scholarly journals Reduced sensitivity of infectious SARS-CoV-2 variant B.1.617.2 to monoclonal antibodies and sera from convalescent and vaccinated individuals

2021 ◽  
Author(s):  
Delphine Planas ◽  
David Veyer ◽  
Artem Baidaliuk ◽  
Isabelle Staropoli ◽  
Florence Guivel-Benhassine ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Receptor Binding ◽  
Immune Evasion ◽  
Binding Domain ◽  
The Other ◽  
Receptor Binding Domain ◽  
Terminal Domain

The SARS-CoV-2 B.1.617 lineage emerged in October 2020 in India. It has since then become dominant in some indian regions and further spread to many countries. The lineage includes three main subtypes (B1.617.1, B.1617.2 and B.1.617.3), which harbour diverse Spike mutations in the N-terminal domain (NTD) and the receptor binding domain (RBD) which may increase their immune evasion potential. B.1.617.2 is believed to spread faster than the other versions. Here, we isolated infectious B.1.617.2 from a traveller returning from India. We examined its sensitivity to monoclonal antibodies (mAbs) and to antibodies present in sera from COVID-19 convalescent individuals or vaccine recipients, in comparison to other viral lineages. B.1.617.2 was resistant to neutralization by some anti-NTD and anti-RBD mAbs, including Bamlanivimab, which were impaired in binding to the B.1.617.2 Spike. Sera from convalescent patients collected up to 12 months post symptoms and from Pfizer Comirnaty vaccine recipients were 3 to 6 fold less potent against B.1.617.2, relative to B.1.1.7. Sera from individuals having received one dose of AstraZeneca Vaxzevria barely inhibited B.1.617.2. Thus, B.1.617.2 spread is associated with an escape to antibodies targeting non-RBD and RBD Spike epitopes.

Considerable escape of SARS-CoV-2 variant Omicron to antibody neutralization

2021 ◽  
Author(s):  
Delphine Planas ◽  
Nell Saunders ◽  
Piet Maes ◽  
Florence Guivel Benhassine ◽  
Cyril Planchais ◽  
...  
Keyword(s):  
South Africa ◽  
Monoclonal Antibodies ◽  
Receptor Binding ◽  
Binding Domain ◽  
Viral Fitness ◽  
Receptor Binding Domain ◽  
Antibody Neutralization ◽  
Neutralizing Activity ◽  
Terminal Domain ◽  
Therapeutic Monoclonal Antibodies

The SARS-CoV-2 Omicron variant was first identified in November 2021 in Botswana and South Africa. It has in the meantime spread to many countries and is expected to rapidly become dominant worldwide. The lineage is characterized by the presence of about 32 mutations in the Spike, located mostly in the N-terminal domain (NTD) and the receptor binding domain (RBD), which may enhance viral fitness and allow antibody evasion. Here, we isolated an infectious Omicron virus in Belgium, from a traveller returning from Egypt. We examined its sensitivity to 9 monoclonal antibodies (mAbs) clinically approved or in development, and to antibodies present in 90 sera from COVID-19 vaccine recipients or convalescent individuals. Omicron was totally or partially resistant to neutralization by all mAbs tested. Sera from Pfizer or AstraZeneca vaccine recipients, sampled 5 months after complete vaccination, barely inhibited Omicron. Sera from COVID-19 convalescent patients collected 6 or 12 months post symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titers 5 to 31 fold lower against Omicron than against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and to a large extent vaccine-elicited antibodies.

scholarly journals A neutralizing human antibody binds to the N-terminal domain of the Spike protein of SARS-CoV-2

Science ◽  
2020 ◽  
Vol 369 (6504) ◽  
pp. 650-655 ◽  
Author(s):  
Xiangyang Chi ◽  
Renhong Yan ◽  
Jun Zhang ◽  
Guanying Zhang ◽  
Yuanyuan Zhang ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Receptor Binding ◽  
Binding Domain ◽  
Spike Protein ◽  
Human Antibody ◽  
Receptor Binding Domain ◽  
S Protein ◽  
Terminal Domain ◽  
Promising Target

Developing therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could be guided by the distribution of epitopes, not only on the receptor binding domain (RBD) of the Spike (S) protein but also across the full Spike (S) protein. We isolated and characterized monoclonal antibodies (mAbs) from 10 convalescent COVID-19 patients. Three mAbs showed neutralizing activities against authentic SARS-CoV-2. One mAb, named 4A8, exhibits high neutralization potency against both authentic and pseudotyped SARS-CoV-2 but does not bind the RBD. We defined the epitope of 4A8 as the N-terminal domain (NTD) of the S protein by determining with cryo–eletron microscopy its structure in complex with the S protein to an overall resolution of 3.1 angstroms and local resolution of 3.3 angstroms for the 4A8-NTD interface. This points to the NTD as a promising target for therapeutic mAbs against COVID-19.

scholarly journals Real Concerns over COVID-19 Variants of Concern

2021 ◽  
Author(s):  
Hatem ◽  
Rashika El Rii
Keyword(s):  
United States ◽  
Severe Acute Respiratory Syndrome ◽  
Receptor Binding ◽  
Immune Evasion ◽  
The United States ◽  
Binding Domain ◽  
Receptor Binding Domain ◽  
Spike Glycoprotein ◽  
Terminal Domain ◽  
Corona Virus

Severe acute respiratory syndrome corona virus (SARS-CoV)-2 obtained from patients infected despite being fully vaccinated with either BNT162b2 (Pfizer/BioNTech), mRNA-1273 (Moderna), or JNJ-78436735 (Janssen) showed increased mutations rates in the N-terminal domain (NTD) and receptor-binding domain (RBD) of the spike glycoprotein when compared with virus from unvaccinated controls (1). These changes are associated with immune evasion and diagnostic failures, prominent characteristics of variants of concern (2). Variants of concern (VOC) appeared to be overrepresented in numerous breakthrough infections of fully vaccinated people in the United States and (1, 3-6), and Israel (7). These findings confirm concerns about the relation of SARS-CoV-2 variants with vaccine breakthrough, and urged us to attempt clarifying the likely link between vaccination with the currently used vaccines and VOC emergence.

scholarly journals Decreased neutralization of SARS-CoV-2 global variants by therapeutic anti-spike protein monoclonal antibodies

2021 ◽  
Author(s):  
Takuya Tada ◽  
Belinda M. Dcosta ◽  
Hao Zhou ◽  
Ada Vaill ◽  
Wes Kazmierski ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Receptor Binding ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Neutralization Activity ◽  
Protein Mutations ◽  
Spike Proteins

AbstractMonoclonal antibodies against the SARS-CoV-2 spike protein, notably, those developed by Regeneron Pharmaceuticals and Eli Lilly and Company have proven to provide protection against severe COVID-19. The emergence of SARS-CoV-2 variants with heavily mutated spike proteins raises the concern that the therapy could become less effective if any of the mutations disrupt epitopes engaged by the antibodies. In this study, we tested monoclonal antibodies REGN10933 and REGN10987 that are used in combination, for their ability to neutralize SARS-CoV-2 variants B.1.1.7, B.1.351, mink cluster 5 and COH.20G/677H. We report that REGN10987 maintains most of its neutralization activity against viruses with B.1.1.7, B.1.351 and mink cluster 5 spike proteins but that REGN10933 has lost activity against B.1.351 and mink cluster 5. The failure of REGN10933 to neutralize B.1.351 is caused by the K417N and E484K mutations in the receptor binding domain; the failure to neutralize the mink cluster 5 spike protein is caused by the Y453F mutation. The REGN10933 and REGN10987 combination was 9.1-fold less potent on B.1.351 and 16.2-fold less potent on mink cluster 5, raising concerns of reduced efficacy in the treatment of patients infected with variant viruses. The results suggest that there is a need to develop additional monoclonal antibodies that are not affected by the current spike protein mutations.

scholarly journals Key substitutions in the spike protein of SARS-CoV-2 variants can predict resistance to monoclonal antibodies, but other substitutions can modify the effects

2021 ◽  
Author(s):  
Sabrina Lusvarghi ◽  
Wei Wang ◽  
Rachel Herrup ◽  
Sabari Nath Neerukonda ◽  
Russell Vassell ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Receptor Binding ◽  
Clinical Stage ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Therapeutic Antibodies ◽  
Epistatic Interactions ◽  
Neutralization Activity ◽  
Virus Susceptibility

Mutations in the spike protein of SARS-CoV-2 variants can compromise the effectiveness of therapeutic antibodies. Most clinical-stage therapeutic antibodies target the spike receptor binding domain (RBD), but variants often have multiple mutations in several spike regions. To help predict antibody potency against emerging variants, we evaluated 25 clinical-stage therapeutic antibodies for neutralization activity against 60 pseudoviruses bearing spikes with single or multiple substitutions in several spike domains, including the full set of substitutions in B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.429 (Epsilon), B.1.526 (Iota), A.23.1 and R.1 variants. We found that 14 of 15 single antibodies were vulnerable to at least one RBD substitution, but most combination and polyclonal therapeutic antibodies remained potent. Key substitutions in variants with multiple spike substitutions predicted resistance, but the degree of resistance could be modified in unpredictable ways by other spike substitutions that may reside outside of the RBD. These findings highlight the importance of assessing antibody potency in the context of all substitutions in a variant and show that epistatic interactions in spike can modify virus susceptibility to therapeutic antibodies.

scholarly journals On the interactions of the receptor-binding domain of SARS-CoV-1 and SARS-CoV-2 spike proteins with monoclonal antibodies and the receptor ACE2

2020 ◽  
Author(s):  
Carolina Corrêa Giron ◽  
Aatto Laaksonen ◽  
Fernando L. Barroso da Silva
Keyword(s):  
Monoclonal Antibodies ◽  
Receptor Binding ◽  
International Health ◽  
Binding Domain ◽  
Clinical Aspects ◽  
Receptor Binding Domain ◽  
Health Crisis ◽  
Structural Modifications ◽  
Constant Ph ◽  
Promising Target

ABSTRACTA new betacoronavirus named SARS-CoV-2 has emerged as a new threat to global health and economy. A promising target for both diagnosis and therapeutics treatments of the new disease named COVID-19 is the coronavirus (CoV) spike (S) glycoprotein. By constant-pH Monte Carlo simulations and the PROCEEDpKa method, we have mapped the electrostatic epitopes for four monoclonal antibodies and the angiotensin-converting enzyme 2 (ACE2) on both SARS-CoV-1 and the new SARS-CoV-2 S receptor binding domain (RBD) proteins. We also calculated free energy of interactions and shown that the S RBD proteins from both SARS viruses binds to ACE2 with similar affinities. However, the affinity between the S RBD protein from the new SARS-CoV-2 and ACE2 is higher than for any studied antibody previously found complexed with SARS-CoV-1. Based on physical chemical analysis and free energies estimates, we can shed some light on the involved molecular recognition processes, their clinical aspects, the implications for drug developments, and suggest structural modifications on the CR3022 antibody that would improve its binding affinities for SARS-CoV-2 and contribute to address the ongoing international health crisis.

scholarly journals Functional Effects of Receptor-Binding Domain Mutations of SARS-CoV-2 B.1.351 and P.1 Variants

2021 ◽  
Vol 12 ◽  
Author(s):  
Rafael Bayarri-Olmos ◽  
Ida Jarlhelt ◽  
Laust Bruun Johnsen ◽  
Cecilie Bo Hansen ◽  
Charlotte Helgstrand ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Convergent Evolution ◽  
Binding Domain ◽  
Viral Fitness ◽  
The Other ◽  
Receptor Binding Domain ◽  
Gain Of Function ◽  
Other Hand ◽  
One Step

The recent identification and rise to dominance of the P.1 and B.1.351 SARS-CoV-2 variants have brought international concern because they may confer fitness advantages. The same three positions in the receptor-binding domain (RBD) are affected in both variants, but where the 417 substitution differs, the E484K/N501Y have co-evolved by convergent evolution. Here we characterize the functional and immune evasive consequences of the P.1 and B.1.351 RBD mutations. E484K and N501Y result in gain-of-function with two different outcomes: The N501Y confers a ten-fold affinity increase towards ACE-2, but a modest antibody evasion potential of plasma from convalescent or vaccinated individuals, whereas the E484K displays a significant antibody evasion capacity without a major impact on affinity. On the other hand, the two different 417 substitutions severely impair the RBD/ACE-2 affinity, but in the combined P.1 and B.1.351 RBD variants, this effect is partly counterbalanced by the effect of the E484K and N501Y. Our results suggest that the combination of these three mutations is a two-step forward and one step back in terms of viral fitness.

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