In-vitro evaluation of the immunomodulatory effects of Baricitinib: Implication for COVID-19 therapy

Petrone, Linda; Petruccioli, Elisa; Alonzi, Tonino; Vanini, Valentina; Cuzzi, Gilda; Fard, Saeid Najafi; Castilletti, Concetta; Palmieri, Fabrizio; Gualano, Gina; Vittozzi, Pietro; Nicastri, Emanuele; Lepore, Luciana; Grifoni, Alba; Antinori, Andrea; Vergori, Alessandra; Ippolito, Giuseppe; Cantini, Fabrizio; Goletti, Delia

doi:10.1016/j.jinf.2021.02.023

Cited by 45 publications

(42 citation statements)

References 38 publications

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“…However, the structure of fedratinib suggests that it should have a different pharmacological profile compared to those of ruxolitinib and baricitinib. Some theoretical findings are validated through the reported biological activities associated with these drugs ( Table 1 ), [ 37 , 38 , 39 , 40 , 41 ]. In conclusion, both ruxolitinib and baracitinib may represent promising options for COVID-19 treatment; however, the clinically reported adverse effects of these drugs and our theoretical calculations, especially for fedratinib, raise an alarming concern regarding their safety.…”

Section: Pre-clinical Studiesmentioning

confidence: 85%

“…Petrone et al assessed the effect of baricitinib on the release of IFN-γ and on a panel of soluble factors by multiplex-technology after stimulating whole-blood from COVID-19 patients with SARS-CoV-2 antigens. In mild to moderate cases, baricitinib suppressed the spike protein-specific-response, as demonstrated by significant decrease in a myriad of cytokines including IFN-γ, IL-17, IL-1β, IL-6, TNF-α, IL-4, IL-13, IL-1ra, IL-10, GM-CSF, FGF, IP-10, MCP-1, and MIP-1β [ 39 ].…”

Section: Pre-clinical Studiesmentioning

confidence: 99%

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Current Status of Baricitinib as a Repurposed Therapy for COVID-19

et al. 2021

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The emergence of the COVID-19 pandemic has mandated the instant (re)search for potential drug candidates. In response to the unprecedented situation, it was recognized early that repurposing of available drugs in the market could timely save lives, by skipping the lengthy phases of preclinical and initial safety studies. BenevolentAI’s large knowledge graph repository of structured medical information suggested baricitinib, a Janus-associated kinase inhibitor, as a potential repurposed medicine with a dual mechanism; hindering SARS-CoV2 entry and combatting the cytokine storm; the leading cause of mortality in COVID-19. However, the recently-published Adaptive COVID-19 Treatment Trial-2 (ACTT-2) positioned baricitinib only in combination with remdesivir for treatment of a specific category of COVID-19 patients, whereas the drug is not recommended to be used alone except in clinical trials. The increased pace of data output in all life sciences fields has changed our understanding of data processing and manipulation. For the purpose of drug design, development, or repurposing, the integration of different disciplines of life sciences is highly recommended to achieve the ultimate benefit of using new technologies to mine BIG data, however, the final say remains to be concluded after the drug is used in clinical practice. This review demonstrates different bioinformatics, chemical, pharmacological, and clinical aspects of baricitinib to highlight the repurposing journey of the drug and evaluates its placement in the current guidelines for COVID-19 treatment.

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Section: Pre-clinical Studiesmentioning

confidence: 85%

Section: Pre-clinical Studiesmentioning

confidence: 99%

Current Status of Baricitinib as a Repurposed Therapy for COVID-19

et al. 2021

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“…Much like the use of IGRAs in TB, a simple T-cell response assay could facilitate the detection of an immune response to SARS-CoV-2 infection or vaccination and, moreover, may aid in monitoring the immune response over time or during therapy ( Fig. 1 ) [ 54 , 58 , 59 ]. Proof-of-concept has been demonstrated in COVID-19, where an ELISA-based whole blood IGRA stimulated with epitope pools covering the entire viral proteome was able to accurately distinguish between convalescent and uninfected healthy blood donors [ 60 ].…”

Section: Clinical Utility Of Measuring T-cell Responsesmentioning

confidence: 99%

The potential clinical utility of measuring severe acute respiratory syndrome coronavirus 2-specific T-cell responses

Goletti

Petrone

Manissero

et al. 2021

Clinical Microbiology and Infection

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…SARS-CoV-2 infection decreases the lymphocytes number and increases cytokines release in severe COVID-19-cases [ 14 ]. A significant increase of pro-inflammatory or anti-inflammatory cytokines, including T helper (Th) type-1 and type-2 cytokines and chemokines was described [ 10 , 12 , 16 , 17 ], interleukin (IL)-1β, IL-6, IL-8, and Interferon (IFN)-γ-inducible protein (IP-10) were associated with severe or fatal course of disease [ 7 – 9 ]. Four immune signatures, constituted by growth factors, Th1-, Th2-, Th3-cytokines and chemokines, were correlated with distinct disease courses [ 9 ].…”

Section: Introductionmentioning

confidence: 99%

“…The importance of T-cell response against β-coronavirus infections has been underlined by a study on patients recovered from SARS, demonstrating the persistence of long-lasting memory T-cells reactive to SARS-CoV stimulation, years after the SARS-outbreak in 2003 [ 18 , 19 ]. Recent studies highlighted the use of the whole-blood based IFN-γ released assay as a promising approach to study the antigen-specific SARS-CoV-2 response [ 10 – 12 , 20 , 21 ]. The use of a whole-blood-platform with SARS-CoV2 peptides to discriminate COVID-19-patients and uninfected-individuals [ 10 , 20 , 22 ], is a new potential approach to study the immunogenicity of vaccine candidate, to monitor the immune response in vaccine trial and to support the serological diagnostics.…”

Section: Introductionmentioning

confidence: 99%

Exploratory analysis to identify the best antigen and the best immune biomarkers to study SARS-CoV-2 infection

et al. 2021

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Background Recent studies proposed the whole-blood based IFN-γ-release assay to study the antigen-specific SARS-CoV-2 response. Since the early prediction of disease progression could help to assess the optimal treatment strategies, an integrated knowledge of T-cell and antibody response lays the foundation to develop biomarkers monitoring the COVID-19. Whole-blood-platform tests based on the immune response detection to SARS-CoV2 peptides is a new approach to discriminate COVID-19-patients from uninfected-individuals and to evaluate the immunogenicity of vaccine candidates, monitoring the immune response in vaccine trial and supporting the serological diagnostics results. Here, we aimed to identify in the whole-blood-platform the best immunogenic viral antigen and the best immune biomarker to identify COVID-19-patients. Methods Whole-blood was overnight-stimulated with SARS-CoV-2 peptide pools of nucleoprotein-(NP) Membrane-, ORF3a- and Spike-protein. We evaluated: IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL- 15, IL-17A, eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF, RANTES, TNF-α, VEGF. By a sparse partial least squares discriminant analysis we identified the most important soluble factors discriminating COVID-19- from NO-COVID-19-individuals. Results We identified a COVID-19 signature based on six immune factors: IFN-γ, IP-10 and IL-2 induced by Spike; RANTES and IP-10 induced by NP and IL-2 induced by ORF3a. We demonstrated that the test based on IP-10 induced by Spike had the highest AUC (0.85, p < 0.0001) and that the clinical characteristics of the COVID-19-patients did not affect IP-10 production. Finally, we validated the use of IP-10 as biomarker for SARS-CoV2 infection in two additional COVID-19-patients cohorts. Conclusions We set-up a whole-blood assay identifying the best antigen to induce a T-cell response and the best biomarkers for SARS-CoV-2 infection evaluating patients with acute COVID-19 and recovered patients. We focused on IP-10, already described as a potential biomarker for other infectious disease such as tuberculosis and HCV. An additional application of this test is the evaluation of immune response in SARS-CoV-2 vaccine trials: the IP-10 detection may define the immunogenicity of a Spike-based vaccine, whereas the immune response to the virus may be evaluated detecting other soluble factors induced by other viral-antigens.

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In-vitro evaluation of the immunomodulatory effects of Baricitinib: Implication for COVID-19 therapy

Cited by 45 publications

References 38 publications

Current Status of Baricitinib as a Repurposed Therapy for COVID-19

Current Status of Baricitinib as a Repurposed Therapy for COVID-19

The potential clinical utility of measuring severe acute respiratory syndrome coronavirus 2-specific T-cell responses

Exploratory analysis to identify the best antigen and the best immune biomarkers to study SARS-CoV-2 infection

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