ABSTRACT
Introduction: In patients with Multiple Sclerosis (pwMS), specific disease modifying treatments (DMTs) may compromise immune response following SARS-CoV-2 vaccination. Limited information is available, whether levels of anti-SARS-CoV-2 antibodies are linked to the risk of breakthrough infections in pwMS. Objective(s): To determine the rate of Omicron breakthrough infection and severity of COVID-19 in a cohort of MS patients treated with different DMTs and to estimate the impact of SARSCoV- 2-specific antibody level on breakthrough infection risk. Method(s): This study is nested within the Swiss MS Cohort, a nationwide multicenter study that has recruited 1585 pwMS. Patients who received two doses of SARS-CoV-2 vaccines before Omicron became the dominant variant in Switzerland on Dec-15, 2021 and had a follow-up thereafter were included. Data on SARS-CoV-2 infections, severity of COVID-19 according to the WHO scale and SARS-CoV-2 vaccines were collected by questionnaires. Anti-SARS-CoV-2-S antibody levels were measured after the second vaccine dose. Incidence of infections grouped by antibody level after second vaccination was visualized using Kaplan-Meier curves. Cox regression models were used to estimate the impact of antibody levels on the hazard of breakthrough infection during follow-up. Result(s): 242 pwMS (median age 49y [39,58], 162 (67%) female, 36 (15%) with progressive disease, median EDSS 2.5 [1.5,4.0]) were included. 22 (9%) had SARS-CoV-2 infection and 137 (57%) at least one additional vaccine dose prior to Omicron start. Since then, 57 breakthrough infections were reported. Severity of breakthrough disease on WHO scale ranged from 1-10: 7 were asymptomatic, 46 were symptomatic as outpatients, 3 were hospitalized and 1 died. Patients with antibody levels >150U/ml (n = 95, 39%) after second vaccination had a 64% reduced risk for Omicron breakthrough-infection compared to patients with antibody levels <0.7U/ml (n = 81, 33%) (HR 0.36, 95%CI=0.18- 0.71, p<0.01). This effect was maintained after adjustment for DMT at vaccination and time since second vaccination Conclusion(s): Humoral immune response after second SARSCoV- 2 vaccination is associated with Omicron breakthrough infection rate, a finding contrasting general populations, where antibody levels seem to have little impact on protecting from Omicron infection. Most breakthrough infections in our cohort were mild. Analyses on the effect of booster vaccinations on serology and infection rates will follow.
ABSTRACT
Background: COVID-19 disease course in MS has been described in various cohorts. Limited data is available on humoral immune responses following SARS-CoV-2 infection and vaccination. Objectives: To determine the rate of confirmed SARS-CoV-2 infection and severity of COVID-19 in a cohort of MS patients and to quantify SARS-CoV-2-specific antibody response. Methods: The study is nested within the Swiss MS Cohort, a nationwide multicenter study that has recruited 1504 persons with MS (pwMS) since 2012. PCR-confirmed SARS-CoV-2 infections, severity of COVID-19 according to the WHO clinical progression scale and immunizations with SARS-CoV-2 vaccines were captured by questionnaires used for interviews every 6 or 12 months. Anti-SARS-CoV-2 spike protein and nucleocapsid antibody levels will be determined by electrochemiluminescence immunoassay (ECLIA) (Elecsys, Anti-SARS-CoV-2, Roche Diagnostics) in sera of all participants. Results: Between February 2021 and April 2021, study questionnaires were completed for 253 pwMS (median age 47 years, 162 female). 211 pwMS (83%) had a relapsing, 25 (10%) a secondary progressive, 13 (5%) a primary progressive disease course and 4 (2%) a clinically isolated syndrome. Median disease duration was 12 years and median EDSS was 2.5. 218 (86%) pwMS were treated with DMTs: Ocrelizumab (27%), fingolimod (26%), dimethyl fumarate (15%), rituximab (10%), natalizumab (9%), other DMTs (13%). 15 (5.9%) of 253 pwMS had a positive SARSCoV- 2 PCR test since March 2020. In these pwMS, COVID-19 severity ranged from 1-10 on the WHO clinical progression scale: 1 pwMS was asymptomatic, 10 pwMS were symptomatic as outpatients (8 independently, 2 needed assistance), 3 pwMS were hospitalized (1 without oxygen therapy, 2 with oxygen by mask or nasal prongs) and 1 pwMS died. By April 2021, 24 and 38 pwMS received one and two doses of SARS-CoV-2 mRNA vaccines, respectively. Conclusions and outlook: Since start of the pandemic, rate of PCR-confirmed SARS-CoV-2 infection in our sample was slightly lower compared to incidence of laboratory-confirmed cases in Switzerland. The majority of pwMS had mild COVID-19. The study will continue until 2024 and by ECTRIMS 2021, we anticipate a doubling of completed questionnaires and to report preliminary results of serological measurements. This will allow us to present vaccine- and natural infection induced serological anti-SARS-CoV-2 responses in pwMS and assess differences related to various DMTs or COVID-19 severity.
ABSTRACT
Introduction and Objectives: Long-term use of highly effective disease modifying treatments (DMT) can cause secondary immunodeficiency and consecutive, potentially life-threatening infectious complications. The main objective of this study is to identify factors for increased susceptibility to infections and to establish a prospective infection risk stratification tool for people with MS (pwMS). Methods: InRIMS is a monocentric, prospective, observational and comparative study, enrolling regularly followed pwMS from two cohort studies in Switzerland (SMSC and SUMMIT) since September 2019. Extending a validated infection questionnaire from the large population-based Airway Infection Susceptibility (AWIS) study, we developed an adapted survey with MS-specific items (MS-AWIS questionnaire). At baseline, all participants complete this MS-AWIS questionnaire, which allows calculating an infection risk (IR) score of weighted questionnaire items indicative for increased susceptibility to infections. In analogy to the AWIS study, IR scores ≤4, >4 to <17, and ≥17 correspond to a low, intermediate or high risk for airway infections, respectively. To assess the prognostic value of the IR score, frequency and severity of infections is prospectively recorded over two years using monthly, standardized infection diaries. In response to the SARS-COV2 pandemic, we also document cases of COVID-19 by an additive questionnaire. Results: By May 2021, 297 pwMS were enrolled in InRIMS (9 drop-outs). In a first interim-analysis we included 245 patients with baseline questionnaires (67% female, 87% under DMT, mean age of 48 years (SD ± 12,3 years), mean disease duration 13,3 years (SD ± 9,3 years), median BMI 21,5 (IQR 18,3:24,2)). The mean calculated IR score was 6,8 (SD± 5,5). 6,1% of the InRIMS study population had an IR score ≥17, which was indicative for an increased susceptibility to infections according to results of the population-based AWIS study. Discussion: The InRIMS study assesses risk factors for infections in the real world-setting of a well-defined MS cohort. In the first study phase, most participants enrolled before onset of the SARSCOV2 pandemic in Switzerland - enabling prospective infectious risk assessment. We envisage that the results of the InRIMS study will help to inform counselling of MS patients in clinical practice and support personalized treatment choices as well as preventive measures.
ABSTRACT
Background: Ofatumumab, an FDA-approved fully-human anti-CD20 monoclonal antibody with a 20 mg subcutaneous (s.c.) monthly dosing regimen, is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease. ARTIOS is a Phase 3b study exploring the treatment outcomes in relapsing MS (RMS) patients with disease activity that are switching from commonly used oral disease-modifying therapies. This patient population was relatively under-represented in the ASCLEPIOS I/II studies. Objectives: To present the innovative design of the ARTIOS study in RMS patients. Methods: ARTIOS is a single-arm, prospective, multicenter, open-label study in RMS patients aged 18-60 years with an Expanded Disability Status Scale score of 0-4 and breakthrough disease activity (defined as 1 relapse or 1 disease activity on MRI) after 6 months (m) of treatment with dimethyl fumarate or fingolimod. The study comprises of a screening and transition period (60 days), a treatment period (96 weeks) and a safety follow-up and/or extension period (9m). Ofatumumab 20 mg s.c. is self-administered monthly via an auto-injector. Treatment effectiveness (primary endpoint) will be evaluated as the annualized relapse rate over 96 weeks. Safety evaluations (secondary endpoint) include the proportion of patients with adverse events, laboratory/vital sign results meeting abnormal criteria, and treatment discontinuations. Exploratory endpoints include disability, MRI activity, no evidence of disease activity (NEDA-3) and patient-reported outcomes (MS impact, fatigue, treatment satisfaction and anxiety/depression). This innovative study design employs digital tools such as FloodlightTM (smartphone application), Actigraphy (activity-tracking watch), and an eCOA handheld for electronic diary to allow collection of data on the patient's activity (daily activity, sleep quality and injection reactions). Biomarkers of disease activity (neurofilament light chain [NfL] and glial fibrillary acidic protein [GFAP]) will also be evaluated. Results: The study plans to enroll ~550 patients across 25 countries. The first patient first visit was achieved on 14 July 2020 and study completion is expected in 2023. To account for COVID-19 associated restrictions, the original study was modified to provide more flexibility to patients visiting the clinic only to perform procedures which cannot be done at home with the support of home nurses (e.g., MRI and EDSS). An interim analysis is planned after completion of 1 year of treatment. Conclusions: The ARTIOS study will provide clinical data for the selected MS patient population that was not studied in the pivotal ofatumumab trials. ARTIOS leverages various digital technologies to collect unique and comprehensive data which may enrich treatment outcomes in this patient population.