Pegylated-interferon-λ treatment-induced peripheral interferon stimulated genes are associated with SARS-CoV-2 viral load decline despite delayed T cell response in older individuals

  1. Deanna M Santer
  2. Daniel Li
  3. Yanal Ghosheh
  4. Muhammad Atif Zahoor
  5. Dhanvi Prajapati
  6. D Lorne J Tyrrell
  7. Jordan J Feld
  8. Adam J Gehring

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Abstract

Interferons (IFNs) are antiviral cytokines induced very early after SARS-CoV-2 infection and are crucial for viral clearance, shaping immunity, and preventing the development of severe COVID-19. We previously demonstrated that a single injection of peginterferon-lambda1 (PEG-IFN-λ) accelerated viral clearance in COVID-19 patients. To determine if the rapid viral decline was mediated by enhanced immunity, we assessed in vivo responses to PEG-IFN-λ by single cell RNA sequencing and measured SARS-CoV-2-specific T cell and antibody responses between placebo and PEG-IFN-λ-treated patients. PEG-IFN-λ treatment induced interferon stimulated genes in peripheral immune cells expressing IFNLR1 , with plasmacytoid dendritic cells having the greatest response, followed by B cells. PEG-IFN-λ did not significantly affect SARS-CoV-2-specific antibody levels in plasma or the magnitude or functionality of virus-specific T cells. However, we identified a delayed T cell response in older adults, suggesting that PEG-IFN-λ can overcome the delay in adaptive immunity to accelerate viral clearance in patients most at risk for severe disease. Taken together, PEG-IFN-λ offers an early COVID-19 treatment option for outpatients to boost innate antiviral defenses without dampening peripheral SARS-CoV-2 adaptive immunity

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  1. ScreenIT

    SciScore for 10.1101/2022.02.24.22271438: (What is this?)

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

    Table 1: Rigor

    EthicsIRB: The research ethics boards of all participating institutions approved the study, which was registered (NCT04354259) and done under a Clinical Trial Application approved by Health Canada.
    Consent: All participants provided written informed consent.
    Field Sample Permit: Plasma Collection and PBMC Isolation: Freshly collected blood samples in acid citrate dextrose (ACD) tubes were centrifuged and plasma was frozen and stored in −80°C.
    Sex as a biological variablenot detected.
    RandomizationEthical Statement & Human Subjects: Subjects were recruited for a randomised, double-blind, placebo-controlled study from outpatient testing centers at six institutions in Toronto, Canada.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Total and SARS-CoV-2-specific antibody ELISAs: All plasma was heat-inactivated at 56°C for 45min before diluting for ELISA.
    SARS-CoV-2-specific
    suggested: None
    Secondary antibodies (goat anti-human Ig alkaline phosphatase) were from Jackson Immunoresearch (anti-human IgG, IgM) or Thermo Fisher Scientific (anti-human IgA) and PNPP substrate was from Thermo Fisher Scientific.
    anti-human Ig alkaline phosphatase
    suggested: None
    anti-human IgG
    suggested: None
    anti-human IgA
    suggested: None
    Software and Algorithms
    SentencesResources
    Aggregated expression matrix for all cells was analyzed with the Seurat v4.0.4 R package57.
    Seurat
    suggested: (SEURAT, RRID:SCR_007322)
    Panel generation and compilation was done through R packages (ggplot2 v3.3.5, ggrepel v0.9.1, patchwork v1.1.1, dplyr v1.0.7, reshape2 v1.4.4)60–64.
    ggplot2
    suggested: (ggplot2, RRID:SCR_014601)
    ggrepel
    suggested: (ggrepel, RRID:SCR_017393)
    Statistical analysis was conducted on GraphPad Prism version 9.3 and R v4.1.1.
    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: 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
    NCT04354259RecruitingInterferon Lambda for Immediate Antiviral Therapy at Diagnos…

    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 10.1101/2022.02.24.22271438v1 on medRxiv