Landscape analysis of escape variants identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization

Liu, Zhuoming; La, VanBlargan; Bloyet, Louis-Marie; Rothlauf, Paul W.; Re, Chen; Stumpf, Spencer; Zhao, Hui; Jm, Errico; Theel, ES; Liebeskind, Mariel J.; Alford, Brynn; Wj, Buchser; Ah, Ellebedy; Fremont, Daved H.; Ms, Diamond; Spj, Whelan

doi:10.1101/2020.11.06.372037

Cited by 167 publications

(216 citation statements)

References 44 publications

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“…Y453F and N439K both also increase affinity for ACE2 (Starr et al, 2020b;Thomson et al, 2020) , and both escape some monoclonal antibodies (Baum et al, 2020;Starr et al, 2020a;Thomson et al, 2020) but neither greatly impact serum antibody binding by the samples we tested. Finally, S477N also reduces neutralization by some monoclonal antibodies (Liu et al, 2020b) , but did not greatly affect binding by the samples we tested.…”

Section: Rbd Mutations That Reduce Serum Binding and Neutralization Imentioning

confidence: 74%

“…A multitude of recent studies have identified viral mutations that escape monoclonal antibodies targeting the SARS-CoV-2 spike (Baum et al, 2020;Greaney et al, 2020;Li et al, 2020;Liu et al, 2020b;Starr et al, 2020a;Weisblum et al, 2020) . However, it remains unclear how mutations that escape specific monoclonal antibodies will affect the polyclonal antibody response elicited by infection or vaccination.…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies

Greaney

Loes

Crawford

et al. 2021

Preprint

191

166

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The evolution of SARS-CoV-2 could impair recognition of the virus by human antibody-mediated immunity. To facilitate prospective surveillance for such evolution, we map how convalescent serum antibodies are impacted by all mutations to the spike’s receptor-binding domain (RBD), the main target of serum neutralizing activity. Binding by polyclonal serum antibodies is affected by mutations in three main epitopes in the RBD, but there is substantial variation in the impact of mutations both among individuals and within the same individual over time. Despite this inter- and intra-person heterogeneity, the mutations that most reduce antibody binding usually occur at just a few sites in the RBD’s receptor binding motif. The most important site is E484, where neutralization by some sera is reduced >10-fold by several mutations, including one in emerging viral lineages in South Africa and Brazil. Going forward, these serum escape maps can inform surveillance of SARS-CoV-2 evolution.

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Section: Rbd Mutations That Reduce Serum Binding and Neutralization Imentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies

Greaney

Loes

Crawford

et al. 2021

Preprint

191

166

View full text Add to dashboard Cite

show abstract

“…To investigate potential viral escape from neutralization mediated by the potent neutralizing NTD mAbs, we passaged a replication competent VSV-SARS-CoV-2 chimera in which the native glycoprotein was replaced by the SARS-CoV-2 S Wuhan-1 gene in the presence of S2L28, S2M28, S2×28 and S2×333, as previously described (Case et al, 2020; Liu et al, 2020b). Selective pressure provided by each mAb led to emergence of several escape mutants that clustered within the antigenic supersite i.e.…”

Section: Introductionmentioning

confidence: 99%

N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

McCallum

Marco

Lempp

et al. 2021

Preprint

Self Cite

257

407

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SARS-CoV-2 entry into host cells is orchestrated by the spike (S) glycoprotein that contains an immunodominant receptor-binding domain (RBD) targeted by the largest fraction of neutralizing antibodies (Abs) in COVID-19 patient plasma. Little is known about neutralizing Abs binding to epitopes outside the RBD and their contribution to protection. Here, we describe 41 human monoclonal Abs (mAbs) derived from memory B cells, which recognize the SARS-CoV-2 S N-terminal domain (NTD) and show that a subset of them neutralize SARS-CoV-2 ultrapotently. We define an antigenic map of the SARS-CoV-2 NTD and identify a supersite recognized by all known NTD-specific neutralizing mAbs. These mAbs inhibit cell-to-cell fusion, activate effector functions, and protect Syrian hamsters from SARS-CoV-2 challenge. SARS-CoV-2 variants, including the 501Y.V2 and B.1.1.7 lineages, harbor frequent mutations localized in the NTD supersite suggesting ongoing selective pressure and the importance of NTD-specific neutralizing mAbs to protective immunity.

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“…Here, the supposed mechanism leading to reinfection is a loss of protection elicited after the first episode, as it is known for other human coronaviruses [ 9 ]. The only mutation found in the spike region between the two episodes has not been associated with reduced neutralization by human convalescent sera [ 10 ]. In vitro, this mutation may lead to monoclonal antibodies neutralization resistance but whether this is relevant for human reinfections remains to be studied.…”

Section: Discussionmentioning

confidence: 99%

Clinical, virologic and immunologic features of a mild case of SARS-CoV-2 reinfection

Vetter¹,

Cordey²,

Schibler³

et al. 2021

Clinical Microbiology and Infection

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Objectives We report a case of SARS-CoV-2 reinfection 6 months after the first infection in a young healthy female physician. Both episodes led to mild COVID-19. Methods SARS-CoV-2 infections was detected by RT-PCR on naso-pharyngeal specimens. Reinfection was confirmed by whole-genome sequencing. Kinetics of total anti-S receptor binding domain immunoglobulins (Ig anti-S RBD), anti-nucleoprotein (anti-N) and neutralizing antibodies were determined in serial serum samples retrieved during both infection episodes. Memory B cells responses were assessed at day 12 post reinfection. Results Whole-genome sequencing identified two different SARS-CoV-2 genomes both belonging to clade 20A, with only one non-synonymous mutation in the spike protein, and clustered with viruses circulating in Geneva (Switzerland) at the time of each of the corresponding episodes. Seroconversion was documented with low level of total Ig anti-S RBD and anti-N antibodies at one month after the first infection whereas neutralizing antibodies quickly declined after the first episode and then were boosted by the reinfection, with high titers detectable 4 days after symptoms onset. A strong memory B cell response was detected at day 12 post onset of symptoms during reinfection, indicating that the first episode elicited cellular memory responses. Conclusion Rapid decline of neutralizing antibodies may put medical personnel at risk of reinfection as shown in this case. Reinfection however leads to a significant boosting of previous immune responses. Larger cohorts of reinfected subjects with detailed descriptions of their immune responses are needed to define correlates of protection and their duration after infection.

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Landscape analysis of escape variants identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody neutralization

Cited by 167 publications

References 44 publications

Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies

Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies

N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2

Clinical, virologic and immunologic features of a mild case of SARS-CoV-2 reinfection

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