The variant gambit: COVID-19’s next move

Plante, Jessica A.; Mitchell, Brooke; Plante, Kenneth S.; Debbink, Kari; Weaver, Scott C.; Menachery, Vineet D.

doi:10.1016/j.chom.2021.02.020

Cited by 335 publications

(353 citation statements)

References 54 publications

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“…SARS-CoV-2 is the causative agent of Coronavirus Disease 2019 , which has resulted in a devastating global pandemic with over 100 million cases and 2.4 million deaths worldwide (WHO, 2021). As SARS-CoV-2 has spread across the world, there has been a dramatic increase in the emergence of variants with mutations in the nonstructural and structural proteins (Plante et al, 2021). The viral spike protein is found on the outside of the virion and binds to the ACE2 receptor expressed on cells within the respiratory tract (Walls et al, 2020).…”

mentioning

confidence: 99%

Infection- and vaccine-induced antibody binding and neutralization of the B.1.351 SARS-CoV-2 variant

Edara

Norwood

Floyd

et al. 2021

Cell Host & Microbe

222

182

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The emergence of SARS-CoV-2 variants with mutations in the spike protein is raising concerns about the efficacy of infection-or vaccine-induced antibodies. We compared antibody binding and live virus neutralization of sera from naturally infected and Moderna-vaccinated individuals against two SARS-CoV-2 variants: B.1 containing the spike mutation D614G and the emerging B.1.351 variant containing additional spike mutations and deletions. Sera from acutely infected and convalescent COVID-19 patients exhibited a 3-fold reduction in binding antibody titers to the B.1.351 variant receptor-binding domain of the spike protein and a 3.5-fold reduction in neutralizing antibody titers against SARS-CoV-2 B.1.351 variant compared to the B.1 variant. Similar results were seen with sera from Moderna-vaccinated individuals. Despite reduced antibody titers against the B.1.351 variant, sera from infected and vaccinated individuals containing polyclonal antibodies to the spike protein could still neutralize SARS-CoV-2 B.1.351, suggesting that protective humoral immunity may be retained against this variant.

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mentioning

confidence: 99%

Infection- and vaccine-induced antibody binding and neutralization of the B.1.351 SARS-CoV-2 variant

Edara

Norwood

Floyd

et al. 2021

Cell Host & Microbe

222

182

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“…Recently, SARS-CoV-2 variants have emerged with mutations in the RBD, with two of the key mutations involving interactions with hACE2 residues 30 and 353 (38). Republic of South Africa (RSA) variants (B.1.351 and 501Y.V2) have the RBD mutations K417N and N501Y, and the United Kingdom (UK) variants (B.1.1.7 and 501Y.V1) have the N501Y mutation (38). Modelling predicts that the K417N mutation would result in the gain of an interaction between RBD N417 and mACE2-Q34, whereas the interaction between K417 and hACE2-D30 would be lost (Figure 1F).…”

Section: Resultsmentioning

confidence: 99%

“…Polar interactions (blue lines) or any interactions within 3.5Å (yellow lines) were shown for selected residues. The K417N and N501Y mutations in the UK variant (B.1.1.7) and RSA variant (B.1.351) were introduced (38).…”

Section: Methodsmentioning

confidence: 99%

ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

Rawle

Dumenil

et al. 2021

Preprint

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SARS-CoV-2 uses the human ACE2 receptor (hACE2), with mouse ACE2 (mACE2) unable to support infection. Herein we describe an ACE2-lentivirus system and illustrate its utility in vitro and in vivo. Transduction of non-permissive cell lines with hACE2 imparted replication competence, and transduction with mACE2 containing N30D, N31K, F83Y and H353K mutations, to match hACE2, rescued SARS-CoV-2 replication. hACE2-lentivirus transduction of C57BL/6J, IFNAR-/- and IL-28RA-/- mice lungs indicated type I and III IFN receptor knockout had minimal effect on virus replication. However, RNA-Seq illustrated that they were required for inflammatory responses in C57BL/6J mice, which were similar to those seen in COVID-19 patients. Finally, we illustrate the utility of hACE2 transduction for vaccine evaluation in C57BL/6J mice. The hACE2-lentivirus system thus has broad application in SARS-CoV-2 research, in particular allowing access to GM mice, while also offering the inherent advantages of lentiviral transduction such as stable genomic integration.

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“…Several mutations and deletions in emerging VOCs occur in the NTD and RBD that allow them to avoid antibody recognition, including RBD mutations K417N/T (B.1.351 and B.1.1.28), N439K (B.1.222), L452R (B.1.429), Y453R (B.1.1.298), E484K (B.1.351 and B.1.1.28), and N501Y (B.1.1.7, B.1.351, and B.1.1.28) (reviewed by (Plante et al, 2021)), highlighting the importance of developing mAbs against a variety of spatially distinct epitopes. In our panel, SARS2-38 potently neutralized viruses encoding any of the above mutations, did not readily select for escape mutations with authentic SARS-CoV-2 strains, and retained therapeutic activity in vivo against a virus containing substitutions of one of the key VOCs (B.1.351).…”

Section: Discussionmentioning

confidence: 99%

A potently neutralizing anti-SARS-CoV-2 antibody inhibits variants of concern by binding a highly conserved epitope

VanBlargan

Adams

et al. 2021

Preprint

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SUMMARYWith the emergence of SARS-CoV-2 variants with increased transmissibility and potential resistance, antibodies and vaccines with broadly inhibitory activity are needed. Here we developed a panel of neutralizing anti-SARS-CoV-2 mAbs that bind the receptor binding domain of the spike protein at distinct epitopes and block virus attachment to cells and its receptor, human angiotensin converting enzyme-2 (hACE2). While several potently neutralizing mAbs protected K18-hACE2 transgenic mice against infection caused by historical SARS-CoV-2 strains, others induced escape variantsin vivoand lost activity against emerging strains. We identified one mAb, SARS2-38, that potently neutralizes all SARS-CoV-2 variants of concern tested and protects mice against challenge by multiple SARS-CoV-2 strains. Structural analysis showed that SARS2-38 engages a conserved epitope proximal to the receptor binding motif. Thus, treatment with or induction of inhibitory antibodies that bind conserved spike epitopes may limit the loss of potency of therapies or vaccines against emerging SARS-CoV-2 variants.

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The variant gambit: COVID-19’s next move

Cited by 335 publications

References 54 publications

Infection- and vaccine-induced antibody binding and neutralization of the B.1.351 SARS-CoV-2 variant

Infection- and vaccine-induced antibody binding and neutralization of the B.1.351 SARS-CoV-2 variant

ACE2-lentiviral transduction enables mouse SARS-CoV-2 infection and mapping of receptor interactions

A potently neutralizing anti-SARS-CoV-2 antibody inhibits variants of concern by binding a highly conserved epitope

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