Humoral and cellular responses to mRNA vaccines against SARS-CoV-2 in patients with a history of CD20 B-cell-depleting therapy (RituxiVac): an investigator-initiated, single-centre, open-label study

Abstract

Background B-cell-depleting therapies increase the risk of morbidity and mortality due to COVID-19. Evidence-based SARS-CoV-2 vaccination strategies for patients on B-cell-depleting therapies are scarce. We aimed to investigate humoral and cell-mediated immune responses to SARS-CoV-2 mRNA-based vaccines in patients receiving CD20-targeted B-cell-depleting agents for autoimmune disease, malignancy, or transplantation. Methods The RituxiVac study was an investigator-initiated, single-centre, open-label study done at the Bern University Hospital (Bern, Switzerland). Patients with a treatment history of anti-CD20-depleting agents (rituximab or ocrelizumab) and with no previous history of SARS-CoV-2 infection were enrolled between April 26 and June 30, 2021, for analysis of humoral and cell-mediated immune responses (by interferon-γ [IFNγ] release assay) at least 4 weeks after completing vaccination against SARS-CoV-2. Healthy controls without a history of SARS-CoV-2 infection were also enrolled at least 4 weeks after completing vaccination against SARS-CoV-2. All study participants received two doses of either the Pfizer–BioNTech BNT162b2 vaccine or the Moderna mRNA-1273 vaccine. The primary outcome was the proportion of patients with a history of anti-CD20 treatment who showed a humoral immune response against the SARS-CoV-2 spike protein in comparison with immunocompetent controls. Prespecified secondary endpoints were the effect of anti-CD20 therapy (including time since last treatment and cumulative dose) on humoral or cell-mediated immune responses to SARS-CoV-2 vaccination, and biomarkers of immunocompetence. This study is registered with ClinicalTrials.gov , NCT04877496 . Findings The final study population comprised 96 patients and 29 immunocompetent controls. The median age of patients was 67 years (IQR 57–72) and of controls was 54 years (45–62), and 51 (53%) of 96 patients and 19 (66%) of 29 controls were female. The median time since last anti-CD20 treatment was 1·07 years (IQR 0·48–2·55) and the median cumulative dose of an anti-CD20 depleting agent was 2·80 g (1·50–5·00). Anti-spike IgG antibodies were detected in 47 (49%) of 96 patients 1·79 months (IQR 1·16–2·48) after the second vaccine dose compared to 29 (100%) of 29 controls 1·81 months (1·17–2·48) after the second vaccine dose (p<0·001). SARS-CoV-2-specific IFNγ release was detected in 13 (20%) of 66 patients and 21 (75%) of 28 of healthy controls (p<0·001). Only nine (14%) of 66 patients were double positive for anti-SARS-CoV-2 spike IgG and cell-mediated responses, compared with 21 (75%) of 28 healthy controls (p<0·001). Time since last anti-CD20 therapy (>7·6 months; positive predictive value 0·78), peripheral CD19 + cell count (>27 cells per μL; positive predictive value 0·70), and CD4 + lymphocyte count (>653 cells per μL; positive predictive value 0·71) were ...

Humoral and cellular immune responses upon SARS-CoV-2 vaccines in patients with anti-CD20 therapies: A systematic review and meta-analysis of 1342 patients

“…A key result is our finding that time since last anti-CD20 therapy administration severely impacts seroconversion rates. This is congruent with the results of individual studies of SARS-CoV2 vaccines 9,10,26,38 and has been found for influenza seroconversion in anti-CD20 therapies 4 . This finding may be of particular interest for ideal scheduling of vaccination.…”

“…However, as we have previously reported, some substantial SARS-CoV2 vaccine-induced seroconversion rates can occur in patients with high CD4-positive T cell counts even when treated with anti-CD20 therapy within the last 6 months 10 . Further, we found that the different assays used in studies of cell-mediated immunity led to heterogeneous results.…”

“…Further, no external experts in the field were consulted, and no unpublished studies or clinical study registry data were queried. Some potential sources of heterogeneity in seroconversion rates in the study population were not captured in subgroup analyses, such as the immunosuppressive co-medication 10 , B cell count 10,41 , and potentially circulating CD4-positive T cell counts in patients on anti-CD20 therapy 10 similar as in HIV studies 42 . Finally, we did not perform an analysis of seroconversion rates according to the different vaccines administered, as population-level data did not sufficiently discriminate between vaccine types.…”

“…We defined SARS-CoV-2 vaccine elicited humoral immune response as detection of antispike antibodies (anti-RBD or anti-S1 (spike protein) SARS-CoV2) above the cut-off reported by the manufacturer of the given assay.Vaccine elicited cell-mediated immune response was defined as detection of SARS-CoV-2 specific T-cells either measured by, T-EliSpot [6][7][8][9] , interferon-γ release assays 10,11 or activation-induced marker (AIM) detection 12,13 in flow cytometry-sorted cells. AIM used for the detection of vaccine elicited T-cells response were CD4+CXCR5+PD1+ and CD38+HLA-DR+ 12 as well as S-specific OX40+ 41-BB+ CD4+ and CD69+ 41BB+ CD8+ 13 .…”

“…Study characteristics of the included publications [6][7][8][9][10][11][12][13][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] are summarized in Table 1. Information to assay details of antibody detection and CMI are indicated in Supplementary Appendix, pp.…”