SARS-CoV-2-Specific Immune Cytokine Profiles to mRNA, Viral Vector and Protein-Based Vaccines in Patients with Multiple Sclerosis: Beyond Interferon Gamma.

Disease-modifying therapies (DMTs) impact the cellular immune response to severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) vaccines in patients with multiple sclerosis (pwMS). In this study, we aim to elucidate the characteristics of the involved antigen-specific T cells via the measurement of broad cytokine profiles in pwMS on various DMTs. We examined SARS-CoV-2-specific T cell responses in whole blood cultures characterized by the release of interleukin (IL)-2, IL-4, IL-5, IL-10, IL-13, IL-17A, interferon-gamma (IFN-γ), and tumor necrosis factor-alpha (TNF-α), as well as antibodies (AB) targeting the SARS-CoV-2 spike protein in pwMS following either two or three doses of mRNA or viral vector vaccines (VVV). For mRNA vaccination non-responders, the NVX-CoV2373 protein-based vaccine was administered, and immune responses were evaluated. Our findings indicate that immune responses to SARS-CoV-2 vaccines in pwMS are skewed towards a Th1 phenotype, characterized by IL-2 and IFN-γ. Additionally, a Th2 response characterized by IL-5, and to a lesser extent IL-4, IL-10, and IL-13, is observed. Therefore, the measurement of IL-2 and IL-5 levels could complement traditional IFN-γ assays to more comprehensively characterize the cellular responses to SARS-CoV-2 vaccines. Our results provide a comprehensive cytokine profile for pwMS receiving different DMTs and offer valuable insights for designing vaccination strategies in this patient population.

Differential effects of selective versus unselective sphingosine 1-phosphate receptor modulators on T- and B-cell response to SARS-CoV-2 vaccination.

BACKGROUND: Sphingosine 1-phosphat receptor modulators (S1PRMs) have been linked to attenuated immune response to SARS-CoV-2 vaccines. OBJECTIVE: To characterize differences in the immune response to SARS-CoV-2 vaccines in patients on selective versus unselective S1PRMs. METHODS: Monocentric, longitudinal study on people with multiple sclerosis (pwMS) on fingolimod (FTY), siponimod (SIP), ozanimod (OZA), or without disease-modifying therapy (DMT) following primary and booster SARS-CoV-2 vaccination. Anti-SARS-CoV-2 antibodies and T-cell response was measured with electro-chemiluminescent immunoassay and interferon-γ release assay. RESULTS: Primary vaccination induced a significant antibody response in pwMS without DMT while S1PRM patients exhibited reduced antibody titers. The lowest antibodies were found in patients on FTY, whereas patients on OZA and SIP presented significantly higher levels. Booster vaccinations induced increased antibody levels in untreated patients and comparable titers in patients on OZA and SIP, but no increase in FTY-treated patients. While untreated pwMS developed a T-cell response, patients on S1PRMs presented a diminished/absent response. Patients undergoing SARS-CoV-2 vaccination before onset of S1PRMs presented a preserved, although attenuated humoral response, while T-cellular response was blunted. CONCLUSION: Our data confirm differential effects of selective versus unselective S1PRMs on T- and B-cell response to SARS-CoV-2 vaccination and suggest association with S1PRM selectivity rather than lymphocyte redistribution.

Long-Term Immune Response Profiles to SARS-CoV-2 Vaccination and Infection in People with Multiple Sclerosis on Anti-CD20 Therapy.

Our objective was to analyze longitudinal cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in people with multiple sclerosis (pwMS) on B-cell depleting treatment (BCDT) compared to pwMS without immunotherapy. We further evaluated the impact of COVID-19 infection and vaccination timing. PwMS (n = 439) on BCDT (ocrelizumab, rituximab, ofatumumab) or without immunotherapy were recruited for this prospective cohort study between June 2021 and June 2022. SARS-CoV-2 spike-specific antibodies and interferon-γ release of CD4 and CD8 T-cells upon stimulation with spike protein peptide pools were analyzed at different timepoints (after primary vaccination, 3 and 6 months after primary vaccination, after booster vaccination, 3 months after booster). Humoral response to SARS-CoV-2 was consistently lower whereas T-cell response was higher in patients with BCDT compared to controls. Cellular and humoral responses decreased over time after primary vaccination and increased again upon booster vaccination, with significantly higher antibody titers after booster than after primary vaccination in both untreated and B-cell-depleted pwMS. COVID-19 infection further led to a significant increase in SARS-CoV-2-specific responses. Despite attenuated B-cell responses, a third vaccination for patients with BCDT seems recommendable, since at least partial protection can be expected from the strong T-cell response. Moreover, our data show that an assessment of T-cell responses may be helpful in B-cell-depleted patients to evaluate the efficacy of SARS-CoV-2 vaccination.

NVX-CoV2373-induced T- and B-cellular immunity in immunosuppressed people with multiple sclerosis that failed to respond to mRNA and viral vector SARS-CoV-2 vaccines.

Importance: Immunological response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is important, especially in people with multiple sclerosis (pwMS) on immunosuppressive therapies. Objective: This study aims to determine whether adjuvanted protein-based vaccine NVX-CoV2373 is able to induce an immune response to SARS-CoV-2 in pwMS with inadequate responses to prior triple mRNA/viral vector vaccination. Design setting and participants: We conducted a single-center, prospective longitudinal cohort study at the MS Center in Dresden, Germany. In total, 65 participants were included in the study in accordance with the following eligibility criteria: age > 18 years, immunomodulatory treatment, and insufficient T-cellular and humoral response to prior vaccination with at least two doses of SARS-CoV-2 mRNA (BNT162b2, mRNA-1273) or viral vector vaccines (AZD1222, Ad26.COV2.S). Interventions: Intramuscular vaccination with two doses of NVX-CoV2373 at baseline and 3 weeks of follow-up. Main outcomes and measures: The development of SARS-CoV-2-specific antibodies and T-cell responses was evaluated. Results: For the final analysis, data from 47 patients on stable treatment with sphingosine-1-phosphate receptor (S1PR) modulators and 17 on ocrelizumab were available. The tolerability of the NVX-CoV2373 vaccination was overall good and comparable to the one reported for the general population. After the second NVX-CoV2373 vaccination, 59% of S1PR-modulated patients developed antispike IgG antibodies above the predefined cutoff of 200 binding antibody units (BAU)/ml (mean, 1,204.37 [95% CI, 693.15, 2,092.65] BAU/ml), whereas no clinically significant T-cell response was found. In the subgroup of the patients on ocrelizumab treatment, 23.5% developed antispike IgG > 200 BAU/ml (mean, 116.3 [95% CI, 47.04, 287.51] BAU/ml) and 53% showed positive spike-specific T-cellular responses (IFN-gamma release to antigen 1: mean, 0.2 [95% CI, 0.11, 0.31] IU/ml; antigen 2: mean, 0.24 [95% CI, 0.14, 0.37]) after the second vaccination. Conclusions: Vaccination with two doses of NVX-CoV2373 was able to elicit a SARS-CoV-2-specific immune response in pwMS lacking adequate immune responses to previous mRNA/viral vector vaccination. For patients receiving S1PR modulators, an increase in anti-SARS-CoV-2 IgG antibodies was detected after NVX-CoV2373 vaccination, whereas in ocrelizumab-treated patients, the increase of antiviral T-cell responses was more pronounced. Our data may impact clinical decision-making by influencing the preference for NVX-CoV2373 vaccination in pwMS receiving treatment with S1PR modulation or anti-CD20 treatment.

Timing of SARS-CoV-2 Vaccination Matters in People With Multiple Sclerosis on Pulsed Anti-CD20 Treatment.

BACKGROUND AND OBJECTIVES: Our objective was to investigate cellular and humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in a cohort of people with multiple sclerosis (pwMS) on pulsed B-cell-depleting treatment (BCDT). In particular, we intended to evaluate a possible association between immune responses and the timing of vaccination under BCDT. METHODS: We conducted a cross-sectional study among pwMS on pulsed BCDT or without disease-modifying treatment after completed SARS-CoV-2 vaccination. Samples were collected during routine clinical visits at the Multiple Sclerosis Center Dresden, Germany, between June 2021 and September 2021. Blood was analyzed for SARS-CoV-2 spike protein-specific antibodies and interferon-γ release of CD4 and CD8 T cells on stimulation with spike protein peptide pools. Lymphocyte subpopulations and total immunoglobulin levels in the blood were measured as part of clinical routine. RESULTS: We included 160 pwMS in our analysis, comprising 133 pwMS on BCDT (n = 132 on ocrelizumab and n = 1 on rituximab) and 27 without disease-modifying treatment. Humoral and cellular anti-SARS-CoV-2 responses were reciprocally regulated by the time between the last BCDT cycle and vaccination. Although antibody responses increased with prolonged intervals between the last BCDT cycle and vaccination, CD4 and CD8 T-cell responses were higher in pwMS vaccinated at early time points after the last BCDT cycle compared with untreated pwMS. T-cellular vaccination responses correlated with total, CD3 CD4, and partly with CD3 CD8 lymphocyte counts. Humoral responses correlated with CD19 lymphocyte counts. Status post coronavirus disease 2019 infection led to significantly increased SARS-CoV-2-specific T-cell and antibody responses. DISCUSSION: Delaying BCDT is currently discussed as a strategy to optimize humoral responses to SARS-CoV-2 vaccination. However, T cells represent an important line of defense against SARS-CoV-2 infection as well, especially in light of emerging variants of concern. We observed enhanced CD4 and CD8 T-cellular responses in pwMS receiving vaccination at early time points after their last BCDT cycle. These data may influence clinical decision making with respect to vaccination strategies in patients receiving BCDT.