CN110680913A - 亨德拉和尼帕病毒g糖蛋白免疫原性组合物 - Google Patents
亨德拉和尼帕病毒g糖蛋白免疫原性组合物 Download PDFInfo
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Abstract
本发明提供了亨德拉和尼帕病毒G糖蛋白免疫原性组合物,以及其使用方法。此外,提供了用本发明的免疫原性组合物疫苗接种过的对象和被亨德拉和/或尼帕病毒感染的对象的辨别方法。
Description
本申请是国际申请日2012年5月14日、国际申请号 PCT/US2012/037839于2014年1月7日进入中国国家阶段、申请号 201280033736.8、发明名称“亨德拉和尼帕病毒G糖蛋白免疫原性组合物”的申请的分案申请。
技术领域
本发明涉及包含来自于亨德拉病毒(HeV)和/或尼帕病毒(NiV) 的G糖蛋白的免疫原性和疫苗组合物,以及与其相关的使用方法。
背景技术
最近,引起大量人类死亡的NiV的反复爆发造成问题(参见例如 Butler(2000)Nature 429,7)。也已知HeV在人类和动物中造成死亡,并且它在遗传和免疫原性上与NiV密切相关。目前尚不存在用于预防由尼帕病毒或亨德拉病毒引起的感染或疾病的疫苗或疗法。尼帕病毒和亨德拉病毒两者都是美国国家过敏和传染病研究所(United States,National Institute of Allergy and Infectious Disease)C类优先生物防御关注试剂。此外,由于这些病毒是人畜共患生物安全4级试剂(BSL-4),因此安全地生产疫苗和/或诊断剂是非常高成本且困难的。因此,对于允许疫苗和/或诊断剂的高通量生产的尼帕病毒或亨德拉病毒疫苗或诊断剂,存在着需求。
副黏病毒例如HeV和NiV在病毒粒子的包膜中具有两种主要的膜锚定的糖蛋白。一种糖蛋白为毒粒附着于宿主细胞上的受体所需,并被称为血凝素-神经氨酸苷酶蛋白(HN)或血凝素蛋白(H),另一种是糖蛋白(G),其既没有血凝反应也没有神经氨酸苷酶活性。附着糖蛋白是II型膜蛋白,其中分子的氨基(N)端朝向胞质,蛋白的羧基(C) 端在细胞外。另一种主要糖蛋白是融合(F)糖蛋白,其是三聚体I类融合包膜糖蛋白,含有两个七肽重复(HR)区和疏水的融合肽。HeV 和NiV通过它们的附着G糖蛋白和F糖蛋白在受体结合后的协同作用,通过不依赖于pH的膜融合过程进入受体宿主细胞中以感染细胞。HeV 和NiV附着G糖蛋白的主要功能是啮合宿主细胞表面上的适合受体,所述受体对于大多数清楚表征的副黏病毒来说是唾液酸组成部分。HeV 和NiV G糖蛋白利用宿主细胞的蛋白受体肝配蛋白B2和/或肝配蛋白 B3,并且已开发出阻断通过G糖蛋白的病毒吸附的抗体 (WO2006137931,Bishop(2008)J.Virol.82:11398-11409)。此外,已开发出使用G糖蛋白作为产生针对HeV和NiV感染的免疫保护性应答的手段的疫苗(WO2009117035)。
对于Quil A在疫苗制剂中的兽药用途和人类用途来说,剂量-位点反应性是主要顾虑。避免Quil A的这种毒性的一种方式是使用免疫刺激性复合物(Rajput(2007)J.Zhejiang Univ.Sci.B,8:53-161)。这主要是由于Quil A在掺入到免疫刺激性复合物中时反应性降低,这是因为它与复合物中的胆固醇的结合降低了它从细胞膜提取胆固醇的能力,因此降低了它的细胞裂解效应。此外,为了产生相同水平的佐剂效应,需要的Quil A量更少。Quil A皂角苷的免疫调节性质以及当这些皂角苷被掺入到免疫刺激复合物中时产生的其他益处,已描述在 WO2000041720中。
HeV和/或NiV G糖蛋白与免疫刺激复合物在单一疫苗中的组合,由于这些组分联合给药时提高免疫反应性和降低佐剂副作用的潜力,代表了在开发有效的HeV和NiV疫苗中的进步。
发明概述
本发明涵盖一种免疫原性组合物,其包含亨德拉和/或尼帕病毒G 蛋白、免疫刺激复合物(ISC)和一种或多种赋形剂,其量能够在给药于对象后,有效地引发针对亨德拉和/或尼帕病毒的中和抗体的产生。在某些实施方式中,所述免疫原性组合物包含皂角苷、磷脂和类固醇。
在某些实施方式中,可溶性亨德拉病毒G糖蛋白由天然亨德拉病毒G糖蛋白(SEQID NO:2)的73至604位氨基酸构成。在某些实施方式中,所述可溶性亨德拉病毒G糖蛋白由包含SEQ ID NO:16的 64至1662位核苷酸的核苷酸序列编码。在某些实施方式中,所述可溶性亨德拉病毒G糖蛋白以二聚体形式存在,其中每个可溶性亨德拉病毒G糖蛋白二聚体的亚基通过一个或多个二硫键相连。在某些实施方式中,所述可溶性亨德拉病毒G糖蛋白以四聚体形式存在。在某些实施方式中,所述四聚体形式作为非共价连接的和/或通过一个或多个二硫键相连的二聚体的二聚体存在。在所述免疫原性组合物中,可溶性亨德拉病毒G糖蛋白的浓度可以为约5至100μg/ml。
在某些实施方式中,所述皂角苷从南美石碱木(Quillaja saponaria Molina)分离,并且可以选自QH-A、QH-B、QH-C或QS21。在某些实施方式中,所述磷脂选自磷脂酰胆碱(PC)、二棕榈酰基磷脂酰胆碱(DPPC)、磷脂酸(磷脂酸盐)(PA)、磷脂酰乙醇胺(PE)、磷脂酰丝氨酸(PS)、磷脂酰肌醇(PI)、磷脂酰肌醇磷酸(PIP)、磷脂酰肌醇二磷酸(PIP2)、磷脂酰肌醇三磷酸(PIP3)、磷酸胆碱(SPH)、神经酰胺磷酸乙醇胺(Cer-PE)和神经酰胺磷酸甘油。在某些实施方式中,所述皂角苷是Quil A,所述磷脂是DPPC,并且所述类固醇是胆固醇,并且所述组合物中Quil A:DPPC:胆固醇的比例以重量计为5: 1:1。
本发明还涵盖了在对象中产生针对亨德拉和/或尼帕病毒的中和抗体应答的方法,所述方法包括以有效产生所述中和抗体应答的量和持续时间向所述对象给药本文中所描述的免疫原性组合物。在某些实施方式中,所述中和抗体应答减少亨德拉和/或尼帕病毒在所述对象中的繁殖,并且也可以减少亨德拉和/或尼帕病毒在所述对象中的释放。在某些实施方式中,所述对象已暴露于亨德拉和/或尼帕病毒,而在其他实施方式中,所述对象正患有亨德拉和/或尼帕病毒感染。在某些实施方式中,本发明涵盖了在对象中产生针对亨德拉病毒的中和抗体应答的方法,所述方法包括以有效产生所述中和抗体应答的量和持续时间向所述对象给药本文中所描述的免疫原性组合物。在某些实施方式中,本发明涵盖了在对象中产生针对尼帕病毒的中和抗体应答的方法,所述方法包括以有效产生所述中和抗体应答的量和持续时间向所述对象给药本文中所描述的免疫原性组合物。
在某些实施方式中,所述免疫原性组合物肌肉内给药。在某些实施方式中,所述免疫原性组合物以多剂量给药,并且在第一剂量后给药第二剂量,所述第二剂量在所述第一剂量后至少约21天至约28天。在某些实施方式中,每剂量含有约50或约100μg可溶性亨德拉病毒G 糖蛋白。
本发明还涵盖了区分用本文中所描述的免疫原性组合物疫苗接种过的对象与暴露于亨德拉和/或尼帕病毒的对象的方法,所述方法包括在从所述对象分离的生物样品中,检测针对至少一种选自下列HeV和/ 或NiV病毒蛋白中的任一种的抗体的存在:融合蛋白(F),基质蛋白 (M),磷蛋白(P),大蛋白(L)和核衣壳蛋白(N)。
本发明的免疫原性组合物和方法可以被施用于例如人类、马、牛、绵羊、猪、山羊、鸡、狗或猫的对象。
本发明还涵盖在人类对象中产生针对亨德拉和/或尼帕病毒的中和抗体应答的方法,所述方法包括以有效产生所述中和抗体应答的量和持续时间,向所述对象给药包含亨德拉病毒可溶性G糖蛋白的免疫原性组合物。在某些实施方式中,所述免疫原性组合物还包含佐剂。
附图说明
图1示出了用50或100μg/剂量的重组亨德拉病毒可溶性糖蛋白(sG)和250μg作为佐剂的免疫刺激复合物给药,随后在第0天暴露于活的亨德拉病毒的马的直肠温度随时间的变化。
图2示出了用50或100μg/剂量的重组亨德拉病毒可溶性糖蛋白 (sG)和250μg作为佐剂的免疫刺激复合物给药,随后在第0天暴露于活的亨德拉病毒的马的心率随时间的变化。
图3示出了免疫刺激复合物的制备示意图。
图4示出了sGHeV疫苗接种和NiV激惹时间表的示意图。sGHeV 疫苗接种、NiV激惹和安乐死的日期用箭头指示。正如标出的(*),在激惹后第-42、-7、0、3、5、7、10、14、21和28天收集血液和拭子样本。灰色文本表示激惹时间线(上排);黑色文本表示疫苗接种时间线(下排)。示出了每个疫苗剂量组中对象非洲绿猴(AGM)的数量和一个对照对象。
图5示出了NiV感染的对象的存活曲线。使用来自于对照对象 (n=2)和sGHeV疫苗接种过的对象(n=9)的数据来产生Kaplan-Meier 存活曲线。对照包括来自于一个其他历史对照对象的数据。疫苗接种的对象接受皮下给药10μg、50μg或100μg的sGHeV两次。在对照对象中到达疾病末期的平均时间是11天,而所有疫苗接种过的对象存活到研究结束时的安乐死。
图6示出了疫苗接种过的对象中的NiV-和HeV-特异性免疫球蛋白(Ig)。从疫苗接种过的对象收集血清和鼻拭子,并使用sGHeV和 sGNiV多路微球测定法评估IgG、IgA和IgM应答。单个地测定来自于同一疫苗剂量组中的对象(n=3)的血清或拭子,并计算微球中值荧光强度(M.F.I.)的平均值,其示出在Y-轴上。误差线表示平均值的标准误差。血清sG-特异性Ig用黑色符号显示(sGHeV(空心三角形)、sGNiV (实心三角形)),粘膜sG-特异性IgA用灰色符号显示(sGHeV(空心三角形),sGNiV(实心三角形))。
发明描述
疫苗和免疫原性组合物
本发明的疫苗和免疫原性组合物在已给药所述组合物的对象中诱导许多体液免疫应答和细胞免疫应答中的至少一种,或有效地增强针对至少一种HeV和/或NiV毒株的至少一种免疫应答,使得所述给药适合于疫苗接种目的和/或预防由一种或多种HeV和/或NiV毒株引起的 HeV和/或NiV感染。本发明的组合物向需要的对象递送来自于HeV 和/或NiV的G糖蛋白、包括可溶性G糖蛋白,以及起到佐剂作用的免疫刺激复合物(ISC)。在某些实施方式中,G糖蛋白的量包括但不限于5、10、15、20、25、30、35、40、45、50、75、100、150、200或 250μg/ml,其还可以包含100、125、150、175、200、225、250、275 或300μg/ml的ISC。在某些实施方式中,G糖蛋白的量为5、50或 100μg/ml,ISC的量为250μg/ml。
A.HeV和NiV G蛋白
在某些实施方式中,疫苗和免疫原性组合物包含本文中描述的一种或多种HeV和/或NiV G糖蛋白。术语蛋白在本文中被广义使用,包括多肽或其片段。例如但不是限制性的,HeV G糖蛋白可以采取可溶性形式,并包含Wang(2000)J.Virol.74,9972-9979(也参见Yu(1998) Virology 251,227-233)中HeV G糖蛋白的氨基酸序列的73-604位氨基酸。此外,例如但不是限制性的,NiV G糖蛋白可以采取可溶性形式,并且包含Harcourt(2000)Virology271:334-349,2000(也参见Chua (2000)Science,288,1432-1)中NiV G糖蛋白的氨基酸序列的71-602 位氨基酸。
一般来说,HeV和NiV G糖蛋白的可溶性形式包含HeV或NiV 的G糖蛋白的全部或一部分胞外结构域(例如细胞外的),并且一般通过缺失G糖蛋白的全部或一部分跨膜结构域或G糖蛋白的全部或一部分细胞质尾区来产生。例如,可溶性G糖蛋白可以包含HeV或NiV G糖蛋白的完整胞外结构域。此外,例如但不是限制性的,可溶性G 糖蛋白可以包含HeV或NiVG糖蛋白的全部或一部分胞外结构域和部分跨膜结构域。
本发明的可溶性HeV或NiV G糖蛋白一般保留相应的天然病毒糖蛋白的一种或多种特性,例如与病毒宿主细胞受体相互作用或结合的能力,可以以寡聚体形式生产,或者引发能够识别天然G糖蛋白的抗体(包括但不限于病毒中和抗体)的能力。其他特性的实例包括但不限于阻断或阻止宿主细胞感染的能力。可以使用常规方法来评估可溶性HeV或NiV G糖蛋白的一种或多种特性。
例如但不是限制性的,编码可溶性HeV G糖蛋白的多核苷酸,可以包含编码Wang(2000)J.Virol.74,9972-9979中HeV G糖蛋白的氨基酸序列(SEQ ID NO:2)的73-604位附近氨基酸的多核苷酸序列。此外,例如但不是限制性的,编码可溶性HeV G糖蛋白的多核苷酸,可以包含Wang(2000)J.Virol.74,9972-9979中HeV G糖蛋白的多核苷酸序列的9129至10727位核苷酸。此外,也可以使用编码HeV G糖蛋白的氨基酸序列(SEQ ID NO:2)的73-604位附近氨基酸的、密码子优化过的多核苷酸序列。在某些实施方式中,这些密码子优化过的序列包含SEQ ID NO:16的64至1662位核苷酸或由其构成。在其他实施方式中,所述密码子优化过的序列包含SEQ ID NO:16,或由其构成,SEQ ID NO:16包括编码Igκ前导序列的核苷酸。
例如但不是限制性的,NiV G糖蛋白可以采取可溶形式,并包含 Harcourt(2000)Virology 271,334-349中NiV G糖蛋白的氨基酸序列的71-602位氨基酸。可用于构建可溶性NiV G糖蛋白的序列的非限制性实例,可以在Harcourt(2000)Virology 271,334-349中找到。总的来说,可以使用来自于任何尼帕病毒分离株或毒株的G糖蛋白序列来产生本发明的多核苷酸和多肽。
例如但不是限制性的,编码可溶性NiV G糖蛋白的多核苷酸,可以包含编码Harcourt(2000)Virology 271,334-349中NiV G糖蛋白的氨基酸序列的71-602位附近氨基酸的多核苷酸序列。此外,例如但不是限制性的,编码可溶性NiV G糖蛋白的多核苷酸可以包含Harcourt (2000)Virology 271,334-349中NiV G糖蛋白的多核苷酸序列(SEQ ID NO:4)的234-2042位。此外,也可以使用编码NiV G糖蛋白的氨基酸序列的71-602位附近氨基酸的、密码子优化过的多核苷酸序列。
在本发明的免疫原性和疫苗组合物中可以使用这些G糖蛋白的功能等同物。例如但不是限制性的,功能上等同的多肽具有一种或多种下列特性:能够与病毒宿主细胞受体相互作用或结合的能力,能够以二聚体或四聚体形式生产,引发能够识别天然G糖蛋白的抗体(包括但不限于HeV和/或NiV病毒中和抗体)的能力和/或阻断或阻止宿主细胞感染的能力。
在某些实施方式中,G糖蛋白可以采取二聚体和/或四聚体形式。这样的二聚体依赖于在G糖蛋白中的半胱氨酸残基之间形成的二硫键的形成。这样的二硫键可以与当在HeV或NiV表面中表达时天然G糖蛋白中形成的二硫键相对应(例如半胱氨酸的位置保持不变),或者所述二硫键在G糖蛋白中的存在或位置(例如通过改变氨基酸序列中半胱氨酸的位置)可以被改变,以便形成抗原性增强的不同的G糖蛋白二聚体和/或四聚体形式。此外,非二聚体化和四聚体化的形式也在本发明之内,同样还考虑到G糖蛋白存在大量构象依赖性表位(即由三级三维结构产生的),并且为了提供中和抗体应答,保留大量这样的天然表位是高度优选的。
本发明的HeV免疫原性和疫苗组合物可以含有长度可变但包括 SEQ ID NO:2的73至604位氨基酸残基的蛋白质。在本发明的一种实施方式中,本发明的包膜蛋白与SEQ IDNO:2的HeV糖蛋白(包括73至604位氨基酸)具有至少约85、90、91、92、93、94、95、96、 97、98或99%的同一性。因此,本发明的HeV G糖蛋白包含天然HeV G糖蛋白的具有足以产生构象表位的数量的氨基酸的免疫原性片段。免疫原性片段的非限制性实例包括长度可以为至少530、531、532、533、 534或535个或更多个氨基酸的氨基酸序列。在某些实施方式中,HeV G糖蛋白包含SEQ ID NO:2或由其构成,或者包含进一步包含Igκ前导序列(SEQ ID NO:15)的合成构建物或由其构成。
本发明的NiV免疫原性和疫苗组合物可以含有长度可变但包括 SEQ ID NO:4的71至602位氨基酸残基的蛋白质。在本发明的一种实施方式中,本发明的包膜蛋白与SEQ IDNO:4的NiV糖蛋白(包括71至602位氨基酸)具有至少约85、90、91、92、93、94、95、96、 97、98或99%的同一性。因此,本发明的NiV G糖蛋白包含天然NiV G糖蛋白的具有足以产生构象表位的数量的氨基酸的免疫原性片段。免疫原性片段的非限制性实例包括长度可以为至少528、529、530、531、 532或533个或更多个氨基酸的氨基酸序列。在某些实施方式中,NiV G糖蛋白包含SEQ ID NO:4或由其构成,或者包含进一步包含前导序列的合成构建物或由其构成。
本文中描述的免疫原性片段含有至少一个抗原表位并表现出HeV 和/或NiV抗原性,并且当出现在适合的构建物中,例如当与其他HeV 和/或NiV抗原融合或存在于载体上时,能够引起免疫应答,所述免疫应答针对天然抗原。在本发明的一种实施方式中,免疫原性片段含有来自于HeV和/或NiV抗原的至少20个连续氨基酸,例如来自于HeV 和/或NiV抗原的的至少50、75或100个连续氨基酸。
HeV和NiV G糖蛋白的实施方式还包括分离的多肽,其包含与天然HeV或NiV G糖蛋白具有至少85、90、91、92、93、94、95、96、 97、98、99或100%的同一性的氨基酸序列,其中所述多肽序列可以与天然HeV或NiV G糖蛋白的氨基酸序列相同,或者与天然HeV或NiV G蛋白的氨基酸序列相比可以包括或多达一定整数的氨基酸改变,其中所述改变选自至少一个氨基酸缺失、替换包括保守和非保守替换、或插入,并且其中所述改变可以发生在参比多肽序列的氨基或羧基端位置或那些末端位置之间的任何位置处,单个地散布在参比序列中的氨基酸之间,或作为一个或多个连续组散布在天然HeV或NiV G糖蛋白氨基酸序列内。
在氨基酸序列水平上的序列同一性或同源性,可以使用被定制用于序列相似性搜索的程序blastp、blastn、blastx、tblastn和tblastx (Altschul(1997)Nucleic AcidsRes.25,3389-3402和Karlin(1990) Proc.Natl.Acad.Sci.USA 87,2264-2268)所采用的算法,通过BLAST (基本局部比对搜索工具(Basic Local Alignment Search Tool))分析来确定。BLAST程序使用的方法是首先考虑查询序列与数据库序列之间的带有间隙(不连续)和不带间隙(连续)的相似区段,然后评估鉴定到的所有匹配的统计学显著性,最后仅仅总结那些满足预先选择的显著性阈值的匹配。对于序列数据库的相似性搜索的基本问题的讨论,参见Altschul(1994)Nature Genetics 6,119-129。用于柱状图、描述、比对、预期(即用于报告针对数据库序列的匹配的统计学显著性阈值)、截止值、矩阵和过滤器(低复杂度)的搜索参数,为缺省设定。Blastp、blastx、tblastn和tblastx所使用的缺省评分矩阵是BLOSUM62矩阵(Henikoff(1992)Proc.Natl.Acad.Sci.USA 89, 10915-10919),其被推荐用于长度超过85个氨基酸的查询序列。
本发明的疫苗和免疫原性组合物还可以包含来自于不同毒株的其他HeV和/或NiVG蛋白,其可以进一步增强本发明的免疫接种方法的效能。
B.免疫刺激复合物
总的来说,本发明提供了包含可溶形式的HeV和/或NiV G糖蛋白包膜蛋白与免疫刺激复合物(ISC)的组合的免疫原性组合物、包括疫苗组合物,并涉及使用这些组合物在对象中预防和治疗HeV和/或 NiV感染的方法。在本发明中,疫苗和/或免疫原性组合物包含起到佐剂作用的免疫刺激复合物。当在本文中使用时,“佐剂”是指尽管本身没有任何特异性抗原性效应,但可以刺激免疫系统,提高对抗原的应答的试剂。
ISC具有许多使其成为某些应用的理想佐剂的特点:
抗原节省:正如在例如Wee(2008)Mucosal Immunol.1,489-496 中注意到的,在抗原可获得性受限或抗原成本高的情形中,已显示ISC 允许将抗原节省多达10至100倍。这最可能是因为与其他佐剂相比更高的效率或更适合的作用机制的组合。
交叉呈递:正如在例如Schnurr(2009)J.Immunol.182,1253-1259 中注意到的,由抗原呈递细胞(APC)进行的抗原呈递通常遵从两条途径之一。外来抗原通常被APC吞食,然后在II类主要组织相容性复合体(MHC)分子的背景中被加工并重新表达在APC表面上。然后它们能够被淋巴细胞发现,并且如果存在正确的辅助刺激因子/信号,能够视情况而定产生对其做出的应答。自身或癌抗原和病毒抗原通常在I 类分子的背景中被加工和表达,因为它们存在于APC的细胞质中。对癌症和病毒抗原的有效免疫需要进入I类途径。这在病毒感染或细胞稳态(内部抗原的细胞周转)期间自然地发生。作为疫苗导入的抗原(病毒或自身抗原)需要找到从细胞外部通往细胞的抗原加工机构的道路和II类途径中通往I类途径的入口。这可以在树突状细胞(DC——特化的APC)中自然发生,或者可以通过用与佐剂ISC混合的抗原进行疫苗接种来实现。这种外部来源的抗体找到其进入抗原呈递的I类途径的道路的过程,被称为交叉呈递。ISC实现抗原的交叉呈递的准确机制尚未被完全阐明,但是可能依赖于ISC组分的膜扰乱。
体液应答和细胞介导的应答:正如在例如Maraskovsky(2009) Immunol.CellBiol.87,371-376中提到的,利用ISC的作用机制,使适应性免疫系统的体液和细胞两条支路接合。在某些物种中,这与使用这种佐剂的疫苗接种所刺激的细胞因子分布情况并行。1型免疫应答的特征在于白介素-2和IFN-γ的表达和针对细胞内病原体(细菌、原生动物和病毒)的保护,2型应答的特征在于白介素-4的表达和用于抗毒素和抗病原体相关免疫的中和抗体的产生。ISC在这两个极端之间提供了平衡的细胞因子分布情况,允许更加广泛的免疫应答。此外,许多研究显示,如果疫苗通过鼻内递送,ISC可能是有效的。这允许使粘膜表面敏化,从而在病原体进入的位点处提供了在这种情况下(粘膜免疫)特别相关的相关免疫,也参见(2001)Vaccine 19, 4072-4080。
可无菌过滤且一致的制造标准:ISC粒子的尺寸一般为直径40 nm,使其可以通过晚些时候在配制中用于对制剂进行除菌的滤器。此外,在Quil A中发现的三萜类皂角苷与胆固醇和磷脂结合的天然趋势,已被利用在开发ISC的制造方法中。不形成ISC粒子的QuilA物质从最终产品中被透析掉。通过控制组分的比例,从不均匀Quil A皂角苷谱产生一致的产品。该比例是重要的,因为偏差会产生非特征性40nm 粒子的结构(螺旋、片层等)。ISC胶体自由流动的本性及其可被透射电子显微术、HPLC和其他技术进行测量的能力,使得这种佐剂适合于释放测定法和其他质量测定法的开发。
因此,根据上述,在某些实施方式中,免疫刺激复合物与最适量 G糖蛋白的制剂包括皂角苷、磷脂和类固醇分子。在某些实施方式中,皂角苷、磷脂、类固醇分子的摩尔比为5:1:1的比例。免疫刺激复合物可以含有例如5至10重量%的皂角苷、1至5%的类固醇分子和磷脂,其余部分包含G糖蛋白。G糖蛋白可以直接地,或者通过化学偶联于载体蛋白(例如嵌合或融合蛋白)并在将蛋白掺入到免疫刺激复合物中之后,掺入到免疫刺激复合物中。对免疫刺激复合物的指称应该被理解为包括对其衍生物、化学等同物和类似物的指称。在某些实施方式中,将ISC与HeV和/或NiV G糖蛋白分开进行混合,然后将G 糖蛋白与ISC混合。在某些实施方式中,将G糖蛋白与皂角苷、磷脂和类固醇分子直接混合。
在某些实施方式中,在本发明中使用的皂角苷是Quil A和/或其衍生物。Quil A是从南美树木石碱木(Quillaja saponaria Molina)分离的皂角苷制备物,并且首先被Dalsgaard(1974)“皂角苷佐剂”(Saponin adjuvants),Archiv.für die gesamteVirusforschung,Vol.44,Springer Verlag,pp.243-254描述为具有佐剂活性。已通过HPLC分离到Quil A 的保留佐剂活性而没有与Quil A相关的毒性的纯化片段(EP 0362278),例如QS7和QS21(也称为QA7和QA21)。QS21是源自于南美石碱木的树皮的天然皂角苷,其诱导CD8+细胞毒性T细胞(CTL)、Th1 细胞和显著的IgG2a抗体应答,并且是在本发明的情形中使用的皂角苷。适合在ISC中使用的其他皂角苷包括但不限于Quil A的次级级分 QH-A、QH-B和QH-C,来自于皂皮树(Quillaja saponaria)之外的物种的皂角苷,例如来自于人参属(Panax)(人参)、黄芪属(Astragalus)、牛膝属(Achyranthes)、大豆属、金合欢属(Acacia)和党参属 (Codonopsis)的物种。在某些实施方式中,皂角苷从皂皮树之外的物种分离。
在本发明的免疫原性和疫苗组合物中使用的磷脂的非限制性实例,包括具有二酰基甘油酯结构的分子和鞘磷脂类。具有二酰基甘油酯结构的磷脂的非限制性实例包括磷脂酸(磷脂酸盐)(PA)、磷脂酰乙醇胺(脑磷脂)(PE)、磷脂酰胆碱(卵磷脂)(PC)、二棕榈酰基磷脂酰胆碱(DPPC)或磷脂酰丝氨酸(PS)。具有二酰基甘油酯结构的磷脂的其他非限制性实例包括磷酸肌醇类。示例性的磷酸肌醇类包括但不限于磷脂酰肌醇(PI)、磷脂酰肌醇磷酸(PIP)、磷脂酰肌醇二磷酸(PIP2)或磷脂酰肌醇三磷酸(PIP3)。鞘磷脂类的非限制性实例包括神经酰胺磷酸胆碱(神经鞘磷脂)(SPH)、神经酰胺磷酸乙醇胺(神经鞘磷脂)(Cer-PE)或神经酰胺磷酸甘油。
在本发明的免疫原性和疫苗组合物中使用的类固醇分子,包括包含类固醇作为其结构的一部分的分子。类固醇分子的非限制性实例包括胆固醇、孕烯醇酮、17-α-羟基孕烯醇酮、脱氢表雄酮、雄烯二醇、孕酮、17-α-羟基孕酮、雄烯二酮、睾酮、二羟基睾酮、去氧皮质甾酮、 11-去氧皮质甾酮、皮质醇、皮质酮、醛甾酮、雌酮、雌二醇或雌三醇。
在某些实施方式中,免疫刺激复合物通常但不限于是直径30-40 nm的小笼状结构。在某些实施方式中,免疫刺激复合物的形成具有比例为5:1:1的Quil A、胆固醇、磷脂酰胆碱和G糖蛋白的摩尔比。例如,免疫刺激复合物可以含有5至10重量%的Quil A、1至5%的胆固醇和磷脂,其余部分包含G糖蛋白。G糖蛋白可以直接地,或者通过偶联于载体蛋白(例如嵌合或融合蛋白)并在将蛋白掺入到免疫刺激复合物中之后,掺入到免疫刺激复合物中。对免疫刺激复合物的指称应该被理解为包括对其衍生物、化学等同物和类似物的指称。例如,对免疫刺激复合物的衍生物的指称,包括对如下免疫刺激复合物的指称:所述免疫刺激复合物中,Quil A、胆固醇、磷脂酰胆碱或蛋白中的一种或多种被例如删除、替换,或者向所述复合物中添加除Quil A、胆固醇、磷脂酰胆碱或蛋白之外的组分。免疫刺激复合物的功能等同物,可以是其中四种组分中的一种或多种被功能等同物代替的免疫刺激复合物。在本发明的某些实施方式中,免疫刺激复合物的G糖蛋白组分被删除。这种类型的免疫刺激复合物在本文中被称为无蛋白免疫刺激复合物。
在某些实施方式中,本发明包括但不限于下述免疫原性组合物,其包含分离的HeV或NiV G蛋白以及佐剂,所述G蛋白能够诱导产生在体外针对多种HeV和/或NiV毒株的交叉反应性中和抗血清,以及所述佐剂包含Quil A、DPPC和胆固醇,例如,其中所述组合物含有5、 50或100μg的可溶性HeV或NiV G蛋白,以及适合量的Quil A、DPPC 和胆固醇。免疫刺激复合物及其制备的其他示例性实施方式,描述在 EP 0242380B1和EP 0180564B1以及WO2000041720中(参见例如其中的第3和9页,参考:Cox&Coulter(1992)《佐剂技术进展以及在动物寄生虫控制利用性生物技术中的应用》(Advances in Adjuvant Technology andApplication in Animal Parasite Control Utilizing Biotechnology),第4章,Yong(ed.),CRC Press;Dalsgard(1974) Gesamte Virusforsch,44,243-254;澳大利亚专利公开号558258、589915、590904和632067)。也参见在美国专利6,506,386中描述的代表性流程以及其中对下述公知事实的参考,即可以使用在免疫刺激组合物形成时将蛋白抗原包含在其中的免疫刺激复合物(参见EP 0109942B1),或者提供预先形成的免疫刺激复合物,然后将其与分开添加的抗原等份试样混合以形成疫苗(参见EP 0436620B1)。正如普遍认识到的,也可以将蛋白抗原共价附连于免疫刺激复合物(再参见 EP 0180564B1)。在本领域中还公认免疫刺激复合物可以通过粘膜疫苗接种进行给药(参见Mowat(1991)Immunology 72,317-322),并且本发明的免疫刺激复合物可以通过包含膜定向蛋白而得以进一步改进以用于粘膜疫苗接种(WO 9730728)。
在某些实施方式中,本发明包括但不限于下述免疫原性组合物,其包含分离的HeV或NiV G蛋白以及佐剂,所述G蛋白能够诱导产生在体外针对多种HeV和/或NiV毒株的交叉反应性中和抗血清,以及所述佐剂包含Quil A、DPPC和胆固醇,例如,其中所述组合物含有5、 50或100μg的可溶性HeV或NiV G蛋白,以及适合量的Quil A、DPPC 和胆固醇。免疫刺激复合物的其他示例性实施方式描述在 WO200004720中。
在本发明的另一种实施方式中,疫苗和免疫原性组合物可以是药物组合物的一部分。本发明的药物组合物可以含有适合的可药用载体,其包含促进将活性化合物加工成可药用的、用于递送到作用位点的制剂的赋形剂和辅助剂。
C.赋形剂
本发明的免疫原性和疫苗组合物还可以包含采取冻干制剂或水性溶液形式的可药用载体、赋形剂和/或稳定剂(参见例如《Remington 药物科学与实践》(Remington:TheScience and practice of Pharmacy) (2005)Lippincott Williams)。可接受的载体、赋形剂或稳定剂在使用剂量和浓度下对接受者是无毒的,并且可以包含缓冲剂例如磷酸盐、柠檬酸盐和其他有机酸,包括抗坏血酸和甲硫氨酸的抗氧化剂,防腐剂(例如汞((邻羧基苯基)硫)乙基钠盐(THIOMERSAL)、十八烷基二甲基苯甲基氯化铵、氯化六烃季铵、苯扎氯铵、苄索氯铵、苯酚、丁醇或苯甲醇、对羟基苯甲酸烷基酯例如对羟基苯甲酸甲酯或丙酯、儿茶酚、间苯二酚、环己醇、3-戊醇和间甲酚),蛋白质例如血清白蛋白、明胶或免疫球蛋白,亲水性聚合物例如聚乙烯吡咯烷酮,氨基酸例如甘氨酸、谷氨酰胺、天冬酰胺、组氨酸、精氨酸或赖氨酸,单糖、二糖和其他糖类包括葡萄糖、甘露糖或葡聚糖,螯合剂例如EDTA,糖类例如蔗糖、甘露糖醇、海藻糖或山梨糖醇,形成盐的平衡离子例如钠,金属复合物(例如Zn-蛋白复合物),和/或非离子表面活性剂例如聚乙二醇(PEG)、TWEEN或PLURONICS。
本发明的组合物可以以一定剂量悬浮在足以携带所需剂量的体积的任何适合的药用介质或载体中。一般来说,包括载体、佐剂等的终体积,通常为至少1.0ml。上限由待给药的量的实用性决定,一般不超过约0.5ml至约2.0ml。
使用方法
本发明涵盖了预防和/或治疗亨德拉和/或尼帕病毒感染的方法,所述方法包括将本发明的免疫原性和疫苗组合物给药到任何哺乳动物对象中。由使用HeV和/或NiV G糖蛋白和本文描述的佐剂的疫苗接种引发的主动免疫,可以引起或加强细胞或体液免疫应答。可以将有效量的HeV和/或NiV G糖蛋白或其抗原性片段与佐剂制备成混合物,以制备疫苗。
本发明涵盖了在人类对象中预防和/或治疗亨德拉和/或尼帕病毒感染的方法,所述方法包括给药包含可溶性HeV和/或NiV G糖蛋白或其组合的免疫原性和/或疫苗组合物本身,或将其与适合于在人类中使用的至少一种佐剂组合给药。适合在人类中使用的佐剂可以单独或组合使用。适合用于人类的佐剂的实例包括但不限于铝盐。铝盐的实例包括但不限于氢氧化铝、氢氧化铝凝胶(AlhydrogelTM)、磷酸铝、明矾(硫酸铝钾)或混合的铝盐。适合用于人类的佐剂的其他实例包括但不限于油包水乳液、水包油乳液和AS04(氢氧化铝和单磷酰脂A 的组合)和CpG寡脱氧核苷酸。CpG寡脱氧核苷酸是合成的寡核苷酸,其在特定序列背景中含有未甲基化的CpG二核苷酸(CpG基序)。这些CpG基序在细菌DNA中以比哺乳动物DNA中高20倍的频率出现。 CpG寡脱氧核苷酸被Toll-样受体9(TLR9)识别,引起强烈免疫刺激效应。
本文描述的包含HeV和/或NiV G糖蛋白与一种或多种佐剂的疫苗或免疫原性组合物的给药,可以出于预防或治疗目的。在本发明的一个方面,组合物可用于预防目的。当预防性提供时,疫苗组合物在 HeV和/或NiV感染的任何检测或症状之前提供。有效量的化合物的预防性给药,起到防止或减弱任何随后的HeV和/或NiV感染的作用。
当治疗性提供时,在检测到实际感染的症状之后提供有效量的疫苗。如果组合物的给药可以被接受者耐受,它被称为是“药理学可接受的”。如果给药的量是生理学显著的,这样的组合物被称为以“治疗或预防有效的量”给药。如果本发明的疫苗或免疫原性组合物的存在,通过例如增强对一种或多种HeV和/或NiV毒株的广泛反应性体液免疫应答或细胞免疫应答而引起接受患者的生理学的可检测的改变,则它是生理学显著的。所提供的保护不一定是绝对的(即HeV或NiV 感染不一定被完全阻止或消除),只要相对于对照群体存在统计学显著的改进即可。保护可以局限于减轻疾病症状的严重性或发作的快速性。
本发明的疫苗或免疫原性组合物可以赋予对多种HeV和/或NiV 毒株的抗性。当在本文中使用时,如果疫苗向对象的给药导致感染的症状或病症的完全或部分减弱(即抑制)或个体对感染的完全或部分免疫,则疫苗被称为防止或减弱感染。
本发明的至少一种疫苗或免疫原性组合物可以通过实现所需目的的任何手段,使用本文中所描述的药物组合物来给药。例如,这样的组合物的给药可以通过各种肠胃外途径,例如皮下、静脉内、皮内、肌肉内、腹膜内、鼻内、透皮或口腔途径。在本发明的一种实施方式中,组合物通过皮下给药。肠胃外给药可以通过快速浓注或通过随时间逐渐灌注。
用于预防、抑制或治疗可以通过主动特异性细胞免疫疗法通过细胞免疫应答减轻的疾病或病症的典型治疗方式,包括在长达并包括一周至约24个月的时间段内给药有效量的如上所述的疫苗组合物,其作为单次治疗给药或作为增强或加强剂量重复给药。非限制性实例包括第一剂量以及随后在所述第一剂量(第0天)后至少约10、11、12、 13、14、15、16、17、18、19、20、21、22、23或24天的第二剂量。免疫原性或疫苗组合物的剂量可以低于、等于或高于第0天给药的第一剂量。
根据本发明,疫苗或免疫原性组合物的“有效量”,是足以实现所需生物效应的量,所述生物效应在这种情况下是针对一种或多种 HeV和/或NiV毒株的至少一种细胞或体液免疫应答。应该理解,有效剂量取决于对象的年龄、性别、健康和体重,如果存在的话同时进行的治疗的种类,治疗的频率,以及所需效果的本质。下面提供的有效剂量的范围不打算限制本发明,并且代表了可能适合于给药本发明组合物的剂量范围的实例。然而,正如本领域技术人员理解并且可以不经过多实验确定的,剂量可以根据个体对象来定制。
本发明的疫苗和免疫原性组合物的接受者,可以是能够通过针对 HeV和/或NiV的细胞或体液免疫应答获得特异性免疫的任何对象,其中所述细胞应答由I类或II类MHC蛋白介导。在哺乳动物中,接受者可以是灵长目的哺乳动物(包括人类、黑猩猩、猿和猴)。在本发明的一种实施方式中,提供了使用本发明的疫苗或免疫原性组合物治疗人类的方法。对象可能感染有HeV和/或NiV,或者正如在实验研究中的,提供HeV或NiV感染的模型。在某些实施方式中,对象是驯养哺乳动物,包括但不限于马、牛、公牛、水牛、绵羊、猪(Mingyi(2010)Vet.Res.41,33)、山羊、狗(Biosecurity Alert-Hendra Update,2011 年7月27日,PressRelease,Biosecurity Queensland)或猫。在某些实施方式中,对象是禽类,包括鸡。
本发明的疫苗在用于针对亨德拉病毒感染提供保护的剂量下也提供了针对尼帕病毒的交叉保护性,因此也提供了对抗尼帕病毒的有效的疫苗接种。
对有效免疫应答的指称,应该被理解为是对直接或间接引起有益的预防或治疗效果的免疫应答的指称。在免疫原包含本文所描述的 HeV或NiV G糖蛋白的情形中,这样的应答包括在动物中减少或阻断病毒繁殖和/或病毒释放和/或减轻疾病症状。应该理解,效能是功能性度量,并且不单单由抗HeV和/或抗NiV抗体的滴度决定,因为单独的循环抗体的存在不必然表明所述循环抗体阻断病毒繁殖和释放的能力。
此外,例如但不是限制性的,如果给药本发明的可溶性G蛋白多肽以在被亨德拉或尼帕病毒感染或怀疑被所述病毒感染的对象中增强免疫应答,和/或如果作为被动免疫治疗的形式给药本发明的抗体,则所述组合物可以进一步包含例如其他治疗剂(例如抗病毒剂)。
下面的实施例4提供了关于在马的疫苗接种中使用的某些优选组合物的信息。对于可能被亨德拉病毒感染并因此有必要进行疫苗接种以保护动物和人类两者免于亨德拉病毒和尼帕病毒两者的感染的其他动物来说,下面的信息一般是适用的,并且可以被本领域技术人员容易地改编。总的来说,伴侣动物(狗和猫)有必要接种约25微克亨德拉病毒抗原,并且可以从25-150微克范围内的ISC佐剂获益,其中在使用本文公开的任何组分物质时,优选的ISC组合物中具有5:1:1 的皂角苷、磷脂和甾醇比例。对于伴侣动物来说,最终剂量优选地为约1ml。PolygenTM(MVP Technologies),这种基于共聚物的佐剂,也可以以优选地约5-15%(v/v)的量使用。
总的来说,对于更大的农场动物(绵羊、牛、猪等)来说,本文中为马所提供的抗原和佐剂给药量(以及最终给药体积)是适用的,也就是说50-100微克抗原,并且通常可以使用约250微克ISC,终体积为例如1-3ml。对于猪来说,可替选并且有效的佐剂配方包含(对于近似相同量的抗原来说)ISC与离子性多糖的掺混物,具体来说是1-3 ml最终剂量体积中100mg DEAE葡聚糖和800微克ISC(仍然是5:1: 1的Quil A:磷脂酰胆碱:胆固醇(参见WO2000/41720))。
疫苗接种过的动物的区分
本发明还涵盖了区分健康的疫苗接种过的动物与曾暴露于HeV和 /或NiV的或被其感染的动物的方法。在病毒感染期间,HeV和NiV表达G糖蛋白(G)之外的其他蛋白,包括融合蛋白(F)、基质蛋白(M)、磷蛋白(P)、大蛋白(L)和核衣壳蛋白(N)。这些其他蛋白具有在动物中诱导免疫应答的潜力,所述免疫应答采取与这些蛋白结合的抗体或T细胞免疫的形式。针对这些其他蛋白的抗体应答的水平,通常可以通过诸如酶联免疫测定(EIA)的测定法来测量。在某些实施方式中,本发明的免疫原性和疫苗制剂仅含有G糖蛋白作为HeV和/或 NiV抗原,因此诱导的免疫应答具有仅仅针对HeV和/或NiV的G糖蛋白的抗体。用本文描述的免疫原性组合物疫苗接种并随后被HeV或 NiV感染的动物,将建立针对G糖蛋白的加强的免疫应答,但是也将显示出对G糖蛋白之外的某些其他HeV和NiV蛋白的抗体表现形式的变化。因此,可以在EIA中测量针对任何融合蛋白(F)、基质蛋白(M)、磷蛋白(P)、大蛋白(L)和核衣壳蛋白(N)的抗体的存在,以确定血清样品中特异性针对这些蛋白的抗体的存在或不存在。如果检测到针对这些其他蛋白(即G糖蛋白之外的蛋白)中的任一种的抗体,则所述动物已暴露于HeV和/或NiV。或者,如果没有发现针对这些其他蛋白的抗体并且只检测到与G蛋白结合的抗体,则动物只是接种过疫苗。
在HeV和/或NiV感染的动物和已用本文描述的免疫原性组合物疫苗接种过的动物的检测和区分中,本发明的EIA既具有高特异性又具有高选择性。本发明可以利用各种测定法程序,包括在均相和非均相两种环境中的ELISA。所述测定法程序可以在诸如血液、血清、乳汁或含有抗体的任何其他体液的样品上进行。
在某些实施方式中,在EIA中使用的抗体可以唯一地与通过使用 G糖蛋白的疫苗接种所诱导的抗体竞争,而不与HeV和/或NiV感染在动物中诱导的抗体竞争。这不仅允许HeV和NiV感染的血清学诊断,而且允许在单次测定中区分疫苗接种和感染。EIA程序可以在标准的血清样品或含有抗体的任何体液或分泌物上进行。EIA程序可以利用针对 G糖蛋白和任何其他HeV和/或NiV病毒蛋白(例如融合蛋白(F)、基质蛋白(M)、磷蛋白(P)、大蛋白(L)和核衣壳蛋白(N),因为这样的蛋白在尚未暴露于HeV和/或NiV的、疫苗接种过的健康动物中不存在)的单克隆和/或多克隆抗体。EIA可以在很多可商购的固定或便携的手动、半自动或机器人自动化ELISA设备中,使用或不使用计算机辅助的数据分析还原软件和硬件来进行。在某些实施方式中,区分健康疫苗接种动物与曾暴露于HeV和/或NiV或被其感染的动物的方法,可以在从驯养哺乳动物分离的生物样品上进行,所述驯养哺乳动物包括但不限于马、牛、绵羊、猪、山羊、狗或猫。在某些实施方式中,对象是禽类,包括鸡。在某些实施方式中,对象是人类。
实施例
下面的实施例仅仅说明本发明的某些而不是全部实施方式,因此不应被视为对本发明范围的限制。
实施例1:载体构建物
构建了用于表达跨膜/胞质尾部缺失的HeV G或NiV G的载体。通过PCR扩增全长HeV或NiV G蛋白的克隆的cDNA,以产生编码跨膜结构域/胞质尾部缺失的HeV或NiV G蛋白的约2600个核苷酸的片段。
合成下面的用于HeV G扩增的寡核苷酸引物。
合成下面的用于NiV G扩增的寡核苷酸引物。
所有PCR反应使用Accupol DNA聚合酶(PGS Scientifics Corp),使用下列设置来进行:首先94℃5分钟,然后进行94℃1分钟、56 ℃2分钟、72℃4分钟的25个循环。这些引物产生的PCR产物是侧翼带有Sal 1位点的sHeV G ORF和侧翼带有Xho 1位点的sNiV G ORF。对PCR产物进行凝胶纯化(Qiagen)。在凝胶纯化后,将sHeV G和sNiV G亚克隆到TOPO载体(Invitrogen)中。
购买PSectag2B(Invitrogen)并将其修改成含有S-肽标签或myc- 表位标签。合成重叠寡核苷酸,其编码S-肽和消化的Kpn 1和EcoR 1 突出部分的序列。
合成重叠寡核苷酸,其编码myc-表位标签和消化的Kpn 1和EcoR 1突出部分的序列。
将64pmol SPEPS与64pmol SPEPAS混合并加热至65℃5分钟,缓慢冷却至50℃。将64pmol MTS与64pmol MTAS混合并加热至65 ℃5分钟,缓慢冷却至50℃。将两种混合物稀释并克隆到Kpn 1-EcoR 1消化的pSecTag2B中,以产生S-肽修饰的pSecTag2B或myc-表位修饰的pSecTag2B。所有构建物首先通过限制性消化进行筛选,并通过测序进一步验证。
将TOPO sG构建物用Sal 1消化,凝胶纯化(Qiagen),并同框亚克隆到S-肽修饰的pSecTag2B或myc-表位修饰的pSecTag2B的Xho 1位点中。所有构建物首先通过限制性消化进行筛选,并通过测序进一步验证。
然后将Igκ前导肽-S-肽-s HeVG(sGS-tag)和Igκ前导肽-myc标签 -sHeVG(sGmyc-tag)构建物亚克隆到痘苗病毒穿梭载体pMCO2中。合成寡核苷酸序列: 5’-TCGACCCACCATGGAGACAGACACACTCCTGCTA-3’(SEQ ID NO:13),并将其与寡核苷酸sHGAS组合使用,通过PCR扩增sGs-tag和sGmyc-tag。所有PCR反应使用Accupol DNA聚合酶(PGS Scientifics Corp.),使用下列设置来进行:首先94℃5分钟,然后进行94℃1 分钟、56℃2分钟、72℃4分钟的25个循环。这些引物产生侧翼带有Sal 1位点的PCR产物。对PCR产物进行凝胶纯化(Qiagen)。在凝胶纯化后,将sGS-tag和sGmyc-tag亚克隆到TOPO载体(Invitrogen) 中。将sGS-tag和sGmyc-tag用Sal 1消化,并亚克隆到pMCO2的Sal 1位点中。所有构建物首先通过限制性消化进行筛选,并通过测序进一步验证。随后产生在SEQ ID NO:16中示出的密码子优化的核苷酸序列,以促进在真核细胞系中的生产。
实施例2:使用痘苗病毒进行的可溶性G蛋白的蛋白质生产
为了进行蛋白质生产,使用含有密码子优化的序列的遗传构建物来产生重组痘病毒载体(痘苗病毒,WR毒株)。然后使用标准技术,利用tk选择性和GUS染色,获得重组痘病毒。简单来说,使用磷酸钙转染试剂盒(Promega),将CV-1细胞用pMCO2 sHeV G融合体或pMCO2 sNiV G融合体转染。然后将这些单层用痘苗病毒的Western Reserve(WR)野生型毒株,以0.05PFU/细胞的感染复数(MOI)进行感染。2天后,收集细胞沉淀物作为粗品重组病毒储用物。在25μg/ml 5-溴-2’-脱氧尿苷(BrdU)(Calbiochem)存在下,将TK-细胞用重组的粗品储用物感染。2小时后,将病毒用含有1%低熔点(LMP)琼脂糖(Life Technologies)和25μg/ml BrdU的EMEM-10覆盖层代替。在温育2天后,加入含有1%LMP琼脂糖、25μg/ml BrdU和0.2mg/ml 5- 溴-4-氯-3-吲哚基-β-D-葡萄糖醛酸(X-GLUC)(Clontech)的另外的 EMEM-10覆盖层。在24-48小时内,蓝色噬斑显现,挑取并进行另外两轮双选择噬斑纯化。然后通过标准方法扩增并纯化重组痘苗病毒 vKB16(sHeV G融合体)和vKB22(sNiV G融合体)。简单来说,通过噬斑纯化、细胞培养扩增、在超速离心机中进行蔗糖垫层沉淀和通过噬斑测定法滴定,来纯化重组痘苗病毒。在细胞裂解物和培养上清液中验证sHeV G的表达。
实施例3:使用293F细胞进行的可溶性G蛋白的蛋白质生产
使用含有密码子优化的序列的遗传构建物转化293F细胞 (Invitrogen),以产生表达HeV可溶性G糖蛋白的稳定细胞系。CHO-S 细胞(Invitrogen)也可用于转化和HeV可溶性G糖蛋白的表达。将转化的细胞在含有35ml DMEM-10的162cm2组织培养瓶中铺板。允许细胞粘附并在37℃和5-8%CO2下生长几天。当细胞汇合时,将它们拆分到含有DMEM-10和150μg/ml潮霉素B的多个培养瓶中(30ml/瓶)。当细胞汇合度为70-80%时,将它们用30ml PBS洗涤两次,然后加入 20ml 293SFM II(Invitrogen),并将细胞在37℃和5-8%CO2下温育过夜。第二天,将细胞转移到含有200ml SFM II培养基的Erlenmeyer 瓶中。允许细胞在37℃和5-8%CO2下在125rpm下生长5-6天,直至细胞开始死亡。此时收集上清液。
将来自于每个Erlenmeyer瓶的培养基以3,500rpm离心30分钟。然后将上清液转移到250ml离心瓶中,并以10,000rpm离心1小时。收集得到的上清液并按照制造商的推荐加入蛋白酶抑制剂以及Triton X-100至终浓度为0.1%。然后将上清液通过0.2μm低蛋白结合性滤膜进行过滤。
使用S-蛋白琼脂糖亲和柱纯化HeV sG。将20ml床体积的S-蛋白琼脂糖(Novagen)装入XK 26柱(GE Healthcare)中。将柱用10倍床体积的结合/洗涤缓冲液(0.15M NaCl,20mM Tris-HCl,pH 7.5和 0.1%Triton X-100)洗涤。将制备的HeV sG上清液施加到柱,以维持 3ml/分钟的流速。将柱用10倍床体积(200ml)的结合/洗涤缓冲液I 洗涤,然后用6倍床体积(120ml)的1x洗涤缓冲液(0.15M NaCl 和20mM Tris-HCl,pH 7.5)洗涤。
然后停止泵并允许洗涤缓冲液排出,直至它达到珠子的表面,此时加入30ml洗脱缓冲液(0.2M柠檬酸,pH 2)。收集前10ml流过液(这应该仍然是洗涤缓冲液),然后将洗脱缓冲液与珠子温育10分钟。接下来,将15ml洗出液收集在含有25ml中和缓冲液(1M Tris, pH8)的50ml无菌锥形离心管中。将pH调整到中性,并将洗脱和温育重复三次。将所有中和的洗出液合并并浓缩至约4ml。将收集的HeV sG(4ml)通过0.2μm低蛋白结合性滤膜(带有0.2μmHT Tuffryn膜的Acrodisc 13mm注射式滤器)进行纯化。
可以使用凝胶过滤来进一步纯化HeV sG。在质量控制分析以及纯度和寡聚状态证实后,将合并的四聚体+二聚体、二聚体和单体HeV sG 级分的等分试样储存在-80℃下。
实施例4:疫苗制剂的制备
概述ISC的制备的示意流程示出在图3中并在下面进一步描述。
步骤1:在注射用水(WFI)中制备90g/L癸酰基-n-甲基葡萄糖酰胺(Mega-10去污剂)的溶液。将溶液加热以确保Mega 10完全溶解,然后将它在步骤2中立即使用或过滤除菌。
步骤2:通过将胆固醇和二棕榈酰基磷脂酰胆碱溶解在Mega 10 去污剂的储用溶液中,来制备含有25g/L胆固醇和25g/L二棕榈酰基磷脂酰胆碱(DPPC)的溶液。将溶液加热以溶解所有组分,然后将其在步骤3中立即使用或过滤除菌。
步骤3:使用WFI制备缓冲的等渗盐水,10mM磷酸盐缓冲液,pH 6.2±1(BIS),并且如果不立即使用,则将其过滤除菌。
步骤4:在BIS中制备Quil A至终浓度为100g/L,并且如果不立即使用,则将其除菌过滤。
步骤5:通过顺序添加预热的BIS、胆固醇/DPPC在Mega-10中的溶液(160ml/L)和Quil A溶液(200ml/L),在搅拌的控温容器(22-37 ℃)中配制ISC。通过添加BIS使反应达到目标体积。
步骤6:将整个制剂平衡到所需温度(目标温度为27℃,可接受的操作范围为22-37℃),然后在搅拌下温育15分钟以便于ISC形成。将ISC溶液在步骤7中进一步处理,或除菌过滤用于中间储存。
步骤7:在温度控制下(目标温度为27℃,可接受的操作范围为 21-37℃),通过针对BIS进行至少20倍体积的交换进行透析(膜: Hydrosart 30kDa(Sartorius AGGoettingen))来洗涤ISC反应混合物,以除去未复合的组分。
步骤8:通过使用与用于透析相同的膜进行超滤,将透析过的ISC 浓缩约2倍。将过滤系统用BIS漂洗,以将ISC恢复到原始体积。
步骤9:通过0.22μm纤维素乙酸酯滤膜进行除菌过滤,将ISC转移到无菌储存容器中。
步骤10:将ISC佐剂储存在2-8℃下,直至取出用于疫苗配制。
然后将免疫刺激组合物(250μg/ml)与适合量的可溶性HeV G糖蛋白合并(例如5、50、100μg/ml),并在BIS中调整至终体积。
实施例5:在马中的第一次临床实验
试验疫苗1:含有250μg免疫刺激复合物佐剂的100μg/剂的重组亨德拉病毒可溶性糖蛋白(sG);使用盐水溶液将体积调整至1ml/剂。
试验疫苗2:含有250μg免疫刺激复合物佐剂的50μg/剂的重组亨德拉病毒可溶性糖蛋白(sG);使用盐水溶液将体积调整至1ml/剂。
试验疫苗3:含有250μg免疫刺激复合物佐剂的5μg/剂的重组亨德拉病毒可溶性糖蛋白(sG);使用盐水溶液将体积调整至1ml/剂。
来自于马的血清学和激惹保护数据,从给药含有较高水平抗原的疫苗(50μg/剂和100μg/剂)的两批次的马收集。
血清学:将两匹马各自间隔21天用两剂疫苗(含ISC的100μg sG) 进行免疫。初次免疫后和激惹前的血清学研究证实了疫苗诱导的向 HeV的血清转化(表1)。激惹前病毒中和抗体水平,与已发现在曾暴露于否则就是致死剂量的近缘尼帕病毒的猫中具有保护性的中和抗体水平相当。仅接受佐剂的马(阴性对照)在病毒激惹之前不产生针对 HeV的抗体。
表1
马编号 | 基线滴度 | 初次免疫后滴度 | 激惹前滴度 |
V1 | <2 | 32 | 1024 |
V2 | <2 | 32 | 512 |
V3(对照) | <2 | <2 | <2 |
相应地,在接受加强免疫后27天,在BSL4密闭设施中将每匹马暴露于活的HeV。将病毒鼻内(1x 106TCID50)和口服(1x 106TCID50) 给药。在激惹时以及对于其后的观察时期来说,参与这部分工作的人员并不知道对照马的身份。
V1的临床观察:这匹马在暴露于HeV后的观察期间,除了在激惹后第8天注意到的内置颈静脉插管的进入位点的局部感染之外,在临床上保持良好。这与疾病的任何构成性征兆无关。在病毒激惹后第9 天,将马可选地安乐死。粗略尸检时的异常情况局限于10cm的肠系膜脂肪瘤(偶然发现)和左心肺叶腹侧顶部处可归因于巴比妥酸盐的淋巴管的轻度扩张。组织的初始筛查在这匹马中未发现病损或HeV抗原的迹象。
V2的临床观察:这匹马在第3天发生轻度暂时性流鼻涕,但是其他方面保持良好,直至在第6天体温升高,伴随有其内置颈静脉插管位点处的局部炎性反应。移除插管,但是病损继续扩大,并且马变得相当易怒,因此在下一天(d7)用长效青霉素治疗所述母马。在第8 天,她的体温和性情已恢复正常,并将其可选地安乐死。粗略尸检时的异常情况局限于右心肺叶腹侧顶部处可归因于巴比妥酸盐的淋巴管的轻度扩张。组织的初始筛查在这匹马中未发现病损或HeV抗原的迹象;详细检查目前即将完成。
V3的临床观察:这匹马在第4天发生轻度暂时性流鼻涕,但是其他方面保持良好,直至在第6天体温升高而没有局部征兆。她的心率也升高,并且她具有轻微的皮肤隆起,这与轻度脱水和皱褶的外观相一致。这种征兆群集在我们的实验室条件下是急性HeV感染典型具有的。在随后的12小时内,她的体温和心率继续增加(图1和2),她轻微抑郁,因此在第7天出于人道将她安乐死。在尸检时,在肺的心叶上存在淋巴管的中度严重的扩张,其涉及腹侧8-10cm伴有腹膜增厚和水肿。
在组织学检查时,存在肺血管炎并伴有血管壁的纤维蛋白样坏死、小叶间隔水肿和局灶性坏死性肺泡炎。在肺、脑膜、脑实质、三叉神经节、颌下、支气管、腹股沟和肾淋巴结、脾、肝、心、软腭、肾上腺、肾小球、小肠和大肠、卵巢、咽部和鼻甲以及脾脏的生发中心和偶发的心肌细胞中,在血管的内皮和中层存在广泛的HeV抗原沉积。脊索、咽鼓管囊、膀胱和脑的嗅极(olfactory pole)是阴性的。组织学和免疫组织学与特急性HeV感染相一致。
临床样品的分子分析。在整个临床观察期间从免疫接种过的马V1 和V2收集的任何生物样品中,没有HeV释放的迹象。具体来说,从暴露后任一天,没有从深部鼻拭子或血液回收到基因组。
相反,在未免疫接种的马V3中,从激惹后第3天,在鼻拭子中检测到病毒基因组。在连续的取样日中Ct值的降低,表明病毒在上呼吸道中复制,并且与较早时我们实验室在将未接触过抗原的马暴露于 HeV Redlands 2008后的观察相一致。在发热即将发作之前在血液中以及随后在所有分泌物中病毒基因组的发现,与其他临床征兆例如抑郁的最早识别相一致,也与较早的观察相符。
表2
死后样品。TaqMan PCR(HeV N-基因)证实了激惹病毒在V3(对照)中的复制以及感染向多个组织的散播(表3)。与以前报道的相同,最高复制水平显得出现在肺、脾、肾、心肌和与上下呼吸道相关的淋巴组织中。在免疫过的马(V1和V2)中没有病毒复制的迹象。
表3
激惹后血清学:在HeV激惹后,免疫过的马V1和V2不具有滴度增加(表4)。这与这些动物中没有激惹病毒的显著复制相一致。在激惹后第7天安乐死时,在对照马V3中没有检测到抗体。据认为,在病毒暴露与该动物死亡之间没有足够的时间来产生可检测的抗体,这与我们实验室中以前在马中使用HeV Redlands的观察相一致。
表4
以初免-加强方式用100μg sG+ISC佐剂疫苗接种过的两匹马(V1 和V2),在HeV暴露之前血清转变成HeV。仅接受ISC的一匹马(V3) 保持对激惹病毒血清阴性。
在用否则就是致死剂量的HeV激惹后,免疫过的马在整个观察期间保持临床良好,所述观察时间超过在马中所有试验诱导的HeV病例的发作时间。没有免疫的血清学证据的马(V3)在发生与急性HeV相一致的临床征兆后被安乐死。在免疫过的马中,在激惹后没有检测到抗体滴度的增加,这与在这些动物中没有激惹病毒的复制相一致。
免疫过的马没有病毒释放的迹象,正如由所有每日临床样品的 PCR阴性试验结果所反映的。在未免疫的对照中,在从暴露于病毒后第3天起的鼻拭子中,在发热即将发生之前的血液中,以及在从确立发热的时间起的所有临床样品中,检测到病毒基因组。这种释放模式与在本设施处在较早研究中在暴露于HeV的未接触过抗原的马中发现的模式相一致。
在预期将是急性感染期的时间安乐死后,在尸检时收集的免疫过的马的任何组织中,没有HeV病毒复制的迹象。相反,HeV基因组和抗原分布在整个对照马的组织中,其模式与急性HeV感染相一致,并且也鉴定到HeV感染典型的血管病变。
实施例6:马中的第二次临床试验
将三匹马各自间隔21天用两剂疫苗(含ISC的50μg sG)进行免疫。初次免疫后和激惹前的血清学研究证实了疫苗诱导的向HeV的血清转化(表5)。激惹前病毒中和抗体水平,与已发现在曾暴露于否则就是致死剂量的近缘尼帕病毒的猫中具有保护性的中和抗体水平以及在本文中描述的第一次临床试验中暴露于HeV的马中的中和抗体水平相当。仅接受佐剂的马在免疫过的马的病毒激惹之前不产生针对HeV 的抗体(数据未显示)。
表5
马编号 | 基线滴度 | 初次免疫后滴度 | 激惹前滴度 |
V4 | <2 | 4 | 256/128 |
V5 | <2 | 32 | 2048/>8192 |
V6 | <2 | 4 | 512/1024 |
相应地,在接受加强免疫后27天,在BSL4密闭设施中将每匹免疫接种的马暴露于活的HeV。将病毒鼻内(1x 106TCID50)和口服(1 x 106TCID50)给药。在本研究中使用4只豚鼠作为致病性对照,预计这些豚鼠中的至少一只将死于HeV疾病。通过腹膜内途径将豚鼠暴露于50,000TCID50 HeV。
V4的临床观察:这匹马在暴露于HeV后的观察期间在临床上保持良好,并且体温和心率保持在正常限度内。在病毒激惹后第8天,将马可选地安乐死。在粗略尸检时没有注意到异常情况。组织的初始筛查在这匹马中未发现病损或HeV抗原的迹象;详细检查目前即将完成。
V5的临床观察:这匹马在暴露于HeV后的观察期间在临床上保持良好,并且体温和心率保持在正常限度内(图2)。在病毒激惹后第 7天,将马可选地安乐死。在粗略尸检时没有注意到异常情况。组织的初始筛查在这匹马中未发现病损或HeV抗原的迹象;详细检查目前即将完成。
V6的临床观察:这匹马在暴露于HeV后的观察期间在临床上保持良好,并且体温和心率保持在正常限度内(图2)。在病毒激惹后第 9天,将马可选地安乐死。在粗略尸检时没有注意到异常情况。组织的初始筛查在这匹马中未发现病损或HeV抗原的迹象;详细检查目前即将完成。
豚鼠:在HeV激惹后第3天,4只豚鼠中的一只(No.3)开始体重减轻。体重减轻发展到第5天,此时动物表现出神经学征兆(头部倾斜、震颤)并被安乐死。尸检时的异常情况局限于腹膜后结缔组织的水肿。
在组织学检查时,存在肺血管炎、肾周血管炎、卵巢炎和非化脓性脑炎并伴有HeV抗原沉积。组织学和免疫组织学与急性HeV感染相一致,并证实了激惹病毒的致病性。
除了在第3天来自于V6的直肠拭子之外,在整个临床观察期间从 V4、V5或V6收集的任何生物样品中,没有HeV释放的迹象,在所述直肠拭子样品中,在两复孔的一个中通过TaqMan PCR观察到36.2的 Ct值(HeV N基因),而第二个孔没有显示出扩增(表6)。具体来说,在暴露后的任一天,没有从深部鼻拭子或血液回收到基因组。
表6
死后样品。在免疫过的马V4、V5或V6的组织中没有病毒复制的迹象。在一只豚鼠(No.3)中,在激惹后第5天的血液(Ct 34.2)、脑、肺和脾中检测到病毒基因组,支持了在该动物中急性HeV感染的临床、组织学和免疫组织学发现(表7)。
表7
激惹后血清学:在HeV激惹后,免疫过的马V4、V5和V6不具有滴度增加(表8)。这与这些动物中没有激惹病毒的显著复制相一致。
表8
以初免-加强方式用50μg sG+ISC佐剂疫苗接种过的三匹马(V4、 V5和V6),在HeV暴露之前血清转变成HeV。仅接受ISC的一匹马保持对激惹病毒血清阴性。
在用否则就是致死剂量的HeV激惹后,免疫过的马在整个观察期间保持临床良好,所述观察时间超过在马中所有试验诱导的HeV病例的发作时间。用作致病性对照的一只豚鼠在发生与急性HeV相一致的临床征兆后被安乐死。在免疫过的马中,在激惹后没有检测到抗体滴度的增加,这与在这些动物中没有激惹病毒的复制相一致。
免疫过的马没有病毒释放的迹象,正如由除了第3天来自于V6 的直肠拭子的一份平行样之外所有每日临床样品的PCR阴性试验结果所反映的。正在重复该试验。如果观察到类似结果,一种解释是这代表了低水平的残留接种物。在一只未免疫的豚鼠中,在暴露于病毒后第5天,在主要器官和血液中检测到病毒基因组。
在预期将是急性感染期的时间安乐死后,在尸检时收集的免疫过的马的任何组织中,没有HeV病毒复制的迹象。相反,HeV基因组和抗原分布在整个易感豚鼠的组织中,其模式与急性HeV感染相一致,并且在该动物中也鉴定到HeV感染典型的血管病变。
实施例7:尼帕病毒在灵长动物中的临床试验
统计学:在生物安全4级(BSL-4)下进行动物研究、特别是非人类灵长动物研究,严格限制了动物对象的数量、可以获得的生物样品的体积和独立地重复测定的能力,因此限制了统计学分析。因此,数据被呈现为从平行样品而不是平行测定计算的平均值或中值,并且误差条表示平行样的标准偏差。
病毒。NiV-Malaysia(GenBank登记号AF212302)从疾病控制和预防中心特殊病原体分部(Special Pathogens Branch of the Centers for Disease Control andPrevention,Atlanta,Georgia)获得。如Rockx等, (2010)J.Virol.84,9831中对HeV所述,将NiV在Vera细胞上繁殖并滴定。
疫苗配制。使用三种sGHeV疫苗制剂(10μg、50μg或100μg)。 sGHeV的生产和纯化如以前在Pallister(2011)Vaccine 29,5623中所述进行。每种疫苗制剂还含有AllhydrogelTM(Accurate Chemical& Scientific Corporation)和含有完全硫代磷酸酯骨架的CpG寡脱氧核苷酸(ODN)2006(Invivogen)。含有固定量ODN 2006、不同量sGHeV 和铝离子(以1:25的重量比)的疫苗剂量剂如下配制:100μg剂量剂:100μg sGHeV,2.5mg铝离子和150μg ODN2006;50μg剂量剂: 50μg sGHeV,1.25mg铝离子和150μg ODN 2006;以及10μg剂量剂: 5μgsGHeV,250μg铝离子和150μg ODN 2006。对于所有剂量剂来说,首先将AlhydrogelTM与sGHeV混合,然后加入ODN 2006。将每个疫苗剂量剂用PBS调整到1ml,并在注射前将混合物在转轮上在室温下温育至少2至3小时。每个对象接受相同的1ml剂量剂进行初次免疫和加强,所有疫苗剂量剂通过肌肉内注射给药。
动物。将10只体重4-6kg的年轻的成年非洲绿猴(AGM) (Chlorocebus aethiops)(Three Springs Scientific Inc.)单独地在笼中饲养。通过肌肉内注射氯胺酮(10-15mg/kg)将对象麻醉,并在第-42 天(初免)和第-21天(加强)用sGHeV进行疫苗接种。三个对象接受2次10μg剂量剂(AGM 16、AGM 17、AGM 18),三个对象接受 2次50μg剂量剂(AGM 13、AGM14、AGM 15),三只动物接受2 次100μg剂量剂(AGM 10、AGM 11、AGM 12),一个对象(AGM 9)只接受佐剂。在第0天,将对象麻醉并气管内接种4ml Dulbecco最低基本培养基(DMEM)(Sigma-Aldrich)中的1x 105TCID50(组织培养感染剂量中值)NiV。在感染后(p.i.)第0、3、5、7、10、14、21 和28天,将对象麻醉进行临床检查,包括体温、呼吸率、胸片、抽血和鼻、口腔和直肠粘膜拭子。按照批准的人道终点,在感染后第10日不得不将对照对象(AGM 9)安乐死。所有其他对象存活到研究结束,并在感染后第28天安乐死。在尸检后,收集各种组织用于病毒学和组织病理学。取样的组织包括:结膜,扁桃体,口咽/鼻咽,鼻粘膜,气管,右支气管,左支气管,右肺上叶,右肺中叶,右肺下叶,左肺上叶,左肺中叶,左肺下叶,支气管淋巴结(LN),心,肝,脾,肾,肾上腺,胰,空肠,横结肠,脑(前部),脑(小脑),脑干,颈部脊椎,垂体腺,下颌LN,唾液LN,腹股沟LN,腋窝LN,肠系膜LN,膀胱,睾丸或卵巢,股骨骨髓。疫苗接种在BSL-2密闭度下进行。疫苗接种时间表、激惹和生物样本收集日的时间线示出在图4中。
疫苗接种和NiV激惹。以前,我们证实了用105TCID50(组织培养感染剂量中值)NiV气管内接种AGM引起一致地致死的结果(Rockx 等,(2010)J.Virol.84,9831)。在这些研究中注意到快速发展的临床疾病;临床征兆包括严重抑郁、引起急性呼吸窘迫的呼吸疾病、严重神经疾病和严重的移动性减少;并且达到批准的安乐死人道终点判据的时间在7至12天范围内。这里,我们试图确定用sGHeV疫苗接种是否能够在AGM中预防NiV感染和疾病。如方法中所述将10、50 或100μg剂量的sGHeV与明矾和CpG组成部分混合。将每种疫苗制剂在第0天(初免)并再次在第21天(加强)皮下给药到三个对象,并且一个对照对象(AGM 9)在同样的日期仅接受佐剂初免和加强。在第42天,所有对象用105TCID50 NiV气管内接种。对照对象(AGM 9)显示出食欲不振、严重的持续行为改变(抑郁、活动性减低、驼背)、血小板数量减少和在疾病晚期呼吸率逐渐增加。随后,AGM 9发生急性呼吸窘迫,并在感染后第10天不得不按照批准的人道终点进行安乐死。相反,疫苗接种过的对象没有临床疾病,并且都存活到研究结束。 Kaplan-Meier存活图示出在图5中。
对照对象中NiV介导的疾病。对照对象中的总体病理变化与以前在NiV感染的AGM中发现的相一致(Geisbert等,(2010)PLoS One 5,e10690)。存在脾肿大和脑表面上的血管充血,并且所有肺叶润湿且沉重。从AGM 9血样没有回收到NiV RNA和感染性病毒,并且没有病毒血症的迹象。AGM 9具有显著水平的NiV特异性IgM和可检测的NiV特异性IgG和IgA。组织样品的进一步分析揭示出大范围的NiV 组织嗜性,与以前在AGM中观察到的广泛传播的NiV感染相似 (Geisbert等,(2010)PLoS One 5,e10690)。AGM 9在大部分指出的组织中具有NiV RNA,并且从大量组织回收到感染性病毒。显著病变包括间质性肺炎、亚急性脑炎和脾白髓坏死和出血。肺泡腔被水肿液、血纤维蛋白、核破裂碎片、细胞碎片和肺泡巨噬细胞填充。多灶性脑炎以Virchow-Robins空间被中等数量的淋巴细胞和较少的嗜中性粒细胞扩大为特征。较小数量的这些炎性细胞扩展到相邻实质中。大量神经元膨胀并空泡化(变性),或随着核溶解片段化(坏死)。脾白髓中滤泡的多灶性生发中心被出血和血纤维蛋白以及少量嗜中性粒细胞以及细胞和核破裂碎片抹去。这些发现与脾脏中生发中心的坏死和损失相一致。在脑干中存在大量病毒抗原,表明NiV在中枢神经系统中引起大范围损伤。
sGHeV-疫苗接种过的对象的保护作用。所有生物样本,包括在激惹后收集的所有血样和在尸检后收集的所有组织,对NiV RNA阴性,并且没有从任何样本分离到感染性病毒。在来自于疫苗接种过的对象的组织切片的更仔细检查后,组织结构体系显得正常,并且使用免疫组织化学技术没有在任何组织中检测到NiV抗原。为了进一步仔细分析疫苗引发的保护机制,在疫苗接种过的动物中测量血清和粘膜sGNiV和sGHeV特异性IgM、IgG和IgA以及NiV和HeV血清中和滴度。如图6中所证实,在激惹前7天,接受最低sGHeV剂量的对象具有可检测的抗原特异性血清IgM和最高水平的sGHeV特异性血清 IgG。给药50μg sGHeV的对象在激惹前7天也具有可检测水平的血清 IgM和它们的最高水平的血清IgG。高剂量对象在第-7天没有可检测的血清IgM,并且与其他两个组相比血清IgG水平明显更低。到NiV激惹的当天,高剂量对象中的血清IgG水平已经提高,并且所有疫苗接种过的对象具有相近的IgG水平。在NiV激惹后,在任何对象中血清 IgM水平不变。在中等剂量对象中,在NiV激惹当天血清IgG水平降低,在低剂量对象中,就在NiV激惹后IgG水平降低。有趣的是,在这两个组中IgG水平到p.i.第3天和第5天时增加,但是永远不超过激惹前7天出现的IgG水平,并且在两个组中到p.i.第28天滴度明显降低。
相反,在高剂量组中血清IgG保持高水平,并且在p.i.第28天达到它们的最高值。在疫苗接种后,在所有对象中可以检测到抗原特异性血清;然而水平非常低,并且激惹前和激惹后水平之间显得没有显著差异(图6)。在来自于低剂量对象p.i.第14天的鼻拭子中检测到粘膜抗原特异性IgA的极小增加,然而水平如此之低,以至于这些粘膜抗体可能在预防激惹后NiV的扩散中不发挥作用。来自于血清中和试验(SNT)的结果示出在表9中。对于所有疫苗接种过的对象来说,到 p.i.第28天HeV特异性中和滴度保持相同或降低,并且到p.i.第7天 NiV特异性中和滴度没有显著变化,即使是在激惹前具有最低滴度的对象中。一个低剂量和一个高剂量对象到p.i.第14天具有NiV SNT滴度的对数增加,一个中等剂量对象到p.i.第21天具有NiV SNT滴度的对数增加。对于所有其他疫苗接种过的动物来说,SNT滴度的变化是不连贯的(滴度增加然后降低)或不显著的(滴度增加3-4倍但是不超过一个对数)。最后,在NiV激惹后,在疫苗接种过的对象中测量到向NiV融合(F)包膜糖蛋白的血清转变。在低和中等剂量对象中,分别在p.i.第10天和第21天检测到极低水平的血清抗NiV FIgM,并且这些低的M.F.I.值表明NiV激惹后的弱的初次抗体应答。在高滴度对象中没有检测到血清抗NiV-F IgM,表明这些动物在激惹后仅有很少至没有循环病毒。
实施例8:亨德拉病毒在灵长动物中的临床试验
在AGM中进行第二次临床试验以评估疫苗接种和使用亨德拉病毒的激惹。使用与实施例7中提出的相同制剂作为疫苗,但是也与接受仅含AlhydrogelTM作为佐剂(不存在ODN2006)的sGHeV的另一个组进行比较。动物在第-21天疫苗接种,在第0天加强,并在第21 天激惹。除非另有指明,否则所有条件与实施例7中的条件相同。实验概述如下。
结果:两个组(A和B)中的所有动物(n=4)在气管内接种105 TCID50亨德拉病毒后从亨德拉病毒激惹存活。对照对象在第8天死亡。在任何疫苗接种过的对象中没有观察到临床疾病,它们保持健康和良好直至研究终点。
对于本领域技术人员来说,在考察了本文公开的本发明的详细描述和实践后,本发明的其他实施方式和用途将显而易见。本文中引用的所有参考文献,包括所有出版物、美国和外国专利和专利申请,具体且完全地通过参考并入本文。意图将说明书和实施例紧紧当作是示例性的,本发明的真正范围和精神由权利要求书指明。
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<110> 硕腾有限公司
亨利·M·杰克逊军事医学促进基金会
<120> 亨德拉和尼帕病毒G糖蛋白免疫原性组合物
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Val Arg Pro Lys Ser Asp Ser Gly Asp Tyr Asn Gln Lys Tyr Ile Ala
325 330 335
Ile Thr Lys Val Glu Arg Gly Lys Tyr Asp Lys Val Met Pro Tyr Gly
340 345 350
Pro Ser Gly Ile Lys Gln Gly Asp Thr Leu Tyr Phe Pro Ala Val Gly
355 360 365
Phe Leu Pro Arg Thr Glu Phe Gln Tyr Asn Asp Ser Asn Cys Pro Ile
370 375 380
Ile His Cys Lys Tyr Ser Lys Ala Glu Asn Cys Arg Leu Ser Met Gly
385 390 395 400
Val Asn Ser Lys Ser His Tyr Ile Leu Arg Ser Gly Leu Leu Lys Tyr
405 410 415
Asn Leu Ser Leu Gly Gly Asp Ile Ile Leu Gln Phe Ile Glu Ile Ala
420 425 430
Asp Asn Arg Leu Thr Ile Gly Ser Pro Ser Lys Ile Tyr Asn Ser Leu
435 440 445
Gly Gln Pro Val Phe Tyr Gln Ala Ser Tyr Ser Trp Asp Thr Met Ile
450 455 460
Lys Leu Gly Asp Val Asp Thr Val Asp Pro Leu Arg Val Gln Trp Arg
465 470 475 480
Asn Asn Ser Val Ile Ser Arg Pro Gly Gln Ser Gln Cys Pro Arg Phe
485 490 495
Asn Val Cys Pro Glu Val Cys Trp Glu Gly Thr Tyr Asn Asp Ala Phe
500 505 510
Leu Ile Asp Arg Leu Asn Trp Val Ser Ala Gly Val Tyr Leu Asn Ser
515 520 525
Asn Gln Thr Ala Glu Asn Pro Val Phe Ala Val Phe Lys Asp Asn Glu
530 535 540
Ile Leu Tyr Gln Val Pro Leu Ala Glu Asp Asp Thr Asn Ala Gln Lys
545 550 555 560
Thr Ile Thr Asp Cys Phe Leu Leu Glu Asn Val Ile Trp Cys Ile Ser
565 570 575
Leu Val Glu Ile Tyr Asp Thr Gly Asp Ser Val Ile Arg Pro Lys Leu
580 585 590
Phe Ala Val Lys Ile Pro Ala Gln Cys Ser Glu Ser
595 600
<210> 3
<211> 1809
<212> DNA
<213> 尼帕病毒
<220>
<221> CDS
<222> (1)..(1809)
<400> 3
atg ccg gca gaa aac aag aaa gtt aga ttc gaa aat act act tca gac 48
Met Pro Ala Glu Asn Lys Lys Val Arg Phe Glu Asn Thr Thr Ser Asp
1 5 10 15
aaa ggg aaa att cct agt aaa gtt att aag agc tac tac gga acc atg 96
Lys Gly Lys Ile Pro Ser Lys Val Ile Lys Ser Tyr Tyr Gly Thr Met
20 25 30
gac att aag aaa ata aat gaa gga tta ttg gac agc aaa ata tta agt 144
Asp Ile Lys Lys Ile Asn Glu Gly Leu Leu Asp Ser Lys Ile Leu Ser
35 40 45
gct ttc aac aca gta ata gca ttg ctt gga tct atc gtg atc ata gtg 192
Ala Phe Asn Thr Val Ile Ala Leu Leu Gly Ser Ile Val Ile Ile Val
50 55 60
atg aat ata atg atc atc caa aat tac aca aga tca aca gac aat cag 240
Met Asn Ile Met Ile Ile Gln Asn Tyr Thr Arg Ser Thr Asp Asn Gln
65 70 75 80
gcc gtg atc aaa gat gcg ttg cag ggt atc caa cag cag atc aaa ggg 288
Ala Val Ile Lys Asp Ala Leu Gln Gly Ile Gln Gln Gln Ile Lys Gly
85 90 95
ctt gct gac aaa atc ggc aca gag ata ggg ccc aaa gta tca ctg att 336
Leu Ala Asp Lys Ile Gly Thr Glu Ile Gly Pro Lys Val Ser Leu Ile
100 105 110
gac aca tcc agt acc att act atc cca gct aac att ggg ctg tta ggt 384
Asp Thr Ser Ser Thr Ile Thr Ile Pro Ala Asn Ile Gly Leu Leu Gly
115 120 125
tca aag atc agc cag tcg act gca agt ata aat gag aat gtg aat gaa 432
Ser Lys Ile Ser Gln Ser Thr Ala Ser Ile Asn Glu Asn Val Asn Glu
130 135 140
aaa tgc aaa ttc aca ctg cct ccc ttg aaa atc cac gaa tgt aac att 480
Lys Cys Lys Phe Thr Leu Pro Pro Leu Lys Ile His Glu Cys Asn Ile
145 150 155 160
tct tgt cct aac cca ctc cct ttt aga gag tat agg cca cag aca gaa 528
Ser Cys Pro Asn Pro Leu Pro Phe Arg Glu Tyr Arg Pro Gln Thr Glu
165 170 175
ggg gtg agc aat cta gta gga tta cct aat aat att tgc ctg caa aag 576
Gly Val Ser Asn Leu Val Gly Leu Pro Asn Asn Ile Cys Leu Gln Lys
180 185 190
aca tct aat cag ata ttg aag cca aag ctg att tca tac act tta ccc 624
Thr Ser Asn Gln Ile Leu Lys Pro Lys Leu Ile Ser Tyr Thr Leu Pro
195 200 205
gta gtc ggt caa agt ggt acc tgt atc aca gac cca ttg ctg gct atg 672
Val Val Gly Gln Ser Gly Thr Cys Ile Thr Asp Pro Leu Leu Ala Met
210 215 220
gac gag ggc tat ttt gca tat agc cac ctg gaa aga atc gga tca tgt 720
Asp Glu Gly Tyr Phe Ala Tyr Ser His Leu Glu Arg Ile Gly Ser Cys
225 230 235 240
tca aga ggg gtc tcc aaa caa aga ata ata gga gtt gga gag gta cta 768
Ser Arg Gly Val Ser Lys Gln Arg Ile Ile Gly Val Gly Glu Val Leu
245 250 255
gac aga ggt gat gaa gtt cct tct tta ttt atg acc aat gtc tgg acc 816
Asp Arg Gly Asp Glu Val Pro Ser Leu Phe Met Thr Asn Val Trp Thr
260 265 270
cca cca aat cca aac acc gtt tac cac tgt agt gct gta tac aac aat 864
Pro Pro Asn Pro Asn Thr Val Tyr His Cys Ser Ala Val Tyr Asn Asn
275 280 285
gaa ttc tat tat gta ctt tgt gca gtg tca act gtt gga gac cct att 912
Glu Phe Tyr Tyr Val Leu Cys Ala Val Ser Thr Val Gly Asp Pro Ile
290 295 300
ctg aat agc acc tac tgg tcc gga tct cta atg atg acc cgt cta gct 960
Leu Asn Ser Thr Tyr Trp Ser Gly Ser Leu Met Met Thr Arg Leu Ala
305 310 315 320
gtg aaa ccc aag agt aat ggt ggg ggt tac aat caa cat caa ctt gcc 1008
Val Lys Pro Lys Ser Asn Gly Gly Gly Tyr Asn Gln His Gln Leu Ala
325 330 335
cta cga agt atc gag aaa ggg agg tat gat aaa gtt atg ccg tat gga 1056
Leu Arg Ser Ile Glu Lys Gly Arg Tyr Asp Lys Val Met Pro Tyr Gly
340 345 350
cct tca ggc atc aaa cag ggt gac acc ctg tat ttt cct gct gta gga 1104
Pro Ser Gly Ile Lys Gln Gly Asp Thr Leu Tyr Phe Pro Ala Val Gly
355 360 365
ttt ttg gtc agg aca gag ttt aaa tac aat gat tca aat tgt ccc atc 1152
Phe Leu Val Arg Thr Glu Phe Lys Tyr Asn Asp Ser Asn Cys Pro Ile
370 375 380
acg aag tgt caa tac agt aaa cct gaa aat tgc agg cta tct atg ggg 1200
Thr Lys Cys Gln Tyr Ser Lys Pro Glu Asn Cys Arg Leu Ser Met Gly
385 390 395 400
att aga cca aac agc cat tat atc ctt cga tct gga cta tta aaa tac 1248
Ile Arg Pro Asn Ser His Tyr Ile Leu Arg Ser Gly Leu Leu Lys Tyr
405 410 415
aat cta tca gat ggg gag aac ccc aaa gtt gta ttc att gaa ata tct 1296
Asn Leu Ser Asp Gly Glu Asn Pro Lys Val Val Phe Ile Glu Ile Ser
420 425 430
gat caa aga tta tct att gga tct cct agc aaa atc tat gat tct ttg 1344
Asp Gln Arg Leu Ser Ile Gly Ser Pro Ser Lys Ile Tyr Asp Ser Leu
435 440 445
ggt caa cct gtt ttc tac caa gcg tca ttt tca tgg gat act atg att 1392
Gly Gln Pro Val Phe Tyr Gln Ala Ser Phe Ser Trp Asp Thr Met Ile
450 455 460
aaa ttt gga gat gtt cta aca gtc aac cct ctg gtt gtc aat tgg cgt 1440
Lys Phe Gly Asp Val Leu Thr Val Asn Pro Leu Val Val Asn Trp Arg
465 470 475 480
aat aac acg gta ata tca aga ccc ggg caa tca caa tgc cct aga ttc 1488
Asn Asn Thr Val Ile Ser Arg Pro Gly Gln Ser Gln Cys Pro Arg Phe
485 490 495
aat aca tgt cca gag atc tgc tgg gaa gga gtt tat aat gat gca ttc 1536
Asn Thr Cys Pro Glu Ile Cys Trp Glu Gly Val Tyr Asn Asp Ala Phe
500 505 510
cta att gac aga atc aat tgg ata agc gcg ggt gta ttc ctt gac agc 1584
Leu Ile Asp Arg Ile Asn Trp Ile Ser Ala Gly Val Phe Leu Asp Ser
515 520 525
aat cag acc gca gaa aat cct gtt ttt act gta ttc aaa gat aat gaa 1632
Asn Gln Thr Ala Glu Asn Pro Val Phe Thr Val Phe Lys Asp Asn Glu
530 535 540
ata ctt tat agg gca caa ctg gct tct gag gac acc aat gca caa aaa 1680
Ile Leu Tyr Arg Ala Gln Leu Ala Ser Glu Asp Thr Asn Ala Gln Lys
545 550 555 560
aca ata act aat tgt ttt ctc ttg aag aat aag att tgg tgc ata tca 1728
Thr Ile Thr Asn Cys Phe Leu Leu Lys Asn Lys Ile Trp Cys Ile Ser
565 570 575
ttg gtt gag ata tat gac aca gga gac aat gtc ata aga ccc aaa cta 1776
Leu Val Glu Ile Tyr Asp Thr Gly Asp Asn Val Ile Arg Pro Lys Leu
580 585 590
ttc gcg gtt aag ata cca gag caa tgt aca taa 1809
Phe Ala Val Lys Ile Pro Glu Gln Cys Thr
595 600
<210> 4
<211> 602
<212> PRT
<213> 尼帕病毒
<400> 4
Met Pro Ala Glu Asn Lys Lys Val Arg Phe Glu Asn Thr Thr Ser Asp
1 5 10 15
Lys Gly Lys Ile Pro Ser Lys Val Ile Lys Ser Tyr Tyr Gly Thr Met
20 25 30
Asp Ile Lys Lys Ile Asn Glu Gly Leu Leu Asp Ser Lys Ile Leu Ser
35 40 45
Ala Phe Asn Thr Val Ile Ala Leu Leu Gly Ser Ile Val Ile Ile Val
50 55 60
Met Asn Ile Met Ile Ile Gln Asn Tyr Thr Arg Ser Thr Asp Asn Gln
65 70 75 80
Ala Val Ile Lys Asp Ala Leu Gln Gly Ile Gln Gln Gln Ile Lys Gly
85 90 95
Leu Ala Asp Lys Ile Gly Thr Glu Ile Gly Pro Lys Val Ser Leu Ile
100 105 110
Asp Thr Ser Ser Thr Ile Thr Ile Pro Ala Asn Ile Gly Leu Leu Gly
115 120 125
Ser Lys Ile Ser Gln Ser Thr Ala Ser Ile Asn Glu Asn Val Asn Glu
130 135 140
Lys Cys Lys Phe Thr Leu Pro Pro Leu Lys Ile His Glu Cys Asn Ile
145 150 155 160
Ser Cys Pro Asn Pro Leu Pro Phe Arg Glu Tyr Arg Pro Gln Thr Glu
165 170 175
Gly Val Ser Asn Leu Val Gly Leu Pro Asn Asn Ile Cys Leu Gln Lys
180 185 190
Thr Ser Asn Gln Ile Leu Lys Pro Lys Leu Ile Ser Tyr Thr Leu Pro
195 200 205
Val Val Gly Gln Ser Gly Thr Cys Ile Thr Asp Pro Leu Leu Ala Met
210 215 220
Asp Glu Gly Tyr Phe Ala Tyr Ser His Leu Glu Arg Ile Gly Ser Cys
225 230 235 240
Ser Arg Gly Val Ser Lys Gln Arg Ile Ile Gly Val Gly Glu Val Leu
245 250 255
Asp Arg Gly Asp Glu Val Pro Ser Leu Phe Met Thr Asn Val Trp Thr
260 265 270
Pro Pro Asn Pro Asn Thr Val Tyr His Cys Ser Ala Val Tyr Asn Asn
275 280 285
Glu Phe Tyr Tyr Val Leu Cys Ala Val Ser Thr Val Gly Asp Pro Ile
290 295 300
Leu Asn Ser Thr Tyr Trp Ser Gly Ser Leu Met Met Thr Arg Leu Ala
305 310 315 320
Val Lys Pro Lys Ser Asn Gly Gly Gly Tyr Asn Gln His Gln Leu Ala
325 330 335
Leu Arg Ser Ile Glu Lys Gly Arg Tyr Asp Lys Val Met Pro Tyr Gly
340 345 350
Pro Ser Gly Ile Lys Gln Gly Asp Thr Leu Tyr Phe Pro Ala Val Gly
355 360 365
Phe Leu Val Arg Thr Glu Phe Lys Tyr Asn Asp Ser Asn Cys Pro Ile
370 375 380
Thr Lys Cys Gln Tyr Ser Lys Pro Glu Asn Cys Arg Leu Ser Met Gly
385 390 395 400
Ile Arg Pro Asn Ser His Tyr Ile Leu Arg Ser Gly Leu Leu Lys Tyr
405 410 415
Asn Leu Ser Asp Gly Glu Asn Pro Lys Val Val Phe Ile Glu Ile Ser
420 425 430
Asp Gln Arg Leu Ser Ile Gly Ser Pro Ser Lys Ile Tyr Asp Ser Leu
435 440 445
Gly Gln Pro Val Phe Tyr Gln Ala Ser Phe Ser Trp Asp Thr Met Ile
450 455 460
Lys Phe Gly Asp Val Leu Thr Val Asn Pro Leu Val Val Asn Trp Arg
465 470 475 480
Asn Asn Thr Val Ile Ser Arg Pro Gly Gln Ser Gln Cys Pro Arg Phe
485 490 495
Asn Thr Cys Pro Glu Ile Cys Trp Glu Gly Val Tyr Asn Asp Ala Phe
500 505 510
Leu Ile Asp Arg Ile Asn Trp Ile Ser Ala Gly Val Phe Leu Asp Ser
515 520 525
Asn Gln Thr Ala Glu Asn Pro Val Phe Thr Val Phe Lys Asp Asn Glu
530 535 540
Ile Leu Tyr Arg Ala Gln Leu Ala Ser Glu Asp Thr Asn Ala Gln Lys
545 550 555 560
Thr Ile Thr Asn Cys Phe Leu Leu Lys Asn Lys Ile Trp Cys Ile Ser
565 570 575
Leu Val Glu Ile Tyr Asp Thr Gly Asp Asn Val Ile Arg Pro Lys Leu
580 585 590
Phe Ala Val Lys Ile Pro Glu Gln Cys Thr
595 600
<210> 5
<211> 40
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 5
gtcgaccacc atgcaaaatt acaccagaac gactgataat 40
<210> 6
<211> 45
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 6
gtttaaacgt cgaccaatca actctctgaa cattgggcag gtatc 45
<210> 7
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 7
ctcgagcacc atgcaaaatt acacaagatc aacagacaa 39
<210> 8
<211> 45
<212> DNA
<213> 人工序列
<220>
<223> 引物
<400> 8
ctcgagtagc agccggatca agcttatgta cattgctctg gtatc 45
<210> 9
<211> 46
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 9
caaggagacc gctgctgcta agttcgaacg ccagcacatg gattct 46
<210> 10
<211> 54
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 10
aattagaatc catgtgctgg cgttcgaact tagcagcagc ggtctccttg gtac 54
<210> 11
<211> 31
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 11
cgaacaaaag ctcatctcag aagaggatct g 31
<210> 12
<211> 39
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 12
aattcagatc ctcttctgag atgagctttt gttcggtac 39
<210> 13
<211> 34
<212> DNA
<213> 人工序列
<220>
<223> 合成寡核苷酸
<400> 13
tcgacccacc atggagacag acacactcct gcta 34
<210> 14
<211> 1662
<212> DNA
<213> 人工序列
<220>
<223> HeV sG病毒序列
<220>
<221> CDS
<222> (1)..(1662)
<400> 14
atg gaa acc gac acc ctg ctg ctg tgg gtg ctg ctc ctg tgg gtc ccc 48
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
ggc agc aca ggc gac tac acc aga acg act gat aat cag gca cta atc 96
Gly Ser Thr Gly Asp Tyr Thr Arg Thr Thr Asp Asn Gln Ala Leu Ile
20 25 30
aaa gag tca ctc cag agt gta cag caa caa atc aaa gct tta aca gac 144
Lys Glu Ser Leu Gln Ser Val Gln Gln Gln Ile Lys Ala Leu Thr Asp
35 40 45
aaa atc ggg aca gag ata ggc ccc aaa gtc tca cta att gac aca tcc 192
Lys Ile Gly Thr Glu Ile Gly Pro Lys Val Ser Leu Ile Asp Thr Ser
50 55 60
agc acc atc aca att cct gct aac ata ggg tta ctg gga tcc aag ata 240
Ser Thr Ile Thr Ile Pro Ala Asn Ile Gly Leu Leu Gly Ser Lys Ile
65 70 75 80
agt cag tct acc agc agt att aat gag aat gtt aac gat aaa tgc aaa 288
Ser Gln Ser Thr Ser Ser Ile Asn Glu Asn Val Asn Asp Lys Cys Lys
85 90 95
ttt act ctt cct cct tta aag att cat gag tgt aat atc tct tgt ccg 336
Phe Thr Leu Pro Pro Leu Lys Ile His Glu Cys Asn Ile Ser Cys Pro
100 105 110
aat cct ttg cct ttc aga gaa tac cga cca atc tca caa ggg gtg agt 384
Asn Pro Leu Pro Phe Arg Glu Tyr Arg Pro Ile Ser Gln Gly Val Ser
115 120 125
gat ctt gta gga ctg ccg aac cag atc tgt cta cag aag aca aca tca 432
Asp Leu Val Gly Leu Pro Asn Gln Ile Cys Leu Gln Lys Thr Thr Ser
130 135 140
aca atc tta aag ccc agg ctg ata tcc tat act cta cca att aat acc 480
Thr Ile Leu Lys Pro Arg Leu Ile Ser Tyr Thr Leu Pro Ile Asn Thr
145 150 155 160
aga gaa ggg gtt tgc atc act gac cca ctt ttg gct gtt gat aat ggc 528
Arg Glu Gly Val Cys Ile Thr Asp Pro Leu Leu Ala Val Asp Asn Gly
165 170 175
ttc ttc gcc tat agc cat ctt gaa aag atc gga tca tgt act aga gga 576
Phe Phe Ala Tyr Ser His Leu Glu Lys Ile Gly Ser Cys Thr Arg Gly
180 185 190
att gca aaa caa agg ata ata ggg gtg ggt gag gta ttg gat agg ggt 624
Ile Ala Lys Gln Arg Ile Ile Gly Val Gly Glu Val Leu Asp Arg Gly
195 200 205
gat aag gtg cca tca atg ttt atg acc aat gtt tgg aca cca ccc aat 672
Asp Lys Val Pro Ser Met Phe Met Thr Asn Val Trp Thr Pro Pro Asn
210 215 220
cca agc acc atc cat cat tgc agc tca act tac cat gaa gat ttt tat 720
Pro Ser Thr Ile His His Cys Ser Ser Thr Tyr His Glu Asp Phe Tyr
225 230 235 240
tac aca ttg tgc gca gtg tcc cat gtg gga gat cct atc ctt aac agt 768
Tyr Thr Leu Cys Ala Val Ser His Val Gly Asp Pro Ile Leu Asn Ser
245 250 255
act tcc tgg aca gag tca ctg tct ctg att cgt ctt gct gta aga cca 816
Thr Ser Trp Thr Glu Ser Leu Ser Leu Ile Arg Leu Ala Val Arg Pro
260 265 270
aaa agt gat agt gga gac tac aat cag aaa tac atc gct ata act aaa 864
Lys Ser Asp Ser Gly Asp Tyr Asn Gln Lys Tyr Ile Ala Ile Thr Lys
275 280 285
gtt gaa aga ggg aag tac gat aag gtg atg cct tac ggt cca tca ggt 912
Val Glu Arg Gly Lys Tyr Asp Lys Val Met Pro Tyr Gly Pro Ser Gly
290 295 300
atc aag caa ggg gat aca ttg tac ttt ccg gcc gtc ggt ttt ttg cca 960
Ile Lys Gln Gly Asp Thr Leu Tyr Phe Pro Ala Val Gly Phe Leu Pro
305 310 315 320
agg acc gaa ttt caa tat aat gac tct aat tgt ccc ata att cat tgc 1008
Arg Thr Glu Phe Gln Tyr Asn Asp Ser Asn Cys Pro Ile Ile His Cys
325 330 335
aag tac agc aaa gca gaa aac tgt agg ctt tca atg ggt gtc aac tcc 1056
Lys Tyr Ser Lys Ala Glu Asn Cys Arg Leu Ser Met Gly Val Asn Ser
340 345 350
aaa agt cat tat att ttg aga tca gga cta ttg aag tat aat cta tct 1104
Lys Ser His Tyr Ile Leu Arg Ser Gly Leu Leu Lys Tyr Asn Leu Ser
355 360 365
ctt gga gga gac atc ata ctc caa ttt atc gag att gct gac aat aga 1152
Leu Gly Gly Asp Ile Ile Leu Gln Phe Ile Glu Ile Ala Asp Asn Arg
370 375 380
ttg acc atc ggt tct cct agt aag ata tac aat tcc cta ggt caa ccc 1200
Leu Thr Ile Gly Ser Pro Ser Lys Ile Tyr Asn Ser Leu Gly Gln Pro
385 390 395 400
gtt ttc tac cag gca tca tat tct tgg gat acg atg att aaa tta ggc 1248
Val Phe Tyr Gln Ala Ser Tyr Ser Trp Asp Thr Met Ile Lys Leu Gly
405 410 415
gat gtt gat acc gtt gac cct cta aga gta cag tgg aga aat aac agt 1296
Asp Val Asp Thr Val Asp Pro Leu Arg Val Gln Trp Arg Asn Asn Ser
420 425 430
gtg att tct aga cct gga cag tca cag tgt cct cga ttt aat gtc tgt 1344
Val Ile Ser Arg Pro Gly Gln Ser Gln Cys Pro Arg Phe Asn Val Cys
435 440 445
ccc gag gta tgc tgg gaa ggg aca tat aat gat gct ttt cta ata gac 1392
Pro Glu Val Cys Trp Glu Gly Thr Tyr Asn Asp Ala Phe Leu Ile Asp
450 455 460
cgg cta aac tgg gtt agt gct ggt gtt tat tta aac agt aac caa act 1440
Arg Leu Asn Trp Val Ser Ala Gly Val Tyr Leu Asn Ser Asn Gln Thr
465 470 475 480
gca gag aac cct gtg ttt gcc gta ttc aag gat aac gag atc ctt tac 1488
Ala Glu Asn Pro Val Phe Ala Val Phe Lys Asp Asn Glu Ile Leu Tyr
485 490 495
caa gtt cca ctg gct gaa gat gac aca aat gca caa aaa acc atc aca 1536
Gln Val Pro Leu Ala Glu Asp Asp Thr Asn Ala Gln Lys Thr Ile Thr
500 505 510
gat tgc ttc ttg ctg gag aat gtc ata tgg tgt ata tca cta gta gaa 1584
Asp Cys Phe Leu Leu Glu Asn Val Ile Trp Cys Ile Ser Leu Val Glu
515 520 525
ata tac gat aca gga gac agt gtg ata agg cca aaa cta ttt gca gtc 1632
Ile Tyr Asp Thr Gly Asp Ser Val Ile Arg Pro Lys Leu Phe Ala Val
530 535 540
aag ata cct gcc caa tgt tca gag agt tga 1662
Lys Ile Pro Ala Gln Cys Ser Glu Ser
545 550
<210> 15
<211> 553
<212> PRT
<213> 人工序列
<220>
<223> 合成构建物
<400> 15
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Tyr Thr Arg Thr Thr Asp Asn Gln Ala Leu Ile
20 25 30
Lys Glu Ser Leu Gln Ser Val Gln Gln Gln Ile Lys Ala Leu Thr Asp
35 40 45
Lys Ile Gly Thr Glu Ile Gly Pro Lys Val Ser Leu Ile Asp Thr Ser
50 55 60
Ser Thr Ile Thr Ile Pro Ala Asn Ile Gly Leu Leu Gly Ser Lys Ile
65 70 75 80
Ser Gln Ser Thr Ser Ser Ile Asn Glu Asn Val Asn Asp Lys Cys Lys
85 90 95
Phe Thr Leu Pro Pro Leu Lys Ile His Glu Cys Asn Ile Ser Cys Pro
100 105 110
Asn Pro Leu Pro Phe Arg Glu Tyr Arg Pro Ile Ser Gln Gly Val Ser
115 120 125
Asp Leu Val Gly Leu Pro Asn Gln Ile Cys Leu Gln Lys Thr Thr Ser
130 135 140
Thr Ile Leu Lys Pro Arg Leu Ile Ser Tyr Thr Leu Pro Ile Asn Thr
145 150 155 160
Arg Glu Gly Val Cys Ile Thr Asp Pro Leu Leu Ala Val Asp Asn Gly
165 170 175
Phe Phe Ala Tyr Ser His Leu Glu Lys Ile Gly Ser Cys Thr Arg Gly
180 185 190
Ile Ala Lys Gln Arg Ile Ile Gly Val Gly Glu Val Leu Asp Arg Gly
195 200 205
Asp Lys Val Pro Ser Met Phe Met Thr Asn Val Trp Thr Pro Pro Asn
210 215 220
Pro Ser Thr Ile His His Cys Ser Ser Thr Tyr His Glu Asp Phe Tyr
225 230 235 240
Tyr Thr Leu Cys Ala Val Ser His Val Gly Asp Pro Ile Leu Asn Ser
245 250 255
Thr Ser Trp Thr Glu Ser Leu Ser Leu Ile Arg Leu Ala Val Arg Pro
260 265 270
Lys Ser Asp Ser Gly Asp Tyr Asn Gln Lys Tyr Ile Ala Ile Thr Lys
275 280 285
Val Glu Arg Gly Lys Tyr Asp Lys Val Met Pro Tyr Gly Pro Ser Gly
290 295 300
Ile Lys Gln Gly Asp Thr Leu Tyr Phe Pro Ala Val Gly Phe Leu Pro
305 310 315 320
Arg Thr Glu Phe Gln Tyr Asn Asp Ser Asn Cys Pro Ile Ile His Cys
325 330 335
Lys Tyr Ser Lys Ala Glu Asn Cys Arg Leu Ser Met Gly Val Asn Ser
340 345 350
Lys Ser His Tyr Ile Leu Arg Ser Gly Leu Leu Lys Tyr Asn Leu Ser
355 360 365
Leu Gly Gly Asp Ile Ile Leu Gln Phe Ile Glu Ile Ala Asp Asn Arg
370 375 380
Leu Thr Ile Gly Ser Pro Ser Lys Ile Tyr Asn Ser Leu Gly Gln Pro
385 390 395 400
Val Phe Tyr Gln Ala Ser Tyr Ser Trp Asp Thr Met Ile Lys Leu Gly
405 410 415
Asp Val Asp Thr Val Asp Pro Leu Arg Val Gln Trp Arg Asn Asn Ser
420 425 430
Val Ile Ser Arg Pro Gly Gln Ser Gln Cys Pro Arg Phe Asn Val Cys
435 440 445
Pro Glu Val Cys Trp Glu Gly Thr Tyr Asn Asp Ala Phe Leu Ile Asp
450 455 460
Arg Leu Asn Trp Val Ser Ala Gly Val Tyr Leu Asn Ser Asn Gln Thr
465 470 475 480
Ala Glu Asn Pro Val Phe Ala Val Phe Lys Asp Asn Glu Ile Leu Tyr
485 490 495
Gln Val Pro Leu Ala Glu Asp Asp Thr Asn Ala Gln Lys Thr Ile Thr
500 505 510
Asp Cys Phe Leu Leu Glu Asn Val Ile Trp Cys Ile Ser Leu Val Glu
515 520 525
Ile Tyr Asp Thr Gly Asp Ser Val Ile Arg Pro Lys Leu Phe Ala Val
530 535 540
Lys Ile Pro Ala Gln Cys Ser Glu Ser
545 550
<210> 16
<211> 1662
<212> DNA
<213> 人工序列
<220>
<223> 哺乳动物-密码子优化的亨德拉病毒sG
<220>
<221> CDS
<222> (1)..(1662)
<400> 16
atg gaa acc gac acc ctg ctg ctg tgg gtg ctg ctc ctg tgg gtc ccc 48
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
ggc agc aca ggc gac tac acc cgg acc acc gac aac cag gcc ctg atc 96
Gly Ser Thr Gly Asp Tyr Thr Arg Thr Thr Asp Asn Gln Ala Leu Ile
20 25 30
aaa gag tcc ctg cag agc gtc cag cag cag atc aag gcc ctg acc gac 144
Lys Glu Ser Leu Gln Ser Val Gln Gln Gln Ile Lys Ala Leu Thr Asp
35 40 45
aag atc ggc acc gag atc ggc ccc aaa gtg tcc ctg atc gac acc agc 192
Lys Ile Gly Thr Glu Ile Gly Pro Lys Val Ser Leu Ile Asp Thr Ser
50 55 60
agc acc atc acc atc ccc gcc aac atc ggg ctg ctg ggc tcc aag atc 240
Ser Thr Ile Thr Ile Pro Ala Asn Ile Gly Leu Leu Gly Ser Lys Ile
65 70 75 80
agc cag agc acc agc tcc atc aac gag aac gtg aac gac aag tgc aag 288
Ser Gln Ser Thr Ser Ser Ile Asn Glu Asn Val Asn Asp Lys Cys Lys
85 90 95
ttc acc ctg ccc ccc ctg aag atc cac gag tgc aac atc agc tgc ccc 336
Phe Thr Leu Pro Pro Leu Lys Ile His Glu Cys Asn Ile Ser Cys Pro
100 105 110
aac ccc ctg ccc ttc cgg gag tac cgg ccc atc agc cag ggc gtg agc 384
Asn Pro Leu Pro Phe Arg Glu Tyr Arg Pro Ile Ser Gln Gly Val Ser
115 120 125
gac ctg gtg ggc ctg ccc aac cag atc tgc ctg cag aaa acc acc tcc 432
Asp Leu Val Gly Leu Pro Asn Gln Ile Cys Leu Gln Lys Thr Thr Ser
130 135 140
acc atc ctg aag ccc cgg ctg atc agc tac acc ctg ccc atc aac acc 480
Thr Ile Leu Lys Pro Arg Leu Ile Ser Tyr Thr Leu Pro Ile Asn Thr
145 150 155 160
cgg gag ggc gtg tgc atc acc gac cct ctg ctg gcc gtg gac aac ggc 528
Arg Glu Gly Val Cys Ile Thr Asp Pro Leu Leu Ala Val Asp Asn Gly
165 170 175
ttc ttc gcc tac agc cac ctg gaa aag atc ggc agc tgc acc cgg ggc 576
Phe Phe Ala Tyr Ser His Leu Glu Lys Ile Gly Ser Cys Thr Arg Gly
180 185 190
att gcc aag cag cgg atc atc ggc gtg ggc gag gtg ctg gac cgg ggc 624
Ile Ala Lys Gln Arg Ile Ile Gly Val Gly Glu Val Leu Asp Arg Gly
195 200 205
gac aag gtg ccc agc atg ttc atg acc aac gtg tgg acc ccc ccc aac 672
Asp Lys Val Pro Ser Met Phe Met Thr Asn Val Trp Thr Pro Pro Asn
210 215 220
ccc agc aca atc cac cac tgc agc agc acc tac cac gag gac ttc tac 720
Pro Ser Thr Ile His His Cys Ser Ser Thr Tyr His Glu Asp Phe Tyr
225 230 235 240
tac acc ctg tgc gcc gtg agc cac gtg ggc gac ccc atc ctg aac agc 768
Tyr Thr Leu Cys Ala Val Ser His Val Gly Asp Pro Ile Leu Asn Ser
245 250 255
acc agc tgg acc gag agc ctg agc ctg atc cgg ctg gcc gtg cgg ccc 816
Thr Ser Trp Thr Glu Ser Leu Ser Leu Ile Arg Leu Ala Val Arg Pro
260 265 270
aag agc gac agc ggc gac tac aac cag aag tat atc gcc atc acc aag 864
Lys Ser Asp Ser Gly Asp Tyr Asn Gln Lys Tyr Ile Ala Ile Thr Lys
275 280 285
gtg gag cgg ggc aag tac gac aaa gtg atg ccc tac ggc ccc agc ggc 912
Val Glu Arg Gly Lys Tyr Asp Lys Val Met Pro Tyr Gly Pro Ser Gly
290 295 300
atc aag cag ggc gac aca ctg tac ttc ccc gcc gtg ggc ttc ctg ccc 960
Ile Lys Gln Gly Asp Thr Leu Tyr Phe Pro Ala Val Gly Phe Leu Pro
305 310 315 320
cgg acc gag ttc cag tac aac gac agc aac tgc ccc atc atc cac tgc 1008
Arg Thr Glu Phe Gln Tyr Asn Asp Ser Asn Cys Pro Ile Ile His Cys
325 330 335
aag tac agc aag gcc gag aac tgc aga ctg agc atg ggc gtg aac agc 1056
Lys Tyr Ser Lys Ala Glu Asn Cys Arg Leu Ser Met Gly Val Asn Ser
340 345 350
aag agc cac tac atc ctg cgg agc ggc ctg ctg aag tac aac ctg tcc 1104
Lys Ser His Tyr Ile Leu Arg Ser Gly Leu Leu Lys Tyr Asn Leu Ser
355 360 365
ctg ggc ggc gac atc atc ctg cag ttc atc gag atc gcc gac aac cgg 1152
Leu Gly Gly Asp Ile Ile Leu Gln Phe Ile Glu Ile Ala Asp Asn Arg
370 375 380
ctg acc atc ggc agc ccc agc aag atc tac aac agc ctg ggc cag ccc 1200
Leu Thr Ile Gly Ser Pro Ser Lys Ile Tyr Asn Ser Leu Gly Gln Pro
385 390 395 400
gtg ttc tac cag gcc agc tac agc tgg gac acc atg atc aag ctg ggg 1248
Val Phe Tyr Gln Ala Ser Tyr Ser Trp Asp Thr Met Ile Lys Leu Gly
405 410 415
gac gtg gac acc gtg gac ccc ctg cgg gtg cag tgg cgg aac aac agc 1296
Asp Val Asp Thr Val Asp Pro Leu Arg Val Gln Trp Arg Asn Asn Ser
420 425 430
gtg atc agc aga ccc ggc cag agc cag tgc ccc cgg ttc aac gtg tgc 1344
Val Ile Ser Arg Pro Gly Gln Ser Gln Cys Pro Arg Phe Asn Val Cys
435 440 445
ccc gaa gtg tgc tgg gag ggc acc tac aac gac gcc ttt ctg atc gac 1392
Pro Glu Val Cys Trp Glu Gly Thr Tyr Asn Asp Ala Phe Leu Ile Asp
450 455 460
cgg ctg aac tgg gtg tcc gcc gga gtg tac ctg aac tcc aac cag acc 1440
Arg Leu Asn Trp Val Ser Ala Gly Val Tyr Leu Asn Ser Asn Gln Thr
465 470 475 480
gcc gag aac ccc gtg ttc gcc gtg ttc aag gac aac gag atc ctg tac 1488
Ala Glu Asn Pro Val Phe Ala Val Phe Lys Asp Asn Glu Ile Leu Tyr
485 490 495
cag gtg ccc ctg gcc gag gac gac acc aac gcc cag aaa acc atc acc 1536
Gln Val Pro Leu Ala Glu Asp Asp Thr Asn Ala Gln Lys Thr Ile Thr
500 505 510
gac tgc ttt ctg ctg gaa aac gtg atc tgg tgc atc agc ctg gtg gag 1584
Asp Cys Phe Leu Leu Glu Asn Val Ile Trp Cys Ile Ser Leu Val Glu
515 520 525
atc tac gac acc ggc gac tcc gtg atc cgg ccc aag ctg ttt gcc gtg 1632
Ile Tyr Asp Thr Gly Asp Ser Val Ile Arg Pro Lys Leu Phe Ala Val
530 535 540
aag atc ccc gcc cag tgc agc gag agc tga 1662
Lys Ile Pro Ala Gln Cys Ser Glu Ser
545 550
<210> 17
<211> 553
<212> PRT
<213> 人工序列
<220>
<223> 合成构建物
<400> 17
Met Glu Thr Asp Thr Leu Leu Leu Trp Val Leu Leu Leu Trp Val Pro
1 5 10 15
Gly Ser Thr Gly Asp Tyr Thr Arg Thr Thr Asp Asn Gln Ala Leu Ile
20 25 30
Lys Glu Ser Leu Gln Ser Val Gln Gln Gln Ile Lys Ala Leu Thr Asp
35 40 45
Lys Ile Gly Thr Glu Ile Gly Pro Lys Val Ser Leu Ile Asp Thr Ser
50 55 60
Ser Thr Ile Thr Ile Pro Ala Asn Ile Gly Leu Leu Gly Ser Lys Ile
65 70 75 80
Ser Gln Ser Thr Ser Ser Ile Asn Glu Asn Val Asn Asp Lys Cys Lys
85 90 95
Phe Thr Leu Pro Pro Leu Lys Ile His Glu Cys Asn Ile Ser Cys Pro
100 105 110
Asn Pro Leu Pro Phe Arg Glu Tyr Arg Pro Ile Ser Gln Gly Val Ser
115 120 125
Asp Leu Val Gly Leu Pro Asn Gln Ile Cys Leu Gln Lys Thr Thr Ser
130 135 140
Thr Ile Leu Lys Pro Arg Leu Ile Ser Tyr Thr Leu Pro Ile Asn Thr
145 150 155 160
Arg Glu Gly Val Cys Ile Thr Asp Pro Leu Leu Ala Val Asp Asn Gly
165 170 175
Phe Phe Ala Tyr Ser His Leu Glu Lys Ile Gly Ser Cys Thr Arg Gly
180 185 190
Ile Ala Lys Gln Arg Ile Ile Gly Val Gly Glu Val Leu Asp Arg Gly
195 200 205
Asp Lys Val Pro Ser Met Phe Met Thr Asn Val Trp Thr Pro Pro Asn
210 215 220
Pro Ser Thr Ile His His Cys Ser Ser Thr Tyr His Glu Asp Phe Tyr
225 230 235 240
Tyr Thr Leu Cys Ala Val Ser His Val Gly Asp Pro Ile Leu Asn Ser
245 250 255
Thr Ser Trp Thr Glu Ser Leu Ser Leu Ile Arg Leu Ala Val Arg Pro
260 265 270
Lys Ser Asp Ser Gly Asp Tyr Asn Gln Lys Tyr Ile Ala Ile Thr Lys
275 280 285
Val Glu Arg Gly Lys Tyr Asp Lys Val Met Pro Tyr Gly Pro Ser Gly
290 295 300
Ile Lys Gln Gly Asp Thr Leu Tyr Phe Pro Ala Val Gly Phe Leu Pro
305 310 315 320
Arg Thr Glu Phe Gln Tyr Asn Asp Ser Asn Cys Pro Ile Ile His Cys
325 330 335
Lys Tyr Ser Lys Ala Glu Asn Cys Arg Leu Ser Met Gly Val Asn Ser
340 345 350
Lys Ser His Tyr Ile Leu Arg Ser Gly Leu Leu Lys Tyr Asn Leu Ser
355 360 365
Leu Gly Gly Asp Ile Ile Leu Gln Phe Ile Glu Ile Ala Asp Asn Arg
370 375 380
Leu Thr Ile Gly Ser Pro Ser Lys Ile Tyr Asn Ser Leu Gly Gln Pro
385 390 395 400
Val Phe Tyr Gln Ala Ser Tyr Ser Trp Asp Thr Met Ile Lys Leu Gly
405 410 415
Asp Val Asp Thr Val Asp Pro Leu Arg Val Gln Trp Arg Asn Asn Ser
420 425 430
Val Ile Ser Arg Pro Gly Gln Ser Gln Cys Pro Arg Phe Asn Val Cys
435 440 445
Pro Glu Val Cys Trp Glu Gly Thr Tyr Asn Asp Ala Phe Leu Ile Asp
450 455 460
Arg Leu Asn Trp Val Ser Ala Gly Val Tyr Leu Asn Ser Asn Gln Thr
465 470 475 480
Ala Glu Asn Pro Val Phe Ala Val Phe Lys Asp Asn Glu Ile Leu Tyr
485 490 495
Gln Val Pro Leu Ala Glu Asp Asp Thr Asn Ala Gln Lys Thr Ile Thr
500 505 510
Asp Cys Phe Leu Leu Glu Asn Val Ile Trp Cys Ile Ser Leu Val Glu
515 520 525
Ile Tyr Asp Thr Gly Asp Ser Val Ile Arg Pro Lys Leu Phe Ala Val
530 535 540
Lys Ile Pro Ala Gln Cys Ser Glu Ser
545 550
Claims (16)
1.疫苗组合物在制造用于在对象中产生针对亨德拉和/或尼帕病毒的中和抗体应答的药物中的用途,其中所述疫苗组合物包含亨德拉病毒G糖蛋白的可溶性片段、免疫刺激复合物(ISC)和一种或多种赋形剂,所述片段由SEQ ID NO:2的第73至第604位氨基酸或与其至少90%相同的序列构成,所述ISC包含皂角苷、磷脂和类固醇,所述疫苗组合物包含50-100μg亨德拉病毒G糖蛋白的可溶性片段,并且所述对象是马或猪。
2.权利要求1的用途,其中所述中和抗体应答减少亨德拉和/或尼帕病毒在所述对象中的繁殖。
3.权利要求1的用途,其中所述中和抗体应答减少亨德拉和/或尼帕病毒在所述对象中的释放。
4.权利要求1的用途,其中所述对象已暴露于亨德拉和/或尼帕病毒。
5.权利要求4的用途,其中所述对象患有亨德拉和/或尼帕病毒感染。
6.权利要求1的用途,其中所述疫苗组合物经肌肉内给药。
7.权利要求1的用途,其中所述疫苗组合物以两次剂量方式给药。
8.权利要求7的用途,其中在第一剂量后给药第二剂量,所述第二剂量在所述第一剂量后至少约21天至约28天。
9.权利要求7的用途,其中每剂量含有1ml ISC中的约50μg或约100μg可溶性亨德拉病毒G糖蛋白。
10.权利要求1-9任一项的用途,其中所述对象是马。
11.疫苗组合物在制造用于治疗亨德拉和/或尼帕病毒感染的药物中的用途,其中所述疫苗组合物包含:(1)在所述疫苗组合物中5-100μg的量的亨德拉G糖蛋白的可溶性片段,所述片段由SEQ ID NO:2的第73至第604位氨基酸或与其至少90%相同的序列构成,和(2)免疫刺激复合物(ISC),所述ISC包含皂角苷、磷脂和类固醇,以及一种或多种赋形剂,其中所述疫苗组合物以有效治疗对象的亨德拉和/或尼帕病毒感染的量和持续时间给药于对象,其中所述对象是马或猪。
12.权利要求11的用途,其中所述疫苗组合物经肌肉内给药。
13.权利要求12的用途,其中所述疫苗组合物以两次剂量方式给药。
14.权利要求13的用途,其中在第一剂量后给药第二剂量,所述第二剂量在所述第一剂量后至少约21天至约28天。
15.权利要求13的用途,其中每剂量含有1ml ISC中的约50μg或约100μg可溶性亨德拉病毒G糖蛋白。
16.权利要求11-15任一项的用途,其中所述对象是马。
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CN201280033736.8A Pending CN104244974A (zh) | 2011-05-13 | 2012-05-14 | 亨德拉和尼帕病毒g糖蛋白免疫原性组合物 |
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CN108624602B (zh) * | 2017-03-24 | 2020-10-16 | 华中农业大学 | 一株具有阻断活性的抗尼帕病毒g蛋白的单克隆抗体及其应用 |
CN115403626A (zh) | 2017-05-01 | 2022-11-29 | 吉利德科学公司 | 新结晶形式 |
TW201919648A (zh) | 2017-07-11 | 2019-06-01 | 美商基利科學股份有限公司 | 用於治療病毒感染之含rna聚合酶抑制劑與環糊精的組合物 |
KR20200090836A (ko) | 2017-12-20 | 2020-07-29 | 조에티스 서비시즈 엘엘씨 | Hendra 및 Nipah 바이러스 감염을 대비한 백신 |
CN110951922A (zh) * | 2019-12-25 | 2020-04-03 | 中国动物卫生与流行病学中心 | 一种检测亨德拉病毒的raa引物探针及检测方法 |
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TW202203941A (zh) | 2020-05-29 | 2022-02-01 | 美商基利科學股份有限公司 | 瑞德西韋之治療方法 |
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2012
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- 2013-11-13 CL CL2013003248A patent/CL2013003248A1/es unknown
- 2013-11-20 ZA ZA2013/08701A patent/ZA201308701B/en unknown
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2014
- 2014-09-18 HK HK18107349.3A patent/HK1247833A1/zh unknown
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2017
- 2017-04-06 JP JP2017076265A patent/JP6898024B2/ja active Active
- 2017-08-10 AU AU2017213501A patent/AU2017213501A1/en not_active Abandoned
- 2017-09-22 JP JP2017182552A patent/JP2018030862A/ja active Pending
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2019
- 2019-04-11 JP JP2019075881A patent/JP2019142909A/ja active Pending
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