A broadly neutralizing antibody protects against SARS-CoV, pre-emergent bat CoVs, and SARS-CoV-2 variants in mice

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Abstract

SARS-CoV in 2003, SARS-CoV-2 in 2019, and SARS-CoV-2 variants of concern (VOC) can cause deadly infections, underlining the importance of developing broadly effective countermeasures against Group 2B Sarbecoviruses, which could be key in the rapid prevention and mitigation of future zoonotic events. Here, we demonstrate the neutralization of SARS-CoV, bat CoVs WIV-1 and RsSHC014, and SARS-CoV-2 variants D614G, B.1.1.7, B.1.429, B1.351 by a receptor-binding domain (RBD)-specific antibody DH1047. Prophylactic and therapeutic treatment with DH1047 demonstrated protection against SARS-CoV, WIV-1, RsSHC014, and SARS-CoV-2 B1.351infection in mice. Binding and structural analysis showed high affinity binding of DH1047 to an epitope that is highly conserved among Sarbecoviruses. We conclude that DH1047 is a broadly neutralizing and protective antibody that can prevent infection and mitigate outbreaks caused by SARS-like strains and SARS-CoV-2 variants. Our results argue that the RBD conserved epitope bound by DH1047 is a rational target for pan Group 2B coronavirus vaccines.

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  1. SciScore for 10.1101/2021.04.27.441655: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: The study was carried out in accordance with the recommendations for care and use of animals by the Office of Laboratory Animal Welfare (OLAW), National Institutes of Health and the Institutional Animal Care and Use Committee (IACUC) of University of North Carolina (UNC permit no. A-3410-01).
    Sex as a biological variableAnimals and challenge viruses: Eleven-month-old female BALB/c mice were purchased from Envigo (#047) and were used for the SARS-CoV, SARS-CoV-2 B1.351, and RsSHC014-CoV protection experiments. 8-10-week-old hACE2-transgenic mice were bred at UNC Chapel Hill and were used for WIV-1-CoV protection experiments.
    RandomizationIn a blinded manner, three random fields of lung tissue were chosen and scored for the following: (A) neutrophils in the alveolar space (none = 0, 1–5 cells = 1, > 5 cells = 2), (B) neutrophils in the interstitial septa (none = 0, 1–5 cells = 1, > 5 cells = 2), (C) hyaline membranes (none = 0, one membrane = 1, > 1 membrane = 2), (D) Proteinaceous debris in air spaces (none = 0, one instance = 1, > 1 instance = 2), (E) alveolar septal thickening (< 2x mock thickness = 0, 2–4x mock thickness = 1, > 4x mock thickness = 2).
    BlindingAnalyses and scoring were performed by a board vertified veterinary pathologist who was blinded to the treatment groups as described previously 48.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    HRP conjugated goat anti-mouse IgG secondary antibody (SouthernBiotech 1030-05) was diluted to 1:10,000 in assay diluent without azide, incubated at for 1 hour at room temperature, washed and detected with 20μl SureBlue Reserve (KPL 53-00-03) for 15 minutes.
    anti-mouse IgG
    suggested: (SouthernBiotech Cat# 1030-05, RRID:AB_2619742)
    Antibody-virus and virus only mixtures were then incubated at 37°C with 5% CO2 for one hour.
    Antibody-virus
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    For the 96-well neutralization assay, Vero E6 USAMRID cells were plated at 20,000 cells per well the day prior in clear bottom black walled plates.
    Vero E6
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Animals and challenge viruses: Eleven-month-old female BALB/c mice were purchased from Envigo (#047) and were used for the SARS-CoV, SARS-CoV-2 B1.351, and RsSHC014-CoV protection experiments. 8-10-week-old hACE2-transgenic mice were bred at UNC Chapel Hill and were used for WIV-1-CoV protection experiments.
    BALB/c
    suggested: None
    hACE2-transgenic
    suggested: None
    Software and Algorithms
    SentencesResources
    The RELION 3.0 program was used for all negative stain image processing.
    RELION
    suggested: (RELION, RRID:SCR_016274)
    Data processing was performed using cryoSPARC 39.
    cryoSPARC
    suggested: (cryoSPARC, RRID:SCR_016501)
    Model building and refinement was done using Phenix 40,41
    Phenix
    suggested: (Phenix, RRID:SCR_014224)
    , Coot 42
    Coot
    suggested: (Coot, RRID:SCR_014222)
    , Pymol 43, Chimera 44, ChimeraX 45 and Isolde 46.
    Pymol
    suggested: (PyMOL, RRID:SCR_000305)
    Statistics: All statistical analyses were performed using GraphPad Prism 9.
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)

    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: Please consider improving the rainbow (“jet”) colormap(s) used on page 46. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.


    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.