Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies
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Abstract
The SARS-CoV-2 B.1.1.529 (Omicron) variant contains 15 mutations of the receptor-binding domain (RBD). How Omicron evades RBD-targeted neutralizing antibodies requires immediate investigation. Here we use high-throughput yeast display screening 1,2 to determine the profiles of RBD escaping mutations for 247 human anti-RBD neutralizing antibodies and show that the neutralizing antibodies can be classified by unsupervised clustering into six epitope groups (A–F)—a grouping that is highly concordant with knowledge-based structural classifications 3–5 . Various single mutations of Omicron can impair neutralizing antibodies of different epitope groups. Specifically, neutralizing antibodies in groups A–D, the epitopes of which overlap with the ACE2-binding motif, are largely escaped by K417N, G446S, E484A and Q493R. Antibodies in group E (for example, S309) 6 and group F (for example, CR3022) 7 , which often exhibit broad sarbecovirus neutralizing activity, are less affected by Omicron, but a subset of neutralizing antibodies are still escaped by G339D, N440K and S371L. Furthermore, Omicron pseudovirus neutralization showed that neutralizing antibodies that sustained single mutations could also be escaped, owing to multiple synergetic mutations on their epitopes. In total, over 85% of the tested neutralizing antibodies were escaped by Omicron. With regard to neutralizing-antibody-based drugs, the neutralization potency of LY-CoV016, LY-CoV555, REGN10933, REGN10987, AZD1061, AZD8895 and BRII-196 was greatly undermined by Omicron, whereas VIR-7831 and DXP-604 still functioned at a reduced efficacy. Together, our data suggest that infection with Omicron would result in considerable humoral immune evasion, and that neutralizing antibodies targeting the sarbecovirus conserved region will remain most effective. Our results inform the development of antibody-based drugs and vaccines against Omicron and future variants.
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SciScore for 10.1101/2021.12.07.470392: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources The enriched B cells were stained in FACS buffer (1× PBS, 2% FBS, 1 mM EDTA) with the following anti-human antibodies and antigens: FITC anti-CD19 Antibody (Biolegend), FITC anti-CD20 Antibody (Biolegend), Brilliant Violet 421 anti-CD27 Antibody (Biolegend), PE/Cyanine7 anti-IgM, and fluorophore-labelled RBD (SARS-CoV-2 and SARS-CoV RBD, Sino Biological Inc.) and ovalbumin (Ova) for 30 min on ice. anti-humansuggested: Noneanti-CD19suggested: Noneanti-CD20suggested: Noneanti-CD27suggested: Noneanti-IgMsuggested: NoneThen beads were incubated with neutralizing antibody and rotated at room temperature for … SciScore for 10.1101/2021.12.07.470392: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources The enriched B cells were stained in FACS buffer (1× PBS, 2% FBS, 1 mM EDTA) with the following anti-human antibodies and antigens: FITC anti-CD19 Antibody (Biolegend), FITC anti-CD20 Antibody (Biolegend), Brilliant Violet 421 anti-CD27 Antibody (Biolegend), PE/Cyanine7 anti-IgM, and fluorophore-labelled RBD (SARS-CoV-2 and SARS-CoV RBD, Sino Biological Inc.) and ovalbumin (Ova) for 30 min on ice. anti-humansuggested: Noneanti-CD19suggested: Noneanti-CD20suggested: Noneanti-CD27suggested: Noneanti-IgMsuggested: NoneThen beads were incubated with neutralizing antibody and rotated at room temperature for 30min. 30minsuggested: NoneThe supernatant was separated and proceed to a second round of negative selection to ensure full depletion of antibody-binding yeast. antibody-binding yeast.suggested: NoneFirst, anti-c-Myc magnetic beads (Thermo Fisher) were washed and resuspend with 1X TBST, then the prepared beads were incubated for 30min with the antibody escaping yeasts after two rounds of negative selection. anti-c-Mycsuggested: NoneOvernight cultures of MACS sorted antibody-escaped and ACE2 preselected yeast populations were proceed to yeast plasmid extraction kit (Zymo Research). ACE2suggested: NoneExperimental Models: Cell Lines Sentences Resources Briefly, heavy and light genes were cloned into expression vectors respectively based on Gibson assembly, which were subsequently co-transfected into HEK293 cells. HEK293suggested: CLS Cat# 300192/p777_HEK293, RRID:CVCL_0045)Briefly, serially diluted antibodies were first incubated with pseudotyped virus for 1h, and the mixture was then incubated with Huh-7 cells. Huh-7suggested: CLS Cat# 300156/p7178_HuH7, RRID:CVCL_0336)Recombinant DNA Sentences Resources RBD mutant libraries were then cloned into pETcon 2649 vector and the assembled products were electroporated into electrocompetent DH10B cells to enlarge plasmid yield. pETcon 2649suggested: NoneSoftware and Algorithms Sentences Resources Finally, we built global epistasis models with dms_variants package for each library to estimate single mutation escape scores, utilizing the Python scripts provided by Greaney et al. 18. Pythonsuggested: (IPython, RRID:SCR_001658)Finally, two-dimensional tSNE embeddings were generated with Rtsne package for visualization. Rtsnesuggested: (Rtsne, RRID:SCR_016342)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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