Longitudinal Postvaccine SARS-CoV-2 Immunoglobulin G Titers, Memory B-Cell Responses, and Risk of COVID-19 in Multiple Sclerosis Over 1 Year

BACKGROUND AND OBJECTIVES: Some disease-modifying treatments impair response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in multiple sclerosis (MS), potentially increasing the risk of breakthrough infections. We aimed to investigate longitudinal SARS-CoV-2 antibody dynamics and memory B cells after 2 and 3 messenger RNA (mRNA) vaccine doses and their association with the risk of COVID-19 in patients with MS on different treatments over 1 year. METHODS: Prospective observational cohort study in patients with MS undergoing SARS-CoV-2 mRNA vaccinations. Antispike (anti-S) immunoglobulin G (IgG) titers were measured by chemiluminescence microparticle immunoassay. Frequencies of spike-specific memory B cells were measured on polyclonal stimulation of peripheral blood mononuclear cells and screening of secreted antibodies by ELISA. RESULTS: We recruited 120 patients with MS (58 on anti-CD20 antibodies, 9 on sphingosine 1-phosphate (S1P) receptor modulators, 15 on cladribine, 24 on teriflunomide (TFL), and 14 untreated) and collected 392 samples up to 10.8 months after 2 vaccine doses. When compared with untreated patients, anti-CD20 antibodies (β = −2.07, p < 0.001) and S1P modulators (β = −2.02, p < 0.001) were associated with lower anti-S IgG, while TFL and cladribine were not. Anti-S IgG decreased with months since vaccine (β = −0.14, p < 0.001), independently of treatments. Within anti-CD20 patients, anti-S IgG remained higher in those with greater baseline B-cell counts and were not influenced by postvaccine anti-CD20 infusions. Anti-S IgG increase after a 3rd vaccine was mild on anti-CD20 and S1P modulators. Spike-specific memory B-cell responses were weaker on S1P modulators and anti-CD20 than on TFL and influenced by postvaccine anti-CD20 infusions. The frequency of breakthrough infections was comparable between DMTs, but the risk of COVID-19 was predicted by the last measured anti-S IgG titer before infection (OR = 0.56, 95% CI = 0.37–0.86, p = 0.008). DISCUSSION: Postvaccine anti-S IgG titers decrease over time regardless of MS treatment and are associated with breakthrough COVID-19. Both humoral and specific memory B-cell responses are diminished on S1P modulators. Within anti-CD20–treated patients, B-cell count at first vaccine determines anti-S IgG production, whereas postvaccine anti-CD20 infusions negatively affect spike-specific memory B cells.