The Impact on Infectivity and Neutralization Efficiency of SARS-CoV-2 Lineage B.1.351 Pseudovirus

A new variant of SARS-CoV-2 B.1.351 lineage (first found in South Africa) has been raising global concern due to its harboring of multiple mutations in the spike that potentially increase transmissibility and yield resistance to neutralizing antibodies. We here tested infectivity and neutralization efficiency of SARS-CoV-2 spike pseudoviruses bearing particular mutations of the receptor-binding domain (RBD) derived either from the Wuhan strains (referred to as D614G or with other sites) or the B.1.351 lineage (referred to as N501Y, K417N, and E484K). The three different pseudoviruses B.1.351 lineage related significantly increased infectivity compared with other mutants that indicated Wuhan strains. Interestingly, K417N and E484K mutations dramatically enhanced cell–cell fusion than N501Y even though their infectivity were similar, suggesting that K417N and E484K mutations harboring SARS-CoV-2 variant might be more transmissible than N501Y mutation containing SARS-CoV-2 variant. We also investigated the efficacy of two different monoclonal antibodies, Casirivimab and Imdevimab that neutralized SARS-CoV-2, against several kinds of pseudoviruses which indicated Wuhan or B.1.351 lineage. Remarkably, Imdevimab effectively neutralized B.1.351 lineage pseudoviruses containing N501Y, K417N, and E484K mutations, while Casirivimab partially affected them. Overall, our results underscore the importance of B.1.351 lineage SARS-CoV-2 in the viral spread and its implication for antibody efficacy.

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Epistasis at the SARS-CoV-2 RBD Interface and the Propitiously Boring Implications for Vaccine Escape

10.1101/2021.08.30.458225 ◽

2021 ◽

Cited By ~ 1

Author(s):

Nash D. Rochman ◽

Guilhem Faure ◽

Yuri I. Wolf ◽

Peter L. Freddolino ◽

Feng Zhang ◽

...

Keyword(s):

Receptor Binding ◽

Neutralizing Antibodies ◽

Binding Domain ◽

Receptor Binding Domain ◽

Wild Type ◽

Protein Structure Modeling ◽

Escape Mutants ◽

Small Set ◽

Global Concern ◽

The Impact

AbstractAt the time of this writing, August 2021, potential emergence of vaccine escape variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a grave global concern. The interface between the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein and the host receptor (ACE2) overlap with the binding site of principal neutralizing antibodies (NAb), limiting the repertoire of viable mutations. Nonetheless, variants with multiple mutations in the RBD have rose to dominance. Non-additive, epistatic relationships among RBD mutations are apparent, and assessing the impact of such epistasis on the mutational landscape is crucial. Epistasis can substantially increase the risk of vaccine escape and cannot be completely characterized through the study of the wild type (WT) alone. We employed protein structure modeling using Rosetta to compare the effects of all single mutants at the RBD-NAb and RBD-ACE2 interfaces for the WT, Gamma (417T, 484K, 501Y), and Delta variants (452R, 478K). Overall, epistasis at the RBD surface appears to be limited and the effects of most multiple mutations are additive. Epistasis at the Delta variant interface weakly stabilizes NAb interaction relative to ACE2, whereas in the Gamma variant, epistasis more substantially destabilizes NAb interaction. These results suggest that the repertoire of potential escape mutations for the Delta variant is not substantially different from that of the WT, whereas Gamma poses a moderately greater risk for enhanced vaccine escape. Thus, the modest ensemble of mutations relative to the WT shown to reduce vaccine efficacy might constitute the majority of all possible escape mutations.SignificancePotential emergence of vaccine escape variants of SARS-CoV-2 is arguably the most pressing problem during the COVID-19 pandemic as vaccines are distributed worldwide. We employed a computational approach to assess the risk of antibody escape resulting from mutations in the receptor-binding domain of the spike protein of the wild type SARS-CoV-2 virus as well as the Gamma and Delta variants. The results indicate that emergence of escape mutants is somewhat less likely for the Delta variant than for the wild type and moderately more likely for the Gamma variant. We conclude that the small set of escape-enhancing mutations already identified for the wild type is likely to include the majority of all possible mutations with this effect, a welcome finding.

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

mBio ◽

10.1128/mbio.02395-21 ◽

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).

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Structures of SARS-CoV-2 B.1.351 neutralizing antibodies provide insights into cocktail design against concerning variants

10.1101/2021.07.30.454402 ◽

2021 ◽

Author(s):

Shuo Du ◽

Pulan Liu ◽

Zhiying Zhang ◽

Tianhe Xiao ◽

Ayijiang Yasimayi ◽

...

Keyword(s):

Electron Microscopy ◽

Monoclonal Antibodies ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

Antibody Responses ◽

Spike Protein ◽

Receptor Binding Domain ◽

Humoral Antibody ◽

Cryo Electron Microscopy ◽

Antibody Cocktail

The spread of the SARS-CoV-2 variants could seriously dampen the global effort to tackle the COVID-19 pandemic. Recently, we investigated the humoral antibody responses of SARS-CoV-2 convalescent patients and vaccinees towards circulating variants, and identified a panel of monoclonal antibodies (mAbs) that could efficiently neutralize the B.1.351 (Beta) variant. Here we investigate how these mAbs target the B.1.351 spike protein using cryo-electron microscopy. In particular, we show that two superpotent mAbs, BD-812 and BD-836, have non-overlapping epitopes on the receptor-binding domain (RBD) of spike. Both block the interaction between RBD and the ACE2 receptor; and importantly, both remain fully efficacious towards the B.1.617.1 (Kappa) and B.1.617.2 (Delta) variants. The BD-812/BD-836 pair could thus serve as an ideal antibody cocktail against the SARS-CoV-2 VOCs.

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SARS-CoV-2 escape from a highly neutralizing COVID-19 convalescent plasma

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2103154118 ◽

2021 ◽

Vol 118 (36) ◽

pp. e2103154118 ◽

Cited By ~ 7

Author(s):

Emanuele Andreano ◽

Giulia Piccini ◽

Danilo Licastro ◽

Lorenzo Casalino ◽

Nicole V. Johnson ◽

...

Keyword(s):

South Africa ◽

Immune Response ◽

Severe Acute Respiratory Syndrome ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

Receptor Binding Domain ◽

The United Kingdom ◽

Effective Immune Response ◽

Recent Emergence ◽

Natural Variants

To investigate the evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the immune population, we coincupi bated the authentic virus with a highly neutralizing plasma from a COVID-19 convalescent patient. The plasma fully neutralized the virus for seven passages, but, after 45 d, the deletion of F140 in the spike N-terminal domain (NTD) N3 loop led to partial breakthrough. At day 73, an E484K substitution in the receptor-binding domain (RBD) occurred, followed, at day 80, by an insertion in the NTD N5 loop containing a new glycan sequon, which generated a variant completely resistant to plasma neutralization. Computational modeling predicts that the deletion and insertion in loops N3 and N5 prevent binding of neutralizing antibodies. The recent emergence in the United Kingdom, South Africa, Brazil, and Japan of natural variants with similar changes suggests that SARS-CoV-2 has the potential to escape an effective immune response and that vaccines and antibodies able to control emerging variants should be developed.

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Effect of RBD (Y453F) mutation in spike glycoprotein of SARS-CoV-2 on neutralizing IgG affinity

10.1101/2021.01.28.21250577 ◽

2021 ◽

Author(s):

Takuma Hayashi ◽

Nobuo Yaegashi ◽

Ikuo Konishi

Keyword(s):

Monoclonal Antibodies ◽

Structural Analysis ◽

Severe Acute Respiratory Syndrome ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

Virus Disease ◽

Three Dimensional ◽

Binding Domain ◽

Receptor Binding Domain ◽

Spike Glycoprotein

AbstractBackgroundInfection with receptor binding domain (RBD) mutant (Y453F) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from farmed minks is known to widely spread among humans.MethodsWe investigated the characteristics of SARS-CoV-2 RBD Y453F mutant using three- dimensional structural analysis. We investigated the effect of the RBD Y453F mutant of SARS-CoV- 2 on neutralizing antibodies in serum derived from Corona virus Disease 2019 (COVID-19) positive patients.ResultsOur studies suggest that virus variants with RBD Y453F mutation partially escaped detection by four neutralizing monoclonal antibodies and neutralizing antibodies in serum.ConclusionsConsequently, raising a concern that infection of SARS-CoV-2 mutants that cause serious symptoms in humans may spread globally.

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

10.1101/2020.07.21.214759 ◽

2020 ◽

Cited By ~ 19

Author(s):

Yiska Weisblum ◽

Fabian Schmidt ◽

Fengwen Zhang ◽

Justin DaSilva ◽

Daniel Poston ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

Spike Protein ◽

Receptor Binding Domain ◽

Reporter Virus ◽

Low Frequencies ◽

Protein Variants ◽

Prior Infection ◽

Neutralizing Epitopes

AbstractNeutralizing 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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Sputnik Light booster after Sputnik V vaccination induces robust neutralizing antibody response to B.1.1.529 (Omicron) SARS-CoV-2 variant

10.1101/2021.12.17.21267976 ◽

2021 ◽

Author(s):

Inna V Dolzhikova ◽

Anna A Iliukhina ◽

Anna V Kovyrshina ◽

Alexandra V Kuzina ◽

Vladimir A Gushchin ◽

...

Keyword(s):

Antibody Response ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

Vaccination Campaign ◽

Neutralizing Antibody ◽

Receptor Binding Domain ◽

Protective Properties ◽

New Variant ◽

The World ◽

Variant Analysis

COVID-19 vaccination campaign has been launched around the world. More than 8 billion vaccines doses have been administered, according to the WHO. Published studies shows that vaccination reduces the number of COVID-19 cases and dramatically reduces COVID-19-associated hospitalizations and deaths worldwide. In turn, the emergence of SARS-CoV-2 variants of concern (VOC) with mutations in the receptor-binding domain (RBD) of S glycoprotein poses risks of diminishing the effectiveness of the vaccination campaign. In November 2021, the first information appeared about a new variant of the SARS-CoV-2 virus, which was named Omicron. The Omicron variant is of concern because it contains a large number of mutations, especially in the S glycoprotein (16 mutation in RBD), which could be associated with resistance to neutralizing antibodies (NtAB) and significantly reduce the effectiveness of COVID-19 vaccines. Neutralizing antibodies are one of the important parameters characterizing the protective properties of a vaccine. We conducted a study of neutralizing antibodies in the blood serum of people vaccinated with Sputnik V, as well as those revaccinated with Sputnik Light after Sputnik V. Results showed that a decrease in the level of neutralizing antibodies was observed against SARS-CoV-2 Omicron (B.1.1.529) variant in comparison to B.1.1.1 variant. Analysis of the sera of individuals vaccinated with Sputnik V 6-12 months ago showed that there was a decrease in the level of neutralizing antibodies by 11.76 folds. While no direct comparison with other vaccines declines has been done in this study, we note their reported decline in antibody neutralization at a much more significant level of 40-84 times. At the same time, the analysis of sera of individuals who were vaccinated with Sputnik V, and then revaccinated Sputnik Light, showed that 2-3 months after revaccination the decrease in the level of neutralizing antibodies against the Omicron variant was 7.13 folds. Despite the decrease in NtAb, we showed that all revaccinated individuals had NtAb to Omicron variant. Moreover, the NtAb level to Omicron variant in revaccinated sera are slightly higher than NtAb to B.1.1.1 in vaccinated sera.

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The neutralization potency of anti-SARS-CoV-2 therapeutic human monoclonal antibodies is retained against novel viral variants

10.1101/2021.04.01.438035 ◽

2021 ◽

Author(s):

Efi Makdasi ◽

Anat Zvi ◽

Ron Alcalay ◽

Tal Noy-Porat ◽

Eldar Peretz ◽

...

Keyword(s):

South Africa ◽

Monoclonal Antibodies ◽

Receptor Binding ◽

Clinical Use ◽

Receptor Binding Domain ◽

Spike Glycoprotein ◽

Human Monoclonal Antibodies ◽

Wide Range ◽

The Uk

SummaryA wide range of SARS-CoV-2 neutralizing monoclonal antibodies (mAbs) were reported to date, most of which target the spike glycoprotein and in particular its receptor binding domain (RBD) and N-terminal domain (NTD) of the S1 subunit. The therapeutic implementation of these antibodies has been recently challenged by the emerging SARS-CoV-2 variants, harboring an extensively-mutated spike versions. Consequently, the re-assessment of mAbs, previously reported to neutralize the original early-version of the virus, represents an assignment of high priority.With respect to the evolving mutations in the virus spike RBD, we evaluated the aptitude of four previously selected mAbs, targeting distinct epitopes, to bind RBD versions harboring individual mutations at positions 501, 477, 484, 439, 417 and 453. Mutations of these residues represent the prevailing worldwide distributed modifications of the RBD, previously reported to mediate escape from antibody neutralization. Additionally, the in vitro neutralization efficacies of the four RBD-specific mAbs, as well as two NTD-specific mAbs, were evaluated against two frequent SARS-CoV-2 variants of concern (VOCs): (i) the B.1.1.7 variant, emerged in the UK and (ii) the B.1.351 variant, emerged in South Africa. B.1.351, was previously suggested to escape many therapeutic mAbs, including those authorized for clinical use.The results of the present study, clearly indicate that in spite of mutation accumulation in the spike of the virus, some neutralizing mAbs preserve their potency to combat SARS-CoV-2 emerged variants. In particular, the previously reported highly potent MD65 mAb is shown to retain its ability to bind the prevalent novel viral mutations and to effectively neutralize the B.1.1.7 and B.1.351 variants of high clinical concern.

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

10.1101/2021.12.14.472630 ◽

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.

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Effect of RBD mutations in spike glycoprotein of SARS-CoV-2 on neutralizing IgG affinity

10.21203/rs.3.rs-363352/v1 ◽

2021 ◽

Author(s):

Takuma Hayashi ◽

Nobuo Yaegashi ◽

Ikuo Konishi

Keyword(s):

Monoclonal Antibodies ◽

Structural Analysis ◽

Receptor Binding ◽

Neutralizing Antibodies ◽

Three Dimensional ◽

Binding Domain ◽

Receptor Binding Domain ◽

Spike Glycoprotein ◽

Mutant Strains

Abstract Background: Certain mutant strains of SARS-CoV-2 are known to spread widely among humans, including the receptor binding domain (RBD) mutant, Y453F, from farmed minks, and the RBD mutant, N501Y, a mutation common to three major SARS-CoV-2 subspecies (B.1.1.7, B.1.351, and B.1.1.248). Methods: We investigated the characteristics of the RBD mutants, Y453F and N501Y, using three-dimensional structural analysis. We also investigated the effect of Y453F and N501Y on neutralizing antibodies in serum derived from COVID-19-positive patients. Results: Our results suggest that SARS-CoV-2 subspecies with the RBD mutations Y453F or N501Y partially escaped detection by 4 neutralizing monoclonal antibodies and 21 neutralizing antibodies in serums derived from COVID-19-positive patients.Conclusions: Infection with SARS-CoV-2 subspecies that cause serious symptoms in humans may spread globally.

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