CN112220919A - 以氧化石墨烯为载体的纳米冠状病毒重组疫苗 - Google Patents
以氧化石墨烯为载体的纳米冠状病毒重组疫苗 Download PDFInfo
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Abstract
本发明属于纳米材料和生物医药领域,涉及一种疫苗,具体而言,涉及2019‑nCoV冠状病毒核重组纳米疫苗的开发。本发明还包括该疫苗的制备方法以及在动物试验中的应用。所述的新冠疫苗含有氧化石墨烯、肌肽、CpG、新冠病毒RBD;在氧化石墨烯的骨架上结合肌肽、CpG和新冠病毒RBD;所述的CpG的编码序列如SEQ ID NO 1所示;所述的新冠病毒RBD是指新型冠状病毒蛋白受体结合区域可以在小鼠体内产生高效价的针对RBD的特异性抗体,为新型冠状病毒的防治提供了强有力的支持。
Description
技术领域
本发明属于纳米材料和生物医药领域,涉及一种疫苗开发平台的研制。具体而言,涉及2019 -nCoV冠状病毒核重组纳米疫苗的开发。本发明还包括该疫苗在动物试验中的应用。
技术背景
疫苗是消灭重大传染病的终极武器,疫苗相对于其他疗法有最低的成本,更有先发制敌的优势,无疑成了公众的希望,通过接种疫苗,人类已经消灭了天花,脊髓灰质炎病例也减少了99%,白喉等传染病发病罕见,麻疹、新生儿破伤风等疾病的发病率显著下降。疫苗对人类健康的影响再怎么夸大都不过分,每一种新疫苗的诞生都是人类战胜一种传染病的伟大胜利!至今没有任何一种医疗措施能像疫苗一样对人类的健康产生如此重要、持久和深远的影响;也没有任何一种治疗药品能像疫苗一样以极其低廉的代价把某一种疾病从地球上消灭。
SARS-CoV-2疫情发生不久,中国已有不同实验室完成了病毒毒株的分离,为向疫苗的研发迈近了一大步,相信我们很快就会拥有消灭SARS-CoV-2的终极武器,然而,直到现在为止,还没有一款批准的用于治疗CoV感染的疫苗或药物,因此非常亟需开发一种有效的药物治疗或者预防冠状病毒的传染和爆发。
根据SARS和MERS等冠状病毒疫苗的研究表明,目前针对冠状病毒疫苗的主要靶点为冠状病毒的S蛋白。疫苗不仅需要诱导体液和细胞免疫应答,还需要诱导粘膜免疫应答,并借助佐剂来诱导平衡的Th1和Th2途径,才可以产生真正有效的疫苗。目前更多SARS和MERS疫苗的研究主要集中在病毒载体疫苗和亚单位疫苗上,大量研究表明SARS和MERS的难点在于无法刺激产生长期记忆B细胞,在痊愈的SARS和MERS病人体内长期记忆细胞只能持续2-3年,无法产生免疫记忆,造成疫苗开发失败,截止目前只有6种潜在的冠状病毒疫苗进入临床研究阶段,但是还没有1款有效的疫苗获批上市。
发明内容
本发明目的在于提供一种冠状病毒重组疫苗。
本发明的另一个目的是提供该病毒重组疫苗的制备方法。
本发明的再一个目的是提供该病毒重组疫苗的应用。
鉴于目前传统疫苗存在的各种问题,如何改变现有疫苗存在的问题,增强免疫反应是我们一直在思考的问题,为了提高免疫原的免疫活性,加强机体的免疫应答能力,最基本的方法是将免疫原与佐剂混合,免疫佐剂是一类能够加强机体对免疫原免疫应答的促进剂。CpG寡聚脱氧核苷酸(oligodeoxynucleotide, ODN)是近年来发现的一个非常有前景的佐剂。CpG ODN在动物体内、体外及临床研究证明,其具有较好的佐剂活性,研究最充分的为CpG7909和CpG1018。2017年11月9日,美国FDA批准 Dynavax Technologies公司以CpG1018为佐剂的乙肝疫苗上市,该疫苗是世界上首个获批的CpG ODN佐剂疫苗,用于预防18 岁及以上成人HBV 感染,另外多个不同类型的CpG ODN作为佐剂已应用于多个临床试验中。CpG通过和TLR9结合,激活不成熟的pDC细胞,诱导天然和适应性免疫应答,但是单一的CpG 结构对免疫细胞的激活作用有限,同时易被核酸外切酶快速水解,使其在体内稳定性不足,还会引起副作用;序列中合成的CpG 寡聚脱氧核苷酸(ODN) 也能加强刺激作用,将CpG与抗原等其他蛋白偶联后联用,具有非常显著的免疫激活作用。
石墨烯是一种由碳原子以sp²杂化轨道组成六角型呈蜂巢晶格的二维碳纳米材料。其基本结构单元为有机材料中最稳定的苯六元环,是目前最理想的二维材料。氧化石墨烯(Graphene oxide, GO)作为石墨烯的衍生物,为氧化石墨的剥落物。由于其具备的独特SP2杂化和完美的二维结构以及边缘的高反应活性的特点,使得在设计和开发以其为基础的治疗平台可以作为理想的负载和嫁接载体,在纳米药物运输系统、生物检测、肿瘤治疗以及细胞成像等方面发挥着重大的作用。
本发明在上述研究基础上完成。
本发明基于氧化石墨烯材料为骨架负载CpG分子和重组蛋白,开发了一种全新的疫苗研制方法。基于该技术平台结合SAR-CoV-2的Spike 蛋白的RBD区的重组蛋白制备了一种新的纳米新冠疫苗。制备的纳米新冠疫苗在小鼠试验中现实了较强的免疫原性,可以产生高效价的抗体。
一方面,本发明提供了一种冠状病毒疫苗,含有氧化石墨烯、肌肽、CpG、RBD。在本发明的优选实施例中,称为GO-Car-肌肽-CpG-RBD疫苗。
氧化石墨烯(GO,graphene oxide)是石墨烯的氧化物,因经氧化后,其上含氧官能团增多而使性质较石墨烯更加活泼。例如,在氧化石墨烯单片上随机分布羟基和环氧基,而在单片的边缘则引入了羧基和羰基。常见的氧化石墨烯市售产品有粉末状、片状以及溶液状的,颜色为棕黄色。
肌肽,学名β-丙氨酰-L-组氨酸,是由是一种由β-丙氨酸和L-组氨酸两种氨基酸组成的二肽,结晶状固体。肌肽具有很强的抗氧化能力,可清除在氧化应激过程中使细胞膜的脂肪酸过度氧化而形成的活性氧自由基(ROS)以及α-β不饱和醛。
CpG基序具有激活机体免疫系统的作用,可以作为佐剂。较好的,所述的CpG的编码序列如SEQ ID NO 1所示。
RBD(spike receptor binding domain)即受体结合区域,本发明中的RBD特指冠状病毒蛋白(S蛋白)受体结合区域(RBD)。例如,可以选择序列如下的RBD蛋白:
PNITNLCPFGEVFNATRFASVYAWNRKRISNCVADYSVLYNSASFSTFKCYGVSPTKLNDLCFTNVYADSFVIRGDEVRQIAPGQTGKIADYNYKLPDDFTGCVIAWNSNNLDSKVGGNYNYLYRLFRKSNLKPFERDISTEIYQAGSTPCNGVEGFNCYFPLQSYGFQPTNGVGYQPYRVVVLSFELLHAP(SEQ ID NO 2)。
本发明的冠状病毒疫苗通过在活化的氧化石墨烯上结合肌肽、CpG和新冠病毒RBD而获得。
本发明的冠状病毒疫苗中GO作为骨架基础,通常用量过量,肌肽的用量可以为GO的两倍左右。CpG和新冠病毒RBD作为生物大分子,其用量较少,两者的用量通常是GO的万分之一,质量比。而RBD的用量为CpG的2倍以上,例如CpG:RBD=1:2-10,较好的,RBD的用量为CpG的3-6倍。
另一方面,本发明提供了所述的冠状病毒疫苗的制备方法,所述的制备方法包括如下步骤:
获取CpG、RBD重组蛋白和肌肽;
将GO冻干粉末添加到磷酸盐缓冲液中,超声处理;
添加EDC和NHS以活化GO溶液,通过超滤去除反应溶液中过量的EDC /磺基-NHS,将反应溶液的pH调节至中性;
将肌肽、CpG和RBD重组蛋白添加到反应溶液中,与活化的GO孵育;
从反应溶液中除去过量的未偶联的蛋白,灭菌,备用。
较好的,超声的时长为2-3小时。超声的条件为200 W,40 kHz。
较好的,所述的磷酸盐缓冲液的pH值为中性,例如6.8-7.6,更好的为7.0-7.4,或者7.2。
较好的,所述的去除过量的EDC /磺基-NHS或者未偶联的蛋白的方法是超滤。
本发明的一个优选实施例中,氧化石墨烯、肌肽、CpG、RBD的比例为:26mg:40mg:1.2μg:(3-6)μg。
较好的,所述的反应温度在20-28℃。例如,采用室温。
在本发明的一个优选实施例中,GO-Car-肌肽-CpG-RBD疫苗的制备方法为:采用EDC-NHS反应的改进方法将GO与肌肽偶联,将26 mg的GO冻干粉末添加到5.20 mL的磷酸盐缓冲液(PBS,pH = 7.4)中,在25°C下超声处理(200 W,40 kHz)3 h。于25°C下添加6.82 mgEDC(N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine,中文:1-(3-二甲氨基丙基)-3-乙基碳二亚胺)和7.73 mg NHS(N-N-羟基琥珀酰亚胺)来活化GO溶液。通过超滤将过量的EDC /磺基-NHS从反应溶液中去除,然后将溶液的pH调节至7.4。然后,将40mg的肌肽,1.2ug CpG,和不同浓度的RBD重组蛋白添加到溶液中,在25°C下与活化的GO反应2 h。随后,通过超滤的方法从反应溶液中除去过量的未偶联的蛋白。所制备的产品被标记为GO-Car-肌肽-CpG-RBD疫苗。最后,用无菌过滤器(0.22um)接触GO-Car-肌肽-CpG-RBD疫苗溶液,并将其存储在4°C的无菌容器中以用于后续实验。
本发明建立了一种可以快速激发人体免疫系统的纳米重组蛋白疫苗制备技术平台,在传染性的病毒确认后可以迅速生产大量的预防性疫苗。此技术平台充分利用氧化石墨烯的表面带有COOH、羟基等基团的特点,利用π-π键之间的相互作用,把筛选出的RBD的重组蛋白与CpG分子和肌肽组装在一起,制备成基于氧化石墨烯为骨架的纳米重组蛋白疫苗。该疫苗可以激发机体产生高效价的针对SAR-CoV-2的RBD中和抗体,为防治冠状病毒感染和将来的类似疫情的大爆发打好技术基础。
再一方面,本发明提供了上述GO-Car-肌肽-CpG-RBD疫苗的应用,即GO-Car-肌肽-CpG-RBD疫苗在制备预防新冠病毒的药物中的应用。
较好的,所述的应用时提高机体对新冠病毒的免疫力。
更好的,上述GO-Car-肌肽-CpG-RBD疫苗能够产生针对RBD的特异性抗体,并且该特异性抗体效价高。在本发明的实施例中,纳米新冠疫苗在小鼠试验中现实了较强的免疫原性,可以产生高效价的抗体。
本发明的有益效果在于:
基于氧化石墨烯材料为骨架负载CpG分子和重组蛋白开发了一种全新的疫苗技术平台结合SAR-CoV-2的Spike 蛋白的RBD区的重组蛋白制备了一种新的纳米冠状病毒疫苗,可以在小鼠体内产生高效价的针对RBD的特异性抗体,为新型冠状病毒的防治提供了强有力的支持。
附图说明
为了更清楚地说明本申请实施例中的技术方案,下面将对实施例中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本申请的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动的前提下,还可以根据这些附图获得其他的附图。
图1为 GO-Car-肌肽-CpG-RBD疫苗小鼠免疫的模式图和时间表示意图;
图2为小鼠免疫后28天的血清中特异性RBD抗体的变化和42天时脾脏细胞产生细胞因子的变化情况。
具体实施方式
下面将对本申请实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本申请一部分实施例,而不是全部的实施例。基于本申请中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本申请保护的范围。对于没有具体描述的方法和技术,均可采用本领域的常规公知技术进行操作。例如,参照冷泉港的分子克隆手册等。
实施例1
氧化石墨烯(GO)-肌肽-CpG-RBD重组蛋白疫苗制剂的制备过程
选用对人和鼠均有交叉反应的TLR9受体核酸序列CpG ODN M362,具体序列如下:5’-TCGTCGTCGTTC:GAACGACGTTGAT-3’ (25 mer,SEQ ID NO 1),采用EDC-NHS反应的改进方法将GO与肌肽偶联过程,将26 mg的GO冻干粉末添加到5.20 mL的磷酸盐缓冲液(PBS,pH =7.4)中,在25°C下超声处理(200 W,40 kHz)3 h。于25°C下添加6.82 mg EDC(N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine,中文:1-(3-二甲氨基丙基)-3-乙基碳二亚胺)和7.73 mg NHS(N-N-羟基琥珀酰亚胺)来活化GO溶液。通过超滤将过量的EDC /磺基-NHS从反应溶液中去除,然后将溶液的pH调节至7.4。然后,将40 mg的肌肽,1.2ug CpG,和不同浓度的RBD重组蛋白添加到溶液中,在25°C下与活化的GO反应2 h。随后,通过超滤的方法从反应溶液中除去过量的未偶联的蛋白。所制备的产品被标记为GO-Car-肌肽-CpG-RBD疫苗。最后,用无菌过滤器(0.22um)接触GO-Car-肌肽-CpG-RBD疫苗溶液,并将其存储在4°C的无菌容器中以用于后续实验。
实施例2
氧化石墨烯(GO)-肌肽-CpG-RBD重组蛋白疫苗免疫小鼠的试验
按照图1标示的时间表分别在0,14,28天皮下注射的方式免疫6周龄的雌性BALB/cmice小鼠,直到28天和42天,采用郃下取血的方式采血,分离血清,检测血清中针对RBD的特异性抗体。在42天处死小鼠,分离脾细胞,检测特异性T细胞免疫反应和细胞因子的分泌情况。
免疫小鼠的分组和剂量确定:
1. (氧化石墨烯+肌肽)+ 1.2ug cpG+3ug RBD
2.(氧化石墨烯+肌肽)+ 1.2ug cpG+6ug RBD
3.氢氧化铝+6ug RBD (1:1)
4. 6ug RBD
5.脂质体(lipo)+6ug RBD组
小鼠品系:BALB/c mice(n=6)。
GO-Car-肌肽-CpG-RBD疫苗免疫小鼠的时间表为:采血并首次免疫,作为免疫小鼠起点。第7日第二次采血,考察新冠加病毒系统,掌握原理。第14日第三次采血,加强免疫。第28日第四次采血,加强免疫,检测血清中抗体,如果是阳性,准备采集脾脏细胞。第42日第五次采血,之后处死采血,分离脾细胞,做细胞因子实验。
试验结果表明,GO-Car-肌肽-CpG-RBD疫苗在免疫小鼠后3ug和6ug组均产生了高滴度的针对RBD的特异性抗体,相对于传统佐剂组和RBD组以及脂质体组均有显著性差异(图2)。进一步的分析从脾脏中分离的T细胞的特异性免疫反应,结果显示GO-Car-肌肽-CpG-RBD疫苗可以刺激机体产生特异性的IFN-gamma细胞因子,提高机体的免疫力,对抗新冠病毒的疫情。
以上所述,仅为本申请的具体实施方式,但本申请的保护范围并不局限于此,任何熟悉本领域技术的技术人员在本申请公开的技术范围内,可轻易想到的变化或替换,都应涵盖在本申请的保护范围之内。因此,本申请的保护范围应以所述权利要求的保护范围为准。
SEQUENCE LISTING
<110> 上海纳米技术及应用国家工程研究中心有限公司
<120> 以氧化石墨烯为载体的纳米新冠状病毒重组疫苗
<130> 20200920
<160> 2
<170> PatentIn version 3.5
<210> 1
<211> 25
<212> DNA
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 1
tcgtcgtcgt tcgaacgacg ttgat 25
<210> 2
<211> 192
<212> PRT
<213> Artificial Sequence
<220>
<223> 人工序列
<400> 2
Pro Asn Ile Thr Asn Leu Cys Pro Phe Gly Glu Val Phe Asn Ala Thr
1 5 10 15
Arg Phe Ala Ser Val Tyr Ala Trp Asn Arg Lys Arg Ile Ser Asn Cys
20 25 30
Val Ala Asp Tyr Ser Val Leu Tyr Asn Ser Ala Ser Phe Ser Thr Phe
35 40 45
Lys Cys Tyr Gly Val Ser Pro Thr Lys Leu Asn Asp Leu Cys Phe Thr
50 55 60
Asn Val Tyr Ala Asp Ser Phe Val Ile Arg Gly Asp Glu Val Arg Gln
65 70 75 80
Ile Ala Pro Gly Gln Thr Gly Lys Ile Ala Asp Tyr Asn Tyr Lys Leu
85 90 95
Pro Asp Asp Phe Thr Gly Cys Val Ile Ala Trp Asn Ser Asn Asn Leu
100 105 110
Asp Ser Lys Val Gly Gly Asn Tyr Asn Tyr Leu Tyr Arg Leu Phe Arg
115 120 125
Lys Ser Asn Leu Lys Pro Phe Glu Arg Asp Ile Ser Thr Glu Ile Tyr
130 135 140
Gln Ala Gly Ser Thr Pro Cys Asn Gly Val Glu Gly Phe Asn Cys Tyr
145 150 155 160
Phe Pro Leu Gln Ser Tyr Gly Phe Gln Pro Thr Asn Gly Val Gly Tyr
165 170 175
Gln Pro Tyr Arg Val Val Val Leu Ser Phe Glu Leu Leu His Ala Pro
180 185 190
Claims (10)
1.一种冠状病毒疫苗,其特征在于,所述的冠状病毒含有氧化石墨烯、肌肽、CpG和新冠病毒受体结合区域;在氧化石墨烯的骨架上结合肌肽、CpG和新冠病毒受体结合区域;所述的CpG的编码序列如SEQ ID NO 1所示;所述的新冠病毒受体结合区域是指新型冠状病毒S蛋白受体结合区域。
2.如权利要求1所述的冠状病毒,其特征在于,所述的冠状病毒通过在活化的氧化石墨烯上连接肌肽、CpG和冠状病毒受体结合区域而获得。
3.权利要求1所述的冠状病毒的制备方法,其特征在于,所述的制备方法包括如下步骤:
获取CpG、受体结合区域重组蛋白和肌肽,所述的CpG的编码序列如SEQ ID NO 1所示;
将氧化石墨烯冻干粉末添加到磷酸盐缓冲液中,超声处理;
添加EDC和NHS以活化氧化石墨烯溶液,通过超滤去除反应溶液中过量的EDC /磺基-NHS,将反应溶液的pH调节至中性;
将肌肽、CpG和受体结合区域重组蛋白添加到反应溶液中,与活化的氧化石墨烯孵育;
从反应溶液中除去过量的未偶联的蛋白,灭菌,备用。
4.如权利要求3所述的制备方法,其特征在于,超声的时长为2-3小时。
5.如权利要求3所述的制备方法,其特征在于,所述的磷酸盐缓冲液的pH值为6.8-7.6。
6.如权利要求3所述的制备方法,其特征在于,去除过量的EDC /磺基-NHS或者去除未偶联的蛋白的方法是超滤。
7.如权利要求3所述的制备方法,其特征在于,肌肽用量为氧化石墨烯的1.5倍以上,受体结合区域用量为CpG的2-10倍,CpG的用量为氧化石墨烯的万分之一,质量比。
8.如权利要求3-7中任意一种所述的制备方法,其特征在于,所述的反应温度在20-28℃。
9.权利要求1所述的冠状病毒的应用,其特征在于,所述的新冠疫苗在制备预防冠状病毒的药物中的应用。
10.如权利要求9所述的应用,其特征在于,所述的冠状病毒使机体产生针对受体结合区域重组蛋白的抗体。
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