Molecular basis of Ad5-nCoV vaccine-induced immunogenicity

IF 4.3 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Structure Pub Date : 2025-03-19 DOI:10.1016/j.str.2025.02.009

Dongyang Dong, Yutong Song, Shipo Wu, Busen Wang, Cheng Peng, Weiping Zhang, Weizheng Kong, Zheyuan Zhang, Jingwen Song, Li-Hua Hou, Sai Li

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Abstract

Ad5-nCoV (Convidecia) is listed for emergency use against COVID-19 by the World Health Organization (WHO) and has been globally administered to millions of people. It utilizes human adenovirus 5 (Ad5) replication-incompetent vector to deliver the spike (S) protein gene from various SARS-CoV-2 strains. Despite promising clinical data, the molecular mechanism underlying its high immunogenicity and adverse reactions remain incompletely understood. Here, we primarily applied cryo-electron tomography (cryo-ET), fluorescence microscopy and mass spectrometry to analyze the Ad5-nCoV_Wu and Ad5-nCoV_O vaccine-induced S antigens. These antigens encode the unmodified SARS-CoV-2 Wuhan-Hu-1 S gene and the stabilized Omicron S gene, respectively. Our findings highlight the structural integrity, antigenicity, and dense distribution on cell membrane of the vaccine-induced S proteins. Ad5-nCoV_O induced S proteins exhibit improved stability and reduced syncytia formation among inoculated cells. Our work demonstrates that Ad5-nCoV is a prominent platform for antigen induction and cryo-ET can be a useful technique for vaccine characterization and development.

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Ad5-nCoV疫苗诱导免疫原性的分子基础

Ad5-nCoV （Convidecia）被世界卫生组织（世卫组织）列为针对COVID-19的紧急使用药物，并已在全球范围内对数百万人进行了治疗。该方法利用人腺病毒5 （Ad5）复制能力不强的载体，将不同SARS-CoV-2毒株的刺突(S)蛋白基因传递到体外。尽管有很好的临床数据，但其高免疫原性和不良反应的分子机制仍不完全清楚。本研究主要应用冷冻电子断层扫描（cryo-ET）、荧光显微镜和质谱分析了Ad5-nCoV_Wu和Ad5-nCoV_O疫苗诱导的S抗原。这些抗原分别编码未修饰的SARS-CoV-2武汉-1 - S基因和稳定的Omicron S基因。我们的发现强调了疫苗诱导的S蛋白的结构完整性、抗原性和在细胞膜上的密集分布。Ad5-nCoV_O诱导的S蛋白在接种细胞中表现出更高的稳定性和更少的合胞体形成。我们的工作表明，Ad5-nCoV是抗原诱导的一个重要平台，冷冻- et可以作为一种有用的疫苗表征和开发技术。

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来源期刊

Structure 生物-生化与分子生物学

CiteScore

8.90

自引率

1.80%

发文量

155

审稿时长

3-8 weeks

期刊介绍： Structure aims to publish papers of exceptional interest in the field of structural biology. The journal strives to be essential reading for structural biologists, as well as biologists and biochemists that are interested in macromolecular structure and function. Structure strongly encourages the submission of manuscripts that present structural and molecular insights into biological function and mechanism. Other reports that address fundamental questions in structural biology, such as structure-based examinations of protein evolution, folding, and/or design, will also be considered. We will consider the application of any method, experimental or computational, at high or low resolution, to conduct structural investigations, as long as the method is appropriate for the biological, functional, and mechanistic question(s) being addressed. Likewise, reports describing single-molecule analysis of biological mechanisms are welcome. In general, the editors encourage submission of experimental structural studies that are enriched by an analysis of structure-activity relationships and will not consider studies that solely report structural information unless the structure or analysis is of exceptional and broad interest. Studies reporting only homology models, de novo models, or molecular dynamics simulations are also discouraged unless the models are informed by or validated by novel experimental data; rationalization of a large body of existing experimental evidence and making testable predictions based on a model or simulation is often not considered sufficient.