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    Emergence of multiple SARS-CoV-2 antibody escape variants in an immunocompromised host undergoing convalescent plasma treatment

    Authors: Liang Chen; Michael C Zody; Jose R Mediavilla; Marcus H Cunningham; Kaelea Composto; Kar Fai Chow; Milena Kordalewska; Andre Corvelo; Dayna M Oschwald; Samantha Fennessey; Marygrace Zetkulic; Sophia Dar; Yael Kramer; Barun Mathema; Tom Maniatis; David S Perlin; Barry N Kreiswirth

    doi:10.1101/2021.04.08.21254791 Date: 2021-04-11 Source: medRxiv

    SARS-CoV-2 Variants of Concerns (VOC), e.g., B.1.351 (20H/501Y.V2) and P1 (20J/501Y.V3), harboring N-terminal domain ( NTD HGNC) or the receptor-binding domain (RBD) (e.g., E484K) mutations, exhibit reduced in vitro susceptibility to convalescent serum, commercial antibody cocktails, and vaccine neutralization, and have been associated with reinfection. The accumulation of these mutations could be the consequence of intra-host viral evolution due to prolonged infection MESHD in immunocompromised hosts. In this study, we document the microevolution of SARS-CoV-2 recovered from sequential tracheal aspirates from an immunosuppressed patient on tacrolimus, steroids and convalescent plasma therapy, and identify the emergence of multiple NTD HGNC and RBD mutations associated with reduced antibody neutralization as early as three weeks after infection. SARS-CoV-2 genomes from the first swab (Day 0) and three tracheal aspirates (Day 7, 21 and 27) were compared at the sequence level. We identified five different S protein PROTEIN mutations at the NTD HGNC or RBD regions from the second tracheal aspirate sample (21 Day). The S:Q493R substitution and S:243-244LA deletion had ~70% frequency, while ORF1a PROTEIN:A138T, S:141-144LGVY deletion, S:E484K and S:Q493K substitutions demonstrated ~30%, ~30%, ~20% and ~10% mutation frequency, respectively. However, the third tracheal aspirate sample collected one week later (Day 27) was predominated by the haplotype of ORF1a PROTEIN:A138T, S:141-144LGVY deletion and S:E484K (> 95% mutation frequency). Notably, S protein PROTEIN deletions (141-144LGVY and 243-244LA deletions in NTD HGNC region) and substitutions (Q493K/R and E484K in the RBD region) previously showed reduced susceptibly to monoclonal antibody or convalescent plasma. The observation supports the hypothesis that VOCs can independently arise and that immunocompromised patients on convalescent plasma therapy are potential breeding grounds for immune-escape mutants.

    Machine Learning Identifies Ponatinib as a Potent Inhibitor of SARS-CoV2-induced Cytokine Storm

    Authors: Marina Chan; Siddharth Vijay; M. Juliana McElrath; Eric C Holland; Taranjit S Gujral

    doi:10.1101/2021.04.07.438871 Date: 2021-04-09 Source: bioRxiv

    Although 15-20% of COVID-19 MESHD patients experience hyper-inflammation MESHD induced by massive cytokine production, cellular triggers of this process and strategies to target them remain poorly understood. Here, we show that the N-terminal domain ( NTD HGNC) of the spike protein PROTEIN from the SARS-CoV-2 and emerging variants B1.1.7 and B.1.351 substantially induces multiple inflammatory molecules in human monocytes and PBMCs. Further, we identified several protein kinases, including JAK1 HGNC, EPHA7 HGNC, IRAK1 HGNC, MAPK12 HGNC, and MAP3K8 HGNC, as essential downstream mediators of NTD HGNC-induced cytokine release. Additionally, we found that the FDA-approved, multi-kinase inhibitor Ponatinib is a potent inhibitor of the NTD HGNC-mediated cytokine storm. Taken together, we propose that agents targeting multiple kinases required for the SARS-CoV-2-mediated cytokine storm, such as Ponatinib, may represent an attractive therapeutic option for treating moderate to severe COVID-19 MESHD.

    SARS-CoV-2 immune evasion by variant B.1.427/B.1.429

    Authors: Matthew McCallum; Jessica Bassi; Anna De Marco; Alex Chen; Alexandra C Walls; Julia Di Iulio; M. Alejandra Tortorici; Mary-Jane Navarro; Chiara Silacci-Fregni; Christian Saliba; Maria Agostini; Dora Pinto; Katja Culap; Siro Bianchi; Stefano Jaconi; Elisabetta Cameroni; John E Bowen; Sasha W Tiles; Matteo Samuele Pizzuto; Sonja Bernasconi Guastalla; Giovanni Bona; Alessandra Franzetti Pellanda; Christian Garzoni; Wesley C Van Voorhis; Laura E Rosen; Gyorgy C Snell; Amalio Telenti; Herbert W Virgin; Luca Piccoli; Davide Corti; David Veesler

    doi:10.1101/2021.03.31.437925 Date: 2021-04-01 Source: bioRxiv

    SARS-CoV-2 entry is mediated by the spike ( S) glycoprotein PROTEIN which contains the receptor-binding domain (RBD) and the N-terminal domain ( NTD HGNC) as the two main targets of neutralizing antibodies (Abs). A novel variant of concern (VOC) named CAL.20C (B.1.427/B.1.429) was originally detected in California MESHD and is currently spreading throughout the US and 29 additional countries. It is unclear whether antibody responses to SARS-CoV-2 infection MESHD or to the prototypic Wuhan-1 isolate-based vaccines will be impacted by the three B.1.427/B.1.429 S mutations: S13I, W152C and L452R. Here, we assessed neutralizing Ab responses following natural infection or mRNA vaccination using pseudoviruses expressing the wildtype or the B.1.427/B.1.429 S protein PROTEIN. Plasma from vaccinated or convalescent individuals exhibited neutralizing titers, which were reduced 3-6 fold against the B.1.427/B.1.429 variant relative to wildtype pseudoviruses. The RBD L452R mutation reduced or abolished neutralizing activity of 14 out of 35 RBD-specific monoclonal antibodies (mAbs), including three clinical-stage mAbs. Furthermore, we observed a complete loss of B.1.427/B.1.429 neutralization for a panel of mAbs targeting the N-terminal domain due to a large structural rearrangement of the NTD HGNC antigenic supersite involving an S13I-mediated shift of the signal peptide cleavage site. These data warrant closer monitoring of signal peptide variants and their involvement in immune evasion and show that Abs directed to the NTD HGNC impose a selection pressure driving SARS-CoV-2 viral evolution through conventional and unconventional escape mechanisms.

    Rapid characterization of spike variants via mammalian cell surface display

    Authors: Kamyab Javanmardi; Chia-Wei Chou; Cynthia Terrace; Ankur Annapareddy; Tamer S Kaoud; Qingqing Guo; Josh Lutgens; Hayley Zorkic; Andrew P Horton; Elizabeth C Gardner; Giaochau Nguyen; Daniel R Boutz; Jule Goike; Will N Voss; Hung-Che Kuo; Kevin N Dalby; Jimmy D Gollihar; Ilya J Finkelstein

    doi:10.1101/2021.03.30.437622 Date: 2021-03-30 Source: bioRxiv

    The SARS-CoV-2 spike PROTEIN ( S) protein PROTEIN is a critical component of subunit vaccines and a target for neutralizing antibodies. Spike is also undergoing immunogenic selection with clinical variants that increase infectivity and partially escape convalescent plasma. Here, we describe spike display, a high-throughput platform to rapidly characterize glycosylated spike ectodomains across multiple coronavirus-family proteins. We assayed ~200 variant SARS-CoV-2 spikes PROTEIN for their expression, ACE2 HGNC binding, and recognition by thirteen neutralizing antibodies (nAbs). An alanine scan of the N-terminal domain ( NTD HGNC) highlights a public class of epitopes in the N3 and N5 loops that are recognized by most of the NTD HGNC-binding nAbs assayed in this study. Some clinical NTD HGNC substitutions abrogate binding to these epitopes but are circulating at low frequencies around the globe. NTD HGNC mutations in variants of concern B.1.1.7 (United Kingdom), B.1.351 (South Africa), B.1.1.248 (Brazil), and B.1.427/B.1.429 (California) impact spike expression and escape most NTD HGNC-targeting nAbs. However, two classes of NTD HGNC nAbs still bind B.1.1.7 spikes and neutralize in pseudoviral assays. B.1.1351 and B.1.1.248 include compensatory mutations that either increase spike expression or increase ACE2 HGNC binding affinity. Finally, B.1.351 and B.1.1.248 completely escape a potent ACE2 HGNC peptide mimic. We anticipate that spike display will be useful for rapid antigen design, deep scanning mutagenesis, and epitope mapping of antibody interactions for SARS-CoV-2 and other emerging viral threats.

    Concerns Raised on Blood Group Determinants in Plasma Membrane Interaction of the SARS-CoV-2

    Authors: Klaus Fiedler

    id:10.20944/preprints202103.0460.v2 Date: 2021-03-23 Source: Preprints.org

    The SARS-CoV-2 pandemic has resulted in the generation of evolutionary-related variants. The S-protein PROTEIN of the B.1.1.7 variant (deletion N-terminal domain ( NTD HGNC) His69Val70Tyr144) may contribute to altered infectivity. These mutations may have been presaged by animal mutations in minks housed in mink farms that according to the present analysis by modelling of protein ligand docking altered a high affinity binding site in the S-protein PROTEIN NTD HGNC. These mutants likely occurred only sporadically in humans. Tissue-adaptations and the size of the mink relative to the infected human population size back then may have comparatively increased the relative mutation rate. Simple, multi-threaded automated docking that is widely available, assigns increased binding of the blood type II A antigen to the SARS-Cov-2 S-protein PROTEIN NTD HGNC of B.1.1.7 with an overall increased docking interaction of blood group A harbouring glycolipids relative to group B or H (H, p=0.04). The top scoring glycan is identified as a DSGG (also classified as sialosyl-MSGG or disialosyl-Gb5) that may compete with heparin, which is similar to heparan sulfate linked to proteinaceous receptors on the tissue surface. Other glycolipids are found to interact with lower affinity, except long ligands that have suitable ligand binding poses to match the curved binding pocket.

    Characterisation of B.1.1.7 and Pangolin coronavirus spike provides insights on the evolutionary trajectory of SARS-CoV-2

    Authors: Samuel J Dicken; Matthew J Murray; Lucy G Thorne; Ann-Kathrin Reuschl; Calum Forrest; Maaroothen Ganeshalingham; Luke Muir; Mphatso D Kalemera; Machaela Palor; Laura E McCoy; Clare Jolly; Greg J Towers; Matthew Reeves; Joe Grove

    doi:10.1101/2021.03.22.436468 Date: 2021-03-22 Source: bioRxiv

    The recent emergence of SARS-CoV-2 variants with increased transmission, pathogenesis and immune resistance has jeopardised the global response to the COVID-19 pandemic MESHD. Determining the fundamental biology of viral variants and understanding their evolutionary trajectories will guide current mitigation measures, future genetic surveillance and vaccination strategies. Here we examine virus entry by the B.1.1.7 lineage, commonly referred to as the UK/Kent variant. Pseudovirus infection of model cell lines demonstrate that B.1.1.7 entry is enhanced relative to the Wuhan-Hu-1 reference strain, particularly under low expression of receptor ACE2 HGNC. Moreover, the entry characteristics of B.1.1.7 were distinct from that of its predecessor strain containing the D614G mutation. These data suggest evolutionary tuning of spike protein PROTEIN function. Additionally, we found that amino acid deletions within the N-terminal domain ( NTD HGNC) of spike were important for efficient entry by B.1.1.7. The NTD HGNC is a hotspot of diversity across sarbecoviruses, therefore, we further investigated this region by examining the entry of closely related CoVs. Surprisingly, Pangolin CoV spike entry was 50-100 fold enhanced relative to SARS-CoV-2; suggesting there may be evolutionary pathways by which SARS-CoV-2 may further optimise entry. Swapping the NTD HGNC between Pangolin CoV and SARS-CoV-2 demonstrates that changes in this region alone have the capacity to enhance virus entry. Thus, the NTD HGNC plays a hitherto unrecognised role in modulating spike activity, warranting further investigation and surveillance of NTD HGNC mutations.

    Reduced neutralization of SARS-CoV-2 variants by convalescent plasma and hyperimmune intravenous immunoglobulins for treatment of COVID-19 MESHD

    Authors: Juanjie Tang; Your Lee; Supriya Ravichandran; Gabrielle Grubbs; Chang Huang; Charles Stauft; Tony Wang; Basil Golding; Hana Golding; Surender Khurana

    doi:10.1101/2021.03.19.436183 Date: 2021-03-19 Source: bioRxiv

    Hyperimmune immunoglobulin (hCoV-2IG) preparations generated from SARS-CoV-2 convalescent plasma (CP) are under evaluation in several clinical trials of hospitalized COVID-19 MESHD patients. Here we explored the antibody epitope repertoire, antibody binding and virus neutralizing capacity of six hCoV-2IG batches as well as nine convalescent plasma (CP) lots against SARS-CoV-2 and emerging variants of concern (VOC). The Gene-Fragment Phage display library spanning the SARS-CoV-2 spike PROTEIN demonstrated broad recognition of multiple antigenic sites spanning the entire spike including NTD HGNC, RBD, S1/S2 cleavage site, S2-fusion peptide and S2-heptad repeat regions. Antibody binding to the immunodominant epitopes was higher for hCoV-2IG than CP, with predominant binding to the fusion peptide. In the pseudovirus neutralization assay (PsVNA) and in the wild-type SARS-CoV-2 PRNT assay, hCoV-2IG lots showed higher titers against the WA-1 strain compared with CP. Neutralization of SARS-CoV-2 VOCs from around the globe were reduced to different levels by hCoV-2IG lots. The most significant loss of neutralizing activity was seen against the B.1.351 (9-fold) followed by P.1 (3.5-fold), with minimal loss of activity against the B.1.17 and B.1.429 (<2-fold). Again, the CP showed more pronounced loss of cross-neutralization against the VOCs compared with hCoV-2IG. Significant reduction of hCoV-2IG binding was observed to the RBD-E484K followed by RBD-N501Y and minimal loss of binding to RBD-K417N compared with unmutated RBD. This study suggests that post-exposure treatment with hCoV-2IG is preferable to CP. In countries with co-circulating SARS-CoV-2 variants, identifying the infecting virus strain could inform optimal treatments, but would likely require administration of higher volumes or repeated infusions of hCOV-2IG or CP, in patients infected with the emerging SARS-CoV-2 variants.

    Concerns Raised on Blood Group Determinants in Plasma Membrane Interaction of the SARS-CoV-2

    Authors: Klaus Fiedler

    id:10.20944/preprints202103.0460.v1 Date: 2021-03-18 Source: Preprints.org

    The SARS-CoV-2 pandemic has resulted in the generation of evolutionary-related variants. The S-protein PROTEIN of the B.1.1.7 variant (deletion N-terminal domain ( NTD HGNC) His69Val70Tyr144) may contribute to altered infectivity. These mutations may have been presaged by animal mutations in minks housed in mink farms that according to the present analysis by modelling of protein ligand docking altered a high affinity binding site in the S-protein PROTEIN NTD HGNC. These mutants likely occurred only sporadically in humans. Tissue-adaptations and the size of the mink relative to the infected human population size back then may have comparatively increased the relative mutation rate. Simple, multi-threaded automated docking that is widely available, assigns increased binding of the blood type II A antigen to the SARS-Cov-2 S-protein PROTEIN NTD HGNC of B.1.1.7 with an overall increased docking interaction of blood group A harbouring glycolipids relative to group B or H (H, p=0.04). The top scoring glycan is identified as a DSGG (also classified as sialosyl-MSGG or disialosyl-Gb5) that may compete with heparin, which is similar to heparan sulfate linked to proteinaceous receptors on the tissue surface. Other glycolipids are found to interact with lower affinity, except long ligands that have suitable ligand binding poses to match the curved binding pocket.

    Effect of natural mutations of SARS-CoV-2 on spike PROTEIN structure, conformation and antigenicity

    Authors: Sophie Gobeil; Katarzyna Janowska; Shana McDowell; Katayoun Mansouri; Robert Parks; Victoria Stalls; Megan F. Kopp; Kartik Manne; Robert J Edwards; Barton F Haynes; Rory Henderson; Priyamvada Acharya

    doi:10.1101/2021.03.11.435037 Date: 2021-03-12 Source: bioRxiv

    New SARS-CoV-2 variants that have accumulated multiple mutations in the spike ( S) glycoprotein PROTEIN enable increased transmission and resistance to neutralizing antibodies. Here, we study the antigenic and structural impacts of the S protein PROTEIN mutations from four variants, one that was involved in transmission between minks and humans, and three that rapidly spread in human populations and originated in the United Kingdom, Brazil or South Africa. All variants either retained or improved binding to the ACE2 HGNC receptor. The B.1.1.7 (UK) and B.1.1.28 (Brazil) spike variants showed reduced binding to neutralizing NTD MESHD NTD HGNC and RBD antibodies, respectively, while the B.1.351 (SA) variant showed reduced binding to both NTD HGNC- and RBD-directed antibodies. Cryo-EM structural analyses revealed allosteric effects of the mutations on spike conformations and revealed mechanistic differences that either drive inter-species transmission or promotes viral escape from dominant neutralizing epitopes.

    The plasmablast response to SARS-CoV-2 mRNA vaccination is dominated by non-neutralizing antibodies that target both the NTD HGNC NTD MESHD and the RBD

    Authors: Fatima Amanat; Mahima Thapa; Tingting Lei; Shaza M. Sayed Ahmed; Daniel C. Adelsberg; Juan Manuel Carreno; Shirin Strohmeier; Aaron J. Schmitz; Sarah Zafar; Julian Q Zhou; Willemijn Rijnink; Hala Alshammary; Nicholas Borcherding; Ana Gonzalez Reiche; Komal Srivastava; Emilia Mia Sordillo; Harm van Bakel; Jackson S. Turner; Goran Bajic; Viviana M Simon; Ali H. Ellebedy; Florian Krammer

    doi:10.1101/2021.03.07.21253098 Date: 2021-03-09 Source: medRxiv

    In this study we profiled vaccine-induced polyclonal antibodies as well as plasmablast derived mAbs from subjects who received SARS-CoV-2 spike PROTEIN mRNA vaccine. Polyclonal antibody responses in vaccinees were robust and comparable to or exceeded those seen after natural infection. However, that the ratio of binding to neutralizing antibodies after vaccination was greater than that after natural infection and, at the monoclonal level, we found that the majority of vaccine-induced antibodies did not have neutralizing activity. We also found a co-dominance of mAbs targeting the NTD HGNC and RBD of SARS-CoV-2 spike MESHD SARS-CoV-2 spike PROTEIN and an original antigenic-sin like backboost to seasonal human coronaviruses OC43 and HKU1 spike proteins PROTEIN. Neutralizing activity of NTD HGNC mAbs but not RBD mAbs against a clinical viral isolate carrying E484K as well as extensive changes in the NTD HGNC was abolished, suggesting that a proportion of vaccine induced RBD binding antibodies may provide substantial protection against viral variants carrying E484K.

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MeSH Disease
HGNC Genes
SARS-CoV-2 Proteins


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