ABSTRACT
Background: Disease-modifying therapies (DMTs) in patients with multiple sclerosis (pwMS) are known to impact the cellular immune response to SARS-CoV-2 vaccines. In this study, we aim to elucidate a broader cytokine profile of involved T cells for various DMTs. Method(s): 131 pwMS on different DMTs vaccinated with SARSCoV- 2 mRNA vaccines were recruited for this prospective cohort. Blood was drawn post 2nd and 3rd dose. Using a cartridge based multiplex assay (ELLATM), interleukin (IL)-5, IL-10, IL-2, IL-4, IL-17A, IL-13, interferon-gamma (IFN-gamma), and tumor necrosis factor-alpha (TNF-alpha) were measured in blood stimulated with SARS-CoV-2 antigens (Ag) to evaluate T cell response. In comparison, SARS-CoV-2 spike antibodies were measured. mRNA vaccine non-responders were administered NVX-CoV2373 protein- based vaccine, and the corresponding immune responses were measured. Result(s): After two mRNA vaccines, IFN-gamma, and IL-2 responses were significant and comparable between patients treated with glatiramer acetate (GA) and those untreated (UT). There was also a lower but significant IL-4 and IL-5 response for GA and UT respectively. 100% of GA and UT patients had a positive antibody response (mean 4230 U/ml and 1774U/ml respectively). In ocrelizumab (OCR) patients, IFN-gamma and IL-2 responses were higher compared to GA and UT patients. Lower but significant IL-5, IL-4, and IL-13 responses were found. B cell immunity was much lower as only 32% showed a positive antibody response (mean 337 U/ml). For patients on sphingosine-1-phosphate receptor (S1PR) modulators, only 6.4% had a positive T cell response even after 3 doses. However, 87% had a positive B cell response (mean 725 U/ml). No relevant change in IL-17, IL-10, or TNF-alpha concentration was observed among the previously mentioned DMT groups despite TNF-alpha levels being elevated in all groups upon SARS-CoV2 Ag challenge. Similar patterns were also seen after the third mRNA dose. Conclusion(s): This study corroborates known data that the T helper cell type 1 response is the main T-cell response to SARS-CoV-2 mRNA vaccines with the highest response seen in OCR patients. A lower T helper cell type 2 response is observed and is variable depending on treatment modalities. This however is not the case for patients on S1PR modulators whose cellular responses were severely diminished.
ABSTRACT
Introduction: The generation of humoral and cellular responses by SARS-CoV2 vaccination in patients with multiple sclerosis (pwMS) especially onsphingosin-1-phosphat receptor (S1PR) modulator treatment is not yet understood. In this study we aim to differentiate the immunological response profiles after 2 mRNA SARS-CoV2 vaccinations depending on timing and unselective vs. selective S1PR modulators in pwMS. Method(s): We conducted a cross-sectional study among pwMS on ozanimod (OZA), fingolimod (FTY) or without disease-modifying treatment. Two courses of mRNA SARS-CoV-2 vaccinations were performed on treatment resp. before treatment start. Demographic data on age, sex and disease progression did no significantly differ in selected groups. Blood was analyzed for SARS-CoV-2 spike protein-specific antibodies and for CD4 and CD8 T cell response by interferon-gamma release assay upon stimulation. Result(s): All untreated pwMS (n=31) developed positive antibodies (930.9 +/-803.7 BAU/mL), but only in 50% positive T cell responses were seen (S1 0.39 +/-0.68;S2 0.43 +/-0.67 IU/mL). PwMS on longterm FTY treatment (n=86) showed B cell responses (45.0 +/-117.9 BAU/mL) only in 27,9% and T cell responses (S1 0.11 +/-0.86;S2 0.01 +/-0.05 IU/mL) only in 5,9% both with significant lower titers compared to untreated pwMS. In contrast, pwMS on OZA (n= 22) developed B cell responses in 84.2% of patients (703.8 +/-837.5 BAU/mL) with lower titers than untreated pwMS. T cell responses were present in only 4,5% of patients on OZA (S1 0.02 +/-0.05;S2 0.03 +/-0.09 IU/mL). When patients were vaccinated before OZA start (n=25) and tested later on OZA treatment, all patients presented with positive antibody titers comparable to untreated patients (1466.2 +/-838.8 BAU/mL). However, T cell responses could be detected only in 19,0% of these OZA patients (S1 0.05 +/-0.11;S2 0.06 +/-0.14 IU/mL). In summary, only 15.8% OZA, but 69,8% FTY patients did neither develop B nor T cell response. In contrast untreated patients as well as vaccinated patients before OZA treatment start present with at least one B or T cell response. Conclusion(s): In this study, we present that B and T cell responses to SARS-CoV2 mRNA vaccines are selectively affected by different S1PR modulators. Vaccination before start of S1PR modulation induced a stable B cell response which could be demonstrated on treatment. These findings should be considered for vaccination strategies during S1PR modulatory therapy.