scholarly journals SARS-CoV-2 Omicron variant escapes neutralization by vaccinated and convalescent sera and therapeutic monoclonal antibodies

2021 ◽  
Author(s):  
Nariko Ikemura ◽  
Atsushi Hoshino ◽  
Yusuke Higuchi ◽  
Shunta Taminishi ◽  
Tohru Inaba ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Viral Escape ◽  
Spike Protein ◽  
The Novel ◽  
Neutralization Titer ◽  
Neutralization Activity ◽  
Therapeutic Drugs ◽  
Conserved Region ◽  
Therapeutic Monoclonal Antibodies

The novel SARS-CoV-2 variant, Omicron (B.1.1.529) contains about 30 mutations in the spike protein and the numerous mutations raise the concern of escape from vaccine, convalescent sera and therapeutic drugs. Here we analyze the alteration of their neutralizing titer with Omicron pseudovirus. Sera of 3 months after double BNT162b2 vaccination exhibite ~27-fold lower neutralization titers against Omicron than D614G mutation. Neutralization titer is also reduced in convalescent sera from Alpha and Delta patients. However, some Delta patients have relatively preserved neutralization activity up to the level of 3-month double BNT162b2 vaccination. Omicron escapes from the cocktail of imdevimab and casirivimab, whereas sotrovimab that targets the conserved region to prevent viral escape is effective to Omicron similarly to the original SARS-CoV-2. The ACE2 decoy is another modality that neutralize the virus independently of mutational escape and Omicron is also sensitive to the engineered ACE2.

scholarly journals B.1.526 SARS-CoV-2 variants identified in New York City are neutralized by vaccine-elicited and therapeutic monoclonal antibodies

2021 ◽  
Author(s):  
Hao Zhou ◽  
Belinda M. Dcosta ◽  
Marie I. Samanovic ◽  
Mark J. Mulligan ◽  
Nathaniel R. Landau ◽  
...  
Keyword(s):  
New York ◽  
New York City ◽  
Monoclonal Antibodies ◽  
York City ◽  
Point Mutations ◽  
Spike Protein ◽  
The Novel ◽  
Receptor Binding Domain ◽  
Wide Spread ◽  
Therapeutic Monoclonal Antibodies

DNA sequence analysis recently identified the novel SARS-CoV-2 variant B.1.526 that is spreading at an alarming rate in the New York City area. Two versions of the variant were identified, both with the prevalent D614G mutation in the spike protein together with four novel point mutations and with an E484K or S477N mutation in the receptor binding domain, raising concerns of possible resistance to vaccine-elicited and therapeutic antibodies. We report that convalescent sera and vaccine-elicited antibodies retain full neutralizing titer against the S477N B.1.526 variant and neutralize the E484K version with a modest 3.5-fold decrease in titer as compared to D614G. The E484K version was neutralized with a 12-fold decrease in titer by the REGN10933 monoclonal antibody but the combination cocktail with REGN10987 was fully active. The findings suggest that current vaccines and therapeutic monoclonal antibodies will remain protective against the B.1.526 variants. The findings further support the value of wide-spread vaccination.

scholarly journals Engineered ACE2 counteracts vaccine-evading SARS-CoV-2 Omicron variant

2021 ◽  
Author(s):  
Nariko Ikemura ◽  
Shunta Taminishi ◽  
Tohru Inaba ◽  
Takao Arimori ◽  
Daisuke Motooka ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Mutational Analysis ◽  
High Sensitivity ◽  
Binding Domain ◽  
Spike Protein ◽  
The Novel ◽  
Receptor Binding Domain ◽  
Therapeutic Drugs ◽  
Viral Mutation ◽  
Therapeutic Value

The novel SARS-CoV-2 variant, Omicron (B.1.1.529) contains an unusually high number of mutations (>30) in the spike protein, raising concerns of escape from vaccines, convalescent sera and therapeutic drugs. Here we analyze the alteration of neutralizing titer with Omicron pseudovirus. Sera of 3 months after double BNT162b2 vaccination exhibit approximately 18-fold lower neutralization titers against Omicron. Convalescent sera from Alpha and Delta patients allow similar levels of breakthrough by Omicron. However, some Delta patients have relatively preserved neutralization efficacy, comparable to 3-month double BNT162b2 vaccination. Domain-wise analysis using chimeric spike revealed that this efficient evasion was, at least in part, caused by multiple mutations in the N-terminal domain. Omicron escapes the therapeutic cocktail of imdevimab and casirivimab, whereas sotrovimab, which targets a conserved region to avoid viral mutation, remains effective against Omicron. The ACE2 decoy is another virus-neutralizing drug modality that is free, at least in theory, from mutational escape. Deep mutational analysis demonstrated that, indeed, the engineered ACE2 overcomes every single-residue mutation in the receptor-binding domain, similar to immunized sera. Like previous SARS-CoV-2 variants, Omicron and some other sarbecoviruses showed high sensitivity against engineered ACE2, confirming the therapeutic value against diverse variants, including those that are yet to emerge.

scholarly journals Low-dose in vivo protection and neutralization across SARS-CoV-2 variants by monoclonal antibody combinations

2021 ◽  
Author(s):  
Vincent Dussupt ◽  
Rajeshwer S. Sankhala ◽  
Letzibeth Mendez-Rivera ◽  
Samantha M. Townsley ◽  
Fabian Schmidt ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Low Dose ◽  
Viral Escape ◽  
Spike Protein ◽  
Receptor Binding Domain ◽  
Viral Inactivation ◽  
Angiotensin Converting Enzyme 2 ◽  
Therapeutic Monoclonal Antibodies ◽  
Potent Protection

AbstractPrevention of viral escape and increased coverage against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern require therapeutic monoclonal antibodies (mAbs) targeting multiple sites of vulnerability on the coronavirus spike glycoprotein. Here we identify several potent neutralizing antibodies directed against either the N-terminal domain (NTD) or the receptor-binding domain (RBD) of the spike protein. Administered in combinations, these mAbs provided low-dose protection against SARS-CoV-2 infection in the K18-human angiotensin-converting enzyme 2 mouse model, using both neutralization and Fc effector antibody functions. The RBD mAb WRAIR-2125, which targets residue F486 through a unique heavy-chain and light-chain pairing, demonstrated potent neutralizing activity against all major SARS-CoV-2 variants of concern. In combination with NTD and other RBD mAbs, WRAIR-2125 also prevented viral escape. These data demonstrate that NTD/RBD mAb combinations confer potent protection, likely leveraging complementary mechanisms of viral inactivation and clearance.

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 B.1.526 SARS-CoV-2 Variants Identified in New York City are Neutralized by Vaccine-Elicited and Therapeutic Monoclonal Antibodies

mBio ◽  
2021 ◽  
Author(s):  
Hao Zhou ◽  
Belinda M. Dcosta ◽  
Marie I. Samanovic ◽  
Mark J. Mulligan ◽  
Nathaniel R. Landau ◽  
...  
Keyword(s):  
New York ◽  
Monoclonal Antibody ◽  
New York City ◽  
Monoclonal Antibodies ◽  
York City ◽  
Antibody Therapy ◽  
Spike Protein ◽  
Monoclonal Antibody Therapy ◽  
Therapeutic Monoclonal Antibodies

A novel SARS-CoV-2 variant termed B.1.526 was recently identified in New York City and has been found to be spreading at an alarming rate. The variant has mutations in its spike protein that might allow it to escape neutralization by vaccine-elicited antibodies and might cause monoclonal antibody therapy for COVID-19 to be less successful.

scholarly journals Mass Spectrometry Approaches for Identification and Quantitation of Therapeutic Monoclonal Antibodies in the Clinical Laboratory

2017 ◽  
Vol 24 (5) ◽  
Author(s):  
Paula M. Ladwig ◽  
David R. Barnidge ◽  
Maria A. V. Willrich
Keyword(s):  
Mass Spectrometry ◽  
Monoclonal Antibodies ◽  
Clinical Laboratory ◽  
Enzyme Linked Immunosorbent Assay ◽  
Measurement Tool ◽  
The Past ◽  
Therapeutic Drugs ◽  
Therapeutic Monoclonal Antibodies ◽  
Made In

ABSTRACT Therapeutic monoclonal antibodies (MAbs) are an important class of drugs used to treat diseases ranging from autoimmune disorders to B cell lymphomas to other rare conditions thought to be untreatable in the past. Many advances have been made in the characterization of immunoglobulins as a result of pharmaceutical companies investing in technologies that allow them to better understand MAbs during the development phase. Mass spectrometry is one of the new advancements utilized extensively by pharma to analyze MAbs and is now beginning to be applied in the clinical laboratory setting. The rise in the use of therapeutic MAbs has opened up new challenges for the development of assays for monitoring this class of drugs. MAbs are larger and more complex than typical small-molecule therapeutic drugs routinely analyzed by mass spectrometry. In addition, they must be quantified in samples that contain endogenous immunoglobulins with nearly identical structures. In contrast to an enzyme-linked immunosorbent assay (ELISA) for quantifying MAbs, mass spectrometry-based assays do not rely on MAb-specific reagents such as recombinant antigens and/or anti-idiotypic antibodies, and time for development is usually shorter. Furthermore, using molecular mass as a measurement tool provides increased specificity since it is a first-order principle unique to each MAb. This enables rapid quantification of MAbs and multiplexing. This review describes how mass spectrometry can become an important tool for clinical chemists and especially immunologists, who are starting to develop assays for MAbs in the clinical laboratory and are considering mass spectrometry as a versatile platform for the task.

scholarly journals An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by several therapeutic monoclonal antibodies

2021 ◽  
Author(s):  
Laura A VanBlargan ◽  
John M Errico ◽  
Peter Halfmann ◽  
Seth J Zost ◽  
James E. Crowe ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Severe Acute Respiratory Syndrome ◽  
Clinical Development ◽  
Spike Protein ◽  
Clinical Use ◽  
Receptor Binding Domain ◽  
Antigenic Sites ◽  
Recent Emergence ◽  
Therapeutic Monoclonal Antibodies ◽  
The Impact

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic resulting in millions of deaths worldwide. Despite the development and deployment of highly effective antibody and vaccine countermeasures, rapidly-spreading SARS-CoV-2 variants with mutations at key antigenic sites in the spike protein jeopardize their efficacy. Indeed, the recent emergence of the highly-transmissible B.1.1.529 Omicron variant is especially concerning because of the number of mutations, deletions, and insertions in the spike protein. Here, using a panel of anti-receptor binding domain (RBD) monoclonal antibodies (mAbs) corresponding to those with emergency use authorization (EUA) or in advanced clinical development by Vir Biotechnology (S309, the parent mAbs of VIR-7381), AstraZeneca (COV2-2196 and COV2-2130, the parent mAbs of AZD8895 and AZD1061), Regeneron (REGN10933 and REGN10987), Lilly (LY-CoV555 and LY-CoV016), and Celltrion (CT-P59), we report the impact on neutralization of a prevailing, infectious B.1.1.529 Omicron isolate compared to a historical WA1/2020 D614G strain. Several highly neutralizing mAbs (LY-CoV555, LY-CoV016, REGN10933, REGN10987, and CT-P59) completely lost inhibitory activity against B.1.1.529 virus in both Vero-TMPRSS2 and Vero-hACE2-TMPRSS2 cells, whereas others were reduced (~12-fold decrease, COV2-2196 and COV2-2130 combination) or minimally affected (S309). Our results suggest that several, but not all, of the antibody products in clinical use will lose efficacy against the B.1.1.529 Omicron variant and related strains.

scholarly journals In vitro and in vivo preclinical studies predict REGEN-COV protection against emergence of viral escape in humans

2021 ◽  
Author(s):  
Richard Copin ◽  
Alina Baum ◽  
Elzbieta Wloga ◽  
Kristen E. Pascal ◽  
Stephanie Giordano ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Therapeutic Option ◽  
Viral Escape ◽  
Spike Protein ◽  
In Vivo Studies ◽  
Preclinical Studies ◽  
Global Pandemic ◽  
Emerging Virus

SummaryMonoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. As rapidly emerging virus mutants are becoming the next major concern in the fight against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of minor virus variants in SARS-COV-2 isolates found in nature or identified from preclinical in vitro and in vivo studies and in the clinic. This study demonstrates that a combination of noncompeting antibodies not only provides full coverage against currently circulating variants but also protects against emergence of new such variants and their potential seeding into the population in a clinical setting.

scholarly journals Convalescent-Phase Sera and Vaccine-Elicited Antibodies Largely Maintain Neutralizing Titer against Global SARS-CoV-2 Variant Spikes

mBio ◽  
2021 ◽  
Author(s):  
Takuya Tada ◽  
Belinda M. Dcosta ◽  
Marie I. Samanovic ◽  
Ramin S. Herati ◽  
Amber Cornelius ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Rapid Evolution ◽  
Spike Protein ◽  
Convalescent Phase ◽  
Therapeutic Monoclonal Antibodies

The rapid evolution of SARS-CoV-2 variants has raised concerns with regard to their potential to escape from vaccine-elicited antibodies and anti-spike protein monoclonal antibodies. We report here on an analysis of sera from recovered patients and vaccinated individuals and on neutralization by Regeneron therapeutic monoclonal antibodies.

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