A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS
A Universal Design of Betacoronavirus Vaccines against COVID-19, MERS, and SARS
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DOI：
10.1016/j.cell.2020.06.035
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发表时间：
2020-08-06
期刊：
影响因子：
64.5
通讯作者：
Gao, George F.
中科院分区：
文献类型：
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作者：
Dai, Lianpan;Zheng, Tianyi;Gao, George F.
目前迫切需要疫苗来控制持续的COVID-19大流行和先前出现的由冠状病毒（CoV）感染引起的MERS/ SARS。CoV刺突受体结合域（RBD）是一个有吸引力的疫苗靶点，但受到有限免疫原性的破坏。我们描述了克服这一限制的MERS-CoV RBD的二聚体形式。与常规单体形式相比，RBD-二聚体显著增加中和抗体（NAb）滴度，并保护小鼠免受MERS-CoV感染。晶体结构显示RBD-二聚体完全暴露的双重受体结合基序，NAbs的主要靶点。结构导向设计进一步产生了作为串联重复单链（RBD-sc-二聚体）的RBD-二聚体的稳定形式，其保留了疫苗效力。我们将这一策略推广到设计针对COVID-19和SARS的疫苗，使NAb滴度提高了10至100倍。中试规模生产的RBD-sc-二聚体产生了高产率，支持其用于进一步临床开发的可扩展性。免疫原设计的框架可以普遍应用于其他β-CoV疫苗，以应对新出现的威胁。
Vaccines are urgently needed to control the ongoing pandemic COVID-19 and previously emerging MERS/ SARS caused by coronavirus (CoV) infections. The CoV spike receptor-binding domain (RBD) is an attractive vaccine target but is undermined by limited immunogenicity. We describe a dimeric form of MERS-CoV RBD that overcomes this limitation. The RBD-dimer significantly increased neutralizing antibody (NAb) titers compared to conventional monomeric form and protected mice against MERS-CoV infection. Crystal structure showed RBD-dimer fully exposed dual receptor-binding motifs, the major target for NAbs. Structureguided design further yielded a stable version of RBD-dimer as a tandem repeat single-chain (RBD-sc-dimer) which retained the vaccine potency. We generalized this strategy to design vaccines against COVID-19 and SARS, achieving 10- to 100-fold enhancement of NAb titers. RBD-sc-dimers in pilot scale production yielded high yields, supporting their scalability for further clinical development. The framework of immunogen design can be universally applied to other beta-CoV vaccines to counter emerging threats.