Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Randomized Controlled Trial
. 2025 Jan:111:105511.
doi: 10.1016/j.ebiom.2024.105511. Epub 2024 Dec 27.

Safety of baricitinib in vaccinated patients with severe and critical COVID-19 sub study of the randomised Bari-SolidAct trial

Hans-Kittil Viermyr  1 , Kristian Tonby  2 , Erica Ponzi  3 , Sophie Trouillet-Assant  4 , Julien Poissy  5 , José R Arribas  6 , Virginie Dyon-Tafani  7 , Maude Bouscambert-Duchamp  8 , Lambert Assoumou  9 , Bente Halvorsen  10 , Nuriye Basdag Tekin  10 , Alpha Diallo  11 , Lucie De Gastines  11 , Ludvig A Munthe  12 , Sarah Louise Murphy  10 , Thor Ueland  13 , Annika E Michelsen  10 , Fridtjof Lund-Johansen  14 , Pål Aukrust  10 , Joy Mootien  15 , Benjamin Dervieux  16 , Yoann Zerbib  17 , Jean-Christophe Richard  18 , Renaud Prével  19 , Denis Malvy  20 , Jean-François Timsit  21 , Nathan Peiffer-Smadja  22 , Damien Roux  23 , Lionel Piroth  24 , Hafid Ait-Oufella  25 , Cesar Vieira  26 , Olav Dalgard  27 , Lars Heggelund  28 , Karl Erik Müller  28 , Jannicke Horjen Møller  29 , Anders Benjamin Kildal  30 , Vegard Skogen  31 , Saad Aballi  32 , Jonas Daniel Sjøberg Øgaard  10 , Anne Ma Dyrhol-Riise  2 , Anders Tveita  33 , Amin Alirezaylavasani  34 , Dominique Costagliola  9 , Yazdan Yazdanpanah  35 , Inge Christoffer Olsen  3 , Tuva Børresdatter Dahl  10 , Hassen Kared  12 , Aleksander Rygh Holten  36 , Marius Trøseid  37
Affiliations
Randomized Controlled Trial

Safety of baricitinib in vaccinated patients with severe and critical COVID-19 sub study of the randomised Bari-SolidAct trial

Hans-Kittil Viermyr et al. EBioMedicine. 2025 Jan.

Abstract

Background: The Bari-SolidAct randomized controlled trial compared baricitinib with placebo in patients with severe COVID-19. A post hoc analysis revealed a higher incidence of serious adverse events (SAEs) among SARS-CoV-2-vaccinated participants who had received baricitinib. This sub-study aimed to investigate whether vaccination influences the safety profile of baricitinib in patients with severe COVID-19.

Methods: Biobanked samples from 146 participants (55 vaccinated vs. 91 unvaccinated) were analysed longitudinally for inflammation markers, humoral responses, tissue viral loads, and plasma viral antigens on days 1, 3, and 8. High-dimensional analyses, including RNA sequencing and flow cytometry, were performed on available samples. Mediation analyses were used to assess relationships between SAEs, baseline-adjusted biomarkers, and treatment-vaccination status.

Findings: Vaccinated participants were older, more frequently hospitalized, had more comorbidities, and exhibited higher nasopharyngeal viral loads. Baricitinib treatment did not affect antibody responses or viral clearance, but reduced markers of T-cell and monocyte activation compared to placebo (sCD25, sCD14, sCD163, sTIM-3). Age, baseline levels of plasma viral antigen, and several inflammatory markers, as well as IL-2, IL-6, Neopterin, CXCL16, sCD14, and suPAR on day 8 were associated with the occurrence of SAEs. However, mediation analyses of markers linked to SAEs, baricitinib treatment, or vaccination status did not reveal statistically significant interactions between vaccination status and SAEs.

Interpretation: This sub-study did not identify any virus- or host-related biomarkers significantly associated with the interaction between SARS-CoV-2 vaccination status and the safety of baricitinib. However, caution should be exercised due to the moderate sample size.

Funding: EU Horizon 2020 (grant number 101015736).

Keywords: Baricitinib; COVID-19; Immunomodulation; Inflammation; JAK/STAT-inhibitor; SARS-CoV-2 vaccination; Serious adverse events.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests MT has been a pro bono member of the scientific advisory board for Lilly. JP reports lecture fees from Gilead, Shionogi, and Mundipharma, as well as payment for expert testimony from Gilead, Shionogi, Eumedica, and Pfizer, and support for attending meetings from Gilead, and Shionogi. ARH reports personal fee from Pfizer (2021) for lectures outside the submitted work. RP reports personal fees from MSD (2024) for one lecture and from Gilead (2023) and Pfizer (2023) for congress attendance. LAM reports Helse Sør-Øst UiO and Research Council of Norway grant for developing cellular analyses of COVID-19 (2020–2022), grant from KG Jebsen Stiftelsen, and grant from The Coalition for Epidemic Preparedness Innovation to monitor immune responses in patients (2021–2023). DC reports personal fees from Pfizer (2022) for a lecture outside the submitted work. BD reports support from Amgen for congress attendance. J-FT report honoraria from Shionogi, Merck, Pfizer, and Advanz as well as participation in advisory board for Gilead, Merck, Menarini, and Biomerieux. AEM reports stocks in Pfizer. LP reports honoraria from Gilead, GSK, Moderna, Pfizer, and ViiV Healthcare, as well as support for attending meetings from MSD and Pfizer. YZ reports payments for lectures from Gilead, Shionogi, and Mundipharma, payment for expert testimony from Gilead, Shionogi, Eumedica, and Pfizer, as well as support for attending meetings from Gilead and Shionogi. MB reports support for attending meetings from Gilead and Shionogi. JM reports support for attending meetings from Pfizer and Menarini as well as participation in advisory board for MSD. All other authors have nothing to declare.

Figures

Fig. 1
Fig. 1
Study cohort and end points. a. Graphical abstract of study cohort, workflow, and readouts. (NC, nucleocapsid; RBD, receptor binding domain; SAE, serious adverse events). b. Flow chart of the Bari-Solid Act's sub-study including availability of biobanked samples at baseline, day 3 and day 8.
Fig. 2
Fig. 2
Serology response and viral clearance according to vaccination status. a. Longitudinal follow-up of anti-SARS-CoV-2 RBD IgG and (b) of anti-SARS-CoV-2 nucleocapsid IgG titers during COVID-19 hospitalization. Green area delimits high serological response against SARS-CoV-2 with a cut-off of 2000 BAU/mL for anti-SARS-CoV-2 RBD IgG and 10 AU/mL for anti-NC IgG. Blue area delimits intermediate anti-RBD IgG response (200–2000 BAU/mL). c. Specific humoral signature of vaccinated patients with COVID-19. Visualization by volcano plots of the significant clinical and serological parameters detected longitudinally in vaccinated and non-vaccinated COVID-19 hospitalized patients. Significance levels from the Mann–Whitney tests are indicated: ∗∗ for p < 0.01. (WT, wild type; RBD, receptor binding domain; NC, nucleocapsid, D1-D3-D8 represent baseline, day 3 and day 8 respectively. d. Functional analysis of whole blood transcriptome comparing differentially expressed genes (DEGs) between vaccinated and unvaccinated patients with COVID-19 at admission using Metascape, revealing Gene Ontology pathways related to adaptive immunity to be the most regulated between the two groups (GO:0002250, GO:0016064, and GO:0002377). e. Gene Set Enrichment Analysis demonstrating that transcripts related to Immunoglobulin production was significantly enriched in the non-vaccinated patients with COVID-19 compared to the vaccinated, f. Nasopharyngeal and (g) Plasma SARS-CoV-2 viral loads in patients with COVID-19 during hospitalization according to vaccination status. Green area represents values of detected viral loads and antigenemia above the median value. Significance levels from the Wilcoxon tests are indicated: ∗, ∗∗, ∗∗∗∗ for p < 0.05, p < 0.01, and p < 0.0001 respectively.
Fig. 3
Fig. 3
The effect of baricitinib on serology response and inflammation. a. Longitudinal follow-up of anti-SARS-CoV-2 RBD IgG and (b) of anti-SARS-CoV-2 nucleocapsid IgG titers during COVID-19 hospitalization. Green and blue areas delimit serological responses as in Fig. 2a and b. c. Specific inflammatory signature of baricitinib-treated patients with COVID-19. Visualization by volcano plots of the significant inflammatory molecules detected longitudinally in placebo and baricitinib-treated COVID-19 hospitalized patients. Significance levels from the Mann–Whitney tests are indicated: ∗, ∗∗ for p < 0.05 and p < 0.01. d. Specific cellular signature of baricitinib-treated patients with COVID-19. Visualization by volcano plots of the significant cellular subset's enrichment in placebo vs. baricitinib-treated COVID-19 hospitalized patients. The frequencies of immune cells were assessed by flow cytometry on longitudinally cryo-preserved PBMCs. Significance levels from the Mann–Whitney tests are indicated: ∗ for p < 0.05. e. Longitudinal follow-up of pro-inflammatory molecules in study participants stratified according to the treatment allocation and vaccination status. Red and blue lines represent unvaccinated and vaccinated patients respectively, with stipulated lines for baricitinib-treated patients, and solid lines for placebo-treated patients. Data are represented as medians and interquartile ranges (IQRs). Statistical analysis was performed by comparing baseline adjusted serum concentration in mixed models in participants receiving baricitinib or placebo on day 3 and day 8, and represented with ∗ p < 0.05, ∗∗p < 0.01, ∗∗∗∗p < 0.0001.
Fig. 4
Fig. 4
Inflammatory markers and SAE. a. Proteomic signature of SAE after severe COVID-19. Visualization by a heat map of normalized inflammatory markers according to the occurrence of SAE, vaccination status, treatment arm, time-point, and nasopharyngeal SARS-CoV-2 viral load at baseline (VL_D1). Serological inflammatory markers were automatically clustered according to their co-expression. (SAE, serious adverse events; VL, viral load; NA, not available) b. Longitudinal inflammatory profiles of serum from patients with/without SAE during COVID-19 hospitalization. Significance levels from the Mann–Whitney tests are indicated: ∗∗, ∗∗∗, ∗∗∗∗ for p < 0.01, p < 0.001 and p < 0.0001 respectively. c. Clinical and inflammatory networks of SAE during severe COVID-19. The correlogram described the significant correlation between clinical (age, anti-RBD IgG, duration symptoms, and viral load) and inflammatory markers detected in patients with COVID-19, with or without SAE. Pearson correlations with FDR are indicated with ∗ for p < 0.05 and ∗∗ for p < 0.01.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Hu B., Huang S., Yin L. The cytokine storm and COVID-19. J Med Virol. 2021;93(1):250–256. - PMC - PubMed
    1. Richardson P., Griffin I., Tucker C., et al. Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395(10223):e30–e31. - PMC - PubMed
    1. Tanaka Y., Luo Y., O'Shea J.J., Nakayamada S. Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach. Nat Rev Rheumatol. 2022;18(3):133–145. - PMC - PubMed
    1. Tanaka Y. A review of Janus kinase inhibitors for the treatment of Covid-19 pneumonia. Inflamm Regen. 2023;43(1):3. - PMC - PubMed
    1. Richardson P.J., Robinson B.W.S., Smith D.P., Stebbing J. The AI-assisted identification and clinical efficacy of baricitinib in the treatment of COVID-19. Vaccines (Basel) 2022;10(6):951. - PMC - PubMed

Publication types

MeSH terms