Interferon Beta-1a treatment promotes SARS-CoV-2 mRNA vaccine response in multiple sclerosis subjects

•Disease modifying therapies (DMTs) differentially affect the protective SARS-COV-2 humoral response in MS subjects.•Interferon Beta-1a treatment (IFN) boosts the SARS-COV-2 specific humoral response, which is profoundly impaired in CLAD-, FTY- and OCRE-treated MS subjects.•IFN treatment preserves a good B cell reservoir that correlated with SARS-CoV-2 specific humoral response in MS subjects.•TERI, NAT, CLAD, FTY and OCRE reduce the intrinsic ability to produce anti-spike specific antibodies in MS subjects. Several concerns exist on the immunogenicity of SARS-CoV-2 vaccines in multiple sclerosis (MS) subjects due to their immunomodulating disease modifying therapies (DMTs). Here we report a comparison of the humoral response to BNT162b2-mRNA coronavirus (COVID)-19 vaccine and the immunological phenotype in a cohort of 125 MS subjects undergoing different DMTs, with no history of SARS-CoV-2 infection. We collected serum and blood samples at the first day of vaccine (T0) and 21 days after the second vaccine dose (T1) from 125 MS subjects, undergoing eight different DMTs. Sera were tested using the Elecsys anti-SARS-CoV-2-IgG assay for the detection of IgG antibodies to SARS-CoV-2 spike protein. The anti-spike IgG titres from MS subjects were compared with 24 age- and sex-matched healthy controls (HC). Percentage and absolute number of B and T lymphocytes were evaluated by cytofluorimetric analysis in the same study cohort. When compared with SARS-CoV-2 IgG levels in HC (n = 24, median 1089 (IQR 652.5–1625) U/mL), we observed an increased secretion of SARS-CoV-2 IgG in interferon-beta 1a (IFN)-treated MS subjects (n = 22, median 1916 (IQR 1024–2879) U/mL) and an impaired humoral response in MS subjects undergoing cladribine (CLAD) (n = 10, median 396.9 (IQR 37.52–790.9) U/mL), fingolimod (FTY) (n = 19, median 7.9 (IQR 4.8–147.6) U/mL) and ocrelizumab (OCRE) (n = 15, median 0.67 (IQR 0.4–5.9) U/mL) treatment. Moreover, analysis of geometric mean titre ratio (GMTR) between different DMT's groups of MS subjects revealed that, when compared with IFN-treated MS subjects, intrinsic antibody production was impaired in teriflunomide (TERI)-, natalizumab (NAT)-, CLAD-, FTY- and OCRE-, while preserved in DMF- and GA-treated MS subjects. Humoral response to BNT162b2-mRNA-vaccine was increased in IFN-treated MS subjects while clearly blunted in those under CLAD, FTY and OCRE treatment. This suggests that the DMTs could have a key role in the protection from SARS-CoV-2 r