Has Adaptive Evolution of SARS-CoV-2 Hit a Ceiling?

The ultimate measurement of viral fitness is the ability to maintain high prevalence rates in its host species. Effective transmission, efficient replication, and rapid immune evasion all lead to this end. During the past five years, SARS-CoV-2 has successfully adapted to the human host and established human reservoirs for long term coexistence with mankind. We have observed innovative synergistic mutations in the Spike protein to improve receptor binding. Adaptation to cells of the upper respiratory tract has shortened the incubation period and facilitated viral spread. Such improvements allowed for immune escape mutations even though they may reduce replicative fitness. Adaptive mutations have resulted in intermittent selective sweeps by dominant variants. However, there are limitations to functional improvements. Receptor binding affinity of the Spike protein peaked in 2022-2023. Accumulation of fixed mutations plateaued after the advent of BA.2.86/JN.1 at the turn of 2023 and 2024. Purifying selection has been the main force working on nonsynonymous mutations in the Omicron group and overall fitness effects of missense mutations in major viral proteins have been declining. Moreover, because of weak selection on synonymous mutations, codon adaptation index in the human host has been decreasing among Omicron subvariants. Consequently, Omicron lineages replicated in cell cultures less efficiently than the original virus, and recent Omicron lineages showed signs of further attenuation in animal models. Viral attenuation in the human population manifested as declining COVID-19-related mortality even with high prevalence of infections.