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.

This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

Objective: To evaluate an out of hours cooperative of general practitioners compared with a deputising service. Design: Observational study of two services in overlapping geographical areas. Setting: A general practice cooperative in Kensington, Chelsea, and Westminster and a deputising service operating in that area and the neighbouring area of Brent and Harrow. Subjects: All patients contacting a doctor at either service in an eight week period beginning 1 September 1995. Main outcome measures: Patients' age and sex; rates of home visiting, telephone advice, and attendance at a primary centre; hospital admission rates; prescribing rates; times of patient calls; and response times. Results: Data were collected on 5812 patient contacts. Doctors from the cooperative visited 32.0% (1253/ 3920) of patients, offered telephone advice to 57.8% (2267), and saw 7.1% (278) of patients at the primary care centre. By contrast, the deputising service visited 76.3% (1444/1892) of patients and gave telephone advice to 19.3% (365). Doctors from the cooperative prescribed drugs to fewer patients (37.6%; 1473/3915) than did the deputising service (51.7%; 941/1821) (odds ratio 0.56 (95% confidence interval 0.50 to 0.63) adjusted for age and sex) and admitted 8.7% (339/ 3888) of patients to hospital compared with 6.8% (128/1889) from the deputising service (odds ratio 1.30 (1.05 to 1.61) adjusted for age and sex). Response times for the deputising service were faster (median time to visit 65 minutes) than for the cooperative (median time to visit 75 minutes) but the time to first contact with a doctor was shorter for the cooperative because most people initially received telephone advice. Conclusions: The cooperative in this study dealt with patient contacts very differently from the way the deputising service dealt with contacts, fewer patients being visited and fewer receiving prescriptions. The data presented enable other out of hours services to compare their own performance using a standard data collection and analysis program.

No abstract