B‐cell repopulation dynamics and drug pharmacokinetics impact SARS‐CoV‐2 vaccine efficacy in anti‐CD20‐treated multiple sclerosis patients

Abstract

Background and purpose Recent findings document a blunted humoral response to SARS‐CoV‐2 vaccination in patients on anti‐CD20 treatment. Although most patients develop a cellular response, it is still important to identify predictors of seroconversion to optimize vaccine responses. Methods We determined antibody responses after SARS‐CoV‐2 vaccination in a real‐world cohort of multiple sclerosis patients ( n = 94) treated with anti‐CD20, mainly rituximab, with variable treatment duration (median = 2.9, range = 0.4–9.6 years) and time from last anti‐CD20 infusion to vaccination (median = 190, range = 60–1032 days). Results We find that presence of B cells and/or rituximab in blood predict seroconversion better than time since last infusion. Using multiple logistic regression, presence of >0.5% B cells increased probability of seroconversion with an odds ratio (OR) of 5.0 (95% confidence interval [CI] = 1.0–28.1, p = 0.055), whereas the corresponding OR for ≥6 months since last infusion was 1.45 (95% CI = 0.20–10.15, p = 0.705). In contrast, detectable rituximab levels were negatively associated with seroconversion (OR = 0.05, 95% CI = 0.002–0.392, p = 0.012). Furthermore, naïve and memory IgG + B cells correlated with antibody levels. Although retreatment with rituximab at 4 weeks or more after booster depleted spike‐specific B cells, it did not noticeably affect the rate of decline in antibody titers. Interferon‐γ and/or interleukin‐13 T‐cell responses to the spike S1 domain were observed in most patients, but with no correlation to spike antibody levels. Conclusions These findings are relevant for providing individualized guidance to patients and planning of vaccination schemes, in turn optimizing benefit–risk with anti‐CD20.

Sustained Low Relapse Rate With Highly Variable B-Cell Repopulation Dynamics With Extended Rituximab Dosing Intervals in Multiple Sclerosis

“…In summary, our findings suggest that anti-CD20 dose interval extension could be considered in patients with RRMS with stable disease without incurring risk of return of inflammatory disease activity in the short to medium term, especially in case of treatment-related adverse events or when planning pregnancy. Further studies are needed to determine whether dose interval extension is also associated with a lowered risk of infection, while it has been shown that vaccination responses are improved with B-cell repopulation, 27 in turn improving benefit-risk with anti-CD20 therapies.…”

Ocrelizumab Concentration Is a Good Predictor of SARS‐CoV‐2 Vaccination Response in Patients with Multiple Sclerosis

“…Recently, rituximab concentration was also studied in relation to SARS‐CoV‐2 immunity. 15 In a cohort of patients with MS with variable intervals from the last infusion to vaccination (0.2–2.8 years) and consequently rituximab levels below the detection limit in 55% (33/60), rituximab concentrations were associated with humoral responses after vaccination. We show that also in the approved interval of 6 months, ocrelizumab drug concentration is a good predictor of the humoral response.…”

Central Nervous System Neuroimmunologic Complications of COVID-19

“…112 113 Extended interval dosing and redosing pending B-cell repopulation are strategies that may be beneficial for vaccine seroconversion and are reasonable to consider if patients are at low risk for an inflammatory event but high risk for severe COVID-19. 114 115…”