SARS-CoV-2 escape<i>in vitro</i>from a highly neutralizing COVID-19 convalescent plasma

Andreano, Emanuele; Piccini, Giulia; Licastro, Danilo; Casalino, Lorenzo; Johnson, Nicole V.; Paciello, Ida; Monego, Simeone Dal; Pantano, Elisa; Manganaro, Noemi; Manenti, Alessandro; Manna, Rachele; Casa, Elisa; Hyseni, Inesa; Benincasa, Linda; Montomoli, Emanuele; Amaro, Rommie E.; McLellan, Jason S.; Rappuoli, Rino

doi:10.1101/2020.12.28.424451

Cited by 298 publications

(328 citation statements)

References 50 publications

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“…For the time being, we do not know if the N501Y alone could counterbalance the predicted unfavorable Spike K417N and E484K amino acid replacements. Considering the clinical observations about the South African strain and potentials greater risks relative to the UK strain, as it is definitively unclear that the affinity between the Spike and ACE2 is significantly enhanced (according to our predictions), then, danger is due to some amino acid changes (e.g., Spike residue 484 in this region of the protein and possibly elsewhere) that impede recognition by neutralizing antibodies [39,40]. For the UK strain, could it be that the enhanced affinity to ACE2 not only increases transmissibility but also disease severity (not only due the increased number of infected individuals) as suggested after comparisons between SARS-CoV-2 and other human coronaviruses [41]?…”

Section: Discussionmentioning

confidence: 78%

In silico investigation of the new UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 variants with a focus at the ACE2-Spike RBD interface

Villoutreix

Cálvez

Marcelin

et al. 2021

Preprint

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SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as a receptor to invade cells. It has been reported that the UK and South African strains may have higher transmission capabilities, eventually due to amino acid substitutions on the SARS-CoV-2 Spike protein. The pathogenicity seems modified but is still under investigation. Here we used the experimental structure of the Spike RBD domain co-crystallized with part of the ACE2 receptor and several in silico methods to analyze the possible impacts of three amino acid replacements (Spike K417N, E484K, N501Y) with regard to ACE2 binding. We found that the N501Y replacement in this region of the interface (present in both UK and South African strains) should be favorable for the interaction with ACE2 while the K417N and E484K substitutions (South African) would seem unfavorable. It is unclear if the N501Y substitution in the South African strain could counterbalance the predicted less favorable (regarding binding) K417N and E484K Spike replacements. Our finding suggests that, if indeed the South African strain has a high transmission level, this could be due to the N501Y replacement and/or to substitutions in regions outside the direct Spike-ACE2 interface.HihglightsTransmission of the UK and possibly South African SARS-CoV-2 strains appears substantially increased compared to other variantsThis could be due, in part, to increased affinity between the variant Spike proteins and ACE2We investigated in silico the 3D structure of the Spike-ACE2 complex with a focus on Spike K417N, E484K and N501YThe N501Y substitution is predicted to increase the affinity toward ACE2 (UK strain) with subsequent enhanced transmissibility and possibly pathogenicityAdditional substitutions at positions 417 and 484 (South African strain) may pertub the interaction with ACE2 raising questions about transmissibility and pathogenicity

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Section: Discussionmentioning

confidence: 78%

In silico investigation of the new UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 variants with a focus at the ACE2-Spike RBD interface

Villoutreix

Cálvez

Marcelin

et al. 2021

Preprint

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“…Circulating SARS-CoV-2 mutant variants represent a major ongoing challenge to natural immunity and vaccination. In particular, a lot of attention has been focused on RBD mutation E484K, which has emerged in multiple independently SARS-CoV-2 lineages 63, 64 and can alter the antigenicity of the spike protein [65][66][67] . Another naturally occurring RBD mutation, K417N, which has emerged in South Africa and Brazil (B.1.351 lineage and B.1.1.28, respectively) 63, 64,68 , has recently been shown to also alter antigenicity of the spike protein 66,[69][70][71] .…”

Section: Discussionmentioning

confidence: 99%

Sequence signatures of two IGHV3-53/3-66 public clonotypes to SARS-CoV-2 receptor binding domain

Tan

Yuan

Kuzelka

et al. 2021

Preprint

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Since the COVID-19 pandemic onset, the antibody response to SARS-CoV-2 has been extensively characterized. Antibodies to the receptor binding domain (RBD) on the spike protein are frequently encoded by IGHV3-53/3-66 with a short CDR H3. Germline-encoded sequence motifs in CDRs H1 and H2 play a major role, but whether any common motifs are present in CDR H3, which is often critical for binding specificity, have not been elucidated. Here, we identify two public clonotypes of IGHV3-53/3-66 RBD antibodies with a 9-residue CDR H3 that pair with different light chains. Distinct sequence motifs on CDR H3 are present in the two public clonotypes that appear to be related to differential light chain pairing. Additionally, we show that Y58F is a common somatic hypermutation that results in increased binding affinity of IGHV3-53/3-66 RBD antibodies with a short CDR H3. Overall, our results advance fundamental understanding of the antibody response to SARS-CoV-2.

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“…6a, and Table 5 and 7,8 ). To examine memory B cell antibodies for binding to circulating SARS-CoV-2 variants and antibody resistant mutants we performed ELISAs using mutant RBDs 12,15,[28][29][30][31] . Twenty-two (26%) of the 84 antibodies tested showed at least 5-fold decreased binding to at least one of the mutant RBDs (Extended data Fig.…”

Section: Vaccine-elicited Sars-cov-2 Rbd-specific Monoclonal Antibodiesmentioning

confidence: 99%

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

Wang

Schmidt

Weisblum

et al. 2021

Preprint

279

313

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To date severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 100 million individuals resulting in over two million deaths. Many vaccines are being deployed to prevent coronavirus disease 2019 (COVID-19) including two novel mRNA-based vaccines1,2. These vaccines elicit neutralizing antibodies and appear to be safe and effective, but the precise nature of the elicited antibodies is not known3–6. Here we report on the antibody and memory B cell responses in a cohort of 20 volunteers who received either the Moderna (mRNA-1273) or Pfizer-BioNTech (BNT162b2) vaccines. Consistent with prior reports, 8 weeks after the second vaccine injection volunteers showed high levels of IgM, and IgG anti-SARS-CoV-2 spike protein (S) and receptor binding domain (RBD) binding titers3,5,6. Moreover, the plasma neutralizing activity, and the relative numbers of RBD-specific memory B cells were equivalent to individuals who recovered from natural infection7,8. However, activity against SARS-CoV-2 variants encoding E484K or N501Y or the K417N:E484K:N501Y combination was reduced by a small but significant margin. Consistent with these findings, vaccine-elicited monoclonal antibodies (mAbs) potently neutralize SARS-CoV-2, targeting a number of different RBD epitopes in common with mAbs isolated from infected donors. Structural analyses of mAbs complexed with S trimer suggest that vaccine- and virus-encoded S adopts similar conformations to induce equivalent anti-RBD antibodies. However, neutralization by 14 of the 17 most potent mAbs tested was reduced or abolished by either K417N, or E484K, or N501Y mutations. Notably, the same mutations were selected when recombinant vesicular stomatitis virus (rVSV)/SARS-CoV-2 S was cultured in the presence of the vaccine elicited mAbs. Taken together the results suggest that the monoclonal antibodies in clinical use should be tested against newly arising variants, and that mRNA vaccines may need to be updated periodically to avoid potential loss of clinical efficacy.

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SARS-CoV-2 escapein vitrofrom a highly neutralizing COVID-19 convalescent plasma

Cited by 298 publications

References 50 publications

In silico investigation of the new UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 variants with a focus at the ACE2-Spike RBD interface

In silico investigation of the new UK (B.1.1.7) and South African (501Y.V2) SARS-CoV-2 variants with a focus at the ACE2-Spike RBD interface

Sequence signatures of two IGHV3-53/3-66 public clonotypes to SARS-CoV-2 receptor binding domain

mRNA vaccine-elicited antibodies to SARS-CoV-2 and circulating variants

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