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. 2022 Feb 3;185(3):467-484.e15.
doi: 10.1016/j.cell.2021.12.046. Epub 2022 Jan 4.

SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses

Wanwisa Dejnirattisai  1 , Jiandong Huo  2 , Daming Zhou  3 , Jiří Zahradník  4 , Piyada Supasa  1 , Chang Liu  5 , Helen M E Duyvesteyn  2 , Helen M Ginn  6 , Alexander J Mentzer  7 , Aekkachai Tuekprakhon  1 , Rungtiwa Nutalai  1 , Beibei Wang  1 , Aiste Dijokaite  1 , Suman Khan  4 , Ori Avinoam  4 , Mohammad Bahar  2 , Donal Skelly  8 , Sandra Adele  9 , Sile Ann Johnson  9 , Ali Amini  10 , Thomas G Ritter  11 , Chris Mason  11 , Christina Dold  12 , Daniel Pan  13 , Sara Assadi  14 , Adam Bellass  14 , Nicola Omo-Dare  14 , David Koeckerling  15 , Amy Flaxman  16 , Daniel Jenkin  16 , Parvinder K Aley  17 , Merryn Voysey  17 , Sue Ann Costa Clemens  18 , Felipe Gomes Naveca  19 , Valdinete Nascimento  19 , Fernanda Nascimento  19 , Cristiano Fernandes da Costa  20 , Paola Cristina Resende  21 , Alex Pauvolid-Correa  22 , Marilda M Siqueira  21 , Vicky Baillie  23 , Natali Serafin  23 , Gaurav Kwatra  23 , Kelly Da Silva  23 , Shabir A Madhi  23 , Marta C Nunes  23 , Tariq Malik  24 , Peter J M Openshaw  25 , J Kenneth Baillie  26 , Malcolm G Semple  27 , Alain R Townsend  28 , Kuan-Ying A Huang  29 , Tiong Kit Tan  30 , Miles W Carroll  31 , Paul Klenerman  32 , Eleanor Barnes  32 , Susanna J Dunachie  33 , Bede Constantinides  34 , Hermione Webster  34 , Derrick Crook  34 , Andrew J Pollard  12 , Teresa Lambe  35 ; OPTIC Consortium; ISARIC4C Consortium; Neil G Paterson  6 , Mark A Williams  6 , David R Hall  6 , Elizabeth E Fry  2 , Juthathip Mongkolsapaya  36 , Jingshan Ren  37 , Gideon Schreiber  38 , David I Stuart  39 , Gavin R Screaton  40
Collaborators, Affiliations

SARS-CoV-2 Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses

Wanwisa Dejnirattisai et al. Cell. .

Abstract

On 24th November 2021, the sequence of a new SARS-CoV-2 viral isolate Omicron-B.1.1.529 was announced, containing far more mutations in Spike (S) than previously reported variants. Neutralization titers of Omicron by sera from vaccinees and convalescent subjects infected with early pandemic Alpha, Beta, Gamma, or Delta are substantially reduced, or the sera failed to neutralize. Titers against Omicron are boosted by third vaccine doses and are high in both vaccinated individuals and those infected by Delta. Mutations in Omicron knock out or substantially reduce neutralization by most of the large panel of potent monoclonal antibodies and antibodies under commercial development. Omicron S has structural changes from earlier viruses and uses mutations that confer tight binding to ACE2 to unleash evolution driven by immune escape. This leads to a large number of mutations in the ACE2 binding site and rebalances receptor affinity to that of earlier pandemic viruses.

Keywords: Omicron; RBD; SARS-CoV-2; Spike; immune evasion; receptor interaction; vaccines; variants.

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Conflict of interest statement

Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board and is a founder member of RQ Biotechnology. J.Z. and G.S. declare the Israel patent application no. 23/09/2020—277,546 and United States patent application no. 16/12/2020—63/125,984, entitled methods and compositions for treating coronaviral infections. Oxford University holds intellectual property related to the Oxford-Astra Zeneca vaccine. A.J.P. is Chair of UK Dept. Health and Social Care’s (DHSC) Joint Committee on Vaccination & Immunisation (JCVI) but does not participate in the JCVI COVID-19 committee, and is a member of the WHO’s SAGE. The views expressed in this article do not necessarily represent the views of DHSC, JCVI, or WHO. The University of Oxford has entered into a partnership with AstraZeneca on coronavirus vaccine development. The University of Oxford has protected intellectual property disclosed in this publication. S.C.G. is co-founder of Vaccitech (collaborators in the early development of this vaccine candidate) and is named as an inventor on a patent covering use of ChAdOx1-vectored vaccines and a patent application covering this SARS-CoV-2 vaccine (PCT/GB2012/000467). T.L. is named as an inventor on a patent application covering this SARS-CoV-2 vaccine and was a consultant to Vaccitech for an unrelated project during the conduct of the study. S.J.D. is a Scientific Advisor to the Scottish Parliament on COVID-19.

Figures

None
Graphical abstract
Figure 1
Figure 1
Sarbecovirus RBD sequence analysis Shown with Alpha, Beta, Delta, and Omicron variants (Omicron repeated on the lower line for clarity). Binding sites for the early pandemic potent antibodies (Dejnirattisai et al., 2021a) and the potent Beta antibodies (Liu et al., 2021b) are depicted using iron heat colors (black < straw < yellow < white) to indicate relative levels of antibody contact and commercial antibody contacts are depicted with the pairs of antibodies in red and blue (purple denotes common interactions). Totally conserved residues are boxed on a red background on the upper rows, while on the final row Omicron mutations are boxed in red. Secondary elements are denoted above the alignment. Figure produced in part using ESPript (Robert and Gouet, 2014).
Figure 2
Figure 2
Distribution of Omicron changes (A) Trimeric S model depicted as a gray surface with one monomer highlighted in pale blue, ACE2 binding site in green and changes in Omicron shown in red, left side view, right top view. (B) RBD depicted as a gray surface with the ACE2 footprint in dark gray and changes in Omicron in red, left: top view, right: front and back views. Epitopes are labeled according to the torso analogy and mutations labeled. (C–F) Top view of RBD depicted as a gray surface with the following: (C) ACE2 binding site in green. (D) Alpha change in yellow, (E) Beta changes in cyan, and (F) Delta changes in purple. Figure produced using chimeraX (Pettersen et al., 2021). Related to Figure S1.
Figure S1
Figure S1
Omicron mutations, related to Figures 2 and 7E (A) Number of sequenced mutations per position. The line shows the number of mutations per residue, for high to low along the spike protein. In green are mutations D614G, which is fixed from early virus evolution and position 498, which became dominant only in Omicron. Red are mutations in Omicron identified earlier in multiple linages and blue are mutations with Omicron being the only lineage. (B) Location of the S371L, S373P, and S375F mutations in the context of the conformation change occurring on binding lipid. Cartoons of the apo (blue) and lipid bound (pink) early pandemic RBD are shown. The lipid is shown in red.
Figure 3
Figure 3
Neutralization assays against Omicron (A–H) FRNT50 values for the indicated viruses using serum from convalescent subjects previously infected with (A) early pandemic virus (n = 32), (B) Alpha (n = 18), (C) Beta (n = 14), (D) Gamma (n = 16), (E) Delta (n = 19), (F) Delta before vaccination or Delta after vaccination (n = 17), (G) before and after the third dose of AZD1222 (n = 41), and (H) 4 weeks, 6 months after the second dose, before the third, and after the third dose of BNT162b2 (n = 20). In (A–E) comparison is made with neutralization titers to Victoria, Alpha, Beta, Gamma, and Delta previously reported in Dejnirattisai et al. (2021a, , Supasa et al. (2021), Zhou et al. (2021), and Liu et al. (2021b), in (G) the data points for Victoria and Delta titers on BNT162b2 are taken from Flaxman et al. (2021). Geometric mean titers are shown above each column. The Wilcoxon matched-pairs signed rank test was used for the analysis, and two-tailed p values were calculated.
Figure S2
Figure S2
FRNT50 values for 7 cases of Delta infection before and after vaccination, related to Figure 4
Figure 4
Figure 4
mAb neutralization curves (A–C) FRNT curves for mAb from (A) early pandemic, (B) Beta infected cases or (C) commercial sources. Omicron neutralization is compared with curves for Victoria, Alpha, Beta, Gamma, and Delta, which have been previously reported (Dejnirattisai et al., 2021a, 2021b; Supasa et al., 2021; Zhou et al., 2021; Liu et al., 2021b). Neutralization titers are reported in Table S1. Related to Figure S2.
Figure 5
Figure 5
Relative antibody contact (A–D) RBD surface produced in PyMOL and rendered in mabscape using iron heat colors (gray < blue < glowing red < yellow < white) to indicate relative levels of antibody contact. Antibody contact is calculated for each surface vertex as the number of antibodies within a 10 Å radius by their known or predicted positions from earlier mapping studies (Dejnirattisai et al., 2021a; Liu et al., 2021b). Outward facing cones are placed at the nearest vertex to each mutated residue on the RBD surface. Drawn back and front views for (A) all RBD-reactive antibodies isolated from early pandemic, (B)strongly neutralizing antibodies (<100 ng/mL) from early pandemic. (C) strongly neutralizing antibodies isolated from Beta infected cases and (D) therapeutic antibodies for clinical use (from PDB: 7BEP, 6XDG, 7L7E, 7KMG, 7KMH). (E–G) Front (right) and back (left) views of the RBD drawn as a gray surface with Omicron changes highlighted in magenta and glycans drawn as sticks. (E–G) (E) Outline footprints of a selection of early pandemic mAbs: 58, 88, 222, 253, and 278 are shown by balls representing the centroid of H3 (red), H1(salmon). L3 (blue) and L1 (slate) loops joined by yellow or cyan sticks. (F) As for (E), showing a selection of Beta antibodies: 27, 47, 49, and 53. (G) As for (E) showing a selection of commercial antibodies: REGN10933, REGN10987, S309, AZD1061, AZD8895, LY-CoV555, and LY-CoV016. Related to Figures S3, S4, and S5.
Figure S3
Figure S3
Binding modes of early pandemic mAbs and their contacts to Omicron mutation sites, related to Figure 5 (A) Fabs are drawn as ribbons with the heavy chains in red and light chains in blue and RBDs as gray ribbon or surface representation with Omicron mutation sites highlighted in magenta. Side chains are shown as sticks and hydrogen bonds as dashed lines. (A) Fab 58 does not make any close contacts with the Omicron mutation sites. (B–F) Binding modes and contacts with Omicron mutation sites of Fabs 170, 222, 253, 278, and 316, respectively.
Figure S4
Figure S4
Binding modes of Beta mAbs and their contacts to Omicron mutation sites, related to Figure 5 (A and B) The drawing and coloring schemes are same as in Figure S3. These are structures of Beta-RBD/Beta-Fab complexes. (A) Beta-24 and (B) Beta-54, examples of Beta mAbs targeting the N501Y mutation site. (C) Beta-38, a representative of Beta mAbs targeting the E484K mutation site. (D) Beta-29, a K417N/T-dependent Beta mAb. (E) Beta-44 binds at the top of left shoulder and is sensitive to T478K mutation. (F–I) Beta-27, -47, -49, and -53, respectively. These four Beta mAbs neutralize all the previous variants of concern, as well as the early pandemic Wuhan strain.
Figure S5
Figure S5
Binding modes of the therapeutic mAbs and their contacts to Omicron mutation sites, related to Figure 5 (A–E) The drawing and coloring schemes are same as in Figure S3. (A) REGN10987 and REGN10933, (B) AZD8895 and AZD1061, (C) Vir S309, (D) LY-CoV016, and (E) LY-CoV555.
Figure S6
Figure S6
SPR measurement and crystal structure of the Omicron RBD complexed with Beta-55 and EY6A Fabs, related to Figure 7 (A) SPR measurements. (B) Ternary complex of the Omicron RBD (gray)/Beta-55 (heavy chain red, light chain blue)/EY6A (heavy chain salmon, light chain cyan). (C) Electron density map showing the density for the mutated residues at 446, 498, 501, and 505, and their interactions with the CDR-H3 of Beta-55. (D and E) Comparison of the slightly different binding mode of Beta-55 to Beta-24 (cyan in D) and Beta-40 (cyan in E), the close-up boxes show details of the interactions with Beta-24 and Beta-40 explaining the knockout of Beta-24 and the resilience of Beta-40.
Figure 6
Figure 6
Affinity driving mutations in Omicron RBD have previously been identified by in vitro evolution for tighter binding (A) Analysis of the occurrence and prevalence of Omicron-variant mutations. The background is colored according to S-protein functional domains. The four positions critical for the high affinity of RBD-62 are highlighted in bold. Mutation frequencies within individual lineages are denoted in green (100%–75%), blue (75%–50%), and magenta (50%–25%). Information about the distribution and frequency of S-protein mutations and the spatiotemporal characterization of SARS-CoV-2 lineages were retrieved from www.outbreak.info (Mullen et al., 2020) and GISAID database (Elbe and Buckland-Merrett, 2017).∗ Same evolutionary origin, anumber of evolutionary non-related lineages with given or similar mutation (Zahradnik et al., 2021c), blog(10) number of the observed Omicron mutation at the given position as determined on 14th November 2021, csame as bbut total log(10) number of changes at the given position. dFold-change in binding as determined by yeast-surface display. Fold-change is the ratio between original RBD KD and the mutant RBD KD for binding human ACE2. (B) Comparison of fold-change in binding affinity among selected mutations and their combinations as determined by titrating ACE2 on yeast surface displayed RBD mutations. For Omicron, yeast titration is denoted in violet, SPR (this study) is dark red, SPR as determined in Cameroni et al. (2021) is gray and ELISA as determined in Schubert et al. (2021) is in orange. Data denoted by black dots have been reported previously (Zahradník et al., 2021b). (C) RBD-62 (blue)/ACE2 (green) structure (PDB: 7BH9) overlaid on Omicron RBD structure (orange) as determined bound to Beta-55. All Omicron mutations are shown, overlaid on relevant RBD-62 mutations. (D) Electrostatic potential surface depictions calculated using PyMol. Blue is positive and red negative potential (scale bar shown below).
Figure 7
Figure 7
Antigenic map from neutralization data for Omicron (A) Neutralization data (log titers) showing sera as columns against challenge variants as rows. Sera are grouped into blocks according to the eliciting variant. The reference neutralization titer for each block is calculated as the average of all titers when challenged with the variant that elicited the serum. In the case of vaccine sera this was taken as the average of all best neutralization titers. Therefore, colors within a single block express the relative neutralization titer with respect to this reference. (B) Shows an example of the equivalent model generated from one run of antigenic map refinement using the same reference offsets as calculated for (A). (C) Shows a view of the three-dimensional antigenic map for variants of concern. The distance between two points corresponds to the drop-off in neutralization titer used in (B). (D) Same antigenic space as (C) but rotated 90°, to look downward form Omicron. (E) Overlay of the X-ray structure of Omicron (red) on the early pandemic (Wuhan) RBD (gray) and the predicted model of the Omicron RBD in black, drawn as cartoons. The structural change effected by the S371L, S373P, and S375F mutations is shown enlarged in the inset. (F) X-ray structure of ternary complex of Omicron RBD with Beta-55 and EY6A Fabs. The Omicron RBD is shown as a gray semi-transparent surface with mutated residues in magenta. Fabs are drawn as cartoons, heavy chain in magenta and light chain in blue. Related to Figures S1 and S6 and Video S1.
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Update of

  • Omicron-B.1.1.529 leads to widespread escape from neutralizing antibody responses.
    Dejnirattisai W, Huo J, Zhou D, Zahradník J, Supasa P, Liu C, Duyvesteyn HME, Ginn HM, Mentzer AJ, Tuekprakhon A, Nutalai R, Wang B, Dijokaite A, Khan S, Avinoam O, Bahar M, Skelly D, Adele S, Johnson SA, Amini A, Ritter T, Mason C, Dold C, Pan D, Assadi S, Bellass A, Omo-Dare N, Koeckerling D, Flaxman A, Jenkin D, Aley PK, Voysey M, Clemens SAC, Naveca FG, Nascimento V, Nascimento F, Fernandes da Costa C, Resende PC, Pauvolid-Correa A, Siqueira MM, Baillie V, Serafin N, Ditse Z, Da Silva K, Madhi S, Nunes MC, Malik T, Openshaw PJ, Baillie JK, Semple MG, Townsend AR, Huang KA, Tan TK, Carroll MW, Klenerman P, Barnes E, Dunachie SJ, Constantinides B, Webster H, Crook D, Pollard AJ, Lambe T; OPTIC consortium; ISARIC4C consortium; Paterson NG, Williams MA, Hall DR, Fry EE, Mongkolsapaya J, Ren J, Schreiber G, Stuart DI, Screaton GR. Dejnirattisai W, et al. bioRxiv [Preprint]. 2021 Dec 22:2021.12.03.471045. doi: 10.1101/2021.12.03.471045. bioRxiv. 2021. Update in: Cell. 2022 Feb 3;185(3):467-484.e15. doi: 10.1016/j.cell.2021.12.046 PMID: 34981049 Free PMC article. Updated. Preprint.

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