SARS-CoV-2 Spike protein is critical for virus infection via engagement of ACE21, and is a major
54 antibody target. Here we report chronic SARS-CoV-2 with reduced sensitivity to neutralising
55 antibodies in an immune suppressed individual treated with convalescent plasma, generating
56 whole genome ultradeep sequences over 23 time points spanning 101 days. Little change was
57 observed in the overall viral population structure following two courses of remdesivir over the
58 first 57 days. However, following convalescent plasma therapy we observed large, dynamic
59 virus population shifts, with the emergence of a dominant viral strain bearing D796H in S2 and
60 H69/V70 in the S1 N-terminal domain NTD of the Spike protein. As passively transferred
61 serum antibodies diminished, viruses with the escape genotype diminished in frequency, before
62 returning during a final, unsuccessful course of convalescent plasma. In vitro, the Spike escape
63 double mutant bearing H69/V70 and D796H conferred modestly decreased sensitivity to
64 convalescent plasma, whilst maintaining infectivity similar to wild type. D796H appeared to be
65 the main contributor to decreased susceptibility but incurred an infectivity defect. The
66 H69/V70 single mutant had two-fold higher infectivity compared to wild type, possibly
67 compensating for the reduced infectivity of D796H. These data reveal strong selection on SARS68
CoV-2 during convalescent plasma therapy associated with emergence of viral variants with
69 evidence of reduced susceptibility to neutralising antibodies.COG-UK is supported by funding from the Medical Research Council (MRC) part of UK Research & Innovation (UKRI), the National Institute of Health Research (NIHR) and Genome Research Limited, operating as the Wellcome Sanger Institute