Molecular basis of immune evasion by the Delta and Kappa SARS-CoV-2 variants

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Abstract

In the course of the COVID-19 epidemic, variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, some of which evade immunity or increase transmission. In late 2020, the Delta and Kappa variants were detected, and the Delta variant became globally dominant by June 2021. McCallum et al . show that vaccine-elicited serum-neutralizing activity is reduced against these variants. Based on biochemistry and structural studies, the authors show that mutations in the domain that binds the ACE2 receptor abrogate binding to some monoclonal antibodies but do not improve ACE2 binding, suggesting that they emerged to escape immune recognition. Remodeling of the N-terminal domain allows the variants to escape recognition by most neutralizing antibodies that target it. The work could guide the development of next-generation vaccines and antibody therapies. —VV

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  1. SciScore for 10.1101/2021.08.11.455956: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: This study was approved by the University of Washington Human Subjects Division Institutional Review Board (STUDY00010350).
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    After 2 h, infected cells were washed an additional five times with DMEM prior to adding media supplemented with anti-VSV-G antibody (I1-mouse hybridoma supernatant diluted 1:25, from CRL-2700, ATCC) to reduce parental background.
    anti-VSV-G
    suggested: None
    An anti-S2 SARS-CoV-2 S polyclonal primary antibody (1:1,500 dilution,Invitrogen PA5-114534) and an Alexa Fluor 680-conjugated goat anti-rabbit secondary antibody (1:20,000 dilution, Jackson Laboratory 111-625-144) were used for Western-blotting.
    anti-S2 SARS-CoV-2
    suggested: None
    anti-rabbit
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    At this stage, excess DMEM was removed from the cells and 40 µL from each well (containing sera and pseudovirus) was transferred to the 96-well plate seeded with HEK-293T cells expressing hACE2 and incubated at 37°C for 2 h.
    HEK-293T
    suggested: None
    Recombinant DNA
    SentencesResources
    The SARS-CoV-2 S ectodomain with VFLIP mutations (48), the native furin cleavage site (RRAR), and B.1.617.2 spike mutations (T19R, G142D, E156G, T478K, and D950N substitutions and a deletion of residues 157 and 158) was synthesised by GenScript into pCMV with a C-terminal avi tag followed by an octa-histidine tag.
    pCMV
    suggested: RRID:Addgene_20783)
    The SARS-CoV-2 S ectodomain with hexapro mutations and P.1 spike mutations (L18F, T20N, P26S, D138Y, R190S, K417T, E484K, N501Y, D614G, H655Y, T1027I, and V1176F) was synthesised by GenScript into pCMVR with foldon, a C-terminal avi tag followed by an octa-histidine tag.
    pCMVR
    suggested: None
    Software and Algorithms
    SentencesResources
    2) were obtained from GISAID (using outbreak.info) and plotted using GraphPad PRISM software (version 9.2.0).
    GraphPad PRISM
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Relative luciferase units were plotted and normalized in Prism (GraphPad): cells alone without pseudovirus was defined as 0 % infection, and cells with virus only (no sera) was defined as 100 % infection.
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    Prism (GraphPad) nonlinear regression with “[inhibitor] versus normalized response with a variable slope” was used to determine IC50 values from curve fits.
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Particles in well-formed 3D classes were then used for local refinement in cryoSPARC.
    cryoSPARC
    suggested: (cryoSPARC, RRID:SCR_016501)
    The model was then refined and rebuilt into the map using Coot (89), Rosetta (90, 91), Phenix (92), and ISOLDE (93).
    Coot
    suggested: (Coot, RRID:SCR_014222)
    Model validation and analysis used MolProbity (94), EMringer (95), Phenix (92) and Privateer (96).
    MolProbity
    suggested: (MolProbity, RRID:SCR_014226)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).


    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.


    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.


    Results from JetFighter: We did not find any issues relating to colormaps.


    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.


    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.