Prolonged SARS-CoV-2 Illness in a Patient Receiving Ocrelizumab for Multiple Sclerosis.
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ABSTRACT:
SUBMITTER: Gibson EG
PROVIDER: S-EPMC8083367 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe COVID-19 epidemic raises important questions about the efficacy of vaccines for people treated with ocrelizumab, an anti-CD20 therapy. Ocrelizumab has been shown to reduce the humoral response to SARS-CoV-2 infection and vaccination, but the T-cell response to vaccination has not been fully characterized. We sought to provide data regarding B and T-cell mediated responses to SARS-CoV-2 vaccination in ocrelizumab-treated patients, and to determine what variables correlate with vaccine immunogenicity. We hypothesized that patients without a humoral response to SARS-CoV-2 vaccination would still have intact T-cell responses.MethodsWe conducted a prospective, observational, single center cohort study of patients with MS treated with either ocrelizumab or natalizumab as a comparator between March 2, 2021, and July 1, 2021. Eligible patients were age 18 to 55 and had no known prior infection with, or vaccination against, SARS-CoV-2. Patients with prior use of immunosuppressive or chemotherapeutic agents, or treatment with any anti-CD20 therapy other than ocrelizumab within 12 months of enrollment, were excluded. The Roche Elecsys anti-SARS-CoV-2 S immunoassay was performed prior to and 3-4 weeks post vaccination to evaluate the antibody response to SARS-CoV-2 spike IgG. The Adaptive Biotechnologies T-Detect COVID Test was performed to evaluate the adaptive T-cell immune response to SARS-CoV-2 in OCR-treated patients with no detectable antibodies. Data were analyzed using descriptive statistics, Fisher's exact test, and Wilcoxon rank sum.ResultsForty-eight patients were enrolled in the study, 69% treated with ocrelizumab and 31% treated with natalizumab. Eighteen percent of ocrelizumab and 100% of natalizumab patients had a positive antibody response. In ocrelizumab-treated patients, there was no correlation between age, sex, BMI, total number of infusions, immunoglobulin G, CD19, or absolute lymphocyte count and antibody response. There was a trend suggesting that a longer interval between the last infusion and vaccination increased the likelihood of producing antibodies (P = 0.062). All ocrelizumab patients with negative antibody responses had positive T-cell responses.ConclusionsTreatment with ocrelizumab substantially impaired the humoral response to SAR-CoV-2 vaccination but did not impair T-cell responses. Further research is needed to determine if the T-cell response to SARS-CoV-2 vaccination is sufficient to prevent infection or reduce severity of COVID in patients who did not produce antibodies.
| S-EPMC8575541 | biostudies-literature
Project description:BackgroundOcrelizumab maintains B-cell depletion via six-monthly dosing. Whilst this controls relapsing multiple sclerosis, it also inhibits seroconversion following SARS-CoV-2 vaccination unlike that seen following alemtuzumab and cladribine treatment. Emerging reports suggest that 1-3% B-cell repopulation facilitates seroconversion after CD20-depletion.ObjectiveTo determine the frequency of B-cell repopulation levels during and after ocrelizumab treatment.MethodsRelapse data, lymphocyte and CD19 B-cell numbers were obtained following requests to clinical trial data-repositories. Information was extracted from the phase II ocrelizumab extension (NCT00676715) trial and the phase III cladribine tablet (NCT00213135) and alemtuzumab (NCT00530348/NCT00548405) trials obtained clinical trial data requests RESULTS: Only 3-5% of people with MS exhibit 1% B-cells at 6 months after the last infusion following 3-4 cycles of ocrelizumab, compared to 50-55% at 9 months, and 85-90% at 12 months. During this time relapses occurred at consistent disease-breakthrough rates compared to people during standard therapy. In contrast most people (90-100%) exhibited more than 1% B-cells during treatment with either cladribine or alemtuzumab.ConclusionsMost people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. However, few people repopulate peripheral B-cells with standard ocrelizumab dosing. Controlled studies are warranted to examine a view that delaying the dosing interval by 3-6 months may allow more people to potentially seroconvert after vaccination.
| S-EPMC8642825 | biostudies-literature
Project description:Vaccines will play a key role in ending the COVID-19 pandemic. Vaccination against infections remains an important part of the management of patients with multiple sclerosis. However, there are limited data about the safety and efficacy of the currently available COVID-19 mRNA vaccines in patients with multiple sclerosis receiving concurrent immunosuppressive therapies. Patients on B cell depleting therapy such as ocrelizumab have an attenuated vaccine response. We report the first case of COVID-19 vaccine failure in a patient with relapsing-remitting multiple sclerosis on B cell depleting therapy, ocrelizumab. We offer suggestions to improve vaccine efficacy in these patients.
| S-EPMC8002140 | biostudies-literature
Project description:Ocrelizumab (Ocrevus®) is an intravenously administered, humanized anti-CD20 monoclonal antibody approved for the treatment of adults with relapsing forms of multiple sclerosis (RMS) or primary progressive multiple sclerosis (PPMS). The efficacy of ocrelizumab in reducing relapse rates and disease activity in patients with RMS was demonstrated in pivotal trials (versus interferon β-1a) and supporting single-arm studies in specific subpopulations. In patients with PPMS, ocrelizumab reduced measures of clinical and MRI progression relative to placebo. Clinical benefits were maintained over ≥ 7.5 study years of treatment. Ocrelizumab was generally well tolerated and no new safety signals have emerged with long-term use. Extensive (albeit short-term) real-world data pertaining to ocrelizumab is consistent with that from clinical trials. Ocrelizumab provides the convenience of short, half-yearly infusions. Ocrelizumab continues to represent a generally well-tolerated, high-efficacy disease-modifying therapy (DMT) for RMS and is a valuable treatment for delaying disease progression in patients with PPMS (for whom there are currently no other approved DMTs).
| S-EPMC8862399 | biostudies-literature
Project description:B cells play a central role in the pathogenesis of multiple sclerosis (MS): they are involved in the activation of pro-inflammatory T cells, secretion of pro-inflammatory cytokines and production of autoantibodies directed against myelin. Hence, the use of B cell-depleting monoclonal antibodies as therapy for autoimmune diseases, including MS, has increased in recent years. Previous results with rituximab, the first therapeutic B cell-depleting chimeric monoclonal antibody that showed efficacy in MS clinical trials, encouraged researchers to evaluate the efficacy of a humanized anti-CD20 antibody, ocrelizumab, in MS. A large phase II clinical trial in patients with relapsing-remitting MS (RRMS) designed to explore the effects of two doses of ocrelizumab (600 mg and 2000 mg) compared with placebo showed a pronounced effect on radiological and relapse-related outcomes. These results were confirmed in two phase III trials (OPERA I and II) that compared the efficacies of ocrelizumab with interferon beta-1a in patients with relapsing MS, and showed decreased annualized relapse rates (46% in OPERA I and 47% in OPERA II), as well as fewer numbers of gadolinium-enhanced lesions on magnetic resonance imaging (MRI) scans (94% in OPERA I and 95% in OPERA II). Notably, ocrelizumab is the first drug to lower rates of clinical and MRI-evidenced progression in patients with primary progressive MS (PPMS). The phase III trial (ORATORIO) in patients with PPMS met its primary efficacy endpoint: the percentage of patients with 12-week confirmed disability progression was significantly lower in the active treatment group (32.9%) than in patients receiving placebo (39.3%). In March 2017, this evidence led the US Food and Drug Administration to approve the licence for ocrelizumab (Ocrevus®) as a treatment for MS, as the first treatment approved for PPMS and as the first monoclonal antibody for secondary progressive MS.
| S-EPMC5952271 | biostudies-literature
Project description:Ocrelizumab, a humanized monoclonal anti-CD20 antibody, has shown pronounced effects in reduction of disease activity in multiple sclerosis (MS) patients and has recently been approved for the treatment of patients with relapsing MS (RMS) and primary progressive MS (PPMS). CD20 is mainly expressed by B cells, but a subset of T cells (CD3?CD20? T cells) also expresses CD20, and these CD20? T cells are known to be a highly activated cell population. The blood of MS patients was analyzed with multicolor flow cytometry before and two weeks after treatment with ocrelizumab regarding the phenotype of peripheral blood mononuclear cells. CD20-expressing CD3? T cells were found in blood samples of all MS patients, accounted for 2.4% of CD45? lymphocytes, and constituted a significant proportion (18.4%) of all CD20? cells. CD3?CD20? T cells and CD19?CD20? B cells were effectively depleted two weeks after a single administration of 300 mg ocrelizumab. Our results demonstrate that treatment with ocrelizumab does not exclusively target B cells, but also CD20? T cells, which account for a substantial amount of CD20-expressing cells. Thus, we speculate that the efficacy of ocrelizumab might also be mediated by the depletion of CD20-expressing T cells.
| S-EPMC6356421 | biostudies-literature
Project description:Data regarding effectiveness and safety of ocrelizumab in the post-marking setting are lacking. The aim of our study was to provide effectiveness and safety data of ocrelizumab treatment in patients with relapsing-remitting (RR-) and progressive multiple sclerosis (PMS) and to evaluate clinical and immunological predictors of early treatment response. In this single-center prospective observational study, we investigated effectiveness outcomes (time-to-confirmed disability worsening, time-to-first relapse, time-to-first evidence of MRI activity and time-to-first evidence of disease activity), clinical and immunological predictors of early treatment response, and incidence of adverse events (AEs). One hundred and fifty-three subjects were included (93 RRMS; 84 females). Median follow-up was 1.9 (1.3-2.7). At 2-year follow-up (FU), disability worsening-free survival were 90.5%, 64.7%, and 68.8% for RRMS, primary-progressive MS (PPMS), and secondary-progressive MS (SPMS) patients, respectively. At 2-year FU, 67.1%, 72.7%, and 81.3% of patients with RRMS, PPMS, and SPMS were free of MRI activity, with NEDA-3 percentages of 62.1%, 54.6%, and 55.1%, respectively. Lower baseline EDSS was independently associated with a reduced risk of disability worsening (HR(95%CI) = 1.45(1.05-2.00), p = 0.024) and previous treatment exposure was independently associated with increased probability of radiological activity (HR = 2.53(1.05-6.10), p = 0.039). At 6-month FU, CD8 + cell decrease was less pronounced in patients with inflammatory activity (p = 0.022). Six patients (3.9%) discontinued ocrelizumab due to severe AEs. Our findings suggest that ocrelizumab is an effective treatment in real-world patients with RRMS and PMS, with a manageable safety profile. Better outcomes were observed in treatment-naïve patients and in patients with a low baseline disability level. Depletion of CD8 + cells could underlie early therapeutic effects of ocrelizumab.
| S-EPMC8457546 | biostudies-literature
Project description:ObjectiveThe efficacy and safety of ocrelizumab, versus interferon (IFN) β-1a, for the treatment of relapsing multiple sclerosis (RMS) from the identically designed OPERA I (NCT01247324) and OPERA II (NCT01412333) phase III studies has been reported; here we present subgroup analyses of efficacy endpoints from the pooled OPERA I and OPERA II populations.MethodsPatients with RMS were randomized to either ocrelizumab 600 mg administered by intravenous infusion every 24 weeks or subcutaneous IFN β-1a 44 µg three times per week throughout the 96-week treatment period. Relapse, disability, and MRI outcomes were analyzed for predefined and post hoc subgroups based on demographic and disease characteristics along with prior treatment using appropriate statistical tests to determine the treatment effect in subgroups and treatment-by-subgroup interactions.ResultsThe significant treatment benefit of ocrelizumab, versus IFN β-1a, observed in the overall OPERA I and OPERA II pooled populations was maintained across most subgroup strata for all endpoints, including annualized relapse rate, disability progression, and MRI outputs.ConclusionsThe treatment effect of ocrelizumab versus IFN β-1a, measured by clinical and MRI outcomes, was maintained across most of the subgroups and strata of interest, and the pattern of treatment benefit across all subgroups was consistent with that from the pooled OPERA studies.
| S-EPMC6469695 | biostudies-literature
Project description:A multiple sclerosis patient infected by SARS-CoV-2 during fingolimod therapy was hospitalized with moderate clinical features, and recovered in 15 days. High levels of CCL5 and CCL10 chemokines and of antibody-secreting B cells were detected, while the levels other B- and T-cell subsets were comparable to that of appropriate controls. However, CD4+ and CD8+ cells were oligoclonally expanded and prone to apoptosis when stimulated in vitro. This study suggests that fingolimod-immunosuppressed patients, despite the low circulating lymphocytes, may rapidly expand antibody-secreting cells and mount an effective immune response that favors COVID-19 recovery after drug discontinuation.
| S-EPMC7256606 | biostudies-literature
Project description:ObjectiveThe objective of this study was to determine the impact of multiple sclerosis (MS) disease-modifying therapies (DMTs) on the development of cellular and humoral immunity to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection.MethodsPatients with MS aged 18 to 60 years were evaluated for anti-nucleocapsid and anti-Spike receptor-binding domain (RBD) antibody with electro-chemiluminescence immunoassay; antibody responses to Spike protein, RBD, N-terminal domain with multiepitope bead-based immunoassays (MBI); live virus immunofluorescence-based microneutralization assay; T-cell responses to SARS-CoV-2 Spike using TruCulture enzyme-linked immunosorbent assay (ELISA); and IL-2 and IFNγ ELISpot assays. Assay results were compared by DMT class. Spearman correlation and multivariate analyses were performed to examine associations between immunologic responses and infection severity.ResultsBetween January 6, 2021, and July 21, 2021, 389 patients with MS were recruited (mean age 40.3 years; 74% women; 62% non-White). Most common DMTs were ocrelizumab (OCR)-40%; natalizumab -17%, Sphingosine 1-phosphate receptor (S1P) modulators -12%; and 15% untreated. One hundred seventy-seven patients (46%) had laboratory evidence of SARS-CoV-2 infection; 130 had symptomatic infection, and 47 were asymptomatic. Antibody responses were markedly attenuated in OCR compared with other groups (p ≤0.0001). T-cell responses (IFNγ) were decreased in S1P (p = 0.03), increased in natalizumab (p <0.001), and similar in other DMTs, including OCR. Cellular and humoral responses were moderately correlated in both OCR (r = 0.45, p = 0.0002) and non-OCR (r = 0.64, p <0.0001). Immune responses did not differ by race/ethnicity. Coronavirus disease 2019 (COVID-19) clinical course was mostly non-severe and similar across DMTs; 7% (9/130) were hospitalized.InterpretationDMTs had differential effects on humoral and cellular immune responses to SARS-CoV-2 infection. Immune responses did not correlate with COVID-19 clinical severity in this relatively young and nondisabled group of patients with MS. ANN NEUROL 2022;91:782-795.
| S-EPMC9082484 | biostudies-literature