ABSTRACT
Introduction: Some multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with blunted humoral vaccination responses, but relevance for SARS-CoV-2 infection is unclear. Objective(s): To determine SARS-CoV-2 exposure rates and formation of antibody memory among participants of the COMparison Between All immunoTherapies for MS (COMBAT-MS;NCT03193866) and the Immunomodulation and MS Epidemiology (IMSE) studies. Aim(s): To determine SARS-CoV2 serological response of people living with MS (pwMS). Method(s): Using a multiplex bead-based assay we determined SARS-CoV-2 spike and nucleocapsid antibody levels in 3,723 pwMS in paired serum samples (n=7,157) donated prior (<January 31st 2020) and during the pandemic (July-October 2020);16.6% had natalizumab, 6.4% fingolimod, 9.7% dimethyl fumarate, 1.9% interferon beta, 50.4% rituximab, 1.4% cladribine, 7.6% other DMTs, and 6.1% were untreated. Median fluorescent intensity (MFI) and bead-count were determined for spike and nucleocapsid antibodies, and samples were regarded as positive only when reactive to both viral antigens. Hazard ratios, from multivariable Cox regression models, were derived to assess association between antibody levels above cut-off for each antigen, comparing exposure to rituximab or fingolimod at time of sampling vs. other reference DMTs. All models were adjusted for age, sex, treatment center, time since reported infection, MS severity, disease duration, and number of previous DMTs. Result(s): Specificity and sensitivity of the assay for SARS-CoV-2 was 100% and 99.7%, respectively. The proportion of positive samples for SARS-CoV-2 differed moderately across DMTs with the highest values among cladribine-treated (7.4%) and the lowest number among rituximab-treated pwMS (3.9%). Similarly, the proportion of positive cases not reported in the Swedish MS registry varied from 100% for cladribine to 33.3% among untreated pwMS. Comparing levels of antibodies titers showed that levels were lower among those treated with rituximab or fingolimod vs interferon treated pwMS. Point estimates indicated a similar trend comparing rituximab or fingolimod vs untreated pwMS. Conclusion(s): Overall rates of SARS-CoV-2 antibody positivity after the first COVID-19 wave differed only moderately across DMTs, while antibody levels were lower with rituximab or fingolimod compared to interferon-treated pwMS. This indicates quantitative rather than qualitative differences in the humoral response to infection.
ABSTRACT
Introduction: The new SARS-CoV-2-mRNA-vaccines provide protection against severe COVID-19 infection. Disease modifying therapies (DMTs) for treatment of persons with multiple sclerosis (pwMS) differently impact humoral and cellular immunity and therefore can diminish vaccination outcomes. Thus, it is crucial to investigate the influence of different DMTs on the immune response after SARS-CoV-2 vaccination of pwMS. Objective(s): To investigate antibody and T-cell responses after SARS-CoV-2-vaccination in pwMS treated with different DMTs. Method(s): We studied antibody and T-cell responses in pwMS 4 and 12 weeks after the second dose of mRNA-vaccination against SARS-CoV-2. The results were compared to baseline samples taken before the first dose of SARS-CoV-2-vaccination. We screened and included 148 pwMS treatedwith natalizumab (n=23), dimethylfumarate (n=24), fingolimod (n=39), cladribine (n=31), alemtuzumab (n=17) and teriflunomide (n=14). Healthy controls (HC) (n=43) were used as a comparison. To evaluate humoral immune responses, IgG reactivity was measured towards three different SARS-CoV-2 antigens using a multiplex bead assay: full-length spike glycoprotein (spike S1S2 foldon), spike S1 domain and the nucleocapsid protein C-terminal domain (Nucleocapsid C). Furthermore, the antibody data allowed us to distinguish pwMS who had been vaccinated after a previous SARS-CoV-2-infection. Cellular immune responses were studied using a Fluorospot assay measuring IFNy and IL-13 T-cell responses to the spike S1 domain and Nucleocapsid C. Result(s): Humoral responses to vaccination were comparable between HC and pwMS treated with natalizumab, dimethylfumarate, cladribine, alemtuzumab and teriflunomide, but suppressed with fingolimod. In addition, T-cell responses were nearly absent in the fingolimod group and moderately reduced in the cladribine group. Conclusion(s): In this comprehensive study of both antibody and cellular responses to SARS-CoV-2-vaccination in pwMS on different DMTs, fingolimod was associated with abrogated responses in both aspects, while cladribine-treated individuals displayed reduced cellular response only. These findings are of relevance for risk mitigation strategies and vaccination recommendations for pwMS.
ABSTRACT
Introduction: B cell depletion with rituximab (RTX) is associated with high treatment efficacy in relapsing-remitting multiple sclerosis (RRMS), with low risk of rebound phenomena with treatment interruptions, but also increased risk of mainly bacterial infections. In order to reduce infection risks, further prompted by COVID19, RTX standard dosing intervals were extended up to 24 months in a single centre setting. Aims: To determine risk of disease flares in RRMS patients with extended RTX dosing intervals. Methods: We retrospectively analysed all RRMS patients (n=719) treated with RTX included in two ongoing observational drug trials, COMBAT-MS (EudraCT 2016-003587-39) and MultipleMS (2017-002634-24). Data were extracted from the Swedish MS registry for demographics, diagnosis, treatment history, clinical relapses and magnetic resonance imaging (MRI). Relapses and/or new MRI T2 lesions/contrast enhancing lesions, were recorded at first sign of clinical or MRI disease activity, or the lack thereof, at most recent visit/MRI for patients without signs of disease activity. The maximum interval (MI) between RTX doses before a registered outcome was used as a proxy for the efficacy of different treatment protocols. Results: Out of 697 patients with valid clinical data, 35 (5%) suffered a relapse, 19 of which occurred after the first RTX dose. Of the remainder, 13 patients had a relapse with a MI of 6±3 months (n=181, 7.2%), 3 with MI extended to 12±3 (n=313, 1%), and no relapse was found with MI of 18±3 or & gt;21 months (n=140 and n=63, respectively). MRI activity was detected in 54/572 subjects (including 6 after first dose), of which 24/152 (15,8%) with MI 6±3 month, 16/244 (6.5%) with MI of 12±3 months, 9/116 (7.8%) with MI of 18±3 months and 5/60 (8.3%) with MI of & gt;21 months. No major differences were found among the four groups concerning demographics, type of prior treatment and disability, except for a lower number of RTX doses in the 6±3 month MI group (mean number of RTX doses 3.3, 5.8, 6.8 and 6.1, respectively;ANOVA p<0.001). Flow cytometric B lymphocyte profiles and additional follow up data regarding treatment duration will be included in the final presentation. Conclusions: Extending the RTX dosing intervals was not associated with signs of rebound disease activity. Further studies are needed to establish if dose interval extension of B cell depleting treatments can improve the benefit-risk ratio regarding disease activity versus infections.