Background: The continuing COVID-19 pandemic is partially due to viral evolution decreasing vaccine and treatment efficacies. Predicting viral evolution is difficult. Others have found that serial infections of the original SARS-CoV-2 isolate in non transgenic mice is accompanied with selection of alleles (such as Spike 417N, 493H and 501Y) conferring adaptation and greater binding affinity for the murine ACE2 receptor, enhanced infectivity, and lethal phenotype in mice. We designed a study to investigate long-term viral evolution's impact in K18-ACE2 mice with virus closer related to the Omicron sub-lineage. Methods: We serially infected SARS-CoV-2-naive mice with either the B.1.351 (Beta) or the B.1.617.2 (Delta) variant across twenty passages without selective pressures. We sequenced virus across passages, annotating variant alleles changing in frequency using published tools, tracking alleles suspected of decreasing vaccine/treatment efficacy. We evaluated virulence in animals infected with virus isolated…
