Background: Although FDA-approved COVID vaccines prevent severe infections in the general population, their efficacy in the face of immune modulation or suppression is unclear. Vaccine efficacy is probably partially mediated by the formation of neutralizing antibodies against the COVID Spike protein, although other mechanisms may be important (eg, memory T-cells). The effect of MS DMT’s on spike antibody formation remains controversial. Ocrelizumab attenuates vaccine antibody responses to various bacterial and viral infections (VELOCE). Achiron et al, found that anti-CD20 and S1P agents completely abrogated antibody formation, whereas Gadani et al found 56% prevalence of neutralizing antibodies in anti-cd20 patients. Objectives: The overall aim of our study is the compare the differences in COVID vaccine immunogenicity in the setting of various MS therapies, as reflected by the presence/absence of spike protein IgG. Methods: COVID antibodies were tested in the serum of 134 MS patients at 3-12 weeks post vaccination. Neither DMT administration or vaccine administration was altered (infusions were not delayed) nor were patients encouraged to time COVID vaccinations with therapy administration. Antibody response were evaluated using FDA-authorized assays that generated either a qualitative result (Diasorin) or titer (Labcorp). Assay choice was dictated by payor constraints. Results: COVID antibody responses were less common in patients on anti-cd20 agents (51% of anti-cd20 developed neutralizing antibodies vs 82% other therapies, p = 0.0018) and no difference between Ocrelizumab and Ofatumumab was seen (p=0.60). Cladribine (64%) and S1PR antagonists (67%) demonstrated intermediate immunogenicity and highest responses were seen with T-cell immunomodulators (eg, teriflunomide at 86%, fumarates at 93%). There was no difference in mean neutralizing antibody titers between anti-cd20 therapies vs other therapies (772 vs 796, p = 0.48). Amongst anti-CD20 patients, those who mounted antibody responses demonstrated higher total immunoglobulin levels (p=0.011). None of the vaccinated patients developed moderate-severe COVID infection (ie requiring hospitalization). 3 vaccinated patients tested positive for COVID-PCR, but all had mild symptoms (COVID-19 severity score 1). Conclusions: A major limitation of this study is that T-cell responses were not analyzed. First, analyzing immunogenicity as a prevalence measure (ie, % of patients mounting antibodies) vs mean antibody titers can impact conclusions. There are marked differences between DMTs with regards to COVID vaccine antibody immunogenicity. Total IgG levels may be a biomarker for COVID vaccine immunogenicity in B-cell depleted patients. Further work correlating vaccine immunogenicity with vaccine efficacy is needed. Nonetheless, these data support vaccinating all MS patients regardless of DMT.