Establishment &amp; lineage dynamics of the SARS-CoV-2 epidemic in the UK

Plessis, Louis du; McCrone, John; Zarebski, Alexander E.; Hill, Verity; Ruis, Chris; Gutiérrez, Bernardo; Raghwani, Jayna; Ashworth, Jordan; Colquhoun, Rachel; Connor, Thomas R.; Faria, Nuno Rodrigues; Jackson, Benjamin C.; Loman, Nicholas J.; O’Toole, Áine; Nicholls, Samuel M.; Parag, Kris V; Scher, Emily; Vasylyeva, Tetyana I.; Volz, Erik; Watts, Alexander; Bogoch, Isaac I.; Khan, Kamran; Aanensen, David M.; Kraemer, Moritz U. G.; Rambaut, Andrew; Pybus, Oliver G.

doi:10.1101/2020.10.23.20218446

Cited by 72 publications

(116 citation statements)

References 70 publications

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“…Measurably evolving populations are evolutionary systems that undergo mutation and selection rapidly enough to be detected in longitudinally-sampled timepoints. 4 While this concept is frequently applied to viruses such as HIV 5 and SARS-CoV-2, 6 B cells experience similarly rapid evolution during affinity maturation. B cell affinity maturation is critical for developing high affinity antibodies in response to infection and vaccination.…”

Section: Main Textmentioning

confidence: 99%

Human B cell lineages engaged by germinal centers following influenza vaccination are measurably evolving

Hoehn

Turner

Miller

et al. 2021

Preprint

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Poor efficacy of seasonal influenza virus vaccines is often attributed to pre-existing immunity interfering with the persistence and maturation of vaccine-induced B cell responses.1 Consistent with this notion, no significant increase in somatic hypermutation (SHM) among circulating influenza-binding lineages was detected following seasonal vaccination in humans.2 A more recent study showed that at least a subset of vaccine-induced B cell lineages are recruited into germinal centers (GCs) following vaccination, suggesting that affinity maturation of these lineages can occur.3 Crucially, however, it has not been demonstrated whether these GC-engaged lineages actually accumulate additional SHM. Here, we address this point using a phylogenetic test of measurable evolution. We first validate this test through simulations and demonstrate measurable B cell evolution in known examples of affinity maturation such as the response to HIV infection. We then show that lineages in the blood are rarely measurably evolving following influenza vaccination, but that GC-engaged lineages - likely derived from memory B cells - are frequently measurably evolving. These findings confirm that seasonal influenza virus vaccination can stimulate additional SHM among responding B cell lineages.

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Section: Main Textmentioning

confidence: 99%

Human B cell lineages engaged by germinal centers following influenza vaccination are measurably evolving

Hoehn

Turner

Miller

et al. 2021

Preprint

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“…The United Kingdom (UK) experienced one of the most severe first waves of infection, with over a thousand independent importation events contributing to substantial viral diversity during this period ( 7 ) . In this study, we collected and analysed 1390 samples predominantly from symptomatic individuals (1173 unique individuals plus 93 anonymous samples) who tested positive for COVID-19 during the first wave of infection (March -June 2020; Table S1).…”

Section: Introductionmentioning

confidence: 99%

Within-host genomics of SARS-CoV-2

Lythgoe

Hall

Ferretti

et al. 2020

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SARS-CoV-2, the causative agent of COVID-19, emerged in late 2019 causing a global pandemic, with the United Kingdom (UK) one of the hardest hit countries. Rapid sequencing and publication of consensus genomes have enabled phylogenetic analysis of the virus, demonstrating SARS-CoV-2 evolves relatively slowly 1 , but with multiple sites in the genome that appear inconsistent with the overall consensus phylogeny 2 . To understand these discrepancies, we used veSEQ 3 , a targeted RNA-seq approach, to quantify minor allele frequencies in 413 clinical samples from two UK locations. We show that SARS-CoV-2 infections are characterised by extensive within-host diversity, which is frequently shared among infected individuals with patterns consistent with geographical structure. These results were reproducible in data from other sequencing locations around the UK, where we find evidence of mixed infection by major circulating lineages with patterns that cannot readily be explained by artefacts in the data. We conclude that SARS-CoV-2 diversity is transmissible, and propose that geographic patterns are generated by co-circulation of distinct viral populations. Co-transmission of mixed populations could open opportunities for resolving clusters of transmission and understanding pathogenesis. symptomatic individuals who tested positive for COVID-19 within two geographically-separate hospital trusts (Oxford University Hospitals and Basingstoke and North Hampshire Hospital, located 37 miles (60 km) apart; Supplementary Table 1) . Using veSEQ, a sequencing protocol based on a quantitative targeted enrichment strategy 3 , which we previously validated for other viruses 3 , 11 , 12 , we characterised the full spectrum of within-host diversity in SARS-CoV-2 and contextualised our findings within other high-quality, publicly available deep-sequencing datasets from the UK generated on the high-fidelity Illumina platform 13 , 14 . All genomic data has been made publicly available as part of the COVID-19 Genomics UK (COG-UK) Consortium [cogconsortium.uk] via GISAID 15 and the European Nucleotide Archive (ENA) study PRJEB37886. Within-host diversity is extensive and shared between individualsTo examine patterns of within-host diversity, we first considered the distribution of minor allele frequencies (MAFs) in the mapped reads at every position along the genome. This analysis was supported by data curation to ensure that only high-confidence variants were examined, which included analysis of in-batch quantification controls as well as a stringent computational clean-up to eliminate any residual cross-mapping 16 , previously validated for targeted metagenomics 11 (see Methods and Supplementary Text for a full description). In combination with unique dual indexing (UDI), these procedures generated highly robust minority variant calls, which were reproducible in independent replicates and distinguishable from methodological noise above a threshold of 2% of reads at a given position (Supplementary Figure 1). The distribution of MAFs was a...

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“…For each non-UK clade, the phylogeny was rescaled into units of time with treedater 13 , assuming a strict molecular clock with the rate of SARS-CoV-2 genome evolution drawn from an externally-estimated distribution as described by du Plessis et al 19 . Specifically, for the rate a normal distribution was specified with mean 9.41×10 -4 nucleotide substitutions per site per year and a standard deviation of 4.99×10 -5 .…”

Section: Supplementary Informationmentioning

confidence: 99%

“…For each non-UK VOC lineage, we estimated the timing of introduction by performing molecular clock estimation on 100 replicates based on the clock rate distribution from Plessis et al 19 (see Supplementary Information). Each horizontal bar represent a non-UK cluster.…”

mentioning

confidence: 99%