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.

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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.

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13516 Background: FolateImmune is a folate-receptor (FR)-targeted immunotherapy that induces an immune response against tumor cells by marking them with a folate-hapten conjugate. The conjugate is specifically designed to target FR, which is over-expressed in a variety of cancers. FolateImmune therapy is comprised of a vaccine fluorescein conjugate (EC90), an adjuvant (GP-0100), and a folate-hapten conjugate (EC17). Patients (pts) receive a series of subcutaneous (SQ) injections of EC90 vaccine to stimulate the production of antibodies to the fluorescein-hapten, followed by SQ injections of EC17, which forms a molecular bridge between the tumor cell and the endogenous circulating anti-fluorescein IgG antibody. This is thought to initiate an Fc-mediated immune response leading to antibody-dependent cellular cytotoxicity and/or phagocytosis. IL-2 and IFN are utilized at low doses (7 MIU and 3 MIU, respectively) to further promote an immune response. The Phase Ib objective is to determine the safety of EC90 vaccine/EC17 folate-targeted therapy in combination with IL-2 and IFN. The previous phase I trial explored the safety of FolateImmune without cytokines. Methods: This phase 1b safety study treated eligible patients with FolateImmune therapy at dose levels of 1.2 mg EC90 and EC17 of 0.3 mg/kg. Results: As of Jan 2, 2007, all patients have tolerated therapy without significant toxicity. Grade 1–2 toxicity included: chills, fever, and nausea. One patient has had a minor response and continues on study. Laboratory studies revealed decline in circulating FR+ cells. Of 6 pts enrolled, 5 had a pathologic classification of renal cell cancer (RCC). Conclusion: Preliminary data suggest that FolateImmune therapy, with the addition of low dose cytokines, may be administered in a safe and well-tolerated manner. Phase II trials are planned for RCC. No significant financial relationships to disclose.