The SARS-CoV-2 lineage B.1.1.7, designated variant of concern (VOC) 202012/01 by Public Health England 1 , was first identified in the UK in late summer to early autumn 2020 2 . Whole-genome SARS-CoV-2 sequence data collected from community-based diagnostic testing for COVID-19 show an extremely rapid expansion of the B.1.1.7 lineage during autumn 2020, suggesting that it has a selective advantage. Here we show that changes in VOC frequency inferred from genetic data correspond closely to changes inferred by S gene target failures (SGTF) in community-based diagnostic PCR testing. Analysis of trends in SGTF and non-SGTF case numbers in local areas across England shows that B.1.1.7 has higher transmissibility than non-VOC lineages, even if it has a different latent period or generation time. The SGTF data indicate a transient shift in the age composition of reported cases, with cases of B.1.1.7 including a larger share of under 20-year-olds than non-VOC cases. We estimated time-varying reproduction numbers for B.1.1.7 and co-circulating lineages using SGTF and genomic data. The best-supported models did not indicate a substantial difference in VOC transmissibility among different age groups, but all analyses agreed that B.1.1.7 has a substantial transmission advantage over other lineages, with a 50% to 100% higher reproduction number.Phylogenetic studies carried out by the UK COVID-19 Genomics Consortium (COG-UK) (https://www.cogconsortium.uk) 8 provided the first indication that B.1.1.7 has an unusual accumulation of substitutions and was growing at a higer rate than other circulating lineages. We investigated time trends in the frequency of sampling VOC genomes and the proportion of PCR tests exhibiting SGTF across the UK, which we calibrated as a biomarker of VOC infection. Using multiple approaches and both genetic and SGTF data, we conclude that B.1.1.7 is associated with a higher reproduction number (R) than previous non-VOC lineages.We examined whole-genome SARS-CoV-2 sequences from randomly sampled residual materials obtained from community-based COVID-19 testing in England, collected between 1 October 2020 and 16 January 2021. These data included 31,390 B.1.1.7 sequences for which the time and location of sample collection were known. Over the same period, 52,795 non-VOC genomes were collected. VOC sequences were initially concentrated in London (n = 9,134), the South East (n = 5,609), and the East of England (n = 4,413), but is now widely distributed across England.

Highlights d Increasing frequency of SARS-CoV-2 D614G is consistent with a selective advantage d Phylodynamic analyses do not show significantly different growth of D614G clusters d There is no association of D614G replacement with greater severity of infection d The D614G replacement is associated with higher viral loads and younger patient age

Summary SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE2 1 , and is a major antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising antibodies in an immune suppressed individual treated with convalescent plasma, generating whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was observed in the overall viral population structure following two courses of remdesivir over the first 57 days. However, following convalescent plasma therapy we observed large, dynamic virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and ΔH69/ΔV70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred serum antibodies diminished, viruses with the escape genotype diminished in frequency, before returning during a final, unsuccessful course of convalescent plasma. In vitro , the Spike escape double mutant bearing ΔH69/ΔV70 and D796H conferred modestly decreased sensitivity to convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be the main contributor to decreased susceptibility but incurred an infectivity defect. The ΔH69/ΔV70 single mutant had two-fold higher infectivity compared to wild type, possibly compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy associated with emergence of viral variants with evidence of reduced susceptibility to neutralising antibodies.

The response of the global virus genomics community to the SARS-CoV-2 pandemic has been unprecedented, with significant advances made towards the ‘real-time’ generation and sharing of SARS-CoV-2 genomic data. The rapid growth in virus genome data production has necessitated the development of new analytical methods that can deal with orders of magnitude more genomes than previously available. Here we present and describe pangolin (Phylogenetic Assignment of Named Global Outbreak Lineages), a computational tool that has been developed to assign the most likely lineage to a given SARS-CoV-2 genome sequence according to the Pango dynamic nomenclature scheme described in Rambaut et al. (2020). To date, nearly two million virus genomes have been submitted to the web-application implementation of pangolin, which has facilitated the SARS-CoV-2 genomic epidemiology and provided researchers with access to actionable information about the pandemic’s transmission lineages.

Highlights d The receptor-binding motif (RBM) is a highly variable region of SARS-CoV-2 spike d RBM mutation N439K has emerged independently in multiple lineages d N439K increases spike affinity for hACE2; viral fitness and disease are unchanged d N439K confers resistance to several mAbs and escapes some polyclonal responses