SARS-CoV-2: past present and what have we learned about the future

We are now in the third year of the COVID-19 pandemic. Initially, it was assumed that SARS-CoV-2 has a relative stable genome, and that variants will be rare. This assumption has been proven wrong, with the mutation landscape now including most possible single mutations. While during the early stages of the pandemic, single nucleotide changes drove variant evolution, recently we started to see also two-nucleotide and epistatic mutations, further expanding the scope of possible variants. With these, the virus has an almost limitless sequence space to explore, making the generation of new variants the default rather than the exception. Our work focuses on 1. Using the tools of in vitro evolution to identify the potential evolutionary path of SARS-CoV-2 spike protein. 2. Understanding the evolutionary trajectory of the virus, including the major shift happening with the omicron and its sub-variants, where the virus moved from ACE2 binding optimization towards immune evasion. 3. Designing a drug will work against past and future variants.
Our studies led us to rationalize most variants of concern, including the prediction of the key mutations driving omicron. We will discuss the methods leading to these predictions, and how we work to predict future variants.