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Various studies indicated blunted humoral responses to COVID-19 mRNA and viral vector vaccines among people with multiple sclerosis (pwMS) on sphingosine 1-phosphate receptor (S1PR) modulators and anti-CD20 therapies (aCD20); however, limited evidence was found regarding SARS-CoV-2 serology after inactivated virus vaccination. To provide evidence regarding humoral response to COVID-19 inactivated virus vaccination among pwMS on disease-modifying therapies (DMTs). A cohort study was carried out in Isfahan, Iran, enrolling DMT-exposed pwMS and unexposed (UX) healthy participants. Post-vaccination anti-SARS-CoV-2 Spike IgG serology testing was carried out among the participants and compared between participants based on their DMT exposure, using proper statistical tests. A multivariable logistic regression model was used to control for confounding. Association between the second vaccine dose-to-phlebotomy (vac2phleb) and the humoral response was investigated in each DMT-exposed cohort, using linear regression. Among the aCD20 cohort, the association of the last aCD20 infusion-to-first vaccine dose period with serostatus was investigated using an unpaired t -test. After enrolling 358 participants (144 pwMS and 214 healthy), blunted humoral responses were only observed in fingolimod (Log 10 mean diff. [SE]: 0.72 [0.18], P = 0.001) and aCD20 (Log 10 mean diff. [SE]: 0.75 [0.15], P < 0.001) cohorts compared to the UX cohort. Multivariable analysis confirmed the results. The study did not achieve enough statistical power to detect a significant association between the vac2phleb period and humoral responses. The last aCD20 infusion to first vaccination dose period was longer in the seroconverted pwMS on aCD20 (mean diff. [SE]: 8.43 weeks [2.57], P = 0.005). The results of this study mirrored the results of previous studies among mRNA- or viral vector-vaccinated pwMS on DMTs. Therefore, it can be concluded that mode of action contributes less than timing, to the efficiency of vaccination strategies among pwMS on DMTs – especially the ones on S1PR modulators and aCD20. Meanwhile, the mentioned pwMS should be advised to receive early boosters and remain vigilant until further data becomes available and more efficient vaccination strategies are crafted. [ABSTRACT FROM AUTHOR]