CN116075319A - 针对sars-cov-2的疫苗及其制备 - Google Patents
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Abstract
本发明提供了包含2019‑nCoV刺突‑S蛋白的S基因或S1基因区的DNA构建体。本发明的DNA构建体包含携带2019‑nCoV刺突‑S蛋白的S基因或S1基因区的DNA质粒载体。所述载体还可包含编码IgE信号肽的基因或编码t‑PA信号肽的基因。根据本发明的DNA构建体还用于制备用于治疗或预防冠状病毒或其相关疾病的免疫原性组合物或疫苗。
Description
技术领域
本发明涉及针对SARS-CoV-2的疫苗。根据本发明的疫苗是靶向新型冠状病毒SARS-CoV-2(2019-nCoV)的S基因的DNA疫苗。
背景技术
迄今为止,已鉴定出三种高致病性人冠状病毒(coronavirus,CoV),包括中东呼吸综合征冠状病毒(Middle East respiratory syndrome coronavirus,MERS-CoV)、严重急性呼吸综合征(severe acute respiratory syndrome,SARS)冠状病毒(SARS-CoV)和2019新型冠状病毒(2019novel coronavirus,2019-nCoV),如世界卫生组织(World HealthOrganization,WHO)先前定义的。其中,SARS-CoV于2002年首次被报道。SARS-CoV导致人与人之间传播并导致2003年的爆发,病死率(case fatality rate,CFR)约为10%,而MERS-CoV于2012年6月在沙特阿拉伯被报道。尽管MERS-CoV的人与人之间传播有限,但其显示出约为34.4%的CFR。2019-nCoV于2019年12月从肺炎患者首次报道,并且其在人之间的传播速率超过了SARS-CoV和MERS-CoV二者。国际病毒分类委员会(International Committeeon Taxonomy of Viruses,ICTV)的冠状病毒科研究组(Coronaviridae Study Group,CSG)将2019-nCoV更名为SARS-CoV-2,而中国的病毒学家组将其更名为HCoV-19(为常见的病毒名称)。WHO将该疾病和导致该疾病的病毒分别命名为2019冠状病毒病(CoronavirusDisease 2019,COVID-19)和导致COVID-19的病毒或COVID-19病毒。新型冠状病毒(2019-nCoV)的爆发代表了一种大流行威胁,其已被宣布为国际关注的公共卫生紧急事件(publichealth emergency of international concern,PHEIC)(1)。截至2020年4月21日,在中国、欧洲、美国、印度和至少200个其他国家和/或地区报道了总计为24,99,665例COVID-19的确诊病例,这包括全球范围内的1,71,338例死亡(2)。目前,SARS-CoV-2的中间宿主仍然未知并且没有可用的有效的预防或治疗。这表明迫切需要立即开发用于预防和治疗COVID-19的疫苗和抗病毒药物(1)。正在进行多于100项临床前或临床试验,其包括改用已获批准但具有不同适应证的药物,如抗疟疾、抗病毒、抗寄生虫药物、靶向细胞因子或补体的抗体等。虽然这些药物可能有助于防止冠状病毒感染的恶化。但是对针对新型冠状病毒SARS-CoV-2的疫苗的需求仍未得到满足。本发明提供了可被开发作为针对SARS-CoV-2的疫苗的DNA构建体及其组合物。冠状病毒包含四种结构蛋白,包括刺突(spike,S)、包膜(envelope,E)、膜(membrane,M)和核衣壳(nucleocapsid,N)蛋白。其中S蛋白在病毒附着、融合和进入中起着最重要的作用,并且其用作开发抗体、进入抑制剂和疫苗的靶标。S蛋白通过经由S1亚基中的受体结合结构域(receptor-binding domain,RBD)首先与宿主受体结合来介导病毒进入宿主细胞,并随后通过S2亚基融合该病毒和宿主膜。SARS-CoV将血管紧张素转换酶2(angiotensin-converting enzyme,ACE2)识别为其受体。与SARS-CoV类似,SARS-CoV-2也将ACE2识别为其与病毒S蛋白结合的宿主受体(1)。最近,参考文献3中公开了处于融合前(prefusion)构象的2019-nCoV S三聚体的3.5埃分辨率低温电子显微结构,该文献在此并入本申请。根据这项最新研究,三聚体的主要状态使三个受体结合结构域(RBD)中的一个以受体可及的构象向上旋转。生物物理和结构证据表明,2019-nCoV S蛋白相比于严重急性呼吸综合征(SARS)-CoV S,以更高的亲和力结合血管紧张素转换酶2(ACE2)。另外,测试了数种公开的SARS-CoV RBD特异性单克隆抗体并且发现他们不具有与2019-nCoV S的明显结合,这表明两种RBD之间的抗体交叉反应性可能有限。其表明SARS-CoV-2的S蛋白非常独特并且不能被可抑制常规冠状病毒的S蛋白的常规抗体或其他治疗剂所抑制(3)。但是,开发了卡斯瑞韦单抗(casirivimab)加依米得韦单抗(imdevimab)的组合和巴尼韦单抗(bamlanivimab),他们是特异性抗严重急性呼吸综合征冠状病毒2(SARS-CoV-2)单克隆抗体,通过美国食品药品监督管理局(Food and Drug Administration,FDA)紧急使用授权(Emergency Use Authorizations,EUA)而可用以用于治疗处于进展为严重疾病和/或住院治疗的高风险中的患有轻度至中度COVID-19的门诊患者。
在本申请中,本发明提供了包含这样的DNA质粒载体的新构建体,其携带编码2019-nCoV的刺突-S蛋白的S基因或所述S基因的S1基因区。本发明的新的DNA构建体可被开发为用于预防或治疗冠状病毒或其相关疾病的疫苗。
三种候选物(包括来自Pfize和Modernar的两种基于mRNA的候选物和来自AstraZeneca的基于黑猩猩腺病毒载体的候选物)获得了紧急使用授权。根据3期效力数据批准了紧急使用。来自Pfizer的mRNA疫苗报道有95%的效力(10),而Moderna和AstraZeneca针对其疫苗候选物报道的效力分别为94.5%和70.4%。此外,国家流行病学和微生物学研究中心(the National Research Centre for Epidemiology andMicrobiology)开发了效力为92%的Sputnik V疫苗(11)。
常规的活性疫苗由灭活或减毒形式的感染原制成。在大多数情况下,用减毒活疫苗和灭活疫苗进行疫苗接种导致产生体液介导的免疫应答而不是细胞介导的免疫应答。在这样的情况下需要但不可获得的是安全使用的抗原,其可以通过内源性途径加工并最终激活B细胞应答和T细胞应答二者。所产生的活化的淋巴细胞将破坏病原体感染的细胞。出于这些原因,正在研究涉及注射包含针对目的抗原的基因的一段DNA的新的疫苗接种方法。DNA疫苗是有吸引力的,因为他们确保了多肽的适当折叠,在长时间段内产生抗原,并且不需要佐剂。然后,这些宿主合成的抗原可在经疫苗接种个体的I类主要组织相容性复合体(major histocompatibility complex class I,MHC I)和MHC II蛋白二者的背景下成为免疫监视的对象(12)。相比之下,标准疫苗抗原通过吞噬或内吞作用被细胞摄入,并通过主要刺激抗体应答的MHC II类系统进行加工。除这些特性之外,质粒载体还包含免疫刺激性核苷酸序列-未甲基化的胞苷磷酸鸟苷(cytidine phosphate guanosine,CpG)基序-其诱导强烈的细胞免疫(13)。最后,DNA疫苗已显示出刺激持续的免疫应答。
发明概述
本发明提供了包含编码2019-nCoV的刺突-S蛋白的S基因或所述S基因的S1基因区的DNA构建体。本发明的DNA构建体包含这样的DNA质粒载体,其携带编码2019-nCoV的刺突-S蛋白的S基因或所述S基因的S1基因区。根据本发明的优选载体是pVAX1。在另一方面中,载体还可包含编码IgE信号肽的基因或编码t-PA信号肽的基因。根据本发明的DNA构建体还用于制备用于治疗或预防冠状病毒或其相关疾病的免疫原性组合物或疫苗。SARS-CoV-2DNA疫苗将需要以数百万剂供应。为了实现这一点,本申请在此举例说明了缩短处理时间的规模可缩放、高效和有成本效益的方法以及可提供质粒DNA的高回收的方法。在某些方面中,将根据本发明制备的DNA构建体施用至肌细胞中或皮内注射至对象中。在一个这样的方面中,通过无针注射系统或通过电转化仪系统进行DNA构建体向肌细胞的施用。此外,为了提高肌细胞对DNA疫苗的摄取效力,可使用包含以下中的一种或更多种的不同制剂来制备用于治疗或预防COVID-19或其相关疾病的本发明的免疫原性组合物:水、盐水、缓冲剂、稳定剂、佐剂、赋形剂和脂质制剂。
在另一个这样的方面中,通过无针注射系统和/或通过电转化仪系统进行皮内施用DNA构建体。此外,为了提高肌细胞对DNA疫苗的摄取效力,可使用具有缓冲剂、稳定剂、佐剂、赋形剂和脂质制剂的不同制剂来制备用于治疗或预防COVID-19或其相关疾病的本发明的免疫原性组合物。
附图简述
图1描绘了携带具有IgE前导序列的全长S基因的pVAX1载体的载体图。
图2描绘了携带具有t-PA前导序列的全长S基因的pVAX1载体的载体图。
图3描绘了携带具有IgE前导序列的S基因的S1区的pVAX1载体的载体图。
图4描绘了携带具有t-PA前导序列的S基因的S1区的pVAX1载体的载体图。
图5a描绘了通过免疫荧光获得的显示在用包含SARS-CoV-2的S基因的DNA构建体或空质粒(对照)转染Vero细胞之后S蛋白表达的荧光图像。
图5b描绘了通过免疫荧光获得的显示在用包含SARS-CoV-2的S1基因的DNA构建体或空质粒(对照)转染Vero细胞之后S1蛋白表达的荧光图像。
图6描绘了在BALB/c小鼠中进行DNA疫苗接种之后的抗体应答和长期免疫原性。
图7描绘了在豚鼠中进行DNA疫苗接种之后的抗体应答。
图8描绘了施用DNA疫苗后BALB/c小鼠中的IFN-γ应答。
本发明的核苷酸序列和氨基酸序列的列表
SEQ ID No.:1-全长S蛋白的氨基酸序列
SEQ ID No.:2-S蛋白的S1区的氨基酸序列
SEQ ID NO.:3-具有IgE前导序列的全长S基因的氨基酸序列
第1至18位加下划线的氨基酸残基代表IgE前导序列的氨基酸序列以及第19至1289位氨基酸残基代表全长S蛋白的氨基酸序列。
SEQ ID NO.:4-具有IgE前导序列的全长S基因的核苷酸序列
第1至54位加下划线的核苷酸残基代表IgE前导序列的DNA序列(核苷酸序列)以及第55至3873位核苷酸残基代表S基因的DNA序列(核苷酸序列)。
SEQ ID NO.:5-具有t-PA前导序列的全长S基因的氨基酸序列
第1至22位加下划线的氨基酸残基代表t-PA前导序列的氨基酸序列以及第23至1293位氨基酸残基代表全长S蛋白的氨基酸序列。
SEQ ID NO.:6-具有t-PA前导序列的全长S基因的核苷酸序列
第1至66位加下划线的核苷酸残基代表t-PA前导序列的DNA序列(核苷酸序列)以及第67至3885位核苷酸残基代表S基因的DNA序列(核苷酸序列)。
SEQ ID NO.:7-具有IgE前导序列的S基因的S1区的氨基酸序列
第1至18位加下划线的氨基酸残基代表IgE前导序列的氨基酸序列以及第19至702位氨基酸残基代表S蛋白的全长S1区的氨基酸序列。
SEQ ID NO.:8-具有IgE前导序列的S基因的S1区的核苷酸序列
第1至54位核苷酸残基代表IgE前导序列的DNA序列(核苷酸序列)以及第55至2112位核苷酸残基代表S基因的S1区的DNA序列(核苷酸序列)。
SEQ ID NO.:9-具有t-PA前导序列的S基因的S1区的氨基酸序列
第1至22位加下划线的氨基酸残基代表t-PA前导序列的氨基酸序列以及第23至706位氨基酸残基代表S蛋白的全长S1区的氨基酸序列。
SEQ ID NO.:10-具有t-PA前导序列的S基因的S1区的核苷酸序列
第1至66位加下划线的核苷酸残基代表t-PA前导序列的DNA序列(核苷酸序列)以及第67至2124位核苷酸残基代表S基因的S1区的DNA序列(核苷酸序列)。
SEQ ID NO.:11-具有IgE前导序列的全长S基因(Hexapro)的氨基酸序列
第1至18位加下划线的氨基酸残基代表IgE前导序列的氨基酸序列以及第19至1289位氨基酸残基代表全长S蛋白的氨基酸序列。在第19至1289位区域中另外的加下划线的脯氨酸残基代表六种脯氨酸替换(K986P、V987P、F817P、A892P、A899P和A942P),其在本文中称为Hexapro替换。
SEQ ID NO.:12-具有IgE前导序列的全长S基因(Hexapro)的核苷酸序列
第1至54位加下划线的核苷酸残基代表IgE前导序列的DNA序列(核苷酸序列)以及第55至3873位核苷酸残基代表S基因(Hexapro)的DNA序列(核苷酸序列)。
SEQ ID NO.:13-具有IgE前导序列的全长S基因(2P)的氨基酸序列
第1至18位加下划线的氨基酸残基代表IgE前导序列的氨基酸序列以及第19至1289位氨基酸残基代表全长S蛋白的氨基酸序列。第19至1289位区域中另外的加下划线的脯氨酸残基代表两种脯氨酸替换(K986P、V987P),其在本文中称为2P替换。
定义
本文中使用的术语“SARS-CoV-2”、“2019-nCoV”和“HCoV-19”是指2019年12月爆发并首次报道的冠状病毒。
本文中使用的术语“附加体”是指共表达S基因或S基因的S1区和前导序列的质粒DNA构建体,其可独立于宿主细胞优选人肌肉细胞、皮肤细胞或抗原呈递细胞进行转录和翻译。附加体应进入宿主细胞核并利用宿主细胞机制表达靶蛋白(在此优选S蛋白或S蛋白的S1区)而不整合到宿主细胞基因组中。
本文中所述的术语“信号肽”是肽(有时是指信号序列、靶向信号、定位信号、定位序列、转运肽、前导序列或前导肽),其是存在于注定通往分泌途径的新合成蛋白质的N端的短肽(通常为16至30个氨基酸长)。
本文中使用的术语“多肽”、“蛋白质”和“氨基酸序列”通常是指氨基酸残基的聚合物并且不限于产物的最小长度。因此,肽、寡肽、二聚体、多聚体等均包括在该定义内。该定义涵盖了全长蛋白质及其片段二者。
本文中使用的术语“核苷酸”通常是指核酸残基的序列并不限制于产物的最小长度。该定义涵盖了全长核苷酸及其片段或变体二者。
本文中使用的术语“片段”或“变体”是指全长多肽、蛋白质或核苷酸的功能性部分,其序列与相应的全长多肽、蛋白质或核苷酸不同但保留与全长多肽、蛋白质或核苷酸相同的功能。所述功能性片段或功能性变体可具有比相应天然分子更多、更少或相同数目的残基和/或可包含一个或更多个氨基酸或核苷酸替换。
“免疫原性组合物”、“免疫原性制剂”和“制剂”可互换使用并且是指包含抗原性分子的组合物或制剂,其中向对象施用该组合物导致在对象中产生针对目的抗原性分子的体液免疫应答和/或细胞免疫应答。可将免疫原性组合物直接引入接受者对象中,例如通过注射、吸入、经口、鼻内或任何其他肠胃外、黏膜或经皮(例如直肠内或阴道内)施用途径。
本文中所述的术语“假病毒”是具有其核心和来源于不同病毒的包膜蛋白的合成或重组病毒。实例为表达SARS S蛋白的麻疹病毒。术语“假病毒体”具有与术语“假病毒”相同的含义,但其通常在中和抗体测定下使用。本文中使用的术语“多肽”、“蛋白质”和“氨基酸序列”通常是指氨基酸残基的聚合物并且不限于产物的最小长度。因此,肽、寡肽、二聚体、多聚体等均包括在该定义内。该定义涵盖了全长蛋白质及其片段二者。
术语“药物制剂”是指使活性成分的生物活性明确有效的这样的形式的制备物。术语“药物制剂”、“药物组合物”和“组合物”在此可互换使用。
术语“赋形剂”是指这样的物质,其可被添加至制剂以使经配制形式的活性药物物质稳定以调节和维持药物制剂的渗量浓度(osmolality)和pH。常用赋形剂的一些实例包括但不限于麻醉剂化合物、糖、多元醇、氨基酸、表面活性剂和聚合物。“可药用的”赋形剂是可合理地施用于对象哺乳动物以提供有效剂量的所用活性成分的那些。
本文中使用的术语“治疗”是指在哺乳动物,特别是人中对疾病的任何治疗。其包括:(a)预防疾病在可能易患该疾病或处于患该疾病的风险之中但尚未被诊断为患有该疾病的对象中发生;(b)抑制该疾病,即阻止其发展;以及(c)缓解该疾病,即引起该疾病的消退。
术语“患者”和“对象”可互换使用并以其常规意义使用以指患有病症或具有患该病症之倾向的活生物体,并且包括人和非人动物二者,该病症可通过施用本发明组合物来预防或治疗。对象的一些实例包括但不限于人、黑猩猩和其他猿和猴的物种;农场动物,例如牛、绵羊、猪、山羊和马;家养哺乳动物,例如狗和猫;实验室动物,包括啮齿动物例如小鼠、大鼠和豚鼠;鸟类,包括家养的、野生的和猎鸟类(game bird),例如鸡、火鸡和另一些鹑鸡类鸟类、鸭、鹅等。该术语不表示特定年龄。因此,成年的、未成年的和新生的个体均是目标。
术语“ZVTC_COV”和“VTC_COV”含义相似并且可互换使用。
本文中使用的术语“氨基酸替换”或“替换”是指将亲本多肽序列中特定位置或定位处的氨基酸用另一个氨基酸代替。例如,替换K986P是指变体多肽,在这种情况下是指其中第986位处的赖氨酸被脯氨酸代替的SARS-CoV-2的S蛋白的变体。
表1:本申请中使用的氨基酸的缩写
本申请中使用的缩写
γ:伽玛
2019-nCoV:新型冠状病毒
A:腺嘌呤
ACE2:血管紧张素转换酶2APC:抗原呈递细胞(Antigen presenting cell)BGH:牛生长激素(Bovine growth hormone)BSA:牛血清白蛋白(Bovine Serum albumin)C:胞嘧啶
CMV:巨细胞病毒(Cytomegalovirus)
CL:阳离子脂质(Cationic lipid)
CoV:冠状病毒
CPE:细胞病变作用(Cytopathic effect)DNA:脱氧核糖核酸
DMEM:杜氏改良Eagle培养基(Dulbecco’s modified eagle medium)DOTMA:1,2-二-O-十八碳烯基-3-三甲基铵丙烷
DOTAP:N-[1-(2,3-二油酰基氧基)丙基]-N,N,N-三甲基铵甲基硫酸盐ELISA:酶联免疫吸附测定(Enzyme-linked immunosorbent assay)ELISpot:酶联免疫吸附斑点(Enzyme-linked immune absorbent spot)FACS:荧光激活细胞分选(Fluorescence-activated cell sorting)FBS:胎牛血清(Fetal bovine serum)
FITC:异硫氰酸荧光素(Fluorescein isothiocyanate)
G:鸟嘌呤
h:小时
Hr:小时
HRP:辣根过氧化物酶(Horse radish peroxidase)
ID:皮内(Intradermal)
IFN:干扰素
IM:肌内(Intramuscular)
IgG:免疫球蛋白G(Immunoglobulin G)
IgE:免疫球蛋白E(Immunoglobulin E)
MERS:中东呼吸综合征冠状病毒
MHC:主要组织相容性复合体
ml:毫升
MNT:微中和测试(Micro-neutralization test)
MV:麻疹载体(Measles vector)
%:百分比
℃:摄氏度
nM:纳摩
NFIS:无针注射系统(Needle-free injection system)
OD:光密度(Optical density)
p:质粒
pDNA:质粒DNA(plasmid DNA)
PBS:磷酸缓冲盐水(Phosphate buffer saline)
RBD:受体结合结构域(Receptor binding domain)
RNA:核糖核酸
RPMI:洛斯维帕克纪念研究所(Roswell park memorial institute)
S蛋白:刺突蛋白(Spike protein)
SARS:严重急性呼吸系统综合症
SC:皮下(Subcutaneous)
T:胸腺嘧啶
t-PA:组织纤溶酶原激活物(Tissue plasminogen activator)
TCID50:50%组织培养物感染剂量(50%tissue culture infectious dose)
TMB:3,3’,5,5’-四甲基联苯胺(3,3’,5,5’-tetramethlybenzidine)
TNF:肿瘤坏死因子(Tumor necrosis factor)
VSV:水疱性口炎病毒(Vesicular stomatitis virus)
本发明的实施方案
在一个实施方案中,本发明提供了可被开发作为用于预防SARS-CoV-2的疫苗的DNA构建体。在一个优选实施方案中,根据本发明的DNA构建体包含SARS-CoV-2的S基因或SARS-CoV-2的S蛋白的S1区的基因。
在一个实施方案中,DNA构建体包含编码SARS-CoV-2的S蛋白的基因或SARS-CoV-2的S蛋白的截短基因。本发明的S蛋白的截短基因包括S1区或与人血管紧张素转换酶(ACE)-2受体结合的受体结合结构域RBD。
在一个优选实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的基因的DNA构建体,其具有如SEQ ID NO.:4或SEQ ID NO.:6中所示的核苷酸序列。
在一个优选实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的基因的DNA构建体的氨基酸序列,其中所述氨基酸序列是SEQ IDNO.:3或SEQ ID NO.:5。
在一个优选实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的基因的DNA构建体,其具有来自SEQ ID NO.:4的第55至3873位核苷酸残基的核苷酸序列、或其片段或其变体。
在一个优选实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的基因的DNA构建体,其具有来自SEQ ID NO.:6的第67至3885位核苷酸残基的核苷酸序列、或其片段或其变体。
在一个实施方案中,本发明提供了包含编码具有替换的SARS-CoV-2的融合前稳定S蛋白的基因的DNA构建体,其中SARS-CoV-2的S蛋白具有选自K986P、V987P、F817P、A892P、A899P和A942P的替换。在一个这样的优选实施方案中,本发明提供了包含编码具有替换的SARS-CoV-2的融合前稳定S蛋白的基因的DNA构建体,其中SARS-CoV-2的S蛋白具有选自K986P和V987P替换的替换。在一个这样的优选实施方案中,本发明提供了包含编码具有替换的SARS-CoV-2的融合前稳定S蛋白的基因的DNA构建体,其中SARS-CoV-2的S蛋白具有以下替换:K986P、V987P、F817P、A892P、A899P和A942P替换。
根据本发明的包含编码具有K986P、V987P、F817P、A892P、A899P和A942P替换的SARS-CoV-2的S蛋白的基因的DNA构建体具有如SEQ ID NO.:12中所示的核苷酸序列。在一个优选实施方案中,根据本发明的包含编码具有K986P、V987P、F817P、A892P、A899P和A942P替换的SARS-CoV-2的S蛋白的基因的DNA构建体具有来自SEQ ID NO.:12的第55至3873位核苷酸残基的核苷酸序列或其片段或其变体。
在一个优选实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的截短基因(S1蛋白)的基因的DNA构建体,其具有如SEQ ID NO.:8或SEQ ID NO.:10中所示的核苷酸序列。在一个优选实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的截短基因(S1蛋白)的基因的DNA构建体的氨基酸序列,其中所述氨基酸序列是SEQ ID NO.:7或SEQ IDNO.:9。
在一个优选实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的截短基因(S1蛋白)的基因的DNA构建体,其具有来自SEQ ID NO.:8的第55至2112位核苷酸残基的核苷酸序列或其片段或其变体。
在一个优选实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的截短基因(S1蛋白)的基因的DNA构建体,其具有来自SEQ ID NO.:10的第67至2124位核苷酸残基的核苷酸序列或其片段或其变体。
在一个优选实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的基因的DNA构建体,其具有在如SEQ ID NO.:4或SEQ ID NO.:6中所示的核苷酸序列的整个长度上具有至少95%同一性的核苷酸序列。
在一个优选实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的基因的DNA构建体,其具有在如SEQ ID NO.:12中所示的核苷酸序列的整个长度上具有至少95%同一性的核苷酸序列。
在一个优选实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的截短基因(S1蛋白)的基因的DNA构建体,其具有在如SEQ ID NO.:8或SEQ ID NO.:10中所示的核苷酸序列的整个长度上具有至少95%同一性的核苷酸序列。
在一个实施方案中,本发明提供了DNA构建体或其功能性变体。此外,本发明还提供了用于合适的宿主细胞的具有优化的核苷酸基因序列的DNA构建体或其功能性变体。优选地,根据本发明的合适的宿主细胞是大肠杆菌(E.coli)。
在另一个实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的基因或编码SARS-CoV-2的S蛋白的S1区的基因的载体。根据本发明可使用能够在体内表达靶蛋白的任何载体。在一个优选实施方案中,根据本发明的载体是pVAX1。其他载体例如pCDNA 3.1、pCDNA 4.0、pCMV、PCAGG等也可用于表达靶蛋白。本发明的载体可包含用于在广泛的哺乳动物细胞中高水平表达的人巨细胞病毒即早期(CMV)启动子、用于mRNA的高效转录终止和多腺苷酸化的牛生长激素(BGH)多腺苷酸化信号、用于在大肠杆菌中进行选择的卡那霉素抗性基因或其合适的组合。
在某些实施方案中,本发明提供了包含编码SARS-CoV-2的S蛋白的基因或编码SARS-CoV-2的S蛋白的S1区的基因和编码信号肽的基因的载体。在一个优选实施方案中,信号肽是IgE信号肽或t-PA信号肽。
在一个实施方案中,本发明提供了制备载体的方法,所述载体包含编码SARS-CoV的S蛋白的基因或编码SARS-CoV-2的S蛋白的S1区的基因,任选地具有编码信号肽的基因。在一个优选实施方案中,信号肽是IgE信号肽或t-PA信号肽。
在另一个实施方案中,本发明提供了这样的载体,其包含编码SARS-CoV-2的S蛋白的基因或编码SARS-CoV-2的S蛋白的S1区的基因的功能性变体,并且任选地具有编码信号肽的基因。
在另一个实施方案中,根据本发明制备的载体还包含SARS-CoV-2的S基因或SARS-CoV-2的S基因的S1区表达所需的调节元件。
在另一个实施方案中,本发明提供了将包含SARS-CoV-2的S基因或SARS-CoV-2的S基因的S1区的DNA构建体施用于对象的方法。所述DNA构建体还可包含编码IgE信号肽的基因或编码t-PA信号肽的基因。在一个优选实施方案中,本发明提供了施用载体的方法,所述载体包含编码SARS-CoV-2的S蛋白的基因或编码SARS-CoV-2的S蛋白的S1区的基因,任选地具有编码信号肽的基因。根据本发明的信号肽可以是IgE信号肽或t-PA信号肽。
在本发明的另一个实施方案中,将共表达S基因和信号肽的质粒DNA(pDNA)载体转化到合适的大肠杆菌宿主细胞中,用于大规模产生用于免疫接种的质粒DNA。
在本发明的另一个实施方案中,可在具有合适的不同培养基组合物的情况下使用规模可缩放的生产方法(使用分批方法和补料分批方法),所述培养基组合物包含酵母提取物、胰蛋白胨、丙三醇和可用于高密度大肠杆菌培养的其他合适成分。此外,根据本发明可使用范围为30℃至42℃的温度来提高来自细菌生物质的质粒产率。
在本发明的一个实施方案中,纯化方法包括以下步骤中的一个或更多个:(a)裂解包含质粒DNA的宿主细胞;(b)通过过滤使裂解物澄清以获得澄清的裂解物;(c)处理裂解物以去除内毒素和其他杂质;(d)使用选自亲和色谱(affinity chromatography,AC)、离子交换色谱(ion exchange chromatography,IEC)和/或疏水相互作用色谱(hydrophobicinteraction chromatography,HIC)中的一种或更多种色谱技术来纯化具有质粒DNA的步骤(c)的经处理溶液;(e)对经纯化的质粒进行浓缩,其包括以下步骤中的一个或更多个:(i)沉淀,(ii)渗滤和/或(iii)冻干。
在另一个实施方案中,本发明提供了制备质粒DNA载体的免疫原性组合物的方法,所述质粒DNA载体包含编码SARS-CoV-2的S蛋白的基因或编码SARS-CoV-2的S蛋白的S1区的基因,以及编码前导序列的基因。本发明的免疫原性组合物可以在水或盐水中制备。免疫原性组合物优选地包含缓冲剂、稳定剂、佐剂以及任选的其他合适的药物赋形剂。在本发明的一个优选实施方案中,免疫原性组合物由以下构成:(a)缓冲剂,优选磷酸缓冲盐水(PBS);(b)稳定剂,其选自自由基清除剂和/或金属离子螯合剂;(c)其他药物赋形剂,其选自盐酸丁哌卡因和/或选自Vi-多糖、酶原和/或壳聚糖的糖;以及(d)佐剂,其选自氢氧化铝凝胶、细菌来源的佐剂、亲脂性佐剂、亲水性佐剂、完全弗氏佐剂(complete Freund’sadjuvantCFA)、不完全弗氏佐剂(Incomplete Freund’s adjuvant,IFA)、单磷酰脂质A、β-谷固醇及其合适的组合。
在一个优选实施方案中,本发明的免疫原性组合物或制剂是液体制剂,所述液体制剂包含缓冲剂和具有来自SARS-CoV-2病毒的刺突蛋白基因区的DNA质粒构建体。根据本发明优选的缓冲剂是磷酸缓冲盐水。
在一个优选实施方案中,本发明的免疫原性组合物或制剂是液体制剂,所述液体制剂包含缓冲剂和具有来自SARS-CoV-2病毒的刺突蛋白基因区的S1区的DNA质粒构建体。根据本发明优选的缓冲剂是磷酸缓冲盐水。
在一个优选实施方案中,本发明的免疫原性组合物或制剂是脂质体制剂。在一个这样的实施方案中,可使用使用阳离子脂质(CL)进行的脂质包埋或络合方法以用于质粒DNA递送,所述阳离子脂质包含选自以下的一种或更多种脂质:(a)DOTMA(1,2-二-O-十八碳烯基-3-三甲基铵丙烷)和(b)DOTAP(N-[1-(2,3-二油酰氧基)丙基]-N,N,N-三甲基铵甲基-硫酸盐)。在一个实施方案中,本发明制剂的阳离子脂质氮(N)与pDNA磷酸盐/酯(P)的摩尔比选自1、2和3。在一个实施方案中,对于包含辅助脂质的制剂,制剂的阳离子脂质与辅助脂质的摩尔比为1:1。
在某些实施方案中,根据本发明制备的pDNA脂质体制剂由单瓶制剂(single vialformulation)或双瓶制剂(two-vial formulation)构成。单瓶制剂可以是液体注射剂或注射用冻干粉末。基于双瓶的制剂包括包含pDNA的一个瓶和包含脂质分散体的另一个瓶。两个瓶可在施用时混合。
根据本发明制备的包含免疫原性组合物的DNA疫苗或制剂在5±3℃下稳定持续至少6个月以及在25±2℃下稳定持续3个月。
在另一个实施方案中,本发明的DNA构建体或载体肌内或皮内注射到对象中。根据本发明的免疫接种方法包括无针注射系统(NFIS)或电转化仪或直接针注射中的任一种。
在一个实施方案中,本发明提供了包含本发明的DNA构建体或载体的免疫原性组合物。在另一个实施方案中,本发明提供了制备包含本发明的DNA构建体或载体的免疫原性组合物的方法。
在另一个实施方案中,本发明提供了包含DNA构建体或其功能性变体的免疫原性组合物。
在一个实施方案中,本发明提供了包含本发明的DNA构建体或载体的疫苗。在一个优选实施方案中,本发明提供了包含SARS-CoV-2的S基因或SARS-CoV-2的S基因的S1区的DNA疫苗。在另一个实施方案中,本发明提供了包含SARS-CoV-2的S基因或SARS-CoV-2的S基因的S1区以及编码选自IgE信号肽或t-PA信号肽的信号肽的基因的DNA疫苗。
在一个优选实施方案中,根据本发明的疫苗包括包含编码SARS-CoV-2的S蛋白的基因的载体或包含编码SARS-CoV-2的S蛋白的S1区的基因的载体。在另一个实施方案中,根据本发明的疫苗提供了包含编码SARS-CoV-2的S蛋白的基因或编码SARS-CoV-2的S蛋白的S1区的基因以及编码选自IgE信号肽或t-PA信号肽的信号肽的基因的载体。
在一个实施方案中,根据本发明制备的疫苗在对象中诱导体液免疫应答和/或细胞免疫应答。细胞应答可通过ELISA、FACS或ELISpot测量。在一个实施方案中,根据本发明制备的疫苗诱导产生抗病毒CD8+T细胞应答。在一个实施方案中,根据本发明制备的疫苗诱导产生抗病毒CD4+T细胞应答。在一个实施方案中,根据本发明制备的疫苗诱导IFN-γ表达。
在另一个实施方案中,根据本发明制备的疫苗在对象中诱导冠状病毒中和抗体的产生。
在另一个实施方案中,本发明提供了通过施用合适治疗剂量的根据本发明制备的DNA疫苗来治疗冠状病毒或其相关疾病的方法或预防冠状病毒或其相关疾病的方法。
在一个实施方案中,发现DNA疫苗被良好耐受并且在重复绝对人剂量(6mg)下没有任何明显的毒性迹象。在一个实施方案中,本发明的DNA疫苗与细胞因子共递送以增强在病毒感染中有益的Th1免疫应答的产生。
发明详述
本发明提供了包含SARS-CoV-2的S基因的DNA构建体。本申请所指的S基因可以是全长S基因或S基因的合适截短部分或S基因的功能性变体,优选S基因的S1区,或者包含S基因的一部分或S基因的合适片段的合适的受体结合结构域,其可诱导免疫应答。在一个优选实施方案中,根据本发明的DNA构建体包含SARS-CoV-2的S基因。在一个优选实施方案中,根据本发明的DNA构建体包含SARS-CoV-2的S基因的S1区。根据本发明的DNA构建体具有如SEQID NO.:4或SEQ ID NO.:6或SEQ ID NO.:8或SEQ ID NO.:10中所示的核苷酸序列。由根据本发明制备的DNA构建体表达的氨基酸序列选自SEQ ID NO.:3、SEQ ID NO.:5、SEQ IDNO.:7和SEQ ID NO.:9。本发明还提供了包含SARS-CoV-2的S基因的DNA构建体,其可提供较高的S基因表达。所述包含SARS-CoV-2的S基因的DNA构建体具有耐受热应激、在室温下稳定和在多次冻融循环后稳定的能力。具有耐受热应激、在室温下稳定和在多次冻融循环后稳定的能力的DNA构建体表达具有脯氨酸替换的SARS-CoV-2的融合前稳定S蛋白的氨基酸序列。根据本发明的所述脯氨酸替换选自K986P、V987P、F817P、A892P、A899P、A942P及其合适的组合。脯氨酸替换的优选组合之一是K986P和V987P。其可被称为2P(两种脯氨酸替换)。脯氨酸替换的另一种优选组合是K986P、V987P、F817P、A892P、A899P和A942P。其可被称为hexaPro(六种脯氨酸替换)。编码具有六种脯氨酸替换的SARS-CoV-2的S蛋白的DNA构建体具有如SEQ ID NO.:12中所示的核苷酸序列。编码具有两种脯氨酸替换的SARS-CoV-2的S蛋白的DNA构建体可通过密码子优化方法和本发明的载体来制备,如本文中实施例所举例说明的。由根据本发明的具有耐受热应激、在室温下稳定和在多次冻融循环后稳定的能力的DNA构建体表达的氨基酸序列是SEQ ID NO.:11(Hexapro)或SEQ ID NO.:13(2P)。2019-nCoV利用密集糖基化的刺突(S)蛋白得以进入宿主细胞。S蛋白是以亚稳态融合前构象存在的三聚体I类融合蛋白,其经过大量结构重排以使病毒膜与宿主细胞膜融合。当S1亚基与宿主细胞受体结合时,触发该过程。受体结合使融合前三聚体去稳定,导致S1亚基脱落和S2亚基的转变以成为稳定的融合后(postfusion)构象(3)。
公知的是,2019-nCoV S与SARS-CoV S享有相同的功能性宿主细胞受体ACE2。还报道了ACE2以约为15nM的亲和力与2019-nCoV S外结构域结合,其是ACE2与SARS-CoV S结合的10至20倍高。2019-nCoV S对人ACE2的高亲和力可有助于2019-nCoV可在人与人之间传播的明显便利性(3)。本发明提供了编码SARS-CoV-2的全长S蛋白的DNA构建体或编码SARS-CoV-2的S蛋白的S1区的DNA构建体。
本发明的DNA构建体包含携带编码SARS-CoV-2的S蛋白的基因的载体的构建体。本发明的载体可携带SARS-CoV-2抗原、其片段、其变体,或其组合。包含本发明的DNA构建体的载体可以是质粒DNA(pDNA)。根据本发明的载体可携带SARS-CoV-2的S蛋白的S1区。载体可任选地包含编码IgE信号肽的基因。信号肽参与所表达的S蛋白或S1蛋白向细胞膜的转运,其被从细胞膜分泌到间隙空间中或者可保持结合在细胞膜上,在细胞膜上S蛋白抗原或S蛋白抗原的S1区被交叉呈递至APC。APC通过直接摄取抗原或吞噬表达抗原的体细胞,将抗原通过其MHC I和MHC II复合体呈递至CD4+和CD8+T细胞。分泌的蛋白也通过B细胞受体被B细胞识别,并通过MHC II复合体被呈递,从而诱导病毒中和。
根据本发明优选的载体是pVAX1(Invitrogen,USA)。已良好地建立了载体pVAX1的构建技术,并且该载体已被广泛用于DNA疫苗的构建(4和5)。本发明的载体还可包含全长S蛋白或S蛋白的S1区高水平表达所需的调节元件。这样的调节元件和包含调节元件组合的载体在例如专利文件WO 2008085956、WO 2012046255和WO 2007017903中充分公开。技术人员可通过本领域已知的技术制备包含本发明的新构建体的表达载体。优选地,本发明提供了这样的DNA质粒载体pVAX1,其携带2019-nCoV刺突-S蛋白的全长S基因或S1基因区以及编码IgE信号肽的基因。或者,t-PA信号肽可用于制备携带S基因或S1基因的质粒载体。本发明还提供了制备本发明的载体的方法。此外,本发明提供了DNA构建体或DNA质粒载体进入肌细胞中的注射。其可通过本领域已知的基于针的标准技术进行。这样的转染优选通过无针注射或通过电转化仪系统进行。无针注射系统(NFIS)是本领域技术人员已知的。NFIS的使用消除了疫苗施用期间针的使用,因此消除了与锋针(sharp-needle)废弃物相关的成本和风险。此外,NFIS不需要外部能量来源例如气筒或电以及弹簧来为该装置提供动力。与其中皮内累积在个体之间不一致(如通过鼓泡尺寸测量的)并且在动物物种之间不同的针头和注射器相比,这些注射器产生以高流速渗透至皮肤中2mm的加压流体流,导致细胞中DNA分子的均匀分散和更高摄取。无针注射系统之一可以是装置。所述装置目前在商业上用于某些疫苗接种,例如MMR疫苗、IPV疫苗和流感疫苗的疫苗接种。此外,已在DNA疫苗的临床试验中评价了该装置(6)。在电穿孔装置中,可以使用Trigrid递送系统或装置。这些装置已广泛用于从基因治疗到传染病预防的数种DNA递送试验中(7、8、9)。质粒DNA构建体优选地经肌内注射到肌细胞中。将DNA构建体直接施用到肌细胞中使得其作为附加体保留在核中,而不会整合到宿主细胞DNA中。附加体中插入的克隆DNA可以利用宿主细胞蛋白质翻译机制指导编码的全长S蛋白抗原或S蛋白抗原的S1区的合成。根据本发明制备的DNA构建体也可通过其他肠胃外途径施用至对象中。这样的肠胃外途径选自皮下、静脉内、皮内、经皮和透皮、以及递送至组织的间隙空间。DNA构建体可适于例如以可为无菌且无热原的可注射形式进行的肠胃外施用。在一个实施方案中,本发明提供了这样的免疫原性组合物,其包含本发明的DNA构建体或含有该DNA构建体的载体。这样的免疫原性组合物可任选地包含编码IgE信号肽的基因或编码t-PA信号肽的基因。本发明还提供了制备包含本发明的DNA构建体或基于该DNA构建体的载体的免疫原性组合物的方法。所述方法包括(i)制备DNA构建体或制备包含DNA构建体的载体以及(ii)向步骤(i)的制备物中添加合适的佐剂和/或合适的药物赋形剂。合适的药物赋形剂选自缓冲剂、稳定剂、佐剂及其合适的组合。DNA构建体的制备包括构建这样的DNA构建体,其编码SARS-CoV-2的S蛋白或S蛋白的S1区,任选地具有编码IgE信号肽的基因。用于构建编码SARS-CoV-2的S蛋白或S蛋白的S1区的DNA构建体的载体优选pVAX1。根据本发明制备的免疫原性组合物肠胃外施用于对象。这样的肠胃外途径选自肌内、皮下、静脉内、腹膜内、皮内、经皮和透皮、以及递送至组织的间隙空间。免疫原性组合物可适于例如以可为无菌且无热原的可注射形式进行的肠胃外施用。在一个优选实施方案中,本发明提供了这样的DNA疫苗,其包含本发明的DNA构建体或包含该DNA构建体的载体。所述DNA疫苗的DNA构建体包含编码SARS-CoV-2的S蛋白的基因或编码S蛋白的S1区的基因。这样的疫苗可任选地包含编码IgE信号肽的基因。疫苗可包含SARS-CoV-2抗原肽、SARS-CoV-2抗原蛋白、其变体、其片段,或其组合。根据本发明制备的疫苗肠胃外施用于对象。这样的肠胃外途径选自肌内、皮下、静脉内、腹膜内、皮内、经皮和透皮、以及递送至组织的间隙空间。疫苗可适于例如以可为无菌且无热原的注射形式进行的肠胃外施用。在一个实施方案中,根据本发明制备的疫苗或免疫原性组合物包含含有根据本发明制备的DNA或载体的不同制剂。本发明的免疫原性组合物可以在水或盐水中制备。根据本发明的免疫原性组合物或制剂是用具有不同离子强度的不同缓冲剂、稳定剂、佐剂以及任选的其他合适的药物赋形剂制备的。在本发明的一个优选实施方案中,免疫原性组合物由以下构成:(a)缓冲剂;(b)稳定剂,其选自自由基清除剂和/或金属离子螯合剂;(c)其他药物赋形剂,其选自盐酸丁哌卡因和/或选自Vi-多糖、酶原和/或壳聚糖的糖;以及(d)佐剂,其选自氢氧化铝凝胶、细菌来源的佐剂、亲脂性佐剂、亲水性佐剂、完全弗氏佐剂(CFA)、不完全弗氏佐剂(IFA)、单磷酰脂质A、β-谷固醇及其合适的组合。使用具有不同离子强度或不同pH的缓冲剂制备包含pDNA的多种免疫原性组合物。
优选地,所述制剂或免疫原性组合物是pDNA脂质体制剂。在一个实施方案中,所述制剂使用阳离子脂质(CL)通过脂质包埋方法来制备,所述阳离子脂质包含选自DOTMA(1,2-二-O-十八碳烯基-3-三甲基铵丙烷)和DOTAP(N-[1-(2,3-二油酰基氧基)丙基]-N,N,N-三甲基铵甲基硫酸盐)的一种或更多种脂质。所述制剂可用于质粒DNA递送。CL用作pDNA的载体,因为他们与pDNA形成复合物,并且这样的复合物将pDNA转运到胞质溶胶中。pDNA脂质体的形成取决于阳离子脂质氮(N)与pDNA磷酸盐/酯(P)的摩尔比,在此将其称为N/P比。N/P比影响pDNA脂质体的最终特性,例如尺寸、表面ζ电势和再现性,并因此反映其转染后的效率。pDNA脂质体通常通过添加辅助脂质来制备。辅助脂质是中性脂质,将其并入以增强转染。根据本发明的优选制剂包含选自1、2和3的N/P比。对于包含辅助脂质的制剂,根据本发明的阳离子脂质与辅助脂质的摩尔比为1:1。
pDNA脂质体制剂可由单瓶制剂或双瓶制剂构成。单瓶制剂可以是液体注射剂或注射用冻干粉末。基于双瓶的制剂包括包含pDNA的一个瓶和包含脂质分散体的另一个瓶。两个瓶可以在施用时混合。
更优选地,本发明的制剂或免疫原性组合物是包含pDNA与磷酸缓冲盐水的液体制剂。所述pDNA构建体包含编码全长S基因的基因。所述包含pDNA与磷酸缓冲盐水的免疫原性组合物或液体制剂也可以称为本发明的DNA疫苗,其是最终配制的药物产品。根据本发明制备的最终药物产品在5±3℃下稳定持续至少6个月以及另外地在25±2℃下稳定持续3个月。
根据本发明制备的疫苗在对象中诱导针对冠状病毒(优选SARS-CoV-2)的体液免疫应答和/或细胞免疫应答。在一个实施方案中,根据本发明制备的疫苗诱导产生抗病毒CD8+T细胞应答。引发的CD8+T细胞应答可以是多功能的。所诱导的细胞免疫应答可包括引发CD8+T细胞应答,其中CD8+T细胞产生IFN-γ、TNF-α、IL-2或IFN-γ和TNF-α的组合。免疫应答可通过ELISA来测量,如本申请在此所述的。检测健康对象在免疫接种之后的抗体水平变化。对疫苗作出应答的对象可标记为血清转化(seroconverted)。本文中将血清转化定义为相比于基线或安慰剂组针对S或S1蛋白的抗体效价升高四倍。在不同动物模型中体内评价根据本发明制备的DNA疫苗,并且已经确定了其在不同动物物种中引发针对SARS-CoV-2S抗原的免疫原性应答的能力。甚至在最后一次给药之后三个月,小鼠中针对刺突抗原的血清IgG水平仍得以维持,这表明本发明的DNA疫苗产生了长期免疫应答。这也表明本发明的DNA疫苗可以在再次暴露时诱导由平衡记忆B细胞和辅助T细胞表达而产生的稳健的次级记忆性免疫应答。此外,还可测量细胞因子应答,包括Th-1和Th-2细胞因子,但不限于IFN-γ、TNF-α、IL-2、IL-4、IL-5、IL-6和IL-10。在一个优选实施方案中,根据本发明制备的疫苗提供了指示强的Th1应答的IFN-γ表达的显著增加。
本发明的疫苗可在对象中诱导产生冠状病毒中和抗体。另外,其可诱导产生与SARS-CoV-2刺突抗原反应的免疫球蛋白G(IgG)抗体。用于测试中和抗体的方法可以是使用慢病毒载体或使用VSV载体或使用麻疹载体系统的假病毒体测定。DNA疫苗接种后的血清中和抗体(neutralizing antibody,Nab)效价可通过微中和测定和Genscript中和抗体检测试剂盒进行测试。通过两种方法测试的Nab效价值表明,本发明的DNA疫苗产生了稳健的应答并中和了SARS CoV-2病毒,赋予针对感染的保护性免疫。
本发明提供了通过施用合适治疗剂量的根据本发明制备的DNA疫苗来治疗或预防冠状病毒(优选SARS-CoV-2)或其相关疾病的方法。该疫苗可用于保护以免于任何数目的SARS-CoV-2的毒株,从而治疗、预防基于SARS-CoV-2的病理状况和/或保护免于基于SARS-CoV-2的病理状况。DNA疫苗可以以单次、双次或三次给药方案来施用,每次给药之间间隔14至28天。
在一个实施方案中,本发明的DNA疫苗在经皮内以及经肌内施用时是安全且耐受的。当在大鼠和兔中皮内施用时,本发明的DNA疫苗高至2mg是安全的以及在肌内施用时高至6mg是安全的。在任何动物组中均未观察到治疗相关作用。进一步的组织病理学检查表明内脏器官无严重病变。
在一个实施方案中,本发明的DNA疫苗与细胞因子共递送以增强在病毒感染中有益的Th1免疫应答的产生。一种这样的细胞因子可以是IFN-α或聚乙二醇化的IFN-α或IFNβ,其可与本发明的疫苗共递送以增强在病毒感染中有益的Th1免疫应答的产生。
实施例
给出以下实施例以向本领域普通技术人员提供有关如何制备本文中所要求保护的DNA构建体、其组合物、其疫苗以及方法的公开内容和说明。以下实施例仅旨在纯粹举例说明,并不旨在限制本公开内容的范围。本发明的其他DNA构建体可使用如提供的实施例中所述的方法在进行一些修改的情况下来开发。这样的修饰是本领域技术人员已知的
实施例1:SARS-CoV-2的全长S基因或S1基因的合成或分离
全长S基因(SEQ ID NO.:1)和S基因的S1区(SEQ ID NO.:2)的氨基酸序列从NCBI(MN908947.2.)获得。目的基因是密码子优化的以用于在人中表达并由德国GeneArt化学合成。S基因和S基因的S1区的密码子优化的核苷酸序列在本文中上文给出的核苷酸序列中以粗体突出显示。
实施例2:编码S基因或S1基因以及IgE/t-PA信号肽的载体的构建
将所有化学合成的基因:具有IgE前导序列的全长S基因(SEQ ID NO.:3和SEQ IDNO.:4)、具有t-PA前导序列的全长S基因(SEQ ID NO.:5和SEQ ID NO.:6)、具有IgE前导序列的S基因的S1区(SEQ ID NO.:7和SEQ ID NO.:8)、具有t-PA前导序列的S基因的S1区(SEQID NO.:9和SEQ ID NO.:10)用NheI和ApaI限制性位点消化,并将其插入到用相同的一组限制性酶消化的pVAX1载体中。通过对载体进行桑格测序和限制性酶分析来确定基因的存在和完整性。将携带具有IgE前导序列的全长S基因的pVAX1载体命名为ZVTC_COV1(图1)。将携带具有t-PA前导序列的全长S基因的第二载体命名为ZVTC_COV2(图2)。将携带具有IgE前导序列的S基因的S1区的第三载体命名为ZVTC_COV3(图3)以及将携带具有t-PA前导序列的S基因的S1区的第四载体命名为ZVTC_COV4(图4)。以相同的方式,可通过以下如本文中实施例1和2所举例说明的方法制备编码具有2P替换或具有Hexapro替换的SARS-CoV-2的S蛋白的质粒DNA构建体。在DH5-αTM化学感受态细胞中转化质粒DNA构建体。在热激转化步骤之后,通过在包含卡那霉素抗生素的LB琼脂板上平板接种来分离携带质粒DNA构建体的大肠杆菌克隆。挑选单一菌落并接种到包含来自Hi-Media的LB培养基(broth)和卡那霉素的烧瓶中。将烧瓶在37℃培养箱摇床中以225rpm培养20小时。使用小规模制备(miniprep)质粒分离试剂盒将来自每个克隆的培养物用于质粒分离。使用BamH1、Nhe1和Apa1对所有构建体进行限制性消化,来检查插入物的预期条带释放,以选择阳性克隆。选择阳性克隆用于甘油储备液的制备并储存在-70℃下。
实施例3:DNA构建体的体外表达分析
通过在Vero细胞系中转染DNA疫苗候选物来检查DNA疫苗候选物的体外表达。对于转染实验,将Vero细胞以3×105个细胞/ml的密度接种于6孔板中并在CO2培养箱中保持至达到80至90%的汇合率。24小时后,一旦细胞达到期望的汇合率,用Lipofectamine 2000试剂(Thermo Fisher)在OptiMEM无血清培养基中进行转染。使用两种不同浓度(4μg和8μg)的DNA构建体用于转染实验。转染之后,用包含FBS的新鲜DMEM培养基(Biowest)来补充培养基。72小时后,将板用1:1丙酮和甲醇固定。向每个孔添加抗S1兔多克隆抗体(Novus)并孵育1小时,随后与FITC标记的抗兔抗体(Merck)一起孵育。使用倒置显微镜(ZeissAX10)捕获荧光图像。在此分别以图5a和5b给出荧光图像,其示出了在用DNA构建体或空质粒(对照)转染Vero细胞之后通过免疫荧光获得的S蛋白和S1蛋白的表达。
实施例4:载体进入宿主细胞的转染
本实施例描述了用编码S基因或S1基因的载体转染CHO宿主细胞系。使用2种不同方法在CHO细胞系中进行转染。
(1)使用电穿孔方法在Freestyle CHO-S细胞(Invitrogen)中的转染
将Freestyle CHO-S细胞(Invitrogen)用作转染的宿主。在来自Lonza的PowerCHO 2CD培养基中常规培养细胞。在转染之前约24小时接种细胞以使他们生长处于指数期。利用Neon转染系统(Invitrogen)按照预先优化的条件通过电穿孔进行转染。转染后,将细胞平板接种在包含1ml来自Lonza的预热培养基的24孔板中。在5% CO2存在下于37℃下在加湿培养箱中培养细胞。在1至3周的时间内定期监测合并物的细胞数目。将转染的合并物进一步转移至6孔板并随后转移到T-烧瓶/培养管中。储存转染的合并物细胞和上清液以用于S基因或S1基因的表达分析。
(2)使用基于脂质的方法在ExpiCHO STM细胞(Gibco,ThermoFisher)中的转染
将ExpiCHO STM细胞常规保持在ExpiCHOTM表达培养基中。转染之前一天,使ExpiCHO STM细胞分裂至最终密度为3×106个细胞/ml。第二天,使用ExpiFactamineTM CHO试剂根据制造商的方案(Gibco,ThermoFisher)进行瞬时转染。转染后,添加ExpiFactamineTMCHO增强剂并在第1天将细胞转换至32℃。在第1天和第5天进行进料(feed)。当细胞生存力达到<50%时收获培养物。此外,储存细胞和上清液以用于表达分析。
实施例5:包含pDNA的免疫原性组合物或制剂的制备
免疫原性组合物的制备-
按照最终制剂浓度在持续搅拌下将编码具有IgE信号肽的S基因(本文表示为SEQID NO.4)的纯化的质粒DNA添加至无菌过滤的磷酸缓冲盐水。在确保均匀之后,使用0.2μ过滤器对配制的原料(bulk)过滤除菌。将共混物装入瓶中并进行目视检查。将瓶分开并收集用于质量控制的样品以进行测试。对剩余的瓶进行标记&包装在单纸盒中&储存在2℃至8℃下。
表2:实时条件(5±3℃)下DNA疫苗(药物产品)的稳定性
表3:加速条件(25±2℃)下疫苗(药物产品)的稳定性
稳定性数据显示,根据本发明制备的DNA疫苗可在2至8℃下长期储存以及另外地在25℃下储存3个月。在大流行爆发的情况下,疫苗的稳定性特征对于大规模疫苗接种的容易部署和分配起着至关重要的作用。单瓶制剂:
通过薄膜水合或乙醇注射方法来制备脂质分散体。向所述脂质分散体中添加pDNA并混合以形成pDNA脂质体。通过水浴超声或均质化或合适的方法使pDNA脂质体解聚集。然后通过IM注射来施用pDNA脂质体。此外,可将pDNA脂质体制剂冻干以使所制备的制剂稳定。可通过添加冷冻保护剂例如蔗糖、乳糖或甘露糖醇来冻干pDNA脂质体制剂。然后,对产物进行冻干。在施用时,可将pDNA脂质体制剂瓶用注射用无菌水或合适的缓冲剂重构。然后通过IM注射来施用重构的pDNA脂质体。
双瓶制剂:
瓶1的制备-通过薄膜水合或乙醇注射方法来制备脂质分散体。脂质分散体的尺寸减小至低于200nm。然后将脂质分散体通过0.2μ无菌级过滤器过滤并装入瓶1中。
瓶2的制备-其包含无菌过滤的pDNA溶液。
通过在受控室温下混合瓶1和瓶2的内容物来制备pDNA脂质体。然后通过IM注射来施用pDNA脂质体。
实施例6:使用DNA疫苗的动物免疫接种
在获得机构动物伦理委员会(Institutional Animal Ethics Committee)的伦理批准之后,在近交BALB/C小鼠、豚鼠和新西兰白兔模型中进行了DNA疫苗的免疫原性研究。本研究中使用BALB/c小鼠(5至7周龄)、豚鼠(5至7周龄)和新西兰白兔(6至12周龄)。对于小鼠皮内免疫接种,在第0天使用31号针将25和100μg DNA疫苗施用于皮肤。注射空质粒的动物作为载剂对照。免疫接种之后两周,给予动物第一次加强剂量。类似地,所有小鼠均在第一次加强剂量之后2周给予第二次加强剂量。对于豚鼠研究,使用相同的给药和方案进行皮内免疫接种。在兔中,以相同的3次给药方案和时间表,使用无针注射系统(NFIS)以500μg剂量将DNA疫苗施用于皮肤。在第0天(免疫之前)&第28天(2次剂量之后)以及第42天(3次剂量之后)从动物收集血液,用于免疫评估血清样本。在小鼠模型中,评估了疫苗的长期免疫原性持续多至第126天。此外,评估了第0、28和42天脾细胞的IFN-γ应答。
实施例7:用不同的免疫原性组合物在动物模型中的免疫原性研究
以不同的剂量强度以及不同的免疫原性组合物测试根据本发明制备的DNA疫苗。通过任一IM/ID/SC途径将25μg至100μg SARS-CoV-2DNA疫苗递送至小鼠或豚鼠,所述SARS-CoV-2DNA疫苗包含含有编码全长S基因的基因的质粒DNA构建体。如下表4中所述,将25μg和100μg SARS-CoV-2DNA疫苗皮内施用于Balb/c小鼠和豚鼠。
表4:DNA疫苗免疫原性研究的研究计划
在第0天通过IM/ID/SC途径向小鼠和豚鼠注射0.1mL/0.05ml/0.5ml疫苗制剂。在第14天和第28天重复相同的免疫接种程序。观察动物多至56天。为了通过ELISA和其他方法评估免疫原性,在第0、14、28天(免疫接种之前)以及在第42天和第56天对动物采血。使用如实施例8中所述的标准ELISA来测试针对SARS-CoV-2的重组S1抗原的血清样品。
实施例8:通过ELISA对针对S或S1蛋白的抗体应答的分析
接种疫苗后进行间接ELISA以检测针对S或S1蛋白的IgG抗体。将IgG抗体效价升高4倍视为血清转化。以50ng/孔的在磷酸缓冲盐水(PBS)中的重组纯化的SARS-CoV-2的S1刺突蛋白(Acro,USA)包被96孔板,在4℃下过夜。将板洗涤3次,然后用PBS中的5%脱脂乳(BDDifco)在37℃下封闭1小时。也可用PBS中的牛血清白蛋白(BSA)代替PBS中的脱脂乳。然后将板用PBS洗涤三次,并与小鼠和豚鼠血清的系列稀释液一起孵育并在37℃下孵育2小时。将板再次洗涤三次并随后与辣根过氧化物酶(HRP)缀合的抗鼠IgG二抗(Sigma-Aldrich)的1:2,000稀释液或辣根过氧化物酶(HRP)缀合的抗豚鼠IgG二抗(Sigma-Aldrich)的1:5,000稀释液一起孵育,并在37℃下孵育1小时。可在RT下进行孵育以代替37℃。在使用TMB过氧化物酶底物(KPL)形成最终洗涤板之后,并用TMB终止溶液(1N H2SO4)终止反应。使用多模式读取器(Molecular Devices,USA)在30分钟内在450nm波长处读取板。用DNA疫苗候选物通过皮内途径进行免疫接种在BALB/c小鼠和豚鼠中以剂量依赖性方式引发了针对S蛋白的显著血清IgG应答,其中在3次给药之后在第42天,平均终点效价分别达到在BALB/C小鼠中为约28000以及在豚鼠中为约140000(图6和图7)。在最后一次给药之后近3.5个月,在小鼠中研究了长期抗体应答,并且检测到平均终点IgG效价为约18000(图6),表明DNA疫苗候选物产生了持续的免疫应答。
实施例9:通过测量细胞因子产生的细胞免疫应答的分析
最后一次注射之后两周,制备来自脾或单核细胞的单细胞悬浮液。将在补充有10% FBS的RPMI-1640培养基(Sigma)中的2至3×105个细胞/孔一式三份地接种到96孔板中。在37℃和5%CO2下在多种条件(5μg/ml伴刀豆球蛋白A(阳性对照)、5μg/ml纯化的S抗原(特异性抗原)、5μg/ml BSA(不相关抗原)或单独的培养基(阴性对照))下刺激培养物持续60小时。根据制造商的方案,向每个孔中添加20μl CellTiter 96Aqueous One Solution试剂(Promega,USA)。在37℃下孵育4小时后,在490nm处读取吸光度。使用刺激指数(stimulation indexes,SI)来评估增殖活性。SI被定义为包含抗原的孔的平均OD 490除以不含抗原的孔的平均OD 490。测量了细胞增殖之后获得的上清液以及血清样品中的细胞因子应答。通过ELISA/FACS/ELISpot测定评估对SARS-CoV-2的细胞免疫应答。根据细胞因子检测试剂盒提供的标准操作程序进行测定。
IFN-γELISPOT测定
对于IFN-γELISPOT分析,将来自经免疫接种小鼠的脾收集在包含补充有2X抗生素(抗生素抗真菌,Thermoscientific)的RPMI 1640(Thermoscientific)培养基的无菌管中。通过在无菌培养皿板中用10ml注射器(BD)柱塞的圆盘底部捣碎脾来制备细胞悬浮液。然后向其添加5至10ml补充有1X抗生素的RPMI-1640培养基,并混合内容物以使其匀质。将皿保持不受干扰持续2分钟并将透明上清液缓慢移出至细胞过滤器(BD)中。将过滤物收集在无菌管中并通过在离心机(Thermo Scientific)中以250×g在4℃下离心10分钟来沉淀细胞。收集包含红细胞(red blood cell,RBC)和脾细胞的沉淀。向包含脾细胞的沉淀添加2至3ml RBC裂解缓冲液(Invitrogen),并在室温下孵育5至7分钟。孵育之后,以先前添加RBC裂解缓冲液的3倍体积来添加补充有10%FBS(Biowest)和1X抗生素的RPMI 1640。将沉淀用补充有10% FBS和1X抗生素的RPMI 1640洗涤两次,并重悬于包含10% FBS和1X抗生素的RPMI 1640培养基中,并调节至密度为2.0×106个细胞/ml。取出用纯化的抗小鼠IFN-γ捕获抗体预包被的96孔小鼠IFN-γELISPOT试剂盒(CTL,USA)板,在CO2培养箱中将其用RPMI+10% FBS+1X抗生素封闭1小时。然后将板用PBS洗涤一次并随后向每个孔添加200,000个脾细胞,并在37℃下在5%CO2中用浓度为5.0μg/孔的12-聚体肽合并物(GenScript)以及阴性对照(补充有10% FBS和1X抗生素的RPMI 1640)和阳性对照(伴刀豆球蛋白A,1μg/孔)刺激24小时,所述12-聚体肽合并物涵盖整个SARS-CoV-2S蛋白。刺激之后,将板用PBS洗涤随后用包含0.05%吐温的PBS洗涤,并根据随试剂盒提供的制造商的说明形成斑点。将板干燥并在ELISPOT Reader S6 Versa(CTL USA)上对斑点计数,并用免疫斑点软件(7.0版)进行分析。
对DNA疫苗候选物的细胞免疫应答
通过IFN-γELISpot测定来研究针对SARS-CoV-2刺突抗原的T细胞应答。在施用DNA疫苗(25和100μg剂量)后在第14、28、42天处死BALB/c小鼠组。收获脾细胞,并将单细胞悬浮液用涵盖SARS-CoV-2刺突蛋白的12-聚体重叠肽的合并物刺激24小时。在免疫接种之后42天的小鼠脾细胞中,针对25和100μg剂量二者均观察到针对SARS-CoV-2刺突肽合并物的200至300个SFC/106个脾细胞的IFN-γ表达的显著提高(其指示强的Th1应答)(图8)。
实施例10:使用野生型SARS-CoV-2通过病毒中和测定的病毒中和分析
进行了微中和试验(MNT)。从BEI resources,USA获得病毒(分离株USA-WA1/2020),在Vero-E6细胞中传代并滴定。将从经免疫接种动物收集的血清样品在56℃下热灭活30分钟,随后用细胞培养基进行2倍系列稀释。将稀释的血清样品与100TCID50的病毒悬浮液在96孔板中以1:1的比率混合,随后孵育1小时。随后在实验之前24小时在96孔组织培养板上在接种的Vero-E6细胞(150μl DMEM+10% FBS中的1×104个细胞/孔)上吸附1小时。随后将细胞用150μl无血清培养基和150μl补充有2%FBS的DMEM培养基洗涤,随后在37℃下在5%CO2培养箱中孵育3至5天。在显微镜下记录每个孔中的细胞病变作用(CPE)。中和被定义为与病毒对照相比不存在CPE。通过DNA疫苗候选物在小鼠、豚鼠和兔中引发中和抗体。来自经DNA疫苗候选物免疫接种的BALB/c小鼠的血清可中和野生SARS-CoV-2病毒毒株,其中在25和100μg剂量方案下在第42天的平均MNT效价分别为40和160(表5)。
实施例11:通过竞争性抑制ELISA的中和抗体的检测
使用SARS-CoV-2中和抗体检测试剂盒(Genscript)进行竞争性抑制ELISA。该试剂盒检测针对SARS-CoV-2的循环中和抗体,所述抗体阻断病毒刺突糖蛋白的受体结合结构域(RBD)与ACE2细胞表面受体之间的相互作用。
用试剂盒中提供的稀释缓冲液系列稀释不同动物血清样品。将稀释的血清样品与HRP缀合的RBD以及阳性和阴性对照以1:1比率在37℃下一起孵育30分钟。然后将血清与HRP缀合的RBD的混合物添加至用ACE2蛋白预包被的ELISA板。之后,将板在37℃下孵育15分钟,随后用试剂盒中提供的洗涤溶液洗涤4次。洗涤步骤之后,向孔中添加TMB溶液并在室温下在黑暗中孵育15分钟,随后添加终止溶液。在450nm处读取板。使用Graph pad Prism 8.0.1软件通过在非线性回归曲线拟合中绘制针对每种稀释度与血清稀释度获得的百分比竞争值,来计算血清样品的抑制浓度(IC50)。使用Genscript中和抗体检测试剂盒,在第42天在25和100μg剂量方案下分别获得平均IC50效价为82和168。此外,在BALB/c小鼠的长期免疫原性研究中也检测到中和抗体。在豚鼠和兔中也观察到中和抗体水平显著升高(表5)。
表5:在向BALB/c小鼠、豚鼠和新西兰白兔施用DNA疫苗之后的血清中和抗体效价
实施例12:通过假病毒体测定的中和抗体的分析
产生假病毒并进行滴定。对于这种假病毒系统,由沿SARS-CoV-2刺突(S)蛋白包装表达盒的VSV假型病毒/慢型假型病毒或麻疹假型病毒提供骨架。
使用lipofectamine按照制造商的说明,用携带SARS-CoV-2刺突蛋白和辅助质粒的质粒载体转染293T细胞。在感染之后2小时,将细胞用PBS洗涤3次,并随后添加新的完全培养基。感染之后2至15天(取决于所使用的假病毒类型),收获包含SARS-CoV-2假病毒的培养物上清液,过滤(0.45-μm孔径),并以2-ml等分试样储存在-70℃下直至使用。使用来自假病毒库的一次性等分试样来确定SARS-CoV-2假病毒的50%组织培养物感染剂量(TCID50)。所有储备物仅使用一次,以避免重复冻融循环可能导致的不一致。对于SARS-CoV-2假病毒的滴定,在96孔培养板中进行2倍初始稀释,随后进行3倍系列稀释(总共9次稀释)。最后一列作为不添加假病毒的细胞对照。然后,用调节至预定浓度的经胰蛋白酶处理的哺乳动物细胞接种96孔板。在5% CO2环境中在37℃下孵育2至9天(取决于所使用的假病毒类型)之后,确定阳性孔。使用Reed-Muench方法计算50%组织培养物感染剂量(TCID50)。
实施例13:DNA质粒的制备方法
a)细胞复苏和发酵:
使用来自工作细胞库的细胞培养物接种预接种培养基。将预接种培养基在30±1℃下培养以实现OD为≥1.5。将预接种培养基接种到种子发酵培养基(seed fermentationmedia)中并在种子发酵器中在30±2℃下培养。在达到约≥2.0的目标光密度之后,将种子发酵培养基用于接种生产发酵器。在30℃至42℃、pH 7.0±0.3、溶解氧浓度维持在0-100%下,通过级联搅动和氧富集来培养培养物。在细菌生长达到稳定期之后终止发酵。将收获的培养基离心并将细胞沉淀储存在-70℃下或低于-70℃下,并仍进行裂解。用包含0.2M NaOH和1% SDS的溶液通过化学方法进行细胞的裂解。将裂解培养物培养基的pH值调节至约pH5至13。裂解后,进行浓缩、通过连续流动离心或深度过滤来使细胞裂解物澄清并收集澄清的裂解物作为过滤物。
b)纯化:
纯化过程以通过中在细胞与缓冲液比率维持在1:5至1:12的范围的情况下悬浮在重悬浮溶液中进行的细胞裂解开始。重悬浮之后,以相同的细胞与缓冲液比率添加包含1%SDS和0.2N NaOH的溶液以进行细胞裂解。裂解后,添加冷冻的乙酸钾缓冲液以将溶液的pH中和至约pH 5.5。中和之后,向相同反应混合物添加CaCl2(其中目标浓度不低于0.5至1.0MCaCl2),以去除RNA杂质。CaCl2处理后,对反应混合物进行澄清随后通过UF/DF进行缓冲液更换,以修复溶液。对经修复的溶液另外进行阴离子交换柱色谱,以去除残留RNA和其他与产品和过程相关的杂质。
澄清的裂解物的纯化由数次浓缩/渗滤操作和阴离子交换色谱组成。使用100-500kDa MWCO(千道尔顿截留分子量,kilo Dalton molecular weight cutoff)过滤器对澄清的裂解物进行渗滤。使用中性pH的AEX平衡缓冲液完成渗滤。在分步洗脱模式下,使用具有洗脱缓冲液的弱阴离子树脂纯化包含DNA质粒的过滤物。这些运行的操作流速为约120-250cm/小时。通过凝胶电泳分析从阴离子交换柱洗脱的质粒DNA。
此外,在TFF中使用100-500kDa截留盒对阴离子交换洗脱液进行渗滤。温度维持在2℃至25℃下。过滤物包含目标DNA质粒。将渗滤的溶液通过0.2μm膜过滤器过滤以得到纯化的DNA质粒。
并入本专利申请的参考文献:
1.Tai et al.,Characterization of the receptor-binding domain(RBD)of2019 novel coronavirus:implication for development of RBD protein as a viralattachment inhibitor and vaccine,Cellular and Molecular Immunology(2020).https//doi.org/10.1038/s41423-020-0400-4
2.https://www.worldometers.info/coronavirus/
3.Wrapp et al.,Cryo-EM structure of the 2019-nCoV spike in theprefusion conformation,Science 367,1260-1263(2020).
4.Tao et al.,2009:Tao P,Luo M,Pan R,Ling D,Zhou S,Tien P,PanZ.Enhanced protective immunity against H5N1 influenza virus challenge byvaccination with DNA expressing a chimeric hemagglutinin in combination withan MHC c1ass I-restricted epitope of nucleoprotein in mice.Antiviralresearch.2009;81(3);253-260
5.Feng K,Zheng X,Wang R,et al.Long-Term Protection Elicited by a DNAVaccine Candidate Expressing the prM-E Antigen of Dengue Virus Serotype 3 inMice.Front Cell Infect Microbiol.2020;10:87.
6.Gaudinski MR et al.,Safety,tolerability,and immunogenicity of twoZika virus DNA vaccine candidates in healthy adults:randomised,open-label,phase 1 clinical trials.Lancet.2018;391(10120):552-562.
7.Quaglino E et al.,Chimeric DNA Vaccines against ErbB2+Carcinomas:From Mice to Humans.Cancers(Basel).2011 Aug 10;3(3):3225-41.
8.Spearman P et al.,A phase 1,randomized,controlled dose-escalationstudy of EP-1300polyepitope DNA vaccine against Plasmodium falciparum malariaadministered via electroporation.Vaccine.2016 Nov 4;34(46):5571-5578.
9.Modjarrad K et al.,Safety and immunogenicity of an anti-Middle Eastrespiratory syndrome coronavirus DNA vaccine:a phase 1,open-label,single-arm,dose-escalation trial.Lancet Infect Dis.2019Sep;19(9):1013-1022.
10.Polack,F.P.et al.Safety and Efficacy of the BNT162b2 mRNA Covid-19Vaccine.N Engl J Med.383(27),2603-2615(2020).
11.Voysey,M.et al.Safety and efficacy of the ChAdOx1 nCoV-19vaccine(AZD1222)against SARS-CoV-2:an interim analysis of four randomised controlledtrials in Brazil,South Africa,and the UK.Lancet 397(10269),99-111(2021)
12.Liu,M A.“DNA vaccines:a review.”Journal of internal medicinevol.253(4),402-410(2003).
13.Klinman,D.M et al.“Contribution of CpG motifs to theimmunogenicity of DNA vaccines.”Journal of immunology(Baltimore,Md.:1950)vol.158(8),3635-3639(1997).
通过引用并入
出于所有目的,本文中引用的每个专利文件和科学文章的全部公开内容通过引用并入。
等同方案
本发明可在不脱离其精神或基本特征的情况下以其他特定形式实施。因此,前述实施方案在所有方面均应被认为是举例说明性的,而不是限制本文中所述的发明。因此,本发明的范围通过所附权利要求书而不是通过前述说明来指示,并且在权利要求书的等同含义和范围内的所有变化均旨在包括在其中。
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Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His
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260 265 270
Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln
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Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp
290 295 300
Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu
305 310 315 320
Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg
325 330 335
Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu
340 345 350
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355 360 365
Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val
370 375 380
Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser
385 390 395 400
Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser
405 410 415
Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr
420 425 430
Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly
435 440 445
Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly
450 455 460
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro
465 470 475 480
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro
485 490 495
Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr
500 505 510
Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val
515 520 525
Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro
530 535 540
Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe
545 550 555 560
Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe
565 570 575
Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala
580 585 590
Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser
595 600 605
Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln
610 615 620
Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala
625 630 635 640
Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly
645 650 655
Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His
660 665 670
Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys
675 680 685
Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val
690 695 700
Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn
705 710 715 720
Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr
725 730 735
Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser
740 745 750
Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn
755 760 765
Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu
770 775 780
Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala
785 790 795 800
Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly
805 810 815
Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg
820 825 830
Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala
835 840 845
Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg
850 855 860
Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro
865 870 875 880
Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala
885 890 895
Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln
900 905 910
Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val
915 920 925
Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe
930 935 940
Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser
945 950 955 960
Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu
965 970 975
Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser
980 985 990
Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val Glu Ala Glu Val
995 1000 1005
Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr
1010 1015 1020
Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser
1025 1030 1035
Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln
1040 1045 1050
Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser
1055 1060 1065
Phe Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr
1070 1075 1080
Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile
1085 1090 1095
Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val
1100 1105 1110
Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu
1115 1120 1125
Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys
1130 1135 1140
Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu
1145 1150 1155
Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe
1160 1165 1170
Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly
1175 1180 1185
Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu
1190 1195 1200
Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln
1205 1210 1215
Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile
1220 1225 1230
Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr
1235 1240 1245
Ile Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly
1250 1255 1260
Cys Cys Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser
1265 1270 1275
Glu Pro Val Leu Lys Gly Val Lys Leu His Tyr
1280 1285
<210> 4
<211> 3873
<212> DNA
<213> 人工序列
<220>
<223> 具有IgE前导序列的全长S基因的核苷酸序列
<400> 4
atggattgga cctggattct gtttctggtg gccgctgcca caagagtgca tagcttcgtc 60
tttctcgtgc tgctgcctct ggtgtccagc cagtgtgtga acctgaccac aagaacacag 120
ctgcctccag cctacaccaa cagctttacc agaggcgtgt actaccccga caaggtgttc 180
agatctagcg tgctgcacag cacccaggac ctgtttctgc ccttcttcag caacgtgacc 240
tggttccacg ccatccatgt gtccggcacc aatggcacca agagattcga caaccccgtg 300
ctgcccttca acgatggggt gtactttgcc agcaccgaga agtccaacat catcagaggc 360
tggatcttcg gcaccacact ggacagcaag acccagagcc tgctgatcgt gaacaacgcc 420
accaacgtgg tcatcaaagt gtgcgagttc cagttctgca acgacccctt cctgggcgtc 480
tactaccaca aaaacaacaa gagctggatg gaaagcgagt tccgggtgta cagcagcgcc 540
aacaactgca ccttcgagta cgtgtcccag cctttcctga tggatctgga aggcaagcag 600
ggcaacttca agaacctgcg cgagttcgtg ttcaagaaca tcgacggcta cttcaagatc 660
tacagcaagc acacccctat caacctcgtg cgggatctgc ctcagggctt ttctgctctg 720
gaacctctgg tggacctgcc tatcggcatc aacatcaccc ggtttcagac cctgctggcc 780
ctgcacagat cttacctgac acctggcgat agcagctctg gatggacagc tggcgccgct 840
gcctattatg tgggctacct gcagcctcgg accttcctgc tgaagtacaa cgagaacggc 900
accatcaccg acgccgtgga ttgtgctctg gatcccctga gcgagacaaa gtgtaccctg 960
aagtccttca ccgtggaaaa gggcatctac cagaccagca acttcagagt gcagcccacc 1020
gagagcatcg tgcggttccc caatatcacc aatctgtgcc ccttcggcga ggtgttcaat 1080
gccaccagat ttgccagcgt gtacgcctgg aaccggaaga gaatcagcaa ctgcgtggcc 1140
gactacagcg tgctgtacaa tagcgccagc ttcagcacct tcaagtgcta cggcgtgtcc 1200
cctaccaagc tgaacgacct gtgcttcacc aatgtgtacg ccgacagctt cgtgatcaga 1260
ggcgacgaag ttcggcagat cgctcctgga cagacaggca agatcgccga ttacaactac 1320
aagctgcccg acgacttcac cggctgcgtg atcgcctgga atagcaacaa cctggactcc 1380
aaagtcggcg gcaactacaa ctacctgtac cggctgttcc ggaagtccaa tctgaagccc 1440
ttcgagcggg acatctccac cgaaatctat caggccggca gcaccccttg taacggcgtg 1500
gaaggcttca actgctactt cccactgcag tcctacggct ttcagcctac caatggcgtg 1560
ggctatcagc cctatagagt ggtggtgctg agcttcgaac tgctgcatgc ccctgctacc 1620
gtgtgcggcc ctaagaagtc taccaacctg gtcaagaaca aatgcgtgaa cttcaacttc 1680
aacggcctga ccggcacagg cgtgctgaca gagagcaaca agaagttcct gcctttccag 1740
cagtttggcc gggatatcgc cgataccaca gacgccgtta gagatcccca gacactggaa 1800
atcctggaca tcaccccatg cagctttggc ggagtgtctg tgatcacccc tggcaccaat 1860
accagcaatc aggtggccgt gctgtatcag gacgtgaact gtacagaggt gccagtggcc 1920
attcacgccg atcagctgac acccacttgg agagtgtact ccaccggctc caacgtgttc 1980
cagactagag ccggatgtct gatcggagcc gagcatgtga acaacagcta cgagtgcgac 2040
atccccatcg gagctggcat ctgtgccagc taccagacac agacaaatag ccccagacgg 2100
gccagaagcg tggcctctca gagcatcatt gcctacacaa tgagcctggg cgccgagaat 2160
tctgtggcct acagcaacaa ctctatcgct atccccacca acttcaccat cagcgtgacc 2220
accgagatcc tgcctgtgtc catgaccaag accagcgtgg actgcaccat gtacatctgc 2280
ggcgattcca ccgagtgcag caacctgctg ctgcagtacg gcagcttctg cacccagctg 2340
aatagagccc tgacagggat cgccgtggaa caggacaaga atacccaaga ggtgttcgcc 2400
caagtgaagc agatctacaa gacccctcct atcaaggact tcggcggctt caatttcagc 2460
cagattctgc ccgatcctag caagcccagc aagcggagct ttatcgagga cctgctgttc 2520
aacaaagtga cactggccga cgccggcttc atcaagcagt atggcgattg cctgggcgac 2580
attgccgcca gagatctgat ttgcgcccag aagtttaacg gactgacagt gctgcctcct 2640
ctgctgaccg atgagatgat cgcccagtac acatctgctc tgctggccgg cacaatcacc 2700
agcggatgga catttggagc tggcgcagcc ctgcagatcc cctttgctat gcagatggcc 2760
taccggttca acggcatcgg agtgacccag aatgtgctgt acgagaacca gaagctgatc 2820
gccaaccagt tcaacagcgc catcggcaag atccaggata gcctgtctag cacagccagc 2880
gctctgggca aactgcagga cgtggtcaat cagaacgctc aggccctgaa caccctcgtg 2940
aagcagctga gcagcaattt cggcgccatc agctccgtgc tgaacgatat cctgagccgg 3000
ctggataagg tggaagccga ggtgcagatc gacagactga tcacaggcag actgcagagc 3060
ctccagacat acgtgaccca gcagctgatc agagccgccg agattagagc ctctgccaat 3120
ctggccgcca caaagatgtc tgagtgtgtg ctgggccaga gcaagagagt ggatttctgc 3180
ggcaagggct accacctgat gagctttcca cagtctgctc ctcacggcgt ggtgtttctg 3240
catgtgacct acgtgcccgc tcaagagaag aacttcacaa cagcccctgc catctgccac 3300
gacggaaagg cccattttcc tagagaaggc gtgttcgtgt ccaacggcac ccattggttc 3360
gtgacacagc ggaacttcta cgagccccag atcatcacca ccgacaacac cttcgtgtct 3420
ggcaactgtg acgtcgtgat cggcattgtg aacaataccg tgtacgaccc tctgcagccc 3480
gagctggaca gcttcaaaga ggaactggac aagtacttta agaaccacac aagccccgac 3540
gtggacctgg gcgatattag cggcatcaat gccagcgtcg tgaacatcca gaaagagatc 3600
gaccggctga acgaggtggc caagaatctg aacgagagcc tgatcgacct gcaagaactg 3660
gggaagtacg agcagtacat caagtggccc tggtacatct ggctgggctt tatcgccgga 3720
ctgattgcca tcgtgatggt cacaatcatg ctgtgctgca tgaccagctg ctgtagctgc 3780
ctgaagggct gttgcagctg tggcagctgc tgcaagttcg acgaggatga tagcgagcct 3840
gtgctgaagg gcgtgaaact gcactactaa tga 3873
<210> 5
<211> 1293
<212> PRT
<213> 人工序列
<220>
<223> 具有t-PA前导序列的全长S基因的氨基酸序列
<400> 5
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Phe Val Phe Leu Val Leu Leu Pro Leu Val
20 25 30
Ser Ser Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala
35 40 45
Tyr Thr Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe
50 55 60
Arg Ser Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe
65 70 75 80
Ser Asn Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly
85 90 95
Thr Lys Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr
100 105 110
Phe Ala Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly
115 120 125
Thr Thr Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala
130 135 140
Thr Asn Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro
145 150 155 160
Phe Leu Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser
165 170 175
Glu Phe Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val
180 185 190
Ser Gln Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys
195 200 205
Asn Leu Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile
210 215 220
Tyr Ser Lys His Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly
225 230 235 240
Phe Ser Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile
245 250 255
Thr Arg Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro
260 265 270
Gly Asp Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val
275 280 285
Gly Tyr Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly
290 295 300
Thr Ile Thr Asp Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr
305 310 315 320
Lys Cys Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr
325 330 335
Ser Asn Phe Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn
340 345 350
Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe
355 360 365
Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala
370 375 380
Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys
385 390 395 400
Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val
405 410 415
Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala
420 425 430
Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp
435 440 445
Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser
450 455 460
Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser
465 470 475 480
Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala
485 490 495
Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro
500 505 510
Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro
515 520 525
Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr
530 535 540
Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val
545 550 555 560
Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser
565 570 575
Asn Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp
580 585 590
Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile
595 600 605
Thr Pro Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn
610 615 620
Thr Ser Asn Gln Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu
625 630 635 640
Val Pro Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val
645 650 655
Tyr Ser Thr Gly Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile
660 665 670
Gly Ala Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly
675 680 685
Ala Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg
690 695 700
Ala Arg Ser Val Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu
705 710 715 720
Gly Ala Glu Asn Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro
725 730 735
Thr Asn Phe Thr Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met
740 745 750
Thr Lys Thr Ser Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr
755 760 765
Glu Cys Ser Asn Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu
770 775 780
Asn Arg Ala Leu Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln
785 790 795 800
Glu Val Phe Ala Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys
805 810 815
Asp Phe Gly Gly Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys
820 825 830
Pro Ser Lys Arg Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr
835 840 845
Leu Ala Asp Ala Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp
850 855 860
Ile Ala Ala Arg Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr
865 870 875 880
Val Leu Pro Pro Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser
885 890 895
Ala Leu Leu Ala Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly
900 905 910
Ala Ala Leu Gln Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn
915 920 925
Gly Ile Gly Val Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile
930 935 940
Ala Asn Gln Phe Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser
945 950 955 960
Ser Thr Ala Ser Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn
965 970 975
Ala Gln Ala Leu Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly
980 985 990
Ala Ile Ser Ser Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Lys Val
995 1000 1005
Glu Ala Glu Val Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln
1010 1015 1020
Ser Leu Gln Thr Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu
1025 1030 1035
Ile Arg Ala Ser Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys
1040 1045 1050
Val Leu Gly Gln Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr
1055 1060 1065
His Leu Met Ser Phe Pro Gln Ser Ala Pro His Gly Val Val Phe
1070 1075 1080
Leu His Val Thr Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr
1085 1090 1095
Ala Pro Ala Ile Cys His Asp Gly Lys Ala His Phe Pro Arg Glu
1100 1105 1110
Gly Val Phe Val Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg
1115 1120 1125
Asn Phe Tyr Glu Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val
1130 1135 1140
Ser Gly Asn Cys Asp Val Val Ile Gly Ile Val Asn Asn Thr Val
1145 1150 1155
Tyr Asp Pro Leu Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu
1160 1165 1170
Asp Lys Tyr Phe Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly
1175 1180 1185
Asp Ile Ser Gly Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu
1190 1195 1200
Ile Asp Arg Leu Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu
1205 1210 1215
Ile Asp Leu Gln Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp
1220 1225 1230
Pro Trp Tyr Ile Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile
1235 1240 1245
Val Met Val Thr Ile Met Leu Cys Cys Met Thr Ser Cys Cys Ser
1250 1255 1260
Cys Leu Lys Gly Cys Cys Ser Cys Gly Ser Cys Cys Lys Phe Asp
1265 1270 1275
Glu Asp Asp Ser Glu Pro Val Leu Lys Gly Val Lys Leu His Tyr
1280 1285 1290
<210> 6
<211> 3885
<212> DNA
<213> 人工序列
<220>
<223> 具有t-PA前导序列的全长S基因的核苷酸序列
<400> 6
atggatgcta tgaagcgagg actgtgctgc gtgctgctgc tgtgtggtgc agtgttcgtg 60
tcccctttcg tgttcctggt cctgctgcct ctggtgtcca gccagtgtgt gaacctgacc 120
accagaacac agctgcctcc agcctacacc aatagcttca ccaggggcgt gtactacccc 180
gacaaggtgt tcagatctag cgtgctgcac agcacccagg acctgtttct gcccttcttc 240
agcaacgtga cctggttcca cgccatccat gtgtccggca ccaatggcac caagagattc 300
gacaaccccg tgctgccctt caacgatggg gtgtactttg ccagcaccga gaagtccaac 360
atcatcagag gctggatctt cggcaccaca ctggacagca agacccagag cctgctgatc 420
gtgaacaacg ccaccaacgt ggtcatcaaa gtgtgcgagt tccagttctg caacgaccca 480
ttcctgggag tctactacca caagaacaac aagagctgga tggaaagcga gttccgggtg 540
tacagcagcg ccaacaactg caccttcgag tacgtgtccc agcctttcct gatggacctg 600
gaaggcaagc agggcaactt caagaacctg cgcgagttcg tgttcaagaa catcgacggc 660
tacttcaaga tctacagcaa gcacacccct atcaacctcg tgcgggatct gcctcagggc 720
ttttctgctc tggaacctct ggtggacctg cctatcggca tcaacatcac ccggtttcag 780
accctgctgg ccctgcacag atcttacctg acacctggcg atagcagctc tggatggaca 840
gctggcgccg ctgcctatta tgtgggctac ctgcagcctc ggaccttcct gctgaagtac 900
aacgagaacg gcaccatcac cgacgccgtg gattgtgctc tggatcccct gagcgagaca 960
aagtgtaccc tgaagtcctt caccgtggaa aagggcatct accagaccag caacttcaga 1020
gtgcagccca ccgagagcat cgtgcggttc cccaatatca ccaatctgtg ccccttcggc 1080
gaggtgttca atgccacaag atttgccagc gtgtacgcct ggaaccggaa gagaatcagc 1140
aactgcgtgg ccgactacag cgtgctgtac aatagcgcca gcttcagcac cttcaagtgc 1200
tacggcgtgt cacccaccaa gctgaacgac ctgtgcttca ccaatgtgta cgccgacagc 1260
ttcgtgatca gaggcgacga agttcggcag atcgctcctg gacagacagg caagatcgcc 1320
gattacaact acaagctgcc cgacgacttc accggctgcg tgatcgcctg gaatagcaac 1380
aacctggact ccaaagtcgg cggcaactac aactacctgt accggctgtt ccggaagtcc 1440
aatctgaagc ccttcgagcg ggacatctcc accgaaatct atcaggccgg cagcacccct 1500
tgtaacggcg tggaaggctt caactgctac ttcccactgc agtcctacgg ctttcagcct 1560
accaatggcg tgggctatca gccctataga gtggtggtgc tgagcttcga actgctgcat 1620
gcccctgcta ccgtgtgcgg ccctaagaag tctaccaacc tggtcaagaa caaatgcgtg 1680
aacttcaact tcaacggcct gaccggcaca ggcgtgctga cagagagcaa caagaagttc 1740
ctgcctttcc agcagtttgg ccgggatatc gccgatacca cagacgccgt tagagatccc 1800
cagacactgg aaatcctgga catcacccca tgcagctttg gcggcgtgtc cgtgatcaca 1860
cctggcacca ataccagcaa tcaggtggcc gtgctgtatc aggacgtgaa ctgtacagag 1920
gtgccagtgg ccattcacgc cgatcagctg acacccactt ggagagtgta ctccaccggc 1980
tccaacgtgt tccagactag agccggatgt ctgatcggag ccgagcatgt gaacaacagc 2040
tacgagtgcg acatccccat cggagctggc atctgtgcca gctaccagac acagacaaat 2100
agccccagac gggccagaag cgtggcctct cagagcatca ttgcctacac aatgagcctg 2160
ggcgccgaga attctgtggc ctacagcaac aactctatcg ctatccccac caacttcacc 2220
atcagcgtga ccaccgagat cctgcctgtg tccatgacca agaccagcgt ggactgcacc 2280
atgtacatct gcggcgattc caccgagtgc agcaacctgc tgctgcagta cggcagcttc 2340
tgcacccagc tgaatagagc cctgacaggg atcgccgtgg aacaggacaa gaacacccaa 2400
gaggtgttcg cccaagtgaa gcagatctac aagacccctc ctatcaagga cttcggcggc 2460
ttcaatttca gccagattct gcccgatcct agcaagccca gcaagcggag ctttatcgag 2520
gacctgctgt tcaacaaagt gacactggcc gacgccggct tcatcaagca gtatggcgat 2580
tgcctgggcg acattgccgc cagagatctg atttgcgccc agaagtttaa cggactgaca 2640
gtgctgcctc ctctgctgac cgatgagatg atcgcccagt acacatctgc tctgctggcc 2700
ggcacaatca ccagcggatg gacatttgga gctggcgcag ccctgcagat cccctttgct 2760
atgcagatgg cctaccggtt caacggcatc ggagtgaccc agaatgtgct gtacgagaac 2820
cagaagctga tcgccaacca gttcaacagc gccatcggca agatccagga tagcctgtct 2880
agcacagcca gcgctctggg caaactgcag gacgtggtca atcagaacgc tcaggccctg 2940
aacaccctcg tgaagcagct gagcagcaat ttcggcgcca tcagctccgt gctgaacgat 3000
atcctgagcc ggctggataa ggtggaagcc gaggtgcaga tcgacagact gatcacaggc 3060
agactgcaga gcctccagac atacgtgacc cagcagctga tcagagccgc cgagattaga 3120
gcctctgcca atctggccgc cacaaagatg tctgagtgtg tgctgggcca gagcaagaga 3180
gtggatttct gcggcaaggg ctaccacctg atgagctttc cacagtctgc tcctcacggc 3240
gtggtgtttc tgcatgtgac ctacgtgccc gctcaagaga agaacttcac aacagcccct 3300
gccatctgcc acgacggaaa ggcccatttt cctagagaag gcgtgttcgt cagcaacggc 3360
acccattggt tcgtgacaca gcggaacttc tacgagcccc agatcatcac caccgacaac 3420
accttcgtgt ctggcaactg tgacgtcgtg atcggcattg tgaacaatac cgtgtacgac 3480
cctctgcagc ccgagctgga cagcttcaaa gaggaactgg acaagtactt taagaaccac 3540
acaagccccg acgtggacct gggcgatatt agcggcatca atgccagcgt cgtgaacatc 3600
cagaaagaga tcgaccggct gaacgaggtg gccaagaatc tgaacgagag cctgatcgac 3660
ctgcaagaac tggggaagta cgagcagtac atcaagtggc cctggtacat ctggctgggc 3720
tttatcgccg gactgattgc catcgtgatg gtcacaatca tgctgtgctg catgaccagc 3780
tgctgtagct gcctgaaggg ctgttgcagc tgtggcagct gctgcaagtt cgacgaggat 3840
gatagcgagc ctgtgctgaa gggcgtgaaa ctgcactact aatga 3885
<210> 7
<211> 702
<212> PRT
<213> 人工序列
<220>
<223> 具有IgE前导序列的S基因的S1区的氨基酸序列
<400> 7
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys
20 25 30
Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser
35 40 45
Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val
50 55 60
Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr
65 70 75 80
Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe
85 90 95
Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr
100 105 110
Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp
115 120 125
Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val
130 135 140
Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val
145 150 155 160
Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val
165 170 175
Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe
180 185 190
Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu
195 200 205
Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His
210 215 220
Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu
225 230 235 240
Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln
245 250 255
Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser
260 265 270
Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln
275 280 285
Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp
290 295 300
Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu
305 310 315 320
Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg
325 330 335
Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu
340 345 350
Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr
355 360 365
Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val
370 375 380
Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser
385 390 395 400
Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser
405 410 415
Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr
420 425 430
Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly
435 440 445
Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly
450 455 460
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro
465 470 475 480
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro
485 490 495
Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr
500 505 510
Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val
515 520 525
Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro
530 535 540
Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe
545 550 555 560
Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe
565 570 575
Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala
580 585 590
Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser
595 600 605
Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln
610 615 620
Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala
625 630 635 640
Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly
645 650 655
Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His
660 665 670
Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys
675 680 685
Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg
690 695 700
<210> 8
<211> 2112
<212> DNA
<213> 人工序列
<220>
<223> 具有IgE前导序列的S基因的S1区的核苷酸序列
<400> 8
atggattgga cctggattct gtttctggtg gccgctgcca caagagtgca tagcttcgtc 60
tttctcgtgc tgctgcctct ggtgtccagc cagtgtgtga acctgaccac aagaacacag 120
ctgcctccag cctacaccaa cagctttacc agaggcgtgt actaccccga caaggtgttc 180
agatctagcg tgctgcacag cacccaggac ctgtttctgc ccttcttcag caacgtgacc 240
tggttccacg ccatccatgt gtccggcacc aatggcacca agagattcga caaccccgtg 300
ctgcccttca acgatggggt gtactttgcc agcaccgaga agtccaacat catcagaggc 360
tggatcttcg gcaccacact ggacagcaag acccagagcc tgctgatcgt gaacaacgcc 420
accaacgtgg tcatcaaagt gtgcgagttc cagttctgca acgacccctt cctgggcgtc 480
tactaccaca aaaacaacaa gagctggatg gaaagcgagt tccgggtgta cagcagcgcc 540
aacaactgca ccttcgagta cgtgtcccag cctttcctga tggatctgga aggcaagcag 600
ggcaacttca agaacctgcg cgagttcgtg ttcaagaaca tcgacggcta cttcaagatc 660
tacagcaagc acacccctat caacctcgtg cgggatctgc ctcagggctt ttctgctctg 720
gaacctctgg tggacctgcc tatcggcatc aacatcaccc ggtttcagac cctgctggcc 780
ctgcacagat cttacctgac acctggcgat agcagctctg gatggacagc tggcgccgct 840
gcctattatg tgggctacct gcagcctcgg accttcctgc tgaagtacaa cgagaacggc 900
accatcaccg acgccgtgga ttgtgctctg gatcccctga gcgagacaaa gtgtaccctg 960
aagtccttca ccgtggaaaa gggcatctac cagaccagca acttcagagt gcagcccacc 1020
gagagcatcg tgcggttccc caatatcacc aatctgtgcc ccttcggcga ggtgttcaat 1080
gccaccagat ttgccagcgt gtacgcctgg aaccggaaga gaatcagcaa ctgcgtggcc 1140
gactacagcg tgctgtacaa tagcgccagc ttcagcacct tcaagtgcta cggcgtgtcc 1200
cctaccaagc tgaacgacct gtgcttcacc aatgtgtacg ccgacagctt cgtgatcaga 1260
ggcgacgaag ttcggcagat cgctcctgga cagacaggca agatcgccga ttacaactac 1320
aagctgcccg acgacttcac cggctgcgtg atcgcctgga atagcaacaa cctggactcc 1380
aaagtcggcg gcaactacaa ctacctgtac cggctgttcc ggaagtccaa tctgaagccc 1440
ttcgagcggg acatctccac cgaaatctat caggccggca gcaccccttg taacggcgtg 1500
gaaggcttca actgctactt cccactgcag tcctacggct ttcagcctac caatggcgtg 1560
ggctatcagc cctatagagt ggtggtgctg agcttcgaac tgctgcatgc ccctgctacc 1620
gtgtgcggcc ctaagaagtc taccaacctg gtcaagaaca aatgcgtgaa cttcaacttc 1680
aacggcctga ccggcacagg cgtgctgaca gagagcaaca agaagttcct gcctttccag 1740
cagtttggcc gggatatcgc cgataccaca gacgccgtta gagatcccca gacactggaa 1800
atcctggaca tcaccccatg cagctttggc ggagtgtctg tgatcacccc tggcaccaat 1860
accagcaatc aggtggccgt gctgtatcag gacgtgaact gtacagaggt gccagtggcc 1920
attcacgccg atcagctgac acccacttgg agagtgtact ccaccggctc caacgtgttc 1980
cagactagag ccggatgtct gatcggagcc gagcatgtga acaacagcta cgagtgcgac 2040
atccccatcg gagctggcat ctgtgccagc taccagacac agacaaacag ccccagacgg 2100
gccagataat ga 2112
<210> 9
<211> 706
<212> PRT
<213> 人工序列
<220>
<223> 具有t-PA前导序列的S基因的S1区的氨基酸序列
<400> 9
Met Asp Ala Met Lys Arg Gly Leu Cys Cys Val Leu Leu Leu Cys Gly
1 5 10 15
Ala Val Phe Val Ser Pro Phe Val Phe Leu Val Leu Leu Pro Leu Val
20 25 30
Ser Ser Gln Cys Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala
35 40 45
Tyr Thr Asn Ser Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe
50 55 60
Arg Ser Ser Val Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe
65 70 75 80
Ser Asn Val Thr Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly
85 90 95
Thr Lys Arg Phe Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr
100 105 110
Phe Ala Ser Thr Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly
115 120 125
Thr Thr Leu Asp Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala
130 135 140
Thr Asn Val Val Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro
145 150 155 160
Phe Leu Gly Val Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser
165 170 175
Glu Phe Arg Val Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val
180 185 190
Ser Gln Pro Phe Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys
195 200 205
Asn Leu Arg Glu Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile
210 215 220
Tyr Ser Lys His Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly
225 230 235 240
Phe Ser Ala Leu Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile
245 250 255
Thr Arg Phe Gln Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro
260 265 270
Gly Asp Ser Ser Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val
275 280 285
Gly Tyr Leu Gln Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly
290 295 300
Thr Ile Thr Asp Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr
305 310 315 320
Lys Cys Thr Leu Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr
325 330 335
Ser Asn Phe Arg Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn
340 345 350
Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe
355 360 365
Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala
370 375 380
Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys
385 390 395 400
Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val
405 410 415
Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala
420 425 430
Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp
435 440 445
Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser
450 455 460
Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser
465 470 475 480
Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala
485 490 495
Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro
500 505 510
Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro
515 520 525
Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr
530 535 540
Val Cys Gly Pro Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val
545 550 555 560
Asn Phe Asn Phe Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser
565 570 575
Asn Lys Lys Phe Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp
580 585 590
Thr Thr Asp Ala Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile
595 600 605
Thr Pro Cys Ser Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn
610 615 620
Thr Ser Asn Gln Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu
625 630 635 640
Val Pro Val Ala Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val
645 650 655
Tyr Ser Thr Gly Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile
660 665 670
Gly Ala Glu His Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly
675 680 685
Ala Gly Ile Cys Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg
690 695 700
Ala Arg
705
<210> 10
<211> 2124
<212> DNA
<213> 人工序列
<220>
<223> 具有t-PA前导序列的S基因的S1区的核苷酸序列
<400> 10
atggatgcta tgaagcgagg actgtgctgc gtgctgctgc tgtgtggtgc agtgttcgtg 60
tcccctttcg tgttcctggt cctgctgcct ctggtgtcca gccagtgtgt gaacctgacc 120
accagaacac agctgcctcc agcctacacc aatagcttca ccaggggcgt gtactacccc 180
gacaaggtgt tcagatctag cgtgctgcac agcacccagg acctgtttct gcccttcttc 240
agcaacgtga cctggttcca cgccatccat gtgtccggca ccaatggcac caagagattc 300
gacaaccccg tgctgccctt caacgatggg gtgtactttg ccagcaccga gaagtccaac 360
atcatcagag gctggatctt cggcaccaca ctggacagca agacccagag cctgctgatc 420
gtgaacaacg ccaccaacgt ggtcatcaaa gtgtgcgagt tccagttctg caacgaccca 480
ttcctgggag tctactacca caagaacaac aagagctgga tggaaagcga gttccgggtg 540
tacagcagcg ccaacaactg caccttcgag tacgtgtccc agcctttcct gatggacctg 600
gaaggcaagc agggcaactt caagaacctg cgcgagttcg tgttcaagaa catcgacggc 660
tacttcaaga tctacagcaa gcacacccct atcaacctcg tgcgggatct gcctcagggc 720
ttttctgctc tggaacctct ggtggacctg cctatcggca tcaacatcac ccggtttcag 780
accctgctgg ccctgcacag atcttacctg acacctggcg atagcagctc tggatggaca 840
gctggcgccg ctgcctatta tgtgggctac ctgcagcctc ggaccttcct gctgaagtac 900
aacgagaacg gcaccatcac cgacgccgtg gattgtgctc tggatcccct gagcgagaca 960
aagtgtaccc tgaagtcctt caccgtggaa aagggcatct accagaccag caacttcaga 1020
gtgcagccca ccgagagcat cgtgcggttc cccaatatca ccaatctgtg ccccttcggc 1080
gaggtgttca atgccacaag atttgccagc gtgtacgcct ggaaccggaa gagaatcagc 1140
aactgcgtgg ccgactacag cgtgctgtac aatagcgcca gcttcagcac cttcaagtgc 1200
tacggcgtgt cacccaccaa gctgaacgac ctgtgcttca ccaatgtgta cgccgacagc 1260
ttcgtgatca gaggcgacga agttcggcag atcgctcctg gacagacagg caagatcgcc 1320
gattacaact acaagctgcc cgacgacttc accggctgcg tgatcgcctg gaatagcaac 1380
aacctggact ccaaagtcgg cggcaactac aactacctgt accggctgtt ccggaagtcc 1440
aatctgaagc ccttcgagcg ggacatctcc accgaaatct atcaggccgg cagcacccct 1500
tgtaacggcg tggaaggctt caactgctac ttcccactgc agtcctacgg ctttcagcct 1560
accaatggcg tgggctatca gccctataga gtggtggtgc tgagcttcga actgctgcat 1620
gcccctgcta ccgtgtgcgg ccctaagaag tctaccaacc tggtcaagaa caaatgcgtg 1680
aacttcaact tcaacggcct gaccggcaca ggcgtgctga cagagagcaa caagaagttc 1740
ctgcctttcc agcagtttgg ccgggatatc gccgatacca cagacgccgt tagagatccc 1800
cagacactgg aaatcctgga catcacccca tgcagctttg gcggcgtgtc cgtgatcaca 1860
cctggcacca ataccagcaa tcaggtggcc gtgctgtatc aggacgtgaa ctgtacagag 1920
gtgccagtgg ccattcacgc cgatcagctg acacccactt ggagagtgta ctccaccggc 1980
tccaacgtgt tccagactag agccggatgt ctgatcggag ccgagcatgt gaacaacagc 2040
tacgagtgcg acatccccat cggagctggc atctgtgcca gctaccagac acagacaaac 2100
agccccagac gggccagata atga 2124
<210> 11
<211> 1289
<212> PRT
<213> 人工序列
<220>
<223> 具有IgE前导序列的全长S基因(Hexapro)的氨基酸序列
<400> 11
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys
20 25 30
Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser
35 40 45
Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val
50 55 60
Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr
65 70 75 80
Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe
85 90 95
Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr
100 105 110
Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp
115 120 125
Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val
130 135 140
Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val
145 150 155 160
Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val
165 170 175
Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe
180 185 190
Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu
195 200 205
Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His
210 215 220
Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu
225 230 235 240
Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln
245 250 255
Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser
260 265 270
Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln
275 280 285
Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp
290 295 300
Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu
305 310 315 320
Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg
325 330 335
Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu
340 345 350
Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr
355 360 365
Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val
370 375 380
Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser
385 390 395 400
Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser
405 410 415
Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr
420 425 430
Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly
435 440 445
Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly
450 455 460
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro
465 470 475 480
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro
485 490 495
Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr
500 505 510
Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val
515 520 525
Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro
530 535 540
Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe
545 550 555 560
Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe
565 570 575
Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala
580 585 590
Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser
595 600 605
Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln
610 615 620
Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala
625 630 635 640
Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly
645 650 655
Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His
660 665 670
Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys
675 680 685
Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val
690 695 700
Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn
705 710 715 720
Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr
725 730 735
Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser
740 745 750
Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn
755 760 765
Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu
770 775 780
Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala
785 790 795 800
Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly
805 810 815
Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg
820 825 830
Ser Pro Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala
835 840 845
Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg
850 855 860
Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro
865 870 875 880
Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala
885 890 895
Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Pro Ala Leu Gln
900 905 910
Ile Pro Phe Pro Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val
915 920 925
Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe
930 935 940
Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Pro Ser
945 950 955 960
Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu
965 970 975
Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser
980 985 990
Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val
995 1000 1005
Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr
1010 1015 1020
Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser
1025 1030 1035
Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln
1040 1045 1050
Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser
1055 1060 1065
Phe Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr
1070 1075 1080
Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile
1085 1090 1095
Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val
1100 1105 1110
Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu
1115 1120 1125
Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys
1130 1135 1140
Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu
1145 1150 1155
Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe
1160 1165 1170
Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly
1175 1180 1185
Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu
1190 1195 1200
Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln
1205 1210 1215
Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile
1220 1225 1230
Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr
1235 1240 1245
Ile Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly
1250 1255 1260
Cys Cys Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser
1265 1270 1275
Glu Pro Val Leu Lys Gly Val Lys Leu His Tyr
1280 1285
<210> 12
<211> 3873
<212> DNA
<213> 人工序列
<220>
<223> 具有IgE前导序列的全长S基因(Hexapro)的核苷酸序列
<400> 12
atggattgga cctggattct gtttctggtg gccgctgcca caagagtgca cagctttgtc 60
tttctcgtgc tgctgcctct ggtgtccagc cagtgtgtga acctgaccac aagaacacag 120
ctgcctccag cctacaccaa cagctttacc agaggcgtgt actaccccga caaggtgttc 180
agatctagcg tgctgcacag cacccaggac ctgtttctgc ccttcttcag caacgtgacc 240
tggttccacg ccatccacgt gtccggcacc aatggcacca agagattcga caaccccgtg 300
ctgcccttca acgatggggt gtactttgcc agcaccgaga agtccaacat catcagaggc 360
tggatcttcg gcaccacact ggacagcaag acccagagcc tgctgatcgt gaacaacgcc 420
accaacgtgg tcatcaaagt gtgcgagttc cagttctgca acgacccctt cctgggcgtc 480
tactaccaca aaaacaacaa gagctggatg gaaagcgagt tccgggtgta cagcagcgcc 540
aacaactgca ccttcgagta cgtgtcccag cctttcctga tggatctgga aggcaagcag 600
ggcaacttca agaacctgcg cgagttcgtg ttcaagaaca tcgacggcta cttcaagatc 660
tacagcaagc acacccctat caacctcgtg cgggatctgc ctcagggctt ttctgctctg 720
gaacctctgg tggacctgcc tatcggcatc aacatcaccc ggtttcagac cctgctggcc 780
ctgcacagat cttacctgac acctggcgat agcagctctg gatggacagc tggcgccgct 840
gcctattatg tgggctacct gcagcctcgg accttcctgc tgaagtacaa cgagaacggc 900
accatcaccg acgccgtgga ttgtgctctg gatcccctga gcgagacaaa gtgcaccctg 960
aagtccttca ccgtggaaaa gggcatctac cagaccagca acttcagagt gcagcccacc 1020
gagagcatcg tgcggttccc caatatcacc aatctgtgcc ccttcggcga ggtgttcaat 1080
gccaccagat ttgccagcgt gtacgcctgg aaccggaaga gaatcagcaa ctgcgtggcc 1140
gactacagcg tgctgtacaa tagcgccagc ttcagcacct tcaagtgcta cggcgtgtcc 1200
cctaccaagc tgaacgacct gtgcttcacc aatgtgtacg ccgacagctt cgtgatcaga 1260
ggcgacgaag ttcggcagat cgctcctgga cagacaggca agatcgccga ttacaactac 1320
aagctgcccg acgacttcac cggctgcgtg atcgcctgga atagcaacaa cctggactcc 1380
aaagtcggcg gcaactacaa ctacctgtac cggctgttcc ggaagtccaa tctgaagccc 1440
ttcgagcggg acatctccac cgaaatctat caggccggca gcaccccttg taacggcgtg 1500
gaaggcttca actgctactt cccactgcag tcctacggct ttcagcctac caatggcgtg 1560
ggctatcagc cctatagagt ggtggtgctg agcttcgaac tgctgcatgc ccctgctacc 1620
gtgtgcggcc ctaagaagtc taccaacctg gtcaagaaca aatgcgtgaa cttcaacttc 1680
aacggcctga ccggcacagg cgtgctgaca gagagcaaca agaagttcct gcctttccag 1740
cagtttggcc gggatatcgc cgataccaca gacgccgtta gagatcccca gacactggaa 1800
atcctggaca tcaccccatg cagctttggc ggagtgtctg tgatcacccc tggcaccaat 1860
accagcaatc aggtggccgt gctgtatcag gacgtgaact gtacagaggt gcccgtggcc 1920
attcacgccg atcaactgac acccacttgg agagtgtact ccaccggctc caacgtgttc 1980
cagactagag ccggatgtct gatcggagcc gagcacgtga acaatagcta cgagtgcgac 2040
atccccatcg gcgctggcat ctgtgccagc taccagacac agacaaatag ccccagacgg 2100
gccagaagcg tggcctctca gagcatcatt gcctacacaa tgagcctggg cgccgagaat 2160
tctgtggcct acagcaacaa ctctatcgct atccccacca acttcaccat cagcgtgacc 2220
accgagatcc tgcctgtgtc catgaccaag accagcgtgg actgcaccat gtacatctgc 2280
ggcgattcca ccgagtgcag caacctgctg ctgcagtacg gcagcttctg cacccagctg 2340
aatagagccc tgacagggat cgccgtggaa caggacaaga atacccaaga ggtgttcgcc 2400
caagtgaagc agatctacaa gacccctcct atcaaggact tcggcggctt caatttcagc 2460
cagattctgc ccgatcctag caagcccagc aagagaagcc caatcgagga cctgctgttc 2520
aacaaagtga cactggccga cgccggcttc atcaagcagt atggcgattg cctgggcgac 2580
attgccgcca gagatctgat ttgcgcccag aagtttaacg gactgacagt gctgcctcct 2640
ctgctgaccg atgagatgat cgcccagtac acatctgctc tgctggccgg cacaatcacc 2700
agcggatgga catttggagc aggcccagct ctgcagatcc catttccaat gcagatggcc 2760
taccggttca acggcatcgg agtgacccag aatgtgctgt acgagaacca gaagctgatc 2820
gccaaccagt tcaacagcgc catcggcaag atccaggaca gcctgtctag cacacctagc 2880
gctctgggca agctgcagga cgtggtcaat cagaacgctc aggccctgaa caccctcgtg 2940
aagcagctga gcagcaattt cggcgccatc agctccgtgc tgaacgatat cctgagcaga 3000
ctggatcctc cagaggccga ggtgcagatc gatagactga tcacaggccg gctgcagtcc 3060
ctgcagacat atgtgacaca gcagctgatc agagccgccg agattagagc ctctgccaat 3120
ctggccgcca caaagatgtc tgagtgtgtg ctgggccaga gcaagagagt ggatttctgc 3180
ggcaagggct accacctgat gagctttcca cagtctgccc ctcacggcgt ggtgtttctg 3240
catgtgacat acgtgcccgc tcaagagaag aacttcacaa cagcccctgc catctgccac 3300
gacggaaagg cccattttcc tagagaaggc gtgttcgtgt ccaacggcac ccattggttc 3360
gtgacccagc ggaacttcta cgagccccag atcatcacca ccgacaacac cttcgtgtct 3420
ggcaactgtg acgtcgtgat cggcattgtg aacaacaccg tgtacgaccc tctgcagccc 3480
gagctggaca gcttcaaaga ggaactggac aagtacttta agaaccacac aagccccgac 3540
gtggacctgg gcgatattag cggcatcaat gcctccgtgg tcaacatcca gaaagagatc 3600
gaccggctga acgaggtggc caagaatctg aacgagagcc tgatcgacct gcaagaactg 3660
gggaagtacg agcagtacat caagtggccc tggtacatct ggctgggctt tatcgccgga 3720
ctgattgcca tcgtgatggt cacaatcatg ctgtgctgca tgaccagctg ttgcagctgc 3780
ctgaagggct gctgtagctg tggctcctgc tgcaagttcg acgaggatga tagcgagcct 3840
gtgctgaagg gcgtgaaact gcactactaa tga 3873
<210> 13
<211> 1289
<212> PRT
<213> 人工序列
<220>
<223> 具有IgE前导序列的全长S基因(2P)的氨基酸序列
<400> 13
Met Asp Trp Thr Trp Ile Leu Phe Leu Val Ala Ala Ala Thr Arg Val
1 5 10 15
His Ser Phe Val Phe Leu Val Leu Leu Pro Leu Val Ser Ser Gln Cys
20 25 30
Val Asn Leu Thr Thr Arg Thr Gln Leu Pro Pro Ala Tyr Thr Asn Ser
35 40 45
Phe Thr Arg Gly Val Tyr Tyr Pro Asp Lys Val Phe Arg Ser Ser Val
50 55 60
Leu His Ser Thr Gln Asp Leu Phe Leu Pro Phe Phe Ser Asn Val Thr
65 70 75 80
Trp Phe His Ala Ile His Val Ser Gly Thr Asn Gly Thr Lys Arg Phe
85 90 95
Asp Asn Pro Val Leu Pro Phe Asn Asp Gly Val Tyr Phe Ala Ser Thr
100 105 110
Glu Lys Ser Asn Ile Ile Arg Gly Trp Ile Phe Gly Thr Thr Leu Asp
115 120 125
Ser Lys Thr Gln Ser Leu Leu Ile Val Asn Asn Ala Thr Asn Val Val
130 135 140
Ile Lys Val Cys Glu Phe Gln Phe Cys Asn Asp Pro Phe Leu Gly Val
145 150 155 160
Tyr Tyr His Lys Asn Asn Lys Ser Trp Met Glu Ser Glu Phe Arg Val
165 170 175
Tyr Ser Ser Ala Asn Asn Cys Thr Phe Glu Tyr Val Ser Gln Pro Phe
180 185 190
Leu Met Asp Leu Glu Gly Lys Gln Gly Asn Phe Lys Asn Leu Arg Glu
195 200 205
Phe Val Phe Lys Asn Ile Asp Gly Tyr Phe Lys Ile Tyr Ser Lys His
210 215 220
Thr Pro Ile Asn Leu Val Arg Asp Leu Pro Gln Gly Phe Ser Ala Leu
225 230 235 240
Glu Pro Leu Val Asp Leu Pro Ile Gly Ile Asn Ile Thr Arg Phe Gln
245 250 255
Thr Leu Leu Ala Leu His Arg Ser Tyr Leu Thr Pro Gly Asp Ser Ser
260 265 270
Ser Gly Trp Thr Ala Gly Ala Ala Ala Tyr Tyr Val Gly Tyr Leu Gln
275 280 285
Pro Arg Thr Phe Leu Leu Lys Tyr Asn Glu Asn Gly Thr Ile Thr Asp
290 295 300
Ala Val Asp Cys Ala Leu Asp Pro Leu Ser Glu Thr Lys Cys Thr Leu
305 310 315 320
Lys Ser Phe Thr Val Glu Lys Gly Ile Tyr Gln Thr Ser Asn Phe Arg
325 330 335
Val Gln Pro Thr Glu Ser Ile Val Arg Phe Pro Asn Ile Thr Asn Leu
340 345 350
Cys Pro Phe Gly Glu Val Phe Asn Ala Thr Arg Phe Ala Ser Val Tyr
355 360 365
Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys Val Ala Asp Tyr Ser Val
370 375 380
Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe Lys Cys Tyr Gly Val Ser
385 390 395 400
Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr Asn Val Tyr Ala Asp Ser
405 410 415
Phe Val Ile Arg Gly Asp Glu Val Arg Gln Ile Ala Pro Gly Gln Thr
420 425 430
Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu Pro Asp Asp Phe Thr Gly
435 440 445
Cys Val Ile Ala Trp Asn Ser Asn Asn Leu Asp Ser Lys Val Gly Gly
450 455 460
Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg Lys Ser Asn Leu Lys Pro
465 470 475 480
Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr Gln Ala Gly Ser Thr Pro
485 490 495
Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr Phe Pro Leu Gln Ser Tyr
500 505 510
Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr Gln Pro Tyr Arg Val Val
515 520 525
Val Leu Ser Phe Glu Leu Leu His Ala Pro Ala Thr Val Cys Gly Pro
530 535 540
Lys Lys Ser Thr Asn Leu Val Lys Asn Lys Cys Val Asn Phe Asn Phe
545 550 555 560
Asn Gly Leu Thr Gly Thr Gly Val Leu Thr Glu Ser Asn Lys Lys Phe
565 570 575
Leu Pro Phe Gln Gln Phe Gly Arg Asp Ile Ala Asp Thr Thr Asp Ala
580 585 590
Val Arg Asp Pro Gln Thr Leu Glu Ile Leu Asp Ile Thr Pro Cys Ser
595 600 605
Phe Gly Gly Val Ser Val Ile Thr Pro Gly Thr Asn Thr Ser Asn Gln
610 615 620
Val Ala Val Leu Tyr Gln Asp Val Asn Cys Thr Glu Val Pro Val Ala
625 630 635 640
Ile His Ala Asp Gln Leu Thr Pro Thr Trp Arg Val Tyr Ser Thr Gly
645 650 655
Ser Asn Val Phe Gln Thr Arg Ala Gly Cys Leu Ile Gly Ala Glu His
660 665 670
Val Asn Asn Ser Tyr Glu Cys Asp Ile Pro Ile Gly Ala Gly Ile Cys
675 680 685
Ala Ser Tyr Gln Thr Gln Thr Asn Ser Pro Arg Arg Ala Arg Ser Val
690 695 700
Ala Ser Gln Ser Ile Ile Ala Tyr Thr Met Ser Leu Gly Ala Glu Asn
705 710 715 720
Ser Val Ala Tyr Ser Asn Asn Ser Ile Ala Ile Pro Thr Asn Phe Thr
725 730 735
Ile Ser Val Thr Thr Glu Ile Leu Pro Val Ser Met Thr Lys Thr Ser
740 745 750
Val Asp Cys Thr Met Tyr Ile Cys Gly Asp Ser Thr Glu Cys Ser Asn
755 760 765
Leu Leu Leu Gln Tyr Gly Ser Phe Cys Thr Gln Leu Asn Arg Ala Leu
770 775 780
Thr Gly Ile Ala Val Glu Gln Asp Lys Asn Thr Gln Glu Val Phe Ala
785 790 795 800
Gln Val Lys Gln Ile Tyr Lys Thr Pro Pro Ile Lys Asp Phe Gly Gly
805 810 815
Phe Asn Phe Ser Gln Ile Leu Pro Asp Pro Ser Lys Pro Ser Lys Arg
820 825 830
Ser Phe Ile Glu Asp Leu Leu Phe Asn Lys Val Thr Leu Ala Asp Ala
835 840 845
Gly Phe Ile Lys Gln Tyr Gly Asp Cys Leu Gly Asp Ile Ala Ala Arg
850 855 860
Asp Leu Ile Cys Ala Gln Lys Phe Asn Gly Leu Thr Val Leu Pro Pro
865 870 875 880
Leu Leu Thr Asp Glu Met Ile Ala Gln Tyr Thr Ser Ala Leu Leu Ala
885 890 895
Gly Thr Ile Thr Ser Gly Trp Thr Phe Gly Ala Gly Ala Ala Leu Gln
900 905 910
Ile Pro Phe Ala Met Gln Met Ala Tyr Arg Phe Asn Gly Ile Gly Val
915 920 925
Thr Gln Asn Val Leu Tyr Glu Asn Gln Lys Leu Ile Ala Asn Gln Phe
930 935 940
Asn Ser Ala Ile Gly Lys Ile Gln Asp Ser Leu Ser Ser Thr Ala Ser
945 950 955 960
Ala Leu Gly Lys Leu Gln Asp Val Val Asn Gln Asn Ala Gln Ala Leu
965 970 975
Asn Thr Leu Val Lys Gln Leu Ser Ser Asn Phe Gly Ala Ile Ser Ser
980 985 990
Val Leu Asn Asp Ile Leu Ser Arg Leu Asp Pro Pro Glu Ala Glu Val
995 1000 1005
Gln Ile Asp Arg Leu Ile Thr Gly Arg Leu Gln Ser Leu Gln Thr
1010 1015 1020
Tyr Val Thr Gln Gln Leu Ile Arg Ala Ala Glu Ile Arg Ala Ser
1025 1030 1035
Ala Asn Leu Ala Ala Thr Lys Met Ser Glu Cys Val Leu Gly Gln
1040 1045 1050
Ser Lys Arg Val Asp Phe Cys Gly Lys Gly Tyr His Leu Met Ser
1055 1060 1065
Phe Pro Gln Ser Ala Pro His Gly Val Val Phe Leu His Val Thr
1070 1075 1080
Tyr Val Pro Ala Gln Glu Lys Asn Phe Thr Thr Ala Pro Ala Ile
1085 1090 1095
Cys His Asp Gly Lys Ala His Phe Pro Arg Glu Gly Val Phe Val
1100 1105 1110
Ser Asn Gly Thr His Trp Phe Val Thr Gln Arg Asn Phe Tyr Glu
1115 1120 1125
Pro Gln Ile Ile Thr Thr Asp Asn Thr Phe Val Ser Gly Asn Cys
1130 1135 1140
Asp Val Val Ile Gly Ile Val Asn Asn Thr Val Tyr Asp Pro Leu
1145 1150 1155
Gln Pro Glu Leu Asp Ser Phe Lys Glu Glu Leu Asp Lys Tyr Phe
1160 1165 1170
Lys Asn His Thr Ser Pro Asp Val Asp Leu Gly Asp Ile Ser Gly
1175 1180 1185
Ile Asn Ala Ser Val Val Asn Ile Gln Lys Glu Ile Asp Arg Leu
1190 1195 1200
Asn Glu Val Ala Lys Asn Leu Asn Glu Ser Leu Ile Asp Leu Gln
1205 1210 1215
Glu Leu Gly Lys Tyr Glu Gln Tyr Ile Lys Trp Pro Trp Tyr Ile
1220 1225 1230
Trp Leu Gly Phe Ile Ala Gly Leu Ile Ala Ile Val Met Val Thr
1235 1240 1245
Ile Met Leu Cys Cys Met Thr Ser Cys Cys Ser Cys Leu Lys Gly
1250 1255 1260
Cys Cys Ser Cys Gly Ser Cys Cys Lys Phe Asp Glu Asp Asp Ser
1265 1270 1275
Glu Pro Val Leu Lys Gly Val Lys Leu His Tyr
1280 1285
Claims (23)
1.DNA构建体,其包含编码SARS-CoV-2的S蛋白的基因或SARS-CoV-2的S蛋白的截短基因以及任选的编码信号肽的基因。
2.如权利要求1所述的SARS-CoV-2的S蛋白的截短基因,其为S1区或与人血管紧张素转换酶-2(ACE-2)受体结合的受体结合结构域RBD。
3.载体,其包含编码SARS-CoV-2的S蛋白的基因或SARS-CoV-2的S蛋白的S1区以及任选的编码信号肽的基因。
4.如权利要求3所述的载体,其还包含SARS-CoV-2的S基因或SARS-CoV-2的S基因的S1区表达所需的调节元件。
5.如权利要求3所述的载体,其还包含人巨细胞病毒即早期(CMV)启动子、牛生长激素(BGH)多腺苷酸化信号、卡那霉素抗性基因或其合适的组合。
6.如权利要求3所述的载体,其选自pVAX1、pCDNA 3.1、pCDNA 4.0、pCMV和PCAGG。
7.如权利要求1或权利要求3所述的信号肽,其为IgE信号肽或t-PA信号肽。
8.免疫原性组合物,其包含任一前述权利要求所述的DNA构建体或载体。
9.制备如权利要求8所述的免疫原性组合物的方法,其包括以下步骤:
(i)制备DNA构建体或制备包含DNA构建体的载体,以及
(ii)向步骤(i)的制备物中添加合适的佐剂和/或合适的药物赋形剂。
10.如权利要求9所述的合适的赋形剂,其选自缓冲剂、稳定剂及其合适的组合。
11.如任一前述权利要求所述的DNA构建体或载体,其经肌内或经皮内注射到对象中。
12.如任一前述权利要求所述的DNA构建体或载体,其通过无针注射或通过电转化仪系统进行注射。
13.疫苗,其包含如任一前述权利要求所述的DNA构建体或载体。
14.如权利要求13所述的疫苗,其在所述对象中诱导体液免疫应答和/或细胞免疫应答。
15.如权利要求14所述的疫苗,其与细胞因子共递送以增强在病毒感染中有益的Th1免疫应答的产生。
16.如权利要求1所述的编码SARS-CoV-2的S蛋白的基因,其表达SARS-CoV-2的S蛋白,其中SARS-CoV-2的S蛋白具有选自K986P、V987P、F817P、A892P、A899P、A942P及其合适的组合的脯氨酸替换。
17.如权利要求16所述的组合,其选自两种脯氨酸替换(K986P、V987P)和六种脯氨酸替换(K986P、V987P、F817P、A892P、A899P、A942P)。
18.如任一前述权利要求所述的编码SARS-CoV-2的S蛋白的基因,所述基因具有来自SEQ ID NO.:4的第55至3873位核苷酸残基的核苷酸序列或其片段或其变体、来自SEQ IDNO.:6的第67至3885位核苷酸残基的核苷酸序列或其片段或其变体以及来自SEQ ID NO.:12的第55至3873位核苷酸残基的核苷酸序列或其片段或其变体。
19.具有前导序列的如任一前述权利要求所述的编码SARS-CoV-2的S蛋白的基因,其选自SEQ ID NO.:4、在SEQ ID NO.:4中所示的核苷酸序列的整个长度上具有至少95%同一性的核苷酸序列、SEQ ID NO.:6、在SEQ ID NO.:6中所示的核苷酸序列的整个长度上具有至少95%同一性的核苷酸序列、SEQ ID NO.:12以及在SEQ ID NO.:12中所示的核苷酸序列的整个长度上具有至少95%同一性的核苷酸序列。
20.如任一前述权利要求所述的编码SARS-CoV-2的S蛋白的S1区的基因,所述基因具有来自SEQ ID NO.:8的第55至2112位核苷酸残基的核苷酸序列或其片段或其变体以及来自SEQ ID NO.:10的第67至2124位核苷酸残基的核苷酸序列或其片段或其变体。
21.具有前导序列的如任一前述权利要求所述的编码SARS-CoV-2的S蛋白的S1区的基因,其选自SEQ ID NO.:8、在SEQ ID NO.:8中所示的核苷酸序列的整个长度上具有至少95%同一性的核苷酸序列、SEQ ID NO.:10以及在SEQ ID NO.:10中所示的核苷酸序列的整个长度上具有至少95%同一性的核苷酸序列。
22.如任一前述权利要求所述的DNA构建体,其通过用合适的培养基组合物使用分批或补料分批方法进行规模可缩放的生产方法产生,所述培养基组合物包含酵母提取物、胰蛋白胨、丙三醇和可用于高密度大肠杆菌(E.coil)培养的其他合适成分。此外,根据本发明可使用范围为30℃至42℃的温度以提高来自细菌生物质的质粒产率。
23.如任一前述权利要求所述的构建体,其通过包括以下步骤中的一个或更多个的纯化方法来纯化:(a)裂解包含质粒DNA的宿主细胞;(b)通过过滤使所述裂解物澄清以获得澄清的裂解物;(c)处理裂解物以去除内毒素和其他杂质;(d)使用选自亲和色谱(AC)、离子交换色谱(IEC)和/或疏水相互作用色谱(HIC)中的一种或更多种色谱技术来纯化具有质粒DNA的步骤(c)的经处理溶液;(e)对所述经纯化的质粒进行浓缩,其包括以下步骤中的一个或更多个:(i)沉淀,(ii)渗滤和/或(iii)冻干。
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PCT/IB2021/053321 WO2021214703A1 (en) | 2020-04-23 | 2021-04-22 | A vaccine against sars-cov-2 and preparation thereof |
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CN115335390A (zh) * | 2022-01-10 | 2022-11-11 | 广州市锐博生物科技有限公司 | 基于SARS-CoV-2的S蛋白的疫苗和组合物 |
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EP3532095A1 (en) * | 2016-10-25 | 2019-09-04 | The U.S.A. as represented by the Secretary, Department of Health and Human Services | Prefusion coronavirus spike proteins and their use |
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2021
- 2021-04-22 AR ARP210101078A patent/AR121910A1/es unknown
- 2021-04-22 EP EP21793685.5A patent/EP4138908A1/en not_active Withdrawn
- 2021-04-22 BR BR112022021374A patent/BR112022021374A2/pt not_active Application Discontinuation
- 2021-04-22 US US17/920,158 patent/US20230174588A1/en active Pending
- 2021-04-22 MX MX2022013028A patent/MX2022013028A/es unknown
- 2021-04-22 CN CN202180043085.XA patent/CN116075319A/zh active Pending
- 2021-04-22 KR KR1020227040871A patent/KR20230005265A/ko unknown
- 2021-04-22 TW TW110114524A patent/TW202206598A/zh unknown
- 2021-04-22 WO PCT/IB2021/053321 patent/WO2021214703A1/en active Search and Examination
- 2021-04-22 JP JP2022564444A patent/JP2023523423A/ja active Pending
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Publication number | Publication date |
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WO2021214703A1 (en) | 2021-10-28 |
BR112022021374A2 (pt) | 2023-01-10 |
TW202206598A (zh) | 2022-02-16 |
MX2022013028A (es) | 2022-11-30 |
EP4138908A1 (en) | 2023-03-01 |
AR121910A1 (es) | 2022-07-20 |
KR20230005265A (ko) | 2023-01-09 |
JP2023523423A (ja) | 2023-06-05 |
US20230174588A1 (en) | 2023-06-08 |
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