CN113905759A - 用于预防和控制马的马流感病毒(eiv)的多价减毒活流感疫苗 - Google Patents
用于预防和控制马的马流感病毒(eiv)的多价减毒活流感疫苗 Download PDFInfo
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Abstract
本发明提供与马减毒活流感疫苗相关的组合物和方法。在一方面，本发明涉及包含多价马减毒活流感疫苗的组合物，其包括表达进化枝1H3N8马流感病毒的一种或多种抗原的第一减毒活流感病毒；和表达进化枝2H3N8马流感病毒的一种或多种抗原的第二减毒活流感病毒，其中第二减毒活流感病毒表达A/马/Lancashire/1/2016H3N8的HA、NA或其组合。
Description
关于联邦政府资助研究或开发的声明
本发明是根据国家卫生研究院颁发的HHSN272201400005C在政府支持下进行的。政府对本发明具有一定权利。
相关申请的交叉引用
本申请要求2019年2月27日提交的美国临时专利申请序列号62/811,112的优先权，所述申请以引用的方式整体并入本文。
发明背景
目前由H3N8 EIV引起的马流感是最常见和最重要的马呼吸道传染病(Daly等人，2011,Vet J,189:7-14；Timoney,2000,Vet.Clin.North Am.Equine Pract.16,537–551)。H3N8 EIV具有高度传染性，并且有可能通过咳嗽散播的雾化飞沫在幼马群中迅速传播(Daly等人，2011,Vet J,189:7-14；Timoney,2000,Vet.Clin.North Am.Equine Pract.16,537–551)。马的H3N8 EIV感染已导致重大马术赛事中断并造成重大经济损失(Daly等人，2011,Vet J,189:7-14；Timoney,2000,Vet.Clin.North Am.Equine Pract.16,537–551)。马群的流动性很强，并且为了竞争和繁殖目的，马可以通过公路和/或空中长途跋涉。当受感染的马被引入易感群体中时，H3N8 EIV的传播可能是爆发性的。H3N8 EIV的大规模爆发通常与马术比赛中马的聚集有关。在这些事件发生后，它们的扩散会导致病毒进一步广泛传播。目前估计，H3N8 EIV的爆发造成数亿美元的经济损失。在流行国家，H3N8 EIV感染造成的重大经济损失可以通过对高度流动的马进行疫苗接种降至最低程度。事实上，许多赛马和马术当局都有强制性的疫苗接种政策来作为商业保险。另一方面，非流行国家依靠进口马的疫苗接种和检疫来防止H3N8 EIV的入侵。这些非流行国家中的大多数还要求对其本土马群进行疫苗接种，以减少H3N8 EIV入侵的潜在影响。
传统的疫苗接种策略支持疫苗株必须代表传播中的病毒，并且疫苗公司只有通过监测才能决定应该使用哪些抗原。因此，EIV监测和毒株鉴定是基于疫苗接种的H3N8 EIV控制计划的基础。重要的是，疫苗制造商需要有一种动态的疫苗接种方法，以允许快速产生新疫苗来使马群受益(Cullinane等人，2010,Influenza Other Respir.Virus.4,339–344；Paillot,2014,Vaccines 2,797–831；Paillot等人，2016,Pathogens 5)。交叉保护研究的结果表明，大多数灭活疫苗或当前市售的LAIV Flu Avert I.N.如果在面临即将爆发的疫情时使用，将提供较弱的保护水平，因为疫苗中的病毒与目前流行的H3N8 EIV毒株之间存在抗原差异(Paillot等人，2016,Pathogens 5)。值得注意的是，最近一些H3N8 EIV爆发发生在先前接种过疫苗的动物中，其中疫苗株与流行病毒不匹配(Daly等人，2003,EquineVet.J.35,458–462；Garner等人，2011,Prev.Vet.Med.99,15–27；Timoney,2000,Vet.Clin.North Am.Equine Pract.16,537–551)。H3N8 EIV爆发的频率、H3N8 EIV的持续抗原变异(抗原漂移)以及由于抗原匹配不佳导致疫苗失效的例子表明需要定期更新EIV疫苗以预防马群中的马流感。此外，根据OIE的建议，EIV疫苗应该包括佛罗里达亚系的进化枝1和进化枝2代表毒株(Paillot等人，2016，Pathogens 5)。
因此，本领域需要改进的EIV疫苗。本发明满足了这一未被满足的需求。
发明内容
在一方面，本发明提供多价免疫组合物。在一个实施方案中，多价免疫组合物包含两种或更多种马减毒活流感病毒(LAIV)，其包括：表达进化枝1 H3N8马流感病毒的一种或多种抗原的第一LAIV；和表达进化枝2 H3N8马流感病毒的一种或多种抗原的第二LAIV，其中第二LAIV表达A/马/Lancashire/1/2016 H3N8的HA、NA或其组合，其中每种LAIV包含在以下一项或多项中发生的一个或多个突变：病毒基因组的区段1和区段2。
在一个实施方案中，第一LAIV表达A/马/Ohio/1/2003 H3N8的HA、NA或其组合。
在一个实施方案中，第一LAIV表达A/马/Texas/6/2017 H3N8的HA、NA或其组合。
在一个实施方案中，区段1包含在SEQ ID NO:1中列出的核酸序列。在一个实施方案中，区段2包含在SEQ ID NO:3中列出的核酸序列。
在一个实施方案中，至少一种LAIV在编码突变PB2的区段1中包含一个或多个突变。在一个实施方案中，突变PB2包含N265S点突变。在一个实施方案中，突变PB2包含在SEQID NO:2中列出的氨基酸序列。
在一个实施方案中，至少一种LAIV在编码突变PB1的区段2中包含一个或多个突变。在一个实施方案中，突变PB1包含下列中的一个或多个：K391E点突变、E581G点突变和A661T点突变。在一个实施方案中，突变PB1包含K391E点突变、E581G点突变和A661T点突变。在一个实施方案中，突变PB1包含在SEQ ID NO:4中列出的氨基酸序列。
在一个实施方案中，每种LAIV在编码突变PB2的区段1中包含一个或多个突变；并在编码突变PB1的区段2中包含一个或多个突变。在一个实施方案中，突变PB2包含N265S点突变并且其中突变PB1包含K391E点突变、E581G点突变和A661T点突变。
在一个实施方案中，组合物用于治疗受试者的马流感。
在一个实施方案中，每种LAIV的区段1源自A/马/Ohio/1/2003的区段1；并且其中每种LAIV的区段2源自A/马/Ohio/1/2003的区段2。
在一方面，本发明提供一种在受试者中诱导针对多种马流感病毒的免疫反应的方法，该方法包括向受试者施用包含两种或更多种马减毒活流感病毒(LAIV)的多价免疫组合物，该免疫组合物包含：第一LAIV，其表达进化枝1 H3N8马流感病毒的一种或多种抗原；和第二LAIV，其表达进化枝2 H3N8马流感病毒的一种或多种抗原，其中第二LAIV表达A/马/Lancashire/1/2016 H3N8的HA、NA或其组合，其中每种LAIV包含在以下一项或多项中发生的一个或多个突变：病毒基因组的区段1和区段2。
在一个实施方案中，受试者未患有马流感，并且其中该方法诱导针对马流感的免疫。在一个实施方案中，受试者感染了马流感，并且其中该方法诱导治疗性免疫反应。
在一个实施方案中，免疫组合物经鼻内、气管内、口服、皮内、肌肉内、腹膜内、静脉内或皮下施用。在一个实施方案中，受试者是马。
附图说明
当结合附图阅读时，能更好地理解本发明的优选实施方案的以下详细描述。为了说明本发明，在附图中示出了目前优选的实施方案。然而，应该理解，本发明不限于附图中所示的实施方案的精确布置和手段。
图1包括A和B，示出了证明温度对A/马/Ohio/1/2003 H3N8(EIV)减毒活流感疫苗(LAIV)聚合酶活性的影响的实验结果。A：WT(黑色)和LAIV(白色)EIV(A/马/Ohio/1/2003)的区段1(PB2)和区段2(PB1)的示意图：指示了A/马/Ohio/1/2003 H3N8的聚合酶PB2(N265S)和PB1(K391E、E581G和A661T)亚基中的氨基酸取代。B：微基因组活性：将马真皮细胞(12孔板格式，5×105个细胞/孔，一式三份)用0.25μg编码病毒基因组复制和基因转录的最低要求(PB2、PB1、PA和NP)的双义pDZ表达质粒以及0.5μg编码高斯荧光素酶(Gluc)的vRNA样表达质粒和0.1μg pCAGGS Cypridina荧光素酶(Cluc)质粒瞬时共转染，以使转染效率标准化。在转染后6小时，将细胞置于33℃、37℃或39℃下，并在转染后48小时，通过发光(Gluc)评估病毒复制和转录。Gluc活性被标准化为Cluc的活性。数据代表三次重复测定的结果的平均值±SD。标准化报告基因表达是相对于在没有pDZ NP质粒的情况下的微基因组活性。将每个温度下的WT EIV聚合酶活性视为100％，数据表示为相对活性。使用学生T检验，*，P<0.005；**，P<0.001；NS，无统计学差异。
图2包括A和B，示出了评估EIV LAIV体外表征的实验的结果。A：多循环生长动力学：用A/马/Ohio/1/2003 H3N8 WT(黑色菱形)和LAIV(白色菱形)感染(MOI，0.001)MDCK细胞(12孔板格式，5×105个细胞/孔，一式三份)并在33℃、37℃和39℃下培养。作为内部对照，还用Flu Avert I.N.(灰色三角形)感染MDCK细胞。使用抗NP mAb(HB-65)通过免疫聚焦测定确定在感染后指定时间的TCS中的病毒滴度(FFU/ml)。数据代表在一式三份孔中确定的结果的平均值+/-SD。黑色虚线指示检测限(200FFU/ml)。P<0.05：*野生型对比LAIV，**野生型对比Flu Avert I.N.，使用学生T检验。B：空斑表型：用A/马/Ohio/1/2003 H3N8 WT和LAIV感染MDCK细胞(6孔板格式，1×106个细胞/孔)，并用含有琼脂的培养基覆盖。包括感染Flu Avert I.N.的MDCK细胞作为内部对照。将平板在33℃、37℃和39℃下培养，并在感染后三天，用抗NP mAb(HB-65)对单层细胞进行免疫染色。
图3包括A和B，示出了证明EIV LAIV在小鼠中衰减的示例实验的结果：使用1×105个FFU的A/马/Ohio/1/2003 H3N8 WT或LAIV鼻内感染(i.n.)6至8周龄的雌性C57BL/6小鼠(N＝6)。还用1×105个FFU的Flu Avert I.N.感染小鼠以作为内部对照。在感染后第2天(N＝3)和第4天(N＝3)，使用抗NP mAb(HB-65)，通过免疫聚焦测定(FFU/ml)评估受感染小鼠的肺(A)和鼻粘膜(B)中病毒的存在。数据代表平均值±SD。黑色虚线指示检测限(200FFU/ml)。ND，未检测到。*，P<0.05，使用学生T检验。
图4包括A和B，示出了证明EIV LAIV在小鼠中诱导体液反应的示例实验的结果：6至8周龄的雌性C57BL/6小鼠(N＝6)接种(鼻内)1×103个FFU的A/马/Ohio/1/2003 H3N8 WT或LAIV。小鼠还被模拟(PBS)接种或接种(鼻内)1×103个FFU的Flu Avert I.N.，分别作为阴性和阳性对照。在接种后14天，将小鼠放血并收集血清，并且分别通过ELISA(A)和HAI(B)评估针对A/马/Ohio/1/2003 H3N8的总抗体的存在和中和抗体的存在。OD，光密度。数据代表6只个体小鼠的结果的平均值+/-SD。ND，未检测到。*，P<0.05：野生型对比LAIV；**，P<0.005：野生型对比Flu Avert I.N.，使用学生T检验。
图5示出了证明EIV LAIV在小鼠中针对EIV攻击的保护作用的示例实验的结果：6至8周龄的雌性C57BL/6小鼠(N＝6)接种1×103个FFU的A/马/Ohio/1/2003 H3N8 WT或LAIV。小鼠还被模拟(PBS)接种或接种(鼻内)1×103个FFU的Flu Avert I.N.，分别作为阴性和阳性对照。在接种后15天，用1×105个FFU的A/马/Ohio/1/2003 H3N8 WT攻击小鼠，并在攻击后第2天(N＝3)和第4天(N＝4)，使用抗NP mAb(HB-65)通过免疫聚焦测定评估肺匀浆中的病毒滴度(FFU/ml)。黑色虚线指示检测限(200FFU/ml)。数据代表平均值±SD。ND，未检测到。
图6包括A和B，示出了证明EIV LAIV在马中衰减的示例实验的结果：两种性别的一到两岁的马(N＝4)鼻内接种4×108个FFU的A/马/Ohio/1/2003 H3N8 LAIV。A：在接种前(第0天)和接种后3天期间测量的每匹马的个体直肠温度的图示。B：通过定量(q)RT-PCR测定鼻咽拭子中的病毒含量，并表示为定量循环阈值(Ct)。在接种前(第0天)和接种后3天期间对每个马鼻孔采集拭子。数据代表每匹马在接种后每个时间点的平均值±SD。黑色虚线指示检测限(Ct＝40)。
图7包括A和B，示出了证明EIV LAIV在马中针对EIV攻击的保护功效的示例实验的结果：两种性别的一到两岁的马(N＝4)通过鼻内插管接种了4×108个FFU的A/马/Ohio/1/2003 H3N8 LAIV。另一组马(N＝2)用作对照(未接种疫苗)。在接种后27天，通过使1×107个EID50单位/m3的野生型EIV(Kentucky/2014毒株)雾化进入帐篷隔间(37.5m3)持续45分钟攻击马。A：在攻击后10天每天测量直肠温度。B：通过(q)RT-PCR分析攻击后7天期间采集的鼻咽拭子中的病毒含量，并表示为循环阈值(Ct)。黑色虚线指示检测限(Ct＝40)。
具体实施方式
本发明涉及用于治疗和预防马流感病毒(EIV)和EIV相关病理的组合物和方法。本发明提供多价免疫组合物，其提供针对多种EIV毒株或进化枝的保护。例如，在一个实施方案中，多价免疫组合物提供针对进化枝1 H3N8 EIV和进化枝2 H3N8 EIV的保护。
本发明部分基于以下发现：EIV基因组的区段1和区段2中的各种突变(从而编码突变PB2和PB1蛋白)使病毒对温度敏感。例如，本文描述了与野生型EIV相比此类突变导致EIV在正常和升高的体温下表现出减少的病毒复制。然而，温度敏感性EIV能够诱导EIV特异性免疫反应。因此，本文所述的温度敏感性EIV是减毒活流感疫苗(LAIV)，本文有时称为EIVLAIV。重要的是，与市售疫苗相比，本发明描述的EIV LAIV在治疗EIV方面更有效。
本文描述了用于预防和控制马的H3N8 EIV的有效且安全的LAIV的开发。使用反向遗传学方法以及在A/马/Ohio/1/2003 H3N8病毒的病毒PB2(N265S)和PB1(K391E、E581G和A661T)聚合酶亚基中的修饰来制造冷适应、温度敏感性EIV H3N8 LAIV。与目前的灭活疫苗相比，本发明描述的冷适应、温度敏感性LAIV方法针对由H3N8 EIV引起的疾病提供更好、更持久的保护，因为LAIV在呼吸道的靶组织中诱导更快、更强的先天性和适应性体液和T细胞免疫反应的产生。此外，在某些情况下，通过鼻喷雾剂施用LAIV，这避免了与灭活疫苗肌肉内感染相关的肿胀和肌肉酸痛。此外，在一些实施方案中，与使用当前灭活疫苗所需的多次剂量相比，使用冷适应、温度敏感性LAIV的单次免疫足以在更短的时间内提供针对H3N8EIV的完全保护。此外，与目前的灭活疫苗相比，本发明的LAIV技术将提供针对抗原性不同的EIV H3N8毒株的更好交叉保护，从而减少H3N8 EIV爆发的机会。
与唯一可用的EIV H3N8 LAIV相比，本发明技术还提供了许多优点。在甲型流感/马/Ohio/1/2003 H3N8的PB2和PB1聚合酶亚基中引入的突变与由当前的甲型流感/马/Kentucky/1/91 H3N8 LAIV的冷适应产生的突变不同；但能够赋予病毒类似的冷适应、温度敏感性表型。此外，与人类LAIV的情况类似，使用最先进的反向遗传学技术促进了用于治疗目前流行的佛罗里达进化枝1和2亚型或新引入的H3N8 EIV毒株的LAIV候选者的快速和准确的开发。因此，由于毒株匹配，本发明LAIV方法比目前可用的LAIV能更有效地治疗马的H3N8 EIV感染。
在某些实施方案中，本发明涉及包含两种或更多种EIV LAIV的多价免疫组合物。例如，在某些实施方案中，使用本文所述的基于甲型流感/马/Ohio/1/2003(进化枝1毒株)的H3N8 LAIV作为主供体病毒(MDV)以表达来自不同毒株的抗原。例如，在一个实施方案中，多价免疫组合物包含第一温度敏感性LAIV和第二温度敏感性LAIV，它们各自包含突变区段1和/或突变区段2，其中第一LAIV表达第一流感毒株的一种或多种抗原并且其中第二LAIV表达第二流感毒株的一种或多种抗原。本发明还包括包含3种或更多种、4种或更多种、5种或更多种、或10种或更多种LAIV的多价免疫组合物，每种LAIV表达不同流感毒株的一种或多种抗原。多价组合物可用于表达来自抗原性不同的进化枝或毒株的抗原，例如HA和NA糖蛋白，从而提供针对各种流行进化枝或毒株的广泛保护。
定义
除非另有定义，否则本文中使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的含义相同的含义。虽然在本发明的实践或测试中可以使用类似或等同于本文所描述的那些方法和材料的任何方法和材料，但描述了优选的方法和材料。
如本文中所用，以下每个术语都具有与其在本节中相关的含义。
冠词“一个/种(a)”和“一个/种(an)”在本文中用于指一个或多于一个(即，至少一个)该冠词的语法对象。举例来说，“元素”意指一个元素或多于一个元素。
如本文所用，“约”在指可测量的值诸如量、持续时间等时意在包括与规定值相差±20％、±10％、±5％、±1％或±0.1％的变化，因为此类变化适用于执行公开的方法。
如本文所用，术语“抗体”是指与抗原特异性结合的免疫球蛋白分子。抗体可以是源自天然来源或重组来源的完整免疫球蛋白并且可以是完整免疫球蛋白的免疫活性部分。本发明中的抗体可以多种形式存在，包括例如多克隆抗体、单克隆抗体、Fv、Fab和F(ab)2，以及单链抗体和人源化抗体(Harlow等人，1999，Using Antibodies:A LaboratoryManual,Cold Spring Harbor Laboratory Press,NY；Harlow等人，1989，Antibodies:ALaboratory Manual,Cold Spring Harbor,New York；Houston等人，1988,Proc.Natl.Acad.Sci.USA 85:5879-5883；Bird等人，1988,Science 242:423-426)。
如本文所用，术语“抗原”或“Ag”被定义为激发免疫反应的分子。这种免疫反应可涉及抗体的产生或特定免疫活性细胞的激活，或两者皆有。技术人员将理解任何大分子，包括几乎所有的蛋白质或肽，都可以作为抗原。此外，抗原可以来自重组或基因组DNA。技术人员将理解，包含编码引发免疫反应的蛋白质的核苷酸序列或部分核苷酸序列的任何DNA因此编码本文所使用的术语“抗原”。此外，本领域技术人员将理解抗原不需要仅由基因的全长核苷酸序列编码。很明显，本发明包括但不限于使用一种以上基因的部分核苷酸序列，并且这些核苷酸序列以各种组合排列以引起所需的免疫反应。此外，技术人员将理解抗原根本不需要由“基因”编码。很明显，抗原可以合成产生或可以从生物样品中获得。
如本文所用，术语“自体的”是指源自同一个体的任何材料，其随后被重新引入该个体中。
如本文所用，“组合疗法”是指第一药剂与另一种药剂联合施用。“联合”是施用一种治疗模式外加另一种治疗模式。因此，“联合”是指在向个体递送另一种治疗模式之前、期间或之后施用一种治疗模式。这种组合被认为是单一治疗方案或体系的一部分。
如本文所用，术语“同时给药”是指组合疗法中第一疗法的施用和第二疗法的施用彼此重叠。
“疾病”是动物的健康状态，其中动物不能维持体内平衡，并且其中如果疾病没有改善，则动物的健康继续恶化。相比之下，动物的“病症”是一种健康状态，其中动物能够维持体内平衡，但动物的健康状态不如在没有该病症时的健康状态。如果不加以治疗，病症不一定会导致动物健康状况进一步下降。
如本文所用，“有效量”是指提供治疗或预防益处的量。
如本文所用，术语“表达”被定义为由其启动子驱动的特定核苷酸序列的转录和/或翻译。
“表达载体”是指包含重组多核苷酸的载体，该重组多核苷酸包含与要表达的核苷酸序列可操作地连接的表达控制序列。表达载体包含足够用于表达的顺式作用元件；其他用于表达的元件可以由宿主细胞或在体外表达系统中提供。表达载体包括本领域已知的所有表达载体，例如掺入重组多核苷酸的粘粒、质粒(例如，裸露的或包含在脂质体中)和病毒(例如，慢病毒、逆转录病毒、腺病毒和腺相关病毒)。
“同源的”是指两个肽之间或两个核酸分子之间的序列同一性。当两个比较序列中的一个位置被相同的碱基或氨基酸单体亚基占据时，例如，如果两个DNA分子各自中的一个位置被腺嘌呤占据，则该分子在该位置是同源的。两个序列之间的同源性百分比是这两个序列共享的匹配或同源位置的数量除以对比的位置数乘以100的函数。例如，如果两个序列中的10个位置中有6个匹配或同源，则这两个序列为60％同源。例如，DNA序列ATTGCC和TATGGC具有50％的同源性。通常，在两个序列对齐时进行比较，以获得最大同源性。
如本文所用，术语“免疫球蛋白”或“Ig”被定义为用作抗体的一类蛋白质。由B细胞表达的抗体有时被称为BCR(B细胞受体)或抗原受体。包括在此类蛋白质中的五个成员是IgA、IgG、IgM、IgD和IgE。IgA是存在于身体分泌物(例如唾液、眼泪、母乳、胃肠道分泌物以及呼吸道和泌尿生殖道的粘液分泌物)中的主要抗体。IgG是最常见的循环抗体。IgM是大多数受试者在初级免疫反应中产生的主要免疫球蛋白。它是凝集、补体固定和其他抗体反应中最有效的免疫球蛋白，并且在防御细菌和病毒方面很重要。IgD是没有已知的抗体功能，但可以作为抗原受体的免疫球蛋白。IgE是通过在暴露于过敏原时导致肥大细胞和嗜碱性粒细胞释放介质来介导即时超敏反应的免疫球蛋白。
如本文所用，术语“免疫反应”包括T细胞介导和/或B细胞介导的免疫反应。示例性免疫反应包括T细胞反应，例如细胞因子产生和细胞毒性；和B细胞反应，例如抗体产生。此外，术语免疫反应包括间接受T细胞活化影响的免疫反应，例如抗体产生(体液反应)和细胞因子反应性细胞(例如巨噬细胞)的活化。参与免疫反应的免疫细胞包括淋巴细胞，诸如B细胞和T细胞(CD4+、CD8+、Th1和Th2细胞)；抗原呈递细胞(例如，专职性抗原呈递细胞，诸如树突细胞、巨噬细胞、B淋巴细胞、郎格罕氏细胞(Langerhans cell)；以及非专职性抗原呈递细胞，诸如角化细胞、内皮细胞、星形细胞、成纤维细胞、少突细胞)；天然杀伤细胞；骨髓细胞，诸如巨噬细胞、嗜酸性粒细胞、肥大细胞、嗜碱性粒细胞以及粒细胞。
“分离的”是指改变或脱离自然状态。例如，天然存在于活体动物中的核酸或肽不是“分离的”，但与其天然状态的共存材料部分或完全分离的相同核酸或肽是“分离的”。分离的核酸或蛋白质可以以基本上纯化的形式存在，或者可以存在于非天然环境例如宿主细胞中。
免疫原组合物的“肠胃外”施用包括例如皮下(s.c.)、静脉内(i.v.)、肌肉内(i.m.)或胸骨内注射或输注技术。
术语“患者”、“受试者”、“个体”等在本文中可互换使用，并且是指无论在体外还是在原位都适用于本文所述的方法的任何动物或其细胞。
如本文所用，术语“同时施用”是指组合疗法中的第一疗法和第二疗法以不超过约15分钟(例如不超过约10、5或1分钟中的任一个)的时间间隔施用。当同时施用第一和第二疗法时，第一和第二疗法可以包含在相同的组合物中(例如，包含第一和第二疗法的组合物)或不同的组合物中(例如，第一疗法在一种组合物中，而第二疗法包含在另一种组合物中)。
如本文所用的关于抗体的术语“特异性结合”是指识别特定抗原但基本上不识别或结合样品中的其他分子的抗体。例如，与来自一个物种的抗原特异性结合的抗体也可以与来自一个或多个物种的该抗原结合。但是，这种跨物种反应性本身不会改变抗体的特异性分类。在另一个例子中，特异性结合抗原的抗体也可以结合抗原的不同等位基因形式。然而，这种交叉反应性本身不会改变抗体的特异性分类。在一些情况下，术语“特异性结合(specific binding)”或“特异性结合(specifically binding)”可用于指抗体、蛋白质或肽与第二化学种类的相互作用，以表示该相互作用取决于该化学种类上存在的特定结构(例如，抗原决定簇或表位)；例如，抗体识别并结合特定的蛋白质结构，而不是一般蛋白质。如果抗体对表位“A”具有特异性，则在含有标记“A”和抗体的反应中，含有表位A(或游离的未标记的A)的分子的存在将减少与抗体结合的标记A的数量。
如本文所用，术语“正常温度”或“正常体温”是指健康受试者的温度。例如，在某些情况下，人类受试者的“正常体温”在约36℃至约38℃的范围内。在某些情况下，在马受试者中，“正常体温”在约37.5℃至约38.7℃的范围内。
如本文所用，术语“升高的温度”或“升高的体温”是指受试者的温度高于给定生物的受试者的“正常体温”。在某些情况下，“升高的体温”可以指示发烧、感染或其他疾病。在某些情况下，人类受试者的体温升高是大于约37℃。在某些情况下，马受试者的体温升高是大于约38.9℃。
如本文所用，术语“治疗”是指治疗和/或预防。通过抑制、缓解或根除疾病状态获得治疗效果。
术语“治疗有效量”是指将引起研究员、兽医、医生或其他临床医师正在寻求的组织、系统或受试者的生物或医学反应的主题化合物的量。术语“治疗有效量”包括在施用时足以预防所治疗的病症或疾病的一种或多种体征或症状的发展或在一定程度上减轻该一种或多种体征或症状的化合物的量。治疗有效量将根据化合物、疾病及其严重程度以及待治疗的受试者的年龄、体重等而变化。
如本文所用的术语“治疗”疾病是指降低受试者所经历的疾病或病症的至少一种体征或症状的频率或严重程度。
如本文所用，术语“转染的”或“转化的”或“转导的”是指将外源核酸转移至或引入宿主细胞的过程。“转染的”或“转化的”或“转导的”细胞是用外源核酸转染、转化或转导的细胞。该细胞包括原代受试者细胞及其后代。
范围：在整个本公开中，本发明的各个方面可以以范围格式呈现。应当理解，以范围格式进行描述只是为了方便和简洁，并且不应被解释为对本发明的范围的僵硬限制。因此，范围的描述应该被认为已明确公开了所有可能的子范围以及该范围内的各个数值。例如，诸如从1至6的范围的描述应该被认为已明确公开了诸如1至3、1至4、1至5、2至4、2至6、3至6等的子范围，以及该范围内的各个数字，例如1、2、2.7、3、4、5、5.3和6。这在任何宽度范围的情况下均适用。
详述
本发明提供了可用于抑制、预防和治疗马流感和马流感相关疾病和病症的免疫组合物和方法。在一个实施方案中，免疫组合物包含减毒活病毒(LAV)。在一个实施方案中，免疫组合物是包含多种LAV的多价组合物，每种LAV表达病毒的不同毒株或进化枝(例如流感病毒的不同毒株或进化枝)的一种或多种抗原。
在一个实施方案中，本发明提供了一种马流感病毒的温度敏感性LAV。例如，本文证明EIV基因组的区段1和/或区段2中的一个或多个突变使病毒对温度敏感。与野生型EIV相比，本发明的温度敏感性EIV LAIV在正常体温和升高或发热的温度下均表现出减少的病毒复制。然而，温度敏感性EIV LAIV提供抗原特异性免疫反应和针对EIV的保护。在一个实施方案中，与野生型EIV相比，EIV LAIV提供至少相同的抗原特异性免疫反应和针对EIV的保护。在某些实施方案中，与灭活的EIV相比，EIV LAIV提供更强的抗原特异性免疫反应和针对EIV的保护。
在一个实施方案中，组合物包含在病毒基因组的区段1和/或区段2中具有一个或多个突变的EIV LAIV。例如，在一个实施方案中，EIV LAIV编码突变PB2和/或突变PB1。在某些实施方案中，突变PB2包含N265S点突变。在某些实施方案中，突变PB1包含K391E点突变、E581G点突变或A661T点突变中的至少一种。
在某些实施方案中，本文所述的EIV LAIV用作主供体病毒(MDV)，其在病毒基因组的区段1和/或区段2中具有一个或多个突变，以表达流感病毒的不同毒株或进化枝的一种或多种抗原。在一个实施方案中，MDV包含突变的H3N8区段1和/或区段2，如本文所述。在某些实施方案中，MDV可用于产生对其他病原体具有保护作用的LAIV。例如，在某些实施方案中，可以通过使用MDV表达其他毒株的一种或多种病毒蛋白(例如HA或NA)来产生针对另一种流感毒株的LAIV。例如，在一个实施方案中，组合物包含含有多种LAIV的多价免疫组合物，每种LAIV被设计成表达流感病毒的不同进化枝或毒株的一种或多种抗原。
在一个实施方案中，组合物包含表达进化枝1 H3N8流感病毒的一种或多种抗原的第一LAIV和表达进化枝2 H3N8流感病毒的一种或多种抗原的第二LAIV。
在一个实施方案中，组合物包含表达进化枝1 A/马/Ohio/1/2003 H3N8的一种或多种抗原的LAIV。在一个实施方案中，组合物包含表达进化枝2 A/马/Richmond/1/2007H3N8的一种或多种抗原的LAIV。在一个实施方案中，组合物包含表达进化枝1A/马/Texas/6/2017 H3N8的一种或多种抗原的LAIV。在一个实施方案中，组合物包含表达进化枝2A/马/Lancashire/1/2016 H3N8的一种或多种抗原的LAIV。
在一个实施方案中，组合物包含表达A/马/Ohio/1/2003 H3N8的一种或多种抗原的第一LAIV和表达A/马/Richmond/1/2007 H3N8的一种或多种抗原的第二LAIV。
在一个实施方案中，组合物包含表达A/马/Texas/6/2017 H3N8的一种或多种抗原的第一LAIV和表达A/马/Lancashire/1/2016 H3N8的一种或多种抗原的第二LAIV。
在一个实施方案中，组合物包含表达A/马/Ohio/1/2003 H3N8的一种或多种抗原的第一LAIV和表达A/马/Lancashire/1/2016 H3N8的一种或多种抗原的第二LAIV。
在一个实施方案中，组合物包含表达A/马/Texas/6/2017 H3N8的一种或多种抗原的第一LAIV和表达A/马/Richmond/1/2007 H3N8的一种或多种抗原的第二LAIV。
在某些实施方案中，本发明提供一种治疗或预防EIV和EIV相关病理的方法，其包括施用包含EIV LAIV的组合物。在某些实施方案中，该方法包括鼻内递送EIV LAIV。
一般而言，野生型流感病毒包含具有8个区段的分段基因组，如下表1所述：
表1：
| 区段 | 基因产物 |
| 1 | PB2(聚合酶(碱性)蛋白2) |
| 2 | PB1(聚合酶(碱性)蛋白1) |
| 3 | PA(聚合酶(酸性)蛋白) |
| 4 | HA(血凝素) |
| 5 | NP(核蛋白) |
| 6 | NA(神经氨酸酶) |
| 7 | M1(基质蛋白1)和M2(基质蛋白2) |
| 8 | NS1(非结构蛋白1)和NEP/NS2(非结构蛋白2) |
在某些实施方案中，本发明提供包含区段1和/或区段2的免疫组合物，其中区段1和/或区段2包含一个或多个突变。例如，在某些实施方案中，免疫组合物包含LAIV，其包含区段1和/或区段2中的一个或多个突变。在一个实施方案中，免疫组合物包含EIV LAIV，其包含区段1和/或区段2中的一个或多个突变。
本发明还提供预防、抑制和治疗EIV以及EIV相关疾病和病症的方法。在一个实施方案中，本发明的方法通过产生针对EIV的免疫反应来诱导针对EIV的免疫。在一个实施方案中，本发明的方法诱导EIV特异性抗体的产生。在一个实施方案中，本发明的方法预防EIV相关病理。在一个实施方案中，本发明的方法包括向有需要的受试者施用包含LAV的免疫组合物，其中所述LAV包含区段1和/或区段2中的一个或多个突变。在一个实施方案中，所述方法包括向有需要的受试者施用免疫组合物，从而诱导对EIV的免疫。
组合物
本发明提供免疫组合物，当施用于有需要的受试者时，所述免疫组合物引起针对马流感病毒(EIV)的免疫反应。在一些实施方案中，组合物包括多肽、核苷酸、载体或疫苗。此外，当组合物施用于受试者时，它们引发免疫反应，用于保护接种的受试者免受马流感。如本文所举例说明，可以大量获得用作疫苗的组合物。
在一个实施方案中，本发明提供了可用作免疫调节剂的组合物，例如，用于刺激免疫反应和预防马流感和马流感相关病理。
减毒活病毒可用作免疫刺激剂，以诱导EIV特异性抗体的产生并预防马流感和马流感相关病理。因此，在一个实施方案中，本发明的组合物包含减毒活EIV(EIV LAIV)，其中EIV LAIV包含病毒基因组中的一个或多个突变以使EIV LAIV对温度敏感。例如，在一个实施方案中，EIV LAIV在病毒基因组的区段1中包含一个或多个突变。病毒基因组的区段1中的一个或多个突变编码突变PB2蛋白。在一个实施方案中，EIV LAIV在病毒基因组的区段2中包含一个或多个突变。病毒基因组的区段2中的一个或多个突变编码突变PB1蛋白。在一个实施方案中，EIV LAIV包含区段1中的一个或多个突变和区段2中的一个或多个突变。
在一个实施方案中，EIV LAIV是基于甲型流感/马/Ohio/1/2003 H3N8的基因组。甲型流感/马/Ohio/1/2003 H3N8每个区段的野生型核酸序列和所编码蛋白质的野生型氨基酸序列汇总在下表2中：
表2
在一个实施方案中，组合物在编码PB2的区段1和/或编码PB1的区段2的核酸序列中包含一个或多个突变。因此，在某些实施方案中，组合物编码突变PB1和/或突变PB2。如本文所述，一个或多个突变使病毒对温度敏感，在正常或升高的温度下表现出减少的病毒复制。
在一些实施方案中，本发明提供了包含区段1中的一个或多个突变的组合物。例如，在一个实施方案中，该组合物包含具有一个或多个突变的区段1，所述一个或多个突变导致产生在氨基酸残基265处具有点突变的突变PB2。例如，在一个实施方案中，突变PB2包含SEQ ID NO:6的氨基酸序列，除了在氨基酸残基265处具有点突变。例如，在一个实施方案中，突变PB2包含N265S点突变，其中突变PB2在氨基酸残基265处包含丝氨酸。
在一个实施方案中，组合物包含编码具有SEQ ID NO:2的氨基酸序列的突变PB2的核酸序列。在一个实施方案中，组合物包含编码与SEQ ID NO:2基本上同源的突变PB2的核酸序列。例如，在某些实施方案中，组合物包含编码突变PB2的核酸序列，该突变PB2与SEQID NO:2至少50％同源、至少60％同源、至少70％同源、至少80％同源、至少与90％同源、至少95％同源、至少98％同源、至少99％同源或至少99.5％同源。在一个实施方案中，组合物包含编码与SEQ ID NO:2基本上同源的突变PB2的核酸序列，其中与SEQ ID NO:2基本上同源的突变PB2包含N265S点突变。
在一个实施方案中，组合物包含含有SEQ ID NO:1的核苷酸序列的突变区段1。在一个实施方案中，组合物包含与SEQ ID NO:1基本上同源的核苷酸序列。例如，在某些实施方案中，组合物包含与SEQ ID NO:1至少50％同源、至少60％同源、至少70％同源、至少80％同源、至少与90％同源、至少95％同源、至少98％同源、至少99％同源或至少99.5％同源的核苷酸序列。在一个实施方案中，组合物包含与SEQ ID NO:1基本上同源的核苷酸序列，其中由与SEQ ID NO:1基本上同源的核苷酸序列编码的突变PB2包含N265S点突变。
在一些实施方案中，本发明提供包含区段2中的一个或多个突变的组合物。例如，在一个实施方案中，该组合物包含具有一个或多个突变的区段2，所述一个或多个突变导致产生在氨基酸残基391、氨基酸残基581和氨基酸残基661中的一处或多处具有点突变的突变PB1。例如，在一个实施方案中，突变PB2包含SEQ ID NO:8的氨基酸序列，除了在氨基酸残基391、氨基酸残基581和氨基酸残基661中的一处或多处具有点突变。例如，在一个实施方案中，突变PB1包含K391E点突变，其中突变PB1在氨基酸残基391处包含谷氨酸。在一个实施方案中，突变PB1包含E581G点突变，其中突变PB1在氨基酸残基581处包含甘氨酸。在一个实施方案中，突变PB1包含A661T点突变，其中突变PB1在氨基酸残基661处包含苏氨酸。
在一个实施方案中，组合物包含编码具有SEQ ID NO:4的氨基酸序列的突变PB1的核酸序列。在一个实施方案中，组合物包含编码与SEQ ID NO:4基本上同源的突变PB1的核酸序列。例如，在某些实施方案中，组合物包含编码突变PB1的核酸序列，该突变PB1与SEQID NO:4至少50％同源、至少60％同源、至少70％同源、至少80％同源、至少与90％同源、至少95％同源、至少98％同源、至少99％同源或至少99.5％同源。在一个实施方案中，组合物包含编码与SEQ ID NO:4基本上同源的突变PB1的核酸序列，其中与SEQ ID NO:4基本上同源的突变PB1包含K391E点突变、E581G点突变和A661T点突变中的一个或多个。
在一个实施方案中，组合物包含含有SEQ ID NO:3的核苷酸序列的突变区段2。在一个实施方案中，组合物包含与SEQ ID NO:3基本上同源的核苷酸序列。例如，在某些实施方案中，组合物包含与SEQ ID NO:3至少50％同源、至少60％同源、至少70％同源、至少80％同源、至少与90％同源、至少95％同源、至少98％同源、至少99％同源或至少99.5％同源的核苷酸序列。在一个实施方案中，组合物包含与SEQ ID NO:3基本上同源的核苷酸序列，其中由与SEQ ID NO:3基本上同源的核苷酸序列编码的突变PB1包含K391E点突变、E581G点突变和A661T点突变中的一个或多个。
在某些实施方案中，组合物包含区段1中的一个或多个突变和区段2中的一个或多个突变。例如，在某些实施方案中，组合物包含具有N265S点突变的区段1和具有K391E点突变、E581G点突变和A661T点突变中的一个或多个的区段2。
在某些实施方案中，组合物包含区段1和/或区段2的核酸序列中的一个或多个突变，同时包含分段基因组的其余部分的野生型核酸序列。例如，在一个实施方案中，EIVLAIV包含区段1中的一个或多个突变并且包含野生型区段2、区段3、区段4、区段5、区段6、区段7和区段8。在一个实施方案中，EIV LAIV包含区段2中的一个或多个突变并且包含野生型区段1、区段3、区段4、区段5、区段6、区段7和区段8。在一个实施方案中，EIV LAIV包含区段1和区段2中的一个或多个突变并且包含野生型区段3、区段4、区段5、区段6、区段7和区段8。
在某些实施方案中，组合物包含区段1和/或区段2中的一个或多个突变，以及病毒基因组的一个或多个其他区段中的一个或多个突变。
在一个实施方案中，组合物包含LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，并且包含A/马/Ohio/1/2003 H3N8的区段4和区段6，从而提供针对进化枝1 H3N8的保护。
A/马/Ohio/1/2003 H3N8的区段4的核苷酸序列由SEQ ID NO:11提供。A/马/Ohio/1/2003 H3N8的HA蛋白的氨基酸序列由SEQ ID NO:12提供。
A/马/Ohio/1/2003 H3N8的区段6的核苷酸序列由SEQ ID NO:15提供。A/马/Ohio/1/2003 H3N8的NA蛋白的氨基酸序列由SEQ ID NO:16提供。
在一个实施方案中，组合物包含LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，并且包含编码A/马/Ohio/1/2003 H3N8的HA的区段4和编码A/马/Ohio/1/2003 H3N8的NA的区段6，其中A/马/Ohio/1/2003 H3N8的HA包含SEQ ID NO:12并且其中A/马/Ohio/1/2003 H3N8的NA包含SEQ ID NO:16。
在一个实施方案中，组合物包含LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，并且包含A/马/Ohio/1/2003 H3N8的区段4和A/马/Ohio/1/2003 H3N8的区段6，其中A/马/Ohio/1/2003 H3N8的区段4包含SEQ ID NO:11并且其中A/马/Ohio/1/2003 H3N8的区段6包含SEQ ID NO:15。
在某些实施方案中，组合物包含如本文所述的突变区段1、突变区段2或其组合和编码另一种抗原的一个或多个核苷酸序列。例如，在某些实施方案中，组合物包含如本文所述的突变区段1、突变区段2或其组合和编码另一种病毒或毒株的一种或多种抗原的一个或多个核苷酸序列。例如，在某些方面，本文所述的包含突变区段1、突变区段2或其组合的H3N8 EIV LAIV可用作主供体病毒(MDV)。例如，可以修饰包含本文所述的含有突变区段1、突变区段2或其组合的H3N8的MDV，以包含编码来自另一种流感毒株的PB2、PB1、PA、NP、HA、NA、M1、M2、NS1或NEP/NS2中的一项或多项的一个或多个核苷酸序列。因此，当包含本文所述的含有突变区段1、突变区段2或其组合的H3N8的组合物表达不同毒株的抗原时，该组合物可以提供针对不同毒株的保护。例如，在一个实施方案中，组合物包含本文所述的含有突变区段1、突变区段2或其组合的H3N8 EIV LAIV的骨架，进一步包含编码来自另一种流感毒株的PB2、PB1、PA、NP、HA、NA、M1、M2、NS1或NEP/NS2中的一项或多项的一个或多个核苷酸序列。在一个实施方案中，组合物包含H3N8 EIV LAIV的骨架，其包含本文所述的突变区段1、突变区段2或其组合，该组合物进一步包含编码不同流感毒株的HA或NA中的一个或多个的一种或多种核苷酸序列。例如，可以修饰包含本文所述的H3N8 EIV LAIV的骨架的组合物以表达新出现毒株的一种或多种病毒蛋白，从而提供针对该新出现毒株的保护。
在一个实施方案中，组合物包含本文所述的H3N8 EIV LAIV的区段1、区段2、区段3、区段5、区段7和区段8，在区段1和区段2中的一个或多个中包含一个或多个点突变，其中组合物进一步包含不同EIV毒株的区段4和区段6。
在一个实施方案中，组合物包含H3N8的突变区段1、H3N8的突变区段2或其组合，进一步包含不同EIV毒株的区段4、区段6或其组合。在某些方面，H3N8的突变区段1、突变区段2或其组合提供EIV LAIV的温度敏感性减毒表型，而不同EIV毒株的区段4、区段6或其组合编码不同EIV毒株的HA、NA或其组合以在受试者中引起针对不同EIV毒株的特异性免疫反应。
在一个实施方案中，组合物包含多价疫苗，所述多价疫苗包含本文所述的多种EIVLAIV。例如，在一个实施方案中，组合物包含第一EIV LAIV，其包含H3N8的突变区段1、突变区段2或其组合，其中第一EIV LAIV包含H3N8的区段4、区段6或其组合；并且组合物进一步包含第二EIV LAIV，其包含H3N8的突变区段1、突变区段2或其组合，其中第二EIV LAIV包含不同EIV毒株的区段4、区段6或其组合。在某些实施方案中，组合物诱导针对H3N8和其他EIV毒株二者的免疫反应。
可以包括在多价疫苗中的示例性EIV毒株包括但不限于佛罗里达进化枝2Newmarket/2003样和佛罗里达进化枝1毒株南非/03样、Ohio/03样和Notss/09样，以及佛罗里达进化枝2毒株Richmond/07样、Lancashire/10样或Hants/10样。
在一个实施方案中，组合物包含LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Richmond/1/2007 H3N8的区段4和区段6，从而提供针对进化枝2 H3N8的保护。
A/马/Richmond/1/2007 H3N8的区段4的核苷酸序列由SEQ ID NO:23提供。A/马/Richmond/1/2007 H3N8的HA蛋白的氨基酸序列由SEQ ID NO:24提供。
A/马/Richmond/1/2007 H3N8的区段6的核苷酸序列由SEQ ID NO:25提供。A/马/Richmond/1/2007 H3N8的NA蛋白的氨基酸序列由SEQ ID NO:26提供。
在一个实施方案中，组合物包含LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含编码A/马/Richmond/1/2007 H3N8的HA的区段4和编码A/马/Richmond/1/2007 H3N8的NA的区段6，其中A/马/Richmond/1/2007 H3N8的HA包含SEQ ID NO:24并且其中A/马/Richmond/1/2007 H3N8的NA包含SEQ ID NO:26。
在一个实施方案中，组合物包含LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Richmond/1/2007 H3N8的区段4和A/马/Richmond/1/2007 H3N8的区段6，其中A/马/Richmond/1/2007 H3N8的区段4包含SEQ IDNO:23并且其中A/马/Richmond/1/2007 H3N8的区段6包含SEQ ID NO:25。
在一个实施方案中，组合物包含(1)第一LAIV，其包含基于A/马/Ohio/1/2003H3N8的突变区段1、突变区段2或其组合，并且进一步包含A/马/Ohio/1/2003 H3N8的区段4和区段6；和(2)第二LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Richmond/1/2007 H3N8中的区段4和区段6，从而提供针对进化枝1和进化枝2 H3N8的保护。
在一个实施方案中，组合物包含第一LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，并且进一步包含编码A/马/Ohio/1/2003 H3N8的HA的区段4和编码A/马/Ohio/1/2003 H3N8的NA的区段6，其中A/马/Ohio/1/2003 H3N8的HA包含SEQID NO:12并且其中A/马/Ohio/1/2003 H3N8的NA包含SEQ ID NO:16。在一个实施方案中，组合物包含第二LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含编码A/马/Richmond/1/2007 H3N8的HA的区段4和编码A/马/Richmond/1/2007 H3N8的NA的区段6，其中A/马/Richmond/1/2007 H3N8的HA包含SEQ ID NO:24并且其中A/马/Richmond/1/2007 H3N8的NA包含SEQ ID NO:26。
在一个实施方案中，组合物包含第一LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，并且进一步包含A/马/Ohio/1/2003 H3N8的区段4和A/马/Ohio/1/2003 H3N8的区段6，其中A/马/Ohio/1/2003 H3N8的区段4包含SEQ ID NO:11并且其中A/马/Ohio/1/2003 H3N8的区段6包含SEQ ID NO:15。在一个实施方案中，组合物包含第二LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Richmond/1/2007 H3N8的区段4和A/马/Richmond/1/2007 H3N8的区段6，其中A/马/Richmond/1/2007 H3N8的区段4包含SEQ ID NO:23并且其中A/马/Richmond/1/2007H3N8的区段6包含SEQ ID NO:25。
在一个实施方案中，组合物包含LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Texas/6/2017 H3N8的区段4和区段6，从而提供针对进化枝1 H3N8的保护。
A/马/Texas/6/2017 H3N8的区段4的核苷酸序列由SEQ ID NO:27提供。A/马/Texas/6/2017 H3N8的HA蛋白的氨基酸序列由SEQ ID NO:28提供。
A/马/Texas/6/2017 H3N8的区段6的核苷酸序列由SEQ ID NO:29提供。A/马/Texas/6/2017 H3N8的NA蛋白的氨基酸序列由SEQ ID NO:30提供。
在一个实施方案中，组合物包含LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含编码A/马/Texas/6/2017 H3N8的HA的区段4和编码A/马/Texas/6/2017 H3N8的NA的区段6，其中A/马/Texas/6/2017 H3N8的HA包含SEQ IDNO:28并且其中A/马/Texas/6/2017 H3N8的NA包含SEQ ID NO:30。
在一个实施方案中，组合物包含LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Texas/6/2017 H3N8的区段4和A/马/Texas/6/2017 H3N8的区段6，其中A/马/Texas/6/2017 H3N8的区段4包含SEQ ID NO:27并且其中A/马/Texas/6/2017 H3N8的区段6包含SEQ ID NO:29。
在一个实施方案中，组合物包含(1)第一LAIV，其包含基于A/马/Ohio/1/2003H3N8的突变区段1、突变区段2或其组合，并且进一步包含A/马/Texas/6/2017 H3N8的区段4和区段6；和(2)第二LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Richmond/1/2007 H3N8的区段4和区段6，从而提供针对进化枝1和进化枝2 H3N8的保护。
在一个实施方案中，组合物包含第一LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，并且进一步包含编码A/马/Texas/6/2017 H3N8的HA的区段4和编码A/马/Texas/6/2017 H3N8的NA的区段6，其中A/马/Texas/6/2017 H3N8的HA包含SEQ ID NO:28并且其中A/马/Texas/6/2017 H3N8的NA包含SEQ ID NO:30。在一个实施方案中，组合物包含第二LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含编码A/马/Richmond/1/2007 H3N8的HA的区段4和编码A/马/Richmond/1/2007 H3N8的NA的区段6，其中A/马/Richmond/1/2007 H3N8的HA包含SEQ IDNO:24并且其中A/马/Richmond/1/2007 H3N8的NA包含SEQ ID NO:26。
在一个实施方案中，组合物包含第一LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，并且进一步包含A/马/Texas/6/2017 H3N8的区段4和A/马/Texas/6/2017 H3N8的区段6，其中A/马/Texas/6/2017 H3N8的区段4包含SEQ ID NO:27并且其中A/马/Texas/6/2017 H3N8的区段6包含SEQ ID NO:29。在一个实施方案中，组合物包含第二LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Richmond/1/2007 H3N8的区段4和A/马/Richmond/1/2007 H3N8的区段6，其中A/马/Richmond/1/2007 H3N8的区段4包含SEQ ID NO:23并且其中A/马/Richmond/1/2007 H3N8的区段6包含SEQ ID NO:25。
在一个实施方案中，组合物包含LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Lancashire/1/2016 H3N8的区段4和区段6，从而提供针对进化枝2 H3N8的保护。
A/马/Lancashire/1/2016 H3N8的区段4的核苷酸序列由SEQ ID NO:31提供。A/马/Lancashire/1/2016 H3N8 HA蛋白的氨基酸序列由SEQ ID NO:32提供。
A/马/Lancashire/1/2016 H3N8的区段6的核苷酸序列由SEQ ID NO:33提供。A/马/Lancashire/1/2016 H3N8 NA蛋白的氨基酸序列由SEQ ID NO:34提供。
在一个实施方案中，组合物包含LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含编码A/马/Lancashire/1/2016 H3N8的HA的区段4和编码A/马/Lancashire/1/2016 H3N8的NA的区段6，其中A/马/Texas/6/2017 H3N8的HA包含SEQ ID NO:32并且其中A/马/Texas/6/2017 H3N8的NA包含SEQ ID NO:34。
在一个实施方案中，组合物包含LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Lancashire/1/2016 H3N8的区段4和A/马/Lancashire/1/2016 H3N8的区段6，其中A/马/Lancashire/1/2016 H3N8的区段4包含SEQID NO:31并且其中A/马/Lancashire/1/2016 H3N8的区段6包含SEQ ID NO:33。
在一个实施方案中，组合物包含(1)第一LAIV，其包含基于A/马/Ohio/1/2003H3N8的突变区段1、突变区段2或其组合，并且进一步包含A/马/Texas/6/2017 H3N8的区段4和区段6；和(2)第二LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Lancashire/1/2016 H3N8的区段4和区段6，从而提供针对进化枝1和进化枝2 H3N8的保护。
在一个实施方案中，组合物包含第一LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，并且进一步包含编码A/马/Texas/6/2017 H3N8的HA的区段4和编码A/马/Texas/6/2017 H3N8的NA的区段6，其中A/马/Texas/6/2017 H3N8的HA包含SEQ ID NO:28并且其中A/马/Texas/6/2017 H3N8的NA包含SEQ ID NO:30。在一个实施方案中，组合物包含第二LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含编码A/马/Lancashire/1/2016 H3N8的HA的区段4和编码A/马/Lancashire/1/2016 H3N8的NA的区段6，其中A/马/Lancashire/1/2016 H3N8的HA包含SEQID NO:32并且其中A/马/Lancashire/1/2016 H3N8的NA包含SEQ ID NO:34。
在一个实施方案中，组合物包含第一LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，并且进一步包含A/马/Texas/6/2017 H3N8的区段4和A/马/Texas/6/2017 H3N8的区段6，其中A/马/Texas/6/2017 H3N8的区段4包含SEQ ID NO:27并且其中A/马/Texas/6/2017 H3N8的区段6包含SEQ ID NO:29。在一个实施方案中，组合物包含第二LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Lancashire/1/2016 H3N8的区段4和A/马/Lancashire/1/2016 H3N8的区段6，其中A/马/Lancashire/1/2016 H3N8的区段4包含SEQ ID NO:31并且其中A/马/Lancashire/1/2016 H3N8的区段6包含SEQ ID NO:33。
在一个实施方案中，组合物包含(1)第一LAIV，其包含基于A/马/Ohio/1/2003H3N8的突变区段1、突变区段2或其组合，并且进一步包含A/马/Ohio/1/2003 H3N8的区段4和区段6；和(2)第二LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Lancashire/1/2016 H3N8的区段4和区段6，从而提供针对进化枝1 H3N8和进化枝2 H3N8的保护。
在一个实施方案中，组合物包含第一LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，并且进一步包含编码A/马/Ohio/1/2003 H3N8的HA的区段4和编码A/马/Ohio/1/2003 H3N8的NA的区段6，其中A/马/Ohio/1/2003 H3N8的HA包含SEQID NO:12并且其中A/马/Ohio/1/2003 H3N8的NA包含SEQ ID NO:16。在一个实施方案中，组合物包含第二LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含编码A/马/Lancashire/1/2016 H3N8的HA的区段4和编码A/马/Lancashire/1/2016 H3N8的NA的区段6，其中A/马/Lancashire/1/2016 H3N8的HA包含SEQID NO:32并且其中A/马/Lancashire/1/2016 H3N8的NA包含SEQ ID NO:34。
在一个实施方案中，组合物包含第一LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，并且进一步包含A/马/Ohio/1/2003 H3N8的区段4和A/马/Ohio/1/2003 H3N8的区段6，其中A/马/Ohio/1/2003 H3N8的区段4包含SEQ ID NO:11并且其中A/马/Ohio/1/2003 H3N8的区段6包含SEQ ID NO:15。在一个实施方案中，组合物包含第二LAIV，其包含基于A/马/Ohio/1/2003 H3N8的突变区段1、突变区段2或其组合，但进一步包含A/马/Lancashire/1/2016 H3N8的区段4和A/马/Lancashire/1/2016 H3N8的区段6，其中A/马/Lancashire/1/2016 H3N8的区段4包含SEQ ID NO:31并且其中A/马/Lancashire/1/2016 H3N8的区段6包含SEQ ID NO:33。
在某些实施方案中，组合物包含编码突变PB2和/或突变PB1的多核苷酸。多核苷酸可以是RNA或DNA。在一个实施方案中，组合物包含DNA疫苗。
核酸序列包括转录成RNA的DNA序列和翻译成多肽的RNA序列。根据其他实施方案，本发明的多核苷酸是由本发明的多肽的氨基酸序列推断的。如本领域中已知的，由于冗余密码子而可能存在几种替代的多核苷酸，同时保留翻译的多肽的生物活性。
此外，本发明包括分离的核酸，其包含与编码本文公开的多肽的分离核酸的核苷酸序列具有基本同源性的核苷酸序列。优选地，编码本发明多肽的分离核酸的核苷酸序列是“基本上同源的”，即与编码本发明多肽的分离核酸的核苷酸序列约60％同源，更优选约70％同源，甚至更优选约80％同源，更优选约90％同源，甚至更优选约95％同源，并且甚至更优选约99％同源。
应明确理解，本发明的范围包括同源物、类似物、变体、片段、衍生物和盐，包括更短和更长的多肽和多核苷酸，以及具有一个或多个氨基酸或核酸取代的多肽和多核苷酸类似物以及本领域已知的氨基酸或核酸衍生物、非天然氨基酸或核酸和合成氨基酸或核酸，规定是这些修饰必须保持原始分子的免疫活性。具体地，根据本发明的原理，本文包括并公开了活性多肽的任何活性片段以及延伸物、缀合物和混合物。
本发明应被解释为包括与本文所述和引用的核酸同源的任何和所有分离的核酸，条件是这些同源核酸编码具有本文公开的多肽的生物学活性的多肽。
技术人员会理解本发明的核酸包括编码本发明多肽的RNA或DNA序列及其任何修饰形式，包括DNA或RNA的化学修饰，其在核苷酸序列为无细胞或与细胞相关联时使得核苷酸序列更稳定。核苷酸的化学修饰也可用于提高核苷酸序列被细胞摄取的效率或它在细胞中表达的效率。本发明考虑了核苷酸序列的任何和所有修饰组合。
此外，使用本领域中众所周知的重组DNA方法，如(例如)Sambrook等人(2012,Molecular Cloning:A Laboratory Manual,Cold Spring Harbor Laboratory,New York)和Ausubel等人(1997,Current Protocols in Molecular Biology,John Wiley&Sons,NewYork)中所述的方法，可以使用任何数量的程序来产生本发明蛋白质的突变体、衍生物或变体形式。通过改变编码多肽的DNA序列在多肽或多肽中引入氨基酸变化的程序是本领域中众所周知的，并且也在这些和其他论著中有所描述。
根据又一个实施方案，包含本发明的核酸序列或核酸序列组合的本发明组合物能够产生EIV特异性免疫反应。在另一个实施方案中，包含本发明的核酸序列或核酸序列组合的本发明组合物能够产生EIV特异性抗体。在某些实施方案中，组合物能够预防EIV，包括H3N8 EIV。在某些实施方案中，组合物能够针对EIV的多种进化枝或毒株提供保护。
在一个实施方案中，本发明的组合物包含具有SEQ ID NO:2和SEQ ID NO:4中的任何一个或多个的序列的多肽或多肽的片段、多肽的同源物、变体、衍生物或盐。
本发明还应被解释为包括与本文公开的多肽具有基本同源性的任何形式的多肽。优选地，“基本上同源的”多肽与本文公开的多肽的氨基酸序列约50％同源，更优选约70％同源，甚至更优选约80％同源，更优选约90％同源，甚至更优选约95％同源，并且甚至更多优选约99％同源。
根据又一个实施方案，包含本发明多肽或多肽组合的本发明组合物能够产生EIV特异性免疫反应。在另一个实施方案中，包含本发明多肽或多肽组合的本发明组合物能够产生EIV特异性抗体。在某些实施方案中，组合物能够预防EIV，包括H3N8 EIV。
本发明还应被解释为涵盖本发明的多肽(或编码本发明多肽的DNA)的“突变体”、“衍生物”和“变体”，所述突变体、衍生物和变体是其中一个或多个氨基酸发生改变的多肽(或者，当提及编码多肽的核苷酸序列时，一个或多个碱基对发生改变)，使得所得的多肽(或DNA)与本文所述的序列不同，但具有与本文公开的多肽相同的生物学特性。
减毒活病毒(LAV)
本发明部分涉及产生EIV特异性免疫反应的减毒活病毒(LAV)的产生、选择和鉴定，以及此类病毒在疫苗和药物制剂中的用途。
如本文所述，在某些实施方案中，EIV LAIV包含区段1中的一个或多个突变和/或区段2中的一个或多个突变，所述突变使得病毒对温度敏感。例如，在一个实施方案中，温度敏感性EIV LAIV在正常和升高的温度下表现出减少的病毒复制。然而，温度敏感性EIVLAIV会诱导EIV特异性免疫反应和抗体产生，因此能够预防EIV和EIV相关病理。
可以根据本发明选择和使用具有至少一个突变的任何突变病毒或毒株。在一个实施方案中，可以选择天然存在的突变体或变体或自发突变体，其如本文别处所述在区段1和/或区段2中包括至少一个突变。在另一个实施方案中，可以通过将病毒暴露于诱变剂，例如紫外线照射或化学诱变剂，或通过多次传代和/或在非许可宿主中传代来产生突变病毒。在差异生长系统中的筛选可用于选择如本文别处所述在区段1和/或区段2中具有至少一个突变的那些突变体。对于具有分段基因组的病毒，可以通过重配(即，通过减毒病毒和所需毒株的共感染，并选择显示两种表型的重配子)将减毒表型转移到具有所需抗原的另一个毒株中。
在另一个实施方案中，可以使用“反向遗传学”方法将突变工程改造至流感病毒(包括但不限于H3N8 EIV)中。以这种方式，可以将赋予减毒表型的天然或其他突变工程改造至疫苗株中。例如，可以对编码PB2的区段1和/或编码PB1的区段2的编码区进行删除、插入或取代。还考虑了区段1和/或区段2的非编码区中的缺失、取代或插入。为此，可以对负责区段1和/或区段2的转录、复制、聚腺苷酸化和/或包装的信号中的突变进行工程改造。
在某些情况下，反向遗传学技术涉及合成重组病毒RNA的制备，这些RNA包含负链病毒RNA的非编码区，所述非编码区对于病毒聚合酶的识别和产生成熟病毒粒子所必需的包装信号是必不可少的。重组RNA由重组DNA模板合成，并在体外用纯化的病毒聚合酶复合物重组，以形成可用于转染细胞的重组核糖核蛋白(RNP)。在一些情况下，如果在合成RNA的体外或体内转录过程中存在病毒聚合酶蛋白，则会实现更有效的转染。合成的重组RNP可以被拯救成传染性病毒颗粒。前述技术描述在1992年11月24日发布的美国专利号5,166,057；1998年12月29日发布的美国专利号5,854,037；1996年2月20日公布的欧洲专利公开EP0702085A1；美国专利申请序列号09/152,845；1997年4月3日公布的国际专利公开PCTWO97/12032；1996年11月7日公布的WO96/34625；欧洲专利公开EP-A780475；1999年1月21日公布的WO 99/02657；1998年11月26日公布的WO 98/53078；1998年1月22日公布的WO 98/02530；1999年4月1日公布的WO 99/15672；1998年4月2日公布的WO 98/13501；1997年2月20日公布的WO 97/06270；和1997年6月25日公布的EPO 780 47SA1中，每篇文献的全部内容通过引用并入本文。
通过反向遗传学方法产生的减毒病毒可用于本文所述的疫苗和药物制剂。反向遗传学技术还可以用于设计对疫苗生产重要的其他病毒基因的额外突变—即，可以将有用疫苗株变体的表位工程改造至减毒病毒中。或者，完全外来表位，包括源自其他病毒或非病毒病原体的抗原，可以被工程改造至减毒株中。
在一个替代实施方案中，反向遗传学技术和重配技术的组合可用于工程改造具有所需表位的减毒病毒。例如，减毒病毒(通过自然选择、诱变或反向遗传学技术产生)和携带所需疫苗表位的毒株(通过自然选择、诱变或反向遗传学技术产生)可以在允许分段基因组重配的宿主中共同感染。然后可以选择同时显示减毒表型和所需表位的重配子。
本发明的减毒病毒本身可用作疫苗或药物制剂中的活性成分。在某些实施方案中，减毒病毒可用作重组生产疫苗的载体或“骨架”。为此，“反向遗传学”技术可用于设计突变或将外源表位引入将作为“亲本”毒株的减毒病毒中。通过这种方式，可以设计疫苗以针对毒株变体产生免疫，或者针对完全不同的传染原或疾病抗原产生免疫。
例如，在一个实施方案中，本发明的免疫组合物包含减毒活病毒，其被工程改造成表达EIV的一个或多个表位或抗原以及另一种病原体的表位或抗原。例如，可以将减毒病毒工程改造成表达其他预选毒株的中和表位。或者，可以将其他病毒的表位构建到减毒突变病毒中。或者，可以将非病毒感染性病原体(例如寄生虫、细菌、真菌)的表位工程改造到病毒中。
在一个实施方案中，被选择用于本发明的减毒病毒能够在宿主中诱导稳健的抗EIV反应—这一特征在用作疫苗时有助于产生强烈的免疫反应，并且具有使病毒可用作预防和/或治疗其他病毒感染或其他疾病的药剂的其他生物学结果。
在宿主中诱导EIV特异性免疫反应的减毒病毒也可以用于预防或治疗其他流感感染或流感相关病理的药物制剂中。在这方面，可以改变减毒病毒的趋向性以在体内或离体使病毒靶向所需的靶器官、组织或细胞。使用这种方法，可以在目标部位局部诱导EIV特异性免疫反应，从而避免或最大限度地减少全身治疗的副作用。为此，可以对减毒病毒进行工程改造以表达对靶器官、组织或细胞的受体具有特异性的配体。
疫苗
在某些方面，免疫组合物可用作疫苗，其中免疫组合物在细胞、组织或哺乳动物中诱导针对抗原的免疫反应。优选地，疫苗在哺乳动物中诱导保护性免疫反应。如本文所用，“免疫组合物”可以包含，例如，减毒活病毒(LAV)、抗原(例如多肽)、编码抗原的核酸(例如抗原表达载体)，或表达或呈递抗原的细胞或细胞组分。在特定实施方案中，免疫组合物包含或编码本文所述的任何多肽抗原的全部或部分，或其免疫功能等效物。在其他实施方案中，免疫组合物呈包含额外的免疫刺激剂或编码此类试剂的核酸的混合物形式。免疫刺激剂包括但不限于额外的抗原、免疫调节剂、抗原呈递细胞或佐剂。在其他实施方案中，一种或多种额外试剂以任何组合共价结合至抗原或免疫刺激剂。在某些实施方案中，抗原组合物与HLA锚定基序氨基酸缀合或包含HLA锚定基序氨基酸。
在本发明的情形中，术语“疫苗”是指在接种到动物中时诱导抗EIV免疫或抑制EIV的物质。
本发明包括包含减毒活病毒(LAV)的疫苗制剂，其中LAV是减毒活马流感病毒(在本文中称为EIV LAIV)。例如，在某些实施方案中，EIV LAIV对温度敏感，与野生型EIV相比，在正常和升高的温度下表现出减少的病毒复制。在一个实施方案中，疫苗包含在区段1和/或区段2中包含一个或多个突变的EIV LAIV和合适的赋形剂。疫苗制剂中使用的病毒可以选自天然存在的突变体或变体、诱变病毒或基因工程病毒。EIV的减毒株也可以通过重配技术产生，或者通过使用反向遗传学方法和重配技术的组合产生。天然存在的变体包括从自然界中分离的病毒以及在病毒繁殖过程中产生的自然发生的变体。减毒病毒本身可用作疫苗制剂中的活性成分。或者，减毒病毒可用作重组生产疫苗的载体或“骨架”。为此，可以使用重组技术如反向遗传学(或者，对于分段病毒，反向遗传学和重配技术的组合)来设计突变或将外源抗原引入疫苗制剂中使用的减毒病毒中。通过这种方式，可以设计疫苗以针对毒株变体产生免疫，或者针对完全不同的传染原或疾病抗原产生免疫。
在一个实施方案中，疫苗制剂包含多种突变EIV。在一个实施方案中，疫苗制剂包含含有本文所述的H3N8 EIV LAIV与第二LAIV的组合的二价疫苗，其中第二LAIV是基于H3N8 EIV LAIV骨架，但经工程改造以表达另一毒株的HA和NA病毒蛋白。例如，在一个实施方案中，第一LAIV表达A/马/Ohio/1/2003 H3N8的HA和NA，并且第二LAIV表达流感病毒的不同进化枝或毒株的HA和NA。在一个实施方案中，第一LAIV表达A/马/Ohio/1/2003 H3N8的HA和NA，并且第二LAIV表达A/马/Richmond/1/2007 H3N8的HA和NA，从而诱导针对进化枝1A/马/Ohio/1/2003 H3N8和进化枝2A/马/Richmond/1/2007 H3N8的免疫反应。
在一个实施方案中，疫苗制剂可以包含一种或多种本文所述的EIV LAIV与诱导抗EIV免疫反应的其他突变EIV的组合。在一个实施方案中，本发明包括一种产生EIV LAIV的方法，其包括使宿主细胞与包含具有本文别处所述的一个或多个突变的区段1和/或区段2的核酸序列的多核苷酸接触。
病毒在培养物中的繁殖是本领域技术人员已知的。简而言之，病毒在通常培养宿主细胞的培养基组合物中生长。适用于EIV复制的宿主细胞包括例如Vero细胞、BHK细胞、MDCK细胞、293细胞、COS细胞和CEK细胞，包括293T细胞、COS7细胞。通常，以例如1:1的比例使用包括两种上述细胞系(例如MDCK细胞和293T或COS细胞)的共培养物，以提高复制效率。通常，在标准商业培养基如补充有血清(例如，10％胎牛血清)的杜尔贝科氏改良伊格尔培养基中或在无血清培养基中，在适合维持中性缓冲pH(例如，7.0和7.2之间的pH)的受控湿度和CO2的浓度下培养细胞。任选地，培养基含有抗生素以防止细菌生长(例如青霉素、链霉素等)和/或附加营养素，例如L-谷氨酰胺、丙酮酸钠、非必需氨基酸、促进有利生长特征的附加补充剂(例如胰蛋白酶、β-巯基乙醇等)。
用于维持培养的哺乳动物细胞的程序已被广泛报道，并且是本领域技术人员已知的。一般方案提供在例如Freshney(1983)Culture of Animal Cells:Manual of BasicTechnique,Alan R.Liss,New York；Paul(1975)Cell and Tissue Culture，第5版，Livingston，Edinburgh；Adams(1980)Laboratory Techniques in Biochemistry andMolecular Biology-Cell Culture for Biochemists，Work和Burdon(编辑)，Elsevier，Amsterdam中。关于在体外生产流感病毒中特别受关注的组织培养程序的其他细节包括例如Merten等人(1996)Production of influenza virus in cell cultures for vaccinepreparation(在Cohen和Shafferman(编辑)Novel Strategies in Design andProduction of Vaccines中)，该文献全文并入本文。此外，适用于本发明的此类程序的变化很容易通过常规实验确定。
用于生产病毒的细胞可以在含血清或无血清培养基中培养。在一些情况下，例如，为了制备纯化的病毒，需要在无血清条件下培养宿主细胞。细胞可以小规模培养，例如在小于25ml的培养基、培养管或烧瓶中或在搅拌的大烧瓶中、在旋转瓶中或在烧瓶、瓶子或反应器培养物中的微载体珠(例如，DEAE-Dextran微载体珠，如Dormacell，Pfeifer&Langen；Superbead，Flow Laboratories；苯乙烯共聚物-三甲胺珠粒，例如Hillex、SoloHill、AnnArbor)上培养。微载体珠是小球体(直径在100-200微米的范围内)，其为单位体积的细胞培养物提供用于贴壁细胞生长的大表面积。例如，一升培养基可以包含超过2000万个微载体珠，提供大于8000平方厘米的生长表面。对于病毒的商业生产，例如疫苗生产，通常需要在生物反应器或发酵罐中培养细胞。可用的生物反应器的体积为低于1升到超过100升，例如，Cyto3生物反应器(Osmonics,Minnetonka,Minn.)；NBS生物反应器(New BrunswickScientific,Edison,N.J.)；来自B.Braun Biotech International(B.Braun Biotech,Melsungen,Germany)的实验室和商用生物反应器。
实际上，可以将几乎任何异源基因序列构建到用于疫苗的本发明的病毒中。优选地，诱导针对多种病原体中任一种的保护性免疫反应的表位或结合中和抗体的抗原可以由病毒表达或作为病毒的一部分表达。例如，可以构建到用于疫苗的本发明病毒中的异源基因序列包括但不限于人类免疫缺陷病毒(HIV)的表位，例如gp120；乙型肝炎病毒表面抗原(HBsAg)；疱疹病毒的糖蛋白(例如gD、gE)；脊髓灰质炎病毒的VP1；非病毒病原体(例如细菌和寄生虫)的抗原决定簇等。在另一个实施方案中，可以表达全部或部分免疫球蛋白基因。例如，可以将模拟此类表位的抗独特型免疫球蛋白的可变区构建到本发明的病毒中。在又一个实施方案中，可以表达肿瘤相关抗原。
可以配制活重组病毒疫苗或灭活重组病毒疫苗。活疫苗可以是优选的，因为在宿主中的增殖会导致与自然感染中发生的刺激具有相似类型和程度的长期刺激，并且因此赋予实质的持久免疫力。此类活重组病毒疫苗制剂的生产可以使用常规方法完成，包括在细胞培养物中或在鸡胚的尿囊中繁殖病毒，然后进行纯化。
许多方法可用于引入上述疫苗制剂，这些方法包括但不限于鼻内、气管内、口服、皮内、肌肉内、腹膜内、静脉内和皮下引入。可以优选通过疫苗所针对的病原体的自然感染途径或通过亲本减毒病毒的自然感染途径引入病毒疫苗制剂。
包含EIV LAIV的本发明疫苗可以施用一次。或者，包含EIV LAIV的本发明疫苗可以以合适的给药时间间隔施用两次或三次或更多次。或者，包含EIV LAIV的本发明疫苗可以根据需要经常施用于动物，优选哺乳动物。
方法
本发明提供一种治疗或预防马流感感染或EIV相关疾病或病症的方法。在一个实施方案中，该方法包括施用包含减毒活病毒(LAV)的免疫组合物，其中LAV是EIV LAIV。在一个实施方案中，该方法包括向有需要的受试者施用包含EIV LAIV的免疫组合物，该EIVLAIV包含区段1和/或区段2中的一个或多个突变。在一个实施方案中，该方法包括施用包含多种LAIV的多价免疫组合物，每种LAIV表达流感病毒的不同进化枝或毒株的一种或多种抗原，从而治疗或预防与流感病毒的每个进化枝或毒株相关的EIV相关疾病或病症。
如本文所述，在某些实施方案中，EIV LAIV对温度敏感，与野生型EIV相比，其在正常和升高的温度下表现出减少的病毒复制。例如，在某些实施方案中，EIV LAIV的病毒复制在正常或升高的体温下比野生型EIV少2倍、少3倍、少5倍、少10倍、少15倍、少20倍、少50倍、少100倍、少500倍或少1000倍。
在某些实施方案中，与灭活的EIV相比，EIV LAIV诱导增强的免疫反应。例如，在某些实施方案中，EIV LAIV诱导的免疫反应比灭活的EIV多2倍、多3倍、多5倍、多10倍、多15倍、多20倍、多50倍、多100倍、多500倍或多1000倍。可以使用标准测定法测量EIV LAIV诱导的免疫反应。例如，在某些实施方案中，通过检测施用EIV LAIV后受试者中产生的EIV特异性抗体的量来测量由EIV LAIV诱导的免疫反应。
本发明的治疗组合物可以预防性或治疗性地施用于患有或有风险发展或易于发展疾病或病症的受试者。可以使用标准临床方法来鉴定此类受试者。在本发明的情形中，预防性施用发生在显现疾病的明显临床症状之前，从而预防疾病或病症或延迟其进展。在医学领域的情形中，术语“预防”包括减少疾病死亡率或发病率负担的任何活动。预防可以发生在一级、二级和三级预防级别。一级预防避免疾病的发展，二级和三级预防包括旨在防止疾病进展和症状出现以及通过恢复功能和减少疾病相关并发症来减少已经形成的疾病的负面影响的活动。
在某些实施方案中，受试者是哺乳动物。例如，受试者可以包括但不限于人、灵长类动物、牛、马、羊、猪、狗、猫或啮齿动物。在一个实施方案中，受试者是马。所述方法可用于治疗或预防任何品种或种类的马的EIV或EIV相关病理。在某些实施方案中，单剂量中活性成分的相对量或剂量频率将根据受试者(例如马)的年龄、性别、体重或品种而变化。
组合物可以与佐剂组合。佐剂是指当与免疫组合物一起(或相继)施用时增强免疫反应的化合物。合适佐剂的实例包括但不限于霍乱毒素、沙门氏菌毒素、明矾、含有皂苷和甾醇的免疫刺激复合物(ISCOM)、含CpG的寡核苷酸、含有聚氧乙烯-聚氧丙烯嵌段共聚物的油乳液、角鲨烷、聚氧乙烯山梨糖醇酐单油酸酯和缓冲盐溶液及其任何组合。此外，佐剂可以包括一种或多种润湿剂或分散剂，其量占佐剂体积的约0.1至25％、约1至10％或约1至3％。在某些实施方案中，润湿剂或分散剂是非离子表面活性剂。有用的非离子表面活性剂包括聚氧乙烯/聚氧丙烯嵌段共聚物，尤其是那些以商标
销售并且可从BASF Corporation(Mt.Olive,N.J.)获得的聚氧乙烯/聚氧丙烯嵌段共聚物。其他有用的非离子表面活性剂包括聚氧乙烯酯，例如以商标TWEEN
获得的聚氧乙烯山梨糖醇酐单油酸酯。可能需要在佐剂中包含多于一种(例如至少两种)润湿剂或分散剂作为本发明疫苗组合物的一部分。佐剂的其他组分可以包括诸如福尔马林和硫柳汞之类的防腐剂化合物，其量高达佐剂的约1％体积/体积。在一个实施方案中，佐剂包含“SP油”，它是指包含聚氧乙烯-聚氧丙烯嵌段共聚物、角鲨烷、聚氧乙烯山梨糖醇酐单油酸酯和缓冲盐溶液的油乳液。一般而言，SP油乳液将包含约1至3％体积/体积的嵌段共聚物、约2至6％体积/体积的角鲨烷(更特别地约3至6％的角鲨烷)和约0.1至0.5％体积/体积的聚氧乙烯山梨糖醇酐单油酸酯，其余为缓冲盐溶液(参见美国专利号7,445,787，其通过引用并入本文)。
此外，本发明的疫苗可以与药学上可接受的载体适当组合。这类载体的实例是无菌水、生理盐水、磷酸盐缓冲液、培养液等。此外，疫苗可以根据需要含有稳定剂、悬浮剂、防腐剂、表面活性剂等。疫苗全身或局部施用。疫苗施用可以通过单次施用进行或通过多次施用加强。
施用
在一个实施方案中，本发明的方法包括将本发明的免疫组合物直接施用于有需要的受试者。组合物的施用可以包括例如鼻内、肌肉内、静脉内、腹膜、皮下、皮内以及局部施用。
此外，实际剂量和时间表可以根据组合物是否与其他药物组合物联合施用，或根据药代动力学、药物处置和代谢的个体间差异而变化。本领域技术人员可以根据特定情况的紧急性容易地进行任何必要的调整。
施用方案可以影响有效量的构成。可以在诊断感染或疾病之前或之后向受试者施用治疗制剂。此外，可以每天或依次施用若干个分开的剂量以及交错的剂量，或者剂量可以连续输注，或者可以是团注。此外，治疗制剂的剂量可以根据治疗或预防情况的紧急程度按比例增加或减少。
可以使用已知程序，以有效预防或治疗疾病的剂量和时间段向受试者施用本发明的组合物。实现治疗效果所需的治疗化合物的有效量可以根据诸如以下各项的因素而变化：所用特定化合物的活性；施用时间；化合物的排泄率；治疗持续时间；与该化合物组合使用的其他药物、化合物或材料；接受治疗的受试者的疾病或病症的状态、年龄、性别、体重、状况、一般健康状况和既往病史；以及医学领域中众所周知的类似因素。可以调整给药方案以提供最佳的治疗响应。例如，可以每天施用若干分开的剂量或者可以根据治疗情况的紧急程度按比例减小剂量。本发明的治疗化合物的有效剂量范围的非限制性实例为约1至5,000mg/kg体重/每天。本领域普通技术人员将能够在无需过多实验的情况下研究相关因素并确定治疗化合物的有效量。
化合物可以按每天数次的频率施用于受试者，或者可以按更低的频率施用，例如每天一次、每周一次、每两周一次、每月一次，或者按甚至更低的频率施用，例如每几个月一次或甚至一年一次或更久一次。
药物组合物
本发明设想通过向有需要的哺乳动物施用本发明的治疗组合物来治疗或预防哺乳动物的EIV或EIV相关病理。根据本发明的组合物的施用可以是连续的或间断的，这取决于例如接受者的生理状况、施用目的是治疗性的还是预防性的以及熟练从业人员已知的其他因素。本发明组合物的施用可以是在预选时间段内基本上连续的，或者可以是一系列间隔的剂量。考虑了局部和全身施用。施用量将根据各种因素而变化，包括但不限于所选的组合物、特定疾病、哺乳动物的体重、身体状况和年龄以及要实现预防还是治疗。这些因素可以容易由临床医生使用动物模型或本领域公知的其他测试系统确定。
本发明包括含有EIV LAIV的药物组合物，该EIV LAIV待用作抗病毒剂或抗EIV相关疾病和病症的药剂。药物组合物具有作为抗病毒预防药的效用，并且可以施用于有感染风险或预期会暴露于病毒的受试者。例如，可以向前往EIV流行的世界部分旅行的受试者施用本发明的药物组合物。在某些实施方案中，可以向预期会与有风险的其他受试者接触的受试者施用本发明的药物组合物。
本发明的EIV LAIV可以使用本文所述的方法进行工程改造，以表达将会使病毒靶向特定部位的蛋白质或肽。在一个实施方案中，当待靶向的部位表达生长因子(例如VEGF、EGF或PDGF)的受体时，EIV LAIV可以经工程改造以表达合适的生长因子或其部分。因此，根据本发明，EIV LAIV可以经工程改造以表达任何靶基因产物，包括肽、蛋白质，例如酶、激素、生长因子、抗原或抗体，所述靶基因产物将用于使病毒靶向需要抗病毒、抗菌、抗微生物或抗癌活性的部位。
引入方法包括但不限于皮内、肌肉内、腹膜内、静脉内、皮下、鼻内、硬膜外和口服途径。本发明的药物组合物可以通过任何方便的途径施用，例如通过输注或团注，通过上皮或皮肤粘膜内层(例如口腔粘膜、直肠粘膜和肠粘膜等)吸收，并且可以与其他生物活性剂一起施用。可以全身或局部施用。此外，在一个优选实施方案中，可能需要通过任何合适的途径将本发明的药物组合物引入肺中。也可以采用肺部施用，例如通过使用吸入器或喷雾器，以及含雾化剂的制剂。
在一个特定实施方案中，可能需要将本发明的药物组合物局部施用到需要治疗的区域，这可以通过例如但不限于以下方式来实现：在手术期间的局部输注；局部施加，例如在手术之后与伤口敷料结合；通过注射；借助于导管；借助于栓剂；或借助于植入物，所述植入物是多孔、非多孔或凝胶状材料，包括膜(如硅橡胶膜)或纤维。
在某些实施方案中，药物组合物是适合施用于兽医受试者(包括但不限于马受试者)的兽用药物组合物。示例性的马受试者包括马属的任何成员，包括但不限于马、斑马、驴和毛驴。
在某些实施方案中，兽用药物组合物是“适口的”，意指容易在无需任何劝诱或需要一些劝诱的情况下被马类(包括马)接受的口服兽用组合物。
在又一个实施方案中，药物组合物可以在控释系统中递送。在一个实施方案中，可以使用泵(参见Langer，同上；Sefton,1987,CRC Crit.Ref.Biomed.Eng.14:201；Buchwald等人，1980,Surgery 88:507；Saudek等人，1989,N.Engl.J.Med.321:574)。在另一个实施方案中，可以使用聚合物材料(参见Medical Applications of Controlled Release,Langer和Wise(编辑),CRC Pres.,Boca Raton,Fla.(1974)；Controlled Drug Bioavailability,Drug Product Design and Performance,Smolen和Ball(编辑),Wiley,New York(1984)；Ranger&Peppas,1983,J.Macromol.Sci.Rev.Macromol.Chem.23:61；还参见Levy等人，1985,Science 228:190；During等人，1989,Ann.Neurol.25:351(1989)；Howard等人，1989,J.Neurosurg.71:105)。在又一个实施方案中，可以将控释系统放置在组合物的靶标(即肺)的附近，从而只需要全身剂量的一部分(参见，例如，Goodson,1984,Medical Applicationsof Controlled Release，同上，第2卷，第115-138页)。其他控释系统论述在Langer所作的综述(1990,Science 249:1527-1533)中。
本发明的药物组合物包含治疗有效量的减毒病毒和药学上可接受的载体。在一个特定实施方案中，术语“药学上可接受的”意指经联邦或州政府的监管机构批准或在美国药典(U.S.Pharmacopeia)或其他公认的药典中列出用于动物的。术语“载体”是指与药物组合物一起施用的稀释剂、佐剂、赋形剂或媒介物。盐溶液以及右旋糖水溶液和甘油水溶液也可以用作液体载体，特别是用于可注射溶液。合适的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、米、面粉、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙烯、乙二醇、水等。这些组合物可以采用溶液、悬浮液、乳液、片剂、丸剂、胶囊、粉剂、缓释制剂等形式。这些组合物可以配制成栓剂。口服制剂可以包括标准载体，例如药用级甘露醇、乳糖、淀粉、硬脂酸镁、糖精钠、纤维素、碳酸镁等。合适的药物载体的例子描述在E.W.Martin的“Remington's Pharmaceutical Sciences”中。此类组合物将包含治疗有效量的治疗剂(优选为纯化形式)以及适量的载体，以提供用于向患者适当施用的形式。制剂应适合施用方式。
可有效治疗或预防特定疾病或病症的本发明药物组合物的量将取决于疾病或病症的性质，并且可通过标准临床技术来确定。此外，可以任选地采用体外测定来帮助确定最佳剂量范围。制剂中待使用的精确剂量还将取决于施用途径以及疾病或病症的严重性，并且应根据从业人员的判断和每个患者的情况来决定。可以由源自体外或动物模型测试系统的剂量-反应曲线外推有效剂量。
在一个实施方案中，可以施用可用于实施本发明方法的药物组合物以递送介于1ng/kg/天和100mg/kg/天之间的剂量。在另一个实施方案中，可以施用可用于实施本发明的药物组合物以递送介于1ng/kg/天和500mg/kg/天之间的剂量。
本发明药物组合物中的活性成分、药学上可接受的载体和任何其他成分的相对量将根据所治疗的受试者的身份、体型和状况而变化，并且进一步取决于组合物的施用途径。举例来说，组合物可以包含0.1％和100％(w/w)之间的活性成分。
实验实施例
参照以下实验实施例进一步详细描述本发明。这些实施例仅仅是为了说明的目的而提供的，除非另有说明，否则这些实施例无意是限制性的。因此，本发明决不应被解释为限于以下实施例，而是应被解释为涵盖由于本文提供的教导而变得明显的任何和所有变化。
无需进一步描述，据信本领域普通技术人员可以使用前面的描述和以下说明性实施例来实现和利用本发明并实践所要求保护的方法。因此，以下工作实施例特别指出本发明的优选实施方案，并且不应被解释为以任何方式限制本公开的其余部分。
实施例1：开发新型马流感病毒减毒活疫苗
H3N8马流感病毒(EIV)是一种重要且显著的马呼吸道病原体。EIV在欧洲和北美流行，主要是由于当前疫苗的功效欠佳。本文描述的是使用反向遗传学方法产生温度敏感性(ts)H3N8 EIV减毒活流感疫苗(LAIV)。EIV LAIV在体内衰减(att)，并且能够在小鼠模型和自然宿主马中在单次鼻内施用后诱导针对H3N8 EIV野生型(WT)攻击的保护。值得注意的是，由于EIV LAIV是使用反向遗传学产生的，因此可以容易使用EIV LAIV的安全骨架作为主供体病毒(MDV)更新疫苗以抵抗漂移或新出现的EIV毒株。EIV LAIV是通过在A/马/Ohio/1/2003 H3N8(佛罗里达亚系进化枝1)的聚合酶碱性2(PB2)和聚合酶碱性1(PB1)病毒蛋白中引入导致A/Ann Arbor/6/60 H2N2 LAIV(人类LAIV(FluMist，MedImmune)的主供体病毒(MDV))的ts、ca和att表型的突变而产生(Cox等人，1988；Snyder等人，1988)，并在小鼠和马中评估其安全性和疗效。这些结果证明了实施一种新的EIV LAIV方法来预防和控制目前在马群中传播的H3N8 EIV的可行性。
现在描述这些实验中使用的材料和方法。
细胞和病毒
在37℃与5％CO2下，使人胚胎肾293T细胞(293T；ATCC CRL-11268)、Madin-Darby犬肾细胞(MDCK；ATCC CCL-34)和马真皮细胞(E.Derm NBL-6；ATCC CCL-57)在补充有10％胎牛血清(FBS)和1％PSG(青霉素，100单位/ml；链霉素100μg/ml；L-谷氨酰胺，2mM)的杜尔贝科氏改良伊格尔培养基(DMEM；Mediatech,Inc.)中生长(Nogales等人，2014,J.Virol.88,10525–10540)。
重组野生型(WT)和减毒活(LAIV)H3N8 EIV使用A/马/Ohio/1/2003质粒反向技术产生(Martinez-Sobrido和Garcia-Sastre,2010,J.Vis.Exp.)并在33℃下在MDCK细胞中生长。市售的A/马/Kentucky/1/1991 H3N8 LAIV(Flu Avert I.N.，Merck)也在33℃下在MDCK细胞中生长。用于马攻击实验的A/马/Kentucky/2014 H3N8在含胚鸡蛋中生长。为了感染，将病毒制剂稀释在含有0.3％牛白蛋白(BA)和1％青霉素和链霉素(PS)(PBS/BA/PS)的磷酸盐缓冲盐水(PBS)中。在室温(RT)下病毒吸附1小时后，用感染后(p.i.)DMEM培养基维持MDCK细胞，该培养基补充有0.3％BA、1％PSG和1μg/ml用N-甲苯磺酰基-L-苯丙氨酸氯甲基酮(TPCK)处理的胰蛋白酶(Sigma)。如前所述(Nogales等人，2014,J.Virol.88,10525–10540)，使用抗NP单克隆抗体(mAb)HB-65(ATCC HB-65、HL16-L10-4R5)，在33℃下通过MDCK细胞中的免疫聚焦测定(荧光形成单位，FFU/ml)测定病毒滴度。
质粒
为了产生H3N8 EIV LAIV，将A/马/Ohio/1/2003 H3N8的PB2和PB1基因亚克隆到pUC19质粒(New England BioLabs)中以通过定点诱变引入ts突变PB2 N265S和PB1 K391E、E581G和A661T。通过测序确认存在引入的突变。将PB2-LAIV和PB1-LAIV病毒区段像其他A/马/Ohio/1/2003 H3N8病毒基因(PB2-WT和PB1-WT、PA、HA、NP、NA、M和NS)一样从pUC19亚克隆到双义pDZ质粒中用于病毒拯救。pDZ是一种双义载体，它包含人RNA聚合酶I启动子和编码负义基因组RNA的小鼠终止子序列，并且在与聚合酶I单元相反的方向上包含编码来自同一病毒基因的病毒蛋白的聚合酶II转录盒(鸡β-肌动蛋白启动子和polyA)(Chambers等人，2009,Equine Vet.J.41,87–92.)。
微基因组测定
为了分析A/马/Ohio/1/2003 H3N8 WT和LAIV聚合酶在不同温度(33℃、37℃和39℃)下复制和转录的能力，使用Lipofectamine 2000(Invitrogen)，将悬浮马真皮细胞(12孔板格式，5×105个细胞/孔，一式三份)用0.25μg的A/马/Ohio/1/2003 H3N8 WT或LAIV双义pDZ-PB2或PB2-LAIV、pDZ-PB1或PB1-LAIV、pDZ-PA和pDZ-NP质粒，以及0.5μg由鼠RNA聚合酶I启动子驱动的编码高斯荧光素酶(Gluc)的报告微基因组(MG)病毒(v)RNA样表达质粒(mpPol-I Gluc)和0.1μg编码Cypridina荧光素酶(Cluc)的哺乳动物表达pCAGGS质粒共转染，以使转染效率标准化(Cheng等人，2015；Nogales等人，2016b)。在无pDZ-NP质粒的情况下转染的细胞被当作阴性对照，并且空pDZ质粒用于使阴性对照中转染的质粒DNA的量保持恒定。在转染后48小时，使用Biolux Gaussia和Cypridina荧光素酶测定试剂盒(NewEngland BioLabs)测定Gluc和Cluc表达水平，并使用Lumicount光度计(Packard)进行定量。报告基因活化(Gluc)被标准化为Cluc活化，并报告为阴性对照(不存在NP)的诱导水平的倍数诱导。计算平均值和标准偏差(SD)，并利用Microsoft Excel软件，使用双尾学生t检验进行统计分析。将每个温度下的A/马/Ohio/1/2003 H3N8 WT聚合酶活性视为100％，数据表示为相对活性。
病毒拯救
如前所述进行A/马/Ohio/1/2003 H3N8 WT和LAIV的病毒拯救(Nogales等人，2014,J.Virol.88,10525–10540)。简而言之，使用Lipofectamine 2000，将悬浮的293T和MDCK细胞(6孔板格式，1×106个细胞/孔，一式三份)的共培养物(1:1)用1μg的8种双义A/马/Ohio/1/2003 H3N8 pDZ-PB2或PB2-LAIV、-PB1或PB1-LAIV、-PA、-HA、-NP、-NA、-M和-NS质粒共转染。在转染后12小时，将培养基更换为补充有0.5μg/ml经TPCK处理的胰蛋白酶的感染后DMEM培养基。在转染后三天收集组织培养上清液(TCS)，澄清并用于感染MDCK细胞的新鲜单层。然后，在感染后三天，在33℃下使用MDCK细胞进行重组病毒的噬斑纯化和扩大(Martinez-Sobrido和Garcia-Sastre，2010，J.Vis.Exp.)。
病毒生长动力学
通过以0.001的感染复数(MOI)用A/马/Ohio/1/2003 H3N8 WT和LAIV感染MDCK细胞(12孔板格式，5×105个细胞/孔，一式三份)来评估多循环病毒生长动力学。还以0.001的MOI用Flu Avert I.N.感染MDCK细胞作为对照，因为它构成ts H3N8 EIV。在室温下进行病毒吸附1小时后，用感染后培养基替换感染培养基。补充有0.5μg/ml经TPCK处理的胰蛋白酶的DMEM培养基和平板在不同温度(33℃、37℃和39℃)下培养。在指定的感染后时间收集TCS，并如前所述(Nogales等人，2014,J.Virol.88,10525–10540)，通过MDCK细胞中的免疫聚焦测定(FFU/ml)测定TCS中的病毒滴度。使用Microsoft Excel软件计算平均值和SD。
空斑测定
将MDCK细胞的汇合单层(6孔板格式，1×106个细胞/孔)在室温下用指定的病毒感染1小时，用琼脂覆盖，并在33℃、37℃或39℃下培养。在感染后三天，将细胞在室温下用4％多聚甲醛(PFA)固定1小时，并去除覆盖物。然后使细胞在室温下透化(Triton X-100的0.5％PBS溶液)15分钟，并准备根据制造商的说明书使用抗NP mAb HB-65和载体试剂盒(Vectastain ABC载体试剂盒和DAB HRP底物试剂盒；Vector)进行免疫染色。
小鼠实验
六到八周龄的雌性C57BL/6小鼠购自美国国家癌症研究所(NCI)，并在无特定病原体条件下供养。为了评估EIV LAIV的体内衰减，六只小鼠用2,2,2-三溴乙醇(Avertin；240mg/kg体重)腹膜内(i.p.)麻醉，然后鼻内(i.n.)接种在PBS中稀释的30μl含有105个FFU的EIV WT或LAIV的病毒制剂(Rodriguez等人，2017a)。作为对照，一组小鼠(N＝6)还鼻内接种了105个FFU的Flu Avert I.N.。通过在感染后第2天(N＝3)和第4天(N＝3)测量受感染小鼠的肺和鼻粘膜中的病毒滴度来测定病毒复制。为此，每组的小鼠通过给予致死剂量的Avertin和放血而安乐死，并回收肺和鼻粘膜，然后使其均质化(Rodriguez等人，2017a)。如前所述(Nogales等人，2014,J.Virol.88,10525–10540；Rodriguez等人，2017,J.Vis.Exp)，通过免疫聚焦测定来确定两种组织中的病毒滴度(FFU/ml)。
对于疫苗接种和攻击实验，6-8周龄雌性C57BL/6小鼠(N＝6)被麻醉并鼻内接种PBS或103个FFU的EIV WT、LAIV或Flu Avert I.N.(A/马/Kentucky/1/1991 H3N8 LAIV)。在接种后14天，通过下颌下出血收集小鼠血清，以通过酶联免疫吸附测定(ELISA)评估总抗体的存在，并通过血凝抑制(HAI)测定评估中和抗体的存在。在小鼠出血后24小时，用105个FFU的A/马/Ohio/1/2003 H3N8 WT鼻内攻击小鼠。攻击后，如上所述(Rodriguez等人，2017,J.Vis.Exp)，在感染后第2天(N＝3)和第4天(N＝3)评估小鼠肺中的病毒复制。
马实验
使用一到两岁的混种雄性和雌性马(主要是Standardbred-Quarter马杂交)。马是作为封闭马群的一部分饲养的，并且之前没有针对EIV接种过疫苗。在研究开始前，通过血凝抑制测定(HAI)测得所有马都是EIV H3N8血清阴性的(数据未示出)。为了评估A/马/Ohio/1/2003 H3N8 LAIV的体内衰减，马(N＝4)通过鼻内插管接种在PBS中稀释的2ml含有4×108个FFU的A/马/Ohio/1/2003 H3N8 LAIV的病毒制剂。该剂量是可用的最大剂量，并且与Heska Corp.对Flu Avert I.N.LAIV进行的试点研究(Wilson和Robinson，2000，J.Equine Vet.Sci.20,8–10)中使用的剂量相似，其被选择来提供显现由LAIV诱导的任何临床体征的最大可能性。通过观察临床体征、测量直肠温度和确定在接种前(第0天)和接种后三天每天采集的鼻咽拭子中病毒的存在，每天测试病毒衰减情况。如前所述，通过定量(q)RT-PCR确定鼻拭子中病毒的存在(Lu等人，2009，J.Clin.Microbiol.47,3907–3913)。
对于疫苗接种和攻击实验，一到两岁的马(N＝4)通过鼻内接种2ml含有4×108个FFU的A/马/Ohio/1/2003 H3N8 LAIV的病毒制剂接种疫苗。另一组马(N＝2)用作对照(未接种疫苗)。为避免对照马暴露于散落的EIV LAIV，后者被分开放牧。在接种后27天，所有马(N＝6)都被带到BSL-2隔离畜舍。攻击病毒(一种异源佛罗里达进化枝1EIV毒株A/马/Kentucky/2014 H3N8)使用DeVillbis Ultra-Neb 99雾化器雾化，并被泵入帐篷隔间(37.5m3)至密度为1×107个50％蛋感染剂量(EID50)单位/m3，让马吸入45分钟(Mumford等人，1990,Equine Vet.J.22,93–98；Townsend等人，2001,Equine Vet.J.33,637–643)。病毒的攻击剂量类似于马的先前实验性感染中所用的剂量(Lunn等人，2001，J.Am.Vet.Med.Assoc.218,900–906.)。此后每天观察马，并在病毒攻击前(第0天)和连续7天每天采集直肠温度、临床体征和鼻咽拭子。如上所述对每个鼻咽拭子进行qRT-PCR，并且还如上所述通过注射到含胚鸡蛋中对每个拭子进行非定量病毒检测(Chambers等人，2001，Equine Vet.J.33,630–636)。通过EID50滴定测定来自攻击后第2天和第3天的鼻咽拭子样品的传染性病毒含量。
ELISA
为了评估接种过疫苗的小鼠的血清中存在的病毒特异性抗体水平，如前所述进行ELISA(Nogales等人，2016,J.Virol.,90:6291-6302；Nogales等人，2017,Virology,500,1-10；Nogales等人，2016,J.Viol,91；Rodriguez等人，2017,J.Vis.Exp.；Rodriguez等人，2017,Virology,504,96-106)。简而言之，用来自模拟或感染EIV的MDCK细胞的细胞裂解物涂覆96孔板，并在4℃下培养过夜(O/N)。动物血清以两倍稀释液(1:100的起始稀释度)进行测定，并如前所述测定滴度。
HAI测定
为了评估EIV中和抗体的存在，用受体破坏酶(RDE；Denka Seiken)在37℃下处理小鼠血清16小时，并在56℃下加热灭活30分钟。然后在96孔V型底板中将血清连续2倍稀释(起始稀释度为1:50)，并在室温下与4个血凝单位(HAU)的A/马/Ohio/1/2003 H3N8按1:1混合30分钟。通过将0.5％的火鸡红细胞添加到病毒-抗体混合物中并在冰上放置30分钟来测定HAI滴度(Nogales等人，2016b)。来自单个小鼠(N＝6)的几何平均滴度和SD是从最后一个血凝被抑制的孔中计算得到。马血清的HAI以基本上相同的方式进行，除了马血清按照描述用胰蛋白酶-高碘酸盐进行预处理(Chambers和Reedy,2014,Methods Mol.Biol.1161,411–422)以去除非特异性血凝抑制剂和使用鸡红细胞以外。
现在描述实验的结果。
A/马/Ohio/1/2003 H3N8(EIV)LAIV的产生和表征
市售EIV LAIV(Flu Avert I.N.)是由25年前传播的EIV毒株(A/马/Kentucky/1/1991 H3N8)制成，并且从未更新过(Youngner等人，2001,Am.J.Vet.Res.62,1290–1294)。为了生成更新的EIV LAIV，导致人A/Ann Arbor/6/60H2N2 LAIV(FluMist)的ts、ca和att表型的五个突变中的四个(Cox等人，1988；Snyder等人，1988)被引入A/马/Ohio/1/2003 H3N8(EIV)的PB2(N265S)和PB1(K391E、E581G、A661T)基因中(图1中A)，其中A/马/Ohio/1/2003H3N8是OIE推荐包括在EIV疫苗中的进化枝1佛罗里达亚系毒株(Paillot等人，2016,Pathogens,5)。A/马/Ohio/1/2003 H3N8 NP病毒区段已经在位置43包含G。然后在不同温度(33℃、37℃或39℃)下在马真皮细胞中进行微基因组复制分析，以分析引入A/马/Ohio/1/2003 H3N8的PB2和PB1基因中的突变是否赋予病毒聚合酶复合物ts表型。在33℃下，A/马/Ohio/1/2003 H3N8 WT和LAIV聚合酶均诱导相似水平的Gluc表达(图1中B)。然而，Gluc表达在37℃下显著降低，并且在39℃下甚至降低更多(图1中B)。
基于在微基因组分析中观察到的ts表型(图1)，接下来评估A/马/Ohio/1/2003H3N8的病毒PB2和PB1聚合酶亚基中引入的突变是否会导致病毒的生长动力学在限制性温度(37–39℃)下受损，但在许可温度(33℃)下不受损。因此，使用先前描述的反向遗传学技术(Martinez-Sobrido和Garcia-Sastre，2010，J.Vis.Exp.；Nogales等人，2014,J.Virol.88,10525–10540)拯救WT和LAIV A/马/Ohio/1/2003 H3N8(在下文中分别称为EIVWT和EIV LAIV)。通过评估在不同温度(33℃、37℃或39℃)下以低(0.001)感染复数(MOI)感染的MDCK细胞中的病毒滴度来测定两种病毒的病毒复制动力学(图2中A)。还包括了FluAvert I.N.作为对照。在33℃下，EIV WT和LAIV以及Flu Avert I.N.具有相似的生长动力学，并在感染后48小时达到峰值滴度。在37℃和39℃下，EIV WT复制与在33℃下观察到的相似。与EIV WT相比，EIV LAIV和Flu Avert I.N.的滴度分别在37℃和39℃下显著降低或未检测到(图2中A)。还在相同温度(33℃、37℃或39℃)下分析了EIV WT和LAIV以及Flu AvertI.N.的空斑表型(图2中B)。EIV WT的空斑大小在33℃和37℃下相似，并且在39℃下略微减小，这与在该温度下动力学中观察到的病毒滴度降低得最少一致(图2中A)。在EIV LAIV和Flu Avert I.N.的情况下，33℃下的空斑大小与EIV WT相似，但在高温下，空斑大小显著减小(37℃)或未检测到空斑(39℃)，从而证实了生长动力学结果(图2中A)。总之，这些结果表明A/马/Ohio/1/2003 H3N8的PB2和PB1聚合酶亚基中的氨基酸取代赋予ts表型。
EIV LAIV在小鼠中的衰减
在阐明EIV LAIV的生长动力学(图2中A)和空斑大小(图2中B)在高温(37℃和39℃)下受影响但在低温(33℃)下不受影响后，分析其在流感感染小鼠模型中的体内复制能力(图3)。为此，用105个FFU的EIV WT或LAIV鼻内感染小鼠(N＝3/时间点)。还用105个FFU的Flu Avert I.N.感染小鼠以作为内部对照。由于在感染EIV WT后未在小鼠中检测到感染迹象，因此通过评估感染后第2天和第4天肺(图3中A)和鼻粘膜(图3中B)中的病毒滴度来测定EIV WT和LAIV的复制。决定使用这种高剂量(105个FFU)来更好地评估新EIV LAIV与其WT对应物相比的安全特性。值得注意的是，在感染后的两个时间点，仅在感染了EIV WT的小鼠的肺中检测到病毒滴度(图3中A)，但在感染了EIV LAIV或Flu Avert I.N.的小鼠的肺中未检测到病毒(图3中A)。另一方面，在感染了三种病毒的小鼠的鼻粘膜中检测到病毒复制(图3中B)，但是在感染EIV LAIV和Flu Avert I.N.的小鼠中获得的病毒滴度在感染后的两个时间点都显著低于EIV WT。这些结果表明，EIV LAIV在高温(肺)下也在体内衰减，但其能够在温度较低的鼻粘膜中复制。重要的是，在使用Flu Avert I.N.时观察到相同的体内ts表型。
用EIV LAIV免疫的小鼠免受H3N8 EIV WT攻击
为了评估由EIV LAIV诱导的免疫，小鼠组(N＝6)鼻内接种103个FFU的WT和LAIVEIV，并模拟接种PBS或鼻内接种103个FFU的Flu Avert I.N.分别作为阴性和阳性对照。选择103个FFU/小鼠的剂量是因为基于安全性结果(图3)。此外，之前与开发针对H3N8(Nogales等人，2016,J.Virol.91)和H3N2(Rodriguez等人，2017,Virology 504,96–106)CIV的LAIV有关的研究表明，该剂量诱导强烈的体液和细胞反应，以及针对WT CIV攻击的完全保护。在接种后14天收集的小鼠血清中评估体液免疫反应。通过利用来自感染病毒的MDCK细胞的细胞提取物进行ELISA，评估针对总EIV蛋白的抗体反应(图4中A)(Nogales等人，2016,J.Virol.91；Rodriguez等人，2017,Virology 504,96–106)。接种EIV LAIV的小鼠的血清引发了针对EIV蛋白的高血清IgG滴度，接近在感染EIV WT的小鼠的血清中获得的血清IgG滴度，而在用Flu Avert I.N.免疫的小鼠的血清中观察到显著降低的抗体滴度(图4中A)。此外，进行HAI测定以评估在接种疫苗的小鼠的血清中中和抗体的存在(图4中B)。在接种EIV LAIV的小鼠的血清中，针对EIV的HAI滴度高于在接种Flu Avert I.N.的小鼠观察到的HAI滴度，并且与在感染EIV WT的小鼠中获得的HAI滴度相似(图4中B)。
接下来，进行实验以评估由EIV LAIV诱导的针对同源A/马/Ohio/1/2003 H3N8 WT攻击的保护功效(图5)。小鼠(N＝6)鼻内接种了103个FFU的WT和LAIV EIV、Flu AvertI.N.，或模拟接种了PBS。在接种后15天，用105个FFU的A/马/Ohio/1/2003 H3N8 WT攻击小鼠，并在攻击后第2天和第4天测定受感染小鼠(N＝3/组)的肺中的病毒滴度(图5)。模拟接种(PBS)的小鼠在攻击后第2天和第4天表现出～3×104个FFU/ml的肺病毒滴度，而接种WT或LAIV EIV的小鼠的肺中在这些时间点没有检测到病毒(图5)。相反，在攻击后第2天，在接种Flu Avert I.N.的小鼠的肺中检测到A/马/Ohio/1/2003 H3N8 WT(～1×103个FFU/ml)，但在攻击后第4天未检测到(图5)。这些结果表明，EIV LAIV比Flu Avert I.N.在小鼠中针对A/马/Ohio/1/2003 H3N8 WT的攻击诱导更好的保护，这可能是因为抗原匹配。
EIV LAIV在马中的衰减
接下来，评估EIV LAIV在其天然宿主马中的安全性和其诱导的保护功效。为此，使四匹马鼻内感染4×108个FFU的EIV LAIV，并监测感染后前3天内的临床症状如咳嗽、流鼻涕、呼吸和抑郁、直肠温度以及病毒脱落(图6)。没有一匹马表现出明显的不良反应。四匹马中有三匹在感染后第2天和第3天出现轻微的双侧浆液状鼻涕，并观察到一次咳嗽，但直肠温度保持正常(接种当天为37.5℃±0.2，接种后第三天为37.6℃±0.4)(图6中A)。为了测量在感染后第0-3天收集的鼻咽拭子中EIV LAIV的存在，对每个拭子(每匹马的每个鼻孔每天取一个拭子)进行qRT-PCR。在感染后第1-3天收集的所有鼻咽拭子中均检测到病毒脱落，其中在感染后第2天出现峰值(图6中B)，这指示病毒复制。另外再每天观察马达25天，但未在感染后第3天之后进一步取拭子以确定脱落的持续时间。在此期间，一匹马因不相关的问题(马原生动物性脊髓炎)被安乐死。从随后受到攻击的一岁马中获得类似的安全性观察结果，包括在2/4马中的轻微浆液状鼻涕(图7)。在接种疫苗后，所有马都出现血清转化，因为它们的HAI抗体滴度从未检测到(<10)增加到20(在安全性和攻击试验的三匹马中)或10(在两个试验的第4匹马中)，并且正如预期的那样，在未接种疫苗的对照组的血清中没有检测到HAI抗体。这些结果证明了EIV LAIV在马中的安全特性及其在上呼吸道中的复制能力，这对于诱导免疫(包括HA特异性抗体反应)是必不可少的。
用EIV LAIV免疫的马免受异源EIV H3N8 WT的攻击
为了评估EIV LAIV在其天然宿主中诱导的保护功效，一组马(N＝4)如先前所述接种4×108个FFU的EIV LAIV，或模拟接种(N＝2)以作为阴性对照(图7)。在接种后27天，通过将马暴露于雾化的野生型病毒(进入帐篷隔间(37.5m3)的1×107个EID50单位/m3的A/马/Kentucky/2014 H3N8 WT)45分钟对其进行攻击。A/马/Kentucky/14(H3N8)病毒是佛罗里达进化枝1毒株，其与EIV LAIV异源，但抗原性相似。在攻击后的前10天，监测马的直肠温度(图7中A)、感染临床症状(咳嗽、流鼻涕、呼吸、抑郁和淋巴结肿大)的存在和病毒脱落(图7中B)。两个未接种疫苗的对照在攻击后第二天表现出特征性发热峰，但在接种EIV LAIV的四匹马中均未发生该情况(图7中A)，而且发现其中一匹未接种疫苗的马(2号)在攻击后第二天嗜睡。两匹对照马的体温在攻击后第3天到第6天恢复至正常或接近正常范围，但未接种疫苗的2号马在攻击后第7天出现第二发热峰(图7中A)。两匹未接种疫苗的马在攻击后的第3天(2号马)和第7天(1号马)都出现咳嗽，而在任何疫苗接种者中均未观察到咳嗽。在攻击后第8天(未接种疫苗的马1)或第2天(未接种疫苗的马2)，在两个对照动物中均观察到流鼻涕。值得注意的是，所有接种疫苗的马都没有咳嗽或流鼻涕。在未接种疫苗的马中观察到的另一个临床症状是在攻击后第6天(未接种疫苗的马1)和第4天(未接种疫苗的马2)出现吸气喘鸣，但在已接种疫苗的马中没有。在四分之三的疫苗接种者和两个对照中观察到下颌下或腮腺淋巴结肿胀；然而，对照组的严重程度和持续时间更长。在研究后期(攻击后第11天)，一项独立的兽医评估导致两匹对照马都接受抗生素治疗以促进完全康复，但所有疫苗接种者都无需该治疗。因此，从临床角度来看，接种疫苗的马似乎可以免受野生型EIV的攻击。
A/马/Kentucky/2014 H3N8 WT病毒在鼻咽拭子中的脱落通过接种含胚鸡蛋和直接qRT-PCR进行评估(图7中B)。当将接种疫苗的马的鼻咽拭子接种到鸡蛋中时，在攻击后可检测到活病毒至少一次，平均为攻击后2.25天至最多5天。在攻击后第2天或第3天收集的拭子材料中的传染性病毒含量的EID50滴定显示滴度在1.7×102和3.16×103个EID50单位/ml之间。另一方面，两匹未接种疫苗的马在攻击后第五天和第六天都排出可检测到的活病毒，并且在接种后第二天尿囊液中的病毒滴度为1.7×105(2号)和4.6×107(1号)个EID50单位/ml。因此，EIV LAIV在单次给药后没有实现针对异源攻击的消除性免疫，但与未接种疫苗的马相比，活病毒脱落似乎至少减少三个数量级。当通过qRT-PCR评估每日鼻咽拭子中病毒的存在时，这些结果得到证实(图7中B)。在两组马(接种或未接种疫苗)中，从攻击后的第一天(或对于接种疫苗的马2为第二天)到第七天停止取拭子时，都可连续检测到病毒扩增。未接种疫苗的马的脱落峰值大于在接种疫苗的马中获得的值，差异在5到15个循环之间，表明目标浓度比在接种疫苗的马中高约500到1500倍。在病毒攻击后14天，所有马的血清HAI抗体滴度均增加了16至32倍。总之，结果表明EIV LAIV诱导针对A/马/Kentucky/2014 H3N8 WT的异源攻击的保护。
H3N8 EIV LAIV
本文描述了使用反向遗传学开发用于预防和控制马流感的更有效LAIV。这是第一次开发基于反向遗传学技术的鼻内竞争性ts LAIV用于预防和控制马的H3N8 EIV。为了产生H3N8 EIV LAIV，导致人MDV A/Ann Arbor/6/60H2N2 LAIV的ca、ts和att表型的突变(Cox等人，1988,Virology 167,554–567；Snyder等人，1988,J.Virol.62,488-495)被引入来自A/马/Ohio/1/2003 H3N8的PB2和PB1病毒基因中，A/马/Ohio/1/2003 H3N8是OIE推荐的作为EIV疫苗一部分的毒株(佛罗里达亚系的进化枝1)(OIE,2017)(图1)。在体外，重组A/马/Ohio/1/2003 H3N8 LAIV(EIV LAIV)在低温(33℃)下有效复制，这对疫苗生产很重要，但在更高(37℃和39℃)温度下复制受限，这是其作为LAIV安全实施的必要条件(图2)。在流感传染的小鼠模型中，与WT对应物相比，EIV LAIV在下呼吸道(肺)中衰减，但在上呼吸道(鼻粘膜)中未衰减(图3)。重要的是，在体内和体外针对EIV LAIV观察到的表型与针对当前可用的H3N8 EIV LAIV(Flu Avert I.N.)观察到的表型相同。值得注意的是，与仅显示部分保护的Flu Avert I.N.相反，EIV LAIV能够在单次鼻内免疫剂量下诱导针对A/马/Ohio/1/2003H3N8 WT的攻击的完全保护(图5)。针对Flu Avert I.N.观察到的这种部分保护可能是由于Flu Avert I.N.基于一种病毒，该病毒与当前传播的EIV毒株，包括在本研究中使用的毒株(A/马/Ohio/1/2003)，在抗原性上相距甚远。体液反应分析表明，在用EIV LAIV免疫的小鼠的血清中，针对A/马/Ohio/1/2003 H3N8 WT的总抗体(图4中A)以及中和抗体(图4中B)的滴度比在接种Flu Avert I.N.的小鼠的血清中高。EIV LAIV在其自然宿主马中是安全的，因为马没有出现任何感染症状包括发烧(图6中A)，并且EIV LAIV能够在上呼吸道复制，因为在温度低的鼻拭子(图6中B)中检测到该病毒，而这对于诱导粘膜免疫是必不可少的。马在接种疫苗后具有低血清抗体滴度，这种情况在马接受单剂量的Flu Avert I.N.LAIV后也有报道(Lunn等人，2001,J.Am.Vet.Med.Assoc.218,900–906；Townsend等人，2001,EquineVet.J.33,637–643)。这些作者认为，免疫反应的其他指标(如局部粘膜免疫)似乎比血清抗体水平具有更高相关性(Lunn等人，2001,J.Am.Vet.Med.Assoc.218,900–906；Townsend等人，2001,Equine Vet.J.33,637–643)。重要的是，在使用异源A/马/Kentucky/2014 H3N8WT病毒(佛罗里达进化枝1毒株)进行的马疫苗接种和攻击实验中，除了下颌下或腮腺淋巴结肿大以外(但严重程度和持续时间比在未接种疫苗的马中观察到的低)，接种EIV LAIV的马在攻击后均未表现出感染的临床症状。事实上，在所有受到攻击的马(接种疫苗或未接种疫苗)中，通过qRT-PCR(图7中B)和在含胚鸡蛋中生长在鼻咽拭子中检测到A/马/Kentucky/2014 H3N8 WT病毒，但在两种系统中，检测到的病毒在接种疫苗的马中低三个数量级。所有这些结果表明，EIV LAIV诱导针对A/马/Kentucky/2014 H3N8 WT的异源攻击的保护。
与当前的H3N8 EIV IIV相比，H3N8 EIV LAIV方法具有几个优点。首先，H3N8 EIVLAIV是鼻内施用并模拟病毒感染的自然途径，因此在感染部位诱导粘膜免疫反应(Kohlmeier和Woodland,2009,Annu Rev.Immunol.27,61–82.；Murphy和Coelingh,2002,Viral Immunol.15,295–323)。其次，与H3N8 EIV IIV相比，H3N8 EIV LAIV中所需的病毒量显著减少(Nogales等人，2016,J.Virol.91；Rodriguez等人，2017,Virology 504,96–106)。第三，已证明LAIV可以刺激更强大的全身体液反应(Cheng等人，2013，J.Infect.Dis.208,594–602；De Villiers等人，2009,Vaccine 28,228–234；Katsura等人，2012,Vaccine 30,6027–6033；Nogales等人，2016,J.Virol.91；Rodriguez等人，2017,Virology 504,96–106；Victor等人，2012,J.Virol)并引起细胞免疫(Cheng等人，2013,J.Infect.Dis.208,594–602；Katsura等人，2012,Vaccine 30,6027–6033)，从而产生呼吸道靶组织中的流感特异性CD8 T细胞的募集(Baker等人，2013,J.Virol.87,8591–8605；Guo等人，2014,J.Virol.88,12006–12016；Katsura等人，2012,Vaccine 30,6027–6033；Nogales等人，2016,J.Virol.91；Powell等人，2012,J.Virol.86,13397–13406；Rodriguez等人，2017；Uraki等人，2013,J.Virol.87,7874–7881)。第四，与当前灭活疫苗所需的多剂量相比，使用H3N8EIV LAIV进行单次免疫将足以在更短的时间内提供针对H3N8 EIV WT的至少部分保护。最后，与EIV IIV相比，H3N8 EIV LAIV针对抗原性不同的H3N8 EIV毒株将提供更好的交叉保护，从而减少EIV爆发的机会。上述一些优点是唯一市售的H3N8 EIV LAIV(即Flu AvertI.N.)所共有的(Chambers等人，2001,Equine Vet.J.33,630–636)。然而，本技术还提供了许多额外的优点。首先，先前已描述过在A/马/Ohio/1/2003 H3N8的PB2和PB1聚合酶亚基中引入的突变产生人A/Ann Arbor/6/60 H2N2 LAIV(FluMist)的MDV中的ts、ca和att表型(Cox等人，1988,Virology 167,554–567；Snyder等人，1988,J.Virol.62,488–495)，历史证明该MDV具有安全性、免疫原性，并且不仅针对人类病毒，而且针对禽流感和马流感病毒也具有保护功效(Baz等人，2015,J.Virol.89,1652–1659；Suguitan等人，2006,PLoS Med.3,e360.)。其次，在其他甲型流感病毒中也引入了相同的ts和ca突变，诱导相同的减毒表型(Cox等人，2015,J.Virol.89,3421–3426.；Jin等人，2004,J.Virol.78,995–998.；Nogales等人，2016,J.Virol.91；Rodriguez等人，2017,Virology 504,96-106；Zhou等人，2012,Vaccine 30,3691–3702)。第三，与人类LAIV的情况类似，使用最新的反向遗传学技术将促进LAIV候选物的快速和准确开发，以控制当前流行的佛罗里达亚系的进化枝1和2毒株，或在马群中具有新爆发的情况下控制新引入的EIV毒株。为此，温度敏感性A/马/Ohio/1/2003H3N8 LAIV可用作MDV，以通过引入来自抗原性不同的H3N8 EIV流行毒株或新引入马群中的EIV(包括具有人畜共患潜力的EIV)的HA和NA来产生更新的LAIV。
实施例2：二价和/或多价EIV LAIV的开发
使用实施例1中描述的LAIV方法开发二价H3N8 EIV LAIV。Ohio/03 LAIV作主供体病毒(MDV)以生成重组进化枝2A/马/1/2007 H3N8 LAIV(Rich/07LAIV)。产生含有来自Ohio/03 LAIV的六个内部基因(PB2、PB1、PA、NP、M和NS)和A/马/1/2007 H3N8 WT(Rich/07WT)的HA和NA基因的病毒。这种二价EIV LAIV由混合的进化枝1Ohio/03和进化枝Rich/07单价LAIV组成。通过总RNA的提取来确认Rich/07重组病毒的适当构建；然后进行HA和NA基因的PCR扩增；PCR产物的限制性内切酶消化和琼脂糖凝胶分离以及测序(数据未示出)。二价EIV LAIV中的两种病毒通过评估在MDCK细胞中的生长动力学以及使用抗NP抗体的空斑测定在体外单独进行表征(数据未示出)。这种二价LAIV遵循当前OIE的建议，即包括H3N8 EIV佛罗里达亚系的进化枝1和2的代表性毒株。
基于相对于H3N8 EIV IIV的多个优点，这个新平台代表了一种更简单、更快捷的方法，该方法可以实现安全且更有效的LAIV以预防和控制马群中的H3N8 EIV，从而减轻马的当前和未来流感疾病的负担。
目前，EIV佛罗里达亚系有两个进化枝(1和2)在马中传播，并且OIE建议将这两个进化枝都包括在EIV疫苗中。目前由OIE推荐包括在疫苗中的EIV毒株的例子包括佛罗里达进化枝2毒株Newmarket/2003样和佛罗里达进化枝1毒株南非/03样、Ohio/03样和Nottinghamshire/09样，以及佛罗里达进化枝2毒株Richmond/07样、Lancashire/10样或Hants/10样。为了产生二价EIV LAIV，使用作为主供体病毒(MDV)的A/马/Ohio/1/2003H3N8(EIV)LAIV的安全骨架以及其他EIV毒株的血凝素(HA)和神经氨酸酶(NA)。为此，利用反向遗传学方法，该方法使用A/马/Ohio/1/2003 H3N8(EIV)LAIV的内部基因(PB2、PB1、PA、NP、M和NS)和其他EIV毒株的表面糖蛋白基因(HA和NA)。生成针对其他EIV毒株的LAIV的反向遗传学和实验方法将类似于实施例1中描述的用于生成A/马/Ohio/1/2003 H3N8 LAIV的方法。EIV进化枝1LAIV与EIV进化枝2 LAIV在混合二价EIV LAIV中组合。也可以使用与针对二价LAIV所述相同的实验方法来开发多价EIV LAIV，其中A/马/Ohio/1/2003 H3N8(EIV)LAIV用作MDV以表达其他EIV毒株的HA和NA。
实施例3：在马中评价进化枝1和进化枝2二价EIV LAIV疫苗。
对两种性别的一到两岁流感血清阴性马进行模拟接种(N＝6)或使用其中在第一剂后29天给予第二剂的加强免疫方案，接种(N＝12)EIV二价LAIV疫苗(3×108个FFU的每种A/马/Ohio/1/2003[进化枝1]和A/马/Richmond/1/2007[进化枝2]LAIV)。A/马/Richmond/1/2007[进化枝2]LAIV是基于使用温度敏感性A/马/Ohio/1/2003 LAIV作为主供体病毒，其中如上所述A/马/Richmond/1/2007[进化枝2]LAIV包含温度敏感性A/马/Ohio/1/2003骨架，但是其经过修饰以表达A/马/Richmond/1/2007 HA和NA。在第一次接种后又增加了两匹血清反应阴性的哨兵马。在每次接种之前和接种后3天内，测量每匹马的个体直肠温度和病毒脱落。在接种后第56天(初免)，收集血清样品，并分别通过HAI和微量中和试验评估血凝和中和抗体(Ab)的存在。在接种后第57天(初免)，用1x107个EID50的Richmond/2007 WT(Rich/07 WT；N＝6疫苗接种者/N＝3模拟接种者)或Kentucky/2014 H3N8 WT(KY/14 WT[进化枝1]；N＝6疫苗接种者/N＝3模拟接种者/N＝2哨兵)攻击接种疫苗的(N＝12)、模拟接种的(N＝6)和哨兵(N＝2)马以分别评估针对进化枝1和2EIV的保护。在攻击后的8天期间，评估直肠温度和病毒脱落。通过使用Flexi-Neb II雾化器/鼻罩，对马单独进行所有疫苗接种和所有攻击接种。
对于进化枝2攻击，6个疫苗接种者有1天表现出温和的体温升高，而3个对照则有3天出现高烧。在进化枝1攻击期间，在6个疫苗接种者和1个哨兵中没有观察到温度升高，而3个对照有2天表现出轻微发烧，而第二个哨兵则有3天出现高烧。基于每天观察呼吸频率、流鼻涕、咳嗽和厌食后分配给每个动物的得分(最高得分可以为7)计算每组的累积临床评分。对于进化枝2攻击，6个疫苗接种者具有<1的平均临床评分，而3个对照在第2-8天的平均评分为3.3(最1.7至最高5)。进化枝1攻击显示相似的结果，其中6个疫苗接种者和1个哨兵具有<1的平均评分，3个对照在第1-8天的平均评分为2.5(最低.3，最高3.3)，而第二个哨兵在第2-8天的平均分为2.7(最低1，最高5)。总体而言，该数据表明，对于两种病毒攻击，疫苗接种者和对照之间均存在临床评分差异。
还通过鼻咽拭子和含胚鸡蛋接种来评估攻击病毒的脱落。当来自接种疫苗的马的鼻咽拭子被接种在鸡蛋中时，除了用KY/14 WT攻击的组中的1个动物之外，每个动物在攻击后都至少一次检测到活病毒。在攻击后第二天从接种疫苗的马收集的拭子材料中的传染性病毒含量的EID50滴定显示Rich/07 WT攻击组中的对数滴度在1.750和4之间，而KY/14 WT攻击组中的对数滴度在0和2之间。另一方面，两个组中未接种疫苗的马在攻击后6或7天内均排出可检测到的活病毒，并且接种后第二天的尿囊液中的对数滴度在Rich/07 WT攻击组中介于6.500和6.667之间，而在KY/14 WT攻击组中介于4.625和7之间。因此，与未接种疫苗的马相比，接种疫苗的马的活病毒脱落似乎减少至少三个数量级或更多。总之，结果表明二价EIV LAIV疫苗在马中诱导针对进化枝1和进化枝2病毒攻击的保护。
实施例4：包含最新进化枝1和进化枝2病毒的二价EIV LAIV的开发。
为了生成满足OIE推荐的更新的EIV LAIV，基于进化枝1A/马/Texas/6/2017(TX/17)和进化枝2A/马/Lancashire/1/2016(LANC/16)的HA和NA产生二价EIV LAIV。使用与实施例2中所述相同的策略-即使用含有来自Ohio/03 LAIV的六个内部基因(PB2、PB1、PA、NP、M和NS)的重组病毒作为主供体病毒(MDV)，而来自最新进化枝1 TX/17和进化枝2 LANC/16的HA和NA基因被分别克隆到其中。以类似于用于确认Ohio/03和Rich/07重组病毒的方法，确认TX/17和LANC/16重组病毒的适当生成。该疫苗符合当前OIE的建议，即包括H3N8 EIV佛罗里达亚系的进化枝1和2的代表性毒株，但提供了进一步的优点，因为它包含每个进化枝的最近流行的病毒株。
实施例5：鼻内施用于马的二价修饰的活马流感病毒疫苗的安全性和功效。
该研究的目的是评估以单剂量形式鼻内施用于马的进化枝1(Texas/6/17)、进化枝2(Lancashire/1/16)以及进化枝1和2组合(Texas/6/17和Lancashire/1/16)修饰的活马流感病毒疫苗的安全性和功效(表3)。在第28天，通过雾化用马流感病毒的强毒株攻击马，并在攻击后观察21天。
表3
IN＝鼻内
CO＝临床观察
[1]安慰剂＝磷酸盐缓冲盐水(PBS)
[2]TX17＝Texas/6/17；LANC16＝Lancashire/1/16
使用完全随机设计将动物分配到治疗组。动物在接种阶段1前有至少7天的适应期，在接种疫苗前圈养。在攻击前至少2天将动物迁移到攻击阶段房间。经赞助者和临床代表批准，马在抵达前被给予适当的抗生素(头孢噻呋
)和驱虫药(芬苯达唑
)。如果T01对照组中的动物在攻击前保持EIV血清阴性(HAI测定滴度<8)，并且大约75％的T01动物在攻击后表现出临床疾病(定义如下)，则该研究被视为有效的。
从第-3天到第4天采集并记录个体动物的直肠温度。如果动物在第0天之前的直肠温度>102.5℉，则延迟开始研究以允许体温恢复正常(至少连续2天温度≤102.5℉)。如果个体动物在第4天发热(直肠温度>102.5℉)，则每天采集并记录该动物的直肠温度，直到温度恢复到≤102.5℉。在第0天，在接种后约30分钟测量直肠温度。所有马在攻击前必须连续两天(第26天和第27天)具有正常直肠温度(≤102.5℉)。
生病、受伤或垂死的动物在必要时由兽医在与研究人员和临床或赞助者代表协商后进行治疗或移除。将所有治疗记录在案。攻击后，马没有接受抗生素、消炎药或其他可能掩盖疾病的临床体征或进展的疗法的治疗。如果动物奄奄一息(躺卧且无法站起来进食和/或饮水)，则对动物实施安乐死。如果可能，在对任何动物实施安乐死之前通知研究人员和临床或赞助者代表。如果延迟咨询临床或赞助者代表会给动物造成过度痛苦或不适，则研究人员选择立即对动物实施安乐死，并尽快(24小时内)通知临床代表。安乐死符合现行的AVMA安乐死指南(2007年6月)，并被记录在案。
对研究期间死亡或被安乐死的动物进行尸检，并且如果可能，确定死亡原因。记录尸检结果和收集的样本。
在第-1、7、14、27、35、42和49天通过颈静脉穿刺从个体动物身上采集血液(1x12.5mL SST)。将样品标记，并处理成血清。将血清分成2x1mL等分试样，并将剩余的血清置于第三等分试样中。记录样品收集。
在第-1、1-14、27天(攻击前)和第29天至研究完成当天，收集个体动物的鼻拭子。使用一个拭子从单个鼻孔收集材料并放置到病毒运送介质中。样品用唯一的样品ID标记并在收集时置于冰上。鼻拭子样品冷冻保存(≤-70℃)直至测试时。记录样品收集。
个体动物在第0天接种分配给它们的IVP/CP。使用适当大小的注射器和鼻套管将IVP/CP以1mL剂量施用到单个鼻孔中。记录疫苗接种。
在第-1天、第0天(接种后约30分钟)和第1至7天每天观察个体动物的异常临床体征至少一次，包括但不限于流鼻涕、嗜睡、呼吸急促(快速呼吸；>40次呼吸/分钟[bpm])和颤抖。记录接种后的临床观察结果。在第0天，在接种后约30分钟记录接种后的临床观察结果。
在第28天，通过马面罩湿式雾化器(
ES)用毒性异源进化枝1 EIV毒株(KY/5/12)鼻内攻击个体动物。记录攻击。
由合格的(即受过训练的)人员每天至少观察一次个体动物的抑郁、呼吸努力、咳嗽和流鼻涕，持续至少30分钟。根据临床评分系统对每种临床体征进行评分。在第27天直至研究完成时记录攻击阶段临床评分。在第28天(攻击日)，攻击阶段临床观察在攻击后约30分钟进行。
根据ARS兽医在与临床代表和/或赞助者协商后提出的建议，将任何表现出无关疾病的临床体征的动物从研究的攻击阶段移除。
基于以下单独或组合使用的标准来确定疫苗功效：
1)临床疾病：如果一组内的疫苗接种者与对照相比，临床疾病显著减少(P<0.10)，则疫苗的功效被视为可接受的。如果动物的直肠温度>103.0℉(在攻击后的任一天)，并且在攻击后的任一天具有至少一个关于抑郁、呼吸努力、咳嗽(评分为1)或流鼻涕(评分为2)的异常临床评分，则认为该动物患有临床疾病。发热和阳性临床评分不必在同一天发生。
2)病毒分离(VI)：结果报告为阳性/阴性(定性)。通过病毒分离测试鼻拭子是否存在EIV。拭子在室温下解冻；表达以收集培养基；并使用0.45微米注射器过滤器过滤培养基。使用含胚鸡蛋测试鼻拭子等分试样。简而言之，将100μL样品接种到9至11天大的含胚鸡蛋中。将鸡蛋在36℃下培养72小时，并在接种后1天观察胚胎死亡。丢弃在前24小时内死亡的任何鸡蛋。在接种后72小时，将所有剩余的鸡蛋置于4℃下过夜，收集尿囊液并测试HA活性。
3)血凝抑制(HAI)：用高碘酸钾预处理血清样品并进行热灭活以去除任何非特异性抑制剂。将处理过的血清的系列稀释液与等体积的含有8个HA单位的病毒悬浮液混合，并观察HA活性。
4)qPCR：使鼻拭子解冻并表达以收集培养基。从拭子培养基中提取RNA。使用实时PCR对RNA进行定量，其中引物和探针靶向每个疫苗株的特异性HA基因的保守区域。
在研究结束时，动物被人道地安乐死，并根据现场SOP进行掩埋或化学消化。
针对每个治疗组和时间点计算在接种阶段期间采集的温度(包括攻击日之前采集的温度)的描述性统计数据(平均值、标准偏差、最小值和最大值)。使用如VI分析部分中所定义的相同模型分析攻击阶段的温度，包括攻击当天的温度。计算每个时间点的治疗最小二乘平均值、标准误差、90％置信界限、最小值和最大值。使用对比选项在每个时间点比较治疗组。
计算每个治疗组和时间点的接种后临床观察结果(抑郁、颤抖、呼吸急促、流鼻涕等)的频率分布。计算每个治疗组的曾经具有每种接种后临床观察结果的频率分布。
按治疗组和收集数据的时间点计算攻击后临床评分的频率分布。计算每个治疗组的曾经具有每种攻击后临床观察结果的频率分布。
按治疗组计算动物在攻击后是否曾被认为患病(攻击后存在临床疾病)的频率分布。如果可能，使用具有二项式分布和logit链接函数的一般线性混合模型分析患病/未患病。该模型中的固定效应是治疗，而模型中没有随机效应。计算每个治疗组的最小二乘平均值、标准误差和90％置信界限并进行反向转换。如果无法使用广义混合模型，则使用Fisher精确检验来分析数据。使用对比选项比较治疗组T01与治疗组T02-T04。
病毒脱落的持续时间和数量数据被作为疫苗功效的支持数据加以分析。关于病毒分离，针对每个治疗组和时间点计算动物是否排出病毒的频率分布。确定每个动物的攻击后病毒脱落的持续时间，并计算为((最后存在的时间点)-(首次存在的时间点))+1。对于没有病毒分离阳性的时间点的动物，将病毒脱落的持续时间设置为零。计算每个治疗组的病毒脱落持续时间的最小值、最大值、中值和四分位数非参数统计数据(五数概括法)。
用一般线性混合模型分析病毒脱落的持续时间。模型中的固定效应为治疗，并且随机效应为残差。计算治疗最小二乘平均值、标准误差、90％置信界限、最小值和最大值。使用对比选项比较治疗组T01与治疗组T02-T04。
如有必要，在使用一般线性混合模型分析重复测量值之前对攻击VI数据进行对数转换。模型中的固定效应是治疗、时间点和治疗x时间点相互作用。模型中的固定效应是治疗内的动物和残差。如有必要，对每个时间点的治疗最小二乘平均值、标准误差和90％置信界限进行反向转换。还计算了每个时间点的治疗最小值和最大值。使用对比选项在每个时间点比较治疗组T01与治疗组T02-T04。
关于qPCR，计算每个动物在攻击阶段期间的曲线下面积(AUC)。在使用一般线性混合模型进行分析之前，对AUC进行自然对数转换。模型中的固定效应为治疗，并且随机效应为残差。对治疗最小二乘平均值、标准误差和90％置信界限进行反向转换。还计算了治疗最小值和最大值。
结果
该研究是有效的，因为T01对照组中的动物在攻击前保持EIV血清阴性(HAI测定滴度<8)，表明没有发生无意暴露于EIV。在T01对照组中，71.43％(5/7*)的T01对照动物在攻击后表现出临床疾病。(*T01对照组中的一匹马在第39天(攻击后11天)被安乐死，原因是与攻击相关的继发性细菌性肺炎。)因此，攻击被认为是有效的，即使它不符合对照组中75％疾病频率的标准。
按治疗组统计的临床疾病频率分布和治疗比较提供在表4中。在T01对照动物中，71.43％(5/7)发展临床疾病。T02接种组(TX17)中没有动物(0/8)发展临床疾病，而T04接种组(TX17+LANC16)中只有1个动物(1/7)发展临床疾病。与T01对照组相比，T02接种组(TX17)中的临床疾病显著减少(P＝0.0070)。与T01对照组相比，T03(LANC16)和T04(TX17+LANC16)接种组的临床疾病频率均降低；然而，差异并不显著(分别为P＝1.0000和0.1026)。
表4.
(1)是＝在攻击后任一天至少发烧一次，并且至少有一项关于抑郁、呼吸努力和咳嗽的临床评分为1或关于流鼻涕为2
*值与对照组T01值相比有显著差异
攻击后曾经出现临床体征(咳嗽、抑郁、流鼻涕或呼吸努力)的频率分布提供在表5中。100％的T01对照动物出现咳嗽。在接种组中，T02(TX17)组的咳嗽发生率最低(1/7；12.50％)，其次是T04组(TX17+LANC16；4/7；57.14％)和T03组(LANC16；5/8；62.50％)。研究期间仅在2个动物中观察到抑郁：一个在T01对照组中，另一个在T03接种组(LANC16)中。100％的T01对照动物出现流鼻涕。在接种组中，T04(TX17+LANC16)组的咳嗽发生率最低(0％)，其次是T02组(TX17；2/8；25％)和T03组(LANC16；4/8；50％)。
在57.14％(4/7)的T01对照动物中观察到呼吸努力。在接种组中，在0％的T04(TX17+LANC16)、12.50％(1/8)的T02(TX17)和25％(2/8)的T03中观察到呼吸努力。
表5.
从第-3天(接种前)到第4天(接种后)记录个体动物的直肠温度(℉)。在第0天(接种疫苗的当天)，在接种前测量直肠温度。从第-3天到第4天，所有马的直肠温度均正常(范围为99.0至101.9℉)。
攻击阶段
从第25天(攻击前3天)到第49天(攻击后21天)记录个体动物的直肠温度(℉)。在第28天(攻击日)，在攻击前测量直肠温度。如果动物的直肠温度≥103.0℉，则认为动物是发烧的(发热阳性)。
所有动物的直肠温度在攻击前(第25-28天)是正常的。为响应EIV攻击，动物最早在第30天(攻击后2天)并且最晚在第39天(攻击后11天)出现发热。按治疗组和研究日统计的直肠温度的最小二乘平均值(LSM)提供在表6中。在第31-34、36-37和39天(7个时间点)，所有接种组(T02-T04)的LSM温度显著低于T01对照组。此外，在第30、35和40天(总共10个时间点)，T02(TX17)和T04(TX17+LANC16)组的LSM温度显著低于T01对照组。在某些时间点(第28、43、45和46天)，一个或多个接种组的温度明显高于T01对照组。然而，在这些时间点，所有动物的体温都是正常的。因此，在这些时间点，治疗组之间的温度差异的临床影响是值得怀疑的。
按治疗组统计的曾经发烧的频率分布如表7所示。T01对照组中出现发烧的动物最多(5/7；71.43％)，其次是T03(LANC16；5/8；62.50％)、T04(TX17+LANC16；14.29％)和T02(TX17；0.00％)接种组。
表6.
表7.
来自T01对照组、T02(TX17)或T04(TX 17+LANC16)的动物在接种后都没有出现临床异常。T03组(LANC16)有两只动物出现流鼻涕：第-1天和第0天的动物203，以及第0天和第1天的动物207。
讨论和结论
攻击是有效的，因为71.43％(5/7)的T01对照动物在攻击后表现出临床疾病。由于发生与攻击相关的继发性细菌性肺炎，一匹T01的马在攻击后11天被安乐死。
没有马在接种后出现发烧(T01-T04)。两匹接种LANC16单价疫苗的马(T03)出现流鼻涕；然而，这种体征在接种后48小时内消失。在接种后研究中，任何其他马都没有出现其他临床异常。因此，单价疫苗(T02[TX17]和T03[LANC16])以及二价疫苗(T04[TX17+LANC16])在以1mL单剂量鼻内施用至一个鼻孔内时都被认为是安全的。
咳嗽和流鼻涕是在攻击后对照动物中观察到的最常见的临床体征(两者的频率均为100％)。在57％(4/7)的对照动物中观察到呼吸努力(呼吸困难)，并且在一个对照动物(14.29％)中观察到抑郁。攻击后接种组中的临床体征的频率降低(在大多数情况下)或与对照组相同。有趣的是，T04二价组100％免受呼吸努力、抑郁和流鼻涕。
治疗组中发热的频率分布与临床疾病的分布相匹配，其中在对照组(T01)中观察到的频率最高，其次是T03(LANC16)、T04(TX17+LANC16)和T02(TX17)组。在攻击后时期，T02组无动物发烧，并且T04组仅有一只动物发烧。在T03和T01组中，五(5)只动物发烧(T03中为62.5％；T01中为71.43％)。
TX17单价疫苗(T02；进化枝1)可有效地显著降低用毒性进化枝1EIV毒株(KY/5/12)攻击的马的EIV临床疾病的频率。T02组中的所有马(100％)在攻击后均免受EIV临床疾病的影响。
LANC16单价疫苗(T03；进化枝2)对用毒性进化枝1EIV毒株(KY/5/12)攻击的马的EIV临床疾病具有部分功效。攻击后T03组中有5/8(62.5％)的马出现临床疾病。TX17接种组比LANC16接种组具有更好的临床疾病保护。该结果表明，与进化枝1疫苗相比，这种进化枝2EIV毒株(LANC16)对进化枝1EIV攻击的交叉保护较少，并且突出了在未来研究中测试LANC16疫苗株对抗进化枝2EIV攻击的重要性。
二价疫苗(T04；TX17+LANC16)有效地降低被毒性进化枝1 EIV毒株(KY/5/12)攻击的马的EIV临床疾病的频率。与T01对照组中的7匹马中有5匹(71.43％)呈EIV临床疾病阳性相比，T04接种组中的7匹马中有一(1)匹(14.26％)呈EIV临床疾病阳性。二价(T04；TX17+LANC16)疫苗是测试的三种疫苗中在降低疾病严重程度方面最有效的。
该研究没有显示LANC16(进化枝2)毒株干扰TX17(进化枝1)毒株抵抗进化枝1攻击的功效。尽管与二价进化枝1+进化枝2疫苗(TX17+LANC16；T04)相比，单价进化枝1疫苗(TX17；T02)使更大比例的马免受进化枝1攻击，但两组之间患病动物的差异(T02对比T04)仅为一只动物。
实施例6：基于A/马/Ohio/1/2003 H3N8的温度敏感性减毒活马流感病毒
突变区段1或PB2：
1.区段1(PB2)的突变核苷酸序列：粗体表示导致PB2蛋白中的N265S氨基酸变化的核苷酸变化。斜体是在修饰的PB2区段中引入的ClaI限制性位点。
2.突变EIV PB2蛋白的氨基酸序列：粗体表示氨基酸变化N265S。
突变区段2或PB1：
1.区段2(PB1)的突变核苷酸序列：粗体表示导致PB2蛋白中的K391E、E581G和A661T氨基酸变化的核苷酸变化。AatI限制性位点(aggcct；以斜体表示)和Hind III限制性位点(aagctt；以斜体表示)被引入修饰的PB1区段中。以粗斜体表示的是从原始PB1序列突变以去除BamHI限制性位点的核苷酸。
2.突变EIV PB1蛋白的氨基酸序列：粗体表示氨基酸变化K391E、E581G和A661T。
野生型区段1或PB2：
1.野生型A/马/Ohio/1/2003 H3N8区段1(PB2)的核苷酸序列。粗体核苷酸是指经过突变以达到修饰的区段1的野生型残基：
2.野生型A/马/Ohio/1/2003 H3N8 PB2蛋白的氨基酸序列。粗体氨基酸是指经过突变以达到突变PB2的野生型残基：
野生型区段2或PB1：
1.野生型A/马/Ohio/1/2003 H3N8区段2(PB1)的核苷酸序列。粗体核苷酸是指经过突变以达到修饰的区段2的野生型残基：
2.野生型A/马/Ohio/1/2003 H3N8 PB1蛋白的氨基酸序列。粗体氨基酸是指经过突变以达到突变PB1的野生型残基：
区段3或PA：
1.A/马/Ohio/1/2003 H3N8区段3(PA)的核苷酸序列：
2.A/马/Ohio/1/2003 H3N8 PA蛋白的氨基酸序列：
区段4或HA：
1.A/马/Ohio/1/2003 H3N8区段4(HA)的核苷酸序列：
2.A/马/Ohio/1/2003 H3N8 HA蛋白的氨基酸序列：
区段5或NP：
1.A/马/Ohio/1/2003 H3N8区段5(NP)的核苷酸序列：
2.A/马/Ohio/1/2003 H3N8 NP蛋白的氨基酸序列：
区段6或NA：
1.A/马/Ohio/1/2003 H3N8区段6(NA)的核苷酸序列：
2.A/马/Ohio/1/2003 H3N8 NA蛋白的氨基酸序列：
区段7或M：
1.A/马/Ohio/1/2003 H3N8区段7(M)的核苷酸序列：
2.A/马/Ohio/1/2003 H3N8 M1蛋白的氨基酸序列：
3.A/马/Ohio/1/2003 H3N8 M2蛋白的氨基酸序列：
区段8或NS：
1.A/马/Ohio/1/2003 H3N8区段8(NS)的核苷酸序列：
2.A/马/Ohio/1/2003 H3N8 M1蛋白的氨基酸序列：
3.A/马/Ohio/1/2003 H3N8 M2蛋白的氨基酸序列：
实施例7：A/马/Richmond/1/2007 H3N8区段4(HA)和区段6(NA)序列
A/马/Richmond/1/2007 H3N8区段4(HA)的核苷酸序列
A/马/Richmond/1/2007 H3N8的HA蛋白的氨基酸序列
A/马/Richmond/1/2007 H3N8的区段6(NA)的核苷酸序列
A/马/Richmond/1/2007 H3N8的NA蛋白的氨基酸序列
实施例8.甲型流感/马/Texas/6/2017 H3N8的区段4(HA)和区段6(NA)序列
甲型流感/马/Texas/6/2017的区段4(HA)的核苷酸序列
甲型流感/马/Texas/6/2017的HA蛋白的氨基酸序列
甲型流感/马/Texas/6/2017的区段6(NA)的核苷酸序列
甲型流感/马/Texas/6/2017的NA蛋白的氨基酸序列
实施例9.A/马/Lancashire/1/2016 H3N8的区段4(HA)和区段6(NA)序列
A/马/Lancashire/1/2016的区段4(HA)的核苷酸序列
A/马/Lancashire/1/2016的HA蛋白的氨基酸序列
A/马/Lancashire/1/2016的区段6(NA)的核苷酸序列
A/马/Lancashire/1/2016的NA蛋白的氨基酸序列
本文引用的每一个专利、专利申请和出版物的公开内容在此通过引用整体并入本文。虽然已参考特定实施方案公开了本发明，但很明显，在不脱离本发明的真实精神和范围的情况下，本领域的其他技术人员可以设计出本发明的其他实施方案和变型。所附权利要求书旨在被解释为包括所有此类实施方案和等同变化。
序列表
<110> 罗切斯特大学(University of Rochester)
肯塔基大学研究基金会(University of Kentucky Research Foundation)
硕腾服务有限责任公司(Zoetis Services LLC)
马丁内斯-桑普力多(Martinez-Sobrido), 路易斯·钱伯斯(Luis
Chambers), 托马斯·金(Thomas
King), Kendall W(肯德尔肯·W)
<120> 用于预防和控制马的马流感病毒(EIV)的多价减毒活流感疫苗
<130> 204606-0115-00WO
<150> US 62/811,112
<151> 2019-02-27
<160> 34
<170> PatentIn version 3.5
<210> 1
<211> 2341
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 化学合成的 - 基于A/马/Ohio/1/2003 H3N8 EIV的突变区段1
<400> 1
agcgaaagca ggtcaaatat attcaatatg gagagaataa aagaactgag agatctgatg 60
ttacaatccc gcacccgcga gatactaaca aaaactactg tggaccacat ggccataatc 120
aagaaataca catcaggaag acaagagaag aaccctgcac ttaggatgaa atggatgatg 180
gcaatgaaat acccaatcac ggcagataag aggataatgg agatgattcc tgagagaaat 240
gaacagggac aaaccctttg gagcaaaacg aacgatgctg gctcagaccg cgtaatggta 300
tcacctctgg cagtgacatg gtggaatagg aatggaccaa caacaagcac aattcattat 360
ccaaaagtct acaaaactta ttttgaaaag gttgaaagat tgaaacacgg aacctttggc 420
cccgttcatt ttaggaatca agtcaagata agacgaagag ttgatgtaaa ccctggtcac 480
gcggacctca gtgccaaaga agcacaagat gtgatcatgg aagttgtttt cccaaatgaa 540
gtgggagcca gaattctaac atcggaatca caactaacaa taaccaaaga gaaaaaggaa 600
gaacttcagg actgcaaaat tgctcccttg atggtagcat acatgctaga aagagagttg 660
gtccgaaaaa caaggttcct cccagtagca ggcggaacaa gcagtgtata cattgaagtg 720
ttgcatctga ctcagggaac atgctgggag caaatgtaca ccccaggagg agaagttaga 780
aacgatgata ttgatcaaag tttaattatt gcagcacgat cgatagtgag aagagcaaca 840
gtatcagcag atccactagc atccctactg gaaatgtgcc acagtacaca gattggtgga 900
ataaggatgg tagacatcct taagcagaat ccaacagagg aacaagctgt ggatatatgc 960
aaagcagcaa tgggattgag aattagctca tcattcagct ttggtggatt caccttcaaa 1020
agaacaagtg gatcatcagt caagagagaa gaagaaatgc ttacgggcaa ccttcaaaca 1080
ttgaaaataa gaatgcatga gggctatgaa gaattcacaa tggtcggaag aagagcaaca 1140
gctattctca gaaaggcaac cagaagattg attcaattga tagtaagtgg gagagatgaa 1200
caatcaattg ctgaagcaat aattgtagcc atggtgtttt cgcaagaaga ttgcatgata 1260
aaagcagttc gaggcgattt gaactttgtt aatagagcaa atcagcgttt gaaccccatg 1320
catcaactct tgaggcattt ccaaaaagat gcaaaagtgc ttttccaaaa ttggggaatt 1380
gaacccatcg acaatgtaat ggggatgatt ggaatattgc ctgacatgac cccaagcacc 1440
gagatgtcat tgagaggagt gagagtcagc aaaatgggag tggatgagta ctccagcact 1500
gagagagtgg tggtgagcat tgaccgtttt ttaagagttc gggatcaaag gggaaacata 1560
ctactgtccc ctgaagaagt cagtgaaaca caaggaacgg aaaagctgac aataatttat 1620
tcgtcatcaa tgatgtggga gattaatggt cccgaatcag tgttggtcaa tacttatcaa 1680
tggatcatca ggaactggga aattgtaaaa attcagtggt cacaggaccc cacaatgtta 1740
tacaataaga tagaatttga gccattccaa tccctggtcc ctagggccac cagaagccaa 1800
tacagcggtt tcgtaagaac cctgtttcag caaatgcgag atgtacttgg aacatttgat 1860
actgctcaaa taataaaact cctccctttt gccgctgctc ctccggaaca gagtaggatg 1920
cagttctctt ctttgactgt taatgtaaga ggttcgggaa tgaggatact tgtaagaggc 1980
aattccccag tgttcaacta caataaagcc actaaaaggc tcacagtcct cggaaaggat 2040
gcaggtgcgc ttactgagga cccagatgaa ggtacggctg gagtagaatc tgctgttcta 2100
agagggtttc tcattttagg taaagaaaac aagagatatg gcccagcact aagcatcaat 2160
gaactaagca aacttgcaaa aggggagaaa gccaatgtac taattgggca aggggacgta 2220
gtgttggtaa tgaaacggaa acgtgactct agcatactta ctgacagcca gacagcgacc 2280
aaaaggattc ggatggccat caattagtgt tgaattgttt aaaaacgacc ttgtttctac 2340
t 2341
<210> 2
<211> 759
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化学合成的 - 基于A/马/Ohio/1/2003 H3N8 EIV的突变PB2
<400> 2
Met Glu Arg Ile Lys Glu Leu Arg Asp Leu Met Leu Gln Ser Arg Thr
1 5 10 15
Arg Glu Ile Leu Thr Lys Thr Thr Val Asp His Met Ala Ile Ile Lys
20 25 30
Lys Tyr Thr Ser Gly Arg Gln Glu Lys Asn Pro Ala Leu Arg Met Lys
35 40 45
Trp Met Met Ala Met Lys Tyr Pro Ile Thr Ala Asp Lys Arg Ile Met
50 55 60
Glu Met Ile Pro Glu Arg Asn Glu Gln Gly Gln Thr Leu Trp Ser Lys
65 70 75 80
Thr Asn Asp Ala Gly Ser Asp Arg Val Met Val Ser Pro Leu Ala Val
85 90 95
Thr Trp Trp Asn Arg Asn Gly Pro Thr Thr Ser Thr Ile His Tyr Pro
100 105 110
Lys Val Tyr Lys Thr Tyr Phe Glu Lys Val Glu Arg Leu Lys His Gly
115 120 125
Thr Phe Gly Pro Val His Phe Arg Asn Gln Val Lys Ile Arg Arg Arg
130 135 140
Val Asp Val Asn Pro Gly His Ala Asp Leu Ser Ala Lys Glu Ala Gln
145 150 155 160
Asp Val Ile Met Glu Val Val Phe Pro Asn Glu Val Gly Ala Arg Ile
165 170 175
Leu Thr Ser Glu Ser Gln Leu Thr Ile Thr Lys Glu Lys Lys Glu Glu
180 185 190
Leu Gln Asp Cys Lys Ile Ala Pro Leu Met Val Ala Tyr Met Leu Glu
195 200 205
Arg Glu Leu Val Arg Lys Thr Arg Phe Leu Pro Val Ala Gly Gly Thr
210 215 220
Ser Ser Val Tyr Ile Glu Val Leu His Leu Thr Gln Gly Thr Cys Trp
225 230 235 240
Glu Gln Met Tyr Thr Pro Gly Gly Glu Val Arg Asn Asp Asp Ile Asp
245 250 255
Gln Ser Leu Ile Ile Ala Ala Arg Ser Ile Val Arg Arg Ala Thr Val
260 265 270
Ser Ala Asp Pro Leu Ala Ser Leu Leu Glu Met Cys His Ser Thr Gln
275 280 285
Ile Gly Gly Ile Arg Met Val Asp Ile Leu Lys Gln Asn Pro Thr Glu
290 295 300
Glu Gln Ala Val Asp Ile Cys Lys Ala Ala Met Gly Leu Arg Ile Ser
305 310 315 320
Ser Ser Phe Ser Phe Gly Gly Phe Thr Phe Lys Arg Thr Ser Gly Ser
325 330 335
Ser Val Lys Arg Glu Glu Glu Met Leu Thr Gly Asn Leu Gln Thr Leu
340 345 350
Lys Ile Arg Met His Glu Gly Tyr Glu Glu Phe Thr Met Val Gly Arg
355 360 365
Arg Ala Thr Ala Ile Leu Arg Lys Ala Thr Arg Arg Leu Ile Gln Leu
370 375 380
Ile Val Ser Gly Arg Asp Glu Gln Ser Ile Ala Glu Ala Ile Ile Val
385 390 395 400
Ala Met Val Phe Ser Gln Glu Asp Cys Met Ile Lys Ala Val Arg Gly
405 410 415
Asp Leu Asn Phe Val Asn Arg Ala Asn Gln Arg Leu Asn Pro Met His
420 425 430
Gln Leu Leu Arg His Phe Gln Lys Asp Ala Lys Val Leu Phe Gln Asn
435 440 445
Trp Gly Ile Glu Pro Ile Asp Asn Val Met Gly Met Ile Gly Ile Leu
450 455 460
Pro Asp Met Thr Pro Ser Thr Glu Met Ser Leu Arg Gly Val Arg Val
465 470 475 480
Ser Lys Met Gly Val Asp Glu Tyr Ser Ser Thr Glu Arg Val Val Val
485 490 495
Ser Ile Asp Arg Phe Leu Arg Val Arg Asp Gln Arg Gly Asn Ile Leu
500 505 510
Leu Ser Pro Glu Glu Val Ser Glu Thr Gln Gly Thr Glu Lys Leu Thr
515 520 525
Ile Ile Tyr Ser Ser Ser Met Met Trp Glu Ile Asn Gly Pro Glu Ser
530 535 540
Val Leu Val Asn Thr Tyr Gln Trp Ile Ile Arg Asn Trp Glu Ile Val
545 550 555 560
Lys Ile Gln Trp Ser Gln Asp Pro Thr Met Leu Tyr Asn Lys Ile Glu
565 570 575
Phe Glu Pro Phe Gln Ser Leu Val Pro Arg Ala Thr Arg Ser Gln Tyr
580 585 590
Ser Gly Phe Val Arg Thr Leu Phe Gln Gln Met Arg Asp Val Leu Gly
595 600 605
Thr Phe Asp Thr Ala Gln Ile Ile Lys Leu Leu Pro Phe Ala Ala Ala
610 615 620
Pro Pro Glu Gln Ser Arg Met Gln Phe Ser Ser Leu Thr Val Asn Val
625 630 635 640
Arg Gly Ser Gly Met Arg Ile Leu Val Arg Gly Asn Ser Pro Val Phe
645 650 655
Asn Tyr Asn Lys Ala Thr Lys Arg Leu Thr Val Leu Gly Lys Asp Ala
660 665 670
Gly Ala Leu Thr Glu Asp Pro Asp Glu Gly Thr Ala Gly Val Glu Ser
675 680 685
Ala Val Leu Arg Gly Phe Leu Ile Leu Gly Lys Glu Asn Lys Arg Tyr
690 695 700
Gly Pro Ala Leu Ser Ile Asn Glu Leu Ser Lys Leu Ala Lys Gly Glu
705 710 715 720
Lys Ala Asn Val Leu Ile Gly Gln Gly Asp Val Val Leu Val Met Lys
725 730 735
Arg Lys Arg Asp Ser Ser Ile Leu Thr Asp Ser Gln Thr Ala Thr Lys
740 745 750
Arg Ile Arg Met Ala Ile Asn
755
<210> 3
<211> 2341
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 化学合成的 - 基于A/马/Ohio/1/2003 H3N8 EIV的突变区段2
<400> 3
agcgaaagca ggcaaaccat ttgaatggat gtcaatccga ctctactttt cttaaaggtg 60
ccagcgcaaa atgctataag cacaacattc ccttatactg gagatcctcc ctacagtcat 120
ggaacaggga caggatacac catggatact gtcaacagaa cacaccaata ttcagaaaaa 180
gggaaatgga caacaaacac tgagattgga gcaccacaac ttaatccaat cgatggacca 240
cttcctgaag acaatgaacc aagtgggtac gcccaaacag attgtgtatt ggaagcaatg 300
gctttccttg aagaatccca tcccggaatc tttgaaaatt cgtgtcttga aacgatggag 360
gtgattcagc agacaagagt ggacaaacta acacaaggcc gacaaactta tgattggacc 420
ttgaatagga atcaacctgc cgcaacagca cttgctaata cgattgaagt attcagatca 480
aatggtctga cttccaatga atcggggaga ttgatggact tcctcaaaga tgtcatggag 540
tccatgaaca aggaagaaat ggaaataaca acacacttcc aacggaagag aagagtaaga 600
gacaacatga caaagagaat ggtaacacag agaaccatag ggaagaagaa acaacgatta 660
aacagaaaga gctatctaat cagaacatta accctaaaca caatgaccaa ggacgctgag 720
agagggaaat tgaaacgacg agcaatcgct accccaggga tgcagataag agggtttgta 780
tattttgttg aaacactagc ccgaagaata tgtgaaaagc ttgaacaatc aggattgcca 840
gttggcggta atgagaaaaa ggccaaactg gctaatgtcg tcagaaaaat gatgactaat 900
tcccaagaca ctgaactctc cttcaccatc actggggaca ataccaaatg gaatgaaaat 960
cagaacccac gcatattcct ggcaatgatc acatacataa ctagaaacca gccagaatgg 1020
ttcagaaatg ttctaagcat tgcaccgatt atgttctcaa ataaaatggc aagactgggg 1080
aaaggatata tgtttgaaag caaaagtatg aaattgagaa ctcaaatacc agcagaaatg 1140
ctagcaagca ttgacctgaa atatttcaat gattcaacaa aaaagaaaat tgaagaaata 1200
aggcctcttc tggttgacgg gactgcttca ctgagtcctg gcatgatgat gggaatgttc 1260
aacatgttga gcactgtgct gggtgtatcc atattaaacc tgggccagag gaaatacaca 1320
aagaccacat actggtggga tggtctgcaa tcatccgatg actttgcttt gatagtgaat 1380
gcgcctaatc atgaaggaat acaagctgga gtagacagat tctatagaac ttgcaaactg 1440
gtcgggatca acatgagcaa aaagaagtcc tacataaata gaactggaac attcgaattc 1500
acaagctttt tctaccggta tggttttgta gccaatttca gcatggaact acccagtttt 1560
ggggtttccg gaataaatga atctgcagac atgagcattg gagtgacagt catcaaaaac 1620
aacatgataa ataatgatct cggtcctgcc acggcacaaa tggcactcca actcttcatt 1680
aaggattatc ggtacacata ccggtgccat agaggtgata cccagataca aaccagaaga 1740
tcttttgagt tgaagaagct ttgggggcag actcgatcaa agactggtct actggtatca 1800
gatgggggtc caaacctata taacatcaga aacctacaca tcccggaagt ctgtttaaaa 1860
tgggagctaa tggatgaaga ttataagggg aggctatgca atccattgaa tcctttcgtt 1920
agtcacaaag aaattgaatc agtcaacagt gcagtagtaa tgtctgcgca tggccctgcc 1980
aaaagcatgg agtatgatgc tgttactaca acacattctt ggatacccaa gaggaaccgg 2040
tccatattga acacaagcca aaggggaata ctcgaagatg agcagatgta tcagaaatgc 2100
tgcaacctgt ttgaaaaatt cttccccagc agctcataca gaagaccagt cggaatttct 2160
agtatggttg aggccatggt gtccagggcc cgcattgatg cacgaattga cttcgaatct 2220
ggacggataa agaaggatga gttcgctgag atcatgaaga tctgttccac cattgaagag 2280
ctcagacggc aaaaatagtg aatttagctt gatcttcatg aaaaaatgcc ttgtttctac 2340
t 2341
<210> 4
<211> 757
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化学合成的 - 基于A/马/Ohio/1/2003 H3N8 EIV的突变PB1
<400> 4
Met Asp Val Asn Pro Thr Leu Leu Phe Leu Lys Val Pro Ala Gln Asn
1 5 10 15
Ala Ile Ser Thr Thr Phe Pro Tyr Thr Gly Asp Pro Pro Tyr Ser His
20 25 30
Gly Thr Gly Thr Gly Tyr Thr Met Asp Thr Val Asn Arg Thr His Gln
35 40 45
Tyr Ser Glu Lys Gly Lys Trp Thr Thr Asn Thr Glu Ile Gly Ala Pro
50 55 60
Gln Leu Asn Pro Ile Asp Gly Pro Leu Pro Glu Asp Asn Glu Pro Ser
65 70 75 80
Gly Tyr Ala Gln Thr Asp Cys Val Leu Glu Ala Met Ala Phe Leu Glu
85 90 95
Glu Ser His Pro Gly Ile Phe Glu Asn Ser Cys Leu Glu Thr Met Glu
100 105 110
Val Ile Gln Gln Thr Arg Val Asp Lys Leu Thr Gln Gly Arg Gln Thr
115 120 125
Tyr Asp Trp Thr Leu Asn Arg Asn Gln Pro Ala Ala Thr Ala Leu Ala
130 135 140
Asn Thr Ile Glu Val Phe Arg Ser Asn Gly Leu Thr Ser Asn Glu Ser
145 150 155 160
Gly Arg Leu Met Asp Phe Leu Lys Asp Val Met Glu Ser Met Asn Lys
165 170 175
Glu Glu Met Glu Ile Thr Thr His Phe Gln Arg Lys Arg Arg Val Arg
180 185 190
Asp Asn Met Thr Lys Arg Met Val Thr Gln Arg Thr Ile Gly Lys Lys
195 200 205
Lys Gln Arg Leu Asn Arg Lys Ser Tyr Leu Ile Arg Thr Leu Thr Leu
210 215 220
Asn Thr Met Thr Lys Asp Ala Glu Arg Gly Lys Leu Lys Arg Arg Ala
225 230 235 240
Ile Ala Thr Pro Gly Met Gln Ile Arg Gly Phe Val Tyr Phe Val Glu
245 250 255
Thr Leu Ala Arg Arg Ile Cys Glu Lys Leu Glu Gln Ser Gly Leu Pro
260 265 270
Val Gly Gly Asn Glu Lys Lys Ala Lys Leu Ala Asn Val Val Arg Lys
275 280 285
Met Met Thr Asn Ser Gln Asp Thr Glu Leu Ser Phe Thr Ile Thr Gly
290 295 300
Asp Asn Thr Lys Trp Asn Glu Asn Gln Asn Pro Arg Ile Phe Leu Ala
305 310 315 320
Met Ile Thr Tyr Ile Thr Arg Asn Gln Pro Glu Trp Phe Arg Asn Val
325 330 335
Leu Ser Ile Ala Pro Ile Met Phe Ser Asn Lys Met Ala Arg Leu Gly
340 345 350
Lys Gly Tyr Met Phe Glu Ser Lys Ser Met Lys Leu Arg Thr Gln Ile
355 360 365
Pro Ala Glu Met Leu Ala Ser Ile Asp Leu Lys Tyr Phe Asn Asp Ser
370 375 380
Thr Lys Lys Lys Ile Glu Glu Ile Arg Pro Leu Leu Val Asp Gly Thr
385 390 395 400
Ala Ser Leu Ser Pro Gly Met Met Met Gly Met Phe Asn Met Leu Ser
405 410 415
Thr Val Leu Gly Val Ser Ile Leu Asn Leu Gly Gln Arg Lys Tyr Thr
420 425 430
Lys Thr Thr Tyr Trp Trp Asp Gly Leu Gln Ser Ser Asp Asp Phe Ala
435 440 445
Leu Ile Val Asn Ala Pro Asn His Glu Gly Ile Gln Ala Gly Val Asp
450 455 460
Arg Phe Tyr Arg Thr Cys Lys Leu Val Gly Ile Asn Met Ser Lys Lys
465 470 475 480
Lys Ser Tyr Ile Asn Arg Thr Gly Thr Phe Glu Phe Thr Ser Phe Phe
485 490 495
Tyr Arg Tyr Gly Phe Val Ala Asn Phe Ser Met Glu Leu Pro Ser Phe
500 505 510
Gly Val Ser Gly Ile Asn Glu Ser Ala Asp Met Ser Ile Gly Val Thr
515 520 525
Val Ile Lys Asn Asn Met Ile Asn Asn Asp Leu Gly Pro Ala Thr Ala
530 535 540
Gln Met Ala Leu Gln Leu Phe Ile Lys Asp Tyr Arg Tyr Thr Tyr Arg
545 550 555 560
Cys His Arg Gly Asp Thr Gln Ile Gln Thr Arg Arg Ser Phe Glu Leu
565 570 575
Lys Lys Leu Trp Gly Gln Thr Arg Ser Lys Thr Gly Leu Leu Val Ser
580 585 590
Asp Gly Gly Pro Asn Leu Tyr Asn Ile Arg Asn Leu His Ile Pro Glu
595 600 605
Val Cys Leu Lys Trp Glu Leu Met Asp Glu Asp Tyr Lys Gly Arg Leu
610 615 620
Cys Asn Pro Leu Asn Pro Phe Val Ser His Lys Glu Ile Glu Ser Val
625 630 635 640
Asn Ser Ala Val Val Met Ser Ala His Gly Pro Ala Lys Ser Met Glu
645 650 655
Tyr Asp Ala Val Thr Thr Thr His Ser Trp Ile Pro Lys Arg Asn Arg
660 665 670
Ser Ile Leu Asn Thr Ser Gln Arg Gly Ile Leu Glu Asp Glu Gln Met
675 680 685
Tyr Gln Lys Cys Cys Asn Leu Phe Glu Lys Phe Phe Pro Ser Ser Ser
690 695 700
Tyr Arg Arg Pro Val Gly Ile Ser Ser Met Val Glu Ala Met Val Ser
705 710 715 720
Arg Ala Arg Ile Asp Ala Arg Ile Asp Phe Glu Ser Gly Arg Ile Lys
725 730 735
Lys Asp Glu Phe Ala Glu Ile Met Lys Ile Cys Ser Thr Ile Glu Glu
740 745 750
Leu Arg Arg Gln Lys
755
<210> 5
<211> 2341
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 5
agcgaaagca ggtcaaatat attcaatatg gagagaataa aagaactgag agatctgatg 60
ttacaatccc gcacccgcga gatactaaca aaaactactg tggaccacat ggccataatc 120
aagaaataca catcaggaag acaagagaag aaccctgcac ttaggatgaa atggatgatg 180
gcaatgaaat acccaatcac ggcagataag aggataatgg agatgattcc tgagagaaat 240
gaacagggac aaaccctttg gagcaaaacg aacgatgctg gctcagaccg cgtaatggta 300
tcacctctgg cagtgacatg gtggaatagg aatggaccaa caacaagcac aattcattat 360
ccaaaagtct acaaaactta ttttgaaaag gttgaaagat tgaaacacgg aacctttggc 420
cccgttcatt ttaggaatca agtcaagata agacgaagag ttgatgtaaa ccctggtcac 480
gcggacctca gtgccaaaga agcacaagat gtgatcatgg aagttgtttt cccaaatgaa 540
gtgggagcca gaattctaac atcggaatca caactaacaa taaccaaaga gaaaaaggaa 600
gaacttcagg actgcaaaat tgctcccttg atggtagcat acatgctaga aagagagttg 660
gtccgaaaaa caaggttcct cccagtagca ggcggaacaa gcagtgtata cattgaagtg 720
ttgcatctga ctcagggaac atgctgggag caaatgtaca ccccaggagg agaagttaga 780
aacgatgata ttgatcaaag tttaattatt gcagcacgga acatagtgag aagagcaaca 840
gtatcagcag atccactagc atccctactg gaaatgtgcc acagtacaca gattggtgga 900
ataaggatgg tagacatcct taagcagaat ccaacagagg aacaagctgt ggatatatgc 960
aaagcagcaa tgggattgag aattagctca tcattcagct ttggtggatt caccttcaaa 1020
agaacaagtg gatcatcagt caagagagaa gaagaaatgc ttacgggcaa ccttcaaaca 1080
ttgaaaataa gaatgcatga gggctatgaa gaattcacaa tggtcggaag aagagcaaca 1140
gctattctca gaaaggcaac cagaagattg attcaattga tagtaagtgg gagagatgaa 1200
caatcaattg ctgaagcaat aattgtagcc atggtgtttt cgcaagaaga ttgcatgata 1260
aaagcagttc gaggcgattt gaactttgtt aatagagcaa atcagcgttt gaaccccatg 1320
catcaactct tgaggcattt ccaaaaagat gcaaaagtgc ttttccaaaa ttggggaatt 1380
gaacccatcg acaatgtaat ggggatgatt ggaatattgc ctgacatgac cccaagcacc 1440
gagatgtcat tgagaggagt gagagtcagc aaaatgggag tggatgagta ctccagcact 1500
gagagagtgg tggtgagcat tgaccgtttt ttaagagttc gggatcaaag gggaaacata 1560
ctactgtccc ctgaagaagt cagtgaaaca caaggaacgg aaaagctgac aataatttat 1620
tcgtcatcaa tgatgtggga gattaatggt cccgaatcag tgttggtcaa tacttatcaa 1680
tggatcatca ggaactggga aattgtaaaa attcagtggt cacaggaccc cacaatgtta 1740
tacaataaga tagaatttga gccattccaa tccctggtcc ctagggccac cagaagccaa 1800
tacagcggtt tcgtaagaac cctgtttcag caaatgcgag atgtacttgg aacatttgat 1860
actgctcaaa taataaaact cctccctttt gccgctgctc ctccggaaca gagtaggatg 1920
cagttctctt ctttgactgt taatgtaaga ggttcgggaa tgaggatact tgtaagaggc 1980
aattccccag tgttcaacta caataaagcc actaaaaggc tcacagtcct cggaaaggat 2040
gcaggtgcgc ttactgagga cccagatgaa ggtacggctg gagtagaatc tgctgttcta 2100
agagggtttc tcattttagg taaagaaaac aagagatatg gcccagcact aagcatcaat 2160
gaactaagca aacttgcaaa aggggagaaa gccaatgtac taattgggca aggggacgta 2220
gtgttggtaa tgaaacggaa acgtgactct agcatactta ctgacagcca gacagcgacc 2280
aaaaggattc ggatggccat caattagtgt tgaattgttt aaaaacgacc ttgtttctac 2340
t 2341
<210> 6
<211> 759
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 6
Met Glu Arg Ile Lys Glu Leu Arg Asp Leu Met Leu Gln Ser Arg Thr
1 5 10 15
Arg Glu Ile Leu Thr Lys Thr Thr Val Asp His Met Ala Ile Ile Lys
20 25 30
Lys Tyr Thr Ser Gly Arg Gln Glu Lys Asn Pro Ala Leu Arg Met Lys
35 40 45
Trp Met Met Ala Met Lys Tyr Pro Ile Thr Ala Asp Lys Arg Ile Met
50 55 60
Glu Met Ile Pro Glu Arg Asn Glu Gln Gly Gln Thr Leu Trp Ser Lys
65 70 75 80
Thr Asn Asp Ala Gly Ser Asp Arg Val Met Val Ser Pro Leu Ala Val
85 90 95
Thr Trp Trp Asn Arg Asn Gly Pro Thr Thr Ser Thr Ile His Tyr Pro
100 105 110
Lys Val Tyr Lys Thr Tyr Phe Glu Lys Val Glu Arg Leu Lys His Gly
115 120 125
Thr Phe Gly Pro Val His Phe Arg Asn Gln Val Lys Ile Arg Arg Arg
130 135 140
Val Asp Val Asn Pro Gly His Ala Asp Leu Ser Ala Lys Glu Ala Gln
145 150 155 160
Asp Val Ile Met Glu Val Val Phe Pro Asn Glu Val Gly Ala Arg Ile
165 170 175
Leu Thr Ser Glu Ser Gln Leu Thr Ile Thr Lys Glu Lys Lys Glu Glu
180 185 190
Leu Gln Asp Cys Lys Ile Ala Pro Leu Met Val Ala Tyr Met Leu Glu
195 200 205
Arg Glu Leu Val Arg Lys Thr Arg Phe Leu Pro Val Ala Gly Gly Thr
210 215 220
Ser Ser Val Tyr Ile Glu Val Leu His Leu Thr Gln Gly Thr Cys Trp
225 230 235 240
Glu Gln Met Tyr Thr Pro Gly Gly Glu Val Arg Asn Asp Asp Ile Asp
245 250 255
Gln Ser Leu Ile Ile Ala Ala Arg Asn Ile Val Arg Arg Ala Thr Val
260 265 270
Ser Ala Asp Pro Leu Ala Ser Leu Leu Glu Met Cys His Ser Thr Gln
275 280 285
Ile Gly Gly Ile Arg Met Val Asp Ile Leu Lys Gln Asn Pro Thr Glu
290 295 300
Glu Gln Ala Val Asp Ile Cys Lys Ala Ala Met Gly Leu Arg Ile Ser
305 310 315 320
Ser Ser Phe Ser Phe Gly Gly Phe Thr Phe Lys Arg Thr Ser Gly Ser
325 330 335
Ser Val Lys Arg Glu Glu Glu Met Leu Thr Gly Asn Leu Gln Thr Leu
340 345 350
Lys Ile Arg Met His Glu Gly Tyr Glu Glu Phe Thr Met Val Gly Arg
355 360 365
Arg Ala Thr Ala Ile Leu Arg Lys Ala Thr Arg Arg Leu Ile Gln Leu
370 375 380
Ile Val Ser Gly Arg Asp Glu Gln Ser Ile Ala Glu Ala Ile Ile Val
385 390 395 400
Ala Met Val Phe Ser Gln Glu Asp Cys Met Ile Lys Ala Val Arg Gly
405 410 415
Asp Leu Asn Phe Val Asn Arg Ala Asn Gln Arg Leu Asn Pro Met His
420 425 430
Gln Leu Leu Arg His Phe Gln Lys Asp Ala Lys Val Leu Phe Gln Asn
435 440 445
Trp Gly Ile Glu Pro Ile Asp Asn Val Met Gly Met Ile Gly Ile Leu
450 455 460
Pro Asp Met Thr Pro Ser Thr Glu Met Ser Leu Arg Gly Val Arg Val
465 470 475 480
Ser Lys Met Gly Val Asp Glu Tyr Ser Ser Thr Glu Arg Val Val Val
485 490 495
Ser Ile Asp Arg Phe Leu Arg Val Arg Asp Gln Arg Gly Asn Ile Leu
500 505 510
Leu Ser Pro Glu Glu Val Ser Glu Thr Gln Gly Thr Glu Lys Leu Thr
515 520 525
Ile Ile Tyr Ser Ser Ser Met Met Trp Glu Ile Asn Gly Pro Glu Ser
530 535 540
Val Leu Val Asn Thr Tyr Gln Trp Ile Ile Arg Asn Trp Glu Ile Val
545 550 555 560
Lys Ile Gln Trp Ser Gln Asp Pro Thr Met Leu Tyr Asn Lys Ile Glu
565 570 575
Phe Glu Pro Phe Gln Ser Leu Val Pro Arg Ala Thr Arg Ser Gln Tyr
580 585 590
Ser Gly Phe Val Arg Thr Leu Phe Gln Gln Met Arg Asp Val Leu Gly
595 600 605
Thr Phe Asp Thr Ala Gln Ile Ile Lys Leu Leu Pro Phe Ala Ala Ala
610 615 620
Pro Pro Glu Gln Ser Arg Met Gln Phe Ser Ser Leu Thr Val Asn Val
625 630 635 640
Arg Gly Ser Gly Met Arg Ile Leu Val Arg Gly Asn Ser Pro Val Phe
645 650 655
Asn Tyr Asn Lys Ala Thr Lys Arg Leu Thr Val Leu Gly Lys Asp Ala
660 665 670
Gly Ala Leu Thr Glu Asp Pro Asp Glu Gly Thr Ala Gly Val Glu Ser
675 680 685
Ala Val Leu Arg Gly Phe Leu Ile Leu Gly Lys Glu Asn Lys Arg Tyr
690 695 700
Gly Pro Ala Leu Ser Ile Asn Glu Leu Ser Lys Leu Ala Lys Gly Glu
705 710 715 720
Lys Ala Asn Val Leu Ile Gly Gln Gly Asp Val Val Leu Val Met Lys
725 730 735
Arg Lys Arg Asp Ser Ser Ile Leu Thr Asp Ser Gln Thr Ala Thr Lys
740 745 750
Arg Ile Arg Met Ala Ile Asn
755
<210> 7
<211> 2341
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 7
agcgaaagca ggcaaaccat ttgaatggat gtcaatccga ctctactttt cttaaaggtg 60
ccagcgcaaa atgctataag cacaacattc ccttatactg gagatcctcc ctacagtcat 120
ggaacaggga caggatacac catggatact gtcaacagaa cacaccaata ttcagaaaaa 180
gggaaatgga caacaaacac tgagattgga gcaccacaac ttaatccaat cgatggacca 240
cttcctgaag acaatgaacc aagtgggtac gcccaaacag attgtgtatt ggaagcaatg 300
gctttccttg aagaatccca tcccggaatc tttgaaaatt cgtgtcttga aacgatggag 360
gtgattcagc agacaagagt ggacaaacta acacaaggcc gacaaactta tgattggacc 420
ttgaatagga atcaacctgc cgcaacagca cttgctaata cgattgaagt attcagatca 480
aatggtctga cttccaatga atcggggaga ttgatggact tcctcaaaga tgtcatggag 540
tccatgaaca aggaagaaat ggaaataaca acacacttcc aacggaagag aagagtaaga 600
gacaacatga caaagagaat ggtaacacag agaaccatag ggaagaagaa acaacgatta 660
aacagaaaga gctatctaat cagaacatta accctaaaca caatgaccaa ggacgctgag 720
agagggaaat tgaaacgacg agcaatcgct accccaggga tgcagataag agggtttgta 780
tattttgttg aaacactagc ccgaagaata tgtgaaaagc ttgaacaatc aggattgcca 840
gttggcggta atgagaaaaa ggccaaactg gctaatgtcg tcagaaaaat gatgactaat 900
tcccaagaca ctgaactctc cttcaccatc actggggaca ataccaaatg gaatgaaaat 960
cagaacccac gcatattcct ggcaatgatc acatacataa ctagaaacca gccagaatgg 1020
ttcagaaatg ttctaagcat tgcaccgatt atgttctcaa ataaaatggc aagactgggg 1080
aaaggatata tgtttgaaag caaaagtatg aaattgagaa ctcaaatacc agcagaaatg 1140
ctagcaagca ttgacctgaa atatttcaat gattcaacaa aaaagaaaat tgaaaagata 1200
cgaccacttc tggttgacgg gactgcttca ctgagtcctg gcatgatgat gggaatgttc 1260
aacatgttga gcactgtgct gggtgtatcc atattaaacc tgggccagag gaaatacaca 1320
aagaccacat actggtggga tggtctgcaa tcatccgatg actttgcttt gatagtgaat 1380
gcgcctaatc atgaaggaat acaagctgga gtagacagat tctatagaac ttgcaaactg 1440
gtcgggatca acatgagcaa aaagaagtcc tacataaata gaactggaac attcgaattc 1500
acaagctttt tctaccggta tggttttgta gccaatttca gcatggaact acccagtttt 1560
ggggtttccg gaataaatga atctgcagac atgagcattg gagtgacagt catcaaaaac 1620
aacatgataa ataatgatct cggtcctgcc acggcacaaa tggcactcca actcttcatt 1680
aaggattatc ggtacacata ccggtgccat agaggtgata cccagataca aaccagaaga 1740
tcttttgagt tgaagaaact gtgggaacag actcgatcaa agactggtct actggtatca 1800
gatgggggtc caaacctata taacatcaga aacctacaca tcccggaagt ctgtttaaaa 1860
tgggagctaa tggatgaaga ttataagggg aggctatgca atccattgaa tcctttcgtt 1920
agtcacaaag aaattgaatc agtcaacagt gcagtagtaa tgtctgcgca tggccctgcc 1980
aaaagcatgg agtatgatgc tgttgcaaca acacattctt ggatccccaa gaggaaccgg 2040
tccatattga acacaagcca aaggggaata ctcgaagatg agcagatgta tcagaaatgc 2100
tgcaacctgt ttgaaaaatt cttccccagc agctcataca gaagaccagt cggaatttct 2160
agtatggttg aggccatggt gtccagggcc cgcattgatg cacgaattga cttcgaatct 2220
ggacggataa agaaggatga gttcgctgag atcatgaaga tctgttccac cattgaagag 2280
ctcagacggc aaaaatagtg aatttagctt gatcttcatg aaaaaatgcc ttgtttctac 2340
t 2341
<210> 8
<211> 757
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 8
Met Asp Val Asn Pro Thr Leu Leu Phe Leu Lys Val Pro Ala Gln Asn
1 5 10 15
Ala Ile Ser Thr Thr Phe Pro Tyr Thr Gly Asp Pro Pro Tyr Ser His
20 25 30
Gly Thr Gly Thr Gly Tyr Thr Met Asp Thr Val Asn Arg Thr His Gln
35 40 45
Tyr Ser Glu Lys Gly Lys Trp Thr Thr Asn Thr Glu Ile Gly Ala Pro
50 55 60
Gln Leu Asn Pro Ile Asp Gly Pro Leu Pro Glu Asp Asn Glu Pro Ser
65 70 75 80
Gly Tyr Ala Gln Thr Asp Cys Val Leu Glu Ala Met Ala Phe Leu Glu
85 90 95
Glu Ser His Pro Gly Ile Phe Glu Asn Ser Cys Leu Glu Thr Met Glu
100 105 110
Val Ile Gln Gln Thr Arg Val Asp Lys Leu Thr Gln Gly Arg Gln Thr
115 120 125
Tyr Asp Trp Thr Leu Asn Arg Asn Gln Pro Ala Ala Thr Ala Leu Ala
130 135 140
Asn Thr Ile Glu Val Phe Arg Ser Asn Gly Leu Thr Ser Asn Glu Ser
145 150 155 160
Gly Arg Leu Met Asp Phe Leu Lys Asp Val Met Glu Ser Met Asn Lys
165 170 175
Glu Glu Met Glu Ile Thr Thr His Phe Gln Arg Lys Arg Arg Val Arg
180 185 190
Asp Asn Met Thr Lys Arg Met Val Thr Gln Arg Thr Ile Gly Lys Lys
195 200 205
Lys Gln Arg Leu Asn Arg Lys Ser Tyr Leu Ile Arg Thr Leu Thr Leu
210 215 220
Asn Thr Met Thr Lys Asp Ala Glu Arg Gly Lys Leu Lys Arg Arg Ala
225 230 235 240
Ile Ala Thr Pro Gly Met Gln Ile Arg Gly Phe Val Tyr Phe Val Glu
245 250 255
Thr Leu Ala Arg Arg Ile Cys Glu Lys Leu Glu Gln Ser Gly Leu Pro
260 265 270
Val Gly Gly Asn Glu Lys Lys Ala Lys Leu Ala Asn Val Val Arg Lys
275 280 285
Met Met Thr Asn Ser Gln Asp Thr Glu Leu Ser Phe Thr Ile Thr Gly
290 295 300
Asp Asn Thr Lys Trp Asn Glu Asn Gln Asn Pro Arg Ile Phe Leu Ala
305 310 315 320
Met Ile Thr Tyr Ile Thr Arg Asn Gln Pro Glu Trp Phe Arg Asn Val
325 330 335
Leu Ser Ile Ala Pro Ile Met Phe Ser Asn Lys Met Ala Arg Leu Gly
340 345 350
Lys Gly Tyr Met Phe Glu Ser Lys Ser Met Lys Leu Arg Thr Gln Ile
355 360 365
Pro Ala Glu Met Leu Ala Ser Ile Asp Leu Lys Tyr Phe Asn Asp Ser
370 375 380
Thr Lys Lys Lys Ile Glu Lys Ile Arg Pro Leu Leu Val Asp Gly Thr
385 390 395 400
Ala Ser Leu Ser Pro Gly Met Met Met Gly Met Phe Asn Met Leu Ser
405 410 415
Thr Val Leu Gly Val Ser Ile Leu Asn Leu Gly Gln Arg Lys Tyr Thr
420 425 430
Lys Thr Thr Tyr Trp Trp Asp Gly Leu Gln Ser Ser Asp Asp Phe Ala
435 440 445
Leu Ile Val Asn Ala Pro Asn His Glu Gly Ile Gln Ala Gly Val Asp
450 455 460
Arg Phe Tyr Arg Thr Cys Lys Leu Val Gly Ile Asn Met Ser Lys Lys
465 470 475 480
Lys Ser Tyr Ile Asn Arg Thr Gly Thr Phe Glu Phe Thr Ser Phe Phe
485 490 495
Tyr Arg Tyr Gly Phe Val Ala Asn Phe Ser Met Glu Leu Pro Ser Phe
500 505 510
Gly Val Ser Gly Ile Asn Glu Ser Ala Asp Met Ser Ile Gly Val Thr
515 520 525
Val Ile Lys Asn Asn Met Ile Asn Asn Asp Leu Gly Pro Ala Thr Ala
530 535 540
Gln Met Ala Leu Gln Leu Phe Ile Lys Asp Tyr Arg Tyr Thr Tyr Arg
545 550 555 560
Cys His Arg Gly Asp Thr Gln Ile Gln Thr Arg Arg Ser Phe Glu Leu
565 570 575
Lys Lys Leu Trp Glu Gln Thr Arg Ser Lys Thr Gly Leu Leu Val Ser
580 585 590
Asp Gly Gly Pro Asn Leu Tyr Asn Ile Arg Asn Leu His Ile Pro Glu
595 600 605
Val Cys Leu Lys Trp Glu Leu Met Asp Glu Asp Tyr Lys Gly Arg Leu
610 615 620
Cys Asn Pro Leu Asn Pro Phe Val Ser His Lys Glu Ile Glu Ser Val
625 630 635 640
Asn Ser Ala Val Val Met Ser Ala His Gly Pro Ala Lys Ser Met Glu
645 650 655
Tyr Asp Ala Val Ala Thr Thr His Ser Trp Ile Pro Lys Arg Asn Arg
660 665 670
Ser Ile Leu Asn Thr Ser Gln Arg Gly Ile Leu Glu Asp Glu Gln Met
675 680 685
Tyr Gln Lys Cys Cys Asn Leu Phe Glu Lys Phe Phe Pro Ser Ser Ser
690 695 700
Tyr Arg Arg Pro Val Gly Ile Ser Ser Met Val Glu Ala Met Val Ser
705 710 715 720
Arg Ala Arg Ile Asp Ala Arg Ile Asp Phe Glu Ser Gly Arg Ile Lys
725 730 735
Lys Asp Glu Phe Ala Glu Ile Met Lys Ile Cys Ser Thr Ile Glu Glu
740 745 750
Leu Arg Arg Gln Lys
755
<210> 9
<211> 2233
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 9
agcgaaagca ggtactgatc caaaatggaa gactttgtgc gacagtgctt caatccaatg 60
atcgtcgagc ttgcggaaaa ggcaatgaaa gaatatggag aggacccgaa aatcgaaaca 120
aacaaatttg cagcaatatg cactcacttg gaagtctgct tcatgtactc ggatttccac 180
tttattaatg aactgggtga gtcagtggtc atagagtctg gtgacccaaa tgctcttttg 240
aaacacagat ttgaaatcat tgaggggaga gatcgaacaa tggcatggac agtagtaaac 300
agcatctgca acaccacaag agctgaaaaa cctaaatttc ttccagattt atacgactat 360
aaggagaaca gatttgttga aattggtgtg acaaggagag aagttcacat atactacctg 420
gagaaggcca acaaaataaa gtctgagaaa acacatatcc acattttctc atttacagga 480
gaggaaatgg ctacaaaagc ggactatact cttgatgaag agagtagagc caggatcaag 540
accagactat tcactataag acaagaaatg gccagtagag gcctctggga ttcctttcgt 600
cagtccgaga gaggcgaaga gacaattgaa gaaagatttg aaatcacagg gacgatgcgc 660
aagcttgcca attacagtct cccaccgaac ttctccagcc ttgaaaattt tagagtctat 720
gtggatggat tcgaaccgaa cggcttcatt gagagtaagc tttctcaaat gtccaaagaa 780
gtaaatgcca gaatcgaacc attttcaaag acaacacccc gaccactcaa aatgccaggt 840
ggtccaccct gccatcagcg atctaaattc ttgctaatgg atgctctgaa actgagcatt 900
gaggacccaa gtcacgaggg agagggaata ccactatatg atgcaatcaa atgcatgaaa 960
actttctttg gatggaaaga gcccagtatt gttaaaccac atgaaaaggg tataaacccg 1020
aactatctcc aaacttggaa gcaagtatta gaagaaatac aagaccttga gaacgaagaa 1080
aggaccccca agaccaagaa tatgaaaaaa acaagccaat tgaaatgggc actaggtgaa 1140
aatatggcac cagagaaagt ggattttgag gattgtaaag acatcagtga tttaaaacag 1200
tatgacagtg atgagccaga aacaaggtct cttgcaagtt ggattcaaag tgagttcaac 1260
aaagcttgtg agctgacaga ttcaagctgg atagagctcg atgaaattgg ggaggatgtc 1320
gccccaatag aatacattgc gagcatgagg agaaattatt ttactgctga gatttcccat 1380
tgtagagcaa cagaatatat aatgaaagga gtgtacatca acactgctct actcaatgca 1440
tcctgtgctg cgatggatga atttcaatta attccgatga taagtaaatg caggaccaaa 1500
gaagggagaa ggaaaacaaa tttatatgga ttcataataa agggaagatc ccatttaaga 1560
aatgatactg acgtggtgaa ctttgtaagt atggaatttt ctctcactga tccaagattt 1620
gagccacaca aatgggaaaa atactgcgtt ctagaaattg gagacatgct tctaagaact 1680
gctgtaggtc aagtgtcaag acccatgttt ttgtatgtaa ggacaaatgg aacctctaaa 1740
attaaaatga aatggggaat ggaaatgagg cgctgcctcc ttcagtctct gcaacagatt 1800
gaaagcatga tcgaagctga gtcctcggtc aaagaaaagg acatgaccaa agaatttttt 1860
gagaacaaat cagagacatg gcctatagga gagtccccca aaggagtgga agagggctca 1920
atcgggaagg tttgcaggac cttattagca aaatctgtgt ttaacagttt gtatgcatct 1980
ccacaactgg aagggttttc agctgaatct aggaaattac ttctcattgt tcaggctctt 2040
agggataacc tggaacctgg aacatttgat attggggggt tatatgaatc aattgaggag 2100
tgcctgatta atgatccctg ggttttgctt aatgcatctt ggttcaactc cttccttaca 2160
catgcactga agtagttgtg gcaatgctac tatttgctat ccatactgtc caaaaaagta 2220
ccttgtttct act 2233
<210> 10
<211> 716
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 10
Met Glu Asp Phe Val Arg Gln Cys Phe Asn Pro Met Ile Val Glu Leu
1 5 10 15
Ala Glu Lys Ala Met Lys Glu Tyr Gly Glu Asp Pro Lys Ile Glu Thr
20 25 30
Asn Lys Phe Ala Ala Ile Cys Thr His Leu Glu Val Cys Phe Met Tyr
35 40 45
Ser Asp Phe His Phe Ile Asn Glu Leu Gly Glu Ser Val Val Ile Glu
50 55 60
Ser Gly Asp Pro Asn Ala Leu Leu Lys His Arg Phe Glu Ile Ile Glu
65 70 75 80
Gly Arg Asp Arg Thr Met Ala Trp Thr Val Val Asn Ser Ile Cys Asn
85 90 95
Thr Thr Arg Ala Glu Lys Pro Lys Phe Leu Pro Asp Leu Tyr Asp Tyr
100 105 110
Lys Glu Asn Arg Phe Val Glu Ile Gly Val Thr Arg Arg Glu Val His
115 120 125
Ile Tyr Tyr Leu Glu Lys Ala Asn Lys Ile Lys Ser Glu Lys Thr His
130 135 140
Ile His Ile Phe Ser Phe Thr Gly Glu Glu Met Ala Thr Lys Ala Asp
145 150 155 160
Tyr Thr Leu Asp Glu Glu Ser Arg Ala Arg Ile Lys Thr Arg Leu Phe
165 170 175
Thr Ile Arg Gln Glu Met Ala Ser Arg Gly Leu Trp Asp Ser Phe Arg
180 185 190
Gln Ser Glu Arg Gly Glu Glu Thr Ile Glu Glu Arg Phe Glu Ile Thr
195 200 205
Gly Thr Met Arg Lys Leu Ala Asn Tyr Ser Leu Pro Pro Asn Phe Ser
210 215 220
Ser Leu Glu Asn Phe Arg Val Tyr Val Asp Gly Phe Glu Pro Asn Gly
225 230 235 240
Phe Ile Glu Ser Lys Leu Ser Gln Met Ser Lys Glu Val Asn Ala Arg
245 250 255
Ile Glu Pro Phe Ser Lys Thr Thr Pro Arg Pro Leu Lys Met Pro Gly
260 265 270
Gly Pro Pro Cys His Gln Arg Ser Lys Phe Leu Leu Met Asp Ala Leu
275 280 285
Lys Leu Ser Ile Glu Asp Pro Ser His Glu Gly Glu Gly Ile Pro Leu
290 295 300
Tyr Asp Ala Ile Lys Cys Met Lys Thr Phe Phe Gly Trp Lys Glu Pro
305 310 315 320
Ser Ile Val Lys Pro His Glu Lys Gly Ile Asn Pro Asn Tyr Leu Gln
325 330 335
Thr Trp Lys Gln Val Leu Glu Glu Ile Gln Asp Leu Glu Asn Glu Glu
340 345 350
Arg Thr Pro Lys Thr Lys Asn Met Lys Lys Thr Ser Gln Leu Lys Trp
355 360 365
Ala Leu Gly Glu Asn Met Ala Pro Glu Lys Val Asp Phe Glu Asp Cys
370 375 380
Lys Asp Ile Ser Asp Leu Lys Gln Tyr Asp Ser Asp Glu Pro Glu Thr
385 390 395 400
Arg Ser Leu Ala Ser Trp Ile Gln Ser Glu Phe Asn Lys Ala Cys Glu
405 410 415
Leu Thr Asp Ser Ser Trp Ile Glu Leu Asp Glu Ile Gly Glu Asp Val
420 425 430
Ala Pro Ile Glu Tyr Ile Ala Ser Met Arg Arg Asn Tyr Phe Thr Ala
435 440 445
Glu Ile Ser His Cys Arg Ala Thr Glu Tyr Ile Met Lys Gly Val Tyr
450 455 460
Ile Asn Thr Ala Leu Leu Asn Ala Ser Cys Ala Ala Met Asp Glu Phe
465 470 475 480
Gln Leu Ile Pro Met Ile Ser Lys Cys Arg Thr Lys Glu Gly Arg Arg
485 490 495
Lys Thr Asn Leu Tyr Gly Phe Ile Ile Lys Gly Arg Ser His Leu Arg
500 505 510
Asn Asp Thr Asp Val Val Asn Phe Val Ser Met Glu Phe Ser Leu Thr
515 520 525
Asp Pro Arg Phe Glu Pro His Lys Trp Glu Lys Tyr Cys Val Leu Glu
530 535 540
Ile Gly Asp Met Leu Leu Arg Thr Ala Val Gly Gln Val Ser Arg Pro
545 550 555 560
Met Phe Leu Tyr Val Arg Thr Asn Gly Thr Ser Lys Ile Lys Met Lys
565 570 575
Trp Gly Met Glu Met Arg Arg Cys Leu Leu Gln Ser Leu Gln Gln Ile
580 585 590
Glu Ser Met Ile Glu Ala Glu Ser Ser Val Lys Glu Lys Asp Met Thr
595 600 605
Lys Glu Phe Phe Glu Asn Lys Ser Glu Thr Trp Pro Ile Gly Glu Ser
610 615 620
Pro Lys Gly Val Glu Glu Gly Ser Ile Gly Lys Val Cys Arg Thr Leu
625 630 635 640
Leu Ala Lys Ser Val Phe Asn Ser Leu Tyr Ala Ser Pro Gln Leu Glu
645 650 655
Gly Phe Ser Ala Glu Ser Arg Lys Leu Leu Leu Ile Val Gln Ala Leu
660 665 670
Arg Asp Asn Leu Glu Pro Gly Thr Phe Asp Ile Gly Gly Leu Tyr Glu
675 680 685
Ser Ile Glu Glu Cys Leu Ile Asn Asp Pro Trp Val Leu Leu Asn Ala
690 695 700
Ser Trp Phe Asn Ser Phe Leu Thr His Ala Leu Lys
705 710 715
<210> 11
<211> 1762
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 11
agcaaaagca ggggatattt ctgtcaatca tgaagacaac cattattttg atactactga 60
cccattgggc ctacagtcaa aacccaatca gtggcaacaa cacagccaca ttgtgtctgg 120
gacgccatgc agtagcaaat ggaacattgg taaaaacaat aagtgatgat caaattgagg 180
tgacaaatgc tacagaatta gttcagagca tttcaacggg gaaaatatgc aacaactcat 240
atagaattct agatggaaga aattgcacat taatagatgc aatgctagga gacccccact 300
gtgacgcctt tcagtatgag aattgggacc tctttataga aagaagcagc gctttcagca 360
attgctaccc atatgacatc cctgactatg catcgctccg atccattgta gcatcctcag 420
gaacattgga attcacagca gagggattca catggacagg tgtcactcaa aacggaataa 480
gtggagcctg caaaagggga tcagccgata gtttctttag ccgactgaat tggctaacaa 540
aatctggaag ctcttacccc acattgaatg tgacaatgcc taacaataaa aatttcgaca 600
agctatacat ctgggggatt catcacccga gctcaaatca agagcagaca aaattgtaca 660
tccaagaatc aggacgagta acagtctcaa caaaaagaag tcaacaaaca ataatcccta 720
acatcggatc tagaccgtgg gtcagaggtc aatcaggcag gataagcata tactggacca 780
ttgtaaaacc tggagatatc ctaatgataa acagtaatgg caacttagtt gcaccgcggg 840
gatattttaa attgaaaaca gggaaaagct ctgtaatgag atcagatgta cccatagaaa 900
tttgtgtgtc tgaatgtatt acaccaaatg gaagcatctc caacgacaag ccattccaaa 960
atgtgaacaa agttacatat ggaaaatgcc ccaagtatat caggcaaaac actttaaagc 1020
tggccactgg gatgaggaat gtaccagaaa agcaaatcag aggaatcttc ggagcaatag 1080
cgggattcat cgaaaacggc tgggaaggaa tggttgatgg gtggtatggg ttccgatatc 1140
aaaactctga aggaacaggg caagctgcag atctaaagag cactcaagca gccatcgacc 1200
agattaatgg aaagttaaac agagtgattg aaagaaccaa tgagaaattc catcaaatag 1260
agaaggaatt ctcagaagta gaaggaagaa ttcaggactt ggagaaatat gtagaagaca 1320
ccaaaataga cctatggtcc tacaatgcag aattgctggt ggctctagaa aatcaacata 1380
caattgactt aacagatgca gaaatgaata aattatttga gaagactaga cgccagttaa 1440
gagaaaacgc agaagacatg ggaggtggat gtttcaagat ttaccacaaa tgtgataatg 1500
catgcattgg atcaataaga aatgggacat atgaccatta catatacaga gatgaagcat 1560
taaacaaccg atttcagatc aaaggtgtag agttgaaatc aggctacaaa gattggatac 1620
tgtggatttc attcgccata tcatgcttct taatttgcgt tgttctattg ggtttcatta 1680
tgtgggcttg ccaaaaaggc aacatcagat gcaacatttg catttgagta aactgatagt 1740
taaaaacacc cttgtttcta ct 1762
<210> 12
<211> 565
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 12
Met Lys Thr Thr Ile Ile Leu Ile Leu Leu Thr His Trp Ala Tyr Ser
1 5 10 15
Gln Asn Pro Ile Ser Gly Asn Asn Thr Ala Thr Leu Cys Leu Gly Arg
20 25 30
His Ala Val Ala Asn Gly Thr Leu Val Lys Thr Ile Ser Asp Asp Gln
35 40 45
Ile Glu Val Thr Asn Ala Thr Glu Leu Val Gln Ser Ile Ser Thr Gly
50 55 60
Lys Ile Cys Asn Asn Ser Tyr Arg Ile Leu Asp Gly Arg Asn Cys Thr
65 70 75 80
Leu Ile Asp Ala Met Leu Gly Asp Pro His Cys Asp Ala Phe Gln Tyr
85 90 95
Glu Asn Trp Asp Leu Phe Ile Glu Arg Ser Ser Ala Phe Ser Asn Cys
100 105 110
Tyr Pro Tyr Asp Ile Pro Asp Tyr Ala Ser Leu Arg Ser Ile Val Ala
115 120 125
Ser Ser Gly Thr Leu Glu Phe Thr Ala Glu Gly Phe Thr Trp Thr Gly
130 135 140
Val Thr Gln Asn Gly Ile Ser Gly Ala Cys Lys Arg Gly Ser Ala Asp
145 150 155 160
Ser Phe Phe Ser Arg Leu Asn Trp Leu Thr Lys Ser Gly Ser Ser Tyr
165 170 175
Pro Thr Leu Asn Val Thr Met Pro Asn Asn Lys Asn Phe Asp Lys Leu
180 185 190
Tyr Ile Trp Gly Ile His His Pro Ser Ser Asn Gln Glu Gln Thr Lys
195 200 205
Leu Tyr Ile Gln Glu Ser Gly Arg Val Thr Val Ser Thr Lys Arg Ser
210 215 220
Gln Gln Thr Ile Ile Pro Asn Ile Gly Ser Arg Pro Trp Val Arg Gly
225 230 235 240
Gln Ser Gly Arg Ile Ser Ile Tyr Trp Thr Ile Val Lys Pro Gly Asp
245 250 255
Ile Leu Met Ile Asn Ser Asn Gly Asn Leu Val Ala Pro Arg Gly Tyr
260 265 270
Phe Lys Leu Lys Thr Gly Lys Ser Ser Val Met Arg Ser Asp Val Pro
275 280 285
Ile Glu Ile Cys Val Ser Glu Cys Ile Thr Pro Asn Gly Ser Ile Ser
290 295 300
Asn Asp Lys Pro Phe Gln Asn Val Asn Lys Val Thr Tyr Gly Lys Cys
305 310 315 320
Pro Lys Tyr Ile Arg Gln Asn Thr Leu Lys Leu Ala Thr Gly Met Arg
325 330 335
Asn Val Pro Glu Lys Gln Ile Arg Gly Ile Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Asn Gly Trp Glu Gly Met Val Asp Gly Trp Tyr Gly Phe
355 360 365
Arg Tyr Gln Asn Ser Glu Gly Thr Gly Gln Ala Ala Asp Leu Lys Ser
370 375 380
Thr Gln Ala Ala Ile Asp Gln Ile Asn Gly Lys Leu Asn Arg Val Ile
385 390 395 400
Glu Arg Thr Asn Glu Lys Phe His Gln Ile Glu Lys Glu Phe Ser Glu
405 410 415
Val Glu Gly Arg Ile Gln Asp Leu Glu Lys Tyr Val Glu Asp Thr Lys
420 425 430
Ile Asp Leu Trp Ser Tyr Asn Ala Glu Leu Leu Val Ala Leu Glu Asn
435 440 445
Gln His Thr Ile Asp Leu Thr Asp Ala Glu Met Asn Lys Leu Phe Glu
450 455 460
Lys Thr Arg Arg Gln Leu Arg Glu Asn Ala Glu Asp Met Gly Gly Gly
465 470 475 480
Cys Phe Lys Ile Tyr His Lys Cys Asp Asn Ala Cys Ile Gly Ser Ile
485 490 495
Arg Asn Gly Thr Tyr Asp His Tyr Ile Tyr Arg Asp Glu Ala Leu Asn
500 505 510
Asn Arg Phe Gln Ile Lys Gly Val Glu Leu Lys Ser Gly Tyr Lys Asp
515 520 525
Trp Ile Leu Trp Ile Ser Phe Ala Ile Ser Cys Phe Leu Ile Cys Val
530 535 540
Val Leu Leu Gly Phe Ile Met Trp Ala Cys Gln Lys Gly Asn Ile Arg
545 550 555 560
Cys Asn Ile Cys Ile
565
<210> 13
<211> 1565
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 13
agcaaaagca gggtagataa tcactcactg agtgacatca aagtcatggc gtctcaaggc 60
accaaacgat cctatgaaca gatggaaact gatggggaac gccagaatgc aactgaaatc 120
agagcatctg tcggaaggat ggtgggagga atcggccggt tttatgttca gatgtgtact 180
gagcttaaac taaacgacca tgaagggcgg ctgattcaga acagcataac aatagaaagg 240
atggtacttt cggcattcga cgaaagaaga aacaagtatc tcgaggagca tcccagtgct 300
gggaaagacc ctaagaaaac gggaggcccg atatacagaa ggaaagatgg gaaatggatg 360
agggaactca tcctccatga taaagaagaa atcatgagaa tctggcgtca ggccaacaat 420
ggtgaagacg ctactgctgg tcttactcat atgatgatct ggcactccaa tctcaatgac 480
accacatacc aaagaacaag ggctcttgtt cggactggga tggatcccag aatgtgctct 540
ctgatgcaag gctcaaccct cccacggaga tctggagccg ctggtgctgc agtaaaaggt 600
gttggaacaa tggtaatgga actcatcaga atgatcaaac gcggaataaa tgatcggaat 660
ttctggagag gtgaaaatgg tcgaagaacc agaattgctt atgaaagaat gtgcaatatc 720
ctcaaaggga aatttcagac agcagcacaa cgggctatga tggaccaggt gagggaaggc 780
cgcaatcctg gaaacgctga gattgaggat ctcattttct tggcacgatc agcacttatt 840
ttgagaggat cagtagccca taaatcatgc ctacctgcct gtgtttatgg ccttgcagta 900
accagtgggt atgactttga gaaggaagga tactctctgg ttggaattga tcctttcaaa 960
ctactccaga acagtcaaat tttcagtcta atcagaccaa aagaaaaccc agcacacaag 1020
agccagttgg tgtggatggc atgccattct gcagcatttg aggacctgag agttttaaat 1080
ttcattagag gaaccaaagt aatcccaaga ggacagttaa caaccagagg agttcaaata 1140
gcttcaaatg aaaacatgga gacaatagat tctagcacac ttgaactgag aagcaaatat 1200
tgggcaataa ggaccagaag cggaggaaac accagtcaac agagagcatc tgcaggacag 1260
ataagtgtgc aacctacttt ctcagtacag agaaatcttc cctttgagag agcaaccatt 1320
atggctgcat tcactggtaa cactgaaggg aggacttccg acatgagaac ggaaatcata 1380
aggatgatgg aaaatgccaa atcagaagat gtgtctttcc aggggcgggg agtcttcgag 1440
ctctcggacg aaaaggcaac gaacccgatc gtgccttcct ttgacatgag caatgaaggg 1500
tcttatttct tcggagacaa tgctgaggag tttgacaatt aaagaaaaat acccttgttt 1560
ctact 1565
<210> 14
<211> 498
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 14
Met Ala Ser Gln Gly Thr Lys Arg Ser Tyr Glu Gln Met Glu Thr Asp
1 5 10 15
Gly Glu Arg Gln Asn Ala Thr Glu Ile Arg Ala Ser Val Gly Arg Met
20 25 30
Val Gly Gly Ile Gly Arg Phe Tyr Val Gln Met Cys Thr Glu Leu Lys
35 40 45
Leu Asn Asp His Glu Gly Arg Leu Ile Gln Asn Ser Ile Thr Ile Glu
50 55 60
Arg Met Val Leu Ser Ala Phe Asp Glu Arg Arg Asn Lys Tyr Leu Glu
65 70 75 80
Glu His Pro Ser Ala Gly Lys Asp Pro Lys Lys Thr Gly Gly Pro Ile
85 90 95
Tyr Arg Arg Lys Asp Gly Lys Trp Met Arg Glu Leu Ile Leu His Asp
100 105 110
Lys Glu Glu Ile Met Arg Ile Trp Arg Gln Ala Asn Asn Gly Glu Asp
115 120 125
Ala Thr Ala Gly Leu Thr His Met Met Ile Trp His Ser Asn Leu Asn
130 135 140
Asp Thr Thr Tyr Gln Arg Thr Arg Ala Leu Val Arg Thr Gly Met Asp
145 150 155 160
Pro Arg Met Cys Ser Leu Met Gln Gly Ser Thr Leu Pro Arg Arg Ser
165 170 175
Gly Ala Ala Gly Ala Ala Val Lys Gly Val Gly Thr Met Val Met Glu
180 185 190
Leu Ile Arg Met Ile Lys Arg Gly Ile Asn Asp Arg Asn Phe Trp Arg
195 200 205
Gly Glu Asn Gly Arg Arg Thr Arg Ile Ala Tyr Glu Arg Met Cys Asn
210 215 220
Ile Leu Lys Gly Lys Phe Gln Thr Ala Ala Gln Arg Ala Met Met Asp
225 230 235 240
Gln Val Arg Glu Gly Arg Asn Pro Gly Asn Ala Glu Ile Glu Asp Leu
245 250 255
Ile Phe Leu Ala Arg Ser Ala Leu Ile Leu Arg Gly Ser Val Ala His
260 265 270
Lys Ser Cys Leu Pro Ala Cys Val Tyr Gly Leu Ala Val Thr Ser Gly
275 280 285
Tyr Asp Phe Glu Lys Glu Gly Tyr Ser Leu Val Gly Ile Asp Pro Phe
290 295 300
Lys Leu Leu Gln Asn Ser Gln Ile Phe Ser Leu Ile Arg Pro Lys Glu
305 310 315 320
Asn Pro Ala His Lys Ser Gln Leu Val Trp Met Ala Cys His Ser Ala
325 330 335
Ala Phe Glu Asp Leu Arg Val Leu Asn Phe Ile Arg Gly Thr Lys Val
340 345 350
Ile Pro Arg Gly Gln Leu Thr Thr Arg Gly Val Gln Ile Ala Ser Asn
355 360 365
Glu Asn Met Glu Thr Ile Asp Ser Ser Thr Leu Glu Leu Arg Ser Lys
370 375 380
Tyr Trp Ala Ile Arg Thr Arg Ser Gly Gly Asn Thr Ser Gln Gln Arg
385 390 395 400
Ala Ser Ala Gly Gln Ile Ser Val Gln Pro Thr Phe Ser Val Gln Arg
405 410 415
Asn Leu Pro Phe Glu Arg Ala Thr Ile Met Ala Ala Phe Thr Gly Asn
420 425 430
Thr Glu Gly Arg Thr Ser Asp Met Arg Thr Glu Ile Ile Arg Met Met
435 440 445
Glu Asn Ala Lys Ser Glu Asp Val Ser Phe Gln Gly Arg Gly Val Phe
450 455 460
Glu Leu Ser Asp Glu Lys Ala Thr Asn Pro Ile Val Pro Ser Phe Asp
465 470 475 480
Met Ser Asn Glu Gly Ser Tyr Phe Phe Gly Asp Asn Ala Glu Glu Phe
485 490 495
Asp Asn
<210> 15
<211> 1460
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 15
agcaaaagca ggagtttaaa atgaatccaa atcaaaagat aatagcaatt ggatttgcat 60
cattggggat attaatcatt aatgtcattc tccatgtagt cagcattata gtaacagtac 120
tggtcctcaa taacaataga acagatctga actgcaaagg gacgatcata agagagtgca 180
atgaaacagt aagagtagaa aaaattactc aatggtataa taccagtaca attaagtaca 240
tagagagacc ttcaaatgaa tactacatga acaacactga accactttgt gaggcccaag 300
gctttgcacc attttccaaa gataatggaa tacgaattgg gtcgagaggc catgtttttg 360
tgataagaga accttttgta tcatgttcgc cctcagaatg tagaaccttt ttcctcacac 420
agggctcatt actcaatgac aaacattcta acggcacagt aaaggaccga agtccgtata 480
ggactttgat gagtgtcaga atagggcaat cacctaatgt atatcaagct aggtttgaat 540
cggtagcatg gtcagcaaca gcatgccatg atggaaaaaa atggatgaca gttggagtca 600
cagggcccga caatcaagca attgcagtag tgaactatgg aggtgttccg gttgatatta 660
ttaattcatg ggcaggggat attttaagaa cccaagaatc atcatgcacc tgcattaaag 720
gagactgtta ttgggtaatg actgatggac cggcaaatag gcaagctaaa tataggatat 780
tcaaagcaaa agatggaaga gtaattggac agactgatat aagtttcaat gggggacaca 840
tagaggagtg ttcttgttac cccaatgaag ggaaggtgga atgcatatgc agggacaatt 900
ggactggaac aaatagacca attctggtaa tatcttctga tctatcgtac acagttggat 960
atttgtgtgc tggcattccc actgacactc ctaggggaga ggatagtcaa ttcacaggct 1020
catgtacaag tcctttggga aataaaggat acggtgtaaa aggtttcggg tttcgacaag 1080
gaactgacgt atgggccgga aggacaatta gtaggacttc aagatcagga ttcgaaataa 1140
taaaaatcag gaatggttgg acacagaaca gtaaagacca aatcaggagg caagtgatta 1200
tcgatgaccc aaattggtca ggatatagcg gttctttcac attgccggtt gaactaacaa 1260
aaaagggatg tttggtcccc tgtttctggg ttgaaatgat tagaggtaaa cctgaagaaa 1320
caacaatatg gacctctagc agctccattg tgatgtgtgg agtagatcat aaaattgcca 1380
gttggtcatg gcacgatgga gctattcttc cctttgacat cgataagatg taatttacga 1440
aaaaactcct tgtttctact 1460
<210> 16
<211> 470
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 16
Met Asn Pro Asn Gln Lys Ile Ile Ala Ile Gly Phe Ala Ser Leu Gly
1 5 10 15
Ile Leu Ile Ile Asn Val Ile Leu His Val Val Ser Ile Ile Val Thr
20 25 30
Val Leu Val Leu Asn Asn Asn Arg Thr Asp Leu Asn Cys Lys Gly Thr
35 40 45
Ile Ile Arg Glu Cys Asn Glu Thr Val Arg Val Glu Lys Ile Thr Gln
50 55 60
Trp Tyr Asn Thr Ser Thr Ile Lys Tyr Ile Glu Arg Pro Ser Asn Glu
65 70 75 80
Tyr Tyr Met Asn Asn Thr Glu Pro Leu Cys Glu Ala Gln Gly Phe Ala
85 90 95
Pro Phe Ser Lys Asp Asn Gly Ile Arg Ile Gly Ser Arg Gly His Val
100 105 110
Phe Val Ile Arg Glu Pro Phe Val Ser Cys Ser Pro Ser Glu Cys Arg
115 120 125
Thr Phe Phe Leu Thr Gln Gly Ser Leu Leu Asn Asp Lys His Ser Asn
130 135 140
Gly Thr Val Lys Asp Arg Ser Pro Tyr Arg Thr Leu Met Ser Val Arg
145 150 155 160
Ile Gly Gln Ser Pro Asn Val Tyr Gln Ala Arg Phe Glu Ser Val Ala
165 170 175
Trp Ser Ala Thr Ala Cys His Asp Gly Lys Lys Trp Met Thr Val Gly
180 185 190
Val Thr Gly Pro Asp Asn Gln Ala Ile Ala Val Val Asn Tyr Gly Gly
195 200 205
Val Pro Val Asp Ile Ile Asn Ser Trp Ala Gly Asp Ile Leu Arg Thr
210 215 220
Gln Glu Ser Ser Cys Thr Cys Ile Lys Gly Asp Cys Tyr Trp Val Met
225 230 235 240
Thr Asp Gly Pro Ala Asn Arg Gln Ala Lys Tyr Arg Ile Phe Lys Ala
245 250 255
Lys Asp Gly Arg Val Ile Gly Gln Thr Asp Ile Ser Phe Asn Gly Gly
260 265 270
His Ile Glu Glu Cys Ser Cys Tyr Pro Asn Glu Gly Lys Val Glu Cys
275 280 285
Ile Cys Arg Asp Asn Trp Thr Gly Thr Asn Arg Pro Ile Leu Val Ile
290 295 300
Ser Ser Asp Leu Ser Tyr Thr Val Gly Tyr Leu Cys Ala Gly Ile Pro
305 310 315 320
Thr Asp Thr Pro Arg Gly Glu Asp Ser Gln Phe Thr Gly Ser Cys Thr
325 330 335
Ser Pro Leu Gly Asn Lys Gly Tyr Gly Val Lys Gly Phe Gly Phe Arg
340 345 350
Gln Gly Thr Asp Val Trp Ala Gly Arg Thr Ile Ser Arg Thr Ser Arg
355 360 365
Ser Gly Phe Glu Ile Ile Lys Ile Arg Asn Gly Trp Thr Gln Asn Ser
370 375 380
Lys Asp Gln Ile Arg Arg Gln Val Ile Ile Asp Asp Pro Asn Trp Ser
385 390 395 400
Gly Tyr Ser Gly Ser Phe Thr Leu Pro Val Glu Leu Thr Lys Lys Gly
405 410 415
Cys Leu Val Pro Cys Phe Trp Val Glu Met Ile Arg Gly Lys Pro Glu
420 425 430
Glu Thr Thr Ile Trp Thr Ser Ser Ser Ser Ile Val Met Cys Gly Val
435 440 445
Asp His Lys Ile Ala Ser Trp Ser Trp His Asp Gly Ala Ile Leu Pro
450 455 460
Phe Asp Ile Asp Lys Met
465 470
<210> 17
<211> 1027
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 17
agcaaaagca ggtagatatt taaagatgag tcttctaacc gaggtcgaaa cgtacgttct 60
ctctatcgta ccatcaggcc ccctcaaagc cgagatcgcg cagagacttg aagatgtctt 120
tgcagggaag aacaccgatc ttgaggcact catggaatgg ctaaagacaa gaccaatcct 180
gtcacctctg actaaaggga ttttaggatt tgtattcacg ctcaccgtgc ccagtgagcg 240
aggactgcag cgtagacgct ttgtccaaaa tgcccttagt ggaaacggag atccaaacaa 300
catggacaga gcagtaaaac tgtacaggaa gcttaaaaga gaaataacat tccatggggc 360
aaaagaggtg gcactcagct attccactgg tgcactagcc agctgcatgg gactcatata 420
caacagaatg ggaactgtta caaccgaagt ggcatttggc ctggtatgcg ccacatgtga 480
acagattgct gattcccagc atcgatctca caggcagatg gtgacaacaa ccaacccatt 540
aatcagacat gaaaacagaa tggtattagc cagtaccacg gctaaagcca tggaacagat 600
ggcaggatcg agtgagcagg cagcagaggc catggaggtt gctagtaggg ctaggcagat 660
ggtacaggca atgagaacca ttgggaccca ccctagctcc agtgccggtt tgaaagatga 720
tctcattgaa aatttacagg cctaccagaa acggatggga gtgcaaatgc agcgattcaa 780
gtgatcctct cgttattgca gcaagtatca ttgggatctt gcacttgata ttgtggattc 840
ttgatcgtct tttcttcaaa ttcatttatc gtcgccttaa atacgggttg aaaagagggc 900
cttctacgga aggagtacct gagtctatga gggaagaata tcggcaggaa cagcagaatg 960
ctgtggatgt tgacgatggt cattttgtca acatagagct ggagtaaaaa actaccttgt 1020
ttctact 1027
<210> 18
<211> 252
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 18
Met Ser Leu Leu Thr Glu Val Glu Thr Tyr Val Leu Ser Ile Val Pro
1 5 10 15
Ser Gly Pro Leu Lys Ala Glu Ile Ala Gln Arg Leu Glu Asp Val Phe
20 25 30
Ala Gly Lys Asn Thr Asp Leu Glu Ala Leu Met Glu Trp Leu Lys Thr
35 40 45
Arg Pro Ile Leu Ser Pro Leu Thr Lys Gly Ile Leu Gly Phe Val Phe
50 55 60
Thr Leu Thr Val Pro Ser Glu Arg Gly Leu Gln Arg Arg Arg Phe Val
65 70 75 80
Gln Asn Ala Leu Ser Gly Asn Gly Asp Pro Asn Asn Met Asp Arg Ala
85 90 95
Val Lys Leu Tyr Arg Lys Leu Lys Arg Glu Ile Thr Phe His Gly Ala
100 105 110
Lys Glu Val Ala Leu Ser Tyr Ser Thr Gly Ala Leu Ala Ser Cys Met
115 120 125
Gly Leu Ile Tyr Asn Arg Met Gly Thr Val Thr Thr Glu Val Ala Phe
130 135 140
Gly Leu Val Cys Ala Thr Cys Glu Gln Ile Ala Asp Ser Gln His Arg
145 150 155 160
Ser His Arg Gln Met Val Thr Thr Thr Asn Pro Leu Ile Arg His Glu
165 170 175
Asn Arg Met Val Leu Ala Ser Thr Thr Ala Lys Ala Met Glu Gln Met
180 185 190
Ala Gly Ser Ser Glu Gln Ala Ala Glu Ala Met Glu Val Ala Ser Arg
195 200 205
Ala Arg Gln Met Val Gln Ala Met Arg Thr Ile Gly Thr His Pro Ser
210 215 220
Ser Ser Ala Gly Leu Lys Asp Asp Leu Ile Glu Asn Leu Gln Ala Tyr
225 230 235 240
Gln Lys Arg Met Gly Val Gln Met Gln Arg Phe Lys
245 250
<210> 19
<211> 97
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 19
Met Ser Leu Leu Thr Glu Val Glu Thr Pro Thr Arg Asn Gly Trp Glu
1 5 10 15
Cys Lys Cys Ser Asp Ser Ser Asp Pro Leu Val Ile Ala Ala Ser Ile
20 25 30
Ile Gly Ile Leu His Leu Ile Leu Trp Ile Leu Asp Arg Leu Phe Phe
35 40 45
Lys Phe Ile Tyr Arg Arg Leu Lys Tyr Gly Leu Lys Arg Gly Pro Ser
50 55 60
Thr Glu Gly Val Pro Glu Ser Met Arg Glu Glu Tyr Arg Gln Glu Gln
65 70 75 80
Gln Asn Ala Val Asp Val Asp Asp Gly His Phe Val Asn Ile Glu Leu
85 90 95
Glu
<210> 20
<211> 890
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 20
agcaaaagca gggtgacaaa aacataatgg attccaacac tgtgtcaagc tttcaggtag 60
actgttttct ttggcatgtc cgcaaacgat tcgcagacca agaactgggt gatgccccat 120
tccttgaccg gcttcgccga gaccagaagt ccctaagggg aagaggtagc actcttggtc 180
tggacatcga aacagccact catgcaggaa agcagatagt ggagcagatt ctggaaaagg 240
aatcagatga ggcacttaaa atgaccattg cctctgttcc tacttcacgc tacttaactg 300
acatgactct tgatgagatg tcaagagact ggttcatgct catgcccaag caaaaagtaa 360
caggctccct atgtataaga atggaccagg caatcatgga taagaacatc atacttaaag 420
caaactttag tgtgattttc gaaaggctgg aaacactaat actacttaga gccttcaccg 480
aagaaggagc agtcgttggc gaaatttcac cattaccttc tcttccagga catactaatg 540
aggatgtcaa aaatgcaatt ggggtcctca tcggaggact taaatggaat gataatacgg 600
ttagaatctc tgaaactcta cagagattcg cttggagaag cagtcatgag aatgggagac 660
cttcattccc ttcaaagcag aaatgaaaaa tggagagaac aattaagcca gaaatttgaa 720
gaaataagat ggttgattga agaagtgcga catagattga aaaatacaga aaatagtttt 780
gaacaaataa catttatgca agccttacaa ctattgcttg aagtagaaca agagataaga 840
actttctcgt ttcagcttat ttaatgataa aaaacaccct tgtttctact 890
<210> 21
<211> 219
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 21
Met Asp Ser Asn Thr Val Ser Ser Phe Gln Val Asp Cys Phe Leu Trp
1 5 10 15
His Val Arg Lys Arg Phe Ala Asp Gln Glu Leu Gly Asp Ala Pro Phe
20 25 30
Leu Asp Arg Leu Arg Arg Asp Gln Lys Ser Leu Arg Gly Arg Gly Ser
35 40 45
Thr Leu Gly Leu Asp Ile Glu Thr Ala Thr His Ala Gly Lys Gln Ile
50 55 60
Val Glu Gln Ile Leu Glu Lys Glu Ser Asp Glu Ala Leu Lys Met Thr
65 70 75 80
Ile Ala Ser Val Pro Thr Ser Arg Tyr Leu Thr Asp Met Thr Leu Asp
85 90 95
Glu Met Ser Arg Asp Trp Phe Met Leu Met Pro Lys Gln Lys Val Thr
100 105 110
Gly Ser Leu Cys Ile Arg Met Asp Gln Ala Ile Met Asp Lys Asn Ile
115 120 125
Ile Leu Lys Ala Asn Phe Ser Val Ile Phe Glu Arg Leu Glu Thr Leu
130 135 140
Ile Leu Leu Arg Ala Phe Thr Glu Glu Gly Ala Val Val Gly Glu Ile
145 150 155 160
Ser Pro Leu Pro Ser Leu Pro Gly His Thr Asn Glu Asp Val Lys Asn
165 170 175
Ala Ile Gly Val Leu Ile Gly Gly Leu Lys Trp Asn Asp Asn Thr Val
180 185 190
Arg Ile Ser Glu Thr Leu Gln Arg Phe Ala Trp Arg Ser Ser His Glu
195 200 205
Asn Gly Arg Pro Ser Phe Pro Ser Lys Gln Lys
210 215
<210> 22
<211> 121
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 22
Met Asp Ser Asn Thr Val Ser Ser Phe Gln Asp Ile Leu Met Arg Met
1 5 10 15
Ser Lys Met Gln Leu Gly Ser Ser Ser Glu Asp Leu Asn Gly Met Ile
20 25 30
Ile Arg Leu Glu Ser Leu Lys Leu Tyr Arg Asp Ser Leu Gly Glu Ala
35 40 45
Val Met Arg Met Gly Asp Leu His Ser Leu Gln Ser Arg Asn Glu Lys
50 55 60
Trp Arg Glu Gln Leu Ser Gln Lys Phe Glu Glu Ile Arg Trp Leu Ile
65 70 75 80
Glu Glu Val Arg His Arg Leu Lys Asn Thr Glu Asn Ser Phe Glu Gln
85 90 95
Ile Thr Phe Met Gln Ala Leu Gln Leu Leu Leu Glu Val Glu Gln Glu
100 105 110
Ile Arg Thr Phe Ser Phe Gln Leu Ile
115 120
<210> 23
<211> 1768
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 23
agcaaaagca ggggatattt ctgtcaatca tgaagacaac cattattttt atttttatac 60
tactgaccca ttgggcctac agtcaaaacc caatcagtaa caacaacaca gccacattgt 120
gtctgggaca ccatgcagta gcaaatggaa cattagtaaa aacaataagt gatgatcaaa 180
ttgaggtgac aaatgctaca gaattagttc agagcatttc aatggggaaa atatgcaaca 240
actcatatag aattctagat ggaagaaatt gcacattaat agatgcaatg ctaggagacc 300
cccactgtga cgtctttcag tatgagaatt gggacctctt tatagaaaga agcagcgctt 360
tcagcaattg ctacccatat gacatccctg actatgcatc gctccgatca attgtagcat 420
cctcaggaac attggaattc acagcagagg gattcacatg gacaggtgtc actcaaaacg 480
gaagaagtgg agcctgcaaa aggggatcag ccgatagttt ctttagccga ctgaattggc 540
taacaaaatc tggaaactct tatcccacat tgaatgtgac aatgcctaac aataaaaatt 600
tcgacaagct atacatctgg gggattcatc acccgagttc aaatcaagag cagacaaaat 660
tgtatatcca agaatcagga cgagtaacag tctcaacaaa aagaagtcaa caaacaataa 720
tccctaacat cggatctaga ccgtgggtca gaggtcaatc aggcaggata agcatatact 780
ggaccattgt aaaacctgga gatatcctaa tgataaacag taatggcaac ttagttgcac 840
cgcggggata ttttaaattg aaaacaggga aaagctctgt aatgagatca gatgtaccca 900
tagacatttg tgtgtctgaa tgtattacac caaatggaag catctccaac gaaaagccat 960
tccaaaatgt aaacaaagtt acatatggaa aatgccccaa atatatcagg caaaacactt 1020
taaagttggc cactggaatg agaaatgtac cagaaaagca aatcagagga atctttggag 1080
caatagcggg attcatcgaa aacggctggg aaggaatggt tgatgggtgg tatgggttcc 1140
gataccaaaa ctctgaagga acaggacaag ctgcagatct aaagagcact caaacagcca 1200
tcgaccagat taatgaaaag ttaaacagag tgattgaaag aaccaatgaa aaattccatc 1260
agatagagaa ggaattctca gaagtagaag gaagaattca ggacttggag aaatatgtgg 1320
aagacaccaa aatagaccta tggtcctaca atgcagaatt gctggtggct ctagaaaatc 1380
aacatacaat tgacttaaca gatgcagaaa tgaataaatt attcgagaag actagacgcc 1440
agttaagaga aaacgcagaa gacatgggag gtggatgttt caagatttac cacaaatgtg 1500
ataatgcatg cattggatca ataagaaatg ggacatatga ccattacata tacagagatg 1560
aagcattaaa caaccgattt caaatcaaag gtgttgagtt gaaatcaggc tacaaagatt 1620
ggatactgtg gatttcattc gccatatcat gcttcttaat ttgcgttgtt ctattgggtt 1680
ttattatgtg ggcttgccaa aaaggcaaca tcagatgcaa catttgcatt tgagtaaact 1740
gatagttaaa aacacccttg tttctact 1768
<210> 24
<211> 567
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 24
Met Lys Thr Thr Ile Ile Phe Ile Phe Ile Leu Leu Thr His Trp Ala
1 5 10 15
Tyr Ser Gln Asn Pro Ile Ser Asn Asn Asn Thr Ala Thr Leu Cys Leu
20 25 30
Gly His His Ala Val Ala Asn Gly Thr Leu Val Lys Thr Ile Ser Asp
35 40 45
Asp Gln Ile Glu Val Thr Asn Ala Thr Glu Leu Val Gln Ser Ile Ser
50 55 60
Met Gly Lys Ile Cys Asn Asn Ser Tyr Arg Ile Leu Asp Gly Arg Asn
65 70 75 80
Cys Thr Leu Ile Asp Ala Met Leu Gly Asp Pro His Cys Asp Val Phe
85 90 95
Gln Tyr Glu Asn Trp Asp Leu Phe Ile Glu Arg Ser Ser Ala Phe Ser
100 105 110
Asn Cys Tyr Pro Tyr Asp Ile Pro Asp Tyr Ala Ser Leu Arg Ser Ile
115 120 125
Val Ala Ser Ser Gly Thr Leu Glu Phe Thr Ala Glu Gly Phe Thr Trp
130 135 140
Thr Gly Val Thr Gln Asn Gly Arg Ser Gly Ala Cys Lys Arg Gly Ser
145 150 155 160
Ala Asp Ser Phe Phe Ser Arg Leu Asn Trp Leu Thr Lys Ser Gly Asn
165 170 175
Ser Tyr Pro Thr Leu Asn Val Thr Met Pro Asn Asn Lys Asn Phe Asp
180 185 190
Lys Leu Tyr Ile Trp Gly Ile His His Pro Ser Ser Asn Gln Glu Gln
195 200 205
Thr Lys Leu Tyr Ile Gln Glu Ser Gly Arg Val Thr Val Ser Thr Lys
210 215 220
Arg Ser Gln Gln Thr Ile Ile Pro Asn Ile Gly Ser Arg Pro Trp Val
225 230 235 240
Arg Gly Gln Ser Gly Arg Ile Ser Ile Tyr Trp Thr Ile Val Lys Pro
245 250 255
Gly Asp Ile Leu Met Ile Asn Ser Asn Gly Asn Leu Val Ala Pro Arg
260 265 270
Gly Tyr Phe Lys Leu Lys Thr Gly Lys Ser Ser Val Met Arg Ser Asp
275 280 285
Val Pro Ile Asp Ile Cys Val Ser Glu Cys Ile Thr Pro Asn Gly Ser
290 295 300
Ile Ser Asn Glu Lys Pro Phe Gln Asn Val Asn Lys Val Thr Tyr Gly
305 310 315 320
Lys Cys Pro Lys Tyr Ile Arg Gln Asn Thr Leu Lys Leu Ala Thr Gly
325 330 335
Met Arg Asn Val Pro Glu Lys Gln Ile Arg Gly Ile Phe Gly Ala Ile
340 345 350
Ala Gly Phe Ile Glu Asn Gly Trp Glu Gly Met Val Asp Gly Trp Tyr
355 360 365
Gly Phe Arg Tyr Gln Asn Ser Glu Gly Thr Gly Gln Ala Ala Asp Leu
370 375 380
Lys Ser Thr Gln Thr Ala Ile Asp Gln Ile Asn Glu Lys Leu Asn Arg
385 390 395 400
Val Ile Glu Arg Thr Asn Glu Lys Phe His Gln Ile Glu Lys Glu Phe
405 410 415
Ser Glu Val Glu Gly Arg Ile Gln Asp Leu Glu Lys Tyr Val Glu Asp
420 425 430
Thr Lys Ile Asp Leu Trp Ser Tyr Asn Ala Glu Leu Leu Val Ala Leu
435 440 445
Glu Asn Gln His Thr Ile Asp Leu Thr Asp Ala Glu Met Asn Lys Leu
450 455 460
Phe Glu Lys Thr Arg Arg Gln Leu Arg Glu Asn Ala Glu Asp Met Gly
465 470 475 480
Gly Gly Cys Phe Lys Ile Tyr His Lys Cys Asp Asn Ala Cys Ile Gly
485 490 495
Ser Ile Arg Asn Gly Thr Tyr Asp His Tyr Ile Tyr Arg Asp Glu Ala
500 505 510
Leu Asn Asn Arg Phe Gln Ile Lys Gly Val Glu Leu Lys Ser Gly Tyr
515 520 525
Lys Asp Trp Ile Leu Trp Ile Ser Phe Ala Ile Ser Cys Phe Leu Ile
530 535 540
Cys Val Val Leu Leu Gly Phe Ile Met Trp Ala Cys Gln Lys Gly Asn
545 550 555 560
Ile Arg Cys Asn Ile Cys Ile
565
<210> 25
<211> 1460
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 25
agcaaaagca ggagtttaaa atgaatccaa atcaaaagat aataacaatt ggatctgcat 60
cattggggat attaatcatt aacgtcattc tccatgtagt cagcattata gtaacagtac 120
tggtcctcaa taacaatgaa acaggtctga actgcaaagg gacgatcata agagagtaca 180
atgaaacagt aagagtagaa aaaattactc aatggcataa taccagtgca attaagtaca 240
tagagagacc tccaaatgaa tactacatga acaacaccga accactttgt gaggcccaag 300
gctttgcacc attttccaaa gataatggaa tacgaattgg gtcgagaggc catgtttttg 360
tgataagaga accttttgta tcatgttcgc cctcagaatg tagaaccttt ttcctcacac 420
agggctcatt actcaatgac aaacattcta acggcacagt aaaggatcga agtccatata 480
ggactttgat gagtgtcaaa atagggcaat cacctaatgt gtatcaagct aggtttgaat 540
cggtggcatg gtcagcaaca gcatgccatg atggaaaaaa atggatgaca attggagtca 600
cagggcccga caatcaagca attgcagtag tgaactatgg gggtgttccg gttgatatta 660
ttaattcatg ggcaggggac atcttaagaa cccaagaatc atcatgcacc tgcattaaag 720
gaaactgtta ttgggtaatg actgatggac cggcaaatag gcaagctaaa tatagaatat 780
tcaaagcaaa agatggaaga gtaattggac agactgatat aagcttcaat gggggacaca 840
tagaggagtg ttcttgttac cccaatgaag ggaaggtgga atgcatatgc agggacaatt 900
ggactggaac aaatagacca attctggtaa tatcttctga tctatcgtac acagttggat 960
atttgtgtgc tggcattccc actgacactc ctaggggaga ggatagtcaa ttcacaggct 1020
catgtacaag tcctttggga aataaaggat acggtgtaaa aggtttcggg tttcgacaag 1080
gaactgacgt atgggccgga aggacaatta gtaggacttc gagatcagga ttcgaaataa 1140
taaaaatcag gaatggttgg acacagaaca gtaaagacca aatcaggagg caagtgatta 1200
tcgatgaccc aaattggtca ggatatagcg gttctttcac attgccgatt gaactaacaa 1260
aaaagggatg tttggtcccc tgtttctggg ttgaaatgat tagaggtaaa cctgaagaaa 1320
caacaatatg gacctctagc agctccattg tgatgtgtgg agtagatcat aaaattgcca 1380
gttggtcatg gcacgatgga gctattcttc cctttgacat cgataagatg taatttacga 1440
aaaaactcct tgtttctact 1460
<210> 26
<211> 470
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 26
Met Asn Pro Asn Gln Lys Ile Ile Thr Ile Gly Ser Ala Ser Leu Gly
1 5 10 15
Ile Leu Ile Ile Asn Val Ile Leu His Val Val Ser Ile Ile Val Thr
20 25 30
Val Leu Val Leu Asn Asn Asn Glu Thr Gly Leu Asn Cys Lys Gly Thr
35 40 45
Ile Ile Arg Glu Tyr Asn Glu Thr Val Arg Val Glu Lys Ile Thr Gln
50 55 60
Trp His Asn Thr Ser Ala Ile Lys Tyr Ile Glu Arg Pro Pro Asn Glu
65 70 75 80
Tyr Tyr Met Asn Asn Thr Glu Pro Leu Cys Glu Ala Gln Gly Phe Ala
85 90 95
Pro Phe Ser Lys Asp Asn Gly Ile Arg Ile Gly Ser Arg Gly His Val
100 105 110
Phe Val Ile Arg Glu Pro Phe Val Ser Cys Ser Pro Ser Glu Cys Arg
115 120 125
Thr Phe Phe Leu Thr Gln Gly Ser Leu Leu Asn Asp Lys His Ser Asn
130 135 140
Gly Thr Val Lys Asp Arg Ser Pro Tyr Arg Thr Leu Met Ser Val Lys
145 150 155 160
Ile Gly Gln Ser Pro Asn Val Tyr Gln Ala Arg Phe Glu Ser Val Ala
165 170 175
Trp Ser Ala Thr Ala Cys His Asp Gly Lys Lys Trp Met Thr Ile Gly
180 185 190
Val Thr Gly Pro Asp Asn Gln Ala Ile Ala Val Val Asn Tyr Gly Gly
195 200 205
Val Pro Val Asp Ile Ile Asn Ser Trp Ala Gly Asp Ile Leu Arg Thr
210 215 220
Gln Glu Ser Ser Cys Thr Cys Ile Lys Gly Asn Cys Tyr Trp Val Met
225 230 235 240
Thr Asp Gly Pro Ala Asn Arg Gln Ala Lys Tyr Arg Ile Phe Lys Ala
245 250 255
Lys Asp Gly Arg Val Ile Gly Gln Thr Asp Ile Ser Phe Asn Gly Gly
260 265 270
His Ile Glu Glu Cys Ser Cys Tyr Pro Asn Glu Gly Lys Val Glu Cys
275 280 285
Ile Cys Arg Asp Asn Trp Thr Gly Thr Asn Arg Pro Ile Leu Val Ile
290 295 300
Ser Ser Asp Leu Ser Tyr Thr Val Gly Tyr Leu Cys Ala Gly Ile Pro
305 310 315 320
Thr Asp Thr Pro Arg Gly Glu Asp Ser Gln Phe Thr Gly Ser Cys Thr
325 330 335
Ser Pro Leu Gly Asn Lys Gly Tyr Gly Val Lys Gly Phe Gly Phe Arg
340 345 350
Gln Gly Thr Asp Val Trp Ala Gly Arg Thr Ile Ser Arg Thr Ser Arg
355 360 365
Ser Gly Phe Glu Ile Ile Lys Ile Arg Asn Gly Trp Thr Gln Asn Ser
370 375 380
Lys Asp Gln Ile Arg Arg Gln Val Ile Ile Asp Asp Pro Asn Trp Ser
385 390 395 400
Gly Tyr Ser Gly Ser Phe Thr Leu Pro Ile Glu Leu Thr Lys Lys Gly
405 410 415
Cys Leu Val Pro Cys Phe Trp Val Glu Met Ile Arg Gly Lys Pro Glu
420 425 430
Glu Thr Thr Ile Trp Thr Ser Ser Ser Ser Ile Val Met Cys Gly Val
435 440 445
Asp His Lys Ile Ala Ser Trp Ser Trp His Asp Gly Ala Ile Leu Pro
450 455 460
Phe Asp Ile Asp Lys Met
465 470
<210> 27
<211> 1762
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 27
agcgaaagca ggggatattt ctgtcaatca tgacgataac cattattttg atactactga 60
cccattgggc ttacagtcaa aacccaatca atgacaacaa cacagccaca ttgtgtctag 120
gacaccatgc agtagcaaat ggaacattgg taaaaacaat aagtgatgat caaattgagg 180
tgacaaatgc tacagaatta gttcagagca ttccaatggg gaaaatatgc aacaattcgt 240
atagaattct agatggaaag gattgcacat taatagatgc aatgctagga gacccccact 300
gtgacgcctt tcagtatgag aattgggacc tctttataga aagaagcagc gccttcagca 360
attgctaccc atatgacatc cctaactatg catcgctccg atccattgta gcatcctcag 420
gaacattgga attcacagca gagggattca catggacagg tgtcactcaa aacggaagaa 480
gcggatcctg caaaagggga tcagccgata gtttctttag ccgactgaat tggctaacaa 540
aatccggaag ctcttacccc acattgaatg tgacaatgcc taacaataaa aacttcgaca 600
agctatacat ctgggggatc catcacccga gctcaactca agagcagaca aaattgtata 660
tccaggaatc agggcgagta acagtctcaa caaaaagaag tcaacaaaca ataatcccta 720
acattgggtc tagaccatgg atcagaggtc aatcaggtag gataagcata tactggacca 780
ttgtaaaacc tggagatatt ctaatgataa acagtaatgg caacttagtt gcaccgcggg 840
gatactttaa attgaaaaca gggaaaagct ctgtaatgag atcagatgta cccatagaca 900
tttgtgtgtc tgaatgtatt acaccaaatg gaagcatctc caacgacaag ccattccaaa 960
atgtgaacaa agttacatat ggaaaatgtc ccaagtatat cagacaaaac actttaaagc 1020
tggccactgg gatgaggaat gtaccagaaa agcaaatcag aggaatcttc ggggcaatag 1080
cgggattcat cgaaaacggc tgggaaggaa tggttgatgg atggtatggg ttccgatacc 1140
aaaactctga aggaacaggg caagctgcag atctaaagag cactcaagca gccatcgacc 1200
agatcaatgg aaagttaaac agagtgattg aaagaacaaa tgagaaattc catcaaatag 1260
agaaggaatt ctcagaagta gaaggaagaa ttcaggactt ggagaaatat gtagaagaca 1320
ccaaaataga cctatggtcc tacaatgcag aattgctggt ggctctagaa aatcaacata 1380
caattgactt aacagatgca gaaatgaata aattgtttga gagaactaga cgcctgttaa 1440
gagaaaacgc agaagacatg ggaggtggat gtttcaagat ttaccacaaa tgtaataatg 1500
catgcattgg atcaataaga aatgggacat atgaccatta catatacaga gatgaagcat 1560
taaacaaccg atttcagatc aaaggtgtag agttgaaatc aggctacaaa gattggatac 1620
tctggatttc attcgccata tcatgcttct taatttgcgt tgttctattg ggttttatta 1680
tgtgggcttg ccaaaaaggc aacatcagat gcaacatttg catttgagta gattaatagt 1740
taaaaacacc cttgtttcta ct 1762
<210> 28
<211> 565
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 28
Met Thr Ile Thr Ile Ile Leu Ile Leu Leu Thr His Trp Ala Tyr Ser
1 5 10 15
Gln Asn Pro Ile Asn Asp Asn Asn Thr Ala Thr Leu Cys Leu Gly His
20 25 30
His Ala Val Ala Asn Gly Thr Leu Val Lys Thr Ile Ser Asp Asp Gln
35 40 45
Ile Glu Val Thr Asn Ala Thr Glu Leu Val Gln Ser Ile Pro Met Gly
50 55 60
Lys Ile Cys Asn Asn Ser Tyr Arg Ile Leu Asp Gly Lys Asp Cys Thr
65 70 75 80
Leu Ile Asp Ala Met Leu Gly Asp Pro His Cys Asp Ala Phe Gln Tyr
85 90 95
Glu Asn Trp Asp Leu Phe Ile Glu Arg Ser Ser Ala Phe Ser Asn Cys
100 105 110
Tyr Pro Tyr Asp Ile Pro Asn Tyr Ala Ser Leu Arg Ser Ile Val Ala
115 120 125
Ser Ser Gly Thr Leu Glu Phe Thr Ala Glu Gly Phe Thr Trp Thr Gly
130 135 140
Val Thr Gln Asn Gly Arg Ser Gly Ser Cys Lys Arg Gly Ser Ala Asp
145 150 155 160
Ser Phe Phe Ser Arg Leu Asn Trp Leu Thr Lys Ser Gly Ser Ser Tyr
165 170 175
Pro Thr Leu Asn Val Thr Met Pro Asn Asn Lys Asn Phe Asp Lys Leu
180 185 190
Tyr Ile Trp Gly Ile His His Pro Ser Ser Thr Gln Glu Gln Thr Lys
195 200 205
Leu Tyr Ile Gln Glu Ser Gly Arg Val Thr Val Ser Thr Lys Arg Ser
210 215 220
Gln Gln Thr Ile Ile Pro Asn Ile Gly Ser Arg Pro Trp Ile Arg Gly
225 230 235 240
Gln Ser Gly Arg Ile Ser Ile Tyr Trp Thr Ile Val Lys Pro Gly Asp
245 250 255
Ile Leu Met Ile Asn Ser Asn Gly Asn Leu Val Ala Pro Arg Gly Tyr
260 265 270
Phe Lys Leu Lys Thr Gly Lys Ser Ser Val Met Arg Ser Asp Val Pro
275 280 285
Ile Asp Ile Cys Val Ser Glu Cys Ile Thr Pro Asn Gly Ser Ile Ser
290 295 300
Asn Asp Lys Pro Phe Gln Asn Val Asn Lys Val Thr Tyr Gly Lys Cys
305 310 315 320
Pro Lys Tyr Ile Arg Gln Asn Thr Leu Lys Leu Ala Thr Gly Met Arg
325 330 335
Asn Val Pro Glu Lys Gln Ile Arg Gly Ile Phe Gly Ala Ile Ala Gly
340 345 350
Phe Ile Glu Asn Gly Trp Glu Gly Met Val Asp Gly Trp Tyr Gly Phe
355 360 365
Arg Tyr Gln Asn Ser Glu Gly Thr Gly Gln Ala Ala Asp Leu Lys Ser
370 375 380
Thr Gln Ala Ala Ile Asp Gln Ile Asn Gly Lys Leu Asn Arg Val Ile
385 390 395 400
Glu Arg Thr Asn Glu Lys Phe His Gln Ile Glu Lys Glu Phe Ser Glu
405 410 415
Val Glu Gly Arg Ile Gln Asp Leu Glu Lys Tyr Val Glu Asp Thr Lys
420 425 430
Ile Asp Leu Trp Ser Tyr Asn Ala Glu Leu Leu Val Ala Leu Glu Asn
435 440 445
Gln His Thr Ile Asp Leu Thr Asp Ala Glu Met Asn Lys Leu Phe Glu
450 455 460
Arg Thr Arg Arg Leu Leu Arg Glu Asn Ala Glu Asp Met Gly Gly Gly
465 470 475 480
Cys Phe Lys Ile Tyr His Lys Cys Asn Asn Ala Cys Ile Gly Ser Ile
485 490 495
Arg Asn Gly Thr Tyr Asp His Tyr Ile Tyr Arg Asp Glu Ala Leu Asn
500 505 510
Asn Arg Phe Gln Ile Lys Gly Val Glu Leu Lys Ser Gly Tyr Lys Asp
515 520 525
Trp Ile Leu Trp Ile Ser Phe Ala Ile Ser Cys Phe Leu Ile Cys Val
530 535 540
Val Leu Leu Gly Phe Ile Met Trp Ala Cys Gln Lys Gly Asn Ile Arg
545 550 555 560
Cys Asn Ile Cys Ile
565
<210> 29
<211> 1460
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 29
agcaaaagca ggagtttaaa atgaatccaa atcaaaagat aatagcaatt ggatttacat 60
cattggggat attaatcatt agtgtcattc tccatgtagt cagcattata gtaacagtac 120
tggccctaaa taacaacaga acagatctga actgcaaaga gacgatcata agggagtaca 180
atgaaacagt aagagtagaa aaaattactc aatggtataa tatcagtaca attaagtaca 240
tagagaaacc ttcaaatgaa tactatatga acaacactga accactttgt gaggcccaag 300
gctttgcacc attttccaaa gataatggaa tacgaattgg atcgaggggc catgtttttg 360
tgataagaga accttttgta tcatgttcgc cttcagaatg tagaaccttt ttcctcacac 420
agggctcatt actcaatgac aaacattcta acggcacaat aaaggaccga agtccgtata 480
gaactctgat gagtgtcaaa atagggcaat cacctaatgt atatcaagct aggtttgaat 540
cagtggcatg gtcagcaaca gcatgccatg atggaaaaaa atggatgacg gttggagtca 600
cagggcctga caaccaagca attgcagtag tgaactatgg gggtgttccg gttgatatta 660
ttaattcatg ggcaggggat attttaagaa cccaagaatc gtcatgcacc tgcatcaaag 720
gagattgtta ttgggtaatg actgatgggc cggcgaatag gcaagccaaa tataagatat 780
tcaaagcaaa aaatggaaaa gtaattggac aaactgatat aagtttcaat ggaggacaca 840
tagaggagtg ttcttgttac cccaatgaag ggaaggtgga atgcatatgc agggacaatt 900
ggactggaac aaatagacca attttggtaa tatcttctga tctatcatac acagttggat 960
atttgtgtgc tggcattccc actgacactc ctaggggaga ggatagtcaa ttcacgggct 1020
catgtacaaa ccctttggga aataaaggat acggtgtaaa aggtttcgga tttcgacaag 1080
gaactgacgt atgggccgga aggacaatta gtagaacttc aagatcagga ttcgaaataa 1140
taaaaatcag gaatggttgg acacagaaca gtaaagacca aataaggagg caagtgatta 1200
tcgatgatca aaattggtca ggatatagcg gttctttcac attgccggtt gaactaacaa 1260
aaaaagaatg tttggtgccc tgtttctggg ttgaaatgat tagaggtaaa cctgaagaaa 1320
aaacaatatg gacctctagc agctccattg tgatgtgtgg agtagatcat aaaattgcca 1380
gttggtcatg gcacgatgga gctattcttc cctttgacat cgataagatg taatttacga 1440
aaaaactcct tgtttctact 1460
<210> 30
<211> 470
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 30
Met Asn Pro Asn Gln Lys Ile Ile Ala Ile Gly Phe Thr Ser Leu Gly
1 5 10 15
Ile Leu Ile Ile Ser Val Ile Leu His Val Val Ser Ile Ile Val Thr
20 25 30
Val Leu Ala Leu Asn Asn Asn Arg Thr Asp Leu Asn Cys Lys Glu Thr
35 40 45
Ile Ile Arg Glu Tyr Asn Glu Thr Val Arg Val Glu Lys Ile Thr Gln
50 55 60
Trp Tyr Asn Ile Ser Thr Ile Lys Tyr Ile Glu Lys Pro Ser Asn Glu
65 70 75 80
Tyr Tyr Met Asn Asn Thr Glu Pro Leu Cys Glu Ala Gln Gly Phe Ala
85 90 95
Pro Phe Ser Lys Asp Asn Gly Ile Arg Ile Gly Ser Arg Gly His Val
100 105 110
Phe Val Ile Arg Glu Pro Phe Val Ser Cys Ser Pro Ser Glu Cys Arg
115 120 125
Thr Phe Phe Leu Thr Gln Gly Ser Leu Leu Asn Asp Lys His Ser Asn
130 135 140
Gly Thr Ile Lys Asp Arg Ser Pro Tyr Arg Thr Leu Met Ser Val Lys
145 150 155 160
Ile Gly Gln Ser Pro Asn Val Tyr Gln Ala Arg Phe Glu Ser Val Ala
165 170 175
Trp Ser Ala Thr Ala Cys His Asp Gly Lys Lys Trp Met Thr Val Gly
180 185 190
Val Thr Gly Pro Asp Asn Gln Ala Ile Ala Val Val Asn Tyr Gly Gly
195 200 205
Val Pro Val Asp Ile Ile Asn Ser Trp Ala Gly Asp Ile Leu Arg Thr
210 215 220
Gln Glu Ser Ser Cys Thr Cys Ile Lys Gly Asp Cys Tyr Trp Val Met
225 230 235 240
Thr Asp Gly Pro Ala Asn Arg Gln Ala Lys Tyr Lys Ile Phe Lys Ala
245 250 255
Lys Asn Gly Lys Val Ile Gly Gln Thr Asp Ile Ser Phe Asn Gly Gly
260 265 270
His Ile Glu Glu Cys Ser Cys Tyr Pro Asn Glu Gly Lys Val Glu Cys
275 280 285
Ile Cys Arg Asp Asn Trp Thr Gly Thr Asn Arg Pro Ile Leu Val Ile
290 295 300
Ser Ser Asp Leu Ser Tyr Thr Val Gly Tyr Leu Cys Ala Gly Ile Pro
305 310 315 320
Thr Asp Thr Pro Arg Gly Glu Asp Ser Gln Phe Thr Gly Ser Cys Thr
325 330 335
Asn Pro Leu Gly Asn Lys Gly Tyr Gly Val Lys Gly Phe Gly Phe Arg
340 345 350
Gln Gly Thr Asp Val Trp Ala Gly Arg Thr Ile Ser Arg Thr Ser Arg
355 360 365
Ser Gly Phe Glu Ile Ile Lys Ile Arg Asn Gly Trp Thr Gln Asn Ser
370 375 380
Lys Asp Gln Ile Arg Arg Gln Val Ile Ile Asp Asp Gln Asn Trp Ser
385 390 395 400
Gly Tyr Ser Gly Ser Phe Thr Leu Pro Val Glu Leu Thr Lys Lys Glu
405 410 415
Cys Leu Val Pro Cys Phe Trp Val Glu Met Ile Arg Gly Lys Pro Glu
420 425 430
Glu Lys Thr Ile Trp Thr Ser Ser Ser Ser Ile Val Met Cys Gly Val
435 440 445
Asp His Lys Ile Ala Ser Trp Ser Trp His Asp Gly Ala Ile Leu Pro
450 455 460
Phe Asp Ile Asp Lys Met
465 470
<210> 31
<211> 1768
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 31
agcgaaagca ggggatattt ctgtcaatca tgaagacaac cattattttt aattttatac 60
tactgaccca ttgggcctac agtcaaaacc caatcagtaa caacaacaca gccacattgt 120
gtctgggaca ccatgcagta gcaaatggaa cattagtaaa aacaataagt gatgatcaaa 180
ttgaggtgac aaatgctaca gaattagttc agagcatttc aatggggaaa atatgcaaca 240
actcatatag aattctagat ggaagaaatt gcacgttaat agatgcaatg ttaggagacc 300
cccactgtga tgtctttcag tatgagaatt gggacctctt tatagaaaga agcagcgctt 360
tcagcaattg ctacccatat gacatcctcg actatgcatc gcttcgatca attatagcat 420
cctcaggaac attggaattc acagcagagg gattcacatg gacaggtgtc actcagaacg 480
gaagaagtgg agcctgcaaa aggggatcgg tcgatagttt ctttagccga ctgaattggc 540
taacgaaatc tggaaactct tatcccacat tgaatgtgac aatgcctaac aataaaaatt 600
tcgacaagct atacatctgg gggattcatc acccgagttc aaatcaagag cagaaaaaat 660
tgtatatcca agaatcagga cgagtaacag tctcaacaaa aagaagtcaa cagacaataa 720
ttcctaatat cggatctaga ccgtgggtca gaggtcaatc aggcagaata agcatatact 780
ggaccattgt aaaacctgga gatatcctaa tgataaacag taatggcaac ttagttgcgc 840
cgcggggata ttttaaattg aaaacaggga aaagctctat aatgagatca gacgtaccca 900
tagacatttg tgtgtctgaa tgtattacac caaatggaag catctccaac gacaagccat 960
tccaaaatgt aaacaaaatt acatatggaa aatgccccaa atatatcagg caaaacactt 1020
taaagttggc cactggaatg agaaatgtac cagaaaagca aatcagagga atctttggag 1080
caatagcggg attcatcgaa aacggctggg aaggaatggt tgatgggtgg tatgggttcc 1140
gataccaaaa ctctgaagga acaggacaag ctgcagatct aaagagcact caagcagcca 1200
tcgaccagat taatgaaaag ttaaatagag tgattgaaag aaccaatgag aaattccatc 1260
agatagagaa ggaattctca gaagtagaag gaagaattca ggacttggag aaatatgtgg 1320
aagacaccaa aatagaccta tggtcctaca atgcagaatt gctggtggct ctagaaaatc 1380
aacatacaat tgacttaaca gatgcagaaa tgaataaatt gttcgagaag actagacgcc 1440
agttaagaga aaacgcagaa gacatggggg gtggatgttt caagatttac cacaaatgtg 1500
ataatgcatg cattggatca ataagaaatg gaacatatga ccattacata tacagagatg 1560
aagcattaaa caaccgattt cagatcaaag gtgttgagtt gaaatcaggc tataaagatt 1620
ggataatatg gatttcattt gccatatcat gcttcttaat ttgcgttgtt ctattgggtt 1680
ttattatgtg ggcttgccaa aaaggcaaca tcagatgcaa catttgcatt tgagtaaact 1740
gatagttaaa aacacccttg tttctact 1768
<210> 32
<211> 567
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 32
Met Lys Thr Thr Ile Ile Phe Asn Phe Ile Leu Leu Thr His Trp Ala
1 5 10 15
Tyr Ser Gln Asn Pro Ile Ser Asn Asn Asn Thr Ala Thr Leu Cys Leu
20 25 30
Gly His His Ala Val Ala Asn Gly Thr Leu Val Lys Thr Ile Ser Asp
35 40 45
Asp Gln Ile Glu Val Thr Asn Ala Thr Glu Leu Val Gln Ser Ile Ser
50 55 60
Met Gly Lys Ile Cys Asn Asn Ser Tyr Arg Ile Leu Asp Gly Arg Asn
65 70 75 80
Cys Thr Leu Ile Asp Ala Met Leu Gly Asp Pro His Cys Asp Val Phe
85 90 95
Gln Tyr Glu Asn Trp Asp Leu Phe Ile Glu Arg Ser Ser Ala Phe Ser
100 105 110
Asn Cys Tyr Pro Tyr Asp Ile Leu Asp Tyr Ala Ser Leu Arg Ser Ile
115 120 125
Ile Ala Ser Ser Gly Thr Leu Glu Phe Thr Ala Glu Gly Phe Thr Trp
130 135 140
Thr Gly Val Thr Gln Asn Gly Arg Ser Gly Ala Cys Lys Arg Gly Ser
145 150 155 160
Val Asp Ser Phe Phe Ser Arg Leu Asn Trp Leu Thr Lys Ser Gly Asn
165 170 175
Ser Tyr Pro Thr Leu Asn Val Thr Met Pro Asn Asn Lys Asn Phe Asp
180 185 190
Lys Leu Tyr Ile Trp Gly Ile His His Pro Ser Ser Asn Gln Glu Gln
195 200 205
Lys Lys Leu Tyr Ile Gln Glu Ser Gly Arg Val Thr Val Ser Thr Lys
210 215 220
Arg Ser Gln Gln Thr Ile Ile Pro Asn Ile Gly Ser Arg Pro Trp Val
225 230 235 240
Arg Gly Gln Ser Gly Arg Ile Ser Ile Tyr Trp Thr Ile Val Lys Pro
245 250 255
Gly Asp Ile Leu Met Ile Asn Ser Asn Gly Asn Leu Val Ala Pro Arg
260 265 270
Gly Tyr Phe Lys Leu Lys Thr Gly Lys Ser Ser Ile Met Arg Ser Asp
275 280 285
Val Pro Ile Asp Ile Cys Val Ser Glu Cys Ile Thr Pro Asn Gly Ser
290 295 300
Ile Ser Asn Asp Lys Pro Phe Gln Asn Val Asn Lys Ile Thr Tyr Gly
305 310 315 320
Lys Cys Pro Lys Tyr Ile Arg Gln Asn Thr Leu Lys Leu Ala Thr Gly
325 330 335
Met Arg Asn Val Pro Glu Lys Gln Ile Arg Gly Ile Phe Gly Ala Ile
340 345 350
Ala Gly Phe Ile Glu Asn Gly Trp Glu Gly Met Val Asp Gly Trp Tyr
355 360 365
Gly Phe Arg Tyr Gln Asn Ser Glu Gly Thr Gly Gln Ala Ala Asp Leu
370 375 380
Lys Ser Thr Gln Ala Ala Ile Asp Gln Ile Asn Glu Lys Leu Asn Arg
385 390 395 400
Val Ile Glu Arg Thr Asn Glu Lys Phe His Gln Ile Glu Lys Glu Phe
405 410 415
Ser Glu Val Glu Gly Arg Ile Gln Asp Leu Glu Lys Tyr Val Glu Asp
420 425 430
Thr Lys Ile Asp Leu Trp Ser Tyr Asn Ala Glu Leu Leu Val Ala Leu
435 440 445
Glu Asn Gln His Thr Ile Asp Leu Thr Asp Ala Glu Met Asn Lys Leu
450 455 460
Phe Glu Lys Thr Arg Arg Gln Leu Arg Glu Asn Ala Glu Asp Met Gly
465 470 475 480
Gly Gly Cys Phe Lys Ile Tyr His Lys Cys Asp Asn Ala Cys Ile Gly
485 490 495
Ser Ile Arg Asn Gly Thr Tyr Asp His Tyr Ile Tyr Arg Asp Glu Ala
500 505 510
Leu Asn Asn Arg Phe Gln Ile Lys Gly Val Glu Leu Lys Ser Gly Tyr
515 520 525
Lys Asp Trp Ile Ile Trp Ile Ser Phe Ala Ile Ser Cys Phe Leu Ile
530 535 540
Cys Val Val Leu Leu Gly Phe Ile Met Trp Ala Cys Gln Lys Gly Asn
545 550 555 560
Ile Arg Cys Asn Ile Cys Ile
565
<210> 33
<211> 1460
<212> DNA
<213> 甲型流感病毒(Influenza A virus)
<400> 33
agcaaaagca ggagtttaaa atgaatccga atcaaaagat aataacaatt ggatctgcat 60
cattggggat attaatcatt aacgtcattc tcaatgtagt cagcattata ataacagtac 120
tggtcctcaa taacaatgaa acatgtctga actgcaaagg gacgatcata agagagtaca 180
atgaaacagt aagagtagaa aaaattactc aatggcataa tacaagtgca attaagtaca 240
tagagagacc tccaaatgaa tactacatga acaacaccga accactttgt gaggcccaag 300
gctttgcacc attttccaaa gataatggaa tacgaattgg gtcgaaaggc catgtttttg 360
tgataagaga accctttgta tcatgttcgc cctcagaatg tagaaccttt ttcctcacac 420
agggctcatt actcaatgac aaacattcta acggcacagt aaaggatcga agtccataca 480
ggactttgat gagtgtcaaa atagggcaat cacccaatgt gtatcaagct aggtttgaat 540
cggtggcatg gtcagcaaca gcatgccatg atggaaaaaa atggatgaca attggagtca 600
cagggcccga caatcaagca attgcagtag tgaactatgg gggtgttccg gttgatatta 660
tcaattcatg ggcaggggac atcttaagaa cccaagaatc atcatgcacc tgcattaaag 720
gaaactgtta ttgggtaatg actgatggac cggcaaatag gcaagctaaa tataggatat 780
tcaaagcaaa agatgggaga gtaattggac agattgatat aaatttcaat gggggacaca 840
tagaggagtg ttcttgttac cccaatgaag ggaaagtgga atgcatatgc agggacaatt 900
ggactggaac aaatagaccg attctggtaa tatcttctga tctatcgtac acagttggat 960
atttgtgtgc tggcattccc actgacactc ctaggggaga ggatagtcaa ttcacaggct 1020
catgtacaag tcctttggga aataaaggat acggtgtaaa aggtttcggg tttcgacaag 1080
gaactgacgt atgggtcgga aggacaatta gtaggacttc gagatcagga ttcgaaataa 1140
taaaaatcag gaatggttgg acacagaata gtaaagacca aatcaggagg caagtgatca 1200
tcgatgaccc aaattggtca ggatatagcg gttctttcac attgccggtt gaattaacaa 1260
aaagaggatg tttggtcccc tgtttctggg ttgaaatgat tagaggtaaa cctgaagaat 1320
caacaatatg gacctctagc agctccattg tgatgtgtgg agtagatcat aaaattgcca 1380
gttggtcatg gcacgatgga gctattcttc cctttgacat cgataagatg taatttatga 1440
aaaaactcct tgtttctact 1460
<210> 34
<211> 470
<212> PRT
<213> 甲型流感病毒(Influenza A virus)
<400> 34
Met Asn Pro Asn Gln Lys Ile Ile Thr Ile Gly Ser Ala Ser Leu Gly
1 5 10 15
Ile Leu Ile Ile Asn Val Ile Leu Asn Val Val Ser Ile Ile Ile Thr
20 25 30
Val Leu Val Leu Asn Asn Asn Glu Thr Cys Leu Asn Cys Lys Gly Thr
35 40 45
Ile Ile Arg Glu Tyr Asn Glu Thr Val Arg Val Glu Lys Ile Thr Gln
50 55 60
Trp His Asn Thr Ser Ala Ile Lys Tyr Ile Glu Arg Pro Pro Asn Glu
65 70 75 80
Tyr Tyr Met Asn Asn Thr Glu Pro Leu Cys Glu Ala Gln Gly Phe Ala
85 90 95
Pro Phe Ser Lys Asp Asn Gly Ile Arg Ile Gly Ser Lys Gly His Val
100 105 110
Phe Val Ile Arg Glu Pro Phe Val Ser Cys Ser Pro Ser Glu Cys Arg
115 120 125
Thr Phe Phe Leu Thr Gln Gly Ser Leu Leu Asn Asp Lys His Ser Asn
130 135 140
Gly Thr Val Lys Asp Arg Ser Pro Tyr Arg Thr Leu Met Ser Val Lys
145 150 155 160
Ile Gly Gln Ser Pro Asn Val Tyr Gln Ala Arg Phe Glu Ser Val Ala
165 170 175
Trp Ser Ala Thr Ala Cys His Asp Gly Lys Lys Trp Met Thr Ile Gly
180 185 190
Val Thr Gly Pro Asp Asn Gln Ala Ile Ala Val Val Asn Tyr Gly Gly
195 200 205
Val Pro Val Asp Ile Ile Asn Ser Trp Ala Gly Asp Ile Leu Arg Thr
210 215 220
Gln Glu Ser Ser Cys Thr Cys Ile Lys Gly Asn Cys Tyr Trp Val Met
225 230 235 240
Thr Asp Gly Pro Ala Asn Arg Gln Ala Lys Tyr Arg Ile Phe Lys Ala
245 250 255
Lys Asp Gly Arg Val Ile Gly Gln Ile Asp Ile Asn Phe Asn Gly Gly
260 265 270
His Ile Glu Glu Cys Ser Cys Tyr Pro Asn Glu Gly Lys Val Glu Cys
275 280 285
Ile Cys Arg Asp Asn Trp Thr Gly Thr Asn Arg Pro Ile Leu Val Ile
290 295 300
Ser Ser Asp Leu Ser Tyr Thr Val Gly Tyr Leu Cys Ala Gly Ile Pro
305 310 315 320
Thr Asp Thr Pro Arg Gly Glu Asp Ser Gln Phe Thr Gly Ser Cys Thr
325 330 335
Ser Pro Leu Gly Asn Lys Gly Tyr Gly Val Lys Gly Phe Gly Phe Arg
340 345 350
Gln Gly Thr Asp Val Trp Val Gly Arg Thr Ile Ser Arg Thr Ser Arg
355 360 365
Ser Gly Phe Glu Ile Ile Lys Ile Arg Asn Gly Trp Thr Gln Asn Ser
370 375 380
Lys Asp Gln Ile Arg Arg Gln Val Ile Ile Asp Asp Pro Asn Trp Ser
385 390 395 400
Gly Tyr Ser Gly Ser Phe Thr Leu Pro Val Glu Leu Thr Lys Arg Gly
405 410 415
Cys Leu Val Pro Cys Phe Trp Val Glu Met Ile Arg Gly Lys Pro Glu
420 425 430
Glu Ser Thr Ile Trp Thr Ser Ser Ser Ser Ile Val Met Cys Gly Val
435 440 445
Asp His Lys Ile Ala Ser Trp Ser Trp His Asp Gly Ala Ile Leu Pro
450 455 460
Phe Asp Ile Asp Lys Met
465 470
Claims (21)
1.一种多价免疫组合物，其包含两种或更多种马减毒活流感病毒(LAIV)，所述组合物包括：
表达进化枝1H3N8马流感病毒的一种或多种抗原的第一LAIV；和
表达进化枝2H3N8马流感病毒的一种或多种抗原的第二LAIV，其中所述第二LAIV表达A/马/Lancashire/1/2016H3N8的HA、NA或其组合
其中每种LAIV包含在以下一项或多项中发生的一个或多个突变：病毒基因组的区段1和区段2。
2.如权利要求1所述的组合物，其中所述第一LAIV表达A/马/Ohio/1/2003H3N8的HA、NA或其组合。
3.如权利要求1所述的组合物，其中所述第一LAIV表达A/马/Texas/6/2017H3N8的HA、NA或其组合。
4.如权利要求1-3中任一项所述的组合物，其中所述区段1包含在SEQ ID NO:1中列出的核酸序列。
5.如权利要求1-3中任一项所述的组合物，其中所述区段2包含在SEQ ID NO:3中列出的核酸序列。
6.如权利要求1-3中任一项所述的组合物，其中至少一种LAIV在编码突变PB2的区段1中包含一个或多个突变。
7.如权利要求6所述的组合物，其中突变PB2包含N265S点突变。
8.如权利要求6-7中任一项所述的组合物，其中突变PB2包含在SEQ ID NO:2中列出的氨基酸序列。
9.如权利要求1-8中任一项所述的组合物，其中至少一种LAIV在编码突变PB1的区段2中包含一个或多个突变。
10.如权利要求9所述的组合物，其中突变PB1包含下列中的一个或多个：K391E点突变、E581G点突变和A661T点突变。
11.如权利要求9-10中任一项所述的组合物，其中突变PB1包含K391E点突变、E581G点突变和A661T点突变。
12.如权利要求9-11中任一项所述的组合物，其中突变PB1包含在SEQ ID NO:4中列出的氨基酸序列。
13.如权利要求1所述的组合物，其中每种LAIV在编码突变PB2的区段1中包含一个或多个突变；并在编码突变PB1的区段2中包含一个或多个突变。
14.如权利要求13所述的组合物，其中突变PB2包含N265S点突变并且其中突变PB1包含K391E点突变、E581G点突变和A661T点突变。
15.如权利要求1-14中任一项所述的组合物，其中所述组合物用于治疗受试者的马流感。
16.如权利要求1-15中任一项所述的组合物，其中每种LAIV的区段1源自A/马/Ohio/1/2003的区段1；并且其中每种LAIV的区段2源自A/马/Ohio/1/2003的区段2。
17.一种在受试者中诱导针对多种马流感病毒的免疫反应的方法，所述方法包括向所述受试者施用如权利要求1所述的免疫组合物。
18.利要求17所述的方法，其中所述受试者未患有马流感，并且其中所述方法诱导针对马流感的免疫。
19.如权利要求17所述的方法，其中所述受试者感染了马流感，并且其中所述方法诱导治疗性免疫反应。
20.如权利要求17-19中任一项所述的方法，其中所述免疫组合物经鼻内、气管内、口服、皮内、肌肉内、腹膜内、静脉内或皮下施用。
21.如权利要求17-19中任一项所述的方法，其中所述受试者是马。
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201962811112P | 2019-02-27 | 2019-02-27 | |
| US62/811,112 | 2019-02-27 | ||
| PCT/US2020/020050 WO2020176709A1 (en) | 2019-02-27 | 2020-02-27 | Multivalent live-attenuated influenza vaccine for prevention and control of equine influenza virus (eiv) in horses |
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| CN113905759A true CN113905759A (zh) | 2022-01-07 |
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| CN202080020053.3A Pending CN113905759A (zh) | 2019-02-27 | 2020-02-27 | 用于预防和控制马的马流感病毒(eiv)的多价减毒活流感疫苗 |
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| Country | Link |
|---|---|
| US (1) | US20220133877A1 (zh) |
| EP (1) | EP3930749A1 (zh) |
| CN (1) | CN113905759A (zh) |
| AR (1) | AR118202A1 (zh) |
| BR (1) | BR112021016182A2 (zh) |
| CA (1) | CA3130781A1 (zh) |
| MX (1) | MX2021010343A (zh) |
| WO (1) | WO2020176709A1 (zh) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017210528A1 (en) * | 2016-06-03 | 2017-12-07 | University Of Rochester | Equine influenza virus live-attenuated vaccines |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US5854037A (en) | 1989-08-28 | 1998-12-29 | The Mount Sinai School Of Medicine Of The City University Of New York | Recombinant negative strand RNA virus expression systems and vaccines |
| US5166057A (en) | 1989-08-28 | 1992-11-24 | The Mount Sinai School Of Medicine Of The City University Of New York | Recombinant negative strand rna virus expression-systems |
| DK0702085T4 (da) | 1994-07-18 | 2010-04-06 | Conzelmann Karl Klaus Prof Dr | Rekombinant infektiøs ikke-segmenteret negativ-strenget RNA-virus |
| US7153510B1 (en) | 1995-05-04 | 2006-12-26 | Yale University | Recombinant vesiculoviruses and their uses |
| ATE181112T1 (de) | 1995-08-09 | 1999-06-15 | Schweiz Serum & Impfinst | Dem genom von minussträngigen rna-viren entsprechende cdna und verfahren zur herstellung von infektiösen minussträngigen rna-viren |
| JPH11512609A (ja) | 1995-09-27 | 1999-11-02 | アメリカ合衆国 | クローン化されたヌクレオチド配列からの感染性ＲＳウイルス（ｒｅｓｐｉｒａｔｏｒｙ ｓｙｎｃｙｔｉａｌ ｖｉｒｕｓ）の生産 |
| BR9710363A (pt) | 1996-07-15 | 2000-01-11 | Us Gov Health & Human Serv | "vìrus sincicial respirátorio recombinante infeccioso isolado, partìcula do mesmo, processos para estimular o sistema imunológico de um indivìduo para induzir proteção contra o vìrus sincicial respiratório e para produzir uma partìcula de vìrus sincicial respiratório recombinante, vacina para induzir proteção contra o vìrus sincicial respiratório recombinante composição e ceta de vìrus sincicial respiratório recombinante" |
| CA2265554A1 (en) | 1996-09-27 | 1998-04-02 | American Cyanamid Company | 3' genomic promoter region and polymerase gene mutations responsible for attenuation in viruses of the order designated mononegavirales |
| BR9809456B1 (pt) | 1997-05-23 | 2011-06-28 | molécula isolada de polinucleotìdeo, composição de célula ou isenta de célula, partìcula de piv infeciosa, atenuada e imunogênica, e, composição imunogênica. | |
| CA2295858C (en) | 1997-07-11 | 2011-05-10 | Yale University | Rhabdoviruses with reengineered coats |
| JP2001517448A (ja) | 1997-09-19 | 2001-10-09 | アメリカン・サイアナミド・カンパニー | 弱毒化呼吸合胞体ウイルス |
| CN1935258B (zh) | 2001-07-27 | 2013-04-03 | 惠氏公司 | 西尼罗河疫苗 |
| WO2006088481A2 (en) * | 2005-02-15 | 2006-08-24 | Mount Sinai School Of Medicine Of New York University | Genetically engineered equine influenza virus and uses thereof |
| JP2009512449A (ja) * | 2005-10-19 | 2009-03-26 | ユニバーシティ オブ フロリダ リサーチ ファンデーション インコーポレーティッド | イヌにおける呼吸器疾患管理のための材料および方法 |
| TW201125984A (en) * | 2009-10-09 | 2011-08-01 | Univ New York State Res Found | Attenuated influenza viruses and vaccines |
| WO2013030176A2 (en) * | 2011-09-02 | 2013-03-07 | Westfälische Wilhelms-Universität Münster | Live attenuated influenza virus |
| WO2015010073A1 (en) * | 2013-07-19 | 2015-01-22 | University Of Rochester | Attenuated influenza vaccines and uses thereof |
| AR114410A1 (es) * | 2018-02-27 | 2020-09-02 | Univ Rochester | Vacuna multivalente contra influenza viva atenuada para prevenir y controlar el virus influenza equino (vie) en caballos |
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2020
- 2020-02-27 WO PCT/US2020/020050 patent/WO2020176709A1/en unknown
- 2020-02-27 CA CA3130781A patent/CA3130781A1/en active Pending
- 2020-02-27 AR ARP200100536A patent/AR118202A1/es unknown
- 2020-02-27 BR BR112021016182A patent/BR112021016182A2/pt not_active Application Discontinuation
- 2020-02-27 CN CN202080020053.3A patent/CN113905759A/zh active Pending
- 2020-02-27 EP EP20714405.6A patent/EP3930749A1/en active Pending
- 2020-02-27 MX MX2021010343A patent/MX2021010343A/es unknown
- 2020-02-27 US US17/434,489 patent/US20220133877A1/en active Pending
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| WO2017210528A1 (en) * | 2016-06-03 | 2017-12-07 | University Of Rochester | Equine influenza virus live-attenuated vaccines |
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| LAURA RODRIGUEZ ET AL.: "Development of a novel equine influenza virus live-attenuated vaccine", VIROLOGY, 11 January 2018 (2018-01-11), pages 76 - 77 * |
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| AR118202A1 (es) | 2021-09-22 |
| MX2021010343A (es) | 2022-01-18 |
| CA3130781A1 (en) | 2020-09-03 |
| US20220133877A1 (en) | 2022-05-05 |
| EP3930749A1 (en) | 2022-01-05 |
| WO2020176709A1 (en) | 2020-09-03 |
| BR112021016182A2 (pt) | 2021-11-03 |
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