Summary: Multiple sclerosis patients who take Rituximab have a better response to the COVID-19 vaccine if they have a higher B cell count.
Source: Uppsala University
Multiple sclerosis (MS) patients treated with Rituximab have better responses to the COVID-19 vaccine if they have higher B cell counts.
This is the finding of a study from Uppsala University published in the journal JAMA Network Open. In patients with B cell counts of 40/µL (microlitres) or more, 9 of 10 patients developed protective levels of antibodies, while significantly fewer with lower counts had similar responses.
“In our study, the B cell level in patients given Rituximab was the only factor that influenced the ability to form antibodies after vaccination. Previously, it was assumed that it was enough to wait a certain period after administering Rituximab for the vaccine to have a good effect. But to increase the chance of the vaccine causing the body to form antibodies, you first need to measure the level of B cells and ensure there are enough,” says Andreas Tolf, a doctoral student in experimental neurology at Uppsala University and physician at Uppsala University Hospital.
In Sweden, Rituximab is the most common medicine for MS, but it is also used for many other diseases. The medicine is given as a drip, normally once or twice a year, and has a documented good effect on slowing the progression of MS.
The treatment knocks out the body’s B cells, which are an important part of our immune system though they also contribute to the MS disease process. As a result, the treatment increases the risk of patients suffering from serious infections, such as COVID-19.
Having low levels of B cells also makes it more difficult for the body to form protective antibodies against viruses and bacteria, which is the primary purpose of vaccinations. In this case, this concerns the S protein in the SARS-CoV-19 virus.
Researchers at Uppsala University and Uppsala University Hospital have studied how MS patients treated with Rituximab react to vaccination against COVID-19. The purpose was to determine the optimal level of B cells for the patient to form sufficient numbers of antibodies after vaccination.
Blood from a total of 67 individuals with MS was analyzed, of whom 60 were undergoing treatment with Rituximab and 7 were going to begin treatment after their COVID-19 vaccinations. Blood samples were taken before and after vaccination to study the levels of B cells and antibodies for SARS-CoV-2. The patients received two doses of Pfizer’s COVID-19 vaccine Comirnaty, with the active substance tozinameran.
The results show that the levels of B cells varied greatly among the subjects. The longer a patient had been treated with Rituximab, the longer it took their B cells to recover. For some patients, it took over a year before the B cells began to come back.
The patients who responded best to the vaccine and formed sufficiently high levels of antibodies had on average 51 B cells per microlitre (µL) before the vaccination. For the group that did not reach sufficient levels, the average was 22 B cells/µL.
“There was a threshold with a level of B cells at 40/µL or more where 90 percent formed protective levels of antibodies. Of the patients who were undergoing MS treatment with Rituximab, 72 percent formed sufficiently high levels of antibodies. The best effect with the highest percentage of antibodies was found in subjects who had never been treated with Rituximab,” says Anna Wiberg, a researcher in clinical immunology at the Department of Immunology, Genetics and Pathology at Uppsala University.
The researchers have also studied the ability of T cells to react to the virus. No differences were found between subjects who had been treated with Rituximab and those who had never been treated.
The ability of the T cells to react to the virus was just as strong in those who had received treatment. The levels of B cells before vaccination also did not impact the T-cell response, which suggests that all patients have a certain benefit from the vaccination, even if antibodies are not formed.
This prospective cohort study was conducted in a specialized multiple sclerosis clinic at a university hospital from January 21 to December 1, 2021. Of 75 patients evaluated for participation who received a diagnosis of multiple sclerosis with planned or ongoing treatment with rituximab, 69 were included in the study, and data from 67 were analyzed.
Sex, age, number of previous rituximab infusions, accumulated dose of rituximab, previous COVID-19 infection, time since last rituximab treatment, CD19+ B-cell count before vaccination, CD4+ T-cell count, and CD8+ T-cell count were considered potential factors associated with the main outcome.
Main Outcomes and Measures
Serological vaccine responses were measured by quantitation of anti-spike immunoglobulin G (IgG) antibodies, anti–receptor-binding domain (RBD) IgG antibodies, and their neutralizing capacities. Cellular responses to spike protein–derived SARS-CoV-2 peptide pools were assessed by counting interferon gamma spot-forming units in a FluoroSpot assay.
Among 60 patients with ongoing rituximab treatment (49 women [82%]; mean (SD) age, 43  years), the median (range) disease duration was 9 (1-29) years, and the median (range) dose of rituximab was 2750 (500-10 000) mg during a median (range) time of 2.8 (0.5-8.3) years. The median (range) follow-up from the first vaccination dose was 7.3 (4.3-10.0) months.
Vaccine responses were determined before vaccination with tozinameran 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. A cutoff for the B-cell count 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.
No factor associated with the cellular response was identified. Depending on the peptide pool, 21 of 25 patients (84%) to 22 of 25 patients (88%) developed a T-cell response with interferon gamma production at the B-cell count cutoff of at least 40/μL.
Conclusions and Relevance
This cohort study found that for an optimal vaccine response from tozinameran, rituximab-treated patients with multiple sclerosis may be vaccinated as soon as possible, with rituximab treatment delayed until B-cell counts have reached at least 40/μL. An additional vaccination with tozinameran should be considered at that point.