Background In patients with Multiple Sclerosis (pwMS) disease-modifying therapies (DMTs) affects immune response to antigens. Therefore, post-vaccination serological assessments are needed to evaluate the effect of the vaccine on SARS-CoV-2 antibody response. Methods We designed a prospective multicenter cohort study enrolling pwMS who were scheduled for SARS-Cov-2 vaccination with mRNA vaccines (BNT162b2, Pfizer/BioNTech,Inc or mRNA-1273, Moderna Tx,Inc). A blood collection before the first vaccine dose and 4 weeks after the second dose was planned, with a centralized serological assessment (electrochemiluminescence immunoassay, ECLIA, Roche-Diagnostics). The log-transform of the antibody levels was analyzed by multivariable linear regression. Findings 780 pwMS (76% BNT162b2 and 24% mRNA-1273) had pre- and 4-week post-vaccination blood assessments. 87 (11·2%) were untreated, 154 (19·7%) on ocrelizumab, 25 (3·2%) on rituximab, 85 (10·9%) on fingolimod, 25 (3·2%) on cladribine and 404 (51·7%) on other DMTs. 677 patients (86·8%) had detectable post-vaccination SARS-CoV-2 antibodies. At multivariable analysis, the antibody levels of patients on ocrelizumab (201-fold decrease (95%CI=128–317), p < 0·001), fingolimod (26-fold decrease (95%CI=16–42), p < 0·001) and rituximab (20-fold decrease (95%CI=10–43), p < 0·001) were significantly reduced as compared to untreated patients. Vaccination with mRNA-1273 resulted in a systematically 3·25-fold higher antibody level (95%CI=2·46–4·27) than with the BNT162b2 vaccine ( p < 0·001). The antibody levels on anti-CD20 therapies correlated to the time since last infusion, and rituximab had longer intervals (mean=386 days) than ocrelizumab patients (mean=129 days). Interpretation In pwMS, anti-CD20 treatment and fingolimod led to a reduced humoral response to mRNA-based SARS-CoV-2 vaccines. As mRNA-1273 elicits 3·25-higher antibody levels than BNT162b2, this vaccine may be preferentially considered for patients under anti-CD20 treatment or fingolimod. Combining our data with those on the cellular immune response to vaccines, and including clinical follow-up, will contribute to better define the most appropriate SARS-CoV-2 vaccine strategies in the context of DMTs and MS. Funding FISM[2021/Special-Multi/001]; Italian Ministry of Health‘Progetto Z844A 5 × 1000′.

The accumulation of B lymphocyte clones in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) and patients with other neurological disorders was investigated using PCR technologies. Oligoclonal B cell accumulations were detected in 10 of 10 MS patients, but only in 3 of 10 of the patients with other neurological disorders. Analyses of the Ig V(D)J sequences on the CSF from MS patients disclosed that VH3 and VH4 genes were extensively mutated compared with germline sequences. Moreover, a substantial proportion of the molecular clones analyzed shared the same third CDR of the H chain variable region gene (HCDR3) and the same VH genes, albeit with different numbers and locations of point mutations, thus indicating an ongoing process of intraclonal diversification. A larger number of clonally related VH sequences could be obtained by using a VH3 gene-specific PCR so that genealogical trees depicting the process of diversification could be drawn. Analyses of the Ig V(D)J from the CSF of a patient with viral meningitis and oligoclonal B cell accumulations revealed that VH3 genes were extensively mutated. However, no intraclonal diversification could be observed even using VH3 gene-specific PCR methodologies. Clone-specific PCR and sequencing was used to detect the V(D)J found in the CSF of one MS patient in the PBL of the same patient. Only 1/3 of the V(D)J sequences investigated could be demonstrated in the PBL, indicating that the V(D)J genes utilized by B cells in the CSF are much less represented in the PBL. Collectively, the data suggest that in MS there is a compartmentalized clonal expansion.

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