Background and purpose: Recent findings document a blunted humoral response to SARS‐CoV‐2 vaccination in patients on anti‐CD20 treatment. Although most patients develop a cellular response, it is still important to identify predictors of seroconversion to optimize vaccine responses.Methods: We determined antibody responses after SARS‐CoV‐2 vaccination in a real‐world cohort of multiple sclerosis patients (n = 94) treated with anti‐CD20, mainly rituximab, with variable treatment duration (median = 2.9, range = 0.4–9.6 years) and time from last anti‐CD20 infusion to vaccination (median = 190, range = 60–1032 days).Results: We find that presence of B cells and/or rituximab in blood predict seroconversion better than time since last infusion. Using multiple logistic regression, presence of >0.5% B cells increased probability of seroconversion with an odds ratio (OR) of 5.0 (95% confidence interval [CI] = 1.0–28.1, p = 0.055), whereas the corresponding OR for ≥6 months since last infusion was 1.45 (95% CI = 0.20–10.15, p = 0.705). In contrast, detectable rituximab levels were negatively associated with seroconversion (OR = 0.05, 95% CI = 0.002–0.392, p = 0.012). Furthermore, naïve and memory IgG⁺ B cells correlated with antibody levels. Although retreatment with rituximab at 4 weeks or more after booster depleted spike‐specific B cells, it did not noticeably affect the rate of decline in antibody titers. Interferon‐γ and/or interleukin‐13 T‐cell responses to the spike S1 domain were observed in most patients, but with no correlation to spike antibody levels.Conclusions: These findings are relevant for providing individualized guidance to patients and planning of vaccination schemes, in turn optimizing benefit–risk with anti‐CD20.

Objective: To investigate the relation between intrathecal antibody production, as reflected by kappa free light chain (KFLC) metrics, and multiple sclerosis (MS) prognosis‐related markers and study its modulation following MS treatment.Methods: This study comprised matched plasma and cerebrospinal fluid (CSF) samples from a total of 130 persons with MS (pwMS), 99 of whom were untreated at baseline. Paired samples from 73 pwMS (18 on dimethyl fumarate (DMF), 10 on fingolimod, 6 on natalizumab, 25 on rituximab (RTX) and 14 after autologous hematopoietic stem cell transplantation (HSCT)) were used to analyze treatment effects on KFLC metrics. KFLC was measured by nephelometry while clinical and paraclinical data were collected from the patient charts. HLA typing was performed with SNP genotyping.Results: The KFLC local concentration (KFLC loc) and index was higher in HLA‐DRB1*15:01 carriers and correlated with the number of CSF mononuclear cells, IgG index, and CSF levels of CXCL13 and neurofilament light chain, the latter particularly during remission (r = 0.27, p = 0.045). With regard to treatment effects, we found that treatment with DMF, RTX, and HSCT resulted in a decrease of CSF‐KFLC levels and/or KFLC loc and index. Interestingly, the rate of decrease in KFLC index correlated with time since first treatment (r = −0.41, p = 0.045).Conclusion: These findings support an involvement of intrathecal antibodies in non‐relapsing MS pathology and inform on the effect of current treatments. The slow rate of decrease in KFLC index following B cell depletion stresses the need for early treatment start.

Recent studies have highlighted the important role of B cells in the pathogenesis of multiple sclerosis (MS). B cell activating factor (BAFF) and A proliferation inducing ligand (APRIL) play a major role in B cell survival and homeostasis. Here, we studied the association of BAFF and APRIL with B cell immune markers in MS and following B cell depletion and repopulation. We found that BAFF but not APRIL was significantly higher in plasma in untreated MS compared to controls. BAFF increased after rituximab treatment and decreased again during repopulation displaying an inverse correlation with B cell numbers, and more specifically switched memory B cell numbers. Cerebrospinal fluid BAFF inversely correlated with IgG index. BAFF displayed an inverse association to anti-EBV-CA antibodies. In summary, our study identified immune cells and factors that might regulate or be regulated by BAFF and APRIL levels in MS, and during B cell depletion and repopulation.

Background: The presence of intrathecal total IgG production is a hallmark of cerebrospinal fluid (CSF) characteristics in multiple sclerosis (MS). Herein, we systematically analyze how the intensity (instead of mere presence) of intrathecal total IgG production relates to basic CSF parameters in MS. Methods: We retrospectively assessed clinical routine CSF findings from 390 therapy-naïve relapsing-remitting MS patients diagnosed according to 2017 revised McDonald criteria. The intensity of intrathecal total IgG synthesis according to Reiber’s formula was stratified and correlated to demographics, CSF white cell count (WCC), and diversity of MRZ reaction, defined as a polyspecific intrathecal production of IgG reactive against ≥2 of the 3 viruses; measles (M), rubella (R), and varicella zoster (Z) virus. Results: The higher intensity of intrathecal total IgG production significantly correlated with higher CSF WCC (Spearman’s ρ = 0.433, p < 0.001) and with the increasing presence and diversity of positive MRZ reaction (Spearman’s ρ = 0.600, p < 0.001). Female patients showed higher intensity of intrathecal total IgG production and higher prevalence of positive MRZ reaction than males. Conclusions: The intensity of intrathecal total IgG production correlates with the degree of CSF WCC and diversity of MRZ reaction in MS. As yet unidentified female sex-related factors increase the intensity and diversity of intrathecal IgG production in MS.

Background and purpose: Hybrid immunity to severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) develops from a combination of natural infection and vaccine‐generated immunity. Multiple sclerosis (MS) disease‐modifying therapies (DMTs) have the potential to impact humoral and cellular immunity induced by SARS‐CoV‐2 vaccination and infection. The aims were to compare antibody and T‐cell responses after SARS‐CoV‐2 mRNA vaccination in persons with MS (pwMS) treated with different DMTs and to assess differences between naïvely vaccinated pwMS and pwMS with hybrid immunity vaccinated following a previous SARS‐CoV‐2 infection.Methods: Antibody and T‐cell responses were determined in pwMS at baseline and 4 and 12 weeks after the second dose of SARS‐CoV‐2 vaccination in 143 pwMS with or without previous SARS‐CoV‐2 infection and 40 healthy controls (HCs). The MS cohort comprised natalizumab (n = 22), dimethylfumarate (n = 23), fingolimod (n = 38), cladribine (n = 30), alemtuzumab (n = 17) and teriflunomide (n = 13) treated pwMS. Immunoglobulin G antibody responses to SARS‐CoV‐2 antigens were measured using a multiplex bead assay and FluoroSpot was used to assess T‐cell responses (interferon γ and interleukin 13).Results: Humoral and T‐cell responses to vaccination were comparable between naïvely vaccinated HCs and pwMS treated with natalizumab, dimethylfumarate, cladribine, alemtuzumab and teriflunomide, but were suppressed in fingolimod‐treated pwMS. Both fingolimod‐treated pwMS and HCs vaccinated following a previous SARS‐CoV‐2 infection had higher antibody levels 4 weeks after vaccination compared to naïvely vaccinated individuals. Antibody and interferon γ levels 12 weeks after vaccination were positively correlated with time from last treatment course of cladribine.Conclusion: These findings are of relevance for infection risk mitigation and for vaccination strategies amongst pwMS undergoing DMT.