290 295 300
608
609 ata aat atg gca gat tat agc atc gat tcc agt tat gtg tgt tca gga 960
610 Ile Asn Met Ala Asp Tyr Ser Ile Asp Ser Ser Tyr Val Cys Ser Gly
611 305 310 315 320
612
613 ctt gtt ggc gac aca cca agg aat gat gat agc tct agc agc agc aac 1008
614 Leu Val Gly Asp Thr Pro Arg Asn Asp Asp Ser Ser Ser Ser Ser Asn
615 325 330 335
616
617 tgc agg gat cct aat aat gag aga ggg aat cca gga gtg aaa ggg tgg 1056
618 Cys Arg Asp Pro Asn Asn Glu Arg Gly Asn Pro Gly Val Lys Gly Trp
619 340 345 350
620
621 gct ttt gat aat gag aat gac gtt tgg atg ggg agg aca atc agc aaa 1104
622 Ala Phe Asp Asn Glu Asn Asp Val Trp Met Gly Arg Thr Ile Ser Lys
623 355 360 365
624
625 gat ttg cgc tca ggt tat gag act ttc aag gtc att ggt ggc tgg acc 1152
626 Asp Leu Arg Ser Gly Tyr Glu Thr Phe Lys Val Ile Gly Gly Trp Thr
627 370 375 380
628
629 act gct aat tcc aag tta cag gtc aat aga caa gtc ata gtc gat aat 1200
630 Thr Ala Asn Ser Lys Leu Gln Val Asn Arg Gln Val Ile Val Asp Asn
631 385 390 395 400
632
633 aat aac tgg tct ggt tat tct ggt att ttc tcc gtt gaa ggc aaa agc 1248
634 Asn Asn Trp Ser Gly Tyr Ser Gly Ile Phe Ser Val Glu Gly Lys Ser
635 405 410 415
636
637 tgt gtt aat agg tgt ttt tat gtg gag ttg ata aga gga ggg cca caa 1296
638 Cys Val Asn Arg Cys Phe Tyr Val Glu Leu Ile Arg Gly Gly Pro Gln
639 420 425 430
640
641 gag act aga gta tgg tgg act tca aat agc att gtc gta ttt tgt ggt 1344
642 Glu Thr Arg Val Trp Trp Thr Ser Asn Ser Ile Val Val Phe Cys Gly
643 435 440 445
644
645 act tct ggt acc tat gga aca ggc tca tgg cct gat ggg gcg aat atc 1392
646 Thr Ser Gly Thr Tyr Gly Thr Gly Ser Trp Pro Asp Gly Ala Asn Ile
647 450 455 460
648
649 aac ttc atg cct ata taa 1410
650 Asn Phe Met Pro Ile
651 465
652
653
654 <210>12
655 <211>469
656 <212>PRT
657 <213>人工序列(Artificial Sequence)
658
659 <400>12
660 Met Asn Pro Asn Gln Lys Ile Ile Ala Ile Gly Ser Val Ser Leu Thr
661 1 5 10 15
662
663 Ile Ala Thr Val Cys Phe Leu Leu Gln Ile Ala Ile Leu Ala Thr Thr
664 20 25 30
665
666 Val Thr Leu His Phe Lys Gln Asn Glu Cys Asn Ile Pro Ser Asn Ser
667 35 40 45
668
669 Gln Val Val Pro Cys Lys Pro Ile Ile Ile Glu Arg Asn Ile Thr Glu
670 50 55 60
671
672 Val Val Tyr Leu Asn Asn Thr Thr Ile Glu Lys Glu Ile Cys Ser Ile
673 65 70 75 80
674
675 Val Leu Glu Tyr Arg Asn Trp Ser Lys Pro Gln Cys Gln Ile Thr Gly
676 85 90 95
677
678 Phe Ala Pro Phe Ser Lys Asp Asn Ser Ile Arg Leu Ser Ala Gly Gly
679 100 105 110
680
681 Asp Ile Trp Val Thr Arg Glu Pro Tyr Val Ser Cys Asp Pro Ser Lys
682 115 120 125
683
684 Cys Tyr Gln Phe Ala Leu Gly Gln Gly Thr Thr Leu Asn Asn Lys His
685 130 135 140
686
687 Ser Asn Gly Thr Ile His Asp Arg Ile Ser His Arg Thr Leu Leu Met
688 145 150 155 160
689
690 Asn Glu Leu Gly Val Pro Phe His Leu Gly Thr Lys Gln Val Cys Ile
691 165 170 175
692
693 Ala Trp Ser Ser Ser Ser Cys His Asp Gly Lys Ala Trp Leu His Val
694 180 185 190
695
696 Cys Val Thr Gly Asp Asp Arg Asn Ala Thr Ala Ser Phe Val Tyr Asn
697 195 200 205
698
699 Gly Met Leu Val Asp Ser Ile Gly Ser Trp Ser Arg Asn Ile Leu Arg
700 210 215 220
701
702 Thr Gln Glu Ser Glu Cys Val Cys Ile Asn Gly Thr Cys Thr Val Val
703 225 230 235 240
704
705 Met Thr Asp Gly Ser Ala Ser Gly Arg Ala Asp Thr Arg Ile Leu Phe
706 245 250 255
707
708 Ile Arg Glu Gly Lys Ile Val His Ile Ser Pro Leu Ser Gly Ser Ala
709 260 265 270
710
711 Gln His Ile Glu Glu Cys Ser Cys Tyr Pro Arg Tyr Pro Asn Val Arg
712 275 280 285
713
714 Cys Val Cys Arg Asp Asn Trp Lys Gly Ser Asn Arg Pro Val Ile Asp
715 290 295 300
716
717 Ile Asn Met Ala Asp Tyr Ser Ile Asp Ser Ser Tyr Val Cys Ser Gly
718 305 310 315 320
719
720 Leu Val Gly Asp Thr Pro Arg Asn Asp Asp Ser Ser Ser Ser Ser Asn
721 325 330 335
722
723 Cys Arg Asp Pro Asn Asn Glu Arg Gly Asn Pro Gly Val Lys Gly Trp
724 340 345 350
725
726 Ala Phe Asp Asn Glu Asn Asp Val Trp Met Gly Arg Thr Ile Ser Lys
727 355 360 365
728
729 Asp Leu Arg Ser Gly Tyr Glu Thr Phe Lys Val Ile Gly Gly Trp Thr
730 370 375 380
731
732 Thr Ala Asn Ser Lys Leu Gln Val Asn Arg Gln Val Ile Val Asp Asn
733 385 390 395 400
734
735 Asn Asn Trp Ser Gly Tyr Ser Gly Ile Phe Ser Val Glu Gly Lys Ser
736 405 410 415
737
738 Cys Val Asn Arg Cys Phe Tyr Val Glu Leu Ile Arg Gly Gly Pro Gln
739 420 425 430
740
741 Glu Thr Arg Val Trp Trp Thr Ser Asn Ser Ile Val Val Phe Cys Gly
742 435 440 445
743
744 Thr Ser Gly Thr Tyr Gly Thr Gly Ser Trp Pro Asp Gly Ala Asn Ile
745 450 455 460
746
747 Asn Phe Met Pro Ile
748 465
749
750
751 <210>13
752 <211>722
753 <212>DNA
754 <213>人工序列(Artificial Sequence)
755
756 <220>
757 <223>A/Canine/Korea/02/07(H3N2)的HA部分基因
(HA partial gene of A/Canine/Korea/02/07(H3N2))
758
759
760 <400>13
761 cagattgagg tgactaatgc caccgagcta gtccaaaact cctcaacagg gaaaatatgc 60
762
763 aacaatcccc acaagatcct tgatgggagg gactgcacac taatagatgc cctactaggg 120
764
765 gacccgcact gtgatgtctt ccaaaatgag acatgggacc tttttgtgga acgaagcaat 180
766
767 gcttttagca attgttaccc ttatgatgta ccagactatg catcccttcg atccatagtt 240
768
769 gcatcatcag gcacattgga gttcatcact gaaggtttca cttgggcagg agtaactcaa 300
770
771 aatggaggaa gcggtgcttg caaaagggga cctgctaatg gtttcttcag cagattgaat 360
772
773 tggttaacta agtcaggaaa tacatatcca gtgttgaatg tgactatgcc aaacaataac 420
774
775 aatttcgaca aattatacat ttggggagtt tatcacccaa gcactaatca agaacaaacc 480
776
777 agcctgtata ttcaggcctc aggaagagtc acagtctcta ceaggagaag ccaacagacc 540
778
779 ataatcccaa acattggatc tagacccttg gtaaggggcc aatctggcag aataagtgta 600
780
781 tattggacaa tagtcaaacc tggagacgta ctggtaataa acagtaatag aaacctaatc 660
782
783 gctcctcgag gctacttcaa aatgcgcatt gggaaaagct caataatgag atcagatgca 720
784
785 cc 722
786
787
788 <210>14
789 <211>477
790 <212>DNA
791 <213>人工序列(Artificial Sequence)
792
793 <220>
794 <223>A/Canine/Korea/02/07(H3N2)的NA部分基因
(NA partial gene of A/Canine/Korea/02/07(H3N2))
795
796
797 <400>14
798 ccaacaagcc ctgaacacac ataactggaa tcgatgctat aatctgccat atttatatct 60
799
800 ataacgggcc tattagagcc cttccaattg tctctgcaaa cacatctaac atttggatat 120
801
802 cgaggataac aggaacattc ctctatatgt tgagcactcc ctgacaatgg gctaatatgg 180
803
804 acaattttcc cctctctgat gaatagtatt ctagtatcag cccttcctga tgcacttcea 240
805
806 tcagtcatta ctactgtaca agttccattg atgcaaacgc attctgactc ctgagttctg 300
807
808 aggatatttc gagaccatga accaatactg tcaacaagca ttccattata aacgaaacta 360
809
810 gcagtcgcat ttctatcatc cccagtgaca caaacatgta accatgcttt cccatcgtga 420
811
812 caacttgaac tggaccatgc tatgcacact tgtttggttc ccaaatgaaa cggaaca 477
813
814
815 <210>15
816 <211>722
817 <212>DNA
818 <213>人工序列(Artificial Sequence)
819
820 <220>
821 <223>A/Canine/Korea/03/07(H3N2)的HA部分基因
(HA partial gene ofA/Canine/Korea/03/07(H3N2))
822
823
824 <400>15
825 cagattgagg tgaccaatgc caccgagcta gtccaaaact cctcaacagg gaaaatatgc 60
826
827 aacaatcccc acaagatcct tgatgggagg gactgcacac taatagatgc cctactaggg 120
828
829 gacccgcact gtgatgtctt ccaaaatgag acatgggacc tttttgtgga acgaagcaat 180
830
831 gcttttagca attgttaccc ttatgatgta ccagactatg catcccttcg atccatagtt 240
832
833 gcatcatcag gcacattgga gttcatcgct gaaggtttca cttgggcagg agtaactcaa 300
834
835 aatggaggaa gcggtgcttg caaaagggga cctgctaatg gtttcttcag cagattgaat 360
836
837 tggttaacta agtcaggaaa tacatatcca gtgttgaatg tgactatgcc aaacaataac 420
838
839 aatttcgaca aattatacat ttggggagtt catcacccaa gcactaatca agaacaaacc 480
840
841 agcctgtata ttcaggcctc aggaagagtc acagtctcta ccaggagaag ccaacagacc 540
842
843 ataatcccaa acattggatc tagacccttg gtaaggggcc aatctggcag aataagtgta 600
844
845 tattggacaa tagtcaaacc tggggacgta ctggtaataa acagtaatgg aaacctaatc 660
846
847 gctcctcgag gctacttcaa aatgcgcatt gggaaaagct caataatgag atcagatgca 720
848
849 cc 722
850
851
852 <210>16
853 <211>477
854 <212>DNA
855 <213>人工序列(Artificial Sequence)
856
857 <220>
858 <223>A/Canine/Korea/03/07(H3N2)的NA部分基因
(NA partial gene of A/Canine/Korea/03/07(H3N2))
859
860
861 <400>16
862 ccaacaagcc ctgaacacac ataactggaa tcgatgctat aatctgccat atttatatct 60
863
864 ataacgggcc tattagagcc cttccaattg tctctgcaaa cacatctaac atttggatat 120
865
866 cgaggataac aggaacattc ctctatatgt tgagcactcc ctgacaatgg gctaatatgg 180
867
868 acaattttcc cctctctgat gaatagtatt ctagtatcag cccttcctga tgcacttcca 240
869
870 tcagtcatta ctactgtaca agttccattg atgcaaacgc attctgactc ctgagttctg 300
871
872 aggatatttc gagaccatga accaatactg tcaacaagca ttccattata aacgaaacta 360
873
874 gcagtcgcat ttctatcatc cccagtgaca caaacatgta accatgcttt cccatcgtga 420
875
876 caacttgaac tggaccatgc tatgcacact tgtttggttc ccaaatgaaa cggaaca 477
877
878
879 <210>17
880 <211>20
881 <212>DNA
882 <213>人工序列(Artificial Sequence)
883
884 <220>
885 <223>H3的引物(primer for H3)
886
887
888 <400>17
889 carattgarg tgachaatgc 20
890
891
892 <210>18
893 <211>19
894 <212>DNA
895 <213>人工序列(Artificial Sequence)
896
897 <220>
898 <223>H3的引物(primer for H3)
899
900
901 <400>18
902 ggtgcatctg ayctcatta 19
903
904
905 <210>19
906 <211>20
907 <212>DNA
908 <213>人工序列(Artificial Sequence)
909
910 <220>
911 <223>N2的引物(primer for N2)
912
913
914 <400>19
915 tgttccgttt catttgggaa 20
916
917
918 <210>20
919 <211>20
920 <212>DNA
921 <213>人工序列(Artificial Sequence)
922
923 <220>
924 <223>N2的引物(primer for N2)
925
926
927 <400>20
928 ccaacaagcc ctgaacacac 20
929
930
931 <210>21
932 <211>20
933 <212>DNA
934 <213>人工序列(Artificial Sequence)
935
936 <220>
937 <223>PB1的引物(primer for PB1)
938
939
940 <400>21
941 aaagtgccag cacaaaatgc 20
942
943
944 <210>22
945 <211>20
946 <212>DNA
947 <213>人工序列(Artificial Sequence)
948
949 <220>
950 <223>PB1的引物(primer for PB1)
951
952
953 <400>22
954 ttctcacaga tgctcctcgc 20
955
956
957 <210>23
958 <211>20
959 <212>DNA
960 <213>人工序列(Artificial Sequence)
961
962 <220>
963 <223>PB2的引物(primer for PB2)
964
965
966 <400>23
967 tcatggaggt cgtttttcca 20
968
969
970 <210>24
971 <211>20
972 <212>DNA
973 <213>人工序列(Artificial Sequence)
974
975 <220>
976 <223>PB2的引物(primer for PB2)
977
978
979 <400>24
980 tgaatcagcc ttctggttgc 20
981
982
983 <210>25
984 <211>20
985 <212>DNA
986 <213>人工序列(Artificial Sequence)
987
988 <220>
989 <223>PA的引物(primer for PA)
990
991
992 <400>25
993 gaagtgagcg ccaaaattga 20
994
995
996 <210>26
997 <211>20
998 <212>DNA
999 <213>人工序列(Artificial Sequence)
1000
1001 <220>
1002 <223>PA的引物(primer for PA)
1003
1004
1005 <400>26
1006 ctctggctca tcgctgtcat 20
1007
1008
1009 <210>27
1010 <211>20
1011 <212>DNA
1012 <213>人工序列(Artificial Sequence)
1013
1014 <220>
1015 <223>NP的引物(primer for NP)
1016
1017
1018 <400>27
1019 acggtctgca ctcatcctga 20
1020
1021
1022 <210>28
1023 <211>20
1024 <212>DNA
1025 <213>人工序列(Artificial Sequence)
1026
1027 <220>
1028 <223>NP的引物(primer for NP)
1029
1030
1031 <400>28
1032 gcccctggaa agacacatct 20
1033
1034
1035 <210>29
1036 <211>20
1037 <212>DNA
1038 <213>人工序列(A rtificial Sequence)
1039
1040 <220>
1041 <223>M的引物(primer for M)
1042
1043
1044 <400>29
1045 aacattccat ggggctaagg 20
1046
1047
1048 <210>30
1049 <211>20
1050 <212>DNA
1051 <213>人工序列(Artificial Sequence)
1052
1053 <220>
1054 <223>M的引物(primer for M)
1055
1056
1057 <400>30
1058 cggcaataac gagaggatca 20
1059
1060
1061 <210>31
1062 <211>20
1063 <212>DNA
1064 <213>人工序列(Artificial Sequence)
1065
1066 <220>
1067 <223>NS的引物(primer for NS)
1068
1069
1070 <400>31
1071 gactggttca tgctcatgcc 20
1072
1073
1074 <210>32
1075 <211>20
1076 <212>DNA
1077 <213>人工序列(Artificial Sequence)
1078
1079 <220>
1080 <223>NS的引物(primer for NS)
1081
1082
1083 <400>32
1084 gagagagtga aggtccccca 20
Claims (21)
1.一种H3N2血清型流感病毒,它具有由SEQ ID NO.9的氨基酸序列或与其共有95%以上同源性的氨基酸序列表示的红血球凝集素(HA)蛋白。
2.根据权利要求1所述的H3N2血清型流感病毒,其中与SEQ IDNO.9的氨基酸序列共有至少95%同源性的氨基酸序列在位置97、127、142、176、188、209、212和252中的至少一个位置含有与SEQ ID NO.9的氨基酸序列相同的氨基酸残基。
3.根据权利要求1所述的H3N2血清型流感病毒,它具有由SEQ IDNO.11的氨基酸序列或与其共有95%以上同源性的氨基酸序列表示的神经氨酸苷酶(NA)蛋白。
4.根据权利要求3所述的H3N2血清型流感病毒,其还包含选自以下的蛋白:由SEQ ID NO.3的核苷酸序列编码的非结构性蛋白(NS)、由SEQ ID NO.4的核苷酸序列编码的基质蛋白(M)、由SEQ ID NO.5的核苷酸序列编码的核蛋白(NP)、由SEQ ID NO.6的核苷酸序列编码的聚合酶(PA)、由SEQ ID NO.7的核苷酸序列编码的聚合酶碱性蛋白2(PB2)、由SEQ ID NO.8的核苷酸序列编码的聚合酶碱性蛋白1(PB1)及其组合。
5.根据权利要求1所述的H3N2血清型流感病毒,其保藏编号为KCTC 11205BP。
6.根据权利要求1所述的H3N2血清型流感病毒,其保藏编号为KCTC 11206BP。
7.根据权利要求1所述的H3N2血清型流感病毒,其保藏编号为KCTC 11207BP。
8.一种核苷酸序列,其编码权利要求1所述的红血球凝集素(HA)的氨基酸序列。
9.根据权利要求8所述的核苷酸序列,其由SEQ ID NO.9的核苷酸序列表示。
10.一种核苷酸序列,其编码权利要求3所述的神经氨酸苷酶(NA)的氨基酸序列。
11.根据权利要求10所述的核苷酸序列,其由SEQ ID NO.11的核苷酸序列表示。
12.一种流感病毒疫苗组合物,其包含权利要求1~7中任一项所述的病毒或其抗原决定簇作为活性成分。
13.根据权利要求12所述的流感病毒疫苗组合物,其适用于犬类。
14.根据权利要求12所述的流感病毒疫苗组合物,其还包含氢氧化铝凝胶或油作为佐剂。
15.根据权利要求12所述的流感病毒疫苗组合物,其还包含不同于所述活性成分的至少一种病原体。
16.根据权利要求12所述的流感病毒疫苗组合物,其中所述疫苗组合物是一种减毒活疫苗。
17.根据权利要求12所述的流感病毒疫苗组合物,其包含25HAU以上量的所述流感病毒。
18.根据权利要求12所述的流感病毒疫苗组合物,其中所述抗原决定簇为权利要求1或2所述的红血球凝集素(HA)或其抗原片段,并且含量为90%以上。
19.根据权利要求12所述的流感病毒疫苗组合物,其中所述抗原决定簇为权利要求3所述的神经氨酸苷酶(NA)或其抗原片段,并且含量为90%以上。
20.一种用于预防或治疗由流感病毒感染引起的疾病的方法,所述方法包括将权利要求12所述的流感病毒疫苗组合物给予感染流感病毒的个体。
21.一种用于检测H3N2血清型流感病毒的分析试剂盒,所述分析试剂盒包括权利要求1~7中任一项所述的病毒或其抗原决定簇。
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PCT/KR2007/005789 WO2009057843A1 (en) | 2007-10-30 | 2007-11-16 | A novel canine influenza virus and vaccine therefore |
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Cited By (5)
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CN101838708A (zh) * | 2010-03-30 | 2010-09-22 | 华南农业大学 | 一种检测犬流感的方法 |
WO2012159522A1 (zh) * | 2011-05-26 | 2012-11-29 | 中国农业科学院上海兽医研究所 | 犬流感重组病毒及其制备方法和应用 |
CN103223162A (zh) * | 2013-04-03 | 2013-07-31 | 华南农业大学 | 一株h3n2犬流感病毒株cgd1的应用 |
CN105463021A (zh) * | 2015-12-25 | 2016-04-06 | 华南农业大学 | 表达h3n2犬流感ha蛋白的重组犬腺病毒疫苗载体的构建方法 |
CN106248937A (zh) * | 2016-09-09 | 2016-12-21 | 华中农业大学 | 一种检测犬副流感病毒抗体的间接elisa试剂盒 |
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WO2012125525A2 (en) | 2011-03-14 | 2012-09-20 | Boehringer Ingelheim Vetmedica, Inc. | Equine rhinitis vaccine |
KR101390554B1 (ko) | 2012-05-22 | 2014-05-21 | 충남대학교산학협력단 | 신규한 개 인플루엔자 바이러스(h3n2), 이를 포함하는 백신 조성물 및 h3n2 바이러스 검정 키트 |
KR101484588B1 (ko) * | 2012-10-24 | 2015-01-20 | 대한민국 | 개 인플루엔자 vlp 백신의 제조방법 |
KR101511619B1 (ko) * | 2013-04-30 | 2015-04-13 | 한국생명공학연구원 | 개 인플루엔자 바이러스 h3n2의 ha1 단백질을 항원으로 포함하는 개 인플루엔자 바이러스 h3n2에 특이적인 혈청 진단용 키트 |
KR101627623B1 (ko) | 2013-08-29 | 2016-06-08 | 한국생명공학연구원 | 이종 인플루엔자 바이러스에 대한 백신 조성물 |
KR101768600B1 (ko) * | 2015-05-18 | 2017-08-17 | 한국생명공학연구원 | 범용성 개 인플루엔자 바이러스 백신 조성물 |
CA2990633A1 (en) * | 2015-06-26 | 2016-12-29 | Merial, Inc. | Inactivated canine influenza vaccines and methods of making and uses thereof |
WO2017031404A1 (en) | 2015-08-20 | 2017-02-23 | University Of Rochester | Live-attenuated vaccine having mutations in viral polymerase for the treatment and prevention of canine influenza virus |
WO2017031401A2 (en) * | 2015-08-20 | 2017-02-23 | University Of Rochester | Ns1 truncated virus for the development of canine influenza vaccines |
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AU1308495A (en) | 1994-01-11 | 1995-08-01 | Rijksuniversiteit Gent | Influenza vaccine |
AT407958B (de) * | 1999-02-11 | 2001-07-25 | Immuno Ag | Inaktivierte influenza-virus-vakzine zur nasalen oder oralen applikation |
CA2621320C (en) * | 2005-10-07 | 2016-05-24 | Pfizer Products Inc. | Vaccines and methods to treat canine influenza |
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CN101838708A (zh) * | 2010-03-30 | 2010-09-22 | 华南农业大学 | 一种检测犬流感的方法 |
CN101838708B (zh) * | 2010-03-30 | 2012-07-18 | 华南农业大学 | 一种检测犬流感的方法 |
WO2012159522A1 (zh) * | 2011-05-26 | 2012-11-29 | 中国农业科学院上海兽医研究所 | 犬流感重组病毒及其制备方法和应用 |
EP2716752A4 (en) * | 2011-05-26 | 2014-04-30 | Shanghai Veterinary Res Inst Caas | RECOMBINANT DOG INFLUENZA VIRUS, MANUFACTURING METHOD AND APPLICATION THEREOF |
CN103223162A (zh) * | 2013-04-03 | 2013-07-31 | 华南农业大学 | 一株h3n2犬流感病毒株cgd1的应用 |
CN103223162B (zh) * | 2013-04-03 | 2014-07-30 | 华南农业大学 | 一株h3n2犬流感病毒株cgd1的应用 |
CN105463021A (zh) * | 2015-12-25 | 2016-04-06 | 华南农业大学 | 表达h3n2犬流感ha蛋白的重组犬腺病毒疫苗载体的构建方法 |
CN106248937A (zh) * | 2016-09-09 | 2016-12-21 | 华中农业大学 | 一种检测犬副流感病毒抗体的间接elisa试剂盒 |
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US20100285063A1 (en) | 2010-11-11 |
EP2078083A4 (en) | 2009-10-28 |
JP5404636B2 (ja) | 2014-02-05 |
ATE554789T1 (de) | 2012-05-15 |
US8246962B2 (en) | 2012-08-21 |
EP2078083B1 (en) | 2012-04-25 |
EP2078083A1 (en) | 2009-07-15 |
ES2383158T3 (es) | 2012-06-18 |
KR100850545B1 (ko) | 2008-08-05 |
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