病毒载体疫苗研究进展

doi:10.12211/2096-8280.2023-063

摘要/Abstract

摘要：

近十年来，中东呼吸综合征、埃博拉出血热、寨卡病毒感染、新型冠状病毒肺炎等重大传染性疾病疫情相继出现，对疫苗的快速研发提出重大挑战。其中病毒载体疫苗是新型疫苗研发的重要形式，它可以通过雾化吸入或口服等方式进行无创免疫，在没有佐剂的情况下发挥免疫作用，同时诱导体液、细胞和黏膜免疫反应，具有良好的免疫原性和安全性。随着对病毒基因组和结构蛋白等元件认识的不断深入，利用合成生物学研究思路系统设计、改造病毒载体，从而赋予重组病毒载体疫苗高滴度生产、高安全性和高免疫原性等生物学特征，对疫苗研发具有重要指导意义。本文综述了复制型、非复制型等病毒载体疫苗研发策略，以及具有临床应用价值的疫苗病毒载体，如腺病毒载体、痘病毒载体、水疱性口炎病毒载体等，希望对利用合成生物学进行新型病毒载体疫苗的研发提供一定的参考。未来，病毒载体疫苗必将向着更高的安全性、更强的保护性、更好的依从性、更低的生产成本等方向迭代发展。

关键词: 病毒载体, 传染病, 疫苗, 合成生物学, 改造

Abstract:

Recent outbreaks of infectious diseases, such as the middle east respiratory syndrome, Zika infection, Ebola hemorrhagic fever, and Coronavirus disease (COVID-19) pose significant challenges on the rapid development of efficacious vaccines. Virus-vectored vaccines, as an important new vaccine, can be administrated noninvasively through aerosol inhalation or oral administration, which could stimulate humoral, cellular, and mucosal immune responses without the need for adjuvants, showing good immunogenicity and safety in clinical trials or in emergency use. With the deeper understanding of the viral genome and structural proteins, synthetic biology has enabled the design and modification of viruses to produce recombinant viral vector-based vaccines with high titer, safety, and immunogenicity, and such research has significant implications for the vaccine development. This review highlights major strategies employed in the construction of virus-vectored vaccines, including the construction method of replication-competent or replication-defective viral vectors, and the development of viral vectors commonly used in producing the recombinant vaccines. Among these viral vectors, replication-deficient adenovirus-based vectors with gene deletion in the E1 and E3 regions are most mature for use. Currently, adenoviral vectors that have been used in the approved recombinant vaccines include Ad5, Ad26 and ChAdOx1. Vesicular stomatitis virus and flavivirus with small genomes are negative-sense and positive-sense single-stranded RNA viruses, respectively, which are easy to prepare and more suitable for being used in developing recombinant vaccines with small antigen proteins. Poxviruses and herpesviruses have large genomes for high packing capacity, but they are most difficult to be modified with synthetic biology methods. Different viral vectors need to be prepared using different strategies, and consequently vaccines developed with these vectors have different immune effects. The construction strategies of different viral vector vaccines introduced in this review will provide valuable theoretical reference for the research and development of novel viral vector vaccines. In the future, virus-vectored vaccines will be iteratively developed for higher safety, stronger protection, better compliance and lower production cost. {L-End}

Key words: viral vector, infectious disease, vaccine, synthetic biology, modification

中图分类号:

R373

王步森, 徐婧含, 高智强, 侯利华. 病毒载体疫苗研究进展[J]. 合成生物学, 2024, 5(2): 281-293.

Busen WANG, Jinghan XU, Zhiqiang GAO, Lihua HOU. Advances in virus-vectored vaccines[J]. Synthetic Biology Journal, 2024, 5(2): 281-293.

图/表 2

表1 应用于疫苗开发的主要病毒载体类型

Table 1 Major viral vectors used in vaccine development

病毒种类	基因组					主要型别
病毒种类	类型	长度/kb	容量/kb	是否入核	是否整合	主要型别
腺病毒	DNA	36	7～8	是	否	5型^[14]，35型^[15]，黑猩猩3型^[16]
痘病毒	DNA	170～300	25	否	否	痘苗安卡拉株^[17]，金丝雀痘病毒^[18]
水疱性口炎病毒	RNA	11	4.5	否	否	印第安纳株^[19]，新泽西株^[20]
黄病毒	RNA	10	2	否	否	黄热病毒^[21]，日本脑炎病毒^[22]
疱疹病毒	DNA	140～230	30	是	是	水痘-带状疱疹病毒^[2]，人单纯疱疹病毒^[23]

图1 病毒载体重组疫苗基因组结构［（a）AdV载体疫苗的基因组结构。基因组中的E1和E3区域全部缺失，外源基因表达框可以通过体外剪接嵌入E1缺失位点。（b）MVA载体疫苗的基因组结构。基因组中的胸苷激酶（TK）被设计为转基因插入位点，外源基因表达框可以在细胞中通过同源重组嵌入。（c）VSV载体疫苗的基因组结构。VSV的糖蛋白可以被其他包膜病毒的糖蛋白所替代。（d）YFV载体疫苗的基因组结构。YFV基因组中的prM和E蛋白可以被其他黄病毒的prM或E蛋白所替代。（e）HSV载体疫苗的基因组结构。外源基因表达框可以嵌入病毒基因组中的UL或US区］

Fig. 1 Schematic diagrams for the genome structure of virus-vectored vaccines[(a) Genome structure of AdV-vectored vaccines. The E1 and E3 regions in the genome are all deleted, and the expression cassette can be inserted into the E1 deletion site by splicing in vitro. (b) Genome structure of MVA-based vaccines. The thymidine kinase (TK) in the genome is designed as site for gene insertion, and the expression cassette can be inserted by homologous recombination in the sensitive cells. (c) Genome structure of VSV-based vaccines. The glycoprotein of VSV can be replaced by the glycoprotein from other enveloped viruses. (d) Genome structure of YFV-based vaccines. The prM and E proteins in the YFV genome can be replaced by prM and E proteins from other flaviviruses. (e) Genome structure of HSV-based vaccines. The expression cassettes can be inserted into the UL or US regions in the viral genome.]

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