Gunfight at the OK COVID-19 Coral..Get Shot or should I say Get a Shot.

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The first data that was presented on COVID-19 vaccination in Israel has surfaced and says that people treated with fingolimod and ocrelizumab struggle to make a B cell response. On the left graph below the dotted line and you don,t make a good antibody response. So good news for the clad lads….

Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies.Achiron A, Mandel M, Dreyer-Alster S, Harari G, Magalashvili D, Sonis P, Dolev M, Menascu S, Flechter S, Falb R, Gurevich M.Ther Adv Neurol Disord. 2021 Apr 22;14:17562864211012835

So the the first thing you ask is, “Is this data real?” . The answer I would suggest is yes, as a similar thing was presented a couple weeks ago based on work from D Karrusis from Hadassah in n=11 treated with cladribine (100% responded), n=42 treated with ocrelizumab (33% responded) and n=5 with fingolimod.

Can you explain it….yep easy peezy.

Data from Heinz Wiendl AAN 2021 (2235) showed….give Clad and memory B cells are depleted over 95% for at least a year= No MS for at least a year. Immature (transitional B cells) repopulating within 2 months of last dose (130% baseline). Mature B cells repopulating between month one and two after last dose and only about 40% depleted at 4-5 months after dose and essential back to normal at 7-8 months. With ocrelizumab the memory B cells are dpleted by over 90% for at least a year and at least 18 months = No MS. However essentially few mature B cells (>80% depleted at 7-8 months). So no cells to make new antibody response (Baker et al. Clin Exp Immunol. 2020; 202:149) .

But why the gunfight….It seems that someone has made a comment

Clint Eastwood: 25 Essential Movies - Rolling Stone
Clint the Man with No Name, So do we need to name the people arguing

In a recent article by Achiron et al. entitled “Humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies,” the authors measured SARS-CoV-2 IgG response using anti-spike protein-based serology in a group of multiple sclerosis (MS) patients on three different types of disease modifying therapies (DMTs), including cladribine (n = 23), ocrelizumab (n = 44), and fingolimod (n = 26). Given the current COVID-19 pandemic and development of novel vaccines against SARS-CoV-2, there is growing need to understand the effectiveness, immune response, and long-term safety of these vaccines in immunocompromised patients, including MS patients on DMTs. While there is strong need to characterize the immune response in mRNA-COVID-19 vaccines in MS patients on highly efficacious DMTs, this particular article draws several concerning and potentially inaccurate conclusions based on the data provided in the manuscript.

The conclusion drawn to recommend against the mRNA COVID-19 vaccine in MS patients on fingolimod and postponing ocrelizumab treatment in MS patient is not supported based on the data presented in this article and has the potential for severe impacts on an already vulnerable population already documented to have worse outcomes with COVID-19.

So this view supports ProfGs view and that says get it as soon as you can..I think every one should get one too……However, I would say we can optimize chance of B cell response so if possible dont be too Gung-Ho.

The reported mRNA COVID vaccine studies have noted increases in antibody, neutralizing antibodies (NAb), and T-cell responses in healthy controls following vaccination. However, it is unclear which aspect or aspects, or a combination of the immune responses are responsible for immunity to the virus. Additionally, the degree or quantification of these immune responses that correlate to clinical effectiveness of vaccination is not yet known.

Well they should have read our wonderful papers

The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID19 pandemic.Baker D, Amor S, Kang AS, Schmierer K, Giovannoni G.Mult Scler Relat Disord. 2020 Aug;43:102174.

COVID19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.Baker D, Roberts CAK, Pryce G, Kang AS, Marta M, Reyes S, Schmierer K, Giovannoni G, Amor S.Clin Exp Immunol. 2020 Nov;202(2):149-161. 

Then it would be totally clear, which bits of the immune response are important:-)…but as it is a system, optimal response will use each bit of the system….However, we elegantly showed why antibodies may not be necessary for protection, but it is obvious that if present at high levels they will stiffle infection. If the first dose gives such a good protection then the antibody levels are still quite low in many people and this suggests you dont need much

One major issue in the study presented by Achiron et al. is that it disregards the potential importance of T-cell response. While the authors do recognize the limitation of not capturing T-cell response, as indicated in the discussion, the conclusion grossly overstates their findings and the recommendation to forgo vaccination in the setting of fingolimod use and postponing ocrelizumab for 9 months (which has the potential to have detrimental effects in regards to their MS). Because ocrelizumab depletes B cells, it might be expected that antibodies and NAb levels following the SARS-CoV-2 vaccine may be decreased as compared with MS patients not on a DMT or compared with healthy controls. This was shown for other vaccines in the VELOCE study, where patients mounted an attenuated but protective response to tetanus toxoid vaccine and variably attenuated responses to different strains of Streptococcus pneumonia and influenza vaccines. However, this study did not evaluate the cellular immune responses to these vaccines.

The author has been taken to task for not looking at T cells. This could be levelled at essentially ever COVID-19 paper published in Nature, New England Journal, Lancet etc. as many haven’t reported T cell levels but I would say that baseon what I have seen there will be people anti-CD20 treated people without detectable T or B cell responses

Theoretically, T-cell responses should not be affected significantly in patients treated with ocrelizumab.

How the tone changes when it suits you. Because mention ocrelizmab and the mechanism of action in MS and the action is all down to T cells. So it wipes out the T cell response because B cells are either antigen presenting cells to T cells or it is all CD20 T cells in MS and then does nothing to the T cells in COVID-19. Although it is heresy to say this in academic MS circles one can easily make the argument that T cells are not important to the mechanism of action of anti-CD20 in MS..I like to do this, just to wind the T cell immunologists up. However, I must say the effect on CD20T is rather improbable and you are selecting a hard explanation to throw the easy answer away. We know that anti-CD19 works in MS and T cells express vanishingly little CD19, so you can’t use this argument there.

Prior studies have shown only a modest decrease in blood cytotoxic T cells (CD8), but not in cluster of differentiation 4 (CD4) levels in patients on ocrelizumab, and ocrelizumab did not appear to affect the ability of T cells to elicit a functional cytokine response to stimulation. Additionally, recent data presented from New York University in COVID-19 infected, unvaccinated patients with MS demonstrated persistent humoral and T-cell immune memory to SARS-CoV-2 up to 10 months following infection, even in B-cell-depleted patients with MS. These findings suggest that ocrelizumab-treated patients are able to fight off COVID-19 infection despite depressed antibody responses.

We don’t just have to think about the New York or the Swedish data presented and published (pre print) before the US to know that ocrelizumab-treated people are able to fight off COVID, thousands of people on ocrelizumab or rituximab have done this in MS, arthritis, cancer etc etc etc. We showed this a while ago.

COVID19 vaccine-readiness for anti-CD20-depleting therapy in autoimmune diseases.Baker D, Roberts CAK, Pryce G, Kang AS, Marta M, Reyes S, Schmierer K, Giovannoni G, Amor S.Clin Exp Immunol. 2020 Nov;202(2):149-161. 

Furthermore, not only is it problematic to draw this conclusion from the SARS-CoV-2 IgG response alone, the anti-SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) used (Euroimmun) in this study has a reported sensitivity of approximately 90%. Several other commercially available assays (Abbott, Liaison, Roche, Siemens, Oxford) have shown in a head-to-head assessment to achieve sensitivity and specificity of at least 98%, thus making the assay used in this particular study suboptimal.

I’m not so sure I would start attacking the assays because it becomes abit of a weeing competition, The specificity and sensitivity of the assays are only as good as the samples, you test them against. Some of the ones mentoned above are not without significant problems as quantitative outcomes. However the data has replicated and there is additional supportive data from arthritis, Lupus, and cancer to say that anti-CD20 blunt vaccine responses to BNT162b2 (Pfizer)

DrAngray has invented and developed an new detection system a

In summary, clinicians and patients need to know whether administering an mRNA vaccine to MS patients who are receiving DMTs are potentially capable of immune response compatible with immunity to COVID-19. While this study reports the detection of SARS-CoV-2 IgG, albeit interesting data regarding the humoral response to the vaccine, it is inaccurate to declare this confers either the absence or presence of a protective immune response.

So the orignal authors reply

To the Editor,

“We read the letter related to our recent paper on the humoral immune response to COVID-19 mRNA vaccine in patients with multiple sclerosis treated with high-efficacy disease-modifying therapies, but did not find any relevant data they provide to support their criticism, except for theoretical considerations.

Em I am not so sure that they did a good literature review

Indeed, our findings have major implications related to MS patients treated with ocrelizumab and fingolimod. As we showed in our study, these patients failed to develop an appropriate humoral immune response following COVID-19 vaccination and therefore are not protected against SARS-COV-2 infection, in contrast to healthy subjects, untreated MS patients, and MS patients treated with cladribine. Our recommendations are based on the currently obtained data. Theoretically, even if some of the ocrelizumab and fingolimod-treated MS patients will be able to develop a T-cell response, we doubt that this response will be protective in the absence of B cells.

So should have gone to Spec Savers and read the review above. We should tell this to the people with genetic effects that means they have no B cells but have got COVID-19. Did they recover?….Yep.

However the central question is what happens to vaccinated people taking ocrelizimab, when they get infected/re-infected, Are they protected and do they deal with the virus

COI…Multiple but nothing in relation to Spec Savers, except a family member works there.

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.

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MouseDoctor

7 comments

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  • I am only one person and not a trial but on ocrelizumab, 2 doses of Pfizer 2 months ago, zero spike protein antibodies detected and no T cells detected either. Those are the only tests available. We need better testing stat! Or boosters.

      • once the ELISPOT Assey showed a reaction on T-cells (INFg: 12 and IL2: 24 SI threshold >3 – not having detectable B-cell antibodies though) 6 weeks after second pfizer shot and 2 weeks after OCR – you have any idea how long this t-cells last? i read that they should last much longer than antibodies…thank you

  • Is anyone studying the non-mRNA vaccines (J&J, AZ) to see if they do a better job for people on these dmts? Would the different mechanism of action potentially make a difference?

  • What are your thoughts regarding pwMS taking Cladribine who didn’t wait for a lymphocyte rebound to get vaccinated? Many docs are suggesting that patients get the vaccinations as soon as they are available, but what does that mean for patients with grade 3/4 lymphopenia who gets an MRNA vaccine? Thanks in advance for your reply.

    • At the moment most people on cladribine have given an antibody response and this has not related to lymphocyte levels….however do not get a false sense of security there will be failures. This may be the type of vaccine or because there is not enough gap between dose and vaccine. In the positive studies people have been over 4 months from treatment.
      we have to see if less that this is OK. It may be. For most people on cladribine they do not get too much of a depletion grade 3/4 lymphopenia is rare, now the question is what his causing the lymphopenia?.

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