Transmission dynamics of SARS-CoV-2 within-host diversity in two major hospital outbreaks in South Africa

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes acute, highly transmissible respiratory infection in humans and a wide range of animal species. Its rapid global spread has resulted in a major public health emergency, necessitating commensurately rapid research to improve control strategies. In particular, the ability to effectively retrace transmission chains in outbreaks remains a major challenge, partly due to our limited understanding of the virus’ underlying evolutionary dynamics within and between hosts. We used high-throughput sequencing whole-genome data coupled with bottleneck analysis to retrace the pathways of viral transmission in two nosocomial outbreaks that were previously characterised by epidemiological and phylogenetic methods. Additionally, we assessed the mutational landscape, selection pressures, and diversity at the within-host level for both outbreaks. Our findings show evidence of within-host selection and transmission of variants between samples. Both bottleneck and diversity analyses highlight within-host and consensus-level variants shared by putative source-recipient pairs in both outbreaks, suggesting that certain within-host variants in these outbreaks may have been transmitted upon infection rather than arising de novo independently within multiple hosts. Overall, our findings demonstrate the utility of combining within-host diversity and bottleneck estimations for elucidating transmission events in SARS-CoV-2 outbreaks, provide insight into the maintenance of viral genetic diversity, provide a list of candidate targets of positive selection for further investigation, and demonstrate that within-host variants can be transferred between patients. Together these results will help in developing strategies to understand the nature of transmission events and curtail the spread of SARS-CoV-2.

Epidemiological data and genome sequencing reveals that nosocomial transmission of SARS-CoV-2 is underestimated and mostly mediated by a small number of highly infectious individuals

“…The sensitivity and specificity of this SNP threshold for defining linkage varies according to the point during the pandemic at which it is being applied, both in terms of time since the start of the pandemic (greater overall viral diversity afforded by later time points in the pandemic), and the current rate of transmission (locally reduced diversity during exponential periods of spread, such as was observed with the emergence of the alpha variant in the winter of 2020). Improvements in sensitivity and specificity to detect transmission might also be gained from considering patterns of intra-host variation [ 35 , 36 ]. Generally, however, joint epidemiologic and genomic analysis enable the limitations of one method to be compensated for by the strengths of the other, acknowledging both approaches are limited by undiagnosed cases.…”

Comprehensive Contact Tracing, Testing and Sequencing Show Limited Transmission of SARS-CoV-2 between Children in Schools in Norway, August 2020 to May 2021

“…Pairwise single nucleotide polymorphism (SNP) analysis determined possible transmission in contact tracings with primary or secondary cases identified. We considered contacts with a SNP distance of 0-2 SNPs as verified transmissions [19].…”

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

“…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.…”