scholarly journals ANALYSIS OF IMMUNE ESCAPE VARIANTS FROM ANTIBODY-BASED THERAPEUTICS AGAINST COVID-19.

2021 ◽  
Author(s):  
Daniele Focosi ◽  
Fabrizio Maggi ◽  
Massimo Franchini ◽  
Scott McConnell ◽  
Arturo Casadevall
Keyword(s):  
Public Health ◽  
Monoclonal Antibodies ◽  
Immune Evasion ◽  
Immune Escape ◽  
Selective Pressure ◽  
Neutralizing Antibody ◽  
Spike Protein ◽  
Single Amino Acid ◽  
Receptor Binding Domain ◽  
Amino Acid Mutations

Accelerated SARS-CoV-2 evolution under selective pressure by massive deployment of neutralizing antibody-based therapeutics is a concern with potentially severe implications for public health. We review here reports of documented immune escape after treatment with monoclonal antibodies and COVID19 convalescent plasma (CCP). While the former is mainly associated with specific single amino acid mutations at residues within the receptor-binding domain (e.g., E484K/Q, Q493R, and S494P), the few cases of immune evasion after CCP were associated with recurrent deletions within the N-terminal domain of Spike protein (e.g, delHV69-70, delLGVY141-144 and delAL243-244). Continuous genomic monitoring of non-responders is needed to better understand immune escape frequencies and fitness of emerging variants.

scholarly journals Analysis of Immune Escape Variants from Antibody-Based Therapeutics against COVID-19: A Systematic Review

2021 ◽  
Vol 23 (1) ◽  
pp. 29
Author(s):  
Daniele Focosi ◽  
Fabrizio Maggi ◽  
Massimo Franchini ◽  
Scott McConnell ◽  
Arturo Casadevall
Keyword(s):  
Public Health ◽  
Systematic Review ◽  
Immune Evasion ◽  
Immune Escape ◽  
Selective Pressure ◽  
Neutralizing Antibody ◽  
Spike Protein ◽  
Single Amino Acid ◽  
Receptor Binding Domain ◽  
Amino Acid Mutations

The accelerated SARS-CoV-2 evolution under selective pressure by massive deployment of neutralizing antibody-based therapeutics is a concern with potentially severe implications for public health. We review here reports of documented immune escape after treatment with monoclonal antibodies and COVID-19-convalescent plasma (CCP). While the former is mainly associated with specific single amino acid mutations at residues within the receptor-binding domain (e.g., E484K/Q, Q493R, and S494P), a few cases of immune evasion after CCP were associated with recurrent deletions within the N-terminal domain of the spike protein (e.g., ΔHV69-70, ∆LGVY141-144 and ΔAL243-244). The continuous genomic monitoring of non-responders is needed to better understand immune escape frequencies and the fitness of emerging variants.

scholarly journals Ten emerging SARS-CoV-2 spike variants exhibit variable infectivity, animal tropism, and antibody neutralization

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Li Zhang ◽  
Zhimin Cui ◽  
Qianqian Li ◽  
Bo Wang ◽  
Yuanling Yu ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Amino Acid ◽  
Receptor Binding ◽  
Immune Escape ◽  
Cathepsin L ◽  
Single Amino Acid ◽  
Receptor Binding Domain ◽  
Therapeutic Antibodies ◽  
Amino Acid Mutations ◽  
Better Than

AbstractEmerging mutations in SARS-CoV-2 cause several waves of COVID-19 pandemic. Here we investigate the infectivity and antigenicity of ten emerging SARS-CoV-2 variants—B.1.1.298, B.1.1.7(Alpha), B.1.351(Beta), P.1(Gamma), P.2(Zeta), B.1.429(Epsilon), B.1.525(Eta), B.1.526-1(Iota), B.1.526-2(Iota), B.1.1.318—and seven corresponding single amino acid mutations in the receptor-binding domain using SARS-CoV-2 pseudovirus. The results indicate that the pseudovirus of most of the SARS-CoV-2 variants (except B.1.1.298) display slightly increased infectivity in human and monkey cell lines, especially B.1.351, B.1.525 and B.1.526 in Calu-3 cells. The K417N/T, N501Y, or E484K-carrying variants exhibit significantly increased abilities to infect mouse ACE2-overexpressing cells. The activities of furin, TMPRSS2, and cathepsin L are increased against most of the variants. RBD amino acid mutations comprising K417T/N, L452R, Y453F, S477N, E484K, and N501Y cause significant immune escape from 11 of 13 monoclonal antibodies. However, the resistance to neutralization by convalescent serum or vaccines elicited serum is mainly caused by the E484K mutation. The convalescent serum from B.1.1.7- and B.1.351-infected patients neutralized the variants themselves better than other SARS-CoV-2 variants. Our study provides insights regarding therapeutic antibodies and vaccines, and highlights the importance of E484K mutation.

scholarly journals Crucial Mutations of Spike Protein on SARS-CoV-2 Evolved to Variant Strains Escaping Neutralization of Convalescent Plasmas and RBD-Specific Monoclonal Antibodies

2021 ◽  
Vol 12 ◽  
Author(s):  
Chengchao Ding ◽  
Jun He ◽  
Xiangyu Zhang ◽  
Chengcheng Jiang ◽  
Yong Sun ◽  
...  
Keyword(s):  
Immune Response ◽  
Monoclonal Antibodies ◽  
Humoral Immune Response ◽  
Immune Escape ◽  
Spike Protein ◽  
Single Amino Acid ◽  
Humoral Immune ◽  
Cross Neutralization ◽  
Altered Sensitivity ◽  
Single Amino Acid Mutation

Small number of SARS-CoV-2 epidemic lineages did not efficiently exhibit a neutralization profile, while single amino acid mutation in the spike protein has not been confirmed in altering viral antigenicity resulting in immune escape. To identify crucial mutations in spike protein that escape humoral immune response, we evaluated the cross-neutralization of convalescent plasmas and RBD-specific monoclonal antibodies (mAbs) against various spike protein-based pseudoviruses. Three of 24 SARS-CoV-2 pseudoviruses containing different mutations in spike protein, including D614G, A475V, and E484Q, consistently showed an altered sensitivity to neutralization by convalescent plasmas. A475V and E484Q mutants are highly resistant to neutralization by mAb B38 and 2-4, suggesting that some crucial mutations in spike protein might evolve SARS-CoV-2 variants capable of escaping humoral immune response.

scholarly journals SARS-CoV-2 variants of concern Alpha, Beta, Gamma and Delta have extended ACE2 receptor host-ranges

2021 ◽  
Author(s):  
Nazia Thakur ◽  
Giulia Gallo ◽  
Joseph Newman ◽  
Thomas P Peacock ◽  
Luca Biasetti ◽  
...  
Keyword(s):  
Public Health ◽  
Host Range ◽  
Receptor Binding ◽  
Immune Escape ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Public Health Perspective ◽  
Global Prevalence ◽  
Usage Patterns ◽  
Alpha Beta

Following the emergence of SARS-CoV-2 in China in late 2019 a number of variants have emerged, with two of these, Alpha and Delta, subsequently growing to global prevalence. One characteristic of these variants are changes within the Spike protein, in particular the receptor binding domain (RBD). From a public health perspective these changes have important implications for increased transmissibility and immune escape; however, their presence could also modify the intrinsic host-range of the virus. Using viral pseudotyping we examined whether the variants of concern (VOCs) Alpha, Beta, Gamma and Delta have differing host ACE2 receptor usage patterns, focusing on a range of relevant mammalian ACE2 proteins. All four VOCs were able to overcome a previous restriction for mouse ACE2, with demonstrable differences also seen for individual VOCs with rat, ferret or civet ACE2 receptors, changes which we subsequently attribute to N501Y and E484K substitutions within the Spike RBD.

scholarly journals Cross neutralization of emerging SARS-CoV-2 variants of concern by antibodies targeting distinct epitopes on spike

2021 ◽  
Author(s):  
Patrick Wilson ◽  
Siriruk Changrob ◽  
Yanbin Fu ◽  
Jenna Guthmiller ◽  
Peter Halfmann ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Receptor Binding ◽  
Specific Antibody ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Cross Neutralization

Abstract Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have arisen that exhibit increased viral transmissibility and partial evasion of immunity induced by natural infection and vaccination. To address the specific antibody targets that were affected by recent viral variants, we generated 43 monoclonal antibodies (mAbs) from 10 convalescent donors that bound three distinct domains of the SARS-CoV-2 spike. Viral variants harboring mutations at K417, E484 and N501 could escape most of the highly potent antibodies against the receptor binding domain (RBD). Despite this, we identified 12 neutralizing mAbs against three distinct regions of the spike protein that neutralize SARS-CoV-2 and the variants of concern, including B.1.1.7 (alpha), P.1 (gamma) and B.1.617.2 (delta). Notably, antibodies targeting distinct epitopes could neutralize discrete variants, suggesting different variants may have evolved to disrupt the binding of particular neutralizing antibody classes. These results underscore that humans exposed to wildtype (WT) SARS-CoV-2 do possess neutralizing antibodies against current variants and that it is critical to induce antibodies targeting multiple distinct epitopes of the spike that can neutralize emerging variants of concern.

scholarly journals Combining a Fusion Inhibitory Peptide Targeting the MERS-CoV S2 Protein HR1 Domain and a Neutralizing Antibody Specific for the S1 Protein Receptor-Binding Domain (RBD) Showed Potent Synergism against Pseudotyped MERS-CoV with or without Mutations in RBD

Viruses ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 31 ◽  
Author(s):  
Cong Wang ◽  
Chen Hua ◽  
Shuai Xia ◽  
Weihua Li ◽  
Lu Lu ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Neutralizing Antibody ◽  
Binding Domain ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Inhibitory Peptide ◽  
Protein Receptor ◽  
Neutralizing Monoclonal Antibody ◽  
Peptide Targeting ◽  
Combinatorial Strategy

Middle East respiratory syndrome coronavirus (MERS-CoV) has continuously posed a threat to public health worldwide, yet no therapeutics or vaccines are currently available to prevent or treat MERS-CoV infection. We previously identified a fusion inhibitory peptide (HR2P-M2) targeting the MERS-CoV S2 protein HR1 domain and a highly potent neutralizing monoclonal antibody (m336) specific to the S1 spike protein receptor-binding domain (RBD). However, m336 was found to have reduced efficacy against MERS-CoV strains with mutations in RBD, and HR2P-M2 showed low potency, thus limiting the clinical application of each when administered separately. However, we herein report that the combination of m336 and HR2P-M2 exhibited potent synergism in inhibiting MERS-CoV S protein-mediated cell–cell fusion and infection by MERS-CoV pseudoviruses with or without mutations in the RBD, resulting in the enhancement of antiviral activity in contrast to either one administered alone. Thus, this combinatorial strategy could be used in clinics for the urgent treatment of MERS-CoV-infected patients.

scholarly journals Neutralizing Monoclonal Antibodies That Target the Spike Receptor Binding Domain Confer Fc Receptor-Independent Protection against SARS-CoV-2 Infection in Syrian Hamsters

mBio ◽  
2021 ◽  
Author(s):  
Wen Su ◽  
Sin Fun Sia ◽  
Aaron J. Schmitz ◽  
Traci L. Bricker ◽  
Tyler N. Starr ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Fc Receptor ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Syrian Hamsters ◽  
Convalescent Phase ◽  
Main Target

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main target for neutralizing antibodies. These antibodies can be elicited through immunization or passively transferred as therapeutics in the form of convalescent-phase sera or monoclonal antibodies (MAbs).

scholarly journals Evidence for adaptive evolution in the receptor-binding domain of seasonal coronaviruses OC43 and 229e

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Kathryn E Kistler ◽  
Trevor Bedford
Keyword(s):  
Adaptive Evolution ◽  
Immune Evasion ◽  
Human Population ◽  
Seasonal Influenza ◽  
Respiratory Infections ◽  
Antigenic Drift ◽  
Spike Protein ◽  
Immune Memory ◽  
Receptor Binding Domain ◽  
Genetic Changes

Seasonal coronaviruses (OC43, 229E, NL63, and HKU1) are endemic to the human population, regularly infecting and reinfecting humans while typically causing asymptomatic to mild respiratory infections. It is not known to what extent reinfection by these viruses is due to waning immune memory or antigenic drift of the viruses. Here we address the influence of antigenic drift on immune evasion of seasonal coronaviruses. We provide evidence that at least two of these viruses, OC43 and 229E, are undergoing adaptive evolution in regions of the viral spike protein that are exposed to human humoral immunity. This suggests that reinfection may be due, in part, to positively selected genetic changes in these viruses that enable them to escape recognition by the immune system. It is possible that, as with seasonal influenza, these adaptive changes in antigenic regions of the virus would necessitate continual reformulation of a vaccine made against them.

scholarly journals SARS-CoV-2 B.1.1.7 sensitivity to mRNA vaccine-elicited, convalescent and monoclonal antibodies

2021 ◽  
Author(s):  
Dami A. Collier ◽  
Anna De Marco ◽  
Isabella A.T.M. Ferreira ◽  
Bo Meng ◽  
Rawlings Datir ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Immune Responses ◽  
Antibody Responses ◽  
Spike Protein ◽  
Binding Motif ◽  
Wild Type ◽  
Emerging Viruses ◽  
Transmission Potential ◽  
Amino Acid Mutations ◽  
The Uk

AbstractSevere Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant now seen in 50 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b2. We measured neutralising antibody responses following a single immunization using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the Receptor Binding Motif (RBM) (5 out of 31), but not in neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect newly emerging viruses in the UK led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b.

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