T cell responses to COVID-19 infection and vaccination in patients with multiple sclerosis receiving disease-modifying therapy.

BACKGROUND: Multiple sclerosis (MS) is a neurological disorder marked by accumulating immune-mediated damage to the central nervous system. The dysregulated immune system in MS combined with immune effects of disease-modifying therapies (DMTs) used in MS treatment could alter responses to infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that causes coronavirus disease 2019 (COVID-19). Most of the literature on immune response to SARS-CoV-2 infection and COVID-19 vaccination, in both the general population and patients with MS on DMTs, has focused on humoral immunity. However, immune response to COVID-19 involves multiple lines of defense, including T cells. OBJECTIVE AND METHODS: We review innate and adaptive immunity to COVID-19 and expand on the role of T cells in mediating protective immunity against SARS-CoV-2 infection and in responses to COVID-19 vaccination in MS. RESULTS: Innate, humoral, and T cell immune responses combat COVID-19 and generate protective immunity. Assays detecting cytokine expression by T cells show an association between SARS-CoV-2-specific T cell responses and milder/asymptomatic COVID-19 and protective immune memory. CONCLUSION: Studies of COVID-19 immunity in people with MS on DMTs should ideally include comprehensive assessment of innate, humoral, and T cell responses.

Evaluation of immunological responses to third COVID-19 vaccine among people treated with sphingosine receptor-1 modulators and anti-CD20 therapy.

BACKGROUND: People living with multiple sclerosis (MS) and other disorders treated with immunomodulatory therapies remain concerned about suboptimal responses to coronavirus disease 2019 (COVID-19) vaccines. Important questions persist regarding immunological response to third vaccines, particularly with respect to newer virus variants. The objective of this study is to evaluate humoral and cellular immune responses to a third COVID-19 vaccine dose in people on anti-CD20 therapy and sphingosine 1-phosphate receptor (S1PR) modulators, including Omicron-specific assays. METHODS: This is an observational study evaluating immunological responses to third COVID-19 vaccine dose in participants treated with anti-CD20 agents, S1PR modulators, and healthy controls. Neutralizing antibodies against USA-WA1/2020 (WA1) and B.1.1.529 (BA.1) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were measured before and after third vaccine. Groups were compared by one-way ANOVA with Tukey multiple comparisons. Cellular responses to spike peptide pools generated from WA1 and BA.1 were evaluated. Pre-post comparisons were made by Wilcoxon paired t-tests, inter-cohort comparisons by Mann-Whitney t-test. RESULTS: This cohort includes 25 participants on anti-CD20 therapy, 12 on S1PR modulators, and 14 healthy controls. Among those on anti-CD20 therapy, neutralizing antibodies to WA1 were significantly reduced compared to healthy controls (ID50% GM post-vaccination of 8.1 ± 2.8 in anti-CD20 therapy group vs 452.6 ± 8.442 healthy controls, P < 0.0001) and neutralizing antibodies to BA.1 were below the threshold of detection nearly universally. However, cellular responses, including to Omicron-specific peptides, were not significantly different from controls. Among those on S1PR modulators, neutralizing antibodies to WA1 were detected in a minority, and only 3/12 had neutralizing antibodies just at the limit of detection to BA.1. Cellular responses to Spike antigen in those on S1PR modulators were reduced by a factor of 100 compared to controls (median 0.0008% vs. 0.08%, p < 0.001) and were not significantly "boosted" by a third injection. CONCLUSIONS: Participants on anti-CD20 and S1PR modulator therapies had impaired antibody neutralization capacity, particularly to BA.1, even after a third vaccine. T cell responses were not affected by anti-CD20 therapies, but were nearly abrogated by S1PR modulators. These results have clinical implications warranting further study.

Differential antibody response to COVID-19 vaccines across immunomodulatory therapies for multiple sclerosis.

BACKGROUND: Prior studies suggest reduced humoral response to COVID-19 vaccination in immunosuppressed populations. Disease modifying therapies (DMTs) for multiple sclerosis (MS) have variable immunomodulatory effects, and limited data are available for all DMTs. We aimed to determine the impact of DMTs on antibody response to COVID-19 vaccination among MS patients. METHODS: Patients with documented COVID-19 vaccination dates and anti-spike antibody results post-vaccination were identified between March-August 2021. Clinical data were retrospectively abstracted from chart review. Deidentified data were analyzed to evaluate antibody response, and multivariable logistic regression analyses were used to identify clinical and demographic predictors of antibody response. Data analysis was completed with SAS Studio, v3.8. RESULTS: A total of 353 individuals had documented COVID-19 vaccine and antibody test dates (58% Pfizer, 38% Moderna, and 4% Johnson & Johnson). Of these 353 patients, 72% developed antibodies, with a mean antibody test interval of 53 days (median 46) post final vaccine dose. 100% of those on no DMT (n = 34), injectables (n = 20), teriflunomide (n = 10), natalizumab (n = 71), and 97.8% of those on fumarates (n = 46/47) had a positive antibody result. One patient on cladribine (n = 1) had a negative antibody result. Of those on sphingosine-1 phosphate (S1P) modulators, 72.4% (n = 21/29) had a positive antibody result. Of those on anti-CD20 therapies, 37.6% (n = 53/141) had a positive antibody result. Multivariate modeling of the total cohort showed anti-CD20 therapy was significantly associated with lower odds of positive antibody response (OR = 0.024, 95% CI 0.01;0.05, p < 0.0001). Among S1P modulators, increased duration of therapy, and not lymphopenia, may be associated with lower odds of positive antibody response. Multivariate modeling of anti-CD20 therapies showed therapy duration < 1 year (OR 8.14, 95% CI 2.896;22.898 p < .0001) and prior COVID-19 infection (OR = 3.95, 95% CI 1.137;13.726, p = .03) were significantly associated with higher odds of a positive antibody response. In patients with recent B-cell data, mean B-cell count was higher in antibody-positive individuals compared to antibody-negative (32.9 vs. 3.9 cells, p = .0056). CONCLUSION: MS DMTs had variable impact on antibody response with mRNA and viral vector COVID-19 vaccines. All patients on no DMT, interferons, glatiramer acetate, teriflunomide, natalizumab, and nearly all on fumarates had positive antibody responses post-vaccine. S1P modulators and anti-CD20 therapies attenuated antibody response post-vaccine. For patients on anti-CD20 therapies, shorter duration of therapy and prior COVID-19 infection predicted positive antibody response. Further studies are needed to determine clinical significance of antibody testing, development of cellular mediated immunity, and benefits of booster vaccinations.