ABSTRACT
Introduction: Some disease modifying treatments (DMTs) impair response to SARS-CoV-2 vaccines in multiple sclerosis (MS), potentially increasing the risk of breakthrough infections. Objective(s): To investigate longitudinal post-vaccine antibody dynamics and memory B cell responses after 2 and 3 SARSCoV- 2 mRNA vaccine doses, and their association with risk of COVID-19 in MS patients treated with different DMTs. Method(s): Prospective observational monocenter cohort study in MS patients undergoing SARS-CoV-2 mRNA vaccinations. Anti- SARS-CoV-2 spike IgG serum titers were measured by chemiluminescence microparticle immunoassay. Frequency of spike-specific memory B cells were measured upon polyclonal stimulation of total PBMCs and screening of secreted antibodies by ELISA. Result(s): We recruited 120 MS patients (58 on anti-CD20, 9 on S1P-modulators, 15 on cladribine, 24 on teriflunomide and 14 untreated) and collected 392 samples before and up to 10.8 months after a 2nd vaccine dose. Compared to no treatment, anti-CD20 antibodies (beta=-2.07, p<0.001) and S1P-modulators (beta=-2.02, p<0.001) were associated with lower anti-spike IgG titers, while teriflunomide and cladribine were not. Anti-spike IgG titers progressively decreased with months since last vaccine dose (beta=-0.14, p<0.001), independently of DMTs. Within anti-CD20 treated patients, anti-spike IgG remained constantly higher in those with greater baseline CD19+ B cell counts and were not influenced by post-vaccine anti-CD20 infusions. Antispike IgG titers increased after a 3rd vaccine dose on cladribine and teriflunomide and marginally on anti-CD20 and S1Pmodulators. Spike-specific memory B cell responses were weaker on S1P-modulators and anti-CD20 than on teriflunomide and influenced by post-vaccine anti-CD20 infusions. Risk of SARS-CoV-2 infection was predicted by SARS-CoV-2 IgG at last sample before infection (OR=0.56, 95%CI=0.37-0.86, p=0.008). Conclusion(s): Post-vaccine SARS-CoV-2 IgG antibody titers progressively decrease over time in MS regardless of DMTs, and are associated with risk of breakthrough COVID-19. Both immediate humoral and specific memory B cell responses are diminished in patients on S1P-modulator and anti-CD20 antibody treatments. Within the latter group, B cell count at first vaccine dose determines anti-spike IgG production shortly after vaccination, whereas post-vaccine anti-CD20 infusions negatively impact memory B cell responses.