Determinants of SARS-CoV-2 within-host evolutionary rates in persistently infected individuals

Understanding the within-host evolutionary dynamics of SARS-CoV-2, particularly in relation to variant emergence, is crucial for public health. From a community surveillance study, we identified 576 persistent infections, more common among males and those over 60. Our findings show significant variation in evolutionary rates among individuals, driven by nonsynonymous mutations. Longer-lasting infections accumulated mutations faster, with no link to demographics, vaccination status, virus lineage, or prior infection. The nonsynonymous rate was particularly high within the N-terminal and receptor binding domains of Spike. ORF6 was under strong purifying selection, making it a potential therapeutic target. We also identified 379 recurring mutations, with half having a negative fitness effect and very low prevalence at the between-host level, indicating some mutations are favoured during infection but disadvantageous for transmission. Our study highlights the highly heterogenous nature of within-host evolution of SARS-CoV-2 which may in turn help inform future intervention strategies.