Key Substitutions in the Spike Protein of SARS-CoV-2 Variants Can Predict Resistance to Monoclonal Antibodies, but Other Substitutions Can Modify the Effects

  1. Sabrina Lusvarghi
  2. Wei Wang
  3. Rachel Herrup
  4. Sabari Nath Neerukonda
  5. Russell Vassell
  6. Lisa Bentley
  7. Ann E. Eakin
  8. Karl J. Erlandson
  9. Carol D. Weiss

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Abstract

Therapeutic antibodies are effective in preventing severe disease from SARS-CoV-2 infection (COVID-19), but their effectiveness may be reduced by virus variants with mutations affecting the spike protein. To help predict resistance to therapeutic antibodies in emerging variants, we profiled resistance patterns of 25 antibody products in late stages of clinical development against a large panel of variants that include single and multiple substitutions found in the spike protein.

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  1. Version published to 10.1128/jvi.01110-21
  2. ScreenIT

    SciScore for 10.1101/2021.07.16.452748: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    293T-ACE2/TMPRSS2 cells stably expressing ACE2 and transmembrane serine protease 2 (TMPRSS2) were established and maintained as previously described (51).
    293T-ACE2/TMPRSS2
    suggested: None
    Recombinant DNA
    SentencesResources
    Plasmids and cell lines: Codon-optimized full-length S genes of SARS-COV-2 variants (using D614G as the base plasmid) were cloned into pCDNA3.1(+) (GenScript, Piscataway, NJ).
    pCDNA3.1
    suggested: RRID:Addgene_79663)
    The HIV gag/pol (pCMVΔR8.2) and Luciferase reporter (pHR’CMV-Luc) plasmids were obtained from the Vaccine Research Center (National Institutes of Health, Bethesda, MD).
    pCMVΔR8.2
    suggested: None
    pHR’CMV-Luc
    suggested: None
    Software and Algorithms
    SentencesResources
    Titers were calculated using a nonlinear regression curve fit (GraphPad Prism software Inc., La Jolla, CA).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Computational analysis: The amino acid locations on the RBD that affected nAb potency were modeled with PyMOL molecular graphics system (version 1.7.4; Schrödinger, LLC) using the Protein Data Bank (PDB) entries 6ZOZ for the closed conformation and 7A98 for the open conformation.
    PyMOL
    suggested: (PyMOL, RRID:SCR_000305)

    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: We detected the following sentences addressing limitations in the study:
    Finally, the safety and simplicity of pseudovirus neutralization assays offer many advantages for identifying MOCs and screening antibody therapeutics and vaccinee sera, but such assays have limitations. Pseudoviruses do not completely mimic authentic SARS-CoV-2 or virus entry conditions in vivo. In our nAb screens, we found that two antibodies that bind outside of the receptor binding motif could only partially neutralize (< 80%) pseudoviruses bearing WT Spike (data not shown). This inability to achieve complete neutralization by some nAbs has been observed by others using authentic SARS-CoV-2 (54, 68) and may be due to use of engineered target cells that permit efficient virus entry or heterogeneous glycosylation of Spike that affects an antibody epitope. Neutralization assays also cannot measure the potential protective activity afforded by nAb Fc effector functions. To address the limitations of any single assay, several consortia have formed to integrate findings from animal models and in vitro assays involving a variety of formats to inform the development of potent antibody therapeutics and other medical countermeasure that will remain potent against emerging variants.

    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.
    • No funding statement was detected.
    • 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 10.1101/2021.07.16.452748v1 on bioRxiv