Omicron (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 points and extensively validated by experimental data on SARS-CoV-2, reveals that Omicron may be over ten times more contagious than the original virus or about twice as infectious as the Delta variant. Based on 132 three-dimensional (3D) structures of antibody-RBD complexes, we unveil that Omicron may be twice more likely to escape current vaccines than the Delta variant. The 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 Celltrion and Rockefeller University. However, its impact on Regeneron mAb cocktail appears to be mild.

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. 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 132 available antibody and RBD complexes. Positive changes strengthen the binding, while negative changes weaken the binding. a Heat map for 8 antibodies and RBD complexes in various stages of drug development. Gray color stands for no predictions due to incomplete structures. b1-b2 Heat map for 124 antibodies and RBD complexes. c The distribution (counts) of accumulated BFE changes induced by Omicron mutations for 132 antibody and RBD complexes. Overall, there are more complexes that are weakened upon Omicron RBD mutations that complexes that are strengthened. d The distribution (counts) of accumulated BFE changes induced by Delta mutations for 132 antibody and RBD complexes. e The numbers (counts) of antibody and RBD complexes regarded as disrupted by Omicron under different thresholds ranging from 0 kcal/mol, −0.3 kcal/mol, to <−3 kcal/mol. f The numbers (counts) of antibody and RBD complexes regarded as disrupted by Delta under different thresholds ranging from 0 kcal/mol, −0.3 kcal/mol, to <−2.4 kcal/mol.

Figure 3:

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 [22]) and LY-CoV016 (PDB ID: 7C01 [23]) overlap on the S protein RBD. 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 4:

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 [24]). 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.