The evolution of the mechanisms of SARS-CoV-2 evolution revealing vaccine-resistant mutations in Europe and America

Abstract

The importance of understanding SARS-CoV-2 evolution cannot be overemphasized. Recent studies confirm that natural selection is the dominating mechanism of SARS-CoV-2 evolution, which favors mutations that strengthen viral infectivity. We demonstrate that vaccine-breakthrough or antibody-resistant mutations provide a new mechanism of viral evolution. Specifically, vaccine-resistant mutation Y449S in the spike (S) protein receptor-bonding domain (RBD), which occurred in co-mutation [Y449S, N501Y], has reduced infectivity compared to the original SARS-CoV-2 but can disrupt existing antibodies that neutralize the virus. By tracing the evolutionary trajectories of vaccine-resistant mutations in over 1.9 million SARS-CoV-2 genomes, we reveal that the occurrence and frequency of vaccine-resistant mutations correlate strongly with the vaccination rates in Europe and America. We anticipate that as a complementary transmission pathway, vaccine-resistant mutations will become a dominating mechanism of SARS-CoV-2 evolution when most of the world's population is vaccinated. Our study sheds light on SARS-CoV-2 evolution and transmission and enables the design of the next-generation mutation-proof vaccines and antibody drugs.

Figure 1:

a The mechanism of mutagenesis. Nine mechanisms are grouped into three scales: 1) molecular-based mechanism (green color); 2) organism-based mechanism (red color); 3) population-based mechanism (blue color). The random shifts (Random), replication error (Rep), Transcription error (Transcr), viral proofreading (Proof), and recombination (Recomb) are the six molecular-based mechanisms. The gene editing and the host-virus recombination are the organism-based mechanism. In addition, the natural selection (Natural) is the population-based mechanism, which is the mainly driven source in the transmission of SARS-CoV-2. b A sketch of SARS-CoV-2 and its interaction with host cell. c Illustration of 25 single-site RBD mutations with top frequencies. The height of each bar shows the BFE change of each mutation, the color of each bar represents the natural log of frequency of each mutation, and the number at the top of each bar means the AI-predicted number of antibody and RBD complexes that may be significantly disrupted by a single site mutation. d Illustration of SARS-CoV-2 S protein with human ACE2. The blue chain represents the human ACE2, the pink chain represents the S protein, and the purple fragment on the S protein points out the two vaccine-resistant mutations Y449S/H.

Figure 2:

Most significant RBD mutations. a Time evolution of RBD mutations with its mutation-induced BFE changes per 60-day from April 30, 2020, to August 31, 2021. Here, only the top 100 most observed RBD mutations are displayed. The height and color of each bar represent the log frequency and ACE-S BFE change induced by a given RBD mutation. The red star marks the vaccine-resistant mutations with significantly negative BFE changes. b Time evolution of RBD mutations with its experimental mutation-induced log2 enrichment ratio changes per 60-day from April 30, 2020, to August 31, 2021. The height and color of each bar represent the log frequency and enrichment ratio change induced by a given RBD mutation. The red star marks vaccine-resistant mutations with significantly negative BFE changes.

Figure 3:

RBD co-mutation analysis. a Time evolutionary trajectory of RBD 2 co-mutations with its mutation-induced BFE changes per 30-day from January 25, 2021, to August 23, 2021. The height and color of each bar represent the log frequency and ACE-S BFE change induced by a given RBD mutation. Red stars mark the 2 co-mutations with significantly negative BFE changes. b Time evolutionary trajectory of RBD 3 co-mutations with its mutation-induced BFE changes per 30-day from February 24, 2021, to August 23, 2021. The height and color of each bar represent the log frequency and ACE-S BFE change induced by a given RBD mutation. c Time evolutionary trajectory of RBD 4 co-mutations with its mutation-induced BFE changes per 30-day from April 25, 2021, to August 23, 2021. The height and color of each bar represent the log frequency and ACE-S BFE change induced by a given RBD mutation. d Illustration of top 25 most observed RBD co-mutations. Here, the length of each bar represents the total ACE2-S BFE changes induced by a specific RBD co-mutation, the color of each bar represents the natural log frequency of each co-mutation, and the number at the side of each bar is the AI-predicted antibody disruption count.

Figure 4:

a Distribution of vaccine-resistant mutation Y449S. The color bar represents the log10 frequency of Y449S in 12 countries: Denmark (DK), the United Kingdom (UK), France (FR), Bulgaria (BG), the United States (US), Brazil (BR), Sweden(SE), Canada (CA), Germany (DE), Switzerland (CH), Spain (ES), and Belgium (BE). The number located at the side of the country shows the total positive SARS-CoV-2 cases up to August 31. b Time evolution of vaccination rate and the frequency of Y449S in 12 countries from December 26, 2020, to August 23, 2021. The data is collected per 30-day. The red line shows the frequency of mutation Y449S. The orange and purple areas represent at least one dose rate and fully vaccinated rate in each country.