MS COVID and B cell biology

I guess we have all had enough of COVID-19, but events have allowed us to uncovermore about biology of the disease modifying treatments. Anti-CD20 B cell depleting antibodies have come under the spotlight in terms of antibody response and B cell repopulation. We made the point years ago that anti-CD20 may be over-dosedand that many people may not require dosing every 6 months (with ocrelizumab/rituximab). We have suggested that the naive/mature cells are the precursors for antibody responses and the capacity to affect memory B cells are important for control of MS. When depleted it takes on average about 60-70 weeks (after 3-4 doses) for the naive B cells to come back and when they do, you can often make a vaccine response. Diseasemay take sometime to return when you stop taking anti-CD20 and if it is like alemtuzumab it may not in about 50% of people after a few doses, But it needs a trial. Is there evidence for this idea…I would say Duh or course there is, but not enough for the neuros .But here is more evidence, In this study people had had on average 5 infusions (range 1-8) and reach lowere limit of normal levels after 13-18 months (53 weeks-78 weeks). There were two people who relapsed and there was no change on EDSS, but these were people with progressive MS. There is no incentive fpr pharma to resolvethis biology

Moser T, O’Sullivan C, Otto F, Hitzl W, Pilz G, Schwenker K, Mrazek C, Haschke-Becher E, Trinka E, Wipfler P, Harrer A. Long-term immunological consequences of anti-CD20 therapies on humoral responses to COVID-19 vaccines in multiple sclerosis: an observational study. Ther Adv Neurol Disord. 2022 Apr 22;15:17562864221092092.

Background: Anti-CD20 therapies induce pronounced B-cell depletion and blunt humoral responses to vaccines. Recovery kinetics of anti-CD20 therapy-mediated cellular and humoral effects in people with multiple sclerosis (pwMS) are poorly defined.

Objective: To investigate the duration of the anti-CD20 treatment-induced effects on humoral responses to COVID-19 vaccines.

Methods: This retrospective observational study included pwMS who had discontinued anti-CD20 therapy for ⩾12 months and remained without immunomodulation. We retrieved demographics and laboratory parameters including B-cell counts and immunoglobulin (IgG, IgM, IgA) levels prior to anti-CD20 commencement (baseline) and longitudinally after anti-CD20 treatment discontinuation from electronic medical records. Humoral responses to SARS-CoV-2 vaccines were compared with a population of 11 pwMS with ongoing anti-CD20 medication (control cohort).

Results: A total of 24 pwMS had discontinued anti-CD20 therapy for a median of 34 months (range: 16-38 months). Antibody responses to COVID-19 vaccines were available in 17 (71%). Most individuals (n = 15, 88%) elicited a measurable antibody response [mean: 774 BAU/ml (±SD 1283 BAU/ml)] to SARS-CoV-2 immunization on average 22 months (range: 10-30 months) from the last anti-CD20 infusion, which was higher compared with the population with ongoing anti-CD20 therapy (n = 11, mean: 12.36 ± SD 11.94 BAU/ml; p < 0.00001). Significantly increased antibody levels compared with the control cohort were found among pwMS who were vaccinated >18 months after treatment discontinuation (19-24 months: n = 2, p = 0.013; 25-36 months: n = 9; p < 0.001). The interindividual kinetics for B-cell reconstitution were heterogeneous and mean B-cell counts approached normal ranges 18 months after treatment discontinuation. There was no correlation of B-cell repopulation and vaccine responses. Mean total IgG, IgM, and IgA levels remained within the reference range.

Conclusion: Anti-CD20-induced inhibition of humoral responses to COVID-19 vaccines is transient and antibody production was more pronounced (greater than) >18 months after anti-CD20 treatment discontinuation. The immunological effect on B-cell counts appears to wane by the same time

This is cancer but again shows us that if you are dosing to standard 6 monthly schedule then the chances of generating an antibody response is reduced. If you wait a year about 30% of people still don’t make a vaccine response

Promising efficacy of following a third dose of mRNA SARS-CoV-2 vaccination in patients treated with anti-CD20 antibody who failed 2-dose vaccinationFunakoshi, Y., Yakushijin, K., Ohji, G., Hojo, W., Sakai, H., Watanabe, M., Kitao, A., Miyata, Y., Saito, Y., Kawamoto, S., Yamamoto, K., Ito, M., Koyama, T., Imamura, Y., Kiyota, N., Matsuoka, H., Mori, Y., Minami, H. MedRXiv 10.1101/2022.04.28.22274174 

Anti-CD20 antibodies react with CD20 expressed not only on malignant B cells but also on normal B cells. It has been reported that patients treated with anti-CD20 antibodies had an insufficient response to two-dose mRNA SARS-CoV-2 vaccination. To investigate the efficacy of a third dose in these patients, we investigated serum IgG antibody titers for S1 protein after third vaccination in 22 patients treated with anti-CD20 antibody who failed two-dose vaccination. Results showed that overall, 50% of patients seroconverted. Although no patient who received the third dose within 1 year of the last anti-CD20 antibody administration showed an increase in S1 antibody titer, 69% of patients who received the third dose more than 1 year after the last anti-CD20 antibody administration seroconverted. Our data show that a third dose of vaccination is effective in improving seroconversion rate in patients treated with anti-CD20 antibody who failed standard two-dose vaccination.

Antibodies in people who have been infected or vaccinated can be collected and can be given to immune depleted people. What this shows is that in many cases there is benefit and people get better but more slowly and in a few people the virus acquires mutations that have the potential for immune escape (escape from immune control), So another indication that immune compromised people may give rise to new variants

Antibody response and intra-host viral evolution after plasma therapy in COVID-19 patients pre-exposed or not to B-cell depleting agents Gachoud, D., Pillonel, T., Gerasimos, T., Battola, D., Dumas, D., Opota, O., Fontana, S., Vollenweider, P., Manuel, O., Greub, G., Bertelli, C., Rufer, N.10.1101/2022.04.24.22274200 — Posted: 2022-04-26.

Background Administration of plasma therapy may contribute to viral control and survival of COVID-19 patients receiving B-cell depleting agents that hinder the endogenous humoral response. However, little is known on the impact of anti-CD20 pre-exposition and the use of different sources of plasma (convalescent versus vaccinated) on the kinetics of SARS-CoV-2-specific antibodies and viral evolution after plasma therapy.

Methods Eligible COVID-19 patients (n = 36), half of them after anti-CD20 targeted therapy, were treated with therapeutic plasma from convalescent (n = 17) or mRNA-vaccinated (n = 19) donors. Each plasma-transfused patient was thoroughly monitored over time by anti-S IgG quantification and whole-genome SARS-CoV-2 sequencing.

Results The majority of anti-CD20 pre-exposed patients (15/18) showed progressive declines of anti-S protein IgG titers following plasma therapy, indicating that they mostly relied on the passive transfer of anti-SARS-CoV-2 antibodies (Antibodies from the plasma). Such antibody kinetics correlated with prolonged infection before virus clearance, contrasting with the endogenous humoral response predominantly present in patients who had not received B-cell depleting agents (15/18). No relevant differences were observed between patients treated with plasma from convalescent and/or vaccinated donors. Finally, 4/30 genotyped patients showed increased intra-host viral evolution and 3/30 included 1 to 4 spike mutations, potentially associated to immune escape.

Conclusions Convalescent and/or vaccinated plasma therapy (anti-SARS-COV-2 antibody in the blood fluid) may provide anti-SARS-CoV-2 antibodies and clinical benefit to B-cell depleted COVID-19 patients. Only a limited number of patients acquired viral mutations prior to clinical recovery, yet our study further emphasizes the need for long-term surveillance for intra-host variant evolution, to guide best therapeutic strategies.

COI multiple but none relevant

Dislaimer: The views of the author and no one else