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中国生物工程杂志

CHINA BIOTECHNOLOGY
中国生物工程杂志
中国生物工程杂志  2022, Vol. 42 Issue (5): 124-138    DOI: 10.13523/j.cb.2202049
新冠肺炎疫苗的研究策略     
新型冠状病毒亚单位疫苗研究进展及现状*
杨依,张晴云,梅坤荣**()
天津大学药物科学与技术学院 天津 300072
Progress and Current Situation of SARS-CoV-2 Subunit Vaccine Development
YANG Yi,ZHANG Qing-yun,MEI Kun-rong**()
School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China
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摘要：

自新型冠状病毒肺炎在2019年年末暴发以来,如何高效防控疫情一直是紧急的全球公共安全事件。疫苗是有效阻止病毒感染人体、保护高危人群免于疾病快速进展以及遏制疫情进一步扩大的手段之一,其中亚单位疫苗的主要成分为特定的病毒抗原蛋白或多肽,通过加入疫苗佐剂提高抗原的免疫原性。由于机体仅针对重组蛋白表面的特定抗原表位进行识别并产生抗体,因此亚单位疫苗具有较高的保护能力和安全性。通过对目前已上市及处于临床阶段的各类新型冠状病毒亚单位疫苗进行梳理,介绍了各类亚单位疫苗的抗原设计策略和佐剂选择、整体保护能力及研究进展,并对亚单位疫苗的应用及技术优势进行分析,期望能为亚单位疫苗研发及全球疫情防控提供参考。
关键词： 新型冠状病毒肺炎;  新型冠状病毒;  亚单位疫苗    
Abstract:

Since the outbreak of novel coronavirus disease in late 2019, it has been a global public safety emergency to efficiently prevent and control the epidemic. Vaccine is one of the means to effectively prevent the virus from infecting humans, protect high-risk groups from rapid disease progression and minimize further spread of the virus-caused epidemic. Subunit vaccine is a safe and effective strategy that contains recombinant protein antigens of specific viral components and vaccine adjuvant that helps increasing the immunogenicity of the antigen. Since the specific immunogenic viral antigen can activate the immune system, which thus produces antibodies against immunodominant epitopes on the surface of the protein antigen, it offers subunit vaccine a high degree of protection and safety. The major severe acute respiratory symptom coronavirus 2 (SARS-CoV-2) subunit vaccines that have been marketed and are currently in the clinical stage are reviewed. The design concepts of various antigens and types of vaccine adjuvants, the protective capacity, and the research progress of subunit vaccine candidates are introduced. The applications and technical advantages of subunit vaccine are analyzed. This review is expected to provide suggestions for subunit vaccine development and global epidemic prevention and control.
Key words: COVID-19    SARS-CoV-2    Subunit vaccine
收稿日期: 2022-02-28 出版日期: 2022-06-17
ZTFLH:  Q819  
基金资助: *天津市青年人才托举工程(TJSQNTJ-2020-19)
通讯作者: 梅坤荣     E-mail: kmei@tju.edu.cn
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引用本文:

杨依,张晴云,梅坤荣. 新型冠状病毒亚单位疫苗研究进展及现状*[J]. 中国生物工程杂志, 2022, 42(5): 124-138.

YANG Yi,ZHANG Qing-yun,MEI Kun-rong. Progress and Current Situation of SARS-CoV-2 Subunit Vaccine Development. China Biotechnology, 2022, 42(5): 124-138.

链接本文:

https://manu60.magtech.com.cn/biotech/CN/10.13523/j.cb.2202049    或    https://manu60.magtech.com.cn/biotech/CN/Y2022/V42/I5/124

图1  SARS-CoV-2 亚单位疫苗候选抗原的主要类型
佐剂 组成 应用 参考文献
铝佐剂 氢氧化铝 ZF2001/EpiVacCorona/Soberana 01/Soberana 02/Soberana Plus/Abdala/NVSI-06-07/NVSI-06-08/V-01/GBP510/ Recombinant COVID-19 Vaccine (Sf9 cells) [37,53⇓⇓⇓⇓⇓⇓-60]
CpG/铝佐剂 CpG和氢氧化铝 SCB-2019/MVC-COV1901/Corbevax/202-CoV [61⇓⇓-64]
Matrix-M 皂苷、胆固醇和磷脂 NVX-CoV2373/SII B.1.351/SII B.1.617.2/SII Bivalent [65]
AS03 α-生育酚、角鲨烯和聚山梨醇酯80 CoV2 preS dTM/GBP510 [59,66]
MF59 山梨醇三油酸酯、角鲨烯和聚山梨醇酯80 S-clamp [67]
Advax-SM Delta-菊粉颗粒和CpG COVAX-19® (Spikogen®) [68]
表1  SARS-CoV-2亚单位疫苗常用佐剂
疫苗名称 序列及抗原优化 研发单位 佐剂 表达系统 获批情况 参考文献
基于S蛋白设计的亚单位疫苗
MVC-COV1901 1~1208 a.a.R682G/R683S/
R685S/K986P/V987P,C端连接T4纤维蛋白三聚标签		 基亚生物 CpG/
铝佐剂		 哺乳动物细胞 获批:巴拉圭,索马里兰,中国台湾 [69]
COVAX-19®
(Spikogen®)		 /* Vaxine/Cinnagen Advax-SM 昆虫细胞 紧急使用:伊朗 [68]
基于S蛋白设计的纳米颗粒亚单位疫苗
NVX-CoV2373 1~1273 a.a.R682Q/R683Q/R685Q/K986P/V987P 诺瓦瓦克斯 Matrix-M 昆虫细胞 获批:英国,澳大利亚,韩国等36个国家 [65,70-71]
Covovax 1~1273 a.a.R682Q/R683Q/
R685Q/K986P/V987P		 诺瓦瓦克斯/
印度血清研究所		 Matrix-M 昆虫细胞 紧急使用:印度,印度尼西亚,菲律宾 [72]
基于RBD单体设计的亚单位疫苗
Corbevax 332~549 a.a. Biological E CpG/
铝佐剂		 酵母 紧急使用:印度 [63,73]
Abdala
(CIGB-66)		 331~529 a.a. 古巴基因工程与
生物技术中心		 铝佐剂 酵母 获批:古巴,墨西哥,委内瑞拉等6个国家 [58]
基于RBD二聚体设计的亚单位疫苗
ZF2001 319~537 a.a. 智飞龙科马/
中国科学院微
生物研究所		 铝佐剂 哺乳动物细胞 获批:中国,哥伦比亚,印度尼西亚等4个国家 [53,74]
Soberana
Plus		 319~541 a.a. 古巴芬利疫苗
研究所		 铝佐剂 哺乳动物细胞 获批:古巴 [60]
基于RBD三聚体设计的亚单位疫苗
NVSI-06-07 319~537 a.a. 中国生物研究院 铝佐剂 哺乳动物细胞 紧急使用:阿联酋 [54]
NVSI-06-08 319~537 a.a.野生型/Beta突变株(K417N/E484K/N501Y)/
Kappa突变株(L452R/E484K)		 中国生物研究院 铝佐剂 哺乳动物细胞 紧急使用:阿联酋 [75]
基于RBD设计的纳米颗粒亚单位疫苗
Soberana 02 319~541 a.a.连接TT蛋白** 古巴芬利疫苗
研究所		 铝佐剂 哺乳动物细胞 获批:伊朗,古巴,尼加拉瓜等4个国家 [76]
基于多肽设计的亚单位疫苗
EpiVac
Corona		 连接SARS-CoV-2 N蛋白的多肽片段* 俄罗斯矢量国家
病毒学与生物
技术研究中心		 铝佐剂 化学合成 获批:柬埔寨,俄罗斯,委内瑞拉等4个国家 [37]
表2  已获批或用于紧急使用的SARS-CoV-2亚单位疫苗
候选疫苗名称 序列及抗原优化 研发单位 佐剂 临床进展 表达系统 参考文献
基于S蛋白设计的亚单位疫苗
COVAC-2 S1* 萨斯喀彻温大学 SWE 2, NCT05209009 / [93]
Versamune-
CoV-2FC		 S1* Farmacore / 1/2, NCT05016934 / [94]
SCB-2019 1~1211 a.a.C端引入三聚化标签 三叶草生物制药/
德纳维制药		 CpG/
铝佐剂		 3, NCT05012787 哺乳动物细胞 [61,78]
S-clamp 1~1204 a.a.将680~690 a.a.替换为GSG,C端引入clamp三聚标签 CSL/Seqirus/
昆士兰大学		 MF59 2/3, NCT04806529 哺乳动物细胞 [67]
CoV2 preS dTM 1~1208 a.a.R682G/R683S/R685S/K986P/V987P,C端连接T4纤维蛋白三聚标签 赛诺菲/
葛兰素史克		 AS03 3, NCT05124171
PACTR202011523101903		 昆虫细胞 [66]
MVC-COV1901** 1~1208 a.a.R682G/R683S/R685S/K986P/V987P,C端连接T4纤维蛋白三聚标签 基亚生物 CpG/
铝佐剂		 4, NCT05079633 哺乳动物细胞 [62,69,117]
202-CoV R682G/R683G/A684S/R685G/K986P/V987P,C端连接T4纤维蛋白三聚标签* 上海泽润生物/
沃森生物		 CpG∕
铝佐剂		 1, NCT04982068 哺乳动物细胞 [64]
YS-SC2-010 1~1208 a.a.R682G/R683S/R685S/K986P/V987P,C端连接T4纤维蛋白三聚标签 依生生物 PIKA 1, ACTRN12621001009808 哺乳动物细胞 [80-81,118]
COVAX-19®
(Spikogen®)**		 ∕* Vaxine/Cinnagen Advax-SM 3, IRCT
20150303021315N24		 昆虫细胞 [68,119]
SCB-2020S Beta突变株* 三叶草生物制药 CAS-1 2, NCT04950751 哺乳动物细胞 [114]
Bivalent
(2-antigen)
vaccine		 野生型及Beta突变株* 赛诺菲∕
葛兰素史克		 ∕ 3, NTC04904549 昆虫细胞 [113]
基于S蛋白设计的纳米颗粒亚单位疫苗
NVX-CoV2373** 1~1273 a.a.R682Q/R683Q/R685Q/K986P/V987P 诺瓦瓦克斯 Matrix-M 3, NCT04611802 昆虫细胞 [65,71,120]
SpFN 12~1158 a.a.R682G/R683S/R685S/K986P/V987P,C端突变修饰并连接铁蛋白 美国沃尔特里德
陆军研究所		 QS-21 1, NCT04784767 哺乳动物细胞 [85,91]
SII B.1.351 Beta突变株* 诺瓦瓦克斯 Matrix-M 1∕2, NCT05029856 昆虫细胞 [112]
SII B.1.617.2 Delta突变株* 诺瓦瓦克斯 Matrix-M 1∕2, NCT05029858 昆虫细胞 [112]
SII Bivalent 野生型及Beta突变株* 诺瓦瓦克斯 Matrix-M 1∕2, NCT05029857 昆虫细胞 [112]
基于RBD单体设计的亚单位疫苗
Recombinant
COVID-19 Vaccine
(Sf9 cells)		 319~545 a.a. 中国四川大学
华西医院		 铝佐剂 3, NCT04887207 昆虫细胞 [98-99]
Abdala
(CIGB-66)**		 331~529 a.a. 古巴基因工程与
生物技术中心		 铝佐剂 3, RPCEC00000359 酵母 [58,97,121]
Corbevax** 332~549 a.a.C538A Biological E CpG∕
铝佐剂		 3, CTRI∕2021∕
08∕036074		 酵母 [63,122]
候选疫苗名称 序列及抗原优化 研发单位 佐剂 临床进展 表达系统 参考文献
基于RBD二聚体设计的亚单位疫苗
Soberana 01 319~541 a.a. 古巴芬利疫
苗研究所		 铝佐剂∕脑
膜炎奈瑟菌
外膜囊泡		 2, RPCEC00000366 哺乳动物细胞 [60]
VAX1 C端连接Fc蛋白* Baiya Phytopharm ∕ 1, NCT04953078 植物细胞 [103]
AKS-452 C端连接Fc蛋白* 格罗宁根大学医
学中心∕Akston		 Montanide
ISA 720		 2, NCT05124483 哺乳动物细胞 [102]
V-01 319~541 a.a.N端连接IFN-α,C端连接Fc蛋白 丽珠医药 铝佐剂 3, NCT05096832 哺乳动物细胞 [56]
UB-612 340~359 a.a.C端连接Fc蛋白,并加入SARS-CoV-2高保守性多肽和公司专利多肽UBITh®1a Vaxxinity CpG∕AlPO4 2∕3, NCT04683224 哺乳动物细胞 [101]
PHH-1V 333~526 a.a.Alpha突变株 (N501Y) 和Beta突变株(K417N∕E484K∕N501Y) Hipra ∕ 3, NCT05246137 哺乳动物细胞 [115]
基于RBD三聚体设计的亚单位疫苗
ReCOV N端连接S蛋白N端结构域,C端连接T4纤维蛋白标签* 瑞科生物 BFA03 2∕3, NCT05084989 哺乳动物细胞 [104]
NVSI-06-08** 319~537 a.a.野生型,Beta突变株(K417N∕E484K∕N501Y)及Kappa突变株(L452R∕E484K) 中国生物研究院 铝佐剂 1∕2, NCT05069129 哺乳动物细胞 [55,123]
基于RBD设计的纳米颗粒亚单位疫苗
Soberana 02** 319~541 a.a.C端连接TT蛋白 古巴芬利疫苗
研究所		 铝佐剂 3, RPCEC00000354 哺乳动物细胞 [76,124]
KBP-201 加入TMV* 美国肯塔基州
生物加工公司		 CpG 1∕2, NCT04473690 烟草植物细胞 [125]
EuCorVac-19 319~541 a.a.加入脂质体 EuBiologics 单磷酸酯
A∕QS-21		 1∕2, NCT04783311 哺乳动物细胞 [106]
GBP510 328~531 a.a.加入I53-50蛋白 SK∕CEPI AS03或
铝佐剂		 3, NCT05007951 哺乳动物细胞 [59]
基于多肽设计的亚单位疫苗
CoVac-1 S235~249∕N50~64, 221~235∕E56~70∕M176~190∕ORF843~57 图宾根大学 XS15∕
Montanide
ISA51 VG		 1∕2, NCT04954469 化学合成 [109]
表3  处于临床研究阶段的主要SARS-CoV-2亚单位疫苗
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