COVID-19 Vaccine Response in Treated MS Patients

Study Overview
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Brief Summary
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The primary goal of this study is to assess the impact of the two major disease modifying therapy (DMT) classes (B cell therapies and S1P modulators) on humoral and cell-mediated immunity to SARS- CoV-2 vaccination compared to non-MS controls. We have chosen to compare DMT-treated MS patients to non-MS controls because the pivotal vaccine studies were conducted in non-MS healthy control groups in which there is significant clinical data and validated assays for antibody responses.

Detailed Description
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Multiple sclerosis (MS) affects approximately 1 million persons in the United States and is the leading cause of disability in young adults. Disease modifying treatments for MS act through modulation or suppression of immune responses including B and T cell responses. Two major classes of drugs used to treat MS are 1) B cell antibodies, including Kesimpta (ofatumumab) and Ocrevus (ocrelizumab), and 2) S1P (sphingosine-1-phosphate) modulators including Gilenya (fingolimod) and Mayzent (siponimod). SARS-CoV2 is a potentially fatal novel coronavirus, which has claimed over 350,000 lives in the United States. The causative agent of COVID-19 disease, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes the angiotensin converting enzyme II (ACE2) to target cells in the lower airway.(1, 2) Symptoms of COVID-19 infection can cause pneumonia with primarily lymphocytic inflammatory infiltrates.(3) Most people (approximately 81%) experience mild upper respiratory tract infection or mild pneumonia, while approximately 15-20% of cases experience severe or critical disease characterized by dyspnea, lung infiltrates, respiratory failure and multiple organ dysfunction.(4) The case- fatality rate ranges from 0.7-5.8%. SARS-CoV2 vaccines have just been FDA approved, including the Moderna® and Pfizer-BioNTech® vaccines which contain lipid nanoparticle- formulated nucleoside-modified mRNA (messenger ribonucleic acid) that encodes the receptor binding domain (RBD) of the SARS-CoV-2 spike protein.(5, 6) Prior work suggests that vaccine responses may be blunted in patients treated with these two drug classes, however there is currently no controlled data on the efficacy and durability of SARS-CoV2 vaccine responses in treated MS patients. Current data is limited to uncontrolled case reports. Robust studies are needed to inform the efficacy of SARS-CoV2 vaccines in MS patients on DMTs, which will guide infection risk management. The primary goal of this study is to assess the impact of the two major DMT classes (B cell therapies and S1P modulators) on humoral and cell-mediated immunity to SARS- CoV-2 vaccination compared to non-MS controls. We have chosen to compare DMT-treated MS patients to non-MS controls because the pivotal vaccine studies were conducted in non-MS healthy control groups in which there is significant clinical data and validated assays for antibody responses. The primary endpoint of this study is to compare the percentage of MS patients on immunotherapy with a positive SARS-CoV-2 Spike antibody response (positive seroconversion) compared to the percentage of controls who seroconvert at 5-6 months post vaccination. Secondary endpoints of this study are: Comparison of SARS-CoV-2 Spike antibody % seroconversion and titers in MS patients on immunotherapy to titers in controls at 2-3 months and 11-12 months post vaccination. Comparison of T cell responses to SARS-CoV-2 spike protein in MS patients on immunotherapy to titers in controls at 5-6 months post vaccination. Comparison of antibody titers and T cell responses between the four groups of immunotherapies evaluated and to controls at each of the three timepoints.

Official Title
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Immune Response to SARS-CoV2 Vaccinations in Treated MS Patients Compared to Controls

Conditions
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Multiple Sclerosis, Healthy

Intervention / Treatment
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* Other: Blood draw


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For MS Patients: Diagnosis of MS Treatment with one of the four DMTs (Kesimpta (ofatumumab), Ocrevus (ocrelizumab), Gilenya (fingolimod), Mayzent (siponimod)) for at least 3 months prior to first SARS-CoV2 vaccine dose SARS-CoV2 vaccine regimen complete within the past 2-3 or 5-6 months (either Moderna® or Pfizer-BioNTech® mRNA vaccines) Age 18-65, inclusive For Health Controls: 1. Age 18-65, inclusive Exclusion Criteria: For MS Patients: 1. Prior known COVID-19 infection For Health Controls: Prior known COVID-19 infection major autoimmune disorders or current treatment with immunosuppressive or immunomodulatory drugs

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| MS Kesimpta (ofatumumab)<br>MS patients treated with Kesimpta (ofatumumab) for at least 3 months prior to SARS-CoV2 vaccination (completed regimen) Drug administration n/a, following routine clinical care Blood draws at 2-3 months, 5-6 months, and 11-12 months after enrollment | Other: Blood draw<br>* Approximately 120 mL whole blood will be collected from each subject at each timepoint<br>|
| MS Ocrevus (ocrelizumab)<br>MS patients treated with Ocrevus (ocrelizumab) for at least 3 months prior to SARS-CoV2 vaccination (completed regimen) Drug administration n/a, following routine clinical care Blood draws at 2-3 months, 5-6 months, and 11-12 months after enrollment | Other: Blood draw<br>* Approximately 120 mL whole blood will be collected from each subject at each timepoint<br>|
| MS Gilenya (fingolimod) and Mayzent (siponimod)<br>MS patients treated with Gilenya (fingolimod) or Mayzent (siponimod) for at least 3 months prior to SARS-CoV2 vaccination (completed regimen) Drug administration n/a, following routine clinical care Blood draws at 2-3 months, 5-6 months, and 11-12 months after enrollment | Other: Blood draw<br>* Approximately 120 mL whole blood will be collected from each subject at each timepoint<br>|
| Healthy Control<br>Individuals with major autoimmune disorders or current treatment with immunosuppressive or immunomodulatory drugs Received SARS-CoV2 vaccination (completed regimen) within 2-6 months of enrollment Blood draws at 2-3 months, 5-6 months, and 11-12 months after enrollment | Other: Blood draw<br>* Approximately 120 mL whole blood will be collected from each subject at each timepoint<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary endpoint | Compare the percentage of MS patients on immunotherapy with a positive SARS-CoV-2 Spike antibody response, using the Roche Elecsys® Anti-SARS-CoV-2 S immunoassay for the quantitative, in vitro determination of antibodies to SARS-CoV- 2 in human serum and plasma. It is an Electro-chemiluminescence immunoassay (ECLIA) test using a double-antigen sandwich assay. A positive seroconversion defined as level>0.4U/ml. | 11-12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary endpoint 1 | Comparison of SARS-CoV-2 Spike antibody % seroconversion and titers in MS patients on immunotherapy to titers in controls at 2-3 months and 11-12 months post vaccination. This will be measured as a percentage. | 11-12 months | 
| Secondary endpoint 2 | Comparison of percentage of IFN-gamma positive CD4+ T cells measured by flow cytometry reactive to SARS-CoV-2 spike protein in MS patients on immunotherapy to titers in controls at 5-6 months post vaccination. | 5-6 months | 
| Secondary endpoint 3 | Comparison of antibody titers and percentage of IFN-gamma positive CD4+ T cells reactive to SARS-CoV-2 measured by flow cytometry between the four groups of immunotherapies evaluated and to controls at each of the three timepoints 2-3, 5-6, and 11-12 months. | 11-12 months | 
| Secondary endpoint 4 | Comparison of SARS-CoV-2 Spike antibody seroconversion and levels in MS patients on immunotherapy after 2 vaccine doses versus 3 or more vaccine doses, as measured by Roche Elecsys® Anti-SARS-CoV-2 S immunoassay, with a positive seroconversion defined as >0.4U/ml. | 11-12 months | 
| Secondary endpoint 5 | Comparison of percentage SARS-CoV-2 reactive IFN-gamma positive CD4+ T cells measured by flow cytometry in MS patients on immunotherapy after 2 vaccine doses versus 3 or more vaccine doses. | 11-12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Sclerosis, COVID-19, mRNA vaccine