Approach to SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis.
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ABSTRACT:
SUBMITTER: Woopen C
PROVIDER: S-EPMC8256163 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
Publications
Approach to SARS-CoV-2 Vaccination in Patients With Multiple Sclerosis.
Woopen Christina C Schleußner Katharina K Akgün Katja K Ziemssen Tjalf T
Frontiers in immunology 20210621
For more than a year now, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been causing the coronavirus disease (COVID-19) pandemic with high mortality and detrimental effects on society, economy, and individual lives. Great hopes are being placed on vaccination as one of the most potent escape strategies from the pandemic and multiple vaccines are already in clinical use. However, there is still a lot of insecurity about the safety and efficacy of vaccines in patients with autoi ...[more]
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Project description:ObjectiveThe pandemic induced by SARS-CoV-2 has huge implications for patients with immunosuppression that is caused by disorders or specific treatments. Especially approaches targeting B cells via anti-CD20 therapy are associated with impaired humoral immune response but sustained cellular immunity. Ofatumumab is a human anti-CD20 directed antibody applied in low dosages subcutaneously, recently licensed for Multiple Sclerosis (MS). Effects of early ofatumumab treatment on alterations of immune cell composition and immune response towards SARS-CoV-2 are incompletely understood.MethodsWe here investigated immune cell alterations in early ofatumumab (Ofa) treated patients and effects on humoral (titer, neutralization capacity against wild type, Delta and Omicron) and cellular immune responses in Ofa treated MS patients following a third vaccination against SARS-CoV-2 compared to healthy controls.ResultsWe show that a mean treatment duration of three months in the Ofa group led to near complete B cell depletion in line with altered composition of certain CD4+ T cell subpopulations such as enhanced frequencies of naive and a decrease of non-suppressive regulatory T cells (Tregs). Titer and neutralization capacity against SARS-CoV-2 variants was impaired while cellular immune response was sustained, characterized by a strong T helper 1 profile (Th1).InterpretationIn summary, low dosage ofatumumab treatment elicits sustained depletion of B cells in line with alterations of immune cells, mainly Tregs. This is associated with impaired humoral immune response towards SARS-CoV-2 vaccination but preserved, Th1 driven cellular immunity adding crucial information regarding early effects of low dosage anti-CD20 therapy on humoral and cellular immunity.
| S-EPMC9471319 | biostudies-literature
Project description:BackgroundThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has tremendous implications for the management of patients with autoimmune conditions such as multiple sclerosis (MS) under immune therapies targeting CD20+ B cells (aCD20).ObjectivesHere, we investigated humoral and cellular immune responses, including anti-spike titers, neutralization against SARS-CoV-2 wild-type (WT), delta, and omicron variant and T cell responses of aCD20-treated relapsing-remitting MS patients following SARS-CoV-2 vaccination compared with healthy controls.MethodsBlood samples were collected within 4-8 weeks following the second vaccination against SARS-CoV-2. Sera were analyzed for anti-SARS-CoV-2 spike antibodies and neutralization capacity against pseudovirus for wild-type (WT), delta, and omicron variant. Peripheral blood mononuclear cells (PBMCs) were stimulated with a SARS-CoV-2 peptide pool and analyzed via flow cytometry.ResultsThe aCD20-treated MS patients had lower anti-SARS-CoV-2-spike titers, which correlated with B cell repopulation. Sera of aCD20-treated patients had reduced capacity to neutralize WT, delta, and omicron pseudoviruses in vitro. On the contrary, PBMCs of aCD20-treated patients elicited higher frequencies of CD3+ T cells and CD4+ T cells and comparable response of cytotoxic T cells, while Th1 response was reduced following restimulation with SARS-CoV-2.ConclusionIn summary, aCD20-treated patients have a reduced humoral immune response, depending on B cell repopulation, in accordance with preserved cellular immune response, suggesting partial cellular protection against SARS-CoV-2.
| S-EPMC9742512 | biostudies-literature
Project description:BackgroundThe COVID-19 pandemic outbreak raises the question of whether immunization is recommended for patients with CNS demyelinating diseases. On the one hand, existing studies suggested that SARS-CoV-2 vaccinations are not associated with increased risk of relapse activity. On the other hand, case reports with acute CNS demyelinating disease post vaccination were emerging and raising clinicians' attention.MethodsIn this longitudinal observational study, we included 556 patients with neuromyelitis optica spectrum disorder (NMOSD) and 280 patients with relapsing-remitting multiple sclerosis (RRMS). Each vaccinated patient was matched to two unvaccinated patients according to age, gender, ARR and immunotherapy status, based on propensity score matching model (PSM). The primary outcome is the short- and medium-term risk of relapse, which were evaluated by Kaplan-Meier analysis between groups.ResultsIn our cohort, 649 patients (77.6%) have not yet been vaccinated, mainly due to their concerns about relapse. After PSM, 109 vaccinated patients with NMOSD, 218 PS-matched unvaccinated patients with NMOSD, 78 vaccinated patients with RRMS, and 156 PS-matched unvaccinated patients with RRMS were included in the survival analysis to explore the safety of vaccines, with a median of 9-month follow-up. Following the first vaccination dose, 10 patients with NMOSD (9.2%) and four with RRMS (5.1%) experienced an acute relapse. Meanwhile, in the PS-matched unvaccinated group, 15 patients with NMOSD (6.9%) and 12 patients with RRMS (7.7%) presented with an acute relapse. There was no significant difference between the two curves in both NMOSD and RRMS groups over the course of the observation period. There were no significant differences in demographic characteristics, clinical characteristics, and symptoms of relapses between the vaccinated and PS-matched unvaccinated groups. Post vaccination adverse events (ADE) were reported in 39 individuals (20.9%).ConclusionOur results indicate that inactivated SARS-CoV-2 vaccines appear safe for patients with CNS demyelinating diseases.
| S-EPMC9472679 | biostudies-literature
Project description:Peripheral B cell depletion via anti-CD20 treatment is a highly effective disease-modifying treatment for reducing new relapses in multiple sclerosis (MS) patients. A drawback of rituximab (RTX) and other anti-CD20 antibodies is a poor immune response to vaccination. While this can be mitigated by treatment interruption of at least six months prior to vaccination, the timing to resume treatment while maintaining subsequent vaccine responses remains undetermined. Here, we characterized SARS-CoV-2 S-directed antibody and B cell responses throughout three BNT162b2 mRNA vaccine doses in RTX-treated MS patients, with the first two doses given during treatment interruption. We examined B-cell mediated immune responses in blood samples from patients with RTX-treated MS throughout three BNT162b2 vaccine doses, compared to an age- and sex-matched healthy control group. The first vaccine dose was given 1.3 years (median) after the last RTX infusion, the second dose one month after the first, and the third dose four weeks after treatment re-initiation. We analyzed SARS-CoV-2 S-directed antibody levels using enzyme-linked immunosorbent assay (ELISA), and the neutralization capacity of patient serum against SARS-CoV-2 S-pseudotyped lentivirus using luciferase reporter assay. In addition, we assessed switched memory (CD19+CD20+CD27+IgD-), unswitched memory (CD19+CD20+CD27+IgD+), naïve (CD19+CD20+CD27-IgD+), and double negative (DN, CD19+CD20+CD27-IgD-) B cell frequencies, as well as their SARS-CoV-2 S-specific (CoV+) and Decay Accelerating Factor-negative (DAF-) subpopulations, using flow cytometry. After two vaccine doses, S-binding antibody levels and neutralization capacity in SARS-CoV-2-naïve MS patients were comparable to vaccinated healthy controls, albeit with greater variation. Higher antibody response levels and CoV+-DN B cell frequencies after the second vaccine dose were predictive of a boost effect after the third dose, even after re-initiation of rituximab treatment. MS patients also exhibited lower frequencies of DAF- memory B cells, a suggested proxy for germinal centre activity, than control individuals. S-binding antibody levels in RTX-treated MS patients after two vaccine doses could help determine which individuals would need to move up their next vaccine booster dose or postpone their next RTX infusion. Our findings also offer first indications on the potential importance of antigenic stimulation of DN B cells and long-term impairment of germinal centre activity in rituximab-treated MS patients.
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Project description:BackgroundDisease-modifying therapies (DMT) for multiple sclerosis (MS) influence SARS-CoV-2 vaccination response, which might have implications for vaccination regimens in individual patients. Expanding the knowledge of predictors for an insufficient vaccination response as a surrogate for protection against severe disease courses of infection in people with MS (pwMS) under DMT is of great importance in identifying high-risk populations.MethodsCross-sectional analysis of vaccination titre and its modifiers, in a prospective real-world cohort of 386 individuals (285 pwMS and 101 healthy controls) by two independent immunoassays between October 2021 and June 2022.FindingsIn our cohort, no difference in vaccination antibody level was evident between healthy controls (HC) and untreated pwMS. In pwMS lymphocyte levels, times vaccinated and DMT influence SARS-CoV-2 titre following vaccination. Those treated with selective sphingosine-1-phosphate receptor modulators (S1P) showed comparable vaccination titres to untreated; higher CD8 T cell levels prior to vaccination in B cell-depleted patients resulted in increased anti-spike SARS-CoV2 antibody levels.InterpretationPwMS under DMT with anti-CD20 treatment, in particular those with decreased CD8 levels before vaccination, as well as non-selective S1P but not selective S1P are at increased risk for insufficient SARS-CoV-2 vaccination response. This argues for a close monitoring of anti-spike antibodies in order to customize individual vaccination regimens within these patients.FundingThis work was supported by the German Research Foundation (DFG, CRC-TR-128 to TU, SB, and FZ).
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Project description:ImportanceB-cell-depleting therapies may affect the development of a protective immune response following vaccination. Understanding the ability to develop vaccine-specific immunity to COVID-19 in patients with multiple sclerosis (MS) treated with B-cell-depleting therapy is of importance for clinical decisions.ObjectiveTo assess SARS-CoV-2 vaccine-specific humoral and cellular responses in patients treated with ocrelizumab compared with healthy controls.Design, setting, and participantsThis single-center study performed at Hadassah Medical Center in Jerusalem, Israel, included patients with MS treated with ocrelizumab, healthy controls, and untreated patients with MS. Vaccination occurred between December 2020 and April 2021. Participants donated blood 2 to 4 and 2 to 8 weeks after the second vaccine dose for antibody and T-cell assessments, respectively.ExposuresAll participants received 2 doses of BNT162b2 vaccine (Pfizer/BioNTech) and completed the study.Main outcomes and measuresProportion of patients treated with ocrelizumab with SARS-CoV-2-specific serology and/or T-cell responses following vaccination. All participants underwent SARS-CoV-2 antibody testing; 29 patients treated with ocrelizumab and 15 healthy controls had evaluation of SARS-CoV-2-specific T-cell responses.ResultsOf 112 participants, 49 (43.8%) had MS and were treated with ocrelizumab (33 [67.3%] female; mean [SD] age, 47.9 [13.3] years), 23 (20.5%) had MS and were not treated with disease-modifying therapies (18 [78.3%] female; mean [SD] age, 49 [13.4] years), and 40 (35.7%) were healthy controls (25 [62.5%] female; mean [SD] age, 45.3 [16] years). Twenty-six of 29 patients (89.7%) treated with ocrelizumab and 15 of 15 healthy controls (100%) had SARS-CoV-2-specific T cells following vaccination at similar levels (mean [SD], 15.4 [7.6] and 14.3 [6.3] spot-forming cells, respectively). Mean antibody titers and positive serology rate were lower in the group of patients treated with ocrelizumab (mean [SD] antibody titers and positive serology rate, 26.2 [49.2] and 376.5 [907.6] AU/mL; 10 of 40 [25%] and 20 of 49 [40.8%] for S1/S2 and receptor-binding domain, respectively) compared with healthy controls (mean [SD] antibody titers and positive serology rate, 283 [100] and 12 712 [9114] AU/mL; 100% S1/S2 and receptor-binding domain) and untreated patients (mean [SD] antibody titers and positive serology rate, 288.3 [113.8] and 10 877 [9476] AU/mL; 100% S1/S2 and receptor-binding domain), with positive association to time from ocrelizumab infusion (S1/S2: r = 0.7, P < .001; receptor-binding domain: r = 0.4, P = .04).Conclusion and relevanceIn this study, patients with MS who were treated with ocrelizumab generated comparable SARS-CoV-2-specific T-cell responses with healthy controls and had lower antibody response following vaccination. Given the potential role of T cells in protection from severe disease, this is reassuring and will help physicians develop consensus guidelines regarding MS treatment in the era of the COVID-19 pandemic.
| S-EPMC8461553 | biostudies-literature
Project description:ImportanceB-cell-depleting monoclonal antibodies are widely used for treatment of multiple sclerosis but are associated with an impaired response to vaccines.ObjectiveTo identify factors associated with a favorable vaccine response to tozinameran.Design, setting, and participantsThis prospective cohort study was conducted in a specialized multiple sclerosis clinic at a university hospital from January 21 to December 1, 2021. Of 75 patients evaluated for participation who received a diagnosis of multiple sclerosis with planned or ongoing treatment with rituximab, 69 were included in the study, and data from 67 were analyzed.ExposuresSex, age, number of previous rituximab infusions, accumulated dose of rituximab, previous COVID-19 infection, time since last rituximab treatment, CD19+ B-cell count before vaccination, CD4+ T-cell count, and CD8+ T-cell count were considered potential factors associated with the main outcome.Main outcomes and measuresSerological vaccine responses were measured by quantitation of anti-spike immunoglobulin G (IgG) antibodies, anti-receptor-binding domain (RBD) IgG antibodies, and their neutralizing capacities. Cellular responses to spike protein-derived SARS-CoV-2 peptide pools were assessed by counting interferon gamma spot-forming units in a FluoroSpot assay.ResultsAmong 60 patients with ongoing rituximab treatment (49 women [82%]; mean (SD) age, 43 [10] years), the median (range) disease duration was 9 (1-29) years, and the median (range) dose of rituximab was 2750 (500-10 000) mg during a median (range) time of 2.8 (0.5-8.3) years. The median (range) follow-up from the first vaccination dose was 7.3 (4.3-10.0) months. Vaccine responses were determined before vaccination with tozinameran and 6 weeks after vaccination. By using established cutoff values for anti-spike IgG (264 binding antibody units/mL) and anti-RBD IgG (506 binding antibody units/mL), the proportion of patients with a positive response increased with the number of B cells, which was the only factor associated with these outcomes. A cutoff for the B-cell count of at least 40/μL was associated with an optimal serological response. At this cutoff, 26 of 29 patients (90%) had positive test results for anti-spike IgG and 21 of 29 patients (72%) for anti-RBD IgG, and 27 of 29 patients (93%) developed antibodies with greater than 90% inhibition of angiotensin-converting enzyme 2. No factor associated with the cellular response was identified. Depending on the peptide pool, 21 of 25 patients (84%) to 22 of 25 patients (88%) developed a T-cell response with interferon gamma production at the B-cell count cutoff of at least 40/μL.Conclusions and relevanceThis cohort study found that for an optimal vaccine response from tozinameran, rituximab-treated patients with multiple sclerosis may be vaccinated as soon as possible, with rituximab treatment delayed until B-cell counts have reached at least 40/μL. An additional vaccination with tozinameran should be considered at that point.
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Project description:ObjectiveTo investigate the serologic response, predictors of response, and clinical outcomes associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination and infection in ozanimod-treated participants with relapsing multiple sclerosis (RMS) from DAYBREAK.MethodsDAYBREAK (ClinicalTrials.gov-NCT02576717), an open-label extension study of oral ozanimod 0.92 mg, enrolled participants aged 18-55 years with RMS who completed phase 1-3 ozanimod trials. Participants who were fully vaccinated against SARS-CoV-2 with mRNA or non-mRNA vaccines, were unvaccinated, and/or had COVID-19-related adverse events (AEs, with or without vaccination) and postvaccination serum samples were included (n = 288). Spike receptor binding domain (RBD) antibody levels (seroconversion: ≥0.8 U/mL) and serologic evidence of SARS-CoV-2 infection (nucleocapsid IgG: ≥1 U/mL) were assessed (Roche Elecsys/Cobas e411 platform).ResultsIn fully vaccinated participants (n = 148), spike RBD antibody seroconversion occurred in 90% (n = 98/109) of those without serologic evidence of prior SARS-CoV-2 exposure (100% [n = 80/80] seroconversion after mRNA vaccination) and in 100% (n = 39/39) of participants with serologic evidence of viral exposure. mRNA vaccination predicted higher spike RBD antibody levels, whereas absolute lymphocyte count (ALC), age, body mass index, and sex did not. COVID-19-related AEs were reported in 10% (n = 15/148) of fully vaccinated participants-all were nonserious and not severe; all participants recovered.InterpretationMost ozanimod-treated participants with RMS mounted a serologic response to SARS-CoV-2 vaccination and infection, regardless of participant characteristics or ALC levels. In this analysis, all COVID-19-related AEs post-full vaccination in participants taking ozanimod were nonserious and not severe.
| S-EPMC10578897 | biostudies-literature
Project description:IntroductionResponses to SARS-CoV-2 vaccination in patients with MS (pwMS) varies by disease-modifying therapies (DMTs). We perform a meta-analysis and systematic review of immune response to SARS-CoV-2 vaccines in pwMS.MethodsTwo independent reviewers searched PubMed, Google Scholar, and Embase from January 1, 2019-December 31, 2021, excluding prior SARS-CoV-2 infections. The meta-analysis of observational studies in epidemiology (MOOSE) guidelines were applied. The data were pooled using a fixed-effects model.ResultsEight-hundred sixty-four healthy controls and 2203 pwMS from 31 studies were included. Antibodies were detected in 93% healthy controls (HCs), and 77% pwMS, with >93% responses in all DMTs (interferon-beta, glatiramer acetate, cladribine, natalizumab, dimethyl fumarate, alemtuzumab, and teriflunomide) except for 72% sphingosine-1-phosphate modulators (S1PM) and 44% anti-CD20 monoclonal antibodies (mAbs). T-cell responses were detected in most anti-CD20 and decreased in S1PM. Higher antibody response was observed in mRNA vaccines (99.7% HCs) versus non-mRNA vaccines (HCs: 72% inactivated virus; pwMS: 86% vector, 59% inactivated virus). A multivariate logistic regression model to predict vaccine response demonstrated that mRNA versus non-mRNA vaccines had a 3.4 odds ratio (OR) for developing immunity in anti-CD20 (p = 0.0052) and 7.9 OR in pwMS on S1PM or CD20 mAbs (p < 0.0001). Antibody testing timing did not affect antibody detection.ConclusionAntibody responses are decreased in S1PM and anti-CD20; however, cellular responses were positive in most anti-CD20 with decreased T cell responses in S1PM. mRNA vaccines had increased seroconversion rates compared to non-RNA vaccines. Further investigation in how DMTs affect vaccine immunity are needed.
| S-EPMC9349877 | biostudies-literature