Within-host selection pressure does NOT dictate viral evolution and thus does not correlate with the emergence of SARS-CoV-2 variants in highly Covid-19 vaccinated populations.

Contrary to the implications of this publication (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10063955/), studying within-host diversity of SARS-CoV-2 (SC-2) may not always be a scientifically robust approach for investigating viral evolution, especially in the context of mass vaccination against a virus causing acute self-limiting infection (ASLI) or during subsequent vaccine breakthrough infections (VBTIs), such as those caused by Omicron.

In highly Covid-19 (C-19) vaccinated populations, the evolutionary trajectory and dynamics of ASLI-causing viruses are primarily shaped by the immune selection pressure exerted by the entire vaccinated population on viral infectiousness or transmissibility, rather than by individual vaccinated hosts. In other words, the within-host mutation rate does not reflect the impact of mass vaccination or widespread VBTIs. Cross-neutralizing antibodies generated in response to VBTIs caused by Omicron target more conserved antigenic domains within the spike protein and thereby constrain the mutation rate within a single C-19 vaccinated host while driving large-scale immune evasion at the population level within highly C-19 vaccinated populations.

The population-level immune selection pressure on the virus persists as long as herd immunity is not achieved.

In conclusion, since the emergence of Omicron, within-population selection pressure has driven the widespread emergence and co-circulation of a diversified spectrum of immune escape variants within highly C-19 vaccinated populations.