合成生物学在新冠病毒广谱疫苗研发中的应用

doi:10.12211/2096-8280.2023-088

合成生物学 ›› 2024, Vol. 5 ›› Issue (2): 369-384.DOI: 10.12211/2096-8280.2023-088

合成生物学在新冠病毒广谱疫苗研发中的应用

袁为锋, 赵永亮, 吴芷萱, 徐可

武汉大学病毒学国家重点实验室，泰康生命医学中心，生命科学学院，湖北武汉 430072

收稿日期:2023-11-28 修回日期:2024-02-18 出版日期:2024-04-30 发布日期:2024-04-28
通讯作者: 徐可
作者简介:袁为锋（1995—），男，博士后。研究方向为病毒宿主相互作用与抗病毒药物的靶点发现、新型流感/冠状病毒疫苗研发。E-mail：ywf519@whu.edu.cn
徐可（1982—），女，教授，博士生导师。研究方向为呼吸道RNA病毒分子致病机制、呼吸道病毒共感染、抗呼吸道RNA病毒广谱药物靶标发现、广谱疫苗研发等。E-mail：xuke03@whu.edu.cn
基金资助:
国家重点研发计划(2023YFC2307800);湖北省支持企业技术创新发展项目(2021BAB117);武汉大学示范课堂建设项目(2022ZG090)

Applications of synthetic biology in the development of SARS-CoV-2 broad-spectrum vaccines

Weifeng YUAN, Yongliang ZHAO, Zhixuan WU, Ke XU

State Key Laboratory of Virology，College of Life Sciences，Taikang Center for Life and Medical Sciences，Wuhan University，Wuhan 430072，Hubei，China

Received:2023-11-28 Revised:2024-02-18 Online:2024-04-30 Published:2024-04-28
Contact: Ke XU

摘要/Abstract

摘要：

新型冠状病毒（SARS-CoV-2）自2019年底引发疫情至今，已经变异出Alpha、Beta、Delta和Omicron等不同谱系。传统疫苗的抗原序列来源于某一自然分离株的原始序列，疫苗迭代速度跟不上病毒变异的速度，导致突破性感染的发生，研发跨谱系的广谱疫苗是预防这类高变异呼吸道病毒的迫切需求。随着合成生物技术的发展，抗原的多价偶联、核心抗原模块的提取、抗原内部保守表位的工程化设计、抗原表位展示技术、计算指导的抗原重构等抗原“再设计”方案得以实现，提高了抗原的免疫原性和广谱性。合成生物学还体现在疫苗产品的生产工艺环节，基因工程表达的疫苗抗原以纳米颗粒、病毒载体、核酸、亚单位的形式，借助细菌、酵母、植物、昆虫或哺乳动物细胞等表达平台进行规模化生产。本文综述了近年来合成生物技术在广谱疫苗（尤其是广谱新冠病毒疫苗）多种设计策略中的应用情况，总结了合成生物技术如何通过反向疫苗学的设计展示全新的共性抗原表位和交叉抗原位点，达到“以不变应万变”的广谱保护效果。本文还讨论了多种广谱疫苗设计策略的应用场景及面临的挑战。基于合成生物技术的马赛克设计策略、保守表位工程化设计策略、计算共识序列策略和新型佐剂策略，结合不同的疫苗技术路线，可提高疫苗的免疫原性、广谱保护性和安全性。这为高变异病毒的疫苗研发提供了合成生物学的新思路。

关键词: 合成生物学, 反向疫苗学, 新冠广谱疫苗

Abstract:

Since the outbreak of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019, it has evolved into different lineages, including Alpha, Beta, Delta, and Omicron. The development of broad-spectrum vaccines has become a necessity for preventing the highly mutated respiratory viruses. Traditional vaccine antigens, originating from prototype strains, cannot cover rapid mutations with these viruses, leading to breakthrough infections. With the development of synthetic biology, new technologies such as multivalent coupling of antigens, reconstructed dominate antigen modules, engineering design of conserved epitopes, epitope display, and computation-guided reconstruction have enabled redesigning antigens to achieve stronger immunogenicity with broader spectrum. The technology of synthetic biology is also applicable in the vaccine production process, such as antigen expression in nanoparticles, viral vectors, nucleic acids, and subunits. This article reviews the applications of synthetic biology technology in developing broad-spectrum vaccines in recent years, particularly for the broad-spectrum SARS-CoV-2 vaccines, and summarizes how to display common antigens and cross-antigenic sites by the reverse vaccinology for the activation of broad-spectrum immune responses against different mutant strains, achieving broad-spectrum vaccine protection effects through “remaining constant in response to ever-changing”. The article also provides a comprehensive comparison of the strengths and limitations of different broad-spectrum vaccine design strategies and discusses challenges to applying synthetic biology in the development of vaccines, offering valuable insights for universal against highly mutation viruses. {L-End}

Key words: synthetic biology, reverse vaccinology, broad-spectrum COVID-19 vaccines

中图分类号:

Q816

袁为锋, 赵永亮, 吴芷萱, 徐可. 合成生物学在新冠病毒广谱疫苗研发中的应用[J]. 合成生物学, 2024, 5(2): 369-384.

Weifeng YUAN, Yongliang ZHAO, Zhixuan WU, Ke XU. Applications of synthetic biology in the development of SARS-CoV-2 broad-spectrum vaccines[J]. Synthetic Biology Journal, 2024, 5(2): 369-384.

图/表 8

表1 五种技术路线SARS-CoV-2疫苗的研究进展

Table 1 Research progress in SARS-CoV-2 vaccines

疫苗类型	产品名	关键组分或技术	保护率或临床阶段	研发团队或机构
灭活疫苗	CoronaVac	CZ02株	50.4%^[4]	北京科兴中维生物
	BBIBP-CorV	HB02株	78.1%^[5]	北京生物制品研究所
	WIBP	WIV04株	72.8%^[5]	武汉生物制品研究所
	BBV152	NIV-2020-770株	77.8%^[6]	Bharat Biotech
	QazVac	Wuhan-Hu-1株	90%^[7]	Kazakhstan RIBSP
纳米颗粒疫苗	I53-50	RBD	Ⅲ期（原始株）	华盛顿大学^[8]
	铁蛋白	S	Ⅰ期（原始株）	斯坦福大学^[9]
	SC003-mi3	RBD	Ⅱ/Ⅲ期（原始株）	牛津大学^[10]
	铁蛋白	RBD	临床前（突变株）	中山大学^[11]
亚单位疫苗	NVXCoV2373	Matrix-M™佐剂	89.7%^[12]	Novavax
	COVAX-19	Advax-CpG55.2™佐剂	63.55%^[13]	Vaxine Pty Ltd
	SCB-2019	CpG 1018、铝佐剂	67%^[14]	三叶草
	ZF2001	氢氧化铝佐剂	75.7%^[15]	中国科学院微生物研究所
	威克欣	MF59样佐剂	未公布^[16]	威斯克生物
	SCTV01C	水包油佐剂	未公布^[17]	神州细胞
	MVC-COV1901	CpG1018、明矾佐剂	未公布^[18]	Medigen Vaccine Biologics
	Soberana	明矾、B群脑膜炎奈瑟氏菌外膜囊泡	未公布^[19]	古巴芬利疫苗研究所
病毒载体疫苗	Ad26.COV2.S	Ad26腺病毒载体	66.1%^[20]	Janssen
	Sputnik V	rAd26和rAd5腺病毒载体	91.6%^[21]	Gamaleya Center
	Ad5-nCoV	Ad5腺病毒载体	57.5%^[22]	康希诺生物、军事医学科学院
	AZD1222	ChAdOx1腺病毒载体	76%^[23]	阿斯利康、牛津大学
	dNS1-RBD	dNS1流感病毒载体	100%^[24]	厦门大学、香港大学、万泰生物
核酸疫苗	BNT162b2	mRNA疫苗	95%^[25]	Pfizer Inc.
	mRNA-1273	mRNA疫苗	94.1%^[26]	Moderna
	ARCoV	mRNA疫苗	83.75%^[27]	艾博生物
	ZyCov-D	DNA疫苗	67%^[28]	Zydus Cadila

图1 合成生物学在抗原（疫苗）“再设计”中的应用

Fig. 1 Applications of synthetic biology in the reverse design of vaccines

表2 马赛克策略的SARS-CoV-2疫苗研究进展

Table 2 Research progress in developing the SARS-CoV-2 vaccine with the Mosaic strategy

疫苗产品	疫苗类型	抗原	临床阶段	研发机构
SpFN^[68]	亚单位	多种突变株的S蛋白	Ⅰ	美国沃尔特-里德陆军研究所
RBD-scNP^[60]	亚单位	多种突变株的RBD蛋白	临床前	杜克大学
复必泰^[69]	mRNA	WT和BA.4/5的S蛋白	Ⅰ	复星医药
RBD-sc^[70]	亚单位	不同突变株的RBD二聚体	临床前	中国科学院微生物研究所
V-01D-351^[61]	亚单位	Beta和Delta株的RBD二聚体	Ⅰ	丽珠集团
SCTV01C^[71]	亚单位	Alpha和Beta株的S蛋白	Ⅲ	神州细胞
SCTV01E^[72]	亚单位	Alpha、Beta、Delta和Omicron株的S蛋白	Ⅲ	神州细胞

图2 以保守表位HR1、HR2作为广谱疫苗抗原的示意图（新冠病毒S2亚基介导膜融合过程。当新冠病毒结合ACE2受体后，S1与S2解离，S2被宿主蛋白酶切割后发生构象变化，HR1延伸将融合肽FP插入细胞膜，形成融合中间态。随后，HR2折叠结合至HR1三聚体螺旋疏水凹槽中，与HR1形成6螺旋结构，实现病毒包膜与细胞膜融合）

Fig. 2 Schematic diagram for engineering conserved epitopes HR1 and HR2 to develop broad-spectrum vaccine antigens(Membrane fusion mediated by the SARS-CoV-2 S2 subunit. Initially, the standing RBD engages with ACE2, and subsequently, the S1 subunit dissociates from S2, followed by the exposure of the S2 site and the cleavage of S2 by the host proteases. HR1 undergoes a “jack-knife” refolding change to allow the insertion of FP into the host cell membrane. The folding back of the extended SH-HR2 element packs against the long central CH-HR1 coiled-coil, inducing the binding of SH onto the outer region of CH and HR2 to the HR1 groove. Subsequently, membrane fusion occurs between the viral particles and host cells.)

图3 重组蛋白HR121的模式图、3D结构（a）以及重组蛋白HR1LS的模式图、3D结构（b）

Fig. 3 Schematic diagrams of the dimer protein HR121 and predicted structures (a) and the trimeric protein HRILS and predicted structures (b)

表3 SARS-CoV-2靶向病毒保守表位策略的疫苗研究进展

Table 3 Research progress in vaccines against the conserved epitope of SARS-CoV-2

疫苗产品	疫苗类型	抗原	临床阶段	研发机构
HR121^[76]	亚单位	HR1-HR2-HR1串联	临床前	中国科学院昆明动物研究所
HR1LS^[77]	亚单位	HR1-CH-SH串联	临床前	复旦大学
MigVax-101^[81]	亚单位	RBD和N蛋白	临床前	MigVax
STFK1628x/y^[82]	亚单位	B.1.620-NTD和Gamma-RBD-S2	临床前	厦门大学
hAd5 S-Fusion+N-ETSD^[83]	病毒载体	S和N蛋白	Ⅱ	ImmunityBio

图4 共识序列设计策略示意图［62］（以新冠病毒共识序列Span为例。①建立序列库；②将序列库中所有毒株序列进行进化计算；③构建毒株进化树，得到每个分支的代表毒株；④使用代表毒株计算得到共识序列，并带回数据库进行优化与修正；⑤得到位于进化中心的共识序列）

Fig. 4 Schematic diagram of strategy for designing consensus sequences[62](Taking the SARS-CoV-2 consensus sequence Span as an example. ① Establishing the whole sequences library; ② Evolutionary calculations of the viruses; ③ Constructing an evolutionary tree for the viral strains to obtain representative ones for each branch; ④ Utilizing representative strains to calculate the consensus sequences, and refining and optimizing them by incorporating back into the database; ⑤ Obtaining the consensus sequences located at the evolutionary center.)

表4 SARS-CoV-2新型佐剂策略的疫苗研究进展

Table 4 Research progress of the SARS-CoV-2 vaccines developed based on novel adjuvant strategies

疫苗产品	疫苗类型	抗原	佐剂	临床阶段	研发机构
β-CoV-B^[94]	亚单位	WT-RBD	CF501	临床前	复旦大学
NVX-CoV2373^[95]	亚单位	S	Matrix-M	已上市	Novavax
VLA2001^[96]	灭活疫苗	WT毒株	铝佐剂和CpG 1018	已上市	Valneva SE
YS-SC2-010^[97]	亚单位	WT-S	皮卡佐剂	Ⅰ	依生生物

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合成生物学在新冠病毒广谱疫苗研发中的应用

Applications of synthetic biology in the development of SARS-CoV-2 broad-spectrum vaccines

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