Effect of Disease-Modifying Therapies on COVID-19 Vaccination Efficacy in Multiple Sclerosis Patients: A Comprehensive Review.

According to current knowledge, the etiopathogenesis of multiple sclerosis (MS) is complex, involving genetic background as well as several environmental factors that result in dysimmunity in the central nervous system (CNS). MS is an immune-mediated, inflammatory neurological disease affecting the CNS. As part of its attack on the axons of the CNS, MS witnesses varying degrees of myelin and axonal loss. A total of about 20 disease-modifying therapies (DMTs) are available today that, both in clinical trials and in real-world studies, reduce disease activity, such as relapses, magnetic resonance imaging lesions, and disability accumulation. Currently, the world is facing an outbreak of the new coronavirus disease 2019 (COVID-19), which originated in Wuhan, Hubei Province, China, in December 2019 and spread rapidly around the globe. Viral infections play an important role in triggering and maintaining neuroinflammation through direct and indirect mechanisms. There is an old association between MS and viral infections. In the context of MS-related chronic inflammatory damage within the CNS, there has been concern regarding COVID-19 worsening neurological damage. A high rate of disability and increased susceptibility to infection have made MS patients particularly vulnerable. In addition, DMTs have been a concern during the pandemic since many DMTs have immunosuppressive properties. In this article, we discuss the impact of DMTs on COVID-19 risks and the effect of DMTs on COVID-19 vaccination efficacy and outcome in MS patients.

COVID-19 disease modifying treatment guideline adherence in Western Australia

Introduction/Aim: Western Australia had its first wave of COVID-19 cases in March 2022. This retrospective study assessed the adherence to guidelines for prescribing COVID-19 disease modifying therapies (DMT), based on the National COVID-19 Clinical Evidence Taskforce Australian guidelines for the clinical care of people with COVID-19. Method(s): The first 100 cases admitted to the respiratory ward at Fiona Stanley Hospital (FSH) with confirmed COVID-19 were reviewed. Data was collected from the hospital Digital Medical Record to determine clinical severity on presentation and the need for DMT. Prescribing of DMT was assessed for adherence against the National guidelines and/or whether it was recommended by the infectious diseases (ID) team. Disease progression, length of stay, mortality and readmission rates were assessed within 28 days of admission. Result(s): During the audit period (11.03.2022 - 19.04.2022), the National guidelines underwent six updates. In the first 100 cases of COVID-19, the median (IQR) age was 65.11 years, the median (IQR) length of stay was 4 days and the mortality rate was 1%. There was a 7% readmission rate with 6% of patients treated with DMT having disease progression. 16% of patients were immunocompromised and 58% were partially vaccinated or unvaccinated. 63% of unvaccinated patients had severe disease. 84% of patients were recommended a DMT, of which, 63% received the correct combination of DMT. 14% of cases were recommended and not prescribed a DMT, though 71% of these cases were recommended budesonide alone. 12% were not recommended and not prescribed a DMT and 4% were not recommended, yet prescribed a DMT. Conclusion(s): Overall adherence with the National guidelines/ID advice for DMT was >80% excluding inhaled budesonide. The continually evolving nature of the National guidelines added complexity to prescribing. A dedicated medical proforma would aid with risk stratification and DMT prescribing for patients with COVID-19.

T cell responses to COVID-19 infection and vaccination in patients with multiple sclerosis receiving disease-modifying therapy.

BACKGROUND: Multiple sclerosis (MS) is a neurological disorder marked by accumulating immune-mediated damage to the central nervous system. The dysregulated immune system in MS combined with immune effects of disease-modifying therapies (DMTs) used in MS treatment could alter responses to infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Most of the literature on immune response to SARS-CoV-2 infection and COVID-19 vaccination, in both the general population and patients with MS on DMTs, has focused on humoral immunity. However, immune response to COVID-19 involves multiple lines of defense, including T cells. OBJECTIVE AND METHODS: We review innate and adaptive immunity to COVID-19 and expand on the role of T cells in mediating protective immunity against SARS-CoV-2 infection and in responses to COVID-19 vaccination in MS. RESULTS: Innate, humoral, and T cell immune responses combat COVID-19 and generate protective immunity. Assays detecting cytokine expression by T cells show an association between SARS-CoV-2-specific T cell responses and milder/asymptomatic COVID-19 and protective immune memory. CONCLUSION: Studies of COVID-19 immunity in people with MS on DMTs should ideally include comprehensive assessment of innate, humoral, and T cell responses.

Cladribine Tablets: A Review of the Practical Considerations in Multiple Sclerosis Nursing Practice

Nurses specializing in the care of patients with multiple sclerosis (MS) are uniquely positioned to provide personalized care. Patients prescribed cladribine tablets (taken for <=10 days per year for 2 years), indicated for adults with highly active relapsing MS in the EU and Australia, can benefit from an active partnership with their healthcare professionals, including MS nurses, who can promote an understanding of and the adherence to treatment. In clinical studies, patients treated with cladribine tablets had lower annual relapse rates, greater odds of being relapse free, a longer time to sustained progression of disability and a significant reduction in radiological disease activity compared with patients receiving placebo. Patients should be advised that, although everyone will have a different experience, the safety of cladribine tablets is supported by 16 years of clinical trial and post-approval data. Furthermore, there is no indication of a more serious disease course or more severe outcomes for patients with MS treated with cladribine tablets who acquire coronavirus disease 2019 compared with the general population or other patients with MS. This article presents practical considerations that may help achieve a greater understanding of the potential benefits and drawbacks of MS treatment, build the patient-nurse relationship, encourage shared decision-making and ultimately may improve careCopyright © Touch Medical Media 2022

A retrospective evaluation of seroconversion after COVID-19 during the early Omicron wave in fully vaccinated multiple sclerosis patients receiving anti-CD20 therapies.

BACKGROUND: Patients with multiple sclerosis (MS) are commonly treated with anti-CD20 therapies. Reduced seroconversion following COVID-19 vaccination in patients receiving certain anti-CD20 therapies has been reported; however, the immune response following natural infection is poorly characterised. This study aimed to retrospectively evaluate COVID-19 antibody responses after vaccination and natural infection in patients treated with anti-CD20 therapies. METHODS: We performed a retrospective review evaluating COVID-19 seroconversion and anti-spike glycoprotein antibody titres in double-vaccinated patients with MS, or related neuroinflammatory conditions, treated with anti-CD20 therapies (N = 30) with a confirmed history of natural severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (n = 14) or without infection (control; n = 16). This single-centre study was performed at the Yale Multiple Sclerosis Center, where patients treated with anti-CD20 therapies (ocrelizumab, n = 21; rituximab, n = 5; ofatumumab, n = 4) were systematically checked for SARS-CoV-2 anti-spike antibody levels throughout the pandemic. Data were collected from March 2020 to March 2022. All patients had received at least two doses of a Food and Drug Administration (FDA)-approved COVID-19 vaccine. Qualitative anti-spike antibody seropositivity was determined based on test-specific laboratory reference ranges. For a subset of patients (n = 18), quantitative anti-spike antibody levels were assessed via DiaSorin LIAISON® chemiluminescence immunoassay (positive titre was defined as ≥ 13). Vaccination and infection dates were also recorded, and patients were monitored for adverse COVID-19-related health effects. RESULTS: Overall, 15/30 (50.0%) patients seroconverted following double vaccination. After infection, 13/14 (92.9%) seroconverted, while 6/16 (37.5%) uninfected patients seroconverted after vaccination. For the 18 patients with quantitative anti-spike antibody titres, mean titre post-vaccination was 37.4. Mean antibody titres were significantly higher after infection: 540.3 versus 20.1 in the control group (p < 0.05). Of the 14 infected patients, 13 had mild COVID-19 symptoms and one was asymptomatic. No hospitalisations or deaths were reported. CONCLUSIONS: This study reports that SARS-CoV-2 anti-spike antibody titres in double-vaccinated MS patients treated with anti-CD20 therapies were significantly increased post-infection compared with the control group. Patients treated with anti-CD20 therapy who had confirmed infections displayed mild or asymptomatic infection. These results provide reassurance that anti-CD20 therapies in double-vaccinated patients do not preclude an appropriate SARS-CoV-2 antibody response post-infection.

Longitudinal adaptive immune responses following sequential SARS-CoV-2 vaccinations in MS patients on anti-CD20 therapies and sphingosine-1-phosphate receptor modulators.

BACKGROUND: Adequate response to the SARS-CoV-2 vaccine represents an important treatment goal in caring for patients with multiple sclerosis (MS) during the ongoing COVID-19 pandemic. Previous data so far have demonstrated lower spike-specific IgG responses following two SARS-CoV-2 vaccinations in MS patients treated with sphingosine-1-phosphate (S1P) receptor modulators and anti-CD20 monoclonal antibodies (mAb) compared to other disease modifying therapies (DMTs). It is unknown whether subsequent vaccinations can augment antibody responses in these patients. OBJECTIVES: The goal of this observational study was to determine the effects of a third SARS-CoV-2 vaccination on antibody and T cell responses in MS patients treated with anti-CD20 mAb or S1P receptor modulators. METHODS: Vaccine responses in patients treated with anti-CD20 antibodies (ocrelizumab and ofatumumab) or S1P receptor modulators (fingolimod and siponimod) were evaluated before and after third SARS-CoV-2 vaccination as part of an ongoing longitudinal study. Total spike protein and spike receptor binding domain (RBD)-specific IgG responses were measured by Luminex bead-based assay. Spike-specific CD4+ and CD8+ T cell responses were measured by activation-induced marker expression. RESULTS: MS patients and healthy controls were enrolled before and following SARS-CoV-2 vaccination. A total of 31 MS patients (n = 10 ofatumumab, n = 13 ocrelizumab, n = 8 S1P) and 10 healthy controls were evaluated through three SARS-CoV-2 vaccinations. Compared to healthy controls, total spike IgG was significantly lower in anti-CD20 mAb-treated patients and spike RBD IgG was significantly lower in anti-CD20 mAb and S1P-treated patients following a third vaccination. While seropositivity was 100% in healthy controls after a third vaccination, total spike IgG and spike RBD IgG seropositivity were lower in ofatumumab (60% and 60%, respectively), ocrelizumab (85% and 46%, respectively), and S1P-treated patients (100% and 75%, respectively). Longer treatment duration, including prior treatment history, appeared to negatively impact antibody responses. Spike-specific CD4+ and CD8+ T cell responses were well maintained across all groups following a third vaccination. Finally, immune responses were also compared in patients who were vaccinated prior to or following ofatumumab treatment. Antibody responses were significantly higher in those patients who received their primary SARS-CoV-2 vaccination prior to initiating ofatumumab treatment. CONCLUSIONS: This study adds to the evolving understanding of SARS-CoV-2 vaccine responses in people with MS treated with disease-modifying therapies (DMTs) known to suppress humoral immunity. Our findings provide important information for optimizing vaccine immunity in at-risk MS patient populations.

Navigating the landscape of COVID-19 for Multiple Sclerosis patients and clinicians.

The purpose of this literature review was to summarise relevant findings regarding the clinical management of multiple sclerosis (MS) in the COVID-19 pandemic, with the focus on patient risks, and the implications of disease-modifying treatment, both on COVID-19 severity and on the response to the SARS-CoV-2 vaccinations. Although MS per se does not seem to put patients at risk for more severe COVID-19, alongside the risk factors known to apply to the general population, progressive disease course, higher disability status, and B-cell depleting therapies may all negatively affect infection severity. The question of COVID-19 sequelae in patients with MS (pwMS) remains unresolved, challenging researchers to further explore this area. The safety profile of COVID-19 vaccinations in pwMS is similar to that of the general population. The efficacy of the vaccination might be affected by B-cell depletion, as well as by S1PR-modulating medications that attenuate humoral responses to the COVID-19 vaccination. Future research should focus on gathering evidence regarding the clinical course of MS following COVID-19 infection and vaccination in larger studies, as well as on establishing the safest and most efficient schedule of COVID-19 vaccination in pwMS on cell-depleting therapies.

Targeting Neuroinflammation to Alleviate Chronic Olfactory Dysfunction in Long COVID: A Role for Investigating Disease-Modifying Therapy (DMT)?

Chronic olfactory dysfunction after SARS-CoV-2 infection occurs in approximately 10% of patients with COVID-19-induced anosmia, and it is a growing public health concern. A regimen of olfactory training and anti-neuroinflammatory therapy with co-ultramicronized palmitoylethanolamide with luteolin (um-PEA-LUT) has shown promising results in clinical trials; however, approximately 15% of treated patients do not achieve full recovery of a normal olfactory threshold, and almost 5% have no recovery. Disease-modifying therapies (DMTs), which are used to treat autoimmune neuroinflammation in multiple sclerosis (MS), have not been studied for treating persistent inflammation in refractory post-COVID-19 smell disorder. This study evaluated COVID-19-related smell loss and MS-related smell loss, comparing the responses to different therapies. Forty patients with MS and 45 reporting post-COVID-19 olfactory disorders were included in the study. All patients underwent nasal endoscopy and were evaluated by using validated Sniffin' Sticks testing. The patients with long COVID were treated for three months with um-PEA-LUT plus olfactory training. The patients with MS were treated with DMTs. Olfactory functions before and after treatment were analyzed in both groups. At the experimental endpoint, 13 patients in the COVID-19 group treated with um-PEA-LUT had residual olfactory impairment versus 10 patients in the MS group treated with DMTs. The severity of the persistent olfactory loss was lower in the MS group, and the patients with MS treated with IFN-beta and glatiramer acetate had the preservation of olfactory function. These data provide a rationale for considering prospective trials investigating the efficacy of DMTs for post-COVID-19 olfactory disorders that are refractory to um-PEA-LUT with olfactory training. This study is the first to consider the role of DMT in treating refractory post-viral olfactory loss in patients with long COVID.

Predictors for insufficient SARS-CoV-2 vaccination response upon treatment in multiple sclerosis.

BACKGROUND: Disease-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. METHODS: Cross-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. FINDINGS: In 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. INTERPRETATION: PwMS 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. FUNDING: This work was supported by the German Research Foundation (DFG, CRC-TR-128 to TU, SB, and FZ).

Assessing the immune response to SARS-CoV-2 mRNA vaccines in siponimod-treated patients: a nonrandomized controlled clinical trial (AMA-VACC).

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).

Vaccination of multiple sclerosis patients during the COVID-19 era: Novel insights into vaccine safety and immunogenicity.

Multiple sclerosis (MS) is an incurable autoimmune disease known to cause widespread demyelinating lesions in the central nervous system (CNS) and a host of debilitating symptoms in patients. The development of MS is believed to be driven by the breakdown of the blood brain barrier, subsequent infiltration by CD4+ and CD8+ T cells, and widespread CNS inflammation and demyelination. Disease modifying therapies (DMTs) profoundly disrupt these processes and therefore compose an essential component of disease management. However, the effects of these therapeutic agents on vaccine safety and immunogenicity in individuals with MS are not yet fully understood. As such, the primary objective of this review article was to summarize the findings of recently conducted studies on vaccine safety and immunogenicity in MS patients treated with DMTs, particularly in the context of the ongoing coronavirus disease 2019 (COVID-19) pandemic. Discussed in this review are vaccinations against influenza, yellow fever, human papillomavirus, measles, mumps, rubella, Streptococcus pneumoniae, hepatitis B, and COVID-19. This article additionally reviews our current understanding of COVID-19 severity and incidence in this patient population, the risks and benefits of vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and vaccination guidelines set forth by MS societies and organizations.

Low-dose naltrexone reduced anxiety in persons with multiple sclerosis during the COVID-19 pandemic.

Persons with multiple sclerosis (PwMS) have been considered at high risk for vaccination and/or acquisition of COVID-19 related to their reduced immune systems and daily regimen of immune suppressing therapy. Substantiated and unsubstantiated reports on these unknown circumstances increased anxiety and depression. Low-dose naltrexone (LDN) is a potentially effective off-label therapy shown to be effective at controlling fatigue for several autoimmune disorders including MS. This study utilized a small population of PwMS from central Pennsylvania in order to determine whether LDN therapy altered their perceived anxiety or depression during the early months of COVID-19. Utilizing mailed surveys, self-reported anxiety and depression scores were found to be significantly lower for PwMS who were prescribed LDN either alone or as an adjuvant to a standard disease modifying therapy (DMT) in comparison to those on oral disease-modifying therapies (DMTs). The data suggest that the non-toxic, inexpensive biotherapeutic may be beneficial in lessening anxiety.

Multiple Sclerosis immunotherapies and COVID-19 mortality: an analysis of the FDA Adverse Event Reporting System.

Background: Evidence on mortality risks associated with MS-immunotherapies during the SARS-CoV2 pandemic derived thus far mainly from single country experiences. Objective: In this analysis, we aim to determine the frequency of COVID-19 associated fatality reports of patients receiving an MS-immunotherapy as reported to the international Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from February 2020 to March 2021. Methods: In all, 1071 cases for this cross-sectional analysis were retrieved from FAERS and a multivariable logistic regression was performed. We adjusted for sex, age, region, month of report to FDA, immunotherapy-class and additionally for healthcare-system and pandemic-related metrics. Result: Anti-CD20 therapies (60%) followed by sphingosine-1 phosphate modulators (12%) and dimethylfumarat (10%) were reported most frequently. In 50% of the cases, MS-phenotype is not reported, relapsing MS in 35% and progressive MS in 15%. Besides older age (odds ratio [OR]: 1.1; 95% confidence interval [CI]: 1.07-1.13; p < 0.01), anti-CD20 therapies were significantly associated with a higher risk of death (OR: 4.1; 95% CI: 1.17-14.46; p = 0.03), whereas female sex was associated with a reduced mortality risk (OR: 0.4, 95% CI: 0.22-0.72; p < 0.01). Conclusion: Using international open access data and a multidisciplinary approach for risk prediction, we identified an increased mortality risk associated with anti-CD20 therapies, which is in line with national and multi-national cohort studies.

Cross-sectional analysis of the humoral response after SARS-CoV-2 vaccination in Sardinian multiple sclerosis patients, a follow-up study.

Monitoring immune responses to SARS-CoV-2 vaccination and its clinical efficacy over time in Multiple Sclerosis (MS) patients treated with disease-modifying therapies (DMTs) help to establish the optimal strategies to ensure adequate COVID-19 protection without compromising disease control offered by DMTs. Following our previous observations on the humoral response one month after two doses of BNT162b2 vaccine (T1) in MS patients differently treated, here we present a cross-sectional and longitudinal follow-up analysis six months following vaccination (T2, n=662) and one month following the first booster (T3, n=185). Consistent with results at T1, humoral responses were decreased in MS patients treated with fingolimod and anti-CD20 therapies compared with untreated patients also at the time points considered here (T2 and T3). Interestingly, a strong upregulation one month after the booster was observed in patients under every DMTs analyzed, including those treated with fingolimod and anti-CD20 therapies. Although patients taking these latter therapies had a higher rate of COVID-19 infection five months after the first booster, only mild symptoms that did not require hospitalization were reported for all the DMTs analyzed here. Based on these findings we anticipate that additional vaccine booster shots will likely further improve immune responses and COVID-19 protection in MS patients treated with any DMT.

Immunocompetence after SARS-CoV-2 Infection in a Patient with Multiple Sclerosis Treated with Ofatumumab: A Case Report.

Ofatumumab is the first fully human anti-CD20 monoclonal antibody that, on March 26, 2021, was approved by the EMA to treat patients with relapsing multiple sclerosis. This paper aimed to present a case confirming the ability to produce and maintain anti-SARS-CoV-2 antibodies in a patient treated with ofatumumab for over 4 years. The course of the infection was moderate, and the patient did not require hospitalization. Antibody measurements were performed five times post-COVID-19 infection. The first test was performed in the fourth month (131 days), and the last, over 1 year after the infection. To date, only 2 cases have been published describing the ability of a patient treated with the same drug to produce antibodies against SARS-CoV-2, although the observation was conducted over a shorter period. In our case study, we have 15-month follow-up data. The patient was not vaccinated and additionally received suppressive steroid therapy due to the relapse. We observed an increase in antibodies up to 10 months from the infection. The case under analysis suggests that patients treated with ofatumumab, despite complete peripheral B-cell depletion, can produce and maintain a long-lasting immune response.

Three doses of COVID-19 vaccines in multiple sclerosis patients treated with disease-modifying therapies.

OBJECTIVES AND AIMS: Disease modifying therapies used in multiple sclerosis can decrease humoral response after COVID-19 vaccines. This problem must be adequately addressed because new variants evolve, and COVID-19 still poses a risk to patients with comorbidities and immunosuppression. We aimed to evaluate the antibody response after the third dose of the COVID-19 vaccine in people with multiple sclerosis on disease-modifying therapies. METHODS: People with multiple sclerosis who received the third dose of either mRNA or inactivated vaccine after two doses of inactivated vaccine were recruited for the study. Blood samples were collected at least two weeks after the third dose. RESULTS: Blood samples of 339 (female 72.5%) people with multiple sclerosis and 52 (female 71.2%) healthy controls were evaluated. Healthy controls (mean: 4.07 ± 0.66) have higher antibody titers than people with multiple sclerosis (mean: 2.79 ± 2.95). Seronegative cases were observed only in the fingolimod and ocrelizumab treatment groups. Patients on fingolimod who received mRNA as a third dose had significantly higher antibody titer than those who had inactivated vaccines. Longer disease duration, having inactivated vaccine as a third dose, and DMT use was associated with lower antibody response. CONCLUSIONS: The study shows that even after inactivated vaccine schedule, mRNA still offers more protection in people with multiple sclerosis on disease-modifying therapies.

Humoral response to COVID-19 vaccination in MS patients on disease modifying therapy: Immune profiles and clinical outcomes.

BACKGROUND: Patients with multiple sclerosis (MS) on some disease modifying therapies (DMTs), particularly anti-CD20 and sphingosine-1-phosphate (S1P) modulators, are at increased risk of severe Coronavirus Disease 19 (COVID-19) and death. COVID-19 vaccinations are effective in preventing infection and severe disease, but humoral response to vaccination and outcomes of COVID-19 infection after vaccination in MS patients on DMTs remain less understood. METHODS: In this retrospective single-center study, patients enrolled in the CLIMB (Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital) study and biorepository who had been vaccinated against COVID-19 and had SARS-CoV-2 spike antibody (anti-SARS-CoV-2 S Roche-Elecsys) testing were identified and compared to healthy controls. Demographic data, serum immune profiles including lymphocyte count, B-cell count, and immunoglobulins, and clinical outcome of COVID-19 infection were collected. RESULTS: 254 patients (73.2% female, mean (SD) age 52.9 (11.2) years) were identified. When controlling for age, time since vaccination, and vaccine type, patients on fingolimod, ocrelizumab, rituximab, mycophenolate mofetil, natalizumab and teriflunomide had significantly lower levels of spike antibodies compared to healthy controls (n = 34). Longer duration of treatment was associated with lower spike antibody levels in patients on anti-CD20 therapy (p = 0.016) and S1P modulators (p = 0.016) compared to healthy controls. In patients on anti-CD20 therapy, higher spike antibody levels were associated with higher CD20 cell count (p<0.001), and longer time since last anti-CD20 therapy infusion (p<0.001). 92.8% (13/14) vaccine responders (spike antibody titer >100 ug/dL) on anti-CD20 therapy demonstrated B-cell reconstitution (mean CD20 3.6%). Only 1 out of 86 patients with CD20 of 0% had a measurable spike antibody response to vaccination. During follow-up (mean 270 days), five patients were diagnosed with COVID-19 after vaccination (incidence 1.9%), all of whom had spike antibody < 20 ug/dL. No patients required ICU care or died. CONCLUSIONS: Patients on some DMTs demonstrate reduced humoral immunity after Sars-CoV-2 vaccination. Longer duration of anti-CD20 therapy and reduced CD20 cell count is associated with blunted humoral response to vaccination. CD20 reconstitution >0.1% appears necessary, but not always sufficient, for humoral response to vaccination. Breakthrough COVID-19 infection in our cohort of MS patients on DMT was higher than in population studies. We propose that adjustment of B-cell therapy administration to allow for B-cell reconstitution prior to vaccination should be considered.

The Outcome of COVID-19 in Pediatric-Onset Multiple Sclerosis Patients.

BACKGROUND: The pathogenesis of multiple sclerosis (MS) involves immune-mediated mechanisms, and disease-modifying therapies (DMTs) administered in MS have immunomodulatory effects. The concern about MS patients' susceptibility to coronavirus disease 2019 (COVID-19) has prompted several studies based on clinical observations and questionnaires. Information about COVID-19 in pediatric-onset multiple sclerosis (POMS) is scarce. The objective of this study was to collect information on the experience of POMS patients with COVID-19 during the pandemic. METHODS: This cross-sectional study was conducted with POMS patients diagnosed at Hacettepe University Pediatric Neurology Department and under 23 years of age between October 1 and December 31, 2021. Those who experienced COVID-19 or had a history of contact and were found seropositive for COVID-19 were evaluated for the severity of COVID-19, disability, treatment status, and comorbidities. RESULTS: Among the 101 POMS patients, 13 reported having had COVID-19 and five were exposed and seropositive but clinically asymptomatic. Of these 18 patients, 14 were ≤18 years of age at the time of the study. All 13 patients (72%) reported mild symptoms without hospitalization or respiratory support. Four of 18 had a neurological disability (Expanded Disability Status Scale [EDSS] scores ranging between 1 and 7.5), while the remaining had a score of 0. The outcome of COVID-19 was not affected by DMTs, neurological disabilities, and comorbidities. CONCLUSIONS: In this single-center POMS series, the small subgroup of patients who had contacted the SARS-CoV-2 virus or developed COVID-19 had reported no or mild symptoms. This may be partly related to the infrequent use of rituximab in this group. Our results corroborate those in adult-onset MS where no increased risk is reported for patients whose EDSS scores are <6 and who are not on B cell-depleting DMTs. Although less frequently than in adult MS, immunosuppressive DMTs may be needed in POMS; therefore, the importance of appropriate vaccination is to be underlined.

Humoral immune response to SARS-CoV-2 third vaccination in patients with multiple sclerosis and healthy controls: A prospective multicenter study.

BACKGROUND: Third vaccination against SARS-CoV-2 is recommended for patients with multiple sclerosis (pwMS), usually six months after the last vaccination. METHODS: In this prospective multicenter study on 292 pwMS and 46 healthy controls (HC), who had all received two vaccinations prior to study enrollment, SARS-CoV-2 IgG response was measured in the month before and 2-4 months after third vaccination. PwMS were categorized as follows: untreated (N-DMT, n = 32), receiving disease-modifying therapy (DMT) with expected humoral response (er-DMT: interferon-beta preparations, glatiramer acetate, dimethyl fumarate, teriflunomide, natalizumab, cladribine, alemtuzumab; n = 120) or no expected humoral response (nr-DMT: S1PMs, CD20mAb; n = 140). RESULTS: PwMS on nr-DMT had significantly lower median antibody levels before (12.1 U/ml [0.4-2500]) and after third vaccination (305 U/ml [0.4-2500]) in comparison to other groups (p<0.001). We did not find differences in antibody levels after homologous (n = 281; 2500 [0.4-2500]) and heterologous (n = 57; 2500 [0.4-2500]) vaccination regime regardless of the DMT group. The DMT group (ß= -0.60; 95% CI -1195.73, -799.10; p<0.001) was associated with antibody levels after third vaccination, while time to revaccination (6 months [1-13]) was not. After third vaccination, seropositivity was reached in 75.8% and 82.2% of pwMS on anti-CD20 mAbs and S1PMs, respectively. Complete B-cell depletion significantly decreased the probability of seroconversion even after the third vaccination (OR 0.14; p = 0.021), whereas time interval to last DMT intake and time to revaccination did not. Twenty-two patients reported a SARS-CoV-2 infection (3 N-DMT, 9 er-DMT, 10 nr-DMT), one being asymptomatic and the rest having a mild course. CONCLUSION: Humoral response to SARS-CoV-2 third vaccination in pwMS is excellent. While reduced by S1PMs and CD20mAb, protective response is still expected in the majority of patients.

Is humoral and cellular response to SARS-CoV-2 vaccine modified by DMT in patients with multiple sclerosis and other autoimmune diseases?

BACKGROUND: The effect of disease-modifying therapies on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine response is unclear. OBJECTIVES: We aim to determine the immunological responses to SARS-CoV-2 in multiple sclerosis (MS) and anti-CD20-treated patients with other autoimmune diseases (AID). METHODS: Humoral and cellular responses we determined before and 30-90 days after vaccination in patients with MS and anti-CD20-treated patients with other AID in two Catalan centers. RESULTS: 457 patients were enrolled. Findings showed that humoral response decreased under anti-CD20s or sphingosine 1-phosphate receptor modulators (S1PRM) and with longer treatment duration and increased after 4.5 months from the last anti-CD20 infusion. Cellular response decreased in S1PRM-treated. Patients on anti-CD20 can present cellular responses even in the absence of antibodies. CONCLUSION: Anti-CD20s and S1PRM modify the immunological responses to SARS-CoV-2 vaccines.