#MSCOVID19…The CD20 problem


So what do I know or what do I think I know. We have seen a fair amount of data in cancer, arthritis and even abit in MS

(a) Ocrelizumab-induces longer-lasting B cell depletion than rituximab. (b) Ocrelizumab and rituximab both inhibit active MS (c) Antibody responses to novel antigens are blunted by anti-CD20 treatment and this will include response to COVID (d) Antibody responses are blunted for months, because the antibodies hang around for a long time stopping B cell repopulation (e) Ocrelizumab, rituximab and ofatamumab essentiallys knock B cells out of existence during therapy and whilst on therapy your vaccine responses will be blunted (ofatumumab data is unknown) (f) Ocrelizumab, rituximab and ofatumumab will inhibit the development of COVID-19 vaccine response, although I have yet to see sufficient data about ofatumumab, I have seen some. (g) Ocrelizumab will inhibit the development of COVID-19 vaccine response more than that of rituximab because of (a) (h) Ocrelizumab is less likely than rituximab to seroconvert to vaccine quickly because of (a) (i) B cell repopulation is likely to be a (partial) biomarker for seroconvertion and repletion will occur more quickly with rituximab than ocrelizumab because of (a). If you have peripheral blood B cells you probaly can make a vaccine response (j) The longer the interval between infusion and vaccination the more likely you are to get a B cell response. (k) Even if you do make an anybody response it will be lower than untreated people. However you may not need a high level to be protected. (l) Even if you do not make an adequate antibody response there is a good chance that you will make a T cell response to the SARS-CoV-2 virus (m) T cell responses coupled with your innate immune response should give significant protection (against hospitalization)…Reinfection risk at moment is about 1 in a thousand based on some stuff I have read. (n) There could mitigation (safe) processes to optimise your vaccine responsiveness or ways to protect you during the pandemic (I am not going to discuss what these are, what they may look like or how I would do this as I’m not a neuro and for most people with MS in the UK it is abit late…you should have had your jabs…..but looking forward when booster jabs arrive is another matter.

Anti-CD20s were peoples go to treatement before the pandemic….wll COVID-19 SH1 stick?

Yes I am dwelling on anti-CD20 because this is where the data is, but rest assured CD20 is not the only problem. Please bear in mind there may also be some differences btween MS and Cancer/arthrtis etc…so I may modify the above abit. So far cladribine has been “looking good Billy Ray”, but is this because they lucked-out in the timing between dosing and vaccination, I suspect so, but notably fingolimod blunts COVID-19 vaccines responses based on two studies in the public domain. Unlike anti-CD20 the sphingosine-1-phophate modulators are only used in MS so it will take longer for the data to emerge. If there is mud to stick, it will stick to fingolimod because more people use it. Next there should be more information from siponimod. Will there be a difference? If not the important target is S1P1 so not good news, but if there is…..then there are two to three alternatives to fingolimod that do not target S1P3 or S1P4. S1P3 is involved in B cell responses but that may be a mouse thing, and S1P4 is involved in the immune response notably the response of dendritic cells and it is these cells, I predict, that are going to be important in making vaccine immune responses….If you are taking one of these imods and have been vaccinated let us know what has happened…..I have a paper waiting in the wings

COI: Multiple

Vaccination on anti-CD20

Vijenthira A, Gong I, Betschel SD, Cheung M, Hicks LK. Vaccine response following anti-CD20 therapy: a systematic review and meta-analysis of 905 patients. Blood Adv. 2021 Jun 21;5(12):2624-2643.

The objective of this study was to perform a systematic review of the literature on vaccine responsiveness in patients (note this is not just about MS) who have received anti-CD20 therapy. PubMed and EMBASE were searched up to 4 January 2021 to identify studies of vaccine immunogenicity in patients treated with anti-CD20 therapy, including patients with hematologic malignancy or autoimmune disease. The primary outcomes were seroprotection (SP), seroconversion (SC), and/or seroresponse rates for each type of vaccine reported. As the pandemic influenza vaccine (2009 H1N1) has standardized definitions for SP and SC, and represented a novel primary antigen similar to the COVID-19 vaccine, meta-analysis was conducted for SC of studies of this vaccine. Pooled estimates, relative benefit ratios (RBs), and 95% confidence intervals (CIs) were calculated using a random-effects model. Thirty-eight studies (905 patients treated with anti-CD20 therapy) were included (19 studies of patients with hematologic malignancies). Patients on active (<3 months since last dose) anti-CD20 therapy had poor responses to all types of vaccines. The pooled estimate for seroconversion after 1 pandemic influenza vaccine dose in these patients was 3% (95% CI, 0% to 9%), with an RB of 0.05 (95% CI, 0-0.73. Twenty times lower) compared with healthy controls and 0.22 (95% CI, 0.09-0.56. A fifth lower) compared with disease controls. Seroconversion compared with controls seems abrogated for at least 6 months following treatment(remeber most people will be treated with rituximab) (3-6 months post anti-CD20 therapy with an RB of 0.50 [95% CI, 0.24-1.06. A half lower response if you are vaccinated 3-6 months after infusion] compared with healthy and of 0.44 [95% CI, 0.23-0.84. A 60% drop] compared with disease controls). For all vaccine types, response to vaccination improves incrementally over time, but may not reach the level of healthy controls even 12 months after therapy.

Therefore it says with other vaccines you have a low response if used within a 6 monthly dosing schedule and it may not be even 100% if you delay dosing for up to twelve months. With ocrelizumab the time taken to get your B cells to the lower limit of normal takes from about 25 weeks (6 months) to 175 weeks ( 3.25 years) (Data from phase II extension study). However remember the memory B cells are depleted for substantially longer, we don’t know for how long but at least 18 months after ocrelizumab in most people they are still depleted.

What happens to memory B cells?

Memory B cells control SARS-CoV-2 variants upon mRNA vaccination of naive and COVID-19 recovered individuals.Sokal, A., Barba-Spaeth, G., Fernandez, I., Broketa, M., Azzaoui, I., de La Selle, A., Vandenberghe, A., Fourati, S., Roeser, A., Meola, A., Bouvier-Alias, M., Crickx, E., Languille, L., Michel, M., Godeau, B., Gallien, S., Melica, G., Nguyen, Y., Zarrouk, V., Canoui-Poitrine, F., Noizat-Pirenne, F., Megret, J., Pawlotsky, J.-M., Fillatreau, S., Brunhs, P., Rey, F. A., Weill, J.-C., Reynaud, C.-A., Chappert, P., Mahevas, M.10.1101/2021.06.17.448459 — Posted: 2021-06-17

How a previous SARS-CoV-2 infection may amplify and model the memory B cell (MBC) response elicited by mRNA vaccines was addressed by a comparative longitudinal study of two cohorts, naive individuals and disease-recovered patients, up to 2 months after vaccination. The quality of the memory response was assessed by analysis of the repertoire (binding target), affinity (binding strength) and neutralization (blocking potential) against variants of concerns (VOC) (Kent=Alpha SouthAfrican=Beta etc), using cultures of 2452 MBCs. Upon boost, the MBC pool of recovered patients selectively expanded, further matured and harbored potent neutralizers against VOC. Maturation of the MBC response in naive individuals was much less pronounced. Nevertheless, and as opposed to their weaker neutralizing serum response, half of their RBD-specific MBCs displayed high affinity towards multiple VOC and one-third retained neutralizing potency against B.1.351 (South African=beta). Thus, repeated vaccine challenges could reduce these differences by recall of affinity-matured MBCs and allow naive vaccinees to cope efficiently with VOC.

So it says when you get vaccinaed a couple of times you increase the chance that there are memory B cells…No if you are on depleting DMT these cells will be targeted but the vaccine produce antibody secreting cells that will respond to the virus

Immunological features that determine the strength of antibody responses to BNT162b2 mRNA vaccine against SARS-CoV-2

Takahiro Kageyama, Shigeru Tanaka, Keishi Etori, Koto Hattori, Kazusa Miyachi, Tadamichi Kasuya, Taro Iwamoto, Kei Ikeda, Hidetoshi Igari, Koutaro Yokote, Hiroshi Nakajimadoi: https://doi.org/10.1101/2021.06.21.449182

We analyzed peripheral blood mononuclear cells (PBMCs) of each 20 individuals with a high anti-SARS-CoV-2 antibody titer and a low antibody titer out of 1,774 healthcare workers who received BNT162b2 mRNA vaccine. A higher antibody titer was associated with the frequencies of naive and transitional B cells before vaccination. In addition, fold changes in the frequency of activated CD8+ T cells upon vaccination were correlated with the antibody titers.

The polarity and specificity of SARS-CoV2 -specific T lymphocyte responses determine disease susceptibility

 Jean-Eudes FAHRNER, et al. doi: https://doi.org/10.1101/2021.06.18.21258477

. These findings indicate that COVID-19 protection relies on TH1 cell immunity against SARS-CoV-2 S1-RBD which in turn likely drives the phylogenetic escape of the virus. The next generation of COVID-19 vaccines should elicit high-avidity TH1 (rather than TH2)-like T cell responses against the RBD domain of current and emerging viral variants.

General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

Is the COVID-19 vaccine MS data False?

The first data of vaccination has MS surfaced and suggests a blunting of the response by ocrelizumab and fingolimod.

Archiron et al. Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. https://journals.sagepub.com/doi/10.1177/17562864211012835.

However, the authors have taken abit of stick and unusually this has prompted a correspondence trail. The latest

Correspondence: Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies. Ther Adv Neurol Disord. 2021 Jun 3;14:17562864211022581. doi: 10.1177/17562864211022581.

They make some valid points but then seem to start to question the integrity of the data….Which is a slipper path to tread

“As the authors mentioned, the small sample size (it was n=44) might have had an impact, as well as the study design, focusing on one single time point of antibody measurement with no well defined time-lines. The limited half-life of antibodies of about 21 days may contribute to low, or even undetectable, antibody titers in the respective study arms”.

There are hundreds literatlly hundreds of papers about the longevity of SARS-CoV-2 antibodies and looking 1 month after vaccination would not account for 34/44 not having a measurable antibody response, when it was not that hard to find in 79/79 of the controls. Now add to this that the Israely study has been replicated by another Israeli group. Is that dubious too? Furthermore every study in other conditions using anti-CD20 antibodies (quite a few a n ever increasing) has shown a blunting, yes ocrelizumab appears abit worse

“In the case of ocrelizumab, data exist on vaccination 3 months after administration of therapy, so this time window can be followed if possible”.

So keep doing what the manufactureres want when the data shows that only 1/7 (14%) made an antibody response (Achiron et al. 2020) when vaccination was started 4 months after infusion.

We will have to wait for the manufacturers to report their study, which will no doubt be dosing after vaccination as per label, vaccinating 3 months after infusion as per VELOCE study and with a 3 week interval for pfizer vaccine as per label. But a good reason why we need data. That is one thing you can guarentee with covid-19 research and that is there are ten replications for every observation so if something ain’t right we will soon spot it but who will collate the information digest it and them make an opition.

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice. 


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  • From my perspective it’s more about how much I can or should still be doing to minimise the risks of catching covid as someone on ocrevus. I have children at school so there’s nothing I can do about that. But going in to the city on a train one day this week and spending time with several unmasked people in an office (as people don’t wear them unless moving around) made me wonder how much I should be being careful. Especially when the talk is that masks will no longer be required when restrictions are lifted. I’m just hoping they were vaccinated or my T cells will kick in if necessary! Short of wearing proper filter masks when inside or travelling, I’m essentially relying on others and their immunity protecting me.

    Looking forward to the blood spot study results.

    • “Looking forward to the blood spot study results” …it is likely to be in line with the above ideasa….we have lost our post-doc to COVID-induced isolation for the weeked, so whish them a get well out of isolation….we have hundreds of samples to get through

      “Made me wonder how much I should be being careful”…..I went to a london shopping cnetre last week…Know the feeling

      “I’m essentially relying on others and their immunity protecting me”…..The basis of herd immunity.

  • Will be glad when you’re able to provide us with a simplistic version of the info = where each DMT is identified and against which is the vaccine response
    This way if there’s criteria limiting any further doses then we can push for it if we know we’re best to have it.
    Understand it’s gonna take a while for the data to become available.

    • We have alot of blood spots from ocrelizumab (I think over 150 promised) and natalizumab I know whats happening there, we have a few fingolimod, cladribine and dimethyl fumarate. I hope we can see a pattern emerge the MS Margaret keenan waited and they have a response, but the study is being done blinded so I dont know who gets what. Doctor Ruth is working closely with other neuros who have a different range of treatments.

  • Professor Ravi Gupta of Cambridge ( Ravi Gupta is Professor of Clinical Microbiology Department of Medicine University of Cambridge.) ::::::::says::::::::::
    Summary:The Delta variant has significant immune evasion and fitness compared to Alpha. Vaccines will prevent severe disease/death in *most* people, but SPECIAL MEASURES MAY BE NEEDED FOR THOSE WHO RESPOND POORLY TO VACCINATION.Infection in vaccinated HCWs needs to be considered.

    It’s been said up to two thirds on CD20 stuff (such as Ocrevus) won’t have hadproduced a vaccination response.
    So, should we be SHIELDING again, and should we be telling neuros they MUST test us for vaccine response, and should we be jabbed with a DIFFERENT vaccine other than the Oxford Astra Zenica we’ve already had?

    • It’s been said up to two thirds on CD20 stuff (such as Ocrevus) won’t have produced a vaccination response……This is range I have seen with ocrelizumab, rituximab is abit better, however I believe time/B cell levels will help inform to improve this, so I would think better to have third jab when we know how best to optimise it being on the standard 6 monthyl dosing is not optimised. I think people get a T cell response, we have the technology and the reagent looking for a real use to give people an antibody response. Moderna are doing a mix and match study and there is real life data. It is clear that the RNA vaccines give a better antibody response than the adenoviral vaccines amd Moderna gives a bigger response than pfizer (this is a population level andt there is individual variability). It is clear to me that antibodies help as the first line to stop infection and also probably help limit hospitalisation but it is the T cell and the innate response that are the most important. Why say this because givnen infected people antibodies is not that great

      until we

  • What can be taken from this study (solid organ transplant patients), if anything, vis-a-vis anti-cd20 meds, and in particular, Ocrelizumab?


    If it takes potentially 3+ years to have B cells repopulate, perhaps it’s time for a third jab of an mrna vaccine. Shielding for years is not an option for many people.

    • Not alot I think the vaccine response from one jab isnt bad from two jabs it is much much better and three better still but for solid organ transplants anti-CD20 arent used.
      If it takes 3 years to have B cells repopulate (a) I will bet that you do not have to be 100% repopulated, the modellers suggest 20% so that is much quicker, we could speed this up by getting rid of ocrelizumab in the blood and we can give people protection

  • Hi, I’m a fingolimod user of 6 years who’s had 2 Pfizer jabs. After unsuccessfully asking my MS team for an antibody test I managed to strike lucky with getting one through my gp. I found out today that I’d tested positive for antibodies. I don’t know any more details than that I’m afraid!

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