Volume 31, No 7, Jul 2021

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 31 Issue 7, July 2021: 732-741   |  Open Access

ORIGINAL ARTICLES

Humoral immune response to circulating SARS-CoV-2 variants elicited by inactivated and RBD-subunit vaccines

Yunlong Cao^1,2,* , Ayijiang Yisimayi^1,2,3 , Yali Bai^1,4 , Weijin Huang⁵ , Xiaofeng Li⁶ , 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 Wu⁵ , Shuo Liu⁵ , Xuemei Li⁸ , Yonghong Zhang⁸ , Bin Su⁸ , Xianghua Guo⁸ , Yangyang Wei^1,7 , Chuanping Gao^1,3 , Nana Zhang⁶ , Yifei Zhang⁶ , Yang Dou⁹ , Xiaoyu Xu¹⁰ , Rui Shi¹¹ , Bai Lu⁹ , Ronghua Jin¹² , Yingmin Ma⁸ , Chengfeng Qin^6,* , Youchun Wang^5,* , Yingmei Feng^8,* , Junyu Xiao^1,3,* , Xiaoliang Sunney Xie^1,2,3,*

¹Beijing Advanced Innovation Center for Genomics (ICG), Peking University, Beijing, China
²Biomedical Pioneering Innovation Center (BIOPIC), Peking University, Beijing, China
³School of Life Sciences, Peking University, Beijing, China
⁴Joint Graduate Program of Peking-Tsinghua-NIBS, School of Life Sciences, Tsinghua University, Beijing, China
⁵Division of HIV/AIDS and Sex-transmitted Virus Vaccines, Institute for Biological Product Control, National Institutes for Food and Drug Control (NIFDC) and WHO Collaborating Center for Standardization and Evaluation of Biologicals, Beijing, China
⁶State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Academy of Military Medical Sciences, Beijing, China
⁷Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, China
⁸Beijing Youan Hospital, Capital Medical University, Beijing, China
⁹School of Pharmaceutical Sciences, IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China
¹⁰Vazyme Biotech Co., Ltd, Nanjing, Jiangsu, China
¹¹CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China
¹²Beijing Ditan Hospital, Capital Medical University, Beijing, China
These authors contributed equally: Yunlong Cao, Ayijiang Yisimayi, Yali Bai, Weijin Huang, Xiaofeng Li, Zhiying Zhang, Tianjiao Yuan Correspondence: Yunlong Cao(yunlongcao@pku.edu.cn)Chengfeng Qin(qincf@bmi.ac.cn)Youchun Wang(wangyc@nifdc.org.cn)Yingmei Feng(yingmeif13@sina.com)Junyu Xiao(junyuxiao@pku.edu.cn)Xiaoliang Sunney Xie(sunneyxie@biopic.pku.edu.cn)

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.

https://doi.org/10.1038/s41422-021-00514-9

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