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

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.

scholarly journals High resolution linear epitope mapping of the receptor binding domain of SARS-CoV-2 spike protein in COVID-19 mRNA vaccine recipients.

2021 ◽  
Author(s):  
Yuko Nitahara ◽  
Yu Nakagama ◽  
Natsuko Kaku ◽  
Katherine Candray ◽  
Yu Michimuko ◽  
...  
Keyword(s):  
High Resolution ◽  
Receptor Binding ◽  
Messenger Rna ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Binding Domain ◽  
Spike Protein ◽  
Linear Epitope ◽  
Receptor Binding Domain ◽  
Population Immunity

The prompt rollout of the coronavirus disease (COVID-19) messenger RNA (mRNA) vaccine facilitated population immunity, which shall become more dominant than natural infection-induced immunity. At the beginning of the vaccine era, the initial epitope profile in naive individuals will be the first step to build an optimal host defense system towards vaccine-based population immunity. In this study, the high-resolution linear epitope profiles between Pfizer-BioNTech COVID-19 mRNA vaccine recipients and COVID-19 patients were delineated by using microarrays mapped with overlapping peptides of the receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. The vaccine-induced antibodies targeting RBD had broader distribution across the RBD than that induced by the natural infection. The relatively lower neutralizing antibody titers observed in vaccine-induced sera could attribute to less efficient epitope selection and maturation of the vaccine-induced humoral immunity compared to the infection-induced. Furthermore, additional mutation panel assays showed that the vaccine-induced rich epitope variety targeting the RBD may aid antibodies to escape rapid viral evolution, which could grant an advantage to the vaccine immunity.

scholarly journals Synthetic antibodies neutralize SARS-CoV-2 infection of mammalian cells

2020 ◽  
Author(s):  
Shane Miersch ◽  
Mart Ustav ◽  
Zhijie Li ◽  
James B. Case ◽  
Safder Ganaie ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Receptor Binding ◽  
Mammalian Cells ◽  
Rna Viruses ◽  
Large Family ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Highly Pathogenic ◽  
Zoonotic Infections

ABSTRACTCoronaviruses (CoV) are a large family of enveloped, RNA viruses that circulate in mammals and birds. Three highly pathogenic strains have caused zoonotic infections in humans that result in severe respiratory syndromes including the Middle East Respiratory Syndrome CoV (MERS), Severe Acute Respiratory Syndrome CoV (SARS), and the ongoing Coronavirus Disease 2019 (COVID-19) pandemic. Here, we describe a panel of synthetic monoclonal antibodies, built on a human IgG framework, that bind to the spike protein of SARS-CoV-2 (the causative agent of COVID-19), compete for ACE2 binding, and potently inhibit SARS-CoV-2. All antibodies that exhibited neutralization potencies at sub-nanomolar concentrations against SARS-CoV-2/USA/WA1 in Vero E6 cells, also bound to the receptor binding domain (RBD), suggesting competition for the host receptor ACE2. These antibodies represent strong immunotherapeutic candidates for treatment of COVID-19.

scholarly journals The receptor binding domain of SARS-CoV-2 spike is the key target of neutralizing antibody in human polyclonal sera

2020 ◽  
Author(s):  
Tara L. Steffen ◽  
E. Taylor Stone ◽  
Mariah Hassert ◽  
Elizabeth Geerling ◽  
Brian T. Grimberg ◽  
...  
Keyword(s):  
Antibody Response ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Binding Domain ◽  
Antigenic Determinants ◽  
Receptor Binding Domain ◽  
Neutralization Capacity

AbstractNatural infection of SARS-CoV-2 in humans leads to the development of a strong neutralizing antibody response, however the immunodominant targets of the polyclonal neutralizing antibody response are still unknown. Here, we functionally define the role SARS-CoV-2 spike plays as a target of the human neutralizing antibody response. In this study, we identify the spike protein subunits that contain antigenic determinants and examine the neutralization capacity of polyclonal sera from a cohort of patients that tested qRT-PCR-positive for SARS-CoV-2. Using an ELISA format, we assessed binding of human sera to spike subunit 1 (S1), spike subunit 2 (S2) and the receptor binding domain (RBD) of spike. To functionally identify the key target of neutralizing antibody, we depleted sera of subunit-specific antibodies to determine the contribution of these individual subunits to the antigen-specific neutralizing antibody response. We show that epitopes within RBD are the target of a majority of the neutralizing antibodies in the human polyclonal antibody response. These data provide critical information for vaccine development and development of sensitive and specific serological testing.

Escape of SARS-CoV-2 501Y.V2 variants from neutralization by convalescent plasma

2021 ◽  
Author(s):  
Sandile Cele ◽  
Inbal Gazy ◽  
Laurelle Jackson ◽  
Shi-Hsia Hwa ◽  
Houriiyah Tegally ◽  
...  
Keyword(s):  
South Africa ◽  
Antibody Response ◽  
Genome Sequencing ◽  
Receptor Binding ◽  
Natural Infection ◽  
Neutralizing Antibody ◽  
Spike Protein ◽  
Whole Genome ◽  
Receptor Binding Domain ◽  
Neutralization Activity

AbstractNew SARS-CoV-2 variants with mutations in the spike glycoprotein have arisen independently at multiple locations and may have functional significance. The combination of mutations in the 501Y.V2 variant first detected in South Africa include the N501Y, K417N, and E484K mutations in the receptor binding domain (RBD) as well as mutations in the N-terminal domain (NTD). Here we address whether the 501Y.V2 variant could escape the neutralizing antibody response elicited by natural infection with earlier variants. We were the first to outgrow two variants of 501Y.V2 from South Africa, designated 501Y.V2.HV001 and 501Y.V2.HVdF002. We examined the neutralizing effect of convalescent plasma collected from six adults hospitalized with COVID-19 using a microneutralization assay with live (authentic) virus. Whole genome sequencing of the infecting virus of the plasma donors confirmed the absence of the spike mutations which characterize 501Y.V2. We infected with 501Y.V2.HV001 and 501Y.V2.HVdF002 and compared plasma neutralization to first wave virus which contained the D614G mutation but no RBD or NTD mutations. We observed that neutralization of the 501Y.V2 variants was strongly attenuated, with IC50 6 to 200-fold higher relative to first wave virus. The degree of attenuation varied between participants and included a knockout of neutralization activity. This observation indicates that 501Y.V2 may escape the neutralizing antibody response elicited by prior natural infection. It raises a concern of potential reduced protection against re-infection and by vaccines designed to target the spike protein of earlier SARS-CoV-2 variants.

scholarly journals Coronavirus-Specific Antibody Cross Reactivity in Rhesus Macaques Following SARS-CoV-2 Vaccination and Infection

2021 ◽  
Author(s):  
Catherine Jacob-Dolan ◽  
Jared Feldman ◽  
Katherine McMahan ◽  
Jingyou Yu ◽  
Roland Zahn ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Specific Antibody ◽  
Rhesus Macaques ◽  
Rapid Development ◽  
Neutralizing Antibody ◽  
Cross Reactivity ◽  
Antibody Responses ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Before And After

Vaccines are being rapidly developed with the goal of ending the SARS-CoV-2 pandemic. However, the extent to which SARS-CoV-2 vaccination induces serum responses that cross-react with other coronaviruses remains poorly studied. Here we define serum profiles in rhesus macaques after vaccination with DNA or Ad26 based vaccines expressing SARS-CoV-2 Spike protein followed by SARS-CoV-2 challenge, or SARS-CoV-2 infection alone. Analysis of serum responses showed robust reactivity to the SARS-CoV-2 full-length Spike protein and receptor binding domain (RBD), both included in the vaccine. However, serum cross-reactivity to the closely related sarbecovirus SARS-CoV-1 Spike and RBD, was reduced. Reactivity was also measured to the distantly related common cold alpha-coronavirus, 229E and NL63, and beta-coronavirus, OC43 and HKU1, Spike proteins. Using SARS-COV-2 and SARS-CoV-1 lentivirus based pseudoviruses, we show that neutralizing antibody responses were predominantly SARS-CoV-2 specific. These data define patterns of cross-reactive binding and neutralizing serum responses induced by SARS-CoV-2 infection and vaccination in rhesus macaques. Our observations have important implications for understanding polyclonal responses to SARS-CoV-2 Spike, which will facilitate future CoV vaccine assessment and development. Importance The rapid development and deployment of SARS-CoV-2 vaccines has been unprecedented. In this study, we explore the cross-reactivity of SARS-CoV-2 specific antibody responses to other coronaviruses. By analyzing responses from NHPs both before and after immunization with DNA or Ad26 vectored vaccines, we find patterns of cross reactivity that mirror those induced by SARS-CoV-2 infection. These data highlight the similarities between infection and vaccine induced humoral immunity for SARS-CoV-2 and cross-reactivity of these responses to other CoVs.

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

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.

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

2020 ◽  
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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