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Humoral immune response to circulating SARS-CoV-2 variants elicited by inactivated and RBD-subunit vaccines
Cell Research ( IF 44.1 ) Pub Date : 2021-05-21 , DOI: 10.1038/s41422-021-00514-9
Yunlong Cao 1, 2 , Ayijiang Yisimayi 1, 2, 3 , Yali Bai 1, 4 , Weijin Huang 5 , Xiaofeng Li 6 , Zhiying Zhang 1, 3 , Tianjiao Yuan 1, 2, 3 , Ran An 1, 2 , Jing Wang 1, 2, 3 , Tianhe Xiao 1, 2, 7 , Shuo Du 1, 3 , Wenping Ma 1, 2, 7 , Liyang Song 1, 2, 7 , Yongzheng Li 1, 2 , Xiang Li 1, 2, 7 , Weiliang Song 1, 2, 3 , Jiajing Wu 5 , Shuo Liu 5 , Xuemei Li 8 , Yonghong Zhang 8 , Bin Su 8 , Xianghua Guo 8 , Yangyang Wei 1, 7 , Chuanping Gao 1, 3 , Nana Zhang 6 , Yifei Zhang 6 , Yang Dou 9 , Xiaoyu Xu 10 , Rui Shi 11 , Bai Lu 9 , Ronghua Jin 12 , Yingmin Ma 8 , Chengfeng Qin 6 , Youchun Wang 5 , Yingmei Feng 8 , Junyu Xiao 1, 3 , Xiaoliang Sunney Xie 1, 2, 3
Affiliation  

SARS-CoV-2 variants could induce immune escape by mutations on the receptor-binding domain (RBD) and N-terminal domain (NTD). Here we report the humoral immune response to circulating SARS-CoV-2 variants, such as 501Y.V2 (B.1.351), of the plasma and neutralizing antibodies (NAbs) elicited by CoronaVac (inactivated vaccine), ZF2001 (RBD-subunit vaccine) and natural infection. Among 86 potent NAbs identified by high-throughput single-cell VDJ sequencing of peripheral blood mononuclear cells from vaccinees and convalescents, near half anti-RBD NAbs showed major neutralization reductions against the K417N/E484K/N501Y mutation combination, with E484K being the dominant cause. VH3-53/VH3-66 recurrent antibodies respond differently to RBD variants, and K417N compromises the majority of neutralizing activity through reduced polar contacts with complementarity determining regions. In contrast, the 242–244 deletion (242–244Δ) would abolish most neutralization activity of anti-NTD NAbs by interrupting the conformation of NTD antigenic supersite, indicating a much less diversity of anti-NTD NAbs than anti-RBD NAbs. Plasma of convalescents and CoronaVac vaccinees displayed comparable neutralization reductions against pseudo- and authentic 501Y.V2 variants, mainly caused by E484K/N501Y and 242–244Δ, with the effects being additive. Importantly, RBD-subunit vaccinees exhibit markedly higher tolerance to 501Y.V2 than convalescents, since the elicited anti-RBD NAbs display a high diversity and are unaffected by NTD mutations. Moreover, an extended gap between the third and second doses of ZF2001 leads to better neutralizing activity and tolerance to 501Y.V2 than the standard three-dose administration. Together, these results suggest that the deployment of RBD-vaccines, through a third-dose boost, may be ideal for combating SARS-CoV-2 variants when necessary, especially for those carrying mutations that disrupt the NTD supersite.



中文翻译:

灭活疫苗和 RBD 亚单位疫苗引发的对循环 SARS-CoV-2 变体的体液免疫反应

SARS-CoV-2 变体可通过受体结合域 (RBD) 和 N 端域 (NTD) 上的突变诱导免疫逃逸。在这里,我们报告了 CoronaVac(灭活疫苗)、ZF2001(RBD 亚单位疫苗)引发的血浆和中和抗体 (NAb) 对循环 SARS-CoV-2 变体(例如 501Y.V2 (B.1.351))的体液免疫反应) 和自然感染。在通过对来自疫苗接种者和恢复期的外周血单个核细胞的高通量单细胞 VDJ 测序鉴定的 86 种有效 NAb 中,近一半的抗 RBD NAb 显示出对 K417N/E484K/N501Y 突变组合的主要中和减少,其中 E484K 是主要原因. VH3-53/VH3-66 复发性抗体对 RBD 变体的反应不同,K417N 通过减少与互补决定区的极性接触来损害大部分中和活性。相比之下,242-244 缺失(242-244Δ)将通过中断 NTD 抗原超位点的构象来消除抗 NTD NAb 的大部分中和活性,表明抗 NTD NAb 的多样性远低于抗 RBD NAb。恢复期和 CoronaVac 疫苗接种者的血浆显示出与假性和真正的 501Y.V2 变体相当的中和减少,主要由 E484K/N501Y 和 242-244Δ 引起,效果是累加的。重要的是,RBD 亚基疫苗接种者对 501Y.V2 的耐受性明显高于恢复期,因为引发的抗 RBD NAb 显示出高度的多样性并且不受 NTD 突变的影响。而且,与标准的三剂给药相比,第三剂和第二剂 ZF2001 之间的延长间隔导致更好的中和活性和对 501Y.V2 的耐受性。总之,这些结果表明,在必要时通过第三剂加强部署 RBD 疫苗可能是对抗 SARS-CoV-2 变体的理想选择,特别是对于那些携带破坏 NTD 超级位点的突变的人。

更新日期:2021-05-22
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