Metabolic pathways engaged by antigen-specific T and B cells after SARS-CoV-2 vaccination in multiple sclerosis patients on different immunomodulatory drugs reveal immunosenescence and predict vaccine efficacy.

Abstract Disease modifying therapies (DMT) assumed by patients affected by multiple sclerosis (MS) can influence immune response to SARS-CoV-2 and vaccination efficacy. Even if in most treated patients vaccine-induced humoral and cellular responses can be attenuated, scanty data exist on detailed phenotypic, functional and metabolic characteristics of antigen (Ag)-specific cells following the third dose of vaccine. Here, by using flow cytometry and 45-parameter mass cytometry, we broadly investigate the phenotype, function and the single cell metabolic profile (scMEP) of SARS-CoV-2-specific T and B cells up to 8 months after the third dose of mRNA vaccine in a cohort of 93 MS patients treated with different DMT including cladribine, dimethyl fumarate, fingolimod, interferon, natalizumab, teriflunomide or anti-CD20. We find that almost all patients develop a detectable and functional immune response to SARS-CoV-2. In particular, we find that different metabolic profiles characterize antigen-specific T and B cell response in FTY- and natalizumab-treated MS patients, who generate a peculiar immune response which is different from all the other MS treatment. Using prediction analysis, we finally describe a SARS-CoV-2 specific immunological signature that could likely predict protection from breakthrough SARS-CoV-2 infection.