Ronapreve (REGN-CoV; casirivimab and imdevimab) reduces the viral burden and alters the pulmonary response to the SARS-CoV-2 Delta variant (B.1.617.2) in K18-hACE2 mice using an experimental design reflective of a treatment use case

  1. Lee Tatham
  2. Anja Kipar
  3. Jo Sharp
  4. Edyta Kijak
  5. Joanne Herriott
  6. Megan Neary
  7. Helen Box
  8. Eduardo Gallardo Toledo
  9. Anthony Valentijn
  10. Helen Cox
  11. Henry Pertinez
  12. Paul Curley
  13. Usman Arshad
  14. Rajith Kumar Reddy Rajoli
  15. Steve Rannard
  16. James P. Stewart
  17. Andrew Owen

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Abstract

With some exceptions, global policymakers have recommended against the use of existing monoclonal antibodies in COVID-19 due to loss of neutralization of newer variants. The purpose of this study was to investigate the impact of Ronapreve on compartmental viral replication using paradigms for susceptible and insusceptible variants. Virological efficacy and impact on pathogenicity was assessed in K18-hACE2 mice inoculated with either the Delta or BA.1 Omicron variants. Ronapreve reduced sub-genomic viral RNA levels in lung and nasal turbinate, 4 and 6 days post-infection, for the Delta variant but not the Omicron variant. It also blocked brain infection, which is seen with high frequency in K18-hACE2 mice after Delta variant infection. At day 6, the inflammatory response to lung infection with the Delta variant was altered to a multifocal granulomatous inflammation in which the virus appeared to be confined. The current study provides evidence of an altered tissue response to SARS-CoV-2 after treatment with a monoclonal antibody combination that retains neutralization activity. These data demonstrate that experimental designs that reflect treatment use cases are achievable in animal models for monoclonal antibodies. Extreme caution should be taken when interpreting prophylactic experimental designs that may not be representative of treatment.

IMPORTANCE

Following the emergence of the SARS-CoV-2 Omicron variant, the WHO recommended against the use of Ronapreve in its COVID-19 treatment guidelines due to a lack of efficacy based on current pharmacokinetic-pharmacodynamic understanding. However, the continued use of Ronapreve, specifically in vulnerable patients, was advocated by some based on in vitro neutralization data. Here, the virological efficacy of Ronapreve was demonstrated in both the lung and brain compartments using Delta as a paradigm for a susceptible variant. Conversely, a lack of virological efficacy was demonstrated for the Omicron variant. Comparable concentrations of both monoclonal antibodies were observed in the plasma of Delta- and Omicron-infected mice. This study made use of a reliable murine model for SARS-CoV-2 infection, an experimental design reflective of treatment, and demonstrated the utility of this approach when assessing the effectiveness of monoclonal antibodies.

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  1. Version published to 10.1128/spectrum.03916-23
  2. ScreenIT

    SciScore for 10.1101/2022.01.23.477397: (What is this?)

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

    Table 1: Rigor

    EthicsField Sample Permit: All animal studies were conducted in accordance with UK Home Office Animals Scientific Procedures Act (ASPA, 1986).
    IACUC: Additionally, all studies were approved by the local University of Liverpool Animal Welfare and Ethical Review Body and performed under UK Home Office Project License PP4715265.
    Euthanasia Agents: At 4 and 6-days following infection, mice were sacrificed via a lethal IP injection of pentobarbitone, followed by cardiac puncture and immediate exsanguination of blood from the heart.
    Sex as a biological variableMale K18-hACE2 mice were purchased from Charles River (France).
    RandomizationMice were randomly assigned into groups and acclimatized for 7-days.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    The titres of all isolates were confirmed on Vero E6 cells and the sequences of all stocks confirmed.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Experimental Models: Organisms/Strains
    SentencesResources
    Male K18-hACE2 mice were purchased from Charles River (France).
    K18-hACE2
    suggested: RRID:IMSR_GPT:T037657)
    Male mice (20-30 g) carrying the human ACE2 gene under the control of the keratin 18 promoter (K18-hACE2; formally B6.Cg-Tg(K18-ACE2)2Prlmn/J) were housed in individually-ventilated cages with environmental enrichment under SPF barrier conditions and a 12-hour light/dark cycle at 21 °C ± 2 °C.
    B6.Cg-Tg(K18-ACE2)2Prlmn/J
    suggested: RRID:IMSR_JAX:034860)

    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:
    A limitation of the current study is that serum concentrations of the Ronapreve antibodies were not measured in order to facilitate a comparison with exposures observed in humans. However, the lack of virological efficacy for Omicron despite a demonstrable impact upon Delta, coupled with the higher doses used here compared with a previous study with earlier variants11 allows for confidence in the outcome despite this deficit.

    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 10.1101/2022.01.23.477397 on bioRxiv