The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity

Thomson, Emma C.; Rosen, Laura E.; Shepherd, James G.; Spreafico, Roberto; Filipe, Ana da Silva; Wojcechowskyj, Jason A.; Davis, Chris; Piccoli, Luca; Pascall, David; Dillen, Josh R; Lytras, Spyros; Czudnochowski, Nadine; Shah, Rajiv; Meury, Marcel; Jesudason, Natasha; Marco, Anna De; Li, Kathy; Bassi, Jessica; Pinto, Dora; Colquhoun, Rachel; Culap, Katja; Jackson, Ben; Zatta, Fabrizia; Rambaut, Andrew; Jaconi, Stefano; Sreenu, Vattipally B; Nix, Jay C.; Jarrett, Ruth F.; Beltramello, Martina; Nomikou, Kyriaki; Pizzuto, Matteo Samuele; Tong, L.; Cameroni, Elisabetta; Johnson, Natasha; Wickenhagen, Arthur; Ceschi, Alessandro; Mair, Daniel; Ferrari, Paolo; Smollett, Katherine; Sallusto, Federica; Carmichael, Stephen; Garzoni, Christian; Nichols, Jenna; Galli, Massimo; Hughes, Joseph; Riva, Agostino; Ho, Antonia; Openshaw, Peter; Baillie, Kenneth; Rihn, Suzannah J.; Lycett, Samantha; Virgin, Herbert W.; Telenti, Amalio; Corti, Davide; Robertson, David L.; Snell, Gyorgy

doi:10.1101/2020.11.04.355842

Cited by 159 publications

(205 citation statements)

References 64 publications

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“…The changes also included Q493K and F486I that corroborated with an earlier study that had recognised additional mutations (N74K, F79I, T259K, K417E, K444Q, V445A, N450D, Y453F, L455F, E484K, G485D, F490L, F490S, H655Y, R682Q, R685S, V687G, G769E, Q779K and V1128A) to be implicated in antibody resistance ( 28 ) . Besides, N439K mutation in Spike has also been shown to be involved in immune escape from a panel of neutralizing monoclonal antibodies in another study ( 29 ) . 20 out of these 23 positions overlap with sites that are potential sites of editing in our samples (Supplementary Table 3).…”

Section: Potential Functional Consequence Of Hyper-editing On Spike Pmentioning

confidence: 91%

Spatio-temporal dynamics of intra-host variability in SARS-CoV-2 genomes

Pathak

Fatihi

Abbas

et al. 2020

Preprint

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Since its zoonotic transmission in the human host, the SARS-CoV-2 virus has infected millions and has diversified extensively. A hallmark feature of viral system survival is their continuous evolution and adaptation within the host. RNA editing via APOBEC and ADAR family of enzymes has been recently implicated as the major driver of intra-host variability of the SARS-CoV-2 genomes. Analysis of the intra-host single-nucleotide variations (iSNVs) in SARS-CoV-2 genomes at spatio-temporal scales can provide insights on the consequence of RNA editing on the establishment, spread and functional outcomes of the virus. In this study, using 1,347 transcriptomes of COVID-19 infected patients across various populations, we find variable prevalence of iSNVs with distinctly higher levels in Indian population. Our results also suggest that iSNVs can likely establish variants in a population. These iSNVs may also contribute to key structural and functional changes in the Spike protein that confer antibody resistance.

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Section: Potential Functional Consequence Of Hyper-editing On Spike Pmentioning

confidence: 91%

Spatio-temporal dynamics of intra-host variability in SARS-CoV-2 genomes

Pathak

Fatihi

Abbas

et al. 2020

Preprint

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“…However, the only escape mutations present in >0.1% of sequences were the REGN10933 escape-mutant Y453F (0.2% of sequences) ( 10 ) and the REGN10987 escape-mutant N439K (1.2% of sequences, has an effect on neutralization as shown in both Fig. 1C and ( 20 )). Y453F is associated with independent mink-associated outbreaks in the Netherlands and Denmark ( 22 , 23 ); notably the mink sequences themselves sometimes also contain other escape mutations such as F486L ( 21 ).…”

mentioning

confidence: 88%

Prospective mapping of viral mutations that escape antibodies used to treat COVID-19

Starr

Greaney

Addetia

et al. 2020

Preprint

263

397

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Antibodies are becoming a frontline therapy for SARS-CoV-2, but the risk of viral evolutionary escape remains unclear. Here we map how all mutations to SARS-CoV-2's receptor-binding domain (RBD) affect binding by the antibodies in Regeneron's REGN-COV2 cocktail and Eli Lilly's LY-CoV016. These complete maps uncover a single amino-acid mutation that fully escapes the REGN-COV2 cocktail, which consists of two antibodies targeting distinct structural epitopes. The maps also identify viral mutations that are selected in a persistently infected patient treated with REGN-COV2, as well as in lab viral escape selections. Finally, the maps reveal that mutations escaping each individual antibody are already present in circulating SARS-CoV-2 strains. Overall, these complete escape maps enable immediate interpretation of the consequences of mutations observed during viral surveillance.

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“…Clear lineage-defining single nucleotide polymorphisms (SNPs) have emerged ( 1 ) , enabling tracking of viral spread ( 2 , 3 ) , but also raising concerns that new mutations may confer selective advantages on the virus, hampering efforts at control. Most prominently, there is increasing evidence that the D614G mutation (genome position 23403) in the Spike protein (S) increases viral transmissibility ( 4 , 5 ) and N439K (genome position 22879) evades antibodies without loss of fitness ( 6 ) . Most analyses have been focused on mutations observed in viral consensus genomes, which represent the dominant variants within infected individuals.…”

Section: Introductionmentioning

confidence: 99%

Within-host genomics of SARS-CoV-2

Lythgoe

Hall

Ferretti

et al. 2020

Preprint

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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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The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity

Cited by 159 publications

References 64 publications

Spatio-temporal dynamics of intra-host variability in SARS-CoV-2 genomes

Spatio-temporal dynamics of intra-host variability in SARS-CoV-2 genomes

Prospective mapping of viral mutations that escape antibodies used to treat COVID-19

Within-host genomics of SARS-CoV-2

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