A combination of two human neutralizing antibodies prevents SARS-CoV-2 infection in rhesus macaques

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Abstract

Human monoclonal antibody (mAb) treatments are promising for COVID-19 prevention, post-exposure prophylaxis, or therapy. However, the titer of neutralizing antibodies required for protection against SARS-CoV-2 infection remains poorly characterized. We previously described two potently neutralizing mAbs COV2-2130 and COV2-2381 targeting non-overlapping epitopes on the receptor-binding domain of SARS-CoV-2 spike protein. Here, we engineered the Fc-region of these mAbs with mutations to extend their persistence in humans and reduce interactions with Fc gamma receptors. Passive transfer of individual or combinations of the two antibodies (designated ADM03820) given prophylactically by intravenous or intramuscular route conferred virological protection in a non-human primate (NHP) model of SARS-CoV-2 infection, and ADM03820 potently neutralized SARS-CoV-2 variants of concern in vitro . We defined 6,000 as a protective serum neutralizing antibody titer in NHPs against infection for passively transferred human mAbs that acted by direct viral neutralization, which corresponded to a concentration of 20 μg/mL of circulating mAb.

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  1. SciScore for 10.1101/2021.09.27.462074: (What is this?)

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

    Table 1: Rigor

    EthicsField Sample Permit: Studies were conducted in compliance with all relevant local, state, and federal regulations and were approved by the Bioqual Institutional Animal Care and Use Committee (IACUC).
    IACUC: Studies were conducted in compliance with all relevant local, state, and federal regulations and were approved by the Bioqual Institutional Animal Care and Use Committee (IACUC).
    Sex as a biological variableCynomolgus monkeys (Macaca fascicularis) (2.2 – 5.8 kg body weight; 6 to 12 years old) were mixed male and female and randomly assigned to groups.
    RandomizationCynomolgus monkeys (Macaca fascicularis) (2.2 – 5.8 kg body weight; 6 to 12 years old) were mixed male and female and randomly assigned to groups.
    BlindingThese studies were not blinded.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Plates were washed and sequentially incubated with an oligoclonal pool of SARS2-2, SARS2-11, SARS2-16, SARS2-31, SARS2-38, SARS2-57 and SARS2-71 anti-S (VanBlargan et al., 2021) antibodies and HRP-conjugated goat anti-mouse IgG (Sigma, 12-349) in PBS supplemented with 0.1% saponin and 0.1% bovine serum albumin.
    SARS2-38
    suggested: None
    SARS2-57
    suggested: None
    anti-S
    suggested: None
    anti-mouse IgG
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Briefly, stably transfected CHO cells expressing either COV2-2130-YTE-LALA or COV2-2381-YTE-LALA were generated using Leap-In transposon vectors (ATUM) containing the respective antibody heavy and light chain genes and a glutamine synthetase gene as a selectable marker.
    CHO
    suggested: None
    The viral stocks were expanded using Vero E6 cells and harvested on day 5 following inoculation.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Antibody–virus complexes were added to Vero-TMPRSS2 cell monolayers in 96-well plates and incubated at 37 °C for 1 h.
    Vero-TMPRSS2
    suggested: JCRB Cat# JCRB1818, RRID:CVCL_YQ48)
    Software and Algorithms
    SentencesResources
    The time-weighted average (TWA) values for the change of sgRNA viral load in BAL or NP from day 1 to day 10 after viral challenge were calculated as the area under the curve (AUC) of the change in viral load in Prism (version 9.1.2; GraphPad) and then divided by 10 as described previously (Baum et al., 2020a) (Table S1).
    Prism
    suggested: (PRISM, RRID:SCR_005375)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)
    The fitting curves and confidence intervals to visualize the relationship between TWA and antibody levels were estimated using Lowess curve smoothing method using ggplot2 in R software.
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)

    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.