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The majority of multiple sclerosis [MS] patients treated with fingolimod fail to develop a protective level of IgG humoral and adaptive cellular immune responses following full BNT162b2 SARS-CoV-2 vaccination.To compare the efficacy of the third COVID-19 vaccine dose in vaccine non-responders fingolimod-treated MS patients.This is a prospective 3-month, single-center, randomized clinical trial.Twenty relapsing MS patients who had been on fingolimod therapy ≥ 12 months and failed to develop humoral IgG immune response to 2-dose Pfizer BNT162b2 COVID-19 vaccination were randomized into two groups: fingolimod-continuation group and fingolimod-discontinuation group. Humoral and memory cellular immune responses were assessed within 1 and 3 months following the third Pfizer BNT162b2 vaccine dose and compared between the groups.A higher rate of patients in the fingolimod-discontinuation group [n = 8/10] compared to fingolimod-continuation group [n = 2/10] developed positive SARS-COV-2 IgG. Median IgG titer 1 month following the third dose was 202.3 BAU/ml vs. 26.4 BAU/ml, respectively, p = 0.022. The development of IgG humoral response correlated with absolute lymphocyte count. Specific SARS-COV-2 memory B cell and T cell immune responses were not detected in both groups, either at 1 month or 3 months following the third COVID-19 vaccine dose.Short period of fingolimod treatment discontinuation was associated with the development of humoral protection but not with adaptive cellular immunity.

Background: Since vaccination against coronavirus disease 2019 (COVID-19) became available, risks related to vaccinating patients with multiple sclerosis (MS) need to be carefully assessed. Objective: Characterize safety and occurrence of immediate relapses following COVID-19 vaccination in a large cohort of MS patients. Methods: We assessed the safety of BNT162b2 COVID-19 vaccination in adult MS patients. Results: Between 20 December 2020 and 25 January 2021, 555 MS patients received the first dose of BNT162b2 vaccine and 435 received the second dose. There were three cases of COVID-19 infection encountered after the first dose. Safety profile of COVID-19 vaccine was characterized by pain at the injection site, fatigue, and headache. No increased risk of relapse activity was noted over a median follow-up of 20 and 38 days after first and second vaccine doses, respectively. The rate of patients with acute relapse was 2.1% and 1.6% following the first and second doses, respectively, similar to the rate in non-vaccinating patients during the corresponding period. Mild increase in the rate of adverse events was noted in younger patients (18–55 years), among patients with lower disability (Expanded Disability Status Scale (EDSS) ⩽3.0), and in patients treated with immunomodulatory drugs. Conclusion: COVID-19 BNT162b2 vaccine proved safe for MS patients. No increased risk of relapse activity was noted.

Background and Aims: The National Multiple Sclerosis Society and other expert organizations recommended that all patients with multiple sclerosis (MS) should be vaccinated against COVID-19. However, the effect of disease-modifying therapies (DMTs) on the efficacy to mount an appropriate immune response is unknown. We aimed to characterize humoral immunity in mRNA-COVID-19 MS vaccinees treated with high-efficacy DMTs. Methods: We measured SARS-CoV-2 IgG response using anti-spike protein-based serology (EUROIMMUN) in 125 MS patients vaccinated with BNT162b2-COVID-19 vaccine 1 month after the second dose. Patients were either untreated or under treatment with fingolimod, cladribine, or ocrelizumab. A group of healthy subjects similarly vaccinated served as control. The percent of subjects that developed protective antibodies, the titer, and the time from the last dosing were evaluated. Results: Protective humoral immunity of 97.9%, 100%, 100%, 22.7%, and 3.8%, was observed in COVID-19 vaccinated healthy subjects ( N = 47), untreated MS patients ( N = 32), and MS patients treated with cladribine ( N = 23), ocrelizumab ( N = 44), and fingolimod ( N = 26), respectively. SARS-CoV-2 IgG antibody titer was high in healthy subjects, untreated MS patients, and MS patients under cladribine treatment, within 29.5–55 days after the second vaccine dose. Only 22.7% of patients treated with ocrelizumab developed humoral IgG response irrespective to normal absolute lymphocyte count. Most fingolimod-treated MS patients had very low lymphocyte count and failed to develop SARS-COV-2 antibodies. Age, disease duration, and time from the last dosing did not affect humoral response to COVID-19 vaccination. Conclusions: Cladribine treatment does not impair humoral response to COVID-19 vaccination. We recommend postponing ocrelizumab treatment in MS patients willing to be vaccinated as a protective humoral response can be expected only in some. We do not recommend vaccinating MS patients treated with fingolimod as a protective humoral response is not expected.

Background As immunity against SARS-COV-2 wanes following first and second doses of vaccination, a third dose is administered in several countries around the world. Similarly to the first doses, risks related to vaccination and humoral immune response in patients with multiple sclerosis (MS) need to be assessed. Objective Characterize safety and humoral immune response following the third dose of COVID-19 vaccination in a large cohort of MS patients. Methods We assessed the safety of the third dose of the BNT162b2-COVID-19 mRNA vaccination in adult MS patients and evaluated SARS-CoV-2 IgG response. Results Two hundred and eleven adult MS patients received a third dose of BNT162b2 COVID-19 vaccination. Median follow up time was 66 days from vaccine administration (IQR 54–84). The frequency of any adverse event was 54.5%, with the most common reported adverse events being fatigue, local pain at the injection site, fever and muscle or joint pain. Transient increase in MS symptoms was reported in 3.8% of patients, none of them requiring treatment. The rate of acute relapses treated with IV steroids was 3.3%. In a sub-group of 55 patients, 20 untreated and 35 treated with vaccination-safe disease-modifying treatments, SARS-CoV-2 IgG levels increased 21-fold (median ± SD 21.6 ± 53.05). Conclusions The third dose of COVID-19-BNT162b2 vaccine proved safe for MS patients, with no increased risk of relapse activity. Untreated patients and patients treated with vaccination-safe disease-modifying treatments show significant increase in SARS-CoV-2 IgG levels following the third dose of vaccination.

Background: Worldwide spread of COVID-19 disease highlights the need for assessment of long-term humoral immunity in convalescent subjects. Objectives: Evaluate IgG SARS-CoV-2 antibody response and B-cell memory response over-time in COVID-19 convalescent subjects. Methods: Blood samples were collected from a cohort of subjects recovering from COVID-19 disease and from healthy subjects that donated blood. SARS-CoV-2 IgG antibodies were quantitatively detected by ELISA using anti-S1 spike IgG. SARS-CoV-2 spike-specific IgG memory B-cells were evaluated in a randomly selected group of COVID-19 recovering subjects by reversed B-cell FluroSpot based on human IgG SARS-CoV-2 receptor-binding domain. Statistical analysis was performed with clinical variables and time post COVID-19 infection. Results: We evaluated 392 COVID-19 convalescent subjects and 180 healthy subjects for SARS-CoV-2 antibody response. No antibody response was detected in 6.7% of COVID-19 convalescent subjects. Over a period of 9 months the level of antibodies decreased by 50% but stabilized at 6 months and prevailed a protective level up to 9 months. No differences were found regarding IgG SARS-COV-2 antibody levels for age, gender, and major blood types, over-time. COVID-19 asymptomatic subjects did not differ in antibody level overtime from subjects with mild to severe disease. Repeated paired IgG SARS-COV-2 antibody level analyses disclosed that over 6 and 9 months, 15.3% and 15.8% of subjects became SARS-COV-2 IgG seronegative, respectively, all with low antibody level at 3 months. Rate of antibody decline was not affected by age, gender, or clinical symptomatology. Memory B-cell response up to 9 months post COVID-19 infection was undetectable in 31.8% of subjects with no correlation to age, SARS-COV-2 antibody level or time post-infection. Conclusions: Our findings are of importance regarding health care decisions related to the magnitude of protective humoral immunity and the need of vaccination in COVID-19 convalescent subjects particularly in subjects with SARS-COV-2 antibody decay or absence of B-cell memory response. Funding Statement: The Laura Schwarz-Kipp Research Chair of Autoimmune Diseases, Sackler School of Medicine, Tel-Aviv University and Nitzan Research Foundation, Sheba Medical Center, Israel. Declaration of Interests: The authors declare no competing interest. Ethics Approval Statement: This study was approved by Sheba Institutional Review Board SMC- 750320) and informed consent was obtained from all enrolled participants.

Objective: To identify the operating biological pathways which associated with progression from relapsing remitting (RR) to secondary progressive (SP) phase of multiple sclerosis (MS). Background Clinically, 85% of MS patients have a RR course characterized by inflammatory attacks associated with neurological deficits and variable periods of remissions. After a period of 10 years, 50% of RRMS patients progress to the SPMS disease course, which is characterized by progressive neurological deterioration with or without coincidental relapses. The molecular events leading to the evolution from RRMS to SPMS are not clearly understood. Design/Methods: Peripheral blood samples obtained from 38 patients that met the diagnostic criteria for SPMS (EDSS>6.0, at least 1.0 point progression by the expanded disability status scale (EDSS) during the preceding two-year period) and 44 patients with RRMS were applied for gene expression microarray analysis using HG-U133A-2 array (Affymetrix). Data were analyzed by Partek (www.partek.com) and pathway reconstruction was performed by Ingenuity (www.ingenuity.com) for the most informative genes (MIGs) with p Results: A total of 429 MIGs (30 genes passed FDR) differentiated between SPMS patients (25 females, age 51.9±2.2 years, disease duration 16.9±2.5 years, EDSS 6.8±0.3) and RRMS patients (27 females, age 44.5±2.0 years, disease duration 3.4±0.6 years, EDSS 2.2±0.4). The SPMS gene expression signature was characterized by significant enrichment of over-expressed genes associated with inflammatory response related to IL1b, IL6, and IL8 mediated monocytes recruitment. The most significantly enriched pathways were infiltration by neutrophils (p=8.3*10-12, CXCL1,2 and3), transmigration of phagocytes (p=6.2*10-7, CCL3,4 and 20) and activation of chemokines production (p=7.8*10-8, TNFa, IL1b, IL8, IL6) followed by down regulation of cell apoptotic machinery (p=1.9*10-6 to 1.1*10-17, BAX, FADD, CASP8, CFLAR). Conclusions: The inflammatory process in SPMS is characterized by IL1b-IL6-IL8 mediated activation of macrophage recruitment. Disclosure: Dr. Hanael has nothing to disclose. Dr. Rothmann has nothing to disclose. Dr. Zilkha-Falb has nothing to disclose. Dr. Gurevich has nothing to disclose. Dr. Achiron has received personal compensation from Biogen Idec, Teva Pharmaceutical Industries Ltd. and Novartis for serving on scientific advisory board and as a consultant. Dr. Achiron received research support from Bayer-Schering Pharma, Biogen Idec, Teva Pharmaceutical Industries Ltd., Merck Serono, and Novartis.

Background Interferon (IFN) beta-1a is an approved treatment for relapsing remitting multiple sclerosis (RRMS) and has been examined for use in secondary progressive multiple sclerosis (SPMS). However, no information regarding blood transcriptional changes induced by IFN treatment in SPMS patients is available. Our aim was to identify a subgroup of SPMS patients presenting a gene expression signature similar to that of RRMS patients who are clinical responders to IFN treatment. Methods SPMS patients (n = 50, 20 IFN treated and 30 untreated) were classified using unsupervised hierarchical clustering according to IFN inducible gene expression profile identified in RRMS clinical responders to treatment. IFN inducible gene expression profile was determined by finding differentially expressed genes (DEGs) between IFN treated (n = 10) and untreated (n = 25) RRMS patients. Validation was performed on an additional independent group of 27 SPMS IFN treated patients by qRT-PCR. Results One hundred and four DEGs, enriched by IFN signaling pathway (p = 7.4E-08), were identified in IFN treated RRMS patients. Classification of SPMS patients based on these DEGs yielded two patient groups: (1) IFN transcriptional responders (n = 12, 60 % of SPMS treated patients) showing gene-expression profile similar to IFN treated RRMS patients; (2) IFN transcriptional non-responders (n = 8) showing expression profile similar to untreated patients. IFN transcriptional responders were characterized by a more active disease, as defined by higher EDSS progression and annual relapse rate. Conclusion Within the IFN treated SPMS population, 60 % of patients have a transcriptional response to IFN which is similar to that of RRMS patients who are IFN responders to treatment. Electronic supplementary material The online version of this article (doi:10.1186/s12883-015-0495-x) contains supplementary material, which is available to authorized users.