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Genome-first detection of emerging resistance to novel therapeutic agents for SARS-CoV-2
Manon Ragonnet-Cronin; Rungtiwa Nutalai; Jiandong Huo; Aiste Dijokaite-Guraliuc; Raksha Das; Aekkachai Tuekprakhon; Piyada Supasa; Chang Liu; Muneeswaran Selvaraj; Natalie Groves; Hassan Hartman; Nicholas Ellaby; J. Mark Sutton; Mohammad W. Bahar; Daming Zhou; Elizabeth Fry; Jingshan Ren; Colin Brown; Paul Klenerman; Susan J. Dunachie; Juthathip Mongkolsapaya; Susan Hopkins; Meera Chand; David I. Stuart; Gavin R. Screaton; Sakib Rokadiya.
  • Manon Ragonnet-Cronin; Imperial College London
  • Rungtiwa Nutalai; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • Jiandong Huo; Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK
  • Aiste Dijokaite-Guraliuc; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • Raksha Das; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • Aekkachai Tuekprakhon; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • Piyada Supasa; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • Chang Liu; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • Muneeswaran Selvaraj; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • Natalie Groves; Genomics Public Health Analysis, UK Health Security Agency
  • Hassan Hartman; Genomics Public Health Analysis, UK Health Security Agency
  • Nicholas Ellaby; Genomics Public Health Analysis, UK Health Security Agency
  • J. Mark Sutton; Genomics Public Health Analysis, UK Health Security Agency
  • Mohammad W. Bahar; Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK
  • Daming Zhou; Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK
  • Elizabeth Fry; Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK
  • Jingshan Ren; Division of Structural Biology, Nuffield Department of Medicine, University of Oxford, The Wellcome Centre for Human Genetics, Oxford, UK
  • Colin Brown; Genomics Public Health Analysis, UK Health Security Agency
  • Paul Klenerman; Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • Susan J. Dunachie; Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • Juthathip Mongkolsapaya; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • Susan Hopkins; Genomics Public Health Analysis, UK Health Security Agency
  • Meera Chand; Genomics Public Health Analysis, UK Health Security Agency
  • David I. Stuart; Genomics Public Health Analysis, UK Health Security Agency
  • Gavin R. Screaton; Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
  • Sakib Rokadiya; Genomics Public Health Analysis, UK Health Security Agency
Preprint En | PREPRINT-BIORXIV | ID: ppbiorxiv-500063
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.

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