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SARS-CoV-2 evolution and evasion from multiple antibody treatments in a cancer patient (infected with the Delta variant of SARS-CoV-2 for over 8 months)

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  • SARS-CoV-2 evolution and evasion from multiple antibody treatments in a cancer patient (infected with the Delta variant of SARS-CoV-2 for over 8 months)

    Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunocompromised patients may lead to accelerated viral mutation rate, immune evasion and persistent viral shedding over many months. Here we report the case of a severely immunocompromised cancer patient infected with the Delta variant of SARS-CoV-2 for over 8 months. Genome sequencing of samples taken after repeated monoclonal antibody treatments reveal the emergence and accumulation of mutations enabling escape from neutralization by antibodies. Mutations emerging in accessory and non-structural viral proteins target specific residues of immunomodulatory domains, potentially leading to loss of some functions, while preserving others. The mutated virus managed to completely overcome neutralization by monoclonal antibodies while remaining viable and infective. Our results suggest that the loss of specific immunomodulatory viral functions might confer a selective advantage in immunocompromised hosts. We also compare between mutations emerging in the presence and absence of neutralizing antibodies. Highlights ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was supported by the following grants: Horizon 2020 Research and Innovation Framework Programme, PSY\_PGx; The Edmond J. Safra Center for Bioinformatics at Tel Aviv University; The Koret\_UC Berkeley\_Tel Aviv University Initiative in Computational Biology and Bioinformatics; The QBI/UCSF\_Tel Aviv University joint Initiative in Computational Biology and Drug Discovery; Tel Aviv University Richard Eimert Research Fund on Solid Tumors; Collaborative clinical Bioinformatics research of the Edmond J. Safra Center for Bioinformatics and Faculty of Medicine at Tel Aviv University; Israeli Ministry of Science and Technology, Israeli_Russia; Kodesz Institute for Technologies in Healthcare; Tel Aviv University Healthy Longevity Research Center; Tel Aviv University Innovation Laboratories (TILabs). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics Committee of Shamir Medical Center has approved this study. The relevant patients provided consent for their participation and publication of the study, after being properly informed. Patient Data cannot be shared publicly due to patient confidentiality. All data is available from the Shamir Medical Center Institutional Ethics Committee, contact via Shamir Medical Center (Assaf Harofeh) Helsinki committee by email helsinky@shamir.gov.il for researchers who meet the criteria for access to confidential data. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Full sequencing data and reproducible analysis code will be released upon publishing.

    SARS-CoV-2 evolution and evasion from multiple antibody treatments in a cancer patient
    Guy Shapira, Chen Weiner, Reut Sorek Abramovich, Odit Gutwein, Nir Rainy, Patricia Benveniste-Levkovitz, Ezra Gordon, Adina Bar Chaim, Noam Shomron
    medRxiv 2022.06.25.22276445; doi: https://doi.org/10.1101/2022.06.25.22276445
    This article is a preprint and has not been peer-reviewed [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

    Abstract


    Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunocompromised patients may lead to accelerated viral mutation rate, immune evasion and persistent viral shedding over many months. Here we report the case of a severely immunocompromised cancer patient infected with the Delta variant of SARS-CoV-2 for over 8 months. Genome sequencing of samples taken after repeated monoclonal antibody treatments reveal the emergence and accumulation of mutations enabling escape from neutralization by antibodies. Mutations emerging in accessory and non-structural viral proteins target specific residues of immunomodulatory domains, potentially leading to loss of some functions, while preserving others. The mutated virus managed to completely overcome neutralization by monoclonal antibodies while remaining viable and infective. Our results suggest that the loss of specific immunomodulatory viral functions might confer a selective advantage in immunocompromised hosts. We also compare between mutations emerging in the presence and absence of neutralizing antibodies.

    Highlights
    • SARS-CoV-2 undergoes rapid evolution in an immunocompromised, chronically infected cancer patient, overcoming neutralization by two monoclonal antibody cocktail treatments
    • Receptor binding domain (RBD) mutations emerging after monoclonal antibody treatment enable effective escape from neutralization in the absence of adaptive immunity
    • Some emerging mutations are predicted to disrupt immunomodulatory viral proteins, including prevention of ORF8 homodimerization, mis-localization of ORF3a in host cells and alteration of the host-suppressive function of NSP1
    ...
    Clinical presentation of the chronically infected patient


    A female patient aged 60-69 was treated starting in June 2021 at Shamir Medical Center hospital, Be’er Yaacov, Israel as an oncological, immunocompromised patient (complete clinical timeline in Table 1). Oncological findings included: Malignant melanoma, Diffuse large B-cell lymphoma (DLBCL) and Squamous Cell Carcinoma (SCC). Background diseases included: fibromyalgia, treated asthma and Chronic Obstructive Pulmonary Disease (COPD). The patient was identified as Covid-19 positive during a routine visit in September 2021, and since then has tested positive 15 times and borderline positive once. The patient mostly presented as asymptomatic. Three Nasopharyngeal samples were obtained over the duration of infection and sent to viral whole-genome sequencing (Table 1).


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