gms | German Medical Science

Introduction: Patients with autoimmune inflammatory rheumatic diseases (AIRD) receiving rituximab (RTX) therapy are at higher risk for poor COVID-19 outcomes [1] and show substantially impaired anti-SARS-CoV-2 vaccine responses [2]. Thus, the ability to further define and predict vaccination responses in these patients may guide their optimal protection.

Methods: We studied antibody responses to SARS-CoV-2 vaccines and induction of antigen-specific B cells 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. A multidimensional analysis of B cell subsets before vaccination and a correlation matrix were performed to identify predictive biomarkers.

Results: Serologic IgG conversion with formation of neutralizing antibodies was significantly lower and delayed in both, RA and more pronounced in the RTX cohort compared to HC. A minimum of 10 B cells/µL (0,4% lymphocytes) in the peripheral circulation was found necessary in RTX patients to mount seroconversion to anti-S1 IgG upon SARS-CoV-2 vaccination (Figure 1A [Fig. 1]) and there was a positive correlation between absolute B cell numbers and IgG seroconversion (p=0.0044 , r=0,5975) as well as neutralizing antibodies (p=0,003, r=0,7296). Before vaccination, the majority of B cells from IgG seroconverted RTX patients (RTX IgG+) comprised naïve and transitional B cells, whereas vaccination non-responders (RTX IgG-) carried preferentially plasmablasts and double negative B cells (Figure 1B [Fig. 1]). Moreover, there was a positive correlation between neutralizing antibodies and B cells expressing HLA-DR and CXCR5 (involved in antigen presentation and germinal center formation) as well as an inverse correlation with CD95 expression and CD21low expression (marker for activation and exhaustion) on B cells (Figure 1C [Fig. 1]).

Conclusion: In patients receiving RTX, a minimum of 10 B cells/µl in the peripheral circulation candidates as biomarker for a high likelihood of IgG seroconversion upon SARS-CoV-2 vaccination. Substantial repopulation of naïve B cells upon RTX therapy appears to be essential for an adequate vaccination response requiring germinal center formation. In contrast, expression of exhaustion markers (CD21low, CXCR5-, CD95+) indicate negative predictors of vaccination responses. These results should guide optimized vaccination in these patients based on quantitative and qualitative B cell findings.

Disclosures: No relevant financial relationship(s) with ineligible companies to disclose.

Grant/Research Support: ALS is funded by a grant from the German Society of Rheumatology. HRA holds a scholarship of the COLCIENCIAS scholarship No. 727, 2015. ES received a grant from the Federal Ministry of Education and Research (BMBF) (BCOVIT, 01KI20161). ES is participant in the BIH-Charité Clinician Scientist Program funded by the Charité Universitätsmedizin Berlin and the Berlin Institute of Health. JR was supported by a MD scholarship from the Berlin Institute of Health (BIH). HS received funding from the Ministry for Science, Research and Arts of Baden-Württemberg, Germany and the European Commission (HORIZON2020 Project SUPPORT-E, no. 101015756). MFM is supported by the state of Berlin and the “European Regional Development Fund” (ERDF 2014–2020, EFRE 1.8/11, DRFZ), the BIH with the Starting Grant-Multi-Omics Characterization of SARS-CoV-2 infection, Project 6 “Identifying immunological targets in Covid-19” and the Senate of Berlin “Modulation of the mucosal immune response in order to prevent severe COVID-19”. TD received funding by the German Research Foundation (DFG) by projects TRR 130/project 24, Do491/7-5, Do 491/10-1.