B-Cell Count Predicts Covid Vaccine Response in MS Patients on Rituximab

Among multiple sclerosis (MS) patients receiving the B-cell depleting biologic therapy rituximab, serological response to Covid-19 vaccination with an mRNA vaccine was confirmed to be greatly diminished in those with low B-cell counts in a prospective study.

B-cell count proved to be the only factor associated with serological response to the BNT162b2 vaccine, tozinameran, among the 67 MS patients in the study, and researchers identified a B-cell count of at least 40 μL as the optimal cutoff for successful vaccination.

Among the 29 patients with B-cell counts above this cutoff, 90% mounted anti-spike immunoglobulin G (IgG) and 93% developed antibodies with greater than 90% inhibition of angiotensin-converting enzyme 2, noted researcher Andreas Tolf, MD, of Uppsala University, and colleagues, in JAMA Network Open.

Given the B-cell depleting action of rituximab, which is a widely used therapy for MS, delaying Covid-19 vaccination until 3 to 6 months after infusion of the monoclonal antibody has been proposed as a strategy for improving vaccine efficacy in treated patients. It has also been suggested that Covid-19 vaccination should be delayed until CD19+ B-cell count reaches at least 20 μL in rituximab-treated patients.

But Tolf and colleagues concluded that the finding of significant individual variability in patient B-cell recovery following rituximab treatment "favors early vaccination without considering time from last infusion or B-cell count."

"The results also suggest that an additional vaccine dose may be considered when the B-cell count reaches 40/μL to ensure that as many patients as possible will generate an adequate vaccine response," they wrote. "This approach is achievable by delaying treatment with rituximab, which appeared in the present study to be safe."

The multivariate, regression analysis was conducted at a university hospital’s multiple sclerosis clinic from Jan. 21 to Dec. 1, 2021, with data from 67 patients who received a diagnosis of MS with planned or ongoing treatment with rituximab.

Serological vaccine responses were measured by quantitation of anti-spike IgG antibodies, anti–receptor-binding domain (RBD) IgG antibodies, and their neutralizing capacities.

Among 60 patients undergoing rituximab treatment (82% women; mean age, 43 years), the median (range) disease duration was 9 (1-29) years, and the median dose of rituximab was 2,750 mg (500-10,000 mg) over a median time of 2.8 (0.5-8.3) years. The median follow-up from the first vaccination dose was 7.3 (4.3-10.0) months. Vaccine responses were determined before vaccination with the tozinameran vaccine and 6 weeks after vaccination.

"By using established cutoff values for anti-spike IgG (264 binding antibody units/mL) and anti-RBD IgG (506 binding antibody units/mL), the proportion of patients with a positive response increased with the number of B cells, which was the only factor associated with these outcomes," the researchers wrote.

Further, they found that a B-cell count cut-off of at least 40/μL was associated with an optimal serological response.

"At this cutoff, 26 of 29 patients (90%) had positive test results for anti-spike IgG and 21 of 29 patients (72%) for anti-RBD IgG, and 27 of 29 patients (93%) developed antibodies with greater than 90% inhibition of angiotensin-converting enzyme 2," Tolf and colleagues wrote.

"Notably, our data showed a large inter-individual variability in the rate of B-cell recovery," the researchers wrote. "Six months after the last rituximab infusion, 40% of patients had B-cell counts lower than 10/μL. This calls into question the general recommendation of performing vaccinations 3 to 6 months after the last infusion of a B-cell–depleting agent. Instead, relying on the measurement of B-cell counts appears to be the rational approach and is feasible in many hospital settings."

Tolf and colleagues also observed that patients with low initial B-cell counts (<10/μL) were slow mobilizers and increased their B-cell count by a mean of only 7.5 cells per month. In contrast, patients with B-cell counts of at least 10/μL exhibited a much higher rate of recovery, with a mean increase of 18 cells per month.

"Using these data, it should be possible to make a rough estimate of when the target value of the B-cell count can be reached," the researchers wrote.

Tolf and colleagues measured antibody response 6 weeks after the second vaccine dose was given, but they did not measure duration response in the study.

"Booster doses of the vaccination may improve the longevity of vaccines responses, but is was also not investigated," they wrote. "Further studies are needed to address these issues."

Other study limitations included failure to address the effects of vaccine booster doses and T-cell responses.

This study was funded by the Engkvist Foundation, the Marianne and Marcus Wallenberg Foundation, and the Swedish Society for Medical Research.

Tolf reported no disclosures.

Tolf A, et al "Factors associated with serological response to SARS-CoV-2 vaccination in patients with multiple sclerosis treated with rituximab" JAMA Netw Open 2022; DOI:10.1001/jamanetworkopen.2022.11497.