CN113185583A - 一种预防SARS-CoV-2重组蛋白疫苗及其制备方法 - Google Patents
一种预防SARS-CoV-2重组蛋白疫苗及其制备方法 Download PDFInfo
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- CN113185583A CN113185583A CN202110308103.4A CN202110308103A CN113185583A CN 113185583 A CN113185583 A CN 113185583A CN 202110308103 A CN202110308103 A CN 202110308103A CN 113185583 A CN113185583 A CN 113185583A
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Abstract
本发明涉及一种SARS‑CoV‑2重组蛋白疫苗的目的氨基酸序列、所述重组蛋白疫苗的目的基因序列、包含所述目的基因序列的真核细胞表达载体、表达所述目的氨基酸序列的细胞以及以所述目的氨基酸序列为抗原的重组蛋白疫苗。本发明提供的重组蛋白疫苗能够有效诱导机体产生细胞免疫和体液免疫,且可以快速制备,适用于SARS‑CoV‑2的预防。
Description
技术领域
本发明涉及流行病预防及疫苗生产领域,具体涉及一种预防SARS-CoV-2的重组蛋白疫苗及其制备方法。
背景技术
新型冠状病毒SARS-CoV-2是一种以前尚未在人类中发现的新型冠状病毒,能够引起严重急性呼吸道感染。因为人群中缺少对SARS-CoV-2的免疫力,并且经呼吸道飞沫传播,也可通过接触传播,所以人群普遍易感,且目前对于新型冠状病毒所致疾病没有特异治疗方法。
冠状病毒属于套氏病毒目,冠状病毒科,冠状病毒属,是一类具有囊膜、基因组为线性单股正链RNA的病毒,是自然界中广泛存在的一大类病毒,引起的疾病患者表现为从普通感冒到严重肺部感染等不同的临床症状,例如中东呼吸综合征(MERS)和严重急性呼吸道综合症(SARS)。SARS-CoV-2与SARS-CoV同属于冠状病毒β家族。鉴于SARS-CoV-2在全球范围内的持续人传人的感染,现亟需开发能够有效预防引起SARS-CoV-2感染的疫苗,用于有效防止SARS-CoV-2感染引起的肺炎,甚至是严重呼吸道感染在我国乃至全世界范围内的蔓延。
目前应用于人体的预防病毒感染的疫苗主要包括采用病毒经减毒后制备的减毒活疫苗,如水痘减毒活疫苗、麻疹减毒活疫苗等;以及灭活全病毒颗粒疫苗,如肠道病毒EV71型灭活疫苗、甲型肝炎疫苗等。然而,减毒疫苗要费很长时间使病毒繁殖许多代,然后逐渐减除病毒的大部分活性,难以满足急性传染病的预防需要。灭活疫苗则在免疫病理方面存在许多难以解决的问题,例如有些灭活病毒进入人体会在病毒入侵时加重病情。
重组蛋白疫苗是将病毒的目的抗原基因构建在表达载体上,再转化到细菌、酵母、哺乳动物或昆虫细胞中,在一定的诱导条件下,表达出大量的抗原蛋白,通过纯化后制备的疫苗。重组蛋白疫苗能够诱导机体产生体液免疫和细胞免疫,并且可以快速制备,适用于新型冠状病毒的预防。
发明内容
SARS-CoV-2编码的蛋白包括RNA聚合酶蛋白、纤突蛋白、包膜蛋白、膜蛋白和核衣壳蛋白。其中,纤突蛋白(Spike蛋白,下文简称S蛋白)为糖蛋白,S蛋白的氨基酸序列各片段示意图如图1所示。该蛋白既是诱导保护性免疫应答的决定因素,又是与宿主细胞血管紧张素转换酶2(angiotensin-converting enzyme 2,ACE2)受体结合的部位。且在小鼠和非洲绿猴中,S蛋白已被证实可诱导血清中和抗体产生,后者具有中和SARS-CoV的作用。另外,S蛋白可诱导CD4+和CD8+T细胞应答。因此,本发明选择S蛋白作为靶标进行SARS-CoV-2重组蛋白疫苗的研发。
本发明的第一目的是提供一种预防SARS-CoV-2重组蛋白疫苗的目的氨基酸序列,包括含有SEQ1、SEQ2SEQ3中的一个或多个氨基酸序列,或与其相似度为90%以上的氨基酸序列。
上述氨基酸序列参见本发明的序列表,具体如下表1所示。
表1:目的基因编码的氨基酸序列
本发明将Sars-CoV和SARS-CoV-2各自的S蛋白的氨基酸序列进行比对,并选择保守性较高的序列作为重组蛋白疫苗的目标氨基酸序列。这些序列虽然长短不一,但是覆盖了Spike蛋白与ACE2受体结合的部位以及主要的蛋白表面抗原决定簇。
本发明的第二目的是提供所述重组蛋白疫苗的目的基因序列,其包括编码SEQ1、SEQ2和SEQ3中的一个或多个氨基酸序列或与其相似度为90%以上的氨基酸序列。
作为本发明的一种优选方案,所述目的基因序列是经过密码子优化后的DNA序列。
本发明的第三目的是提供一种包含所述重组蛋白疫苗目的基因序列的真核细胞表达载体。其是将所述目的基因序列插入到真核细胞表达载体中构建而成。
所述真核细胞表达载体优选为可以用于人的表达载体。
本发明的第四目的是提供一种表达所述重组蛋白疫苗抗原的细胞,所述细胞中外源转入了包含所述目的基因序列的真核细胞表达载体。
本发明的第五目的是提供一种预防SARS-CoV-2的重组蛋白疫苗,其抗原包含SEQ1、SEQ2和SEQ3中的一个或多个氨基酸序列,或与其相似度为90%以上的氨基酸序列。
作为本发明的一种优选方案,所述重组蛋白疫苗中抗原有效成分的含量为5~200μg/剂。具体而言,所述重组蛋白疫苗中抗原有效成分的含量可以为5μg/剂,20μg/剂,40μg/剂或200μg/剂。在本发明的一些具体实施方式中,所述抗原有效成分的含量是指疫苗产品中疫苗原液的含量。
本发明提供的疫苗中还可以含有免疫佐剂。所述免疫佐剂可以选用无机佐剂,如氢氧化铝佐剂等。所述免疫佐剂还可以选用有机佐剂,如脂多糖、细胞因子等。
本发明提供的疫苗优选为液体疫苗,可以采用多种剂型形式。具体而言,所述重组蛋白疫苗可以是肌肉内液体注射剂、静脉内液体注射剂、鼻腔内液体注射剂、皮内液体注射剂或皮下液体注射剂。在实际应用时,可以根据转染效率、局部免疫监视等临床需要进行调整和选择,如选择单一的剂型进行注射免疫,或者选择多种混合剂型进行注射免疫。
本发明的第六目的是提供所述重组蛋白疫苗的制备方法,包括如下步骤:将包含所述目的基因序列的真核细胞表达载体转入细胞中表达,取上清液纯化,得疫苗原液。
所述纯化可采用本领域常规的疫苗抗原纯化方法。
作为本发明的一种优选方案,所述纯化包括:将所述上清液进行超滤浓缩后,进行分子筛和阴离子交换两步层析,所得层析液经滤膜过滤之后,即为疫苗原液。所述滤膜优选为0.22μm滤膜。
作为本发明的一种优选方案,所述方法还包括:将所述疫苗原液配制成疫苗。所述疫苗原液的用量优选为20~200μg/剂。具体而言,所述重组蛋白疫苗中疫苗原液的含量可以为25μg/剂,50μg/剂,100μg/剂或200μg/剂。
本发明的第七目的是提供所述氨基酸序列、所述基因序列、所述真核细胞表达载体、所述细胞、所述重组蛋白疫苗或所述方法制备而成的重组蛋白疫苗在制备用于预防SARS-CoV-2感染引起的疾病的药物中的应用。
优选地,所述疾病为SARS-CoV-2感染引起的肺炎,严重急性呼吸道感染,肠道疾病,或严重急性呼吸道综合征。
本发明提供的氨基酸序列为冠状病毒β家族较为保守的序列,且这些序列均能与ACE2结合,是引起免疫反应的重要抗原决定簇,既可以预防Sars-CoV也能够预防SARS-CoV-2,能够有效诱导机体产生细胞免疫和体液免疫。且本发明提供的重组蛋白疫苗可以快速制备,适用于SARS-CoV-2的预防。
附图说明
图1为实施例6抗体亲和实验分析结果示意图;
图2为实施例7抗体亲和实验分析结果示意图;
图3为实施例8抗体亲和实验分析结果示意图。
具体实施方式
以下实施例用于说明本发明,但不用来限制本发明的范围。
实施例1
本实施例提供了一种SARS-CoV-2重组蛋白疫苗原液的制备方法,具体为:
(1)将编码SEQ1、SEQ2和SEQ3的基因序列分别进行CHO细胞密码子优化后,插入到CHO的表达载体上,转染CHO细胞,进行蛋白的重组表达;
(2)取细胞培养的上清液,进行超滤浓缩后,通过亲和层析、离子交换和分子筛等层析方法,获得的层析液经0.22μm滤膜过滤,得疫苗原液。
SEQ1、SEQ2和SEQ3分别对应得到三种疫苗原液。
实施例2
本实施例提供了一种SARS-CoV-2重组蛋白疫苗,该疫苗为液体疫苗,其中含有实施例1提供的疫苗原液10μg/剂以及氢氧化铝佐剂50μg/剂。将本实施例所得疫苗编号记为20200601。SEQ1、SEQ2和SEQ3分别对应疫苗20200601-1,20200601-2,20200601-3。
实施例3
本实施例提供了一种SARS-CoV-2重组蛋白疫苗,该疫苗为液体疫苗,其中含有实施例1提供的疫苗原液20μg/剂以及氢氧化铝佐剂50μg/剂。将本实施例所得疫苗编号记为20200602。SEQ1、SEQ2和SEQ3分别对应疫苗20200601-1,20200601-2,20200601-3。
实施例4
本实施例提供了一种SARS-CoV-2重组蛋白疫苗,该疫苗为液体疫苗,其中含有实施例1提供的疫苗原液40μg/剂以及氢氧化铝佐剂50μg/剂。将本实施例所得疫苗编号记为20200603。SEQ1、SEQ2和SEQ3分别对应疫苗20200601-1,20200601-2,20200601-3。
实施例5
本实施例提供了一种SARS-CoV-2重组蛋白疫苗,该疫苗为液体疫苗,其中含有实施例1提供的疫苗原液80μg/剂以及氢氧化铝佐剂50μg/剂。将本实施例所得疫苗编号记为20200604。SEQ1、SEQ2和SEQ3分别对应疫苗20200601-1,20200601-2,20200601-3。
实施例6:抗体亲和实验
采用SEQ1的序列的蛋白制备单克隆抗体,并采用Biacore检测抗原抗体的亲和力,将SARS-CoV-2的Spike蛋白固定在CM5芯片上,固定值大约在600Ru,使用0.05%的PBST作为缓冲液,将抗体进行不同梯度的稀释,共6个梯度,抗体做为流动相,流速30ul/min,流动时间180s,得出的数据用biacore软件进行分析,抗体与抗原的亲和力为KD[M]1.746E-11。以上结果如图1所示。
实施例7:抗体亲和实验
采用SEQ2的序列的蛋白制备单克隆抗体,并采用Biacore检测抗原抗体的亲和力,将SARS-CoV-2的Spike蛋白固定在CM5芯片上,固定值大约在600Ru,使用0.05%的PBST作为缓冲液,将抗体进行不同梯度的稀释,共6个梯度,抗体做为流动相,流速30ul/min,流动时间180s,得出的数据用biacore软件进行分析,抗体与抗原的亲和力为KD[M]4.185E-8。以上结果如图2所示。
实施例8:抗体亲和实验
采用SEQ3的序列的蛋白制备单克隆抗体,并采用Biacore检测抗原抗体的亲和力,将SARS-CoV-2的Spike蛋白固定在CM5芯片上,固定值大约在600Ru,使用0.05%的PBST作为缓冲液,将抗体进行不同梯度的稀释,共6个梯度,抗体做为流动相,流速30ul/min,流动时间180s,得出的数据用biacore软件进行分析,抗体与抗原的亲和力为KD[M]7.240E-10。以上结果如图3所示。
实施例9:疫苗免兔效果
将实施例2~5提供的4组疫苗分别接种新西兰大白兔,每组4只,每只肌肉注射1.0ml(2个剂量),按照0,7天免疫,28天采血的免疫程序,检测血清中和抗体效价。结果如表2所示。
表2:免疫兔效果
疫苗编号 | 中和抗体效价(GMT) |
20200601-2 | 16 |
20200602-2 | 32 |
20200603-2 | 32 |
20200604-2 | 40 |
结果显示,用本发明提供的SARS-CoV-2重组蛋白疫苗免疫兔,均能诱导兔产生良好的中和抗体。
虽然,上文中已经用一般性说明、具体实施方式及试验,对本发明作了详尽的描述,但在本发明基础上,可以对之作一些修改或改进,这对本领域技术人员而言是显而易见的。因此,在不偏离本发明精神的基础上所做的这些修改或改进,均属于本发明要求保护的范围。
序列表
<110> 江苏省疾病预防控制中心(江苏省公共卫生研究院);中国科学院生物物理研究所
<120> 一种预防SARS-CoV-2重组蛋白疫苗及其制备方法
<130> RYP2010730.3
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Claims (10)
1.一种SARS-CoV-2重组蛋白疫苗的目的氨基酸序列,其特征在于,包括SEQ1、SEQ2和SEQ3中的一个或多个氨基酸序列,或与其相似度为90%以上的氨基酸序列。
2.一种SARS-CoV-2重组蛋白疫苗的目的基因序列,其特征在于,包括编码SEQ1、SEQ2和SEQ3中的一个或多个氨基酸序列或与其相似度为90%以上的氨基酸序列的DNA序列;
优选地,所述目的基因序列是经过密码子优化后的DNA序列。
3.一种包含权利要求2所述目的基因序列的真核细胞表达载体;
优选地,所述真核细胞表达载体为可以用于人的表达载体。
4.一种表达SARS-CoV-2重组蛋白疫苗抗原的细胞,所述细胞中外源转入了权利要求3所述真核细胞表达载体。
5.一种预防SARS-CoV-2的重组蛋白疫苗,其抗原包含SEQ1、SEQ2和SEQ3的一个或多个氨基酸序列,或与其相似度为90%以上的氨基酸序列。
6.根据权利要求5所述的重组蛋白疫苗,其特征在于,所述疫苗为液体疫苗;
优选地,所述疫苗为肌肉内液体注射剂、鼻腔内液体注射剂、皮内液体注射剂或皮下液体注射剂。
7.一种预防SARS-CoV-2的重组蛋白疫苗的制备方法,其特征在于,包括如下步骤:将权利要求3所述真核细胞表达载体转入细胞中表达,取上清液纯化,得疫苗原液。
8.根据权利要求7所述的制备方法,其特征在于,所述方法还包括:将所述疫苗原液配制成疫苗。
9.权利要求1所述氨基酸序列、权利要求2所述基因序列、权利要求3所述真核细胞表达载体、权利要求4所述细胞、权利要求5或6所述重组蛋白疫苗或权利要求7或8所述方法制备而成的重组蛋白疫苗在制备用于预防SARS-CoV-2感染引起的疾病的药物中的应用。
10.根据权利要求9所述的应用,其特征在于,所述疾病为SARS-CoV-2感染引起的肺炎,严重急性呼吸道感染,肠道疾病,或严重急性呼吸道综合征。
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