Mapping cross-variant neutralizing sites on the SARS-CoV-2 spike protein

Xu, Shiqi; Wang, Yanxing; Zhang, Chao; Qin, Hong; Gu, Cheng; Xu, Rong; Wang, Tingfeng; Yang, Yong; Zang, Jinkai; Zhou, Yu; Li, Zuyang; Liu, Qixing; Zhou, Bingjie; Bai, Lulu; Zhu, Yuanfei; Deng, Qiang; Wang, Haikun; Lavillette, Dimitri; Wong, Gary; Xie, Youhua; Yao, Cong; Huang, Zijian

doi:10.1080/22221751.2021.2024455

Cited by 23 publications

(26 citation statements)

References 66 publications

(90 reference statements)

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“…The SD1 region targeted by S3H3 is extremely conserved among SARS-CoV-2 variants (Fig. 4f), thus explaining the cross-neutralization ability of S3H3 towards Omicron, Delta and other variants 46 . These findings also suggest a possibility to design SD1-based broad-spectrum SARS-CoV-2 vaccines.…”

Section: Discussionmentioning

confidence: 99%

“…We found that Omicron could escape three RBD antibodies, including 8D3, S5D2 and 3C1 (refs. 45,46 ). Both 8D3 and S5D2 are class 1 RBD antibodies and they share similar epitopes centred around loop [477][478][479][480][481][482][483][484][485][486][487][488][489] (refs.…”

Section: Discussionmentioning

confidence: 99%

“…Both 8D3 and S5D2 are class 1 RBD antibodies and they share similar epitopes centred around loop [477][478][479][480][481][482][483][484][485][486][487][488][489] (refs. 31,46 ). Docking of the RBD-bound 8D3 or S5D2 Fab structures 31,46 onto the Omicron RBD-1 structure revealed that several Omicron residues, especially S477N, may potentially clash with the 8D3 Fab (Extended Data Fig.…”

Section: Discussionmentioning

confidence: 99%

“…We compared five previously generated mAbs-2H2, 3C1, 8D3, S5D2 and S3H3 (refs. 45,46 )-for neutralization of the WT (Wuhan-Hu-1 strain), Delta or Omicron pseudoviruses (Fig. 3a, b).…”

Section: Omicron Sensitivity To Neutralizing Mabsmentioning

confidence: 99%

“…The mAb S3H3 is a unique neutralizing antibody that binds to the SD1 region of the WT S 46 log 10 antigen concentration (μg ml -1 ) log 10 antigen concentration (μg ml -1 ) log 10 antigen concentration (μg ml -1 ) log 10 antigen concentration (μg ml -1 ) log 10 antigen concentration (μg ml -1 ) WT S…”

Section: Structure Of the Omicron S-s3h3 Complexmentioning

confidence: 99%

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Molecular basis of receptor binding and antibody neutralization of Omicron

Qin

Han

et al. 2022

Nature

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The SARS-CoV-2 Omicron variant exhibits striking immune evasion and is spreading rapidly worldwide. Understanding the structural basis of the high transmissibility and enhanced immune evasion of Omicron is of high importance. Here, using cryo-electron microscopy, we present both the closed and the open states of the Omicron spike (S) protein, which appear more compact than the counterparts of the G614 strain 1 , potentially related to enhanced inter-protomer and S1-S2 interactions induced by Omicron residue substitution. The closed state showing dominant population may indicate a conformational masking mechanism for the immune evasion of Omicron. Moreover, we captured three states for the Omicron S-ACE2 complex, revealing that the substitutions on the Omicron RBM result in new salt bridges and hydrogen bonds, more favourable electrostatic surface properties, and an overall strengthened S-ACE2 interaction, in line with the observed higher ACE2 affinity of Omicron S than of G614. Furthermore, we determined the structures of Omicron S in complex with the Fab of S3H3, an antibody that is able to cross-neutralize major variants of concern including Omicron, elucidating the structural basis for S3H3-mediated broad-spectrum neutralization. Our findings shed light on the receptor engagement and antibody neutralization or evasion of Omicron and may also inform the design of broadly effective vaccines against SARS-CoV-2.Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has undergone considerable evolution since its initial discovery, leading to the emergence of several variants of concern (VOCs) including Alpha 2-6 , Beta 5-10 , Gamma 11 and Delta 12,13 . These variants that have multiple mutations on their S protein show enhanced transmissibility and resistance to antibody neutralization 13 . Recently, a new variant named Omicron (B.1.1.529), which was first reported in South Africa in November 2021, was classified as the fifth VOC by the World Health Organization (WHO) 14 . Omicron bears 37 mutations in its S protein relative to the original SARS-CoV-2 strain 15,16 . As a consequence, Omicron has been observed to extensively escape neutralization by previously developed neutralizing monoclonal antibodies (mAbs) or sera from vaccinated or convalescent individuals 15,[17][18][19][20][21][22] . Among all of the Omicron S mutations, 15 are present in the receptor-binding domain (RBD) that mediates binding of the virus to its host cell receptor, angiotensin-converting enzyme 2 (ACE2), which is also a major target for neutralizing antibodies [23][24][25][26][27] . However, Omicron still uses ACE2 as its entry receptor 22 . Moreover, the Omicron S appears to have an increased binding affinity to ACE2 relative to the wild-type (WT) S 15,16,28 .The high transmissibility and greatly enhanced resistance to antibody neutralization observed for Omicron makes this VOC particularly threatening. Therefore, further understanding of the nature of Omicron is of substantial importance and may help in developing countermeasures ag...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…We compared five previously generated mAbs-2H2, 3C1, 8D3, S5D2 and S3H3 (refs. 45,46 )-for neutralization of the WT (Wuhan-Hu-1 strain), Delta or Omicron pseudoviruses (Fig. 3a, b).…”

Section: Omicron Sensitivity To Neutralizing Mabsmentioning

confidence: 99%

Section: Structure Of the Omicron S-s3h3 Complexmentioning

confidence: 99%

See 3 more Smart Citations

Molecular basis of receptor binding and antibody neutralization of Omicron

Qin

Han

et al. 2022

Nature

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165

149

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Broad strategies for neutralizing SARS-CoV-2 and other human coronaviruses with monoclonal antibodies

Ling

Yi²,

Sun³

et al. 2022

Sci. China Life Sci.

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Antibody therapeutics and vaccines for coronavirus disease 2019 (COVID-19) have been approved in many countries, with most being developed based on the original strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 has an exceptional ability to mutate under the pressure of host immunity, especially the immune-dominant spike protein of the virus, which is the target of both antibody drugs and vaccines. Given the continuous evolution of the virus and the identification of critical mutation sites, the World Health Organization (WHO) has named 5 variants of concern (VOCs): 4 are previously circulating VOCs, and 1 is currently circulating (Omicron). Due to multiple mutations in the spike protein, the recently emerged Omicron and descendent lineages have been shown to have the strongest ability to evade the neutralizing antibody (NAb) effects of current antibody drugs and vaccines. The development and characterization of broadly neutralizing antibodies (bNAbs) will provide broad strategies for the control of the sophisticated virus SARS-CoV-2. In this review, we describe how the virus evolves to escape NAbs and the potential neutralization mechanisms that associated with bNAbs. We also summarize progress in the development of bNAbs against SARS-CoV-2, human coronaviruses (CoVs) and other emerging pathogens and highlight their scientific and clinical significance.

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