ABSTRACT
Summary Some COVID-19 patients are unable to clear their infection or are at risk of severe disease, requiring treatment with neutralising monoclonal antibodies (nmAb) and/or antivirals. The rapid roll-out of novel therapeutics means there is limited understanding of the likely genetic barrier to drug resistance. Unprecedented genomic surveillance of SARS-CoV-2 in the UK has enabled a genome-first approach to the detection of emerging drug resistance. Here we report the accrual of mutations in Delta and Omicron cases treated with casirivimab+imdevimab and sotrovimab respectively. Mutations occur within the epitopes of the respective nmAbs. For casirivimab+imdevimab these are present on contiguous raw reads, simultaneously affecting both components. Using surface plasmon resonance and pseudoviral neutralisation assays we demonstrate these mutations reduce or completely abrogate antibody affinity and neutralising activity, suggesting they are driven by immune evasion. In addition, we show that some mutations also reduce the neutralising activity of vaccine-induced serum.
Subject(s)
COVID-19ABSTRACT
The first SARS-CoV-2 variant of concern (VOC) to be designated was lineage B.1.1.7, later labelled by the World Health Organisation (WHO) as Alpha. Originating in early Autumn but discovered in December 2020, it spread rapidly and caused large waves of infections worldwide. The Alpha variant is notable for being defined by a long ancestral phylogenetic branch with an increased evolutionary rate, along which only two sequences have been sampled. Alpha genomes comprise a well-supported monophyletic clade within which the evolutionary rate is more typical of SARS-CoV-2. The Alpha epidemic continued to grow despite the continued restrictions on social mixing across the UK, and the imposition of new restrictions, in particular the English national lockdown in November 2020. While from a case-number perspective these interventions succeeded in reducing the absolute number of cases of SARS-CoV-2 in the UK, the impact of these non-pharmaceutical interventions was predominantly to drive the decline of those SARS-CoV-2 lineages that preceded Alpha. We investigate the only two sampled sequences that fall on the branch ancestral to Alpha. We find that one is likely to be a true intermediate sequence, providing information about the order of mutational events that led to Alpha. We explore alternate hypotheses that can explain how Alpha acquired a large number of mutations yet remained largely unobserved in a region of high genomic surveillance: an under-sampled geographical location, a non-human animal population, or a chronically-infected individual. We conclude that the last hypothesis provides the best explanation of the observed behaviour and dynamics of the variant, although we find that the individual need not be immunocompromised, as persistently-infected immunocompetent hosts also display a higher within-host rate of evolution. Finally, we compare the ancestral branches and mutation profiles of other VOCs to each other, and identify that Delta appears to be an outlier both in terms of the genomic locations of its defining mutations, and its lack of rapid evolutionary rate on the ancestral branch. As new variants, such as Omicron, continue to evolve (potentially through similar mechanisms) it remains important to investigate the origins of other variants to identify ways to potentially disrupt their evolution and emergence.
ABSTRACT
BackgroundMitigation of SARS-CoV-2 transmission from international travel is a priority. Travellers from countries with travel restrictions (closed travel-corridors) were required to quarantine for 14 days over Summer 2020 in England. We describe the genomic epidemiology of travel-related cases in England and evaluate the effectiveness of this travel policy. MethodsBetween 27/05/2020 and 13/09/2020, probable travel-related SARS-CoV-2 cases and their contacts were identified and combined with UK SARS-CoV-2 sequencing data. The epidemiology and demographics of cases was identified, and the number of contacts per case modelled using negative binomial regression to estimate the effect of travel restriction, and any variation by age, sex and calendar date. Unique travel-related SARS-CoV-2 genomes in the COG-UK dataset were identified to estimate the effect travel restrictions on cluster size generated from these. The Polecat Clustering Tool was used to identify a travel-related SARS-CoV-2 cluster of infection. Findings4,207 travel-related SARS-CoV-2 cases are identified. 51.2% (2155/4207) of cases reported travel to one of three countries; 21.0% (882) Greece, 16.3% (685) Croatia and 14.0% (589) Spain. Median number of contacts per case was 3 (IQR 1-5), and greatest for the 16-20 age-group (9.0, 95% C.I.=5.6-14.5), which saw the largest attenuation by travel restriction. Travel restriction was associated with a 40% (rate ratio=0.60, 95% C.I.=0.37-0.95) lower rate of contacts. 827/4207 (19.7%) of cases had high-quality SARS-CoV-2 genomes available. Fewer genomically-linked cases were observed for index cases related to countries with travel restrictions compared to cases from non-travel restriction countries (rate ratio=0.17, 95% C.I.=0.05-0.52). A large travel-related cluster dispersed across England is identified through genomics, confirmed with contact-tracing data. InterpretationThis study demonstrates the efficacy of travel restriction policy in reducing the onward transmission of imported cases. FundingWellcome Trust, Biotechnology and Biological Sciences Research Council, UK Research & Innovation, National Institute of Health Research, Wellcome Sanger Institute. RESEARCH IN CONTEXTO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed, medRxiv, bioRxiv, Web of Science and Scopus for the terms (COVID-19 OR SARS-COV-2) AND (imported or importation) AND (sequenc* OR genom* or WGS). We filtered the 55 articles identified through this search and rejected any that did not undertake SARS-CoV-2 sequencing as part of an epidemiological investigation for importation into a different country. The remaining 20 papers were reviewed in greater detail to understand the patterns of importation and the methods used in each case. Added value of this studyThis is the first published study on importations of SARS-CoV-2 into England using genomics. Plessis et al., (2021) used a predictive model to infer the number of importations in to the UK from all SARS-CoV-2 genomes generated before 26th June 2020. The current study assesses the period 27/05/2020 to 13/09/2020 and presents findings of case-reported travel linked to genomic data. Two unpublished reports exist for Wales and Scotland, although only examine a comparatively small number of importations. Implications of all the available evidenceThis large-scale study has a number of findings that are pertinent to public health and of global significance, not available from prior evidence to our knowledge. The study demonstrates travel restrictions, through the implementation of travel-corridors, are effective in reducing the number of contacts per case based on observational data. Age has a significant effect on the number of contacts and this can be mitigated with travel restrictions. Analysis of divergent clusters indicates travel restrictions can reduce the number of onwards cases following a travel-associated case. Analysis of divergent clusters can allow for importations to be identified from genomics, as subsequently evidenced by cluster characteristics derived from contact tracing. The majority of importations of SARS-CoV-2 in England over Summer 2020 were from coastal European countries. The highest number of cases and onward contacts were from Greece, which was largely exempt from self-isolation requirements (bar some islands in September at the end of the study period). Systematic monitoring of imported SARS-CoV-2 cases would help refine implementation of travel restrictions. Finally, along with multiple studies, this study highlights the use of genomics to monitor and track importations of SARS-CoV-2 mutations of interest; this will be of particular use as the repertoire of clinically relevant SARS-CoV-2 variants expand over time and globally.