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广谱 RBD 三聚体疫苗可中和包括奥密克戎亚变种 XBB/BQ.1.1/BF.7 在内的 SARS-CoV-2。

Broad protective RBD heterotrimer vaccines neutralize SARS-CoV-2 including Omicron sub-variants XBB/BQ.1.1/BF.7.

机构信息

CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.

Savaid Medical School, University of Chinese Academy of Sciences, Beijing, China.

出版信息

PLoS Pathog. 2023 Sep 18;19(9):e1011659. doi: 10.1371/journal.ppat.1011659. eCollection 2023 Sep.

DOI:10.1371/journal.ppat.1011659
PMID:37721934
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10538664/
Abstract

SARS-CoV-2 variants with severe immune evasion are a major challenge for COVID-19 prevention, especially the circulating Omicron XBB/BQ.1.1/BF.7 strains. Thus, the next-generation of broad-spectrum vaccines are urgently needed. Previously, we developed a COVID-19 protein subunit vaccine, ZF2001, based on the RBD-homodimer as the immunogen. To adapt SARS-CoV-2 variants, we developed chimeric RBD-heterodimers to induce broad immune responses. In this study, we further explored the concept of tandem RBD homotrimer and heterotrimer. Prototype SARS-CoV-2 RBD-homotrimer, prototype-Delta-BA.1 (PDO) RBD-heterotrimer and Delta-BA.2-BA.5 (DBA2BA5) RBD-heterotrimer were designed. Biochemical and cryo-EM structural characterization demonstrated total epitope exposure of the RBD-trimers. In mouse experiments, PDO and DBA2BA5 elicited broad SARS-CoV-2 neutralization. Potent protection against SARS-CoV-2 variants was observed in challenge assays and was correlated with neutralizing antibody titer. This study validated the design strategy of tandem RBD-heterotrimers as multivalent immunogens and presented a promising vaccine candidate, DBA2BA5, eliciting broad-spectrum immune responses, including against the circulating XBB/BF.7/BQ.1.1.

摘要

严重免疫逃避的 SARS-CoV-2 变体是 COVID-19 预防的主要挑战，特别是循环的奥密克戎 XBB/BQ.1.1/BF.7 株。因此，迫切需要下一代广谱疫苗。先前，我们基于 RBD-同源二聚体作为免疫原开发了一种 COVID-19 蛋白亚单位疫苗 ZF2001。为了适应 SARS-CoV-2 变体，我们开发了嵌合 RBD-异源二聚体以诱导广泛的免疫反应。在这项研究中，我们进一步探讨了串联 RBD 同源三聚体和异源三聚体的概念。设计了原型 SARS-CoV-2 RBD-同源三聚体、原型-德尔塔-BA.1（PDO）RBD-异源三聚体和德尔塔-BA.2-BA.5（DBA2BA5）RBD-异源三聚体。生化和 cryo-EM 结构表征表明 RBD-三聚体完全暴露了表位。在小鼠实验中，PDO 和 DBA2BA5 引发了广泛的 SARS-CoV-2 中和。在挑战试验中观察到对 SARS-CoV-2 变体的有效保护作用，并与中和抗体滴度相关。这项研究验证了串联 RBD-异源三聚体作为多价免疫原的设计策略，并提出了一种有前途的候选疫苗 DBA2BA5，它能引发广谱免疫反应，包括对流行的 XBB/BF.7/BQ.1.1。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/d5e8bd3185a7/ppat.1011659.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/feeeed428db5/ppat.1011659.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/14602b1cd18e/ppat.1011659.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/ba90842bfc83/ppat.1011659.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/e2eab7e300ad/ppat.1011659.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/e4a4f92cf46c/ppat.1011659.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/d5e8bd3185a7/ppat.1011659.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/feeeed428db5/ppat.1011659.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/14602b1cd18e/ppat.1011659.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/ba90842bfc83/ppat.1011659.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/e2eab7e300ad/ppat.1011659.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/e4a4f92cf46c/ppat.1011659.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/ba5f/10538664/d5e8bd3185a7/ppat.1011659.g006.jpg

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