B cell numbers predict humoral and cellular response upon SARS-CoV-2 vaccination among patients treated with rituximab

Abstract

Objectives: Patients with autoimmune inflammatory rheumatic diseases receiving rituximab (RTX) therapy show substantially impaired anti-SARS-CoV-2 vaccine humoral but partly inducible cellular immune responses. However, the complex relationship between antigen-specific B and T cells and the level of B cell repopulation necessary to achieve anti-vaccine responses remain largely unknown. Methods: Antibody responses to SARS-CoV-2 vaccines and induction of antigen-specific B and CD4/CD8 T cell subsets were studied in 19 rheumatoid arthritis (RA) and ANCA-associated vasculitis (AAV) patients receiving RTX, 12 RA patients on other therapies and 30 healthy controls after SARS-CoV-2 vaccination with either mRNA or vector based vaccines. Results: A minimum of 10 B cells/uL in the peripheral circulation was necessary in RTX patients to mount seroconversion to anti-S1 IgG upon SARS-CoV-2 vaccination. RTX patients lacking IgG seroconversion showed reduced antigen-specific B cells, lower frequency of TfH-like cells as well as less activated CD4 and CD8 T cells compared to IgG seroconverted RTX patients. Functionally relevant B cell depletion resulted in impaired IFNgamma secretion by spike-specific CD4 T cells. In contrast, antigen-specific CD8 T cells were reduced in patients independently of IgG formation. Conclusions: Patients receiving rituximab with B cell numbers above 10 B cells/ul were able to mount humoral and more robust cellular responses after SARS-CoV-2 vaccination that may permit optimization of vaccination in these patients. Mechanistically, the data emphasize the crucial role of co-stimulatory B cell functions for the proper induction of CD4 responses propagating vaccine-specific B and plasma cell differentiation.

COVID-19 mRNA Vaccine in Patients With Lymphoid Malignancy or Anti-CD20 Antibody Therapy: A Systematic Review and Meta-Analysis

“…6 A). 66 , 67 , 68 , 69 , 71 , 72 , 73 , 76 , 78 , 79 , 80 , 81 , 82 , 84 , 85 , 86 The funnel plot did not reveal any publication bias (p = 0.12, Fig. 6 B).…”

“…In addition, four studies examined cellular responses using an activation-induced marker (AIM) assay, two of which revealed no significant difference without available quantitative data. 81 , 82 The meta-analysis of other two articles exhibited no difference between patients treated with anti-CD20 antibody and controls (AIM-positive CD4 cell, RR 0.98 [95% CI 0.82–1.18]; AIM-positive CD8 cell, RR 0.93 [95% CI 0.43–2.04]) 72 , 73 ( Fig. 7 C and 7 D).…”

“…Among them, 52 studies fulfilled the criteria for the present meta-analysis: 30 investigated lymphoid malignancies 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ; and 22 investigated anti-CD20 antibody therapy for non-malignant diseases, such as multiple sclerosis and rheumatic diseases. 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 28 articles were excluded with the following reasons: (1) insufficient data of outcomes, 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 (2) duplicate publications from an overlapping cohort, 97 ...…”

CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis

“…Whilst protection from MS may result from depletion of memory B cells ( Baker et al, 2017a ), seroconversion has been attributed to immature/naïve B cell repletion and occurs following the development of 1-3% B cell repopulation ( Madelon et al, 2021 , Mrak et al, 2021 , Stefanski et al, 2021 , Disanto et al, 2021 ). However, the frequency of people achieving 1% B cell repletion at specific time intervals following ocrelizumab dosing is largely unknown ( Gibiansky et al, 2021 ).…”

Three-month follow-up of heterologous vs homologous third vaccination in kidney transplant recipients

“…The T-cell stimulation flow cytometric (FC) assessment of SARS-CoV-2 specific T-cells have been described before. 10,11 In brief, peripheral blood mononuclear cells (PBMC) were isolated by Ficoll-Paque density gradient centrifugation and cryopreserved until further analysis. For the identification of SARS-CoV-2 specific T-cells 3-5 x 10 6 PBMCs were incubated for 18h with overlapping 15-mer peptides covering the complete SARS-CoV-2 spike protein wild type variant (1 ug/ml per peptide; JPT, Germany) and subsequently subjects to FC analysis.…”