Emergence of SARS-CoV-2 Resistance with Monoclonal Antibody Therapy

  1. Manish C. Choudhary
  2. Kara W. Chew
  3. Rinki Deo
  4. James P. Flynn
  5. James Regan
  6. Charles R. Crain
  7. Carlee Moser
  8. Michael Hughes
  9. Justin Ritz
  10. Ruy M. Ribeiro
  11. Ruian Ke
  12. Joan A. Dragavon
  13. Arzhang C. Javan
  14. Ajay Nirula
  15. Paul Klekotka
  16. Alexander L. Greninger
  17. Courtney V. Fletcher
  18. Eric S. Daar
  19. David A. Wohl
  20. Joseph J. Eron
  21. Judith S. Currier
  22. Urvi M. Parikh
  23. Scott F. Sieg
  24. Alan S. Perelson
  25. Robert W. Coombs
  26. Davey M. Smith
  27. Jonathan Z. Li
  28. for the ACTIV-2/A5401 Study Team

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

Resistance mutations to monoclonal antibody (mAb) therapy has been reported, but in the non-immunosuppressed population, it is unclear if in vivo emergence of SARS-CoV-2 resistance mutations alters either viral replication dynamics or therapeutic efficacy. In ACTIV-2/A5401, non-hospitalized participants with symptomatic SARS-CoV-2 infection were randomized to bamlanivimab (700mg or 7000mg) or placebo. Treatment-emergent resistance mutations were significantly more likely detected after bamlanivimab 700mg treatment than placebo (7% of 111 vs 0% of 112 participants, P=0.003). There were no treatment-emergent resistance mutations among the 48 participants who received bamlanivimab 7000mg. Participants with emerging mAb resistant virus had significantly higher pre-treatment nasopharyngeal and anterior nasal viral load. Intensive respiratory tract viral sampling revealed the dynamic nature of SARS-CoV-2 evolution, with evidence of rapid and sustained viral rebound after emergence of resistance mutations, and worsened symptom severity. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest and associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment, resulting in prolonged high level respiratory tract viral loads and clinical worsening. Careful virologic assessment should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.09.03.21263105: (What is this?)

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

    Table 1: Rigor

    EthicsConsent: All participants provided written informed consent.
    Sex as a biological variablenot detected.
    RandomizationStudy participants and sample collection: The study participants were enrolled in the ACTIV-2/AIDS Clinical Trials Group (ACTG) A5401 phase 2 randomized, placebo-controlled trial of bamlanivimab 7000mg and 700mg mAb therapy.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    IgG was detected by incubation with MSD SULFO-TAG anti-IgG antibody.
    anti-IgG
    suggested: None
    Software and Algorithms
    SentencesResources
    SARS-CoV-2 quantitative Laboratory Developed Test (LDT) was developed utilizing open mode functionality on m2000sp/rt (Abbott, Chicago, IL) by using EUA Abbott SARS-CoV-2 qualitative reagents30.
    Abbott
    suggested: (Abbott, RRID:SCR_010477)
    Raw sequence data were analyzed using PASeq v1.4 (https://www.paseq.org).
    PASeq
    suggested: None
    Briefly, data were quality filtered using Trimmomatic (v0.30), using a Q25/5 bp sliding window and a 70 bp minimum length.
    Trimmomatic
    suggested: (Trimmomatic, RRID:SCR_011848)
    Filtered reads were then merged with pear v0.9.6 aligned to the reference sequence using Bowtie2 v2.1.0)
    pear
    suggested: (PEAR, RRID:SCR_003776)
    Bowtie2
    suggested: (Bowtie 2, RRID:SCR_016368)
    All statistical analyses were performed in GraphPad Prism (Version 9.1.1)
    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: We detected the following sentences addressing limitations in the study:
    One limitation to this study is that bamlanivimab is no longer used clinically as a single agent. These results, though, provide important proof of principle for the role that drug resistance may have on virologic and clinical efficacy of SARS-CoV-2 antiviral therapies. These lessons have implications for the development of novel COVID-19 antiviral therapies and have continued relevance for other clinically-approved single agent monoclonal antibody treatments29 and for combination therapies where one agent may be ineffective due to circulating variants13. Another limitation of this study is the limited sample size of this phase 2 study, especially in the bamlanivimab 7000mg cohort. While treatment-emergent mutations were not found in ACTIV-2 participants receiving the higher 7000mg dose of bamlanivimab, they were frequently detected in the larger BLAZE-1 phase 2 trial of the 7000mg dose7. One difference between these studies was the longer duration since symptom onset for the ACTIV-2 participants, who enrolled a median of 6 days since symptom onset versus 4 days for the BLAZE-1 participants. This likely led to higher pretreatment viral loads, which we found to be a risk factor for resistance emergence. Unfortunately, baseline viral loads could not be compared between studies as the BLAZE-1 study did not use a quantitative SARS-CoV-2 viral load assay. These disparate results highlight the importance of incorporating quantitative viral load testing and resistance testing for CO...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    NCT04518410RecruitingACTIV-2: A Study for Outpatients With COVID-19

    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.

  2. Version published to 10.1101/2021.09.03.21263105v1 on medRxiv