Effective Prophylaxis of COVID-19 in Rhesus Macaques Using a Combination of Two Parenterally-Administered SARS-CoV-2 Neutralizing Antibodies

  1. Brandon J. Beddingfield
  2. Nicholas J. Maness
  3. Alyssa C. Fears
  4. Jay Rappaport
  5. Pyone Pyone Aye
  6. Kasi Russell-Lodrigue
  7. Lara A. Doyle-Meyers
  8. Robert V. Blair
  9. Ann M. Carias
  10. Patrick J. Madden
  11. Ramon Lorenzo Redondo
  12. Hongmei Gao
  13. David Montefiori
  14. Thomas J. Hope
  15. Chad J. Roy

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Abstract

SARS-CoV-2 is a respiratory borne pathogenic beta coronavirus that is the source of a worldwide pandemic and the cause of multiple pathologies in man. The rhesus macaque model of COVID-19 was utilized to test the added benefit of combinatory parenteral administration of two high-affinity anti-SARS-CoV-2 monoclonal antibodies (mAbs; C144-LS and C135-LS) expressly developed to neutralize the virus and modified to extend their pharmacokinetics. After completion of kinetics study of mAbs in the primate, combination treatment was administered prophylactically to mucosal viral challenge. Results showed near complete virus neutralization evidenced by no measurable titer in mucosal tissue swabs, muting of cytokine/chemokine response, and lack of any discernable pathologic sequalae. Blocking infection was a dose-related effect, cohorts receiving lower doses (6, 2 mg/kg) resulted in low grade viral infection in various mucosal sites compared to that of a fully protective dose (20 mg/kg). A subset of animals within this cohort whose infectious challenge was delayed 75 days later after mAb administration were still protected from disease. Results indicate this combination mAb effectively blocks development of COVID-19 in the rhesus disease model and accelerates the prospect of clinical studies with this effective antibody combination.

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  1. Version published to 10.3389/fcimb.2021.753444
  2. ScreenIT

    SciScore for 10.1101/2021.05.26.445878: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: Study Approval: The Tulane University Institutional Animal Care and Use Committee approved all procedures used during this study.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Three RMs were infused with 20 mg/kg of an equal (10 mg/kg each) combination of C-135-LS and C-144-LS monoclonal antibodies raised against SARS-CoV-2 spike protein and monitored for RBD binding as well as neutralizing activity routinely for 75 days to determine pharmacokinetics.
    C-144-LS
    suggested: None
    SARS-CoV-2 spike protein
    suggested: None
    Fluorescent immunohistochemistry was performed on 5um sections of Formalin-fixed, paraffin-embedded lung were incubated for 1 hour with the primary antibodies (SARS, Guinea Pig, (BEI, cat#NR-10361) diluted in NGS at a concentration of 1:1000).
    cat#NR-10361
    suggested: None
    Detection of Neutralizing Antibodies in Serum: The ability of antibodies in serum to disrupt the binding of the receptor binding domain (RBD) of SARS-CoV-2 spike protein to Angiotensin Converting Enzyme (ACE2) was assessed via the Surrogate Virus Neutralization Test (GenScript# L00847) using the included kit protocol modified per the following: Serum samples were diluted from 1:10 to 1:21, 870 in order to determine an IC50 for RBD/ACE2 binding.
    Angiotensin Converting Enzyme ( ACE2
    suggested: None
    Experimental Models: Cell Lines
    SentencesResources
    Positive controls consisted of SARS-CoV-2 infected VeroE6 cell lysate.
    VeroE6
    suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)
    Software and Algorithms
    SentencesResources
    The Tulane National Primate Research Center (TNPRC) is accredited by the Association for the Assessment and Accreditation of Laboratory Animal Care (AAALAC no. 000594).
    TNPRC
    suggested: None
    Heat maps of log2 fold change from raw fluorescence values were generated using the heatmap package in RStudio and normalized to baseline.
    RStudio
    suggested: (RStudio, RRID:SCR_000432)
    Statistical Analysis: Data analysis was performed using Graphpad Prism 9.0.2 software (Graphpad Software, USA).
    Graphpad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Graphpad
    suggested: (GraphPad, RRID:SCR_000306)

    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: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04700163Active, not recruitingRU Anti-SARS-CoV-2 (COVID-19) mAbs in Healthy Volunteers

    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.

  3. Version published to 10.1101/2021.05.26.445878v1 on bioRxiv