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1.
Neurol Neuroimmunol Neuroinflamm ; 9(1)2022 01.
Article in English | MEDLINE | ID: covidwho-1928237

ABSTRACT

BACKGROUND AND OBJECTIVES: It is unclear how multiple sclerosis (MS) affects the severity of COVID-19. The aim of this study is to compare COVID-19-related outcomes collected in an Italian cohort of patients with MS with the outcomes expected in the age- and sex-matched Italian population. METHODS: Hospitalization, intensive care unit (ICU) admission, and death after COVID-19 diagnosis of 1,362 patients with MS were compared with the age- and sex-matched Italian population in a retrospective observational case-cohort study with population-based control. The observed vs the expected events were compared in the whole MS cohort and in different subgroups (higher risk: Expanded Disability Status Scale [EDSS] score > 3 or at least 1 comorbidity, lower risk: EDSS score ≤ 3 and no comorbidities) by the χ2 test, and the risk excess was quantified by risk ratios (RRs). RESULTS: The risk of severe events was about twice the risk in the age- and sex-matched Italian population: RR = 2.12 for hospitalization (p < 0.001), RR = 2.19 for ICU admission (p < 0.001), and RR = 2.43 for death (p < 0.001). The excess of risk was confined to the higher-risk group (n = 553). In lower-risk patients (n = 809), the rate of events was close to that of the Italian age- and sex-matched population (RR = 1.12 for hospitalization, RR = 1.52 for ICU admission, and RR = 1.19 for death). In the lower-risk group, an increased hospitalization risk was detected in patients on anti-CD20 (RR = 3.03, p = 0.005), whereas a decrease was detected in patients on interferon (0 observed vs 4 expected events, p = 0.04). DISCUSSION: Overall, the MS cohort had a risk of severe events that is twice the risk than the age- and sex-matched Italian population. This excess of risk is mainly explained by the EDSS score and comorbidities, whereas a residual increase of hospitalization risk was observed in patients on anti-CD20 therapies and a decrease in people on interferon.


Subject(s)
COVID-19/epidemiology , COVID-19/physiopathology , Multiple Sclerosis/epidemiology , Adult , COVID-19/immunology , COVID-19/therapy , Cohort Studies , Comorbidity , Female , Hospitalization/statistics & numerical data , Humans , Intensive Care Units/statistics & numerical data , Italy/epidemiology , Male , Middle Aged , Multiple Sclerosis/immunology , Multiple Sclerosis/physiopathology , Retrospective Studies , Risk Factors , Severity of Illness Index
2.
Neurol Neuroimmunol Neuroinflamm ; 9(4)2022 07.
Article in English | MEDLINE | ID: covidwho-1833441

ABSTRACT

OBJECTIVES: To evaluate whether a third vaccination shows an added effect on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) T-cell responses in patients with multiple sclerosis treated with ocrelizumab or fingolimod. METHODS: This is a substudy of a prospective multicenter study on SARS-CoV-2 vaccination in patients with immune-mediated diseases. Patients with MS treated with ocrelizumab, fingolimod, and no disease-modifying therapies and healthy controls were included. The number of interferon (IFN)-γ secreting SARS-CoV-2-specific T cells at multiple time points before and after 3 SARS-CoV-2 vaccinations were evaluated. RESULTS: In ocrelizumab-treated patients (N = 24), IFN-γ-producing SARS-CoV-2-specific T-cell responses were induced after 2 vaccinations with median levels comparable to healthy controls (N = 12) and patients with MS without disease-modifying therapies (N = 10). A third vaccination in ocrelizumab-treated patients (N = 8) boosted T-cell responses that had declined after the second vaccination, but did not lead to higher overall T-cell responses as compared to immediately after a second vaccination. In fingolimod-treated patients, no SARS-CoV-2-specific T cells were detected after second (N = 12) and third (N = 9) vaccinations. DISCUSSION: In ocrelizumab-treated patients with MS, a third SARS-CoV-2 vaccination had no additive effect on the maximal T-cell response but did induce a boost response. In fingolimod-treated patients, no T-cell responses could be detected following both a second and third SARS-CoV-2 vaccination.


Subject(s)
COVID-19 Vaccines , COVID-19 , Immunity, Cellular , Multiple Sclerosis , T-Lymphocytes , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Fingolimod Hydrochloride/therapeutic use , Humans , Immunization, Secondary , Interferon-gamma , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Prospective Studies , SARS-CoV-2 , T-Lymphocytes/immunology , Vaccination
3.
Neurol Neuroimmunol Neuroinflamm ; 9(2)2022 03.
Article in English | MEDLINE | ID: covidwho-1745397

ABSTRACT

BACKGROUND AND OBJECTIVES: Information about humoral and cellular responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and antibody persistence in convalescent (COVID-19) patients with multiple sclerosis (PwMS) is scarce. The objectives of this study were to investigate factors influencing humoral and cellular responses to SARS-CoV-2 and its persistence in convalescent COVID-19 PwMS. METHODS: This is a retrospective study of confirmed COVID-19 convalescent PwMS identified between February 2020 and May 2021 by SARS-CoV-2 antibody testing. We examined relationships between demographics, MS characteristics, disease-modifying therapy (DMT), and humoral (immunoglobulin G against spike and nucleocapsid proteins) and cellular (interferon-gamma [IFN-γ]) responses to SARS-CoV-2. RESULTS: A total of 121 (83.45%) of 145 PwMS were seropositive, and 25/42 (59.5%) presented a cellular response up to 13.1 months after COVID-19. Anti-CD20-treated patients had lower antibody titers than those under other DMTs (p < 0.001), but severe COVID-19 and a longer time from last infusion increased the likelihood of producing a humoral response. IFN-γ levels did not differ among DMT. Five of 7 (71.4%) anti--CD20-treated seronegative patients had a cellular response. The humoral response persisted for more than 6 months in 41/56(81.13%) PwMS. In multivariate analysis, seropositivity decreased due to anti-CD20 therapy (OR 0.08 [95% CI 0.01-0.55]) and increased in males (OR 3.59 [1.02-12.68]), whereas the cellular response decreased in those with progressive disease (OR 0.04 [0.001-0.88]). No factors were associated with antibody persistence. DISCUSSION: Humoral and cellular responses to SARS-CoV-2 are present in COVID-19 convalescent PwMS up to 13.10 months after COVID-19. The humoral response decreases under anti-CD20 treatment, although the cellular response can be detected in anti-CD20-treated patients, even in the absence of antibodies.


Subject(s)
COVID-19/immunology , Immunity, Cellular , Immunity, Humoral , Multiple Sclerosis/immunology , Adult , Aged , Antibodies, Viral/analysis , Antigens, CD20/immunology , COVID-19/complications , Female , Humans , Immunoglobulin G/analysis , Interferon-gamma/biosynthesis , Interferon-gamma/immunology , Male , Middle Aged , Multiple Sclerosis/complications , Nucleocapsid/chemistry , Nucleocapsid/immunology , Retrospective Studies
4.
J Neuroimmunol ; 362: 577788, 2022 01 15.
Article in English | MEDLINE | ID: covidwho-1720452

ABSTRACT

OBJECTIVES: To report clinical outcome, development of humoral and T-cell mediated immunity in convalescent COVID-19 people with multiple sclerosis (pwMS) treated with ofatumumab in the ALITHIOS study from a single center. METHODS: Testing for SARS-Cov2 IgG antibodies was performed on two occasions with at least three months apart between the two testing. During the second antibody testing, interferon-γ ELISpot was used to assess cellular immunity. RESULTS: All four subjects had mild COVID-19 infection without any sequelae. In all subjects except subject 2, COVID-19 was confirmed with PCR. Subjects 1, 2 and 4 had normal levels of IgM and IgG without measurable counts of CD19 cells prior to COVID-19. Subject 3 administered the last dose of ofatumumab 24 days prior to COVID-19 symptoms, but had a gap of 28 weeks of ofatumumab application beforehand due to low IgM levels. Subject 4 received COVID-19 vaccinations before second testing, so second testing and T-cell immunity testing were not performed. Subjects who were CD19 depleted did not had measurable levels of SARS-Cov2 IgG antibodies. Subject 3 had first and second SARS-COV2 titer of 118 U/ml and > 250 U/ml, respectively. All three pwMS showed T cell immunity against SARS-CoV-2. Quotient of basal spots divided by interferon-γ secreting spot forming units were 4, 8 and 14.7 SI in subjects 1, 2 and 3, respectively (>3 considered reactive). CONCLUSION: While no antibody response was observed in pwMS who were CD19+ lymphocyte depleted, T cell immunity against SARS-CoV-2 was observed in all three pwMS treated with ofatumumab.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/immunology , Multiple Sclerosis/complications , Multiple Sclerosis/immunology , Adult , Antibodies, Viral/blood , COVID-19/complications , Clinical Trials, Phase III as Topic , Female , Humans , Immunity, Cellular/immunology , Immunity, Humoral/immunology , Male
5.
JCI Insight ; 7(4)2022 02 22.
Article in English | MEDLINE | ID: covidwho-1701616

ABSTRACT

BACKGROUNDVaccine-elicited adaptive immunity is a prerequisite for control of SARS-CoV-2 infection. Multiple sclerosis (MS) disease-modifying therapies (DMTs) differentially target humoral and cellular immunity. A comprehensive comparison of the effects of MS DMTs on SARS-CoV-2 vaccine-specific immunity is needed, including quantitative and functional B and T cell responses.METHODSSpike-specific Ab and T cell responses were measured before and following SARS-CoV-2 vaccination in a cohort of 80 study participants, including healthy controls and patients with MS in 6 DMT groups: untreated and treated with glatiramer acetate (GA), dimethyl fumarate (DMF), natalizumab (NTZ), sphingosine-1-phosphate (S1P) receptor modulators, and anti-CD20 mAbs. Anti-spike-Ab responses were assessed by Luminex assay, VirScan, and pseudovirus neutralization. Spike-specific CD4+ and CD8+ T cell responses were characterized by activation-induced marker and cytokine expression and tetramer.RESULTSAnti-spike IgG levels were similar between healthy control participants and patients with untreated MS and those receiving GA, DMF, or NTZ but were reduced in anti-CD20 mAb- and S1P-treated patients. Anti-spike seropositivity in anti-CD20 mAb-treated patients was correlated with CD19+ B cell levels and inversely correlated with cumulative treatment duration. Spike epitope reactivity and pseudovirus neutralization were reduced in anti-CD20 mAb- and S1P-treated patients. Spike-specific CD4+ and CD8+ T cell reactivity remained robust across all groups, except in S1P-treated patients, in whom postvaccine CD4+ T cell responses were attenuated.CONCLUSIONThese findings from a large cohort of patients with MS exposed to a wide spectrum of MS immunotherapies have important implications for treatment-specific COVID-19 clinical guidelines.FUNDINGNIH grants 1K08NS107619, K08NS096117, R01AI159260, R01NS092835, R01AI131624, and R21NS108159; NMSS grants TA-1903-33713 and RG1701-26628; Westridge Foundation; Chan Zuckerberg Biohub; Maisin Foundation.


Subject(s)
Antibodies, Viral/biosynthesis , COVID-19 Vaccines/immunology , Multiple Sclerosis/therapy , SARS-CoV-2/immunology , T-Lymphocytes/immunology , Antibodies, Viral/immunology , Humans , Multiple Sclerosis/immunology
6.
Neurol Neuroimmunol Neuroinflamm ; 9(1)2022 01.
Article in English | MEDLINE | ID: covidwho-1591928

ABSTRACT

BACKGROUND AND OBJECTIVES: There are limited data on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine reactogenicity in persons with multiple sclerosis (PwMS) and how reactogenicity is affected by disease-modifying therapies (DMTs). The objective of this retrospective cross-sectional study was to generate real-world multiple sclerosis-specific vaccine safety information, particularly in the context of specific DMTs, and provide information to mitigate specific concerns in vaccine hesitant PwMS. METHODS: Between 3/2021 and 6/2021, participants in iConquerMS, an online people-powered research network, reported SARS-CoV-2 vaccines, experiences of local (itch, pain, redness, swelling, or warmth at injection site) and systemic (fever, chills, fatigue, headache, joint pain, malaise, muscle ache, nausea, allergic, and other) reactions within 24 hours (none, mild, moderate, and severe), DMT use, and other attributes. Multivariable models characterized associations between clinical factors and reactogenicity. RESULTS: In 719 PwMS, 64% reported experiencing a reaction after their first vaccination shot, and 17% reported a severe reaction. The most common reactions were pain at injection site (54%), fatigue (34%), headache (28%), and malaise (21%). Younger age, being female, prior SARS-CoV-2 infection, and receiving the ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vs BNT162b2 (Pfizer-BioNTech) vaccine were associated with experiencing a reaction after the first vaccine dose. Similar relationships were observed for a severe reaction, including higher odds of reactions among PwMS with more physical impairment and lower odds of reactions for PwMS on an alpha4-integrin blocker or sphingosine-1-phosphate receptor modulator. In 442 PwMS who received their second vaccination shot, 74% reported experiencing a reaction, whereas 22% reported a severe reaction. Reaction profiles after the second shot were similar to those reported after the first shot. Younger PwMS and those who received the mRNA-1273 (Moderna) vs BNT162b2 vaccine reported higher reactogenicity after the second shot, whereas those on a sphingosine-1-phosphate receptor modulator or fumarate were significantly less likely to report a reaction. DISCUSSION: SARS-CoV-2 vaccine reactogenicity profiles and the associated factors in this convenience sample of PwMS appear similar to those reported in the general population. PwMS on specific DMTs were less likely to report vaccine reactions. Overall, the short-term vaccine reactions experienced in the study population were mostly self-limiting, including pain at the injection site, fatigue, headache, and fever.


Subject(s)
COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , COVID-19/complications , COVID-19/immunology , Immunogenicity, Vaccine/immunology , Multiple Sclerosis/complications , Multiple Sclerosis/immunology , Adult , Aged , COVID-19/prevention & control , COVID-19/virology , Cross-Sectional Studies , Female , Humans , Immunization, Secondary/adverse effects , Internet , Male , Middle Aged , Multiple Sclerosis/virology , Retrospective Studies , SARS-CoV-2/immunology , SARS-CoV-2/pathogenicity , Surveys and Questionnaires , Vaccination/adverse effects , Vaccination/statistics & numerical data
7.
Proc Natl Acad Sci U S A ; 118(51)2021 12 21.
Article in English | MEDLINE | ID: covidwho-1573990

ABSTRACT

The positive impact of meditation on human well-being is well documented, yet its molecular mechanisms are incompletely understood. We applied a comprehensive systems biology approach starting with whole-blood gene expression profiling combined with multilevel bioinformatic analyses to characterize the coexpression, transcriptional, and protein-protein interaction networks to identify a meditation-specific core network after an advanced 8-d Inner Engineering retreat program. We found the response to oxidative stress, detoxification, and cell cycle regulation pathways were down-regulated after meditation. Strikingly, 220 genes directly associated with immune response, including 68 genes related to interferon signaling, were up-regulated, with no significant expression changes in the inflammatory genes. This robust meditation-specific immune response network is significantly dysregulated in multiple sclerosis and severe COVID-19 patients. The work provides a foundation for understanding the effect of meditation and suggests that meditation as a behavioral intervention can voluntarily and nonpharmacologically improve the immune response for treating various conditions associated with excessive or persistent inflammation with a dampened immune system profile.


Subject(s)
Immune System/metabolism , Meditation , Transcriptome , Adult , COVID-19/immunology , COVID-19/metabolism , Diet, Vegan , Female , Genome, Human , Humans , Male , Multiple Sclerosis/immunology , Multiple Sclerosis/metabolism , Protein Interaction Maps
8.
J Steroid Biochem Mol Biol ; 213: 105957, 2021 10.
Article in English | MEDLINE | ID: covidwho-1561628

ABSTRACT

This review examines the beneficial effects of ultraviolet radiation on systemic autoimmune diseases, including multiple sclerosis and type I diabetes, where the epidemiological evidence for the vitamin D-independent effects of sunlight is most apparent. Ultraviolet radiation, in addition to its role in the synthesis of vitamin D, stimulates anti-inflammatory pathways, alters the composition of dendritic cells, T cells, and T regulatory cells, and induces nitric oxide synthase and heme oxygenase metabolic pathways, which may directly or indirectly mitigate disease progression and susceptibility. Recent work has also explored how the immune-modulating functions of ultraviolet radiation affect type II diabetes, cancer, and the current global pandemic caused by SARS-CoV-2. These diseases are particularly important amidst global changes in lifestyle that result in unhealthy eating, increased sedentary habits, and alcohol and tobacco consumption. Compelling epidemiological data shows increased ultraviolet radiation associated with reduced rates of certain cancers, such as colorectal cancer, breast cancer, non-Hodgkins lymphoma, and ultraviolet radiation exposure correlated with susceptibility and mortality rates of COVID-19. Therefore, understanding the effects of ultraviolet radiation on both vitamin D-dependent and -independent pathways is necessary to understand how they influence the course of many human diseases.


Subject(s)
COVID-19/prevention & control , Diabetes Mellitus, Type 1/prevention & control , Diabetes Mellitus, Type 2/prevention & control , Multiple Sclerosis/prevention & control , Neoplasms/prevention & control , Sunlight , Vitamin D/metabolism , Alcohol Drinking/adverse effects , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Dendritic Cells/immunology , Dendritic Cells/radiation effects , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , Diabetes Mellitus, Type 2/immunology , Diabetes Mellitus, Type 2/pathology , Disease Progression , Disease Susceptibility , Heme Oxygenase (Decyclizing)/genetics , Heme Oxygenase (Decyclizing)/immunology , Humans , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Neoplasms/immunology , Neoplasms/pathology , Nitric Oxide Synthase/genetics , Nitric Oxide Synthase/immunology , SARS-CoV-2/pathogenicity , SARS-CoV-2/radiation effects , Sedentary Behavior , T-Lymphocytes/immunology , T-Lymphocytes/radiation effects , Vitamin D/immunology
9.
Nat Med ; 27(11): 1990-2001, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526094

ABSTRACT

SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19. However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients. We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination. Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination. Treatment with aCD20 skewed responses, compromising circulating follicular helper T (TFH) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (TH1) cell priming. Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating TFH responses and more robust CD8 T cell responses. These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.


Subject(s)
COVID-19 Vaccines/therapeutic use , Multiple Sclerosis/immunology , Multiple Sclerosis/therapy , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/analysis , Antibodies, Viral/blood , Antigens, CD20/immunology , COVID-19/prevention & control , Case-Control Studies , Chlorocebus aethiops , HEK293 Cells , Humans , Immunity, Cellular , Immunity, Humoral/drug effects , Immunity, Humoral/physiology , Immunotherapy/methods , Longitudinal Studies , Multiple Sclerosis/blood , RNA, Messenger/immunology , RNA, Viral/immunology , Rituximab/pharmacology , Rituximab/therapeutic use , SARS-CoV-2/genetics , Vaccination , Vero Cells
10.
Ann Neurol ; 91(1): 89-100, 2022 01.
Article in English | MEDLINE | ID: covidwho-1479378

ABSTRACT

OBJECTIVE: The purpose of this study was to investigate the effect of disease modifying therapies on immune response to severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines in people with multiple sclerosis (MS). METHODS: Four hundred seventy-three people with MS provided one or more dried blood spot samples. Information about coronavirus disease 2019 (COVID-19) and vaccine history, medical, and drug history were extracted from questionnaires and medical records. Dried blood spots were eluted and tested for antibodies to SARS-CoV-2. Antibody titers were partitioned into tertiles with people on no disease modifying therapy as a reference. We calculated the odds ratio of seroconversion (univariate logistic regression) and compared quantitative vaccine response (Kruskal Wallis) following the SARS-CoV-2 vaccine according to disease modifying therapy. We used regression modeling to explore the effect of vaccine timing, treatment duration, age, vaccine type, and lymphocyte count on vaccine response. RESULTS: Compared to no disease modifying therapy, the use of anti-CD20 monoclonal antibodies (odds ratio = 0.03, 95% confidence interval [CI] = 0.01-0.06, p < 0.001) and fingolimod (odds ratio = 0.04; 95% CI = 0.01-0.12) were associated with lower seroconversion following the SARS-CoV-2 vaccine. All other drugs did not differ significantly from the untreated cohort. Both time since last anti-CD20 treatment and total time on treatment were significantly associated with the response to the vaccination. The vaccine type significantly predicted seroconversion, but not in those on anti-CD20 medications. Preliminary data on cellular T-cell immunity showed 40% of seronegative subjects had measurable anti-SARS-CoV-2 T cell responses. INTERPRETATION: Some disease modifying therapies convey risk of attenuated serological response to SARS-CoV-2 vaccination in people with MS. We provide recommendations for the practical management of this patient group. ANN NEUROL 20219999:n/a-n/a.


Subject(s)
Antirheumatic Agents/therapeutic use , COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunocompromised Host , Multiple Sclerosis/immunology , Seroconversion/drug effects , Adult , Antibodies, Viral/blood , Antibodies, Viral/drug effects , Female , Humans , Male , Middle Aged , Multiple Sclerosis/drug therapy , SARS-CoV-2 , United Kingdom
11.
J Neuroimmunol ; 361: 577755, 2021 12 15.
Article in English | MEDLINE | ID: covidwho-1472063

ABSTRACT

Vaccine administration may be involved in the development of some central nervous system demyelinating diseases. The COVID-19 vaccine is being administered to the entire population, but to date, little association between vaccination and the risk of developing multiple sclerosis (MS) has been suggested, and only a few case reports have been published. Here, we present a 40-year-old woman who developed cervical myelitis after receiving the COVID-19 vaccine. Myelitis was considered the initial clinical manifestation of MS. Our case suggests a possible link between the vaccination and the clinical MS attack.


Subject(s)
/adverse effects , COVID-19/prevention & control , Multiple Sclerosis/immunology , Adult , Facial Paralysis/complications , Female , Humans , Myelitis/immunology , SARS-CoV-2
12.
Diabetes Metab Res Rev ; 38(1): e3505, 2022 01.
Article in English | MEDLINE | ID: covidwho-1469447

ABSTRACT

Multiple sclerosis (MS) and type 1 diabetes (T1D) are chronic conditions that result from dysfunction of the immune system. Their common root in autoimmunity stimulates interest in the exploration of similarities and differences between the two diseases. Genetic susceptibility is relevant, creating a substrate, on which environmental factors act as a trigger of an aberrant immune response. Despite being both T-cell mediated disorders with a strong involvement of the humoral arm, immunomodulation is a mainstay of MS management, whereas hormone replacement therapy remains the principal approach for T1D. T1D is usually diagnosed in children and adolescents, while MS is typical of young adults. This difference has implications for disease progression and treatment. The SARS-CoV-2 pandemic and its effect on immunity may affect the prevalence of these conditions, as well as their clinical manifestation.


Subject(s)
Diabetes Mellitus, Type 1 , Multiple Sclerosis , COVID-19/epidemiology , COVID-19/immunology , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/immunology , Humans , Multiple Sclerosis/epidemiology , Multiple Sclerosis/immunology , Pandemics
13.
Front Immunol ; 12: 755333, 2021.
Article in English | MEDLINE | ID: covidwho-1468345

ABSTRACT

Current knowledge on Multiple Sclerosis (MS) etiopathogenesis encompasses complex interactions between the host's genetic background and several environmental factors that result in dysimmunity against the central nervous system. An old-aged association exists between MS and viral infections, capable of triggering and sustaining neuroinflammation through direct and indirect mechanisms. The novel Coronavirus, SARS-CoV-2, has a remarkable, and still not fully understood, impact on the immune system: the occurrence and severity of both acute COVID-19 and post-infectious chronic illness (long COVID-19) largely depends on the host's response to the infection, that echoes several aspects of MS pathobiology. Furthermore, other MS-associated viruses, such as the Epstein-Barr Virus (EBV) and Human Endogenous Retroviruses (HERVs), may enhance a mechanistic interplay with the novel Coronavirus, with the potential to interfere in MS natural history. Studies on COVID-19 in people with MS have helped clinicians in adjusting therapeutic strategies during the pandemic; similar efforts are being made for SARS-CoV-2 vaccination campaigns. In this Review, we look over 18 months of SARS-CoV-2 pandemic from the perspective of MS: we dissect neuroinflammatory and demyelinating mechanisms associated with COVID-19, summarize pathophysiological crossroads between MS and SARS-CoV-2 infection, and discuss present evidence on COVID-19 and its vaccination in people with MS.


Subject(s)
COVID-19/immunology , Multiple Sclerosis/immunology , SARS-CoV-2/immunology , Animals , COVID-19/epidemiology , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Host-Pathogen Interactions , Humans , Multiple Sclerosis/epidemiology , Multiple Sclerosis/virology , Prognosis , Risk Factors , SARS-CoV-2/pathogenicity , Vaccination
14.
J Neuroimmunol ; 361: 577746, 2021 12 15.
Article in English | MEDLINE | ID: covidwho-1458508

ABSTRACT

Appropriate immune response following COVID-19 vaccination is important in the context of disease-modifying treatments (DMTs). In a prospective cross-sectional study, we determined SARS-COV-2 IgG response up to 6 months following PfizerBNT162b2 vaccination in 414 multiple sclerosis (MS) patients and 89 healthy subjects. Protective response was demonstrated in untreated MS patients (N = 76, 100%), treated with Cladribine (N = 48, 100%), Dimethyl fumarate (N = 35, 100%), Natalizumab (N = 32, 100%), and Teriflunomide (N = 39, 100%), similarly to healthy subjects (N = 89, 97.8%). Response was decreased in Fingolimod (N = 42, 9.5%), Ocrelizumab (N = 114, 22.8%) and Alemtuzumab (N = 22, 86.4%) treated patients. IgG response can help tailor adequate vaccine guidelines for MS patients under various DMTs.


Subject(s)
Antibodies, Viral/blood , COVID-19/prevention & control , Immunity, Humoral/immunology , Multiple Sclerosis/immunology , Adult , Antirheumatic Agents/therapeutic use , Cross-Sectional Studies , Female , Humans , Immunoglobulin G/blood , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Multiple Sclerosis/drug therapy , Prospective Studies , SARS-CoV-2
15.
J Clin Invest ; 131(11)2021 06 01.
Article in English | MEDLINE | ID: covidwho-1448082

ABSTRACT

First administered to a human subject as a tuberculosis (TB) vaccine on July 18, 1921, Bacillus Calmette-Guérin (BCG) has a long history of use for the prevention of TB and later the immunotherapy of bladder cancer. For TB prevention, BCG is given to infants born globally across over 180 countries and has been in use since the late 1920s. With about 352 million BCG doses procured annually and tens of billions of doses having been administered over the past century, it is estimated to be the most widely used vaccine in human history. While its roles for TB prevention and bladder cancer immunotherapy are widely appreciated, over the past century, BCG has been also studied for nontraditional purposes, which include (a) prevention of viral infections and nontuberculous mycobacterial infections, (b) cancer immunotherapy aside from bladder cancer, and (c) immunologic diseases, including multiple sclerosis, type 1 diabetes, and atopic diseases. The basis for these heterologous effects lies in the ability of BCG to alter immunologic set points via heterologous T cell immunity, as well as epigenetic and metabolomic changes in innate immune cells, a process called "trained immunity." In this Review, we provide an overview of what is known regarding the trained immunity mechanism of heterologous protection, and we describe the current knowledge base for these nontraditional uses of BCG.


Subject(s)
Diabetes Mellitus, Type 1/therapy , Immunity, Cellular , Multiple Sclerosis/therapy , Mycobacterium bovis/immunology , T-Lymphocytes/immunology , Urinary Bladder Neoplasms/therapy , Virus Diseases/therapy , Animals , Diabetes Mellitus, Type 1/history , Diabetes Mellitus, Type 1/immunology , Diabetes Mellitus, Type 1/pathology , History, 20th Century , History, 21st Century , Humans , Multiple Sclerosis/history , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Mycobacterium Infections, Nontuberculous/history , Mycobacterium Infections, Nontuberculous/immunology , Mycobacterium Infections, Nontuberculous/pathology , Mycobacterium Infections, Nontuberculous/prevention & control , Tuberculosis/history , Tuberculosis/immunology , Tuberculosis/prevention & control , Urinary Bladder Neoplasms/history , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/pathology , Virus Diseases/history , Virus Diseases/immunology , Virus Diseases/pathology
17.
JAMA Neurol ; 78(12): 1510-1514, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1432341

ABSTRACT

Importance: B-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. Objective: To assess SARS-CoV-2 vaccine-specific humoral and cellular responses in patients treated with ocrelizumab compared with healthy controls. Design, Setting, and Participants: This 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. Exposures: All participants received 2 doses of BNT162b2 vaccine (Pfizer/BioNTech) and completed the study. Main Outcomes and Measures: Proportion 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. Results: Of 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 Relevance: In 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.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , COVID-19 Vaccines/immunology , Immunity, Humoral/immunology , Immunologic Factors/adverse effects , Multiple Sclerosis/immunology , T-Lymphocytes/immunology , Adult , Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/immunology , COVID-19/prevention & control , Female , Humans , Immunologic Factors/therapeutic use , Lymphocyte Count , Male , Middle Aged , Multiple Sclerosis/drug therapy
18.
Biomolecules ; 11(9)2021 09 17.
Article in English | MEDLINE | ID: covidwho-1430768

ABSTRACT

A growing body of evidence initially suggested that patients with multiple sclerosis (MS) might be more susceptible to coronavirus disease 2019 (COVID-19). Moreover, it was speculated that patients with MS treated with immunosuppressive drugs might be at risk to develop a severe diseases course after infection with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV2). However, the recently published data have shown that MS patients do not have a higher risk for severe COVID-19. Although there is no indication that patients with MS and immunomodulatory/immunosuppressive therapy are generally at a higher risk of severe COVID-19, it is currently being emphasized that the hazards of poorly treated MS may outweigh the putative COVID-19 dangers. In this review, we discuss the challenges and considerations for MS patients in the COVID-19 pandemic.


Subject(s)
COVID-19/epidemiology , Immunosuppressive Agents/therapeutic use , Immunotherapy , Multiple Sclerosis , Pandemics , SARS-CoV-2 , Humans , Immunosuppressive Agents/adverse effects , Multiple Sclerosis/immunology , Multiple Sclerosis/therapy
19.
Nat Med ; 27(11): 1990-2001, 2021 11.
Article in English | MEDLINE | ID: covidwho-1410406

ABSTRACT

SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19. However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients. We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination. Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination. Treatment with aCD20 skewed responses, compromising circulating follicular helper T (TFH) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (TH1) cell priming. Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating TFH responses and more robust CD8 T cell responses. These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.


Subject(s)
COVID-19 Vaccines/therapeutic use , Multiple Sclerosis/immunology , Multiple Sclerosis/therapy , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/analysis , Antibodies, Viral/blood , Antigens, CD20/immunology , COVID-19/prevention & control , Case-Control Studies , Chlorocebus aethiops , HEK293 Cells , Humans , Immunity, Cellular , Immunity, Humoral/drug effects , Immunity, Humoral/physiology , Immunotherapy/methods , Longitudinal Studies , Multiple Sclerosis/blood , RNA, Messenger/immunology , RNA, Viral/immunology , Rituximab/pharmacology , Rituximab/therapeutic use , SARS-CoV-2/genetics , Vaccination , Vero Cells
20.
Neurol Neuroimmunol Neuroinflamm ; 8(6)2021 11.
Article in English | MEDLINE | ID: covidwho-1403284

ABSTRACT

Bruton tyrosine kinase inhibitors (BTKis) encompass a new class of therapeutics currently being evaluated for the treatment of multiple sclerosis (MS). Whether BTKis affect COVID-19 risk or severity or reduce vaccine efficacy are important but unanswered questions. Here, we provide an overview on BTKi mechanisms relevant to COVID-19 infection and vaccination and review preliminary data on BTKi use in patients with COVID-19. BTKis block B-cell receptor- and myeloid fragment crystallizable receptor-mediated signaling, thereby dampening B-cell activation, antibody class-switching, expansion, and cytokine production. Beyond antibodies, COVID-19 severity and vaccine efficacy appear largely linked to T-cell responses and interferon induction, processes not directly affected by BTKis. Given that B cells have clear roles in antigen presentation to T cells, however, it is possible that BTKis may indirectly interfere with beneficial or detrimental T-cell responses during COVID-19 infection or vaccination. In addition to these possible effects on generating a protective immune response, BTKis may attenuate the hyperinflammatory dysregulation often seen in severe cases of COVID-19 that evolves as a key risk factor in this disease. Currently available outcomes from BTKi-treated patients with COVID-19 are discussed. Clinical trials are currently underway to evaluate the safety and efficacy of BTKis in individuals with MS. Although limited data suggest a potential benefit of BTKis on outcomes for some COVID-19 patients, data from adequately powered, prospective and randomized clinical trials are lacking. Likewise, the specific effect of BTKis on the safety and efficacy of COVID-19 vaccines remains to be determined. Any potential unknown risks that BTKi therapy may present to the patient relative to COVID-19 infection, severity, and vaccine efficacy must be balanced with the importance of timely intervention to prevent or minimize MS progression.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , COVID-19 , Multiple Sclerosis/drug therapy , Pandemics , Protein Kinase Inhibitors/therapeutic use , Adult , COVID-19/immunology , COVID-19 Vaccines , Humans , Multiple Sclerosis/immunology , Prospective Studies , T-Lymphocytes/immunology
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