scholarly journals In Silico Molecular-Based Rationale for SARS-CoV-2 Spike Circulating Mutations Able to Escape Bamlanivimab and Etesevimab Monoclonal Antibodies

2021 ◽  
Author(s):  
Erik Laurini ◽  
Domenico Marson ◽  
Suzana Aulic ◽  
Alice Fermeglia ◽  
Sabrina PRICL
Keyword(s):  
Monoclonal Antibodies ◽  
In Silico ◽  
Protective Efficacy ◽  
Protein A ◽  
Immune Surveillance ◽  
Spike Protein ◽  
Wild Type ◽  
Computer Based ◽  
New Challenges ◽  
Experimental Findings

The purpose of this work was to provide an in silico molecular rationale of the role eventually played by currently circulating S-RBDCoV‑2 mutations in evading the immune surveillance effects elicited by the two Eli Lilly LY-CoV555/bamlanivimab and LY-CoV016/etesevimab monoclonal antibodies. The main findings from this study and shows that, compared to the wild-type SARS-CoV-2 spike protein, mutations E484A/G/K/Q/R/V, Q493K/L/R, S494A/P/R, L452R and F490S are predicted to be markedly resistant to neutralization by LY-CoV555, while mutations K417E/N/T, D420A/G/N, N460I/K/S/T, T415P, and Y489C/S are predicted to confer LY-CoV016 escaping advantage to the viral protein. A challenge of our global in silico results against the relevant experimental data resulted in an overall 90% agreement. This achievement not only constitutes a further, robust validation of our computer-based approach but also yields a molecular-based rationale for all relative experimental findings, and leads us to conclude that the current circulating SARS-CoV-2 and all possible emergent variants carrying these mutations in the spike protein can present new challenges for mAb-based therapies and ultimately threaten the fully-protective efficacy of currently available vaccines.

scholarly journals Molecular rationale for SARS-CoV-2 spike circulating mutations able to escape bamlanivimab and etesevimab monoclonal antibodies

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Erik Laurini ◽  
Domenico Marson ◽  
Suzana Aulic ◽  
Alice Fermeglia ◽  
Sabrina Pricl
Keyword(s):  
Monoclonal Antibodies ◽  
In Silico ◽  
Structural Information ◽  
Viral Evolution ◽  
Protein A ◽  
Immune Surveillance ◽  
Protein S ◽  
Spike Protein ◽  
Wild Type ◽  
Experimental Findings

AbstractThe purpose of this work is to provide an in silico molecular rationale of the role eventually played by currently circulating mutations in the receptor binding domain of the SARS-CoV-2 spike protein (S-RBDCoV‑2) in evading the immune surveillance effects elicited by the two Eli Lilly LY-CoV555/bamlanivimab and LY-CoV016/etesevimab monoclonal antibodies. The main findings from this study show that, compared to the wild-type SARS-CoV-2 spike protein, mutations E484A/G/K/Q/R/V, Q493K/L/R, S494A/P/R, L452R and F490S are predicted to be markedly resistant to neutralization by LY-CoV555, while mutations K417E/N/T, D420A/G/N, N460I/K/S/T, T415P, and Y489C/S are predicted to confer LY-CoV016 escaping advantage to the viral protein. A challenge of our global in silico results against relevant experimental data resulted in an overall 90% agreement. Thus, the results presented provide a molecular-based rationale for all relative experimental findings, constitute a fast and reliable tool for identifying and prioritizing all present and newly reported circulating spike SARS-CoV-2 variants with respect to antibody neutralization, and yield substantial structural information for the development of next-generation vaccines and monoclonal antibodies more resilient to viral evolution.

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.

scholarly journals Antibody Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7

2021 ◽  
Author(s):  
Pengfei Wang ◽  
Manoj S. Nair ◽  
Lihong Liu ◽  
Sho Iketani ◽  
Yang Luo ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Protective Efficacy ◽  
Spike Protein ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Effective Interventions ◽  
Recent Emergence ◽  
New Challenges ◽  
The Uk ◽  
Antibody Resistance

The COVID-19 pandemic has ravaged the globe, and its causative agent, SARS-CoV-2, continues to rage. Prospects of ending this pandemic rest on the development of effective interventions. Single and combination monoclonal antibody (mAb) therapeutics have received emergency use authorization1–3, with more in the pipeline4–7. Furthermore, multiple vaccine constructs have shown promise8, including two with ~95% protective efficacy against COVID-199,10. However, these interventions were directed toward the initial SARS-CoV-2 that emerged in 2019. The recent emergence of new SARS-CoV-2 variants B.1.1.7 in the UK11 and B.1.351 in South Africa12 is of concern because of their purported ease of transmission and extensive mutations in the spike protein. We now report that B.1.1.7 is refractory to neutralization by most mAbs to the N-terminal domain (NTD) of spike and relatively resistant to a few mAbs to the receptor-binding domain (RBD). It is not more resistant to convalescent plasma or vaccinee sera. Findings on B.1.351 are more worrisome in that this variant is not only refractory to neutralization by most NTD mAbs but also by multiple individual mAbs to the receptor-binding motif on RBD, largely due to an E484K mutation. Moreover, B.1.351 is markedly more resistant to neutralization by convalescent plasma (9.4 fold) and vaccinee sera (10.3-12.4 fold). B.1.351 and emergent variants13,14 with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines.

scholarly journals A Spike protein-based subunit SARS-CoV-2 vaccine for pets: safety, immunogenicity, and protective efficacy in juvenile cats

2021 ◽  
Author(s):  
Kairat Tabynov ◽  
Madiana Orynbassar ◽  
Leila Yelchibayeva ◽  
Nurkeldi Turebekov ◽  
Toktassyn Yerubayev ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Neutralizing Antibodies ◽  
Large Scale ◽  
Protective Efficacy ◽  
Spike Protein ◽  
Wild Type Virus ◽  
Upper Respiratory Tract ◽  
Wild Type ◽  
Serum Samples ◽  
Virus Shedding

Abstract Whereas multiple vaccine types have been developed to curb the spread of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) among humans, there are very few vaccines being developed for animals including pets. To combat the threat of human-to-animal, animal-to-animal and animal-to-human transmission and the generation of new virus variants, we developed a subunit SARS-CoV-2 vaccine which is based on recombinant spike protein extracellular domain expressed in insect cells then formulated with appropriate adjuvants. Sixteen 8-12-week-old outbred female and male kittens (n=4/group) were randomly assigned into four treatment groups: Group 1, Antigen alone; Group 2, Sepivac SWE™ adjuvant; Group 3, aluminum hydroxide adjuvant; Group 4, PBS administered control animals. All animals were vaccinated twice at day 0 and 14, intramuscularly in a volume of 0.5 mL (Groups 1-3: 5 µg of Spike protein). On days 0 and 28 serum samples were collected to evaluate anti-spike IgG, inhibition of spike binding to angiotensin-converting enzyme 2 (ACE-2), neutralizing antibodies to Wuhan-01 SARS-CoV-2 D614G (wild-type) and Delta variant viruses, and whole blood for hematology studies. At day 28, all groups were challenged with SARS-CoV-2 wild-type virus 106 TCID50 intranasally. On day 31, tissue samples (lung, heart, and nasal turbinates) were collected for histology, viral RNA detection and virus titration. Parameters evaluated in this study included safety, immunogenicity, and protection from infection with wild-type SARS-CoV-2 virus. After two immunizations, both vaccines induced high titers of serum anti-spike IgG, ACE-2 binding inhibitory and neutralizing antibodies against both wild-type and Delta variant virus in the juvenile cats. Both subunit vaccines provided protection of juvenile cats against virus shedding from the upper respiratory tract, and against viral replication in the lower respiratory tract and hearts. These promising data warrant ongoing evaluation of the vaccine’s ability to protect cats against SARS-CoV-2 Delta variant and in particular to prevent transmission of the infection to naïve cats, before proceeding with large-scale field trials.

scholarly journals Cross-Neutralizing Activity of Monoclonal Antibodies Against N501Y Mutant Strain of SARS-CoV-2

2020 ◽  
Vol 9 (4) ◽  
pp. 41-45
Author(s):  
Ruxia Ding ◽  
Haixin Wang ◽  
Yi Yang ◽  
Liangshu Xie ◽  
Li Zhang ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Mutant Strain ◽  
Wild Type Strain ◽  
Neutralization Assay ◽  
Spike Protein ◽  
Wild Type ◽  
Neutralizing Activity ◽  
Theory Result ◽  
Global Concern ◽  
The Uk

The dominant N501Y mutation in the spike protein that SARS-CoV-2 virus uses to bind to the human ACE2 receptor were found in the UK, which has aroused global concern and worried. Mutations in spike protein may, in theory, result in more infectious and spreading more easily. In order to evaluate the broad-spectrum protective effect of the monoclonal antibodies(mAbs), we compared the neutralization activities of six prepared mAbs against SARS-CoV-2 with pseudovirus neutralization assay. Only one of them showed a decrease of 6 folds in neutralizing activity to N501Y mutant strain, compared with the wild type strain. We should continue to monitor emergence of new variants in different regions to study their infectivity and neutralization effect.

scholarly journals Bioinformatics analysis of SARS-CoV-2 RBD mutant variants and insights into antibody and ACE2 receptor binding

2021 ◽  
Author(s):  
Prashant Ranjan ◽  
Neha   ◽  
Chandra Devi ◽  
Parimal Das
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Double Mutant ◽  
Structural Changes ◽  
Protective Efficacy ◽  
Spike Protein ◽  
Wild Type ◽  
Current Vaccine ◽  
New Variant ◽  
The Impact

Prevailing COVID-19 vaccines are based on the spike protein of earlier SARS-CoV-2 strain that emerged in Wuhan, China. Continuously evolving nature of SARS-CoV-2 resulting emergence of new variant/s raise the risk of immune absconds. Several RBD (receptor-binding domain) variants have been reported to affect the vaccine efficacy considerably. In the present study, we performed in silico structural analysis of spike protein of double mutant (L452R & E484Q), a new variant of SARS-CoV-2 recently reported in India along with K417G variants and earlier reported RBD variants and found structural changes in RBD region after comparing with the wild type. Comparison of the binding affinity of the double mutant and earlier reported RBD variant for ACE2 (angiotensin 2 altered enzymes) receptor and CR3022 antibody with the wild-type strain revealed the lowest binding affinity of the double mutant for CR3022 among all other variants. These findings suggest that the newly emerged double mutant could significantly reduce the impact of the current vaccine which threatens the protective efficacy of current vaccine therapy.

scholarly journals In silico Antibody Mutagenesis for Optimizing its Binding to the Spike Protein of SARS-CoV-2

2020 ◽  
Author(s):  
Binquan Luan ◽  
Tien Huynh
Keyword(s):  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Drug Discovery ◽  
In Silico ◽  
Spike Protein ◽  
Computing Power ◽  
Atomic Structures ◽  
Protein Mutagenesis ◽  
Small Molecule Drugs ◽  
Global Pandemic

<p>Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic and there are currently no FDA approved medicines for treatment or prevention. Inspired by promising outcomes for convalescent plasma treatment, developing antibody drugs (biologics) to block SARS-CoV-2 infection has been the focus of drug discovery, along with tremendous efforts in repurposing small-molecule drugs. In the last several months, experimentally, many human neutralizing monoclonal antibodies (mAbs) were successfully extracted from plasma of recovered COVID-19 patients. Currently, several mAbs targeting the SARS-CoV-2's spike protein (Spro) are in clinical trials. With known atomic structures of mAb-Spro complex, it becomes possible to <i>in silico</i> investigate the molecular mechanism of mAb's binding with Spro and design more potent mAbs through protein mutagenesis studies, complementary to existing experimental efforts. Leveraging superb computing power nowadays, we propose a fully automated <i>in silico</i> protocol for quickly identifying possible mutations in a mAb (e.g.~CB6) to enhance its binding affinity with Spro for the design of more efficacious therapeutic mAbs.</p>

scholarly journals Increased Resistance of SARS-CoV-2 Variants B.1.351 and B.1.1.7 to Antibody Neutralization

2021 ◽  
Author(s):  
David Ho ◽  
Pengfei Wang ◽  
Lihong Liu ◽  
Sho Iketani ◽  
Yang Luo ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Protective Efficacy ◽  
Viral Evolution ◽  
Spike Protein ◽  
Binding Motif ◽  
Receptor Binding Domain ◽  
Effective Interventions ◽  
Recent Emergence ◽  
New Challenges ◽  
The Uk

Abstract The Covid-19 pandemic has ravaged the globe, and its causative agent, SARS-CoV-2, continues to rage. Prospects of ending this pandemic rest on the development of effective interventions. Two monoclonal antibody (mAb) therapeutics have received emergency use authorization, and more are in the pipeline. Furthermore, multiple vaccine constructs have shown promise, including two with ~95% protective efficacy against Covid-19. However, these interventions were directed toward the initial SARS-CoV-2 that emerged in 2019. Considerable viral evolution has occurred since, including variants with a D614G mutation that have become dominant. Viruses with this mutation alone do not appear to be antigenically distinct, however. Recent emergence of new SARS-CoV-2 variants B.1.1.7 in the UK and B.1.351 in South Africa is of concern because of their purported ease of transmission and extensive mutations in the spike protein. We now report that B.1.1.7 is refractory to neutralization by most mAbs to the N-terminal domain (NTD) of spike and relatively resistant to a number of mAbs to the receptor-binding domain (RBD). It is modestly more resistant to convalescent plasma (~3 fold) and vaccinee sera (~2 fold). Findings on B.1.351 are more worrisome in that this variant is not only refractory to neutralization by most NTD mAbs but also by multiple potent mAbs to the receptor-binding motif on RBD, largely due to an E484K mutation. Moreover, B.1.351 is markedly more resistant to neutralization by convalescent plasma (~11-33 fold) and vaccinee sera (~6.5-8.6 fold). B.1.351 and emergent variants with similar spike mutations present new challenges for mAb therapy and threaten the protective efficacy of current vaccines.

scholarly journals Relative Mutant N501Y SARS-CoV-2 Spike Protein RBD Inhibition of Anti-Spike Protein IgG and ACE-2 Binding to Spike Protein Species

2021 ◽  
Author(s):  
Melvin E. Klegerman ◽  
Jeffrey D. Cirillo ◽  
David D. McPherson
Keyword(s):  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Spike Protein ◽  
Critical Element ◽  
Amino Acid Residues ◽  
Wild Type ◽  
Igg Antibody ◽  
Significant Difference ◽  
The Individual ◽  
Therapeutic Monoclonal Antibodies

ABSTRACTIn the SARS-CoV-2 coronavirus pandemic of 2019 (COVID-19), it has become evident that the ACE-2 receptor-binding domain (RBD) of the viral spike protein (SP) is the target of neutralizing antibodies that comprise a critical element of protective immunity to the virus. The most definitive confirmation of this contention is that the two mRNA COVID-19 vaccines in general use, which elicit antibodies specific for the RBD, exhibit approximately 95% protective efficacy against COVID-19. A potential challenge to vaccine efficacy is the emergence of SARS-CoV-2 variants possessing multiple mutations affecting amino acid residues in the RBD. Of concern are variants that arose in the United Kingdom, Brazil and South Africa. One of the variants, designated B.1.351, has shown a higher transmissibility due to greater affinity for the ACE-2 receptor and decreased neutralization by convalescent plasma, therapeutic monoclonal antibodies, and post-vaccination plasma. Common to several of the variants is the N501Y mutation in the RBD, which may be responsible for at least part of the observed variant properties. To test this hypothesis, we measured the ability of the Y501 RBD to inhibit binding of the wild type RBD and full SP (S1 + S2) to the ACE-2 protein and a human monoclonal IgG antibody elicited to the wild type RBD, relative to the wild type RBD in two enzyme-linked immunosorbent assays (ELISAs). We found no significant difference in the IC50 of the two RBD species’ inhibition of ACE-2 binding, but unexpectedly found that the IC50 of the wild type RBD inhibition of antibody binding was nearly twice that of the Y501 RBD, reflecting a lower affinity. These results suggest that the individual N501Y mutation does not contribute to altered viral properties by itself, but may contribute to a collective conformational shift produced by multiple mutations.

scholarly journals Characterizing flexibility and mobility in the natural mutations of the SARS-CoV-2 spikes

2021 ◽  
Author(s):  
James Panayis ◽  
Navodya S. Römer ◽  
Dom Bellini ◽  
A. Katrine Wallis ◽  
Rudolf A. Römer
Keyword(s):  
In Silico ◽  
Geometric Modeling ◽  
Protein Structures ◽  
Data Bank ◽  
Spike Protein ◽  
Wild Type ◽  
Drug Molecules ◽  
Elastic Modes ◽  
Novel Drug ◽  
Combining Methods

AbstractWe use in silico modelling of the SARS-CoV-2 spike protein and its mutations, as deposited on the Protein Data Bank (PDB), to ascertain their dynamics, flexibility and rigidity. Identifying the precise nature of the dynamics for the spike proteins enables, in principle, the use of further in silico design methods to quickly screen for existing and novel drug molecules that might prohibit the natural protein dynamics. We employ a recent protein flexibility modeling approach, combining methods for deconstructing a protein structure into a network of rigid and flexible units with a method that explores the elastic modes of motion of this network, and a geometric modeling of flexible motion. Our results thus far indicate that the overall motion of wild-type and mutated spike protein structures remains largely the same.

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