The UK has been deluding itself and its citizens (So what’s new there?) The French and Italian Data show worse signs with anti-CD20 treatment, Swiss data show poor vaccine response in both T and B cells after CD20 depletion and the Dutch support the Italians on delaying tactics.
It seems that the UK government (public health) is coming under fire for suggesting everything is fine with the double jab for clinical risk groups. However, if you have been reading my posts you know this is not the case notably for people with blood cancers, arthritis and MS. The people writing the Green book (UK advice for vaccinations) have been deluding themselves since they wrote chapter 14 in Novemebr 2020, where they implied ebola vaccine studies were in people infected with HIV (read the paper and this was 5% of the trial cohort and none had AIDS. Even in the most recent COVID-19 in people with HIV the level fo CD4 was less than in most people treated with MS drugs).
We know that CD20-depleting antibodies can be associated with worse course. This is re-affirmed with the combined Italian (Reported a problem before) and French (Didn’t report a problem) data show worse signs of COVID-19 if treated with anti-CD20. This is seen in the Swedish data too
DMTs and Covid–19 severity in MS: a pooled analysis from Italy and France.Sormani MP, Salvetti M, Labauge P, Schiavetti I, Zephir H, Carmisciano L, Bensa C, De Rossi N, Pelletier J, Cordioli C, Vukusic S, Moiola L, Kerschen P, Radaelli M, Théaudin M, Immovilli P, Casez O, Capobianco M, Ciron J, Trojano M, Stankoff B, Créange A, Tedeschi G, Clavelou P, Comi G, Thouvenot E, Battaglia MA, Moreau T, Patti F, De Sèze J, Louapre C; Musc-19; Covisep study groups.Ann Clin Transl Neurol. 2021 Jul 7. doi: 10.1002/acn3.51408. Online ahead of print. We evaluated the effect of DMTs on Covid-19 severity in patients with MS, with a pooled-analysis of two large cohorts from Italy and France. The association of baseline characteristics and DMTs with Covid-19 severity was assessed by multivariate ordinal-logistic models and pooled by a fixed-effect meta-analysis. 1066 patients with MS from Italy and 721 from France were included. In the multivariate model, anti-CD20 therapies were significantly associated (OR = 2.05, 95%CI = 1.39-3.02, p < 0.001) with Covid-19 severity, whereas interferon indicated a decreased risk (OR = 0.42, 95%CI = 0.18-0.99, p = 0.047). This pooled-analysis confirms an increased risk of severe Covid-19 in patients on anti-CD20 therapies and supports the protective role of interferon. Both in Italy and France, the number of patients on rituximab was low (n = 20 in Italy and n = 34 in France). However, separating the effect of anti-CD20 agents into rituximab and ocrelizumab, it was possible to detect a higher risk for rituximab (ORItaly = 3.78, ORFrance = 2.56, pooled OR = 3.04 (95%CI = 1.63, 5.67, p < 0.001)) versus other therapies. The effect of ocrelizumab alone was also significant (ORItaly = 1.79, ORFrance = 1.73, pooled OR = 1.77 (95%CI = 1.15, 2.72, p < 0.001)).
So no matter how hard the manufacturers may want us/you to think otherwise (COVID-19 in ocrelizumab-treated people with multiple sclerosis.Hughes R, Whitley L, Fitovski K, Schneble HM, Muros E, Sauter A, Craveiro L, Dillon P, Bonati U, Jessop N, Pedotti R, Koendgen H.Mult Scler Relat Disord. 2021 Apr;49:102725), this story is repeated in many studies in MS and other conditions. However any increased risk is small and remember the benefit that effective treatments have.
Indeed we are seeing over and over again that CD20 antibody inhibits antibody response. What about a T cell response? Whilst we have seen 100% T cell response in some studies, the Swiss report below that the T cell response is reduced in addition to a reduced B cell response. Now some of this is depends on the assay system used, but most studies reported so far in other conditions where the antiibody response is reduced, do not show a 100% T cell responsiveness (Remeber I’m a glass half-empty-type of person…ProfG is half-full). The study below is not MS, but a number of different conditions where B cell depleting agents are used. The T cell response is inhibited too. As I have suggested already vaccine response is better the more B cells you have and a longer interval between dosing.
Humoral and cellular responses to mRNA vaccines against SARS-CoV2 in patients with a history of CD20-B-cell depleting therapyMatthias B. Moor, Franziska Suter-Riniker, Michael P. Horn, Daniel Aeberli, Jennifer Amsler, Burkhard Möller, Linet M. Njue, Cesare Medri, Anne Angelillo-Scherrer, Luca Borradori, Susanne Radonjic-Hoesli, Andrew Chan, Robert Hoepner, Vera Ulrike Bacher, Laila-Yasmin Mani, Joseena Mariam Iype, Cédric Hirzel, Britta Maurer, Daniel SidlermedRxiv 2021.07.04.21259848; doi: https://doi.org/10.1101/2021.07.04.21259848. Background B-cell depleting therapies increase COVID19 morbidity and mortality. For this specific population, evidence-based vaccination strategies are lacking. Here, we investigated humoral and cell mediated immune responses to SARS-CoV2 mRNA-based vaccines in patients receiving CD20-B-cell depleting agents for autoimmune disease, malignancy, or transplantation.Methods Patients at the Bern University Hospital with a treatment history of anti-CD20 depleting agents (rituximab or ocrelizumab) were enrolled for analysis of humoral and cell-mediated immune responses (by interferon-γ release assay) after completing vaccination against SARS-CoV2. Primary outcome was the the anti-spike antibody response in anti-CD20-treated patients (n=96) in comparison to immunocompetent controls (n=29).Results Anti-spike IgG antibodies were detected in 49% of patients 1.79 months after the second vaccine dose (interquartile range, IQR: 1.16-2.48) compared to 100% of controls (p<0.001). SARS-CoV2 specific interferon-γ release was detected in 17% of patients and 86% of healthy controls (p<0.001). Only 5% of patients, but 86% of healthy controls showed positive reactions in both assays, respectively (p<0.001). Time since last anti-CD20 therapy (7.6 months), peripheral CD19+ (>27/µl), and CD4+ lymphocyte count (>653/µl) predicted humoral vaccine response (area under the curve [AUC]: 62% [CI 56-78], 67% [CI 58-80] and 67% [CI 54-79], (positive predictive value [PPV]: 0.76, 0.7 and 0.71).Conclusion This study provides evidence for blunted humoral and cell-mediated immune responses elicited by SARS-CoV2 mRNA vaccines in patients with CD20-depleting treatment history. Lymphocyte subpopulation counts are associated with vaccine response in this highly vulnerable population. (Funded by Bern University Hospital, ClinicalTrials.gov number, NCT04877496)
The Dutch join the Italians and show that if you need to delay the dosing of ocrelizumab in the short term this can be done relatively safetly
Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID–19 pandemic.van Lierop ZY, Toorop AA, van Ballegoij WJ, Olde Dubbelink TB, Strijbis EM, de Jong BA, van Oosten BW, Moraal B, Teunissen CE, Uitdehaag BM, Killestein J, Kempen ZLV.Mult Scler. 2021 Jul 9:13524585211028833. doi: 10.1177/13524585211028833. van Lierop ZY, Toorop AA, van Ballegoij WJ, Olde Dubbelink TB, Strijbis EM, de Jong BA, van Oosten BW, Moraal B, Teunissen CE, Uitdehaag BM, Killestein J, Kempen ZLV. Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic. Mult Scler. 2021 Jul 9:13524585211028833. doi: 10.1177/13524585211028833. In this observational study, 159 patients with multiple sclerosis received personalized dosing of ocrelizumab incentivized by the COVID-19 pandemic. Re-dosing was scheduled when CD19 B-cell count was ⩾10 cells/µL (starting 24 weeks after the previous dose, repeated 4-weekly). Median interval until re-dosing or last B-cell count was 34 [30-38] weeks (Thus dosing was delayed by 6 to 14 weeks) . No clinical relapses were reported and a minority of patients showed Expanded Disability Status Scale (EDSS) progression. Monthly serum neurofilament light levels remained stable during extended intervals. Two (1.9%) of 107 patients with a follow-up magnetic resonance imaging (MRI) scan showed radiological disease activity. Personalized dosing of ocrelizumab could significantly extend intervals with low short-term disease activity incidence, encouraging future research on long-term safety and efficacy.
They delayed infusions in South America also
Chertcoff- A, Bauer J, Silva BA, Aldecoa M, Eizaguirre MB, Rodriguez R, Chereque A, Rodríguez Heudebert ML, Milanesi V, Morales L, Castellón M, Mejía Pineda S, Ferrandina F, Henestroza P, Ruiz Peraza M, Vallecillo Rivas F, Cedeño Lopez L, Herrera L, Sosa M, Cruchet Muñoz V, Barahona AS, Ramírez Gudiño LM, Carballido S, Walton C, Peeters LM, Rijke N, Garcea O, Carrá A, Alonso R. Changes on the health care of people with multiple sclerosis from Latin America during the COVID-19 pandemic. Mult Scler Relat Disord. 2021 Jun 30;54:103120. doi: 10.1016/j.msard.2021.103120.
There is nothing new here, if you are a regular blog reader, but the fact that we are seeing this over and over again suggests the original observations were more or less correct and that you don’t need to examine hundreds of thousands of people to get the answer.
Lastly we can learn from other conditions and this time it is Lupus. However in terms of vaccine response there are boogie drugs like there are in MS, but again the suggestion of one factor that relates to vaccine response is the levels of B cells and notably the number of naive (mature) B cell numbers. Here you can see antibody response and the level of B cells and you can see levels about Q1 (Quartile (Quarter 1) bottom 25%) resulted in better antibody response
BNT162b2 vaccine-induced humoral and cellular responses against SARS-CoV-2 variants in Systemic Lupus ErythematosusMoyon, Q., Sterlin, D., Miyara, M., Anna, F., Mathian, A., Lhote, R., Ghillani-Dalbin, P., Breillat, P., Mudumba, S., de Alba, S., Cohen-Aubart, F., Haroche, J., Pha, M., Boutin, T. H. D., Chaieb, H., Flores, P., Charneau, P., Gorochov, G., Amoura, Z.10.1101/2021.07.07.21260124 — Posted: 2021-07-08
Do we measure B cell numbers?. I don’t think the neuros do.
Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.