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

Abstract

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.

Keywords: SARS-CoV-2; anti-CD20 therapy; interferon-gamma release assay; multiple sclerosis; ocrelizumab; vaccination.

Figure 1

B- and T-cellular responses to primary vaccination in anti-CD20-depleted versus untreated patients (n = 348). B- and T-cell responses in patients with B-cell-depleting therapy (BCDT) (blue, n = 271) and untreated (green, n = 77) patients to the primary vaccination are presented. BCDT is further differentiated regarding timepoint of last BCDT treatment cycle and vaccination: <91 days (n = 95), between 91 and 180 days (n = 165) and >180 days (n = 11) before vaccination. (A) presents the B-cell response, (B) the T-cell response to Ag1, and (C) the T-cell response to Ag2. Means with 95%CI are presented. The dashed line shows the cut-off for a positive T-cell response, defined at 0.015 IU/mL. For the B-cell response, the cut-off level is defined at 0.08 U/mL. Data were analyzed with generalized linear models with gamma distribution and log link function. Sex, age, Expanded Disability Status Scale, time between vaccination and blood sampling, confirmed previous COVID-19 infection, and treatment group served as fixed factors. For pairwise comparisons, contrast tests with Sidak correction were applied. Asterisks indicate level of statistical significance: * p < 0.05, ** p < 0.01, *** p < 0.001. (A): p < 0.001 for untreated compared to d > 180, p < 0.001 for untreated compared to d 91–180, p < 0.001 for untreated compared to d < 91, p = 0.008 for d > 180 compared to d < 91, p = 0.013 d > 180 compared to d 91–180.

Figure 2

Seroconversion rate of B- and T-cellular responses in anti-CD20 depleted versus untreated patients (n = 367). Seroconversion rate regarding B- (A) and T- (B) cell responses is presented for patients with B-cell-depleting therapy (blue, n = 270) and untreated patients (green, n = 77).

Figure 3

Influence of COVID-19 infection on the B- and T-cellular responses to primary and booster vaccination in anti-CD20 depleted versus untreated patients (n = 341). B- and T-cell responses to primary and booster vaccination with additional COVID-19 infection (pink, circle, respective n for each time point: 244, 248) or without COVID-19 infection (purple, triangle, respective n for each time point: 32, 51) are presented. (A) B-cell response, (B) T-cell response to Ag1, (C) T-cell response to Ag2. Means with 95%CI are depicted. The dashed line shows the cut-off for a positive T-cell response, defined at 0.015 IU/mL. For the B-cell response, the cut-off level is defined at 0.8 U/mL. Data were analyzed with generalized linear mixed models (GLMM) with gamma distribution and log link function. Sex, age, Expanded Disability Status Scale as measure of disability, time between vaccination and blood sampling, timepoint, type of vaccination, confirmed previous COVID-19 infection, treatment group, and the interaction of treatment group and timepoint served as fixed factors. For pairwise comparisons, contrast tests with Sidak correction were applied.

Figure 4

B- and T-cellular responses to booster vaccination in anti-CD20 depleted versus untreated patients (n = 305). B- and T-cell responses in patients with B-cell-depleting therapy (BCDT) (blue, n = 253) and untreated (green, n = 52) patients to the booster vaccination are presented. BCDT is further differentiated regarding timepoint of last BCDT treatment cycle and vaccination: <91 days (n = 87), between 91 and 180 days (n = 146) and >180 days before vaccination (n = 20). (A) presents the B-cell response, (B) the T-cell response to Ag1, and (C) the T-cell response to Ag2. Means with 95%CI are presented. The dashed line shows the cut-off for a positive T-cell response, defined at 0.015 IU/mL. For the B-cell response, the cut-off level is defined at 0.8 U/mL. Data were analyzed with generalized linear models with gamma distribution and log link function. Sex, age, Expanded Disability Status Scale, time between vaccination and blood sampling, confirmed previous COVID-19 infection, and treatment group served as fixed factors. For pairwise comparisons, contrast tests with Sidak correction were applied. Asterisks indicate level of statistical significance: * p < 0.05, ** p < 0.01, *** p < 0.001. (A): p < 0.001 for untreated compared to d >180, p = 0.000 for untreated compared to d 91–180, p = 0.000 for untreated compared to d < 91, (C): p = 0.034 for untreated compared to d < 91, p = 0.005 for untreated compared to d 91–180.

Figure 5

Development of B- and T-cellular responses during follow up in anti-CD20 depleted versus untreated patients (n = 218). B- and T-cell responses in patients with B-cell-depleting therapy (BCDT) (blue, n = 165) and untreated (green, n = 53) patients after vaccination and during follow up are presented (respective n for each time point: 218, 84, 10, 149, 36). (A) presents the B-cell response, (B) the T-cell response to Ag1, and (C) the T-cell response to Ag2. Means with 95%CI are presented. The dashed line shows the cut-off for a positive T-cell response, defined at 0.015 IU/mL. For the B-cell response, the cut-off is defined at 0.8 U/mL. Data were analyzed with generalized linear mixed models (GLMM) with gamma distribution and log link function. Sex, age, Expanded Disability Status Scale as measure of disability, time between vaccination and blood sampling, timepoint, type of vaccination, confirmed previous COVID-19 infection, treatment group, and the interaction of treatment group and timepoint served as fixed factors. For pairwise comparisons, contrast tests with Sidak correction were applied. Asterisks indicate level of statistical significance: * p < 0.05, ** p < 0.01, *** p < 0.001. (A): BCDT: p = 0.003 for primary compared to booster, untreated: p < 0.001 for primary compared to booster, p = 0.013 for primary compared to 3 months, p = 0.009 for primary compared to 6 months.