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 are at higher risk for poor COVID-19 outcomes and show substantially impaired humoral anti-SARS-CoV-2 vaccine 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/µL (0,4% of lymphocytes) in the peripheral circulation appeared to be required in RTX patients to mount seroconversion to anti-S1 IgG upon SARS-CoV-2 vaccination. RTX patients lacking IgG seroconversion showed reduced RBD+ 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 IFNγ secretion by spike-specific CD4 T cells. In contrast, antigen-specific CD8 T cells were reduced in patients, independently of IgG formation. CONCLUSIONS: In patients receiving RTX, a minimum of 10 B cells/µl in the peripheral circulation candidates as biomarker for a high likelihood of an appropriate cellular and humoral response after SARS-CoV-2 vaccination. 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.