Emerging Dominant SARS-CoV-2 Variants

Abstract

Accurate and reliable forecasting of emerging dominant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants enables policymakers and vaccine makers to get prepared for future waves of infections. The last three waves of SARS-CoV-2 infections caused by dominant variants, Omicron (BA.1), BA.2, and BA.4/BA.5, were accurately foretold by our artificial intelligence (AI) models built with biophysics, genotyping of viral genomes, experimental data, algebraic topology, and deep learning. On the basis of newly available experimental data, we analyzed the impacts of all possible viral spike (S) protein receptor-binding domain (RBD) mutations on the SARS-CoV-2 infectivity. Our analysis sheds light on viral evolutionary mechanisms, i.e., natural selection through infectivity strengthening and antibody resistance. We forecast that BP.1, BL*, BA.2.75*, BQ.1*, and particularly BN.1* have a high potential to become the new dominant variants to drive the next surge. Our key projection about these variants dominance made on Oct. 18, 2022 (see arXiv:2210.09485) became reality in late November 2022.

Figure 1:

Illustration of six waves of daily COVID-19 cases (light blue) and deaths (red) driven by dominant SARS-CoV-2 variants since 2020 [1]. The curves are smoothed by five-day averages.

Figure 2:

Illustration of unique mutations on SARS-CoV-2 genomes extracted from patients. Each dot represents a unique mutation. The x-axis is the gene position of a mutation and the y-axis represents its observed frequency in the natural logarithmic scale.

Figure 3:

Annotation tree plot of 106 newly occurred Omicron subvariants. BFE changes (kcal/mol) are marked from parent generations to children as well as mutations.

Figure 4:

a. and b. the 3D structure of BA.2 (PDB: 7XB0 [24]) with two sets of mutations (colors are consistent with those in c and integrated colors indicate that mutation appears on multiple variants). a. the mutations of precious VOCs (in cyan) and BA.1 (in blue), BA.2 (in pink), BA.3 (in orange), BA.4, and BA.5 (in green). b. the mutations of the Omicron subvariants with BA.2 sublineages (pink) and BA.5 sublineages (in green). c. A comparison of predicted mutation-induced BFE changes for previous VOCs and Omicron subvariants. Previous VOCs (in cyan): Alpha, Beta, Gamma, Delta, Theta, Kappa, Lambda, and Mu; BA.1 and BA.1.1 (in blue); BA.2 (in pink); BA.3 (in light orange); BA.4 (in orange); BA.5 (in green). d BA.2 sublineages (in pink) e BA.4 sublineages (in orange) and BA.5 sublineages (in green).

Figure 5:

Heatmap of mutation-induced BFE change predictions of BA.1 (top panel) and BA.2 (bottom panel). Residues that have at least one mutation-induced BFE change greater than 0.1 kcal/mol are selected. The sites of BA.2’s six distinct mutations are marked red and framed in the heatmap.

Figure 6:

Weekly viral lineages among infections in the United States from 06/26/2022 to 10/08/2022. AY.1-AY.133, Delta (B.1.617.2), BA.1 and sublineages of BA.1 variant are aggregated to category “Others”. BA.2 sublineages except BA.2.12.1, BA.2.75, BA.2.75.2, BN.1, XBB and their sublineages, are aggregated with BA.2. BA.4 sublineages are aggregated to BA.4 except BA.4.6. Sublineages of BA.5 are aggregated to BA.5 except BF.7, BF.11, BA.5.2.6, BQ.1 and BQ.1.1. The spike substitution R346T is included in lineages BA.2.75.2, XBB, BN.1, BA.4.6, BF.7, BF.11, BA.5.2.6, and BQ.1.1 Data from CDC website [27].