Humoral immune response to circulating SARS-CoV-2 variants elicited by inactivated and RBD-subunit vaccines
Yunlong Cao, Ayijiang Yisimayi, Yali Bai, Weijin Huang, Xiaofeng Li, Zhiying Zhang, Tianjiao Yuan, Ran An, Jing Wang, Tianhe Xiao, Shuo Du, Wenping Ma, Liyang Song, Yongzheng Li, Xiang Li, Weiliang Song, Jiajing Wu, Shuo Liu, Xuemei Li, Yonghong Zhang, Bin Su, Xianghua Guo, Yangyang Wei, Chuanping Gao, Nana Zhang, Yifei Zhang, Yang Dou, Xiaoyu Xu, Rui Shi, Bai Lu, Ronghua Jin, Yingmin Ma, Chengfeng Qin, Youchun Wang, Yingmei Feng, Junyu Xiao, Xiaoliang Sunney Xie, Yunlong Cao, Ayijiang Yisimayi, Yali Bai, Weijin Huang, Xiaofeng Li, Zhiying Zhang, Tianjiao Yuan, Ran An, Jing Wang, Tianhe Xiao, Shuo Du, Wenping Ma, Liyang Song, Yongzheng Li, Xiang Li, Weiliang Song, Jiajing Wu, Shuo Liu, Xuemei Li, Yonghong Zhang, Bin Su, Xianghua Guo, Yangyang Wei, Chuanping Gao, Nana Zhang, Yifei Zhang, Yang Dou, Xiaoyu Xu, Rui Shi, Bai Lu, Ronghua Jin, Yingmin Ma, Chengfeng Qin, Youchun Wang, Yingmei Feng, Junyu Xiao, Xiaoliang Sunney Xie
Abstract
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.
Conflict of interest statement
The authors declare no competing interests.
Figures
References
- Rambaut, A. et al. Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations. Virological (2020).
- Tegally H, et al. Detection of a SARS-CoV-2 variant of concern in South Africa. Nature. 2021;592:438–443. doi: 10.1038/s41586-021-03402-9.
- Voloch CM, et al. Genomic characterization of a novel SARS-CoV-2 lineage from Rio de Janeiro, Brazil. J. Virol. 2021 doi: 10.1128/jvi.00119-21.
- Wibmer CK, et al. SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. Nat. Med. 2021;27:622–625. doi: 10.1038/s41591-021-01285-x.
- Li Q, et al. SARS-CoV-2 501Y.V2 variants lack higher infectivity but do have immune escape. Cell. 2021;184:2362–2371. doi: 10.1016/j.cell.2021.02.042.
- Phillips N, Cyranoski D, Mallapaty S. A leading coronavirus vaccine trial is on hold: scientists react. Nature. 2020 doi: 10.1038/d41586-020-02594-w.
- Callaway E, Mallapaty S. Novavax offers first evidence that COVID vaccines protect people against variants. Nature. 2021;590:17. doi: 10.1038/d41586-021-00268-9.
- Zhou D, et al. Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera. Cell. 2021;184:2348–2361. doi: 10.1016/j.cell.2021.02.037.
- Wang Z, et al. mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants. Nature. 2021;592:616–622. doi: 10.1038/s41586-021-03324-6.
- Wu Z, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect. Dis. 2021 doi: 10.1016/S1473-3099(20)30987-7.
- Yang S, et al. Safety and immunogenicity of a recombinant tandem-repeat dimeric RBD protein vaccine against COVID-19 in adults: Pooled analysis of two randomized, double-blind, placebo-controlled, phase 1 and 2 trials. Lancet Infect. Dis. 2021 doi: 10.1016/S1473-3099(21)00127-4.
- Dai L, et al. A universal design of betacoronavirus vaccines against COVID-19, MERS, and SARS. Cell. 2020;182:722–733. doi: 10.1016/j.cell.2020.06.035.
- Cao Y, et al. Potent neutralizing antibodies against SARS-CoV-2 identified by high-throughput single-cell sequencing of convalescent patients’ B cells. Cell. 2020;182:73–84. doi: 10.1016/j.cell.2020.05.025.
- Liu L, et al. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike. Nature. 2020;584:450–456. doi: 10.1038/s41586-020-2571-7.
- Cerutti G, et al. Potent SARS-CoV-2 neutralizing antibodies directed against spike N-terminal domain target a single supersite. Cell Host Microbe. 2021;29:819–833. doi: 10.1016/j.chom.2021.03.005.
- Chi X, et al. A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2. Science. 2020;369:650–655. doi: 10.1126/science.abc6952.
- Wang N, et al. Structure-based development of human antibody cocktails against SARS-CoV-2. Cell Res. 2021;31:101–103. doi: 10.1038/s41422-020-00446-w.
- McCallum M, et al. N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2. Cell. 2021;184:2332–2347. doi: 10.1016/j.cell.2021.03.028.
- Du S, et al. Structurally resolved SARS-CoV-2 antibody shows high efficacy in severely infected hamsters and provides a potent cocktail pairing strategy. Cell. 2020;183:1013–1023. doi: 10.1016/j.cell.2020.09.035.
- Barnes CO, et al. Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies. Cell. 2020;182:828–842. doi: 10.1016/j.cell.2020.06.025.
- Yuan M, et al. Structural basis of a shared antibody response to SARS-CoV-2. Science. 2020;369:1119–1123. doi: 10.1126/science.abd2321.
- Barnes CO, et al. SARS-CoV-2 neutralizing antibody structures inform therapeutic strategies. Nature. 2020;588:682–687. doi: 10.1038/s41586-020-2852-1.
- Wu NC, et al. An alternative binding mode of IGHV3-53 antibodies to the SARS-CoV-2 receptor binding domain. Cell Rep. 2020;33:108274. doi: 10.1016/j.celrep.2020.108274.
- Gaebler C, et al. Evolution of antibody immunity to SARS-CoV-2. Nature. 2021;591:639–644. doi: 10.1038/s41586-021-03207-w.
- Starr TN, et al. Prospective mapping of viral mutations that escape antibodies used to treat COVID-19. Science. 2021;371:850–854. doi: 10.1126/science.abf9302.
- Wang P, et al. Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7. Nature. 2021;593:130–135. doi: 10.1038/s41586-021-03398-2.
- Qu, L. et al. Circular RNA vaccines against SARS-CoV-2 and emerging variants. bioRxiv10.1101/2021.03.16.435594 (2021).
- Nie J, et al. Establishment and validation of a pseudovirus neutralization assay for SARS-CoV-2. Emerg. Microbes Infect. 2020;9:680–686. doi: 10.1080/22221751.2020.1743767.
- McCoy AJ, et al. Phaser crystallographic software. J. Appl. Crystallogr. 2007;40:658–674. doi: 10.1107/S0021889807021206.
- Liebschner D, et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D Struct. Biol. 2019;75:861–877. doi: 10.1107/S2059798319011471.
- Emsley P, Lohkamp B, Scott WG, Cowtan K. Features and development of Coot. Acta Crystallogr. D Biol. Crystallogr. 2010;66:486–501. doi: 10.1107/S0907444910007493.
- Mastronarde DN. Automated electron microscope tomography using robust prediction of specimen movements. J. Struct. Biol. 2005;152:36–51. doi: 10.1016/j.jsb.2005.07.007.
- Zheng SQ, et al. MotionCor2: anisotropic correction of beam-induced motion for improved cryo-electron microscopy. Nat. Methods. 2017;14:331–332. doi: 10.1038/nmeth.4193.
- Rohou A, Grigorieff N. CTFFIND4: fast and accurate defocus estimation from electron micrographs. J. Struct. Biol. 2015;192:216–221. doi: 10.1016/j.jsb.2015.08.008.
- Zivanov J, et al. New tools for automated high-resolution cryo-EM structure determination in RELION-3. Elife. 2018;7:e42166. doi: 10.7554/eLife.42166.
- Pettersen EF, et al. UCSF Chimera — a visualization system for exploratory research and analysis. J. Comput. Chem. 2004;25:1605–1612. doi: 10.1002/jcc.20084.
- Stuart T, et al. Comprehensive integration of single-cell data. Cell. 2019;177:1888–1902. doi: 10.1016/j.cell.2019.05.031.
- Aran D, et al. Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. Nat. Immunol. 2019;20:163–172. doi: 10.1038/s41590-018-0276-y.
- Monaco G, et al. RNA-Seq signatures normalized by mRNA abundance allow absolute deconvolution of human immune cell types. Cell Rep. 2019;26:1627–1640. doi: 10.1016/j.celrep.2019.01.041.
Source: PubMed