Clinical grade ACE2 effectively inhibits SARS-CoV-2 Omicron infections

  1. Vanessa Monteil
  2. Devignot Stephanie
  3. Jonas Klingström
  4. Charlotte Thålin
  5. Max J. Kellner
  6. Wanda Christ
  7. Sebastian Havervall
  8. Stefan Mereiter
  9. Sylvia Knapp
  10. Nuria Montserrat
  11. Benedict Braunsfeld
  12. Ivona Kozieradzki
  13. Omar Hasan Ali
  14. Astrid Hagelkruys
  15. Johannes Stadlmann
  16. Chris Oostenbrink
  17. Gerald Wirnsberger
  18. Josef M. Penninger
  19. Ali Mirazimi

Reviewed by

Read the full article

Listed in

Log in to save this article

Abstract

The recent emergence of the SARS-CoV-2 variant Omicron has caused considerable concern due to reduced vaccine efficacy and escape from neutralizing antibody therapeutics. Omicron is spreading rapidly around the globe and is suspected to account for most new COVID-19 cases in several countries, though the severity of Omicron-mediated disease is still under debate. It is therefore paramount to identify therapeutic strategies that inhibit the Omicron SARS-CoV-2 variant. Here we report using 3D structural modelling that Spike of Omicron can still associate with human ACE2. Sera collected after the second mRNA-vaccination did not exhibit a protective effect against Omicron while strongly neutralizing infection of VeroE6 cells with the reference Wuhan strain, confirming recent data by other groups on limited vaccine and convalescent sera neutralization efficacy against Omicron. Importantly, clinical grade recombinant human soluble ACE2, a drug candidate currently in clinical development, potently neutralized Omicron infection of VeroE6 cells with markedly enhanced potency when compared to reference SARS-CoV-2 isolates. These data show that SARS-CoV-2 variant Omicron can be readily inhibited by soluble ACE2, providing proof of principle of a viable and effective therapeutic approach against Omicron infections.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2021.12.25.474113: (What is this?)

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

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variableSera of vaccinees: Serum was taken 5-7 weeks after the second immunization with the mRNA vaccine Comirnity (median dose interval 21 days (range 21-24) from four SARS-CoV-2 naïve healthcare workers (75% female, median age 46 [IQR 37-59]) which took part in the COMMUNITY study.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    After the incubation period medium was removed from VeroE6 cells, cells were washed once with PBS to remove any non-attached cells and virus/APN01 mixtures.
    VeroE6
    suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)
    Preparation of recombinant human ACE2: Clinical grade recombinant human ACE2 (amino acids 18-740) was produced by the contract manufacturer Polymun Scientific (Klosterneuburg, Austria) from CHO cells according to GMP guidelines under serum free conditions and formulated as a physiologic aqueous solution, as described previously (Zoufaly et al, 2021, Lancet Respiratory Medicine).
    CHO
    suggested: None
    Software and Algorithms
    SentencesResources
    Visualizations of RBD domains, full-length Spike protein, and Omicron Spike-ACE2 ineractions: Visualizations were rendered with pymol software (the PyMOL Molecular Graphics System, Version 2.0 Schrödinger, LLC), based on a model of the fully glycosylated Spike-ACE2 complex described in Capraz et al. [37] and https://covid.molssi.org//models/#spike-protein-in-complex-with-human-ace2-ace2-spike-binding. Primers: The following tables lists the primers used in this study:
    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:
    Limitations of this study: Our study used VeroE6 cells, the classic cellular model for SARS and SARS-CoV-2 infection studies. The study should be expanded to additional cell types as well as human organoids. Moreover, the affinity of Omicron Spike and Omicron RBD should be determined in direct affinity/avidity measurements as well as the impact of non-RBD Spike mutations on the infection process. Of note, from all our previous studies and studies from other groups, the data on soluble ACE2 inhibiting SARS-CoV-2 infections in VeroE6 cells were always supported by results in all other cell types tested. Moreover, we used sera collected 4-6 weeks after the second mRNA vaccination from 4 SARS-CoV-2 naïve healthcare workers, which needs to be expanded to different vaccine regimens and vaccine types and increased sample numbers, though multiple studies are now being released also demonstrating impaired vaccine efficacies to Omicron.

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

    IdentifierStatusTitle
    NCT04335136CompletedRecombinant Human Angiotensin-converting Enzyme 2 (rhACE2) a…

    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 10.1101/2021.12.25.474113v1 on bioRxiv