Vaccination responses in B‐cell‐depleted multiple sclerosis patients: The role of drug pharmacokinetics

Early reports prior to availability of vaccinations show that treatment with antiCD20 monoclonal antibodies (e.g., rituximab, ocrelizumab) in multiple sclerosis (MS) patients is associated with an increased risk of a more severe COVID19 disease course [1, 2]. Consequently, there is much interest in SARSCoV2 vaccinationrelated immune dynamics of Bcelldepleted MS patients [3]. The humoral responses after SARSCoV2 vaccination or infection in Bcelldepleted MS patients are decreased [4, 5], whereas accumulating evidence suggests that Tcell immunity after vaccination remains largely intact [6, 7]. As lower SARSCoV2 antibody titers after vaccination are associated with breakthrough COVID19 in MS patients [8], the need for reliable and forceful predictors of vaccine responsiveness is obvious. To date, two markers for predicting humoral responses after SARSCoV2 vaccinations in antiCD20 (mainly ocrelizumab)treated MS patients have been identified: Bcell count at the moment of vaccination and interval of vaccination versus last infusion [9]. However, as Bcells are fully depleted in the majority of antiBcelltreated patients prior to redosing [9], this might be a suboptimal biomarker for timing vaccinations. Also, delaying vaccination until at least 3 months after last infusion may be a suboptimal strategy, as the seroconversion rate can still be low in patients receiving vaccination a relatively long time after last infusion. In this issue of the European Journal of Neurology, Asplund Högelin and colleagues extensively address vaccination responses in Bcelldepleted MS patients [10]. The authors confirm Bcell count as a predictor of seroconversion and they show that Bcell count is a better predictor than interval between last infusion and vaccination in their cohort of 94 MS patients on antiCD20 therapies of which 82 were using rituximab. The authors also confirm intact Tcell responses after vaccination in the majority of Bcelldepleted patients as reported by others [3, 6, 7]. Apart from Bcell counts and time since last infusion, they introduce rituximab concentrations as a predictor of SARSCoV2 seroconversion after vaccination in MS patients treated with rituximab. The authors were the first to show this association between rituximab levels and seroconversion after SARSCoV2 vaccination. They present a linear decline in SARSCoV2 antibody titers with increased rituximab concentrations, tested 4 weeks after booster vaccination. More than 95% of MS patients below the detection limit of the rituximab enzymelinked immunosorbent assay (ELISA) assay (n = 33) successfully seroconverted. Importantly, antiCD20 treatment duration varied largely in this cohort (0,4– 9.6 years) and about half the patients included in this cohort received treatment >6 months prior to first vaccination. Obviously, as acknowledged by the authors themselves [10], additional work has to be done to translate their findings to applicability in daily practice. First, clinically relevant drug concentrations and a cutoff drug concentration for seroconversion after vaccination need to be determined and confirmed. Also, the optimal timing of measuring the drug levels in relation to the rituximab infusions needs to be established, taking into account the detection limit of the assay. A pharmacokinetic model, which could predict the decline of drug levels in an individual patient, could further guide the optimal timing for vaccination. Also, similar studies should be performed for other antiCD20 treatments, that is, ocrelizumab and ofatumumab, the latter possibly being more complicated due to the frequent administration of the drug. The interesting association between pharmacokinetics and vaccination responses may have clinical relevance for scheduling vaccinations in antiBcelltreated patients and might also be important for patients on antiCD20 drugs other than rituximab. Furthermore, the findings of Asplund Högelin et al. may be extrapolated and could have consequences for patients undergoing vaccinations for other indications than SARSCoV2 and with other underlying diseases requiring