Acute SARS-CoV-2 infections harbor limited within-host diversity and transmit via tight transmission bottlenecks

Abstract

The emergence of divergent SARS-CoV-2 lineages has raised concern that novel variants eliciting immune escape or the ability to displace circulating lineages could emerge within individual hosts. Though growing evidence suggests that novel variants arise during prolonged infections, most infections are acute. Understanding how efficiently variants emerge and transmit among acutely-infected hosts is therefore critical for predicting the pace of long-term SARS-CoV-2 evolution. To characterize how within-host diversity is generated and propagated, we combine extensive laboratory and bioinformatic controls with metrics of within- and between-host diversity to 133 SARS-CoV-2 genomes from acutely-infected individuals. We find that within-host diversity is low and transmission bottlenecks are narrow, with very few viruses founding most infections. Within-host variants are rarely transmitted, even among individuals within the same household, and are rarely detected along phylogenetically linked infections in the broader community. These findings suggest that most variation generated within-host is lost during transmission.

Narrow transmission bottlenecks and limited within-host viral diversity during a SARS-CoV-2 outbreak on a fishing boat

“…Our results demonstrate that epidemiologically-linked individuals in a superspreading event share little to no intrahost viral diversity even at sites where mutations fix during the event, corroborating studies reporting narrow transmission bottlenecks in other settings [3,4,[6][7][8].…”

“…So far, efforts to understand how transmission shapes the evolution of SARS-CoV-2 have mainly focused on small household events or nosocomial pairs [3][4][5][6][7]. Such studies point to a narrow transmission bottleneck that significantly reduces viral genetic diversity at the start of each infection [3,4,[6][7][8]. While exact estimates of the bottleneck range from 1 to 15 virions, it is clear that a limited number of virions initiate most human infections.…”

Viral infection and transmission in a large, well-traced outbreak caused by the SARS-CoV-2 Delta variant

“…2 ). Good concordance was achieved in replicated sequencing for samples with relatively high viral loads (Ct ≤30), while a high proportion of discordant iSNVs was observed in samples with relatively lower viral loads (Ct >30), possibly generated by PCR biases 16 , 17 (Supplementary Fig. 2c–h ).…”

Drivers of adaptive evolution during chronic SARS-CoV-2 infections

“…Longitudinal sequencing of some cases of chronic infection has uncovered striking mutational patterns of evolution, and revealed that the rate of evolution is much higher than that observed along transmission chains of acutely infected individuals (e.g., [6][7][8] ). Indeed, several recent reports have found that the intra-host variation during acute infections is quite limited [9][10][11][12] .…”