Marie Groth’s research while affiliated with Carl Gustav Carus-Institut and other places

The authors would like to make the following corrections to this published paper [...]

Booster vaccinations against SARS-CoV-2 are recommended 6–12 months after the last dose or infection in elderly and high-risk groups. The present analysis aims to evaluate whether an interval shorter than 12 months is required in multiple sclerosis patients receiving ofatumumab. Neutralizing antibody status over 1 year in patients receiving booster vaccination in the non-interventional, multicenter KYRIOS study under continued ofatumumab treatment was analyzed. Fifteen patients were included. At the time of the first booster vaccination, ten patients were seropositive for neutralizing antibodies, four patients were seronegative, and for one patient, no baseline levels were available. All patients who were seropositive at baseline showed >2-fold increase in neutralizing antibody titers after the first booster and two patients (20%) showed a >10-fold increase. Among seronegative patients, three (75%) had a >10-fold increase in neutralizing antibody titers. Seropositivity was maintained in almost all patients until month 12. One initially seronegative patient had less than 2-fold increase in neutralizing antibody titers after the booster vaccination and can be considered a non-responder. Most patients with continued ofatumumab treatment are able to maintain permanent seropositivity and therefore presumably constant protection against severe courses of COVID-19 if repeated booster vaccinations are applied.

Objective To understand the longitudinal cellular and humoral immune responses to SARS-CoV-2 mRNA vaccines depending on the timing of vaccination and siponimod treatment. Methods AMA-VACC is an open-label, three-cohort, prospective study in Germany with 41 multiple sclerosis patients currently treated with siponimod, any first-line DMT or without treatment at all. Cohort 1 received SARS-CoV-2 mRNA vaccination while continuing siponimod treatment, cohort 2 interrupted siponimod treatment for a full vaccination cycle and cohort 3 received vaccination during continuous treatment with first-line DMTs (glatiramer acetate, interferons, teriflunomide) or no current treatment. Primary endpoint is the rate of patients achieving seroconversion assessed by detection of serum neutralizing antibodies one week after SARS-CoV-2 mRNA vaccination. Furthermore, development and maintenance of SARS-CoV-2 specific T-cells is evaluated in all patients. Both parameters are analyzed in week one and month one and six after initial vaccination cycle and one month after a potential booster vaccination. Results After a positive first interim analysis showing both SARS-CoV-2 neutralizing antibodies and T-cell responses one week after complete vaccination in siponimod patients data will be available in early 2022 for all patients at week one and later time points including first booster vaccinations. Conclusions This analysis will provide first longitudinal data on the immune response after SARS-CoV-2 mRNA vaccination in siponimod treated SPMS patients and enable physicians and patients to make an informed decision on the coordination of SARS-CoV-2 mRNA vaccination and SPMS treatment.

Objective This study aims at understanding the impact of ofatumumab treatment on the development of cellular and humoral immune responses to initial and booster SARS-CoV-2 mRNA vaccines. Methods KYRIOS is an open-label, prospective, two-cohort study at eight sites in Germany including 40 MS patients who receive SARS-CoV-2 mRNA vaccination either before starting ofatumumab treatment (cohort 1) or during stable ofatumumab treatment for at least 4 weeks (cohort 2). The impact of ofatumumab treatment on the proportion of patients having established SARS-CoV-2 reactive T-cells (primary endpoint) and developing SARS-CoV-2 neutralizing antibodies (secondary endpoint) after initial and booster vaccination will be assessed. Additionally, cellular and humoral immune responses will be monitored for up to 18 months and cellular response will be further described by immunophenotyping. Results Results of this second interim analysis show the efficacy of SARS-CoV-2 mRNA vaccines to induce cellular and humoral immune responses in MS patients depending on the timing of ofatumumab treatment initiation. First data indicate that in patients vaccinated during stable ofatumumab treatment, specific immune response is detectable as soon as 1 week after the initial vaccination cycle and further increases afterwards. Conclusions KYRIOS data show for the first time that patients vaccinated during stable ofatumumab treatment can mount immune responses to SARS-CoV-2 mRNA vaccines. The presented data further emphasize the importance of considering both, humoral and cellular immune response, for interpretation of vaccine efficacy.

Background: Evidence on SARS-CoV-2 mRNA vaccination under siponimod treatment is rare. Methods: AMA-VACC is a prospective, open-label clinical study on SARS-CoV-2 mRNA vaccination during ongoing siponimod treatment (cohort 1), during siponimod interruption (cohort 2), or during treatment with other disease-modifying therapies or without therapy (cohort 3). SARS-CoV-2-specific antibodies and T-cell reactivity were measured six months after the initial vaccination and one month after the booster. Results: 41 patients were recruited into cohort 1 (n = 17), cohort 2 (n = 4), and cohort 3 (n = 20). Seroconversion for SARS-CoV-2 neutralizing antibodies was reached by 50.0%, 100.0%, and 90.0% of patients at month 6 and by 81.3%, 100.0%, and 100.0% one month after booster (cohorts 1, 2, and 3, respectively). Antibody levels in cohort 1 increased after the booster compared to month 6 but remained lower compared to cohorts 2 and 3. T-cell responses were seen in 28.5%, 25.0%, and 73.7% at month 6 and in 28.6%, 50.0%, and 83.3% after the booster (cohorts 1, 2, and 3, respectively). In cohort 1, the extent of T-cell response was lower at month 6 compared to cohorts 2 and 3 but reached almost similar levels after the booster. Conclusions: The antibody and T-cell responses support SARS-CoV-2 (booster) vaccines in siponimod-treated patients.

Background: Few data exist on how ofatumumab treatment impacts SARS-CoV-2 booster vaccination response. Methods: KYRIOS is an ongoing prospective open-label multicenter study on the response to initial and booster SARS-CoV-2 mRNA vaccination before or during ofatumumab treatment in relapsing MS patients. The results on the initial vaccination cohort have been published previously. Here, we describe 23 patients who received their initial vaccination outside of the study but booster vaccination during the study. Additionally, we report the booster results of two patients in the initial vaccination cohort. The primary endpoint was SARS-CoV-2-specific T-cell response at month 1. Furthermore, serum total and neutralizing antibodies were measured. Results: The primary endpoint was reached by 87.5% of patients with booster before (booster cohort 1, N = 8) and 46.7% of patients with booster during ofatumumab treatment (booster cohort 2, N = 15). Seroconversion rates for neutralizing antibodies increased from 87.5% at baseline to 100.0% at month 1 in booster cohort 1 and from 71.4% to 93.3% in booster cohort 2. Of note, 3 of 4 initially seronegative patients in booster cohort 2 and one seronegative patient in the initial vaccination cohort seroconverted after the booster during ofatumumab treatment. Conclusions: Booster vaccinations increase neutralizing antibody titers in ofatumumab-treated patients. A booster is recommended in ofatumumab-treated patients.

Background: It is unclear whether multiple sclerosis (MS) patients receiving ofatumumab mount an immune response after SARS-CoV-2 mRNA vaccination. Methods: KYRIOS is an ongoing, multicenter, open-label, prospective clinical study on immune responses in MS patients after initial or booster SARS-CoV-2 mRNA vaccination prior to (cohort 1) or during (cohort 2) ofatumumab treatment. We report one-week and one-month results of the initial vaccination. A comparison with patients vaccinated while receiving beta-interferon, glatiramer acetate, dimethyl fumarate, teriflunomide or no treatment was included (cohort 3). Results: In total, 11 patients received their initial vaccination during the study. The primary endpoint of SARS-CoV-2-specific T-cells at month 1 was reached by 80.0% of patients in cohort 1 (N = 6) and 100.0% in cohort 2 (N = 5). T-cell reactivity peaked at week 1. All cohort 1 patients reached seroconversion for SARS-CoV-2 neutralizing antibodies at week 1 and month 1. In cohort 2, neutralizing antibodies increased in all patients and exceeded the cut-off for seropositivity in 40.0% of patients at week 1 and 25.0% at month 1. Immune responses in cohort 3 were comparable to cohort 1. Conclusion: Presence of T-cell response and increase in levels of neutralizing antibodies, although less pronounced compared to controls, suggest that MS patients receiving ofatumumab are able to mount an immune response to SARS-CoV-2 mRNA vaccination.

Background Systematic data are lacking on the immune response toward SARS-CoV-2 mRNA vaccination in SPMS patients on disease-modifying therapies (DMTs). Objective The AMA-VACC clinical trial was designed to characterize immune responses to SARS-CoV-2 mRNA vaccines in siponimod-treated SPMS patients. Design AMA-VACC is an ongoing three-cohort, multicenter, open-label, prospective clinical study. Methods The study included patients at risk for SPMS or patients with SPMS diagnosis. Patients received SARS-CoV-2 mRNA vaccine as part of their clinical routine during ongoing siponimod treatment (cohort 1), during siponimod treatment interruption (cohort 2), or while on dimethyl fumarate, glatiramer acetate, beta-interferons, teriflunomide, or no current therapy (cohort 3). SARS-CoV-2-specific neutralizing antibodies and T-cell responses were measured 1 week and 1 month after the second dose of vaccination. Results In total, 17 patients, 4 patients, and 20 patients were recruited into cohorts 1, 2, and 3, respectively. The primary endpoint of seroconversion for SARS-CoV-2-neutralizing antibodies at week 1 was reached by 52.9%, 75.0%, and 90.0% of patients in cohorts 1, 2, and 3, respectively. For 64.7% of patients in cohort 1, all patients in cohort 2, and 95% of patients in cohort 3, seroconversion was observed at either week 1 or month 1 or both time points. After 1 week, 71.4% of cohort 1, 75.0% of cohort 2, and 85.0% of cohort 3 were positive for either SARS-CoV-2-neutralizing antibodies or SARS-CoV-2-specific T-cells or both. After 1 month, the rates were 56.3%, 100.0%, and 95.0%, respectively. Conclusion The study shows that the majority of siponimod patients mount humoral and cellular immune response under continuous siponimod treatment. The data do not sufficiently support interruption of treatment for the purpose of vaccination. Registration EU Clinical Trials Register: EudraCT 2020-005752-38 ( www.clinicaltrialsregister.eu ); ClinicalTrials.gov: NCT04792567 ( https://clinicaltrials.gov ).