Diminished responses to mRNA-based SARS-CoV-2 vaccines in individuals with rheumatoid arthritis on immune modifying therapies

Klebanoff, Samuel D.; Rodda, Lauren B.; Morishima, Chihiro; Wener, Mark H.; Yuzefpolskiy, Yevgeniy; Bettelli, Estelle; Buckner, Jane H.; Speake, Cate; Pepper, Marion; Campbell, Daniel

doi:10.1101/2023.01.03.23284167

Cited by 2 publications

(1 citation statement)

References 49 publications

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“…The results were not driven by differences in total IgG levels between subjects. Many of the treatments of RA, including methotrexate, systemic corticosteroids and biological therapies can reduce antibody responses to vaccines (including S. pneumoniae vaccines) [43][44][45][46][47]. These drugs are therefore likely to impair boosting of naturally acquired antibody to protein antigens by repeated S. pneumoniae nasopharyngeal colonisation events and potentially established memory responses.…”

Section: Discussionmentioning

confidence: 99%

Naturally acquired adaptive immunity to Streptococcus pneumoniae is impaired in rheumatoid arthritis patients

Ercoli,

Selway,

Folkmanaite

et al. 2023

Preprint

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Purpose: Patients with rheumatoid arthritis (RA) have an increased susceptibility to infection, including those caused by Streptococcus pneumoniae. Why RA is associated with increased susceptibility to S. pneumoniae is poorly understood. This study aims to assess the effects of RA and B cell depletion therapy on naturally acquired antibody responses to 289 S. pneumoniae protein antigens using a novel protein array. Methods: IgG responses to S. pneumoniae were characterized in serum from RA patients and disease controls (myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)) using whole-cell ELISA, a flow cytometry opsonization assay, and a S. pneumoniae protein array. For the RA patients, results were compared before and after B cell depletion therapy. Results: Compared to a well characterized disease control group of ME/CFS patients, RA patients had reduced antibody responses to multiple S. pneumoniae protein antigens, with significant IgG recognition of approximately half the number of antigens along with reduced median strengths of these responses. Reduction in multiple array antigen-specific responses also correlated with reduced IgG opsonization of S. pneumoniae. Although B cell depletion therapy with rituximab did not reduce overall IgG recognition of S. pneumoniae in the RA group, it was associated with marked disruption of pre-existing IgG repertoire to protein antigens in individual patients. Conclusion: These data show RA is associated with major disruption of naturally acquired adaptive immunity to S. pneumoniae, which can be assessed rapidly using a protein antigen array and is likely to contribute towards the increased incidence of pneumonia in patients with RA.

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Section: Discussionmentioning

confidence: 99%

Naturally acquired adaptive immunity to Streptococcus pneumoniae is impaired in rheumatoid arthritis patients

Ercoli,

Selway,

Folkmanaite

et al. 2023

Preprint

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Computational insights into rational design and virtual screening of pyrazolopyrimidine derivatives targeting Janus kinase 3 (JAK3)

Faris,

Cacciatore,

Alnajjar

et al. 2024

Front. Chem.

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The Janus kinase 3 (JAK3) family, particularly JAK3, is pivotal in initiating autoimmune diseases such as rheumatoid arthritis. Recent advancements have focused on developing antirheumatic drugs targeting JAK3, leading to the discovery of novel pyrazolopyrimidine-based compounds as potential inhibitors. This research employed covalent docking, ADMET (Absorption, Distribution, Metabolism, Excretion, Toxicity) analysis, molecular dynamics modeling, and MM/GBSA (Molecular Mechanics Generalized Born Surface Area) binding free energy techniques to screen 41 in silico-designed pyrazolopyrimidine derivatives. Initially, 3D structures of the JAK3 enzyme were generated using SWISS-MODEL, followed by virtual screening and covalent docking via AutoDock4 (AD4). The selection process involved the AMES test, binding affinity assessment, and ADMET analysis, narrowing down the candidates to 27 compounds that passed the toxicity test. Further covalent docking identified compounds 21 and 41 as the most promising due to their high affinity and favourable ADMET profiles. Subsequent development led to the creation of nine potent molecules, with derivatives 43 and 46 showing exceptional affinity upon evaluation through molecular dynamics simulation and MM/GBSA calculations over 300 nanoseconds, comparable to tofacitinib, an approved RA drug. However, compounds L21 and L46 demonstrated stable performance, suggesting their effectiveness in treating rheumatoid arthritis and other autoimmune conditions associated with JAK3 inhibition.

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Diminished responses to mRNA-based SARS-CoV-2 vaccines in individuals with rheumatoid arthritis on immune modifying therapies

Cited by 2 publications

References 49 publications

Naturally acquired adaptive immunity to Streptococcus pneumoniae is impaired in rheumatoid arthritis patients

Naturally acquired adaptive immunity to Streptococcus pneumoniae is impaired in rheumatoid arthritis patients

Computational insights into rational design and virtual screening of pyrazolopyrimidine derivatives targeting Janus kinase 3 (JAK3)

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