Omicron Variant (B.1.1.529): Infectivity, Vaccine Breakthrough, and Antibody Resistance

Abstract

The latest severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant Omicron (B.1.1.529) has ushered panic responses around the world due to its contagious and vaccine escape mutations. The essential infectivity and antibody resistance of the SARS-CoV-2 variant are determined by its mutations on the spike (S) protein receptor-binding domain (RBD). However, a complete experimental evaluation of Omicron might take weeks or even months. Here, we present a comprehensive quantitative analysis of Omicron's infectivity, vaccine breakthrough, and antibody resistance. An artificial intelligence (AI) model, which has been trained with tens of thousands of experimental data and extensively validated by experimental results on SARS-CoV-2, reveals that Omicron may be over 10 times more contagious than the original virus or about 2.8 times as infectious as the Delta variant. On the basis of 185 three-dimensional (3D) structures of antibody-RBD complexes, we unveil that Omicron may have an 88% likelihood to escape current vaccines. The U.S. Food and Drug Administration (FDA)-approved monoclonal antibodies (mAbs) from Eli Lilly may be seriously compromised. Omicron may also diminish the efficacy of mAbs from AstraZeneca, Regeneron mAb cocktail, Celltrion, and Rockefeller University. However, its impacts on GlaxoSmithKline's sotrovimab appear to be mild. Our work calls for new strategies to develop the next generation mutation-proof SARS-CoV-2 vaccines and antibodies.

Figure 1:

Illustration of the Omicron RBD and ACE2 interaction, RBD mutation-induced BFE changes. a. The 3D structure of the ACE2 and RBD complex (PDB: 6M0J[20]). Omicron mutation sites are labeled. b. Omicron mutation-induced BFE changes. Positive changes strengthen the binding between ACE2 and S protein, while negative changes weaken the binding. c. A comparison of predicted mutation-induced BFE changes for few variants.

Figure 2:

Illustration of Omicron mutation-induced BFE changes of 185 available antibody and RBD complexes and an ACE2-RBD complex. Positive changes strengthen the binding, while negative changes weaken the binding. a Heat map for 12 antibody and RBD complexes in various stages of drug development. Gray color stands for no predictions due to incomplete structures. b1 Heat map for ACE2/antibody and RBD complexes. b2 and b3 Heat map for antibody and RBD complexes.

Figure 3:

Analysis of variant mutation-induced BFE changes of 185 antibody and RBD complexes. a1, b1, c1, d1, e1, f1, and g1 The distributions (counts) of accumulated BFE changes induced by Omicron, Alpha, Beta, Delta, Gamma, Lambda, and Mu mutations respectively for 185 antibody and RBD complexes. Overall, there are more complexes that are weakened upon RBD mutations that complexes that are strengthened. a2, b2, c2, d2, e2, f2, and g2 The numbers (counts) of antibody-RBD complexes regarded as disrupted by Omicron, Alpha, Beta, Delta, Gamma, Lambda, and Mu mutations respectively under different thresholds ranging from 0 kcal/mol, −0.3 kcal/mol, to <−3 kcal/mol.

Figure 4:

Illustration of the Omicron RBD and Eli Lilly antibody interaction and RBD mutation-induced BFE changes. a The 3D structure of the ACE2 and Eli Lilly antibody complex. LY-CoV555 (PDB ID: 7KMG[24]) and LY-CoV016 (PDB ID: 7C01[25]) overlap on the S protein RBD. ACE2 is included as a reference. b Omicron mutation-induced BFE changes for the complex of RBD and LY-CoV016. c Omicron mutation-induced BFE changes for the complex of RBD and LY-CoV555.

Figure 5:

Illustration of the Omicron RBD and Regeneron antibody interaction and RBD mutation-induced BFE changes. a The 3D structure of the ACE2 and Regeneron antibody complex. REGN10987 and REGN10933 do not overlap on the S protein RBD (PDB ID: 6XDG[26]). ACE2 is included as a reference. b Omicron mutation-induced BFE changes for the complex of RBD and REGN10933. c Omicron mutation-induced BFE changes for the complex of RBD and REGN10987. d Omicron mutation-induced BFE changes for the complex of RBD, REGN10933, and REGN10987.

Figure 6:

Illustration of the Omicron RBD and AstraZeneca antibody interaction and RBD mutation-induced BFE changes. a The 3D structure of the ACE2 and AstraZeneca antibody complex. AZD1061 and AZD8895 do not overlap on the S protein RBD (PDB ID: 7L7E[27]). ACE2 is included as a reference. b Omicron mutation-induced BFE changes for the complex of RBD and AZD8895. c Omicron mutation-induced BFE changes for the complex of RBD and AZD1061. d Omicron mutation-induced BFE changes for the complex of RBD, AZD8895, and AZD1061.

Figure 7:

Illustration of the Omicron RBD and other antibodies and RBD mutation-induced BFE changes. a Antibody CT-P59 in reference with ACE2. b BFE changes of Omicron mutation-induced on the binding of CT-P59 and RBD. c Antibody C135 in reference with ACE2. d BFE changes of Omicron mutation-induced on the binding of C135 and RBD. *: no results due to incomplete structure of C135. e Antibody C144 in reference with ACE2. f BFE changes of Omicron mutation-induced on the binding of C144 and RBD. g Antibody S309 in reference with ACE2. h BFE changes of Omicron mutation-induced on the binding of S309 and RBD.

Figure 8:

Comparison of predicted variant vaccine breakthrough potential with experimental data. a Accumulated negative BFE changes induced by Omicron, Alpha, Beta, Delta, Gamma, Lambda, and Mu mutations respectively for 185 antibody-RBD complexes. For each variant, the number on the top is the fold of affinity reduction computed by e^{−BFEchange_average}, where BFEchange_average, denoted by a circle, is the mean value of 185 antibody-RBD negative BFE changes. b The comparison of neutralization activity against Omicron, Alpha, Beta, Delta, Gamma, Lambda, and Mu variants based on 28 convalescence sera [37]. For each variant, the number on the top is the ratio of neutralization ED₅₀ compared to the reference strain D614G.

Figure 9:

Comparison of predicted antibody breakthrough potential with experimental data [38]. Colors indicate three different range. For BFE changes, dark red: BFE changes ≤ −2kcal/mol, median red: −2kcal/mol < BFE changes ≤ −1kcal/mol, and light red: BFE changes > − 1kcal/mol. For fold changes, dark red: fold changes < −1000, median red: −1000 ≤ fold changes < −100, and light red: fold changes ≥ −100.