An intranasal nanoparticle STING agonist has broad protective immunity against respiratory viruses and variants

  1. Ankita Leekha
  2. Arash Saeedi
  3. Monish Kumar
  4. Samiur Rahman Sefat
  5. Melisa Martinez-Paniagua
  6. Mohsen Fathi
  7. Rohan Kulkarni
  8. Sujit Biswas
  9. Daphne Tsitoura
  10. Xinli Liu
  11. Laurence J.N. Cooper
  12. Manu Sebastian
  13. Brett L. Hurst
  14. Navin Varadarajan

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Abstract

Respiratory viral infections, especially Influenza (endemic) or SARS-CoV-2 (pandemic since 2020), cause morbidity and mortality worldwide. Despite remarkable progress in the development and deployment of vaccines, they are clearly impacted by the rapid emergence of viral variants. The development of an off-the-shelf, effective, safe, and low-cost drug for prophylaxis against respiratory viral infections is a major unmet medical need. Here, we developed NanoSTING, a liposomally encapsulated formulation of the endogenous STING agonist, 2’-3’ cGAMP, to function as an immunoantiviral. NanoSTING rapidly activates the body’s innate immune system to facilitate a broad-spectrum antiviral response against SARS-CoV-2 and influenza variants in hamsters and mice. We demonstrate that a single intranasal dose of NanoSTING can: (1) treat infections throughout the respiratory system and minimize clinical symptoms, (2) protect against highly pathogenic strains of SARS-CoV-2 (alpha and delta), (3) provide durable protection against reinfection from the same strains without the need for retreatment, (4) prevent transmission of the highly infectious SARS-CoV-2 Omicron strain, and (5) provide protection against both oseltamivir-sensitive and resistant strains of influenza. Mechanistically, administration of NanoSTING rapidly upregulated interferon-stimulated and antiviral pathways in both the nasal turbinates and lung. Our results support using NanoSTING as a thermostable, immunoantiviral with broad-spectrum antiviral properties making it appealing as a therapeutic for prophylactic or early post-exposure treatment.

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    SciScore for 10.1101/2022.04.18.488695: (What is this?)

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

    Table 1: Rigor

    EthicsIACUC: Mice and NanoSTING treatment: All studies using animal experiments were reviewed and approved by University of Houston (UH) IACUC.
    Field Sample Permit: Influenza A/Hong Kong/2369/2009 (H1N1pdm) was provided by Kwok-Yung Yuen from The University of Hong Kong, Hong Kong Special Administrative Region, People’s Republic of China.
    Sex as a biological variableWe purchased the female 7 to 9-week-old BALB/c mice from Charles River Laboratories.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Experimental Models: Cell Lines
    SentencesResources
    Cell lines: THP-1 dual cell line (Invivogen) was cultured in a humidified incubator at 37°C and 5% CO2 and grown in RPMI/10% FBS (Corning, NY, USA).
    THP-1
    suggested: None
    Isolates of SARS-CoV-2 were obtained from BEI Resources (Manassas, VA) and amplified in Vero E6 cells to create working stocks of the virus.
    Vero E6
    suggested: RRID:CVCL_XD71)
    Homogenized tissue samples were serially diluted in test medium and the virus quantified using an endpoint dilution assay on Vero E6 cells for SARS-CoV-2 and on MDCK cells for influenza virus.
    MDCK
    suggested: CLS Cat# 602280/p823_MDCK_(NBL-2, RRID:CVCL_0422)
    Experimental Models: Organisms/Strains
    SentencesResources
    For influenza virus animal studies, 8-week-old BALB/c mice were purchased from Charles River Laboratories.
    BALB/c
    suggested: RRID:IMSR_ORNL:BALB/cRl)
    Software and Algorithms
    SentencesResources
    We paired and trimmed the fastq files using Trimmomatic (v 0.39) and aligned them to the Syrian golden hamster genome (MesAur 1.0, ensembl) using STAR (v 2.7.9a).
    Trimmomatic
    suggested: None
    STAR
    suggested: None
    We determined the differential gene expression using DESeq2 (v 1.28.1) package63.
    DESeq2
    suggested: (DESeq, RRID:SCR_000154)
    To perform gene set enrichment analysis, we used a pre-ranked gene list of differentially expressed genes in GSEA software (UC San Diego and Broad Institute).
    GSEA
    suggested: (SeqGSEA, RRID:SCR_005724)
    Images were scanned using an Aperio ImageScope.
    ImageScope
    suggested: (ImageScope, RRID:SCR_014311)
    Quantification and statistical analysis: Statistical significance was assigned when P values were <0.05 using GraphPad Prism (v6.07).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    Sample MATLAB code:
    MATLAB
    suggested: None

    Results from OddPub: Thank you for sharing your code.

    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: 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.
    • 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 10.1101/2022.04.18.488695v1 on bioRxiv