Emerging vaccine-breakthrough SARS-CoV-2 variants

The recent global surge in coronavirus disease 2019 (COVID-19) infections have been fueled by new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, namely Alpha, Beta, Gamma, Delta, etc. The molecular mechanism underlying such surge is elusive due to the existence of 28,554, including 4,653 non-degenerate mutations on the spike (S) protein, which is the target of most COVID-19 vaccines. The understanding of the molecular mechanism of SARS-CoV-2 transmission and evolution is a prerequisite to foresee the global trend of emerging vaccine-breakthrough SARS-CoV-2 variants and the design of mutation-proof vaccines and monoclonal antibodies (mAbs). We integrate the genotyping of 1,489,884 SARS-CoV-2 genomes isolated from patients, a library collection of 130 human antibodies, tens of thousands of mutational data points, topological data analysis (TDA), and deep learning to reveal SARS-CoV-2 evolution mechanism and forecast emerging vaccine-escape variants. We show that infectivity-strengthening and antibody-disruptive co-mutations on the S protein receptor-binding domain (RBD) can quantitatively explain the infectivity and virulence of all prevailing variants. We demonstrate that Lambda is as infectious as Delta but is more vaccine-resistant. We analyze emerging vaccine-breakthrough co-mutations in 20 COVID-19 devastated countries, including the United Kingdom (UK), the United States (US), Denmark (DK), Brazil (BR), Germany (DE), Netherlands (NL), Sweden (SE), Italy (IT), Canada (CA), France (FR), India (IN), and Belgium (BE), etc. We envision that natural selection through infectivity will continue to be a main mechanism for viral evolution among unvaccinated populations, while antibody disruptive co-mutations will fuel the future growth of vaccine-breakthrough variants among fully vaccinated populations. Finally, we have identified the following sets of co-mutations that have the great likelihood of becoming dominant: [A411S, L452R, T478K], [L452R, T478K, N501Y], [V401L, L452R, T478K], [K417N, L452R, T478K], [L452R, T478K, E484K, N501Y], and [P384L, K417N, E484K, N501Y]. We predict they, particularly the last four, will break through existing vaccines. We foresee an urgent need to develop new vaccines that target these co-mutations.