Discordant humoral and T cell immune responses to SARS-CoV-2 vaccination in people with multiple sclerosis on anti-CD20 therapy

Abstract

Background: Sphingosine-1-phosphate receptor (S1P) modulators and antiCD20 therapies impair humoral responses to SARS-CoV-2 mRNA vaccines. Whether disease modifying therapies (DMTs) for multiple sclerosis (MS) also impact T cell immune response to vaccination is unknown. Methods: In 101 people with MS, we measured humoral responses via an immunoassay to measure IgG against the COVID-19 spike S1 glycoprotein in serum. We also measured T cell responses using FluoroSpot assay for interferon gamma (IFN-gamma; Mabtech,Sweden) using cryopreserved rested PBMCs and then incubated in cRPMI with 1microg/ml of pooled peptides spanning the entire spike glycoprotein (Genscript, 2 pools; 158 peptides each). Plates were read on an AID iSpot Spectrum to determine number of spot forming cells (SFC)/10 6 PBMCs. We tested for differences in immune responses across DMTs using linear models. Findings: Humoral responses were detected in 22/39 (56.4%) participants on anti-CD20 and in 59/63 (93.6%) participants on no or other DMTs. In a subset with immune cell phenotyping (n=88; 87%), T cell responses were detected in 76/88 (86%), including 32/33 (96.9%) participants on anti-CD20 therapies. AntiCD20 therapies were associated with an increase in IFN-gamma; SFC counts relative to those on no DMT or other DMTs (for antiCD20 vs. no DMT: 425.9% higher [95%CI: 109.6%, 1206.6%] higher; p<0.001; for antiCD20 vs. other DMTs: 289.6% [95%CI: 85.9%, 716.6%] higher; p<0.001). Interpretation: We identified a robust T cell response in individuals on anti-CD20 therapies despite a reduced humoral response to SARS-CoV-2 vaccination. Follow up studies are needed to determine if this translates to protection against COVID-19 infection.

Impact of multiple sclerosis disease-modifying therapies on SARS-CoV-2 vaccine-induced antibody and T cell immunity

“…In contrast, patients on S1P receptor modulators and anti-CD20 mAb had significantly reduced levels of total spike and spike RBD IgG, consistent with recent reports [8][9][10][11] . We did not observe a clear relationship between spike antibody seropositivity and anti-CD20 mAb infusion interval and SARS-CoV-2 vaccination, in contrast to several other studies 7,18,19,21 . It is possible this disparity could be due to differences in patient populations or methodology.…”

“…Interestingly, we observed a trend towards increased CD8+ T cell cytokine production in anti-CD20 mAb-treated compared to untreated MS patients, which was significantly increased in the case of IFNγ+ CD8+ T cells in the RTX cohort. These findings support recent similar reports of increased SARS-CoV-2-specific CD8+ T cell activation in anti-CD20 mAb-treated MS patients 18,21 and suggest that B cell depletion may result in compensatory changes in certain aspects of cellular immunity. However, the mechanism of such T cell-mediated changes and whether this has a protective effect against COVID-19 remain unknown.…”

“…In support of this, recent data suggests that unvaccinated MS patients on anti-CD20 mAb treatments are at higher risk for severe COVID-19 6 . To date, the majority of studies evaluating SARS-CoV-2 vaccine responses in MS patients have been limited to measuring antibody levels 8–11 and those that have explored T cell reactivity have primarily focused on anti-CD20 mAb-treated patients 18,21 . Thus, there is a significant need to comprehensively investigate how different MS DMTs impact SARS-CoV-2 vaccine-elicited antibody and CD4+ and CD8+ T cell immunity.…”

“…To date, the majority of studies evaluating SARS-CoV-2 vaccine responses in MS patients have been limited to measuring antibody titers, demonstrating reduced spike antigen-specific antibody responses in MS patients treated with anti-CD20 mAb and S1P receptor modulators 7,18–20 . Several reports have also indicated largely intact spike antigen-specific T cell responses in vaccinated MS patients on anti-CD20 mAb 18,21 . Nevertheless, there is currently no available data comparing SARS-CoV-2 vaccine-specific CD4+ and CD8+ T cell reactivity across patients on different DMTs, presenting a significant gap in our understanding of COVID-19 susceptibility in at-risk patient populations.…”

Einblicke in die Behandlung der Multiplen Sklerose mit Cladribin-Tabletten seit Beginn der COVID-19-Pandemie

“…Die Serokonversionsrate unter CD20 depletierender Therapie ist allerdings abhängig vom Impfzeitpunkt. Zum anderen gibt es zunehmend Hinweise, dass unter CD20-Depletion trotz fehlender humoraler Immunantwort eine protektive T-Zell-Antwort vorliegen kann [43,[45][46][47]. Die klinische Relevanz der T-Zell-Antwort wurde bislang aber noch nicht ausreichend untersucht.…”