Genetic Variants of SARS-CoV-2—What Do They Mean?

Lauring, Adam S.; Hodcroft, Emma B.

doi:10.1001/jama.2020.27124

Cited by 580 publications

(556 citation statements)

References 10 publications

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“…To determine whether plasma from vaccinated individuals can neutralize circulating SARS-CoV-2 variants of concern and mutants that arise in vitro under antibody pressure 13,14 , we tested vaccinee plasma against a panel of 10 mutant pseudotype viruses including recently reported N501Y (B1.1.7 variant), K417N, E484K and the combination of these 3 RBD mutations (501Y.V2 variant) [15][16][17][18][19][20] . Vaccinee plasma was significantly less effective in neutralizing the HIV-1 virus pseudotyped with certain SARS-CoV-2 mutant S proteins ( Fig.…”

Section: Articlementioning

confidence: 99%

“…To examine the neutralizing breadth of the monoclonal antibodies and begin to map their target epitopes we tested 17 of the most potent antibodies (Extended data Table 6), 8 of which carried IgHV3-53, against a panel of 12 SARS-CoV-2 variants: A475V is resistant to class 1 antibodies (structurally defined as described 7 ); E484K and Q493R are resistant to class 2 antibodies [5][6][7][8]13,14,31,32 ; while R346S, N439K, and N440K are resistant to class 3 antibodies 5-7,13,14,32 . Additionally, K417N, Y453F, S477R, N501Y, and D614G represent circulating variants some of which have been associated with rapidly increasing case numbers 15,16,20,[32][33][34] . Based on their neutralizing activity against the variants, all but 3 of the antibodies were provisionally assigned to a defined antibody class or a combination (Fig.…”

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

confidence: 99%

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

Wang

Schmidt

Weisblum

et al. 2021

Nature

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Rafael C as el la s , T he od or a Hatziioannou, Paul D. Bieniasz & M ic hel C. Nussenzweig This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

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Section: Articlementioning

confidence: 99%

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

Nature

1,328

100

1,304

View full text Add to dashboard Cite

show abstract

“…To determine whether plasma from vaccinated individuals can neutralize circulating SARS-CoV-2 variants of concern and mutants that arise in vitro under antibody pressure 12,13 , we tested vaccinee plasma against a panel of 10 mutant pseudotype viruses including recently reported N501Y (B1.1.7 variant), K417N, E484K and the combination of these 3 RBD mutations (501Y.V2 variant) 14–19 . Vaccinee plasma was significantly less effective in neutralizing the HIV-1 virus pseudotyped with certain SARS-CoV-2 mutant S proteins (Fig.…”

Section: Vaccine Plasma Binding and Neutralizing Activity Against Sarmentioning

confidence: 99%

“…To examine the neutralizing breadth of the monoclonal antibodies and begin to map their target epitopes we tested 17 of the most potent antibodies (Extended data Table 6), 8 of which carried IgHV3-53, against a panel of 12 SARS-CoV-2 variants: A475V is resistant to class 1 antibodies (structurally defined as described 29 ); E484K and Q493R are resistant to class 2 antibodies 7,8,12,13,29,30,32,33 ; while R346S, N439K, and N440K are resistant to class 3 antibodies 7,8,12,13,29,33 . Additionally, K417N, Y453F, S477R, N501Y, and D614G represent circulating variants some of which have been associated with rapidly increasing case numbers 14,15,19,33–35 . Based on their neutralizing activity against the variants, all but 3 of the antibodies were provisionally assigned to a defined antibody class or a combination (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

280

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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“…Notably, the replication complex of coronaviruses includes proofreading activity, leading to greater genome stability as compared to other RNA viruses that typically lack this function [18]. Nevertheless, several mutations in the SARS-CoV-2 genome have already been reported in human-circulating viruses worldwide, and some exhibit increasing prevalence suggestive of positive-selection or fitness advantage in the new human host [19-21]. An important example of this is the D614G substitution in S, which rapidly dominated SARS-CoV-2 sequences following its emergence, and is functionally linked to increased virus infectivity and replication capacity [22-25], potentially aiding virus spread throughout the population.…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Variants Reveal Features Critical for Replication in Primary Human Cells

Pohl

Busnadiego

Kufner

et al. 2020

Preprint

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Since entering the human population, SARS-CoV-2 (the causative agent of COVID-19) has spread across the world, causing >40 million infections and >1 million deaths. While large-scale sequencing efforts have identified numerous genetic mutations in SARS-CoV-2 during its circulation, it remains largely unclear whether these changes impact adaptation, replication or transmission of the virus in its new host. Here, we characterized 14 different low-passage replication-competent human SARS-CoV-2 isolates representing all the major European clades observed during the first pandemic wave in early 2020. By integrating viral sequencing data from patient material, viral stocks and passaging experiments, with kinetic virus replication data from non-human Vero-CCL81 cells and primary differentiated human bronchial epithelial cells (BEpCs), we observed several SARS-CoV-2 sequence features that associate with distinct phenotypes. Notably, naturally-occurring substitutions in Orf3a (Q57H) and nsp2 (T85I) were associated with poor replication in Vero-CCL81 cells but not in BEpCs, while SARS-CoV-2 isolates expressing the Spike D614G substitution generally exhibited enhanced replication abilities in BEpCs. Strikingly, low-passage Vero-derived stock preparation of 3 SARS-CoV-2 isolates selected for substitutions at positions 5/6 of E, and were highly attenuated in BEpCs, revealing a key cell-specific function to this region. Rare isolate-specific deletions were also observed in the Spike furin-cleavage site during Vero-CCL81 passage, but these were rapidly selected against in BEpCs, underscoring the importance of this site for SARS-CoV-2 replication in primary human respiratory cells. Overall, our study uncovers natural sequence features in the SARS-CoV-2 genome that determine efficient virus replication and tropism for the human respiratory epithelium.

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Genetic Variants of SARS-CoV-2—What Do They Mean?

Cited by 580 publications

References 10 publications

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

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

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

SARS-CoV-2 Variants Reveal Features Critical for Replication in Primary Human Cells

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