Immunosenescence and vaccine efficacy revealed by immunometabolic analysis of SARS-CoV-2-specific cells in multiple sclerosis patients

Abstract

Disease-modifying therapies (DMT) administered to patients with multiple sclerosis (MS) can influence immune responses to SARS-CoV-2 and vaccine efficacy. However, data on the detailed phenotypic, functional and metabolic characteristics of antigen (Ag)-specific cells following the third dose of mRNA vaccine remain scarce. Here, using flow cytometry and 45-parameter mass cytometry, we broadly investigate the phenotype, function and the single-cell metabolic profile of SARS-CoV-2-specific T and B cells up to 8 months after the third dose of mRNA vaccine in a cohort of 94 patients with MS treated with different DMT, including cladribine, dimethyl fumarate, fingolimod, interferon, natalizumab, teriflunomide, rituximab or ocrelizumab. Almost all patients display functional immune response to SARS-CoV-2. Different metabolic profiles characterize antigen-specific-T and -B cell response in fingolimod- and natalizumab-treated patients, whose immune response differs from all the other MS treatments.

Implications of disease-modifying therapies for multiple sclerosis on immune cells and response to COVID-19 vaccination

“…In line with previous studies ( 10 , 31 – 33 ), we observed pronounced immune cell dysregulation in FTY-treated patients, characterized by reduction of all lymphocyte cell types considered. However, in contrast to a previous study ( 34 ), we also detected a significant reduction in Th2 frequency accompanied by a nominal increase in Th1.…”

“…This was seen both by evaluating cell surface activation markers and cytokine secretion, and was evident in all MS groups assessed, particularly in FTY-treated patients. These findings are in line with the premature immunosenescence observed in MS and in patients with other inflammatory conditions ( 10 , 39 , 40 ); it includes thymic involution ( 41 ), telomere length shortening ( 42 ), decline in the adaptive immune response, and an expansion of age-associated B cells ( 43 ), with a possible contribution to neurodegeneration ( 44 – 46 ). Overall, these changes also cause a concomitant increase in the pro-inflammatory state, a phenomenon known as inflammaging ( 47 , 48 ), and a reduced immune response to vaccination ( 49 ).…”

“…Previous studies have mainly evaluated humoral response ( 1 – 4 ) or cytokine production after SARS-CoV-2 vaccination ( 5 – 8 ) and few focused on dissection of both the B and T cell compartments of the cellular immune response ( 9 , 10 ). Some have studied the effects of only a specific treatment, such as anti-CD20 antibody drugs ( 11 , 12 ), or only a specific time after vaccination ( 13 – 18 ).…”