Structural basis of a shared antibody response to SARS-CoV-2

Yuan, Meng; Liu, Hejun; Wu, Nicholas C.; Lee, Chang-Chun David; Zhu, Xueyong; Zhao, Fangzhu; Huang, Deli; Yu, Wenli; Hua, Yuanzi; Tien, Henry J; Rogers, Thomas F.; Landais, Elise; Sok, Devin; Jardine, Joseph G.; Burton, Dennis R.; Wilson, Ian A.

doi:10.1126/science.abd2321

Cited by 610 publications

(885 citation statements)

References 50 publications

(81 reference statements)

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“…There are situations that are anticipated to increase the frequency of encounters between SARS-CoV-2 and antibodies that could impact the emergence of antibody resistance. (3,18,19). These findings imply a degree of homogeneity the among neutralizing antibodies that are generated in different individuals.…”

Section: Discussionmentioning

confidence: 80%

“…The low levels of somatic hypermutation and repetitive manner in which similar antibodies (e.g. those based on IGHV3-53 (3,18,19) have been isolated from COVID19 convalescents suggests that potently neutralizing responses should be readily elicited. Paradoxically, a significant fraction of COVID19 convalescents, including some from whom potent neutralizing antibodies have been cloned, exhibit low levels of plasma neutralizing activity (3,20,21).…”

Section: Introductionmentioning

confidence: 99%

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Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

Weisblum

Schmidt

Zhang

et al. 2020

Preprint

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Neutralizing antibodies elicited by prior infection or vaccination are likely to be key for future protection of individuals and populations against SARS-CoV-2. Moreover, passively administered antibodies are among the most promising therapeutic and prophylactic anti-SARS-CoV-2 agents. However, the degree to which SARS-CoV-2 will adapt to evade neutralizing antibodies is unclear. Using a recombinant chimeric VSV/SARS-CoV-2 reporter virus, we show that functional SARS-CoV-2 S protein variants with mutations in the receptor binding domain (RBD) and N-terminal domain that confer resistance to monoclonal antibodies or convalescent plasma can be readily selected. Notably, SARS-CoV-2 S variants that resist commonly elicited neutralizing antibodies are now present at low frequencies in circulating SARS-CoV-2 populations. Finally, the emergence of antibody-resistant SARS-CoV-2 variants that might limit the therapeutic usefulness of monoclonal antibodies can be mitigated by the use of antibody combinations that target distinct neutralizing epitopes.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

Weisblum

Schmidt

Zhang

et al. 2020

Preprint

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“…We found that the majority of the ACE2 blocking antibodies-including CB6 16 , B38 17 , CV30 18 , CC 12.1 19 , CC 12.3 19 and REGN10933 14 -adopt a similar orientation when bound to RBD. Each of these antibodies belong to the immunoglobulin heavy chain variable region genes (IGHV) 3 germline that is the most frequently used IGHV gene among the known SARS-CoV-2 neutralizing antibodies 22 . The neutralizing antibody P2B-2F6 15 which is based on the IGHV4-38 gene, on the other hand, interacts with RBD at about a 90 degree angle from the previous group.…”

Section: Discussionmentioning

confidence: 99%

A Novel Neutralizing Antibody Targeting Receptor Binding Domain of SARS-CoV-2

Lee

Kim

Ryu

et al. 2020

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the current COVID-19 global pandemic. Vaccines and therapeutics are urgently needed for this highly transmissible virus. In this study, we screened human monoclonal antibodies (mAbs) targeting the receptor binding domain (RBD) of the SARS-CoV-2 spike protein from an antibody library constructed from peripheral blood mononuclear cells of a COVID-19 convalescent patient. A potent neutralizing antibody, termed CT-P59, was identified and found to be effective against various SARS-CoV-2 isolates including the D614G spike protein variant without antibody-dependent enhancement effect. Complex crystal structure of CT-P59 Fab/SARS-CoV-2 RBD showed that CT-P59 blocks interaction regions of SARS-CoV-2 RBD for its cellular receptor, angiotensin converting enzyme 2 (ACE2). The binding orientation of CT-P59 is notably different from the previously reported neutralizing mAbs targeting SARS-CoV-2 RBD suggesting that CT-P59 can be a novel binder to SARS-CoV-2 RBD. Therapeutic effects of CT-P59 were evaluated in three animal models (ferret, hamster, and rhesus monkey), and a substantial reduction in viral titre along with alleviation of clinical symptoms was observed. These findings suggest that the human monoclonal antibody, CT-P59, is a promising therapeutic candidate for treatment of COVID-19.

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“…Antibody EY6A (6zdh.pdb) binds the RBD in the region of the cryptic epitope described by Wilson and collaborators 35 (Figure 4). Importantly, our predicted patch (365)YSVLYN(370)-(384)PTKLN(388) covers a significant part of the epitope.…”

Section: A B D E Cmentioning

confidence: 91%

“…On the one hand, this may be important considering the fact that RBD can also be the target on non-neutralizing antibodies, e.g. 3022 35 . Indeed, using cocktails of antibodies to target different regions of S has recently been proposed as a viable therapeutic option 36 .…”

Section: A B D E Cmentioning

confidence: 99%

The answer lies in the energy: how simple atomistic molecular dynamics simulations may hold the key to epitope prediction on the fully glycosylated SARS-CoV-2 spike protein

Serapian

Marchetti

Triveri

et al. 2020

Preprint

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Betacoronavirus SARS-CoV-2 is posing a major threat to human health and its diffusion around the world is having dire socioeconomical consequences. Thanks to the scientific community’s unprecedented efforts, the atomic structure of several viral proteins has been promptly resolved. As the crucial mediator of host cell infection, the heavily glycosylated trimeric viral Spike protein (S) has been attracting the most attention and is at the center of efforts to develop antivirals, vaccines, and diagnostic solutions.Herein, we use an energy-decomposition approach to identify antigenic domains and antibody binding sites on the fully glycosylated S protein. Crucially, all that is required by our method are unbiased atomistic molecular dynamics simulations; no prior knowledge of binding properties or ad hoc combinations of parameters/measures extracted from simulations is needed. Our method simply exploits the analysis of energy interactions between all intra-protomer aminoacid and monosaccharide residue pairs, and cross-compares them with structural information (i.e., residueresidue proximity), identifying potential immunogenic regions as those groups of spatially contiguous residues with poor energetic coupling to the rest of the protein.Our results are validated by several experimentally confirmed structures of the S protein in complex with anti- or nanobodies. We identify poorly coupled sub-domains: on the one hand this indicates their role in hosting (several) epitopes, and on the other hand indicates their involvement in large functional conformational transitions. Finally, we detect two distinct behaviors of the glycan shield: glycans with stronger energetic coupling are structurally relevant and protect underlying peptidic epitopes; those with weaker coupling could themselves be poised for antibody recognition. Predicted Immunoreactive regions can be used to develop optimized antigens (recombinant subdomains, synthetic (glyco)peptidomimetics) for therapeutic applications.

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Structural basis of a shared antibody response to SARS-CoV-2

Cited by 610 publications

References 50 publications

Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants

A Novel Neutralizing Antibody Targeting Receptor Binding Domain of SARS-CoV-2

The answer lies in the energy: how simple atomistic molecular dynamics simulations may hold the key to epitope prediction on the fully glycosylated SARS-CoV-2 spike protein

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