Binding and neutralizing abilities of antibodies towards SARS-CoV-2 S2 domain

Gao, Xingsu; Li, Fan; Zheng, Binyang; Li, Haoze; Wang, Jiwei; Zhang, Li; Li, Jingxin; Zhu, Fengcai

doi:10.1080/21645515.2022.2055373

Cited by 4 publications

(5 citation statements)

References 52 publications

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“…We have identified a mAb, C20.119, that targets a linear epitope in the FP region and has broad but only moderately potent neutralizing activity against SARS-CoV-2 VOCs including the more recent Omicron VOCs XBB.1.5 and BQ.1.1. Compared to other reported FP mAbs, C20.119 has similar potency to 76E1 from Sun, et al (28), and is roughly 10 to 20-fold more potent than several mAbs from other studies (42,43,113) against WH-1. Notably, several of these mAbs demonstrated in vivo protection, as prophylactics and treatments, in animal models challenged with SARS-CoV-2 virus.…”

Section: Discussionmentioning

confidence: 52%

The S2 subunit of spike encodes diverse targets for functional antibody responses to SARS-CoV-2

Guenthoer,

Garrett,

Lilly

et al. 2024

Preprint

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The SARS-CoV-2 virus responsible for the COVID-19 global pandemic has exhibited a striking capacity for viral evolution that drives continued evasion from vaccine and infection-induced immune responses. Mutations in the receptor binding domain of the S1 subunit of the spike glycoprotein have led to considerable escape from antibody responses, reducing the efficacy of vaccines and monoclonal antibody (mAb) therapies. Therefore, there is a need to interrogate more constrained regions of Spike, such as the S2 subdomain. Here, we describe a collection of S2 mAbs from two SARS-CoV-2 convalescent individuals that target multiple regions in the S2 subdomain and can be grouped into at least five epitope classes. Most did not neutralize SARS-CoV-2 with the exception of C20.119, which bound to a highly conserved epitope in the fusion peptide and showed broad binding and neutralization activity across SARS-CoV-2, SARS-CoV-1, and closely related zoonotic sarbecoviruses. Several of the S2 mAbs tested mediated antibody-dependent cellular cytotoxicity (ADCC) at levels similar to the S1 mAb S309 that was previously authorized for treatment of SARS-CoV-2 infections. Three of the mAbs with ADCC function also bound to spike trimers from HCoVs, such as MERS-CoV and HCoV-HKU1. Our findings suggest there are diverse epitopes in S2, including functional S2 mAbs with HCoV and sarbecovirus breadth that likely target functionally constrained regions of spike. These mAbs could be developed for potential future pandemics, while also providing insight into ideal epitopes for eliciting a broad HCoV response.

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Section: Discussionmentioning

confidence: 52%

The S2 subunit of spike encodes diverse targets for functional antibody responses to SARS-CoV-2

Guenthoer,

Garrett,

Lilly

et al. 2024

Preprint

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“…Unfortunately, RBD is the most variable region and has undergone genetic change over time [ 16 ]. Moreover, collective findings showed that neutralizing epitopes are not only present in RBD but also in the other regions of S protein, i.e., the N-terminal domain (NTD) [ 17 – 20 ] and the S2 domain [ 21 , 22 ]. These findings showed that our conventional MNT assay using live virus should provide the most accurate result because the NT antibodies recognized NT epitopes that lined along the S protein.…”

Section: Discussionmentioning

confidence: 99%

Higher correlation between neutralizing antibodies and surrogate neutralizing or binding antibodies in COVID-19 patients than vaccine recipients

Lerdsamran,

Anusorntanawat,

Sangsiriwut

et al. 2024

PLoS ONE

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This study determined the seropositive rates and levels of antibodies to severe acute respiratory syndrome coronavirus-2 in 50 patients and 108 vaccinees using microneutralization test (MNT), surrogate virus neutralization test (sVNT), chemiluminescent microparticle immunoassay (CMIA), and electrochemiluminescence immunoassay (ECLIA). MNT, as the reference method, employed living clade S and Delta viruses to measure neutralizing (NT) antibodies, while sVNT employed wild type strain and Delta receptor-binding domains (RBD) as the test antigens to measure sVNT antibodies. CMIA and ECLIA employed only one version of RBD to measure the binding antibodies. Our study performed S gene sequencing of the test virus to exclude undesired mutants that might lead to changes in antibody levels in MNT assay. We showed that spike protein amino acid sequences of our Delta virus contained 13 amino acid changes, with 3 related to the reduced neutralization. The MNT assay showed a significant reduction in seropositive rates and antibody levels in the patients’ sera when the Delta variant replaced clade S as the test virus. In contrast, the seropositive rates determined by sVNT assay using wild type strain RBD and Delta RBD were non-significantly different, suggesting that sVNT assay could not identify the difference between the antigenicity of wild type RBD and Delta RBD. Furthermore, the correlation between the levels of NT and sVNT antibodies was moderate with the patients’ sera but modest with the post-vaccination sera. The seropositive rates in the patients, as determined by CMIA or ECLIA, were not different from the MNT assay using clade S, but not Delta, as the test virus. In all analyses, the correlations between the antibody levels measured by MNT and the other 3 assays were modest to moderate, with the r-values of 0.3500–0.7882.

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“…NTD was suggested to bind lectin receptors, which in turn may act as alternative entry receptors [ 67 , 77 ]. S2 is also immunogenic and harbors neutralizing epitopes [ 78 ]. Notably, S2 stem helix-recognizing antibodies that have broad neutralizing activity against all SARS-related viruses, as well as human Betacoronaviruses, have been isolated [ 79 , 80 , 81 , 82 ].…”

Section: S and Antibody Recognitionmentioning

confidence: 99%

SARS-CoV-2 S Glycoprotein Stabilization Strategies

Pedenko

Sulbarán

Guilligay

et al. 2023

Viruses

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The SARS-CoV-2 pandemic has again shown that structural biology plays an important role in understanding biological mechanisms and exploiting structural data for therapeutic interventions. Notably, previous work on SARS-related glycoproteins has paved the way for the rapid structural determination of the SARS-CoV-2 S glycoprotein, which is the main target for neutralizing antibodies. Therefore, all vaccine approaches aimed to employ S as an immunogen to induce neutralizing antibodies. Like all enveloped virus glycoproteins, SARS-CoV-2 S native prefusion trimers are in a metastable conformation, which primes the glycoprotein for the entry process via membrane fusion. S-mediated entry is associated with major conformational changes in S, which can expose many off-target epitopes that deviate vaccination approaches from the major aim of inducing neutralizing antibodies, which mainly target the native prefusion trimer conformation. Here, we review the viral glycoprotein stabilization methods developed prior to SARS-CoV-2, and applied to SARS-CoV-2 S, in order to stabilize S in the prefusion conformation. The importance of structure-based approaches is highlighted by the benefits of employing stabilized S trimers versus non-stabilized S in vaccines with respect to their protective efficacy.

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Binding and neutralizing abilities of antibodies towards SARS-CoV-2 S2 domain

Cited by 4 publications

References 52 publications

The S2 subunit of spike encodes diverse targets for functional antibody responses to SARS-CoV-2

The S2 subunit of spike encodes diverse targets for functional antibody responses to SARS-CoV-2

Higher correlation between neutralizing antibodies and surrogate neutralizing or binding antibodies in COVID-19 patients than vaccine recipients

SARS-CoV-2 S Glycoprotein Stabilization Strategies

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