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

Stefanski, A.-L.; Rincon-Arevalo, H.; Schrezenmeier, E.; Karberg, K.; Szelinski, F.; Ritter, J.; Jahrsdoerfer, B.; Schrezenmeier, H.; Ludwig, C.; Sattler, A.; Kotsch, K.; Chen, Y.; Claussnitzer, A.; Haibel, H.; Proft, F.; Guerra, G. M.; Durek, P.; Heinrich, F.; Gomes, M. F.; Burmester, G. R.; Radbruch, A.; Mashreghi, M.-F.; Lino, A. C.; Doerner, T.

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.