PT  - JOURNAL ARTICLE
AU  - Katrina A. Lythgoe
AU  - Matthew Hall
AU  - Luca Ferretti
AU  - Mariateresa de Cesare
AU  - George MacIntyre-Cockett
AU  - Amy Trebes
AU  - Monique Andersson
AU  - Newton Otecko
AU  - Emma L. Wise
AU  - Nathan Moore
AU  - Jessica Lynch
AU  - Stephen Kidd
AU  - Nicholas Cortes
AU  - Matilde Mori
AU  - Rebecca Williams
AU  - Gabrielle Vernet
AU  - Anita Justice
AU  - Angie Green
AU  - Samuel M. Nicholls
AU  - M. Azim Ansari
AU  - Lucie Abeler-Dörner
AU  - Catrin E. Moore
AU  - Timothy E. A. Peto
AU  - David W. Eyre
AU  - Robert Shaw
AU  - Peter Simmonds
AU  - David Buck
AU  - John A. Todd
AU  - on behalf of OVSG Analysis Group
AU  - Thomas R. Connor
AU  - Ana da Silva Filipe
AU  - James Shepherd
AU  - Emma C. Thomson
AU  - The COVID-19 Genomics UK (COG-UK) consortium
AU  - David Bonsall
AU  - Christophe Fraser
AU  - Tanya Golubchik
TI  - Within-host genomics of SARS-CoV-2
AID  - 10.1101/2020.05.28.118992
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.05.28.118992
4099  - http://biorxiv.org/content/early/2020/12/10/2020.05.28.118992.short
4100  - http://biorxiv.org/content/early/2020/12/10/2020.05.28.118992.full
AB  - Extensive global sampling and whole genome sequencing of the pandemic virus SARS-CoV-2 have enabled researchers to characterise its spread, and to identify mutations that may increase transmission or enable the virus to escape therapies or vaccines. Two important components of viral spread are how frequently variants arise within individuals, and how likely they are to be transmitted. Here, we characterise the within-host diversity of SARS-CoV-2, and the extent to which genetic diversity is transmitted, by quantifying variant frequencies in 1390 clinical samples from the UK, many from individuals in known epidemiological clusters. We show that SARS-CoV-2 infections are characterised by low levels of within-host diversity across the entire viral genome, with evidence of strong evolutionary constraint in Spike, a key target of vaccines and antibody-based therapies. Although within-host variants can be observed in multiple individuals in the same phylogenetic or epidemiological cluster, highly infectious individuals with high viral load carry only a limited repertoire of viral diversity. Most viral variants are either lost, or occasionally fixed, at the point of transmission, consistent with a narrow transmission bottleneck. These results suggest potential vaccine-escape mutations are likely to be rare in infectious individuals. Nonetheless, we identified Spike variants present in multiple individuals that may affect receptor binding or neutralisation by antibodies. Since the fitness advantage of escape mutations in highly-vaccinated populations is likely to be substantial, resulting in rapid spread if and when they do emerge, these findings underline the need for continued vigilance and monitoring.Competing Interest StatementDWE declares personal fees from Gilead outside the submitted work. All other authors declare no competing interests.