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 overlooked. Recent studies confirm that natural selection is the dominating mechanism of SARS-CoV-2 evolution, which favors mutations that strengthen viral infectivity. Here, 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-binding domain, which occurred in co-mutations Y449S and N501Y, has reduced infectivity compared to that of the original SARS-CoV-2 but can disrupt existing antibodies that neutralize the virus. By tracking the evolutionary trajectories of vaccine-resistant mutations in more than 2.2 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-breakthrough or antibody-resistant mutations, like those in Omicron, will become a dominating mechanism of SARS-CoV-2 evolution when most of the world's population is either vaccinated or infected. 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); and 3) population-based mechanism (blue color). The reading frame shifts (Shift), 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 30 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 October 22, 2021. Here, only the top 100 most observed RBD mutations are displayed. Each bar represents a RBD single mutation. 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 October 22, 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 October 22, 2021. Each bar represents a RBD 2 co-mutation. 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 June 24, 2021, to October 22, 2021. Each bar represents a RBD 3 co-mutation. 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 June 24, 2021, to October 22, 2021. Each bar represents a RBD 4 co-mutation. 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 50 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), Argentina(AR), Brazil (BR), Sweden(SE), Canada (CA), Germany (DE), Spain (ES), and Belgium (BE). The number located at the side of the country shows the total positive SARS-CoV-2 cases up to October 22. b Time evolution of vaccination rate and the frequency of Y449S in 12 countries from December 26, 2020, to October 22, 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.