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

Greaney, Allison J; Loes, Andrea N; Crawford, Katharine H.D.; Starr, Tyler N; Malone, Keara D.; Chu, Helen Y.; Bloom, Jesse D.

doi:10.1101/2020.12.31.425021

Cited by 191 publications

(174 citation statements)

References 64 publications

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“…These antibodies target epitopes that overlap or are closely associated with RBD residues K417, E484 and N501. They are frequently sensitive to mutation in these residues and select for K417N, E484K and N501Y mutations in SARS-CoV-2 S protein expression libraries in yeast and VSV 12,15,33 . To avert selection and escape, antibody therapies should be composed of combinations of antibodies that target non-overlapping or highly conserved epitopes 8,12,13,33,[40][41][42][43][44] .…”

Section: Discussionmentioning

confidence: 99%

“…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][15][16][17][18][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%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

Section: Vaccine Plasma Binding and Neutralizing Activity Against Sarmentioning

confidence: 99%

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

confidence: 99%

See 1 more Smart Citation

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

Wang

Schmidt

Weisblum

et al. 2021

Preprint

280

313

View full text Add to dashboard Cite

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“…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] . Consistently, we found that K417N dramatically decreased the binding of COV107-23 (clonotype 1) and COVD21-C8 (clonotype 2)…”

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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“…C121 escape mutations at 171 E484 were observed in vitro 14 . Mutations at this residue, present also in the novel South African variant (501Y.V2), reduce neutralization by human sera more than 10-fold 21 . E484D affects intermolecular H-bonds at the core of the C121/RBD interface (Fig.2j) and it is suggested to increase the RBD affinity for ACE2 22 .…”

mentioning

confidence: 97%

Bispecific antibody neutralizes circulating SARS-CoV-2 variants, prevents escape and protects mice from disease

Gasparo¹,

Pedotti²,

Simonelli³

et al. 2021

Preprint

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SummaryNeutralizing antibodies targeting the receptor binding domain (RBD) of the SARS-CoV-2 Spike (S) are among the most promising approaches against coronavirus disease 2019 (COVID-19)1,2. We developed a bispecific, IgG1-like molecule based on two antibodies derived from COVID-19 convalescent donors, C121 and C1353. CoV-X2 simultaneously binds two independent sites on the RBD and, unlike its parental antibodies, completely prevents S binding to Angiotensin-Converting Enzyme 2 (ACE2), the virus cellular receptor. Furthermore, CoV-X2 recognizes a broad panel of RBD variants and neutralizes SARS-CoV-2 and the escape mutants generated by the single monoclonals at sub-nanomolar concentrations. In a novel model of SARS-CoV-2 infection with lung inflammation, CoV-X2 protects mice from disease and suppresses viral escape. Thus, simultaneous targeting of non-overlapping RBD epitopes by IgG-like bispecific antibodies is feasible and effective, combining into a single molecule the advantages of antibody cocktails.

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

Cited by 191 publications

References 64 publications

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

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

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

Bispecific antibody neutralizes circulating SARS-CoV-2 variants, prevents escape and protects mice from disease

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