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- 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.

Objetivo: Identificar los factores influyentes en la postura ante la inmunización SARSCoV-2 en estudiantes de medicina de una universidad de Lambayeque en el año 2021. Materiales y métodos: Se realizó un estudio tipo observacional transversal analítico. Se tomó a toda la población elegible,que constó de aproximadamente 160 estudiantes y se distribuyó con un muestreo probabilístico tipo estratificado. El cuestionario elaborado se basó en la encuesta online de la Organización de Consumidores y Usuarios (OCU) titulada “Encuesta OCU: los españoles y la vacuna” que fue realizada en España. Para el análisis estadístico se empleó la herramienta estadística IBM SPSS Statistics 25.0.0.0. Se tabularon las variables categóricas para la distribución de frecuencia y porcentajes, y se realizó un análisis bivariado entre las variables de interés y las variables de desenlace, mediante la prueba exacta de Fisher. Resultados: Se encuestó a 155 de 160 universitarios, el 94,8% fueron jóvenes (18-25 años). El semestre académico que representó mayor porcentaje fue octavo ciclo. La mayoría de los ítems del cuestionario obtuvieron el puntaje de 3 puntos según la escala de Likert. El 96,8% de universitarios manifestaron que sí se vacunarían tan pronto como pudieran. Se obtuvo que el factor influyente en la postura ante la inmunización SARS-CoV-2 fue el de la efectividad de la vacuna reduciendo la mortalidad por COVID – 19. Conclusiones: Se concluye que la mayoría de los estudiantes se encontraron a favor de la vacunación. Además, la efectividad de la vacuna reduciendo la mortalidad por COVID-19, fue el único factor influyente. / Objective: To identify the influential factors in the posture before SARS-CoV-2 immunization in medical students of a Lambayeque university in the year 2021. Materials and methods: An analytical cross-sectional observational study was carried out. The entire eligible population was taken, which consisted of approximately 160 college students and was distributed with a stratified probabilistic sampling. The questionnaire prepared was based on the online survey of the Organization of Consumers and Users (OCU) entitled "OCU Survey: Spaniards and the vaccine" that was carried out in Spain. For the statistical analysis, the statistical tool IBM SPSS Statistics 25.0.0.0 was used. Categorical variables were tabulated for frequency distribution and percentages, and a bivariate analysis was performed between the variables of interest and the outcome variables, using Fisher's exact test. Results: 155 of 160 university students were surveyed, 94.8% were young (18-25 years). The semester of studies that represented the highest percentage was eighth cycle. Most of the ítems in the questionnaire obtained a score of 3 points according to the Likert scale. 96.8% of university students stated that they would get vaccinated as soon as they could. It was found that the influential factor in the posture before SARS-CoV-2 immunization was the effectiveness of the vaccine in reducing mortality from COVID-19. Conclusions: It is concluded that the majority of students were in favor of vaccination. Also, the effectiveness of the vaccine in reducing mortality from COVID-19 was the only influential factor.

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.

Pat. mit Multipler Sklerose haben ein erhöhtes Risiko, einen schweren Verlauf einer SARS- CoV-2 Infektion zu entwickeln. Durch das fehlregulierte Immunsystem und durch die mit dem Krankheitsbild verbundenen vielen körperlichen Einschränkungen treten bei MS Pat. häufiger schwere Infektionen auf. Eine Anti-CD20-Antikörpertherapie depletiert vor allem B-Zellen, zu einem geringen Teil auch T-Zellen. Mit dieser immunsupprimierenden Therapie haben Pat. ein nochmals erhöhtes Infektionsrisiko. Zur B-Zell depletierenden Therapie (BZDT) werden aktuell Ocrelizumab, Ofatumumab und Rituximab verwendet. Durch eine Impfung könnten die MS Pat. mit BZDT vor einer SARS-CoV-2 Infektion geschützt werden bzw. ein schwerer Verlauf durch sie verhindert werden. Die Beurteilung der Effektivität einer Impfung kann durch die Analyse der B-Zell spezifischen und T-Zell spezifischen Impfantwort untersucht werden. Ziel der Studie ist es, herauszufinden, ob Pat. trotz der MS-Erkrankung und einer Anti-CD20 Antikörpertherapie eine Impfantwort entwickeln und ob die Pat. dadurch von einer SARS- CoV2-Impfung profitieren.:Abkürzungsverzeichnis Abbildungsverzeichnis Tabellenverzeichnis 1. Einleitung 1.1 Multiple Sklerose 1.1.1 Epidemiologie 1.1.2 Ätiologie und Risikofaktoren 1.1.3 Pathophysiologie 1.1.4 Symptome 1.1.5 Verlaufsformen 1.1.6 Diagnostik 1.1.7 Prognosefaktoren 1.1.8 Therapie 1.2 SARS-CoV-2 1.2.1 Epidemiologie 1.2.2 Ätiologie und Risikofaktoren 1.2.3 Infektion und ihre Immunantwort 1.2.4 Impfung 2. Fragestellung und Zielsetzung 3. Material und Methode 3.1 Einschlusskriterien 3.2 Methode 3.2.1 B-Zell Antwort 3.2.2 T-Zell Antwort 3.3 Statistik 3.4 Pat.kollektiv 4. Ergebnisse 4.1 Ergebnisse nach der Grundimmunisierung 4.1.1 B- und T-Zell Antwort nach der Grundimmunisierung 4.1.2 Einfluss einer SARS-CoV-2-Infektion auf die B- und T-Zell Antwort nach der Grundimmunisierung 4.2 Ergebnisse nach der Booster Impfung 4.2.1 B- und T-Zell Antwort nach der Booster Impfung 4.2.2 Einfluss einer SARS-CoV-2-Infektion auf die B- und T-Zell Antwort nach der Booster Impfung 4.3 SARS-CoV-2 spezifische B- und T-Zell Antwort im Verlauf 4.4 Bedeutung des zeitlichen Beginns einer BZDT auf die SARS-CoV-2 spezifische Impfantwort 5. Diskussion 6. Zusammenfassung 7. Summary 8. Literaturverzeichnis 9. Danksagung 10. Anhang (einschließlich Originalpublikationen) / Patients with multiple sclerosis generally face an elevated risk of experiencing a severe course of SARS-CoV-2 infection. This heightened susceptibility results from the dysregulated immune system and various physical limitations associated with the disease. Anti-CD20 therapy primarily leads to B-cell depletion and, to a lesser extent, T-cell depletion. Consequently, patients undergoing BCDT, which includes ocrelizumab, ofatumumab, and rituximab, are at an even greater risk of infection due to this immunosuppressive therapy. Vaccination emerges crucial of protecting MS patients undergoing BCDT from SARS-CoV-2 infection or mitigating the severity of the disease. The effectiveness of a vaccination can be assessed by analyzing the B-cell specific and T-cell specific vaccination response. The study aims to ascertain whether patients with MS, despite the disease and anti-CD20 antibody therapy, develop a vaccination response and whether they indeed benefit from a SARS-CoV-2 vaccination.:Abkürzungsverzeichnis Abbildungsverzeichnis Tabellenverzeichnis 1. Einleitung 1.1 Multiple Sklerose 1.1.1 Epidemiologie 1.1.2 Ätiologie und Risikofaktoren 1.1.3 Pathophysiologie 1.1.4 Symptome 1.1.5 Verlaufsformen 1.1.6 Diagnostik 1.1.7 Prognosefaktoren 1.1.8 Therapie 1.2 SARS-CoV-2 1.2.1 Epidemiologie 1.2.2 Ätiologie und Risikofaktoren 1.2.3 Infektion und ihre Immunantwort 1.2.4 Impfung 2. Fragestellung und Zielsetzung 3. Material und Methode 3.1 Einschlusskriterien 3.2 Methode 3.2.1 B-Zell Antwort 3.2.2 T-Zell Antwort 3.3 Statistik 3.4 Pat.kollektiv 4. Ergebnisse 4.1 Ergebnisse nach der Grundimmunisierung 4.1.1 B- und T-Zell Antwort nach der Grundimmunisierung 4.1.2 Einfluss einer SARS-CoV-2-Infektion auf die B- und T-Zell Antwort nach der Grundimmunisierung 4.2 Ergebnisse nach der Booster Impfung 4.2.1 B- und T-Zell Antwort nach der Booster Impfung 4.2.2 Einfluss einer SARS-CoV-2-Infektion auf die B- und T-Zell Antwort nach der Booster Impfung 4.3 SARS-CoV-2 spezifische B- und T-Zell Antwort im Verlauf 4.4 Bedeutung des zeitlichen Beginns einer BZDT auf die SARS-CoV-2 spezifische Impfantwort 5. Diskussion 6. Zusammenfassung 7. Summary 8. Literaturverzeichnis 9. Danksagung 10. Anhang (einschließlich Originalpublikationen)

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.