The SARS-CoV-2 virus has continually evolved throughout the course of the Coronavirus Disease 2019 (COVID-19) pandemic, resisting numerous attempts at eradication, including vaccination campaigns and booster doses.
Researchers from Michigan State University (MSU) assert, “The occurrence and frequency of vaccine-resistant mutations correlate strongly with the vaccination rates in Europe and America,” according to a study published on Dec. 7 in ACS Publications.
Mutations favoring infectivity and vaccine resistance
While COVID-19 vaccines offered a glimmer of hope to many during early 2021, they have lacked the ability to effectively reduce or eliminate transmission between individuals. According to a Lancet study published on Oct. 29, “Fully vaccinated individuals with breakthrough infections have peak viral load similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts.”
Multiple SARS-CoV-2 variants have emerged with mutations on the spike (S) protein, yet the Michigan study points out that “almost all SARS-CoV-2 vaccines and monoclonal antibodies (mAbs)” are targeted at the S protein, which “have been verified to compromise the efficacy of existing vaccines and mAbs.”
The development of new mutations has been driven by the interplay between multiple factors on the molecular, organism, and population levels. Molecule-based mechanisms such as “reading frame shifts, replication errors, transcription errors, translation errors, viral proofreading, and viral recombination” change the genetic information initially.
At the organism level, gene editing induced by the host’s adaptive immune response and “recombination between the host and virus” create additional mutations.
On the population scale, two “complementary pathways (infectivity and vaccine resistance) regulated by natural selection” drive the evolution of the virus. Mutations in the S protein receptor-binding domain (RBD) regulated by the infectivity-based pathways are present in the current prevailing COVID-19 variants, while “mutations regulated by the vaccine-resistant pathway start to emerge in countries with relatively high vaccination rates.”
In other words, the authors state, “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.”
MSU researchers tout their credibility by citing accurate predictions they made early in the pandemic: “The current prevailing variants…carry at least one vital mutation at residues 452 and 501 on the S protein RBD.”
“Notably, in early 2020, we successfully predicted that residues 452 and 501 ‘have high chances to mutate into significantly more infectious COVID-19 strains.”’
The team continues, “In the same work, we hypothesized that ‘natural selection favors those mutations that enhance the viral transmission’ and provided the first evidence for infectivity-based natural selection. In other words, we revealed the mechanism of SARS-CoV-2 evolution and transmission based on very limited genome data in June 2020. Additionally, we predicted three categories of RBD mutations: (1) most likely (1149 mutations), (2) likely (1912 mutations), and (3) unlikely (625 mutations). To date, almost all of the RBD mutations we detected fall into our first category.”
Correlation with high vaccination rates
For MSU, tracking a specific vaccine-resistant mutation in the “spike (S) protein receptor-binding domain” Y449S, along with co-mutation N501Y, offered additional insight into the evolution of the virus. Y449S has “reduced infectivity compared to that of the original SARS-CoV-2 but can disrupt existing antibodies that neutralize the virus.”
Researchers stated that 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.”
First found in Bulgaria and the U.S. in Dec. 2020, the Y449S mutation “quickly spread to 10 other countries.” Rapid increases were observed in Denmark, the UK, and France, which “have relatively high vaccination ratios (>70% up to late October 2021).”
Furthermore, “the frequency of the Y449S mutation has a tendency to increase similar to that of the fully vaccinated ratio, suggesting that the vaccine-resistant mutations will gradually become one of the main evolution-driving forces of SARS-CoV-2, especially in those areas with high vaccination rates.”
MSU’s scientists believe that similar mutations will continue to appear in the near future, “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.”