The #MSCOVID-19 vacccination window of ocrelizumab/rituximab and more evidence for the importance of memory B cells

T

Want the Quick Read. Do the stuff in Red! (SEE NEW PAPER AT THE BOTTOM)

How long does it take for the vaccination window to open?
DOI: 10.22541/au.159292858.82650822

As you know our initial paper on COVID-19 took a look at the biology of COVID-19 and its relationship to MS disease modifying drugs.

How do MS drugs affect COVID-19. Read this paper. The answer, I think is not alot.

Baker D, Amor S, Kang AS, Schmierer K, Giovannoni G. The underpinning biology relating to multiple sclerosis disease modifying treatments during the COVID-19 pandemic [published online ahead of print, 2020 May 12]. Mult Scler Relat Disord. 2020;43:102174. doi:10.1016/j.msard.2020.102174

This could have been part I. This is because when we first started to write the paper there were only 200-300 COVID-19 papers and there are now there are probably over 29,000 papers….we have a publishing epidemic….Based on the above paper, it is now clear to me why I have given up reading every COVID-19 paper. At 500 new ones a day and most of them are drivel, as you do not need 25-30 papers on report how to re-sterilize a face mask, and as for the countless number papers using meta analysis of this or that. We will probably have a meta analysis of the meta analysis:-). So now I focus on the pre-print websites (new stuff) and the indexing sites.

However, in the new part II we give more reason why COVID-19 will not unduly influence MS-DMT and vice versa. It does not say they will not affect your chances of COVID-19 because if they are good at getting rid of autoimmunity, they will block infection control.

However, in relation to COVID-19 and the call to delay treatment we also reported on the effects of delaying treatment with ocrelizumab. We should have called this part I also. This has yet to surface on PubMed.

You appear to be able to safely delay your ocrelizumab infusion (read this). The inference is that there is overkill on the dosing to control relapsing disease.

The ocrelizumab phase II extension trial suggests the potential to improve the risk:benefit balance in multiple sclerosis.David Baker, Gareth Pryce, Louisa K.James, MonicaMarta, Klaus Schmierer MSARDS 2020.

The dosing schedule is based on keeping B cells away for ever. But is it a subset of those B cells that are important. Eventually this paper will fully surface and we have apologised to Person A for writing up their clinical trial, which they reported in…….2012/2013.

As I have said….Snooze and you lose!. However, whilst pissing off (Means Annoying) person A…why stop there? So today, we have pissed-off Person X, because we have reported their clinical trial …..that they presented at meetings in 2018. I wrote to see if they were going to publish it, no reply.

However, ocrelizumab part II and COVID-II part two has now appeared. This gives details of the potential vaccination window with ocrelizumab and rituximab. It importantly shows more evidence that the memory B cell subset is a key target for effective immunotherapy in MS.

COVID-19 vaccine-readiness for ocrelizumab and other anti-CD20-depleting therapies in multiple sclerosis and other autoimmune diseases. David Baker, Charles AK Roberts, Gareth Pryce, Angray S Kang, Monica Marta, Saul Reyes, Klaus Schmierer, Gavin Giovannoni, Sandra Amor.

If you are a pharma/Neurologist reader read this

The moral of the story is that if company X don’t publish their data, but put the data in the public domain, then it is fair game. If they don’t write it up, so that it is visible in the citable and importantly searchable scientific literature, someone should do it! The AAN and ECTRIMS should house every pharma-sponsored poster so that the contents are visible and do not disappear in a year or two. Yes, this is publishing anarchy, but this should encourage the companies to publish their work and not hide it in a meeting abstracts that are not always findable, yet is routinely cited company talks. Not all news is good news, but this gives balance.

Importantly, this would allow pharma to publish the information in a way that they want it presented. Because to ignore the stuff you don’t quite like means others may present it in a way that companies don’t control and perhaps in a way they don’t want it to be presented. Indeed, the inference from this publication is clear and suggests that dosing with ocreliumab every six months is too much for some people. This may expose them to unnecesary risks from infection and unneccesary risks to their pockets. Now, I do not think that we should unilaterally stop taking the drug, because I think that it should be formally tested to ensure that it is safe. So this publication is a nudge.

Importantly if the company don’t do it, some neuro will do…..In fact they have done already it NCT03853746 , or have they NCT04261790, but with n=10 (group size), it is too small to be really meaning full. Two cycles of ocrelizumab and than watch for 2 years from the last dose, but if it is like alemtuzumab and 50% breakthrough occurs, this may be problematic. Because with the dose (600mg) and the half-life (about a month) of ocrelizumab, the drug is still active for 5-6 half-lives. Therefore this study will show what happens for 18 months.

However, read the papers above and below and will you know what happens for 18 months in people after 3 or 4 cycles. In the COVID-19 era neuros have been advised to delay treatment, so it is clear that those on the inside know the data. but the jobbing neurologist won’t and neither will the person with MS.

Therefore, it was the motivating factor to (a) put on a pre print site and (b) Give-up trying to publish in certain journals and just get it out. As I said to you before, the paper above had been sent out a couple of times and the paper had been monstered by the referees, who seemed to be T cell immunologists. Don’t mention “Th17 cells and T regulatory cells” and you are in for a rough time and generally it is not going to get in the journal of choice. Referees (T cell immunologists) with big labs and loads of people to keep going don’t want the boat rocked and don’t want a simple story.

However, there is another issue with the review process, which I have learned and that is that many MS neurologists work closely with pharma, and if they don’t they are probably a bit rubbish. It seems that their butt-cheeks start to quiver, if you do not report stuff in a pharma-positive way and don’t say “everythings is amazing and we all made out of stardust”. Therefore, the referees get you to water-down the message. Therefore, it is better to keep the papers away from people with vested interests.

So for the next helping, I have moved away from a neurology journal in the hope it doesn’t take 3 months to surface.

However, why have I evoked the Wraith of profGs mates?..Simple….Your safety and for this I may have trampled on a few egos. I may be wrong, but I can see a safety issue of repeatedly dosing anti-CD20. Whilst it may not be a big issue for most people, but if you are one of the few people affected, it is an F…ing big issue.

With repeated B cell depletion you reduce your capacity to make antibody forming cells. The first like of defence as far as antibody is concerned is via the production of IgM antibodies. The B cells then change to produce IgG antibodies, which have high binding capacity than IgM.

With repeated B cell depletion your IgM levels drop by over 50%. As this and IgA which drops by about 20% over time. This was presented at ECTRIMS 2019 by Derfuss, T., Weber, M.S., Hughes, R., et al., Serum immunoglobulin levels and risk of serious infections in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and their open-label extensions65. Mult. Scler. 25 (S2), 20–21.

Will this be another paper that doesn’t see the light of day?

IgM levels start to drop even after the first infusion the mean says within the lower limit of normal

However some people go below normal

Proportion of people with low immunoglobulin levels at 2 and 6 years post ocrleiziumab

If your immunoglobulin levels drop below the lower limit of normal you are at an increased risk (nearly twice [1.7 (IgM) & 2.6 (IgG)] the risk for low IgMof serious (SI) . Perhaps interesting because profG has suggested your risk of COVID-19 infection from being on an anti-CD20 is about twice increased from a very low starting risk.

A delay in IgM production predisposes you to risk of COVID-19 and it is of interest that previous exposure, probably to cold-causing coronaviruses may offer you some protection from COVID-19 infection.

Díez JM et al. Currently available intravenous immunoglobulin (Gamunex®-C and Flebogamma® DIF) contains antibodies reacting against SARS-CoV-2 antigens BioRXiv doi: https://doi.org/10.1101/2020.04.07.029017

Díez JM et al. Cross-neutralization activity against SARS-CoV-2 is present in currently available intravenous immunoglobulins  doi: https://doi.org/10.1101/2020.06.19.160879

Shao et al. Clinical efficacy of intravenous immunoglobulin therapy in critical patients with COVID-19: A multicenter retrospective cohort studyMedRXiv doi: https://doi.org/10.1101/2020.04.11.20061739. This may also block macrophage function by blocking Fc receptors too

Anyway back to the story.

If you are taking a CD20-depleting antibody your potential vaccine response will be diminished . Whilst you keep being treated with ocrelizumab/rituximab/ofatumumab, ublituximab etc, you will never be fully competent to make new antibody responses and this may initially worsen with time.However it does not say you can’t make an anybody response

READ THIS PAPER

COVID-19 vaccine-readiness for ocrelizumab and other anti-CD20-depleting therapies in multiple sclerosis and other autoimmune diseases. David Baker, Charles AK Roberts, Gareth Pryce, Angray S Kang, Monica Marta, Saul Reyes, Klaus Schmierer, Gavin Giovannoni, Sandra Amor. Authorea 2020 DOI: 10.22541/au.159292858.82650822

Although most autoimmune diseases are considered to be CD4 T-cell or antibody-mediated, many respond to CD20-depleting antibodies that have limited influence on CD4 and plasma cells. This includes rituximab that is used in cancer, rheumatoid arthritis and off-label in a large number of other autoimmunities, notably multiple sclerosis, where ofatumumab is in late stage development and ocrelizumab is approved for use. Recently, the COVID-19 pandemic created concerns about immunosuppression in autoimmunity, leading to cessation or a delay in immunotherapy treatments. However, based on the known and emerging biology of multiple sclerosis and COVID-19, it was hypothesised that whilst B-cell depletion should not necessarily expose people to severe SARS-CoV-2-related issues, it may inhibit protective immunity following infection and vaccination. As such, drug-induced B-cell subset inhibition that controls multiple sclerosis and other autoimmunities, would not influence innate and CD8 T-cell responses, which are central to SARS-CoV-2 elimination, nor the hyper-coagulation and innate inflammation causing severe morbidity. This is supported clinically, as the majority (mortality rate n=~5/392) of SARS-CoV-2 infected, CD20-depleted people with multiple sclerosis have recovered. However, protective neutralising-antibody and vaccination responses are predicted to be blunted, until naïve B-cells repopulate, based on B-cell repopulation-kinetics and vaccination responses, from published rituximab and unpublished ocrelizumab (NCT00676715, NCT02545868) trial data, shown here. This suggests that it may be possible to undertake dose-interruption to maintain inflammatory disease control in MS and other autoimmune diseases, whilst allowing effective vaccination against SARS-CoV-29, if and when an effective vaccine is available.

It appears that whilst your naive (not seen their target antigen) and memory B cells are reduced you have a blunted immune response. When the CD19 naive B cells return you can make a vaccine response. By dosing-delay your may allow the naive B cells to recover to increase your chances of making a good response, whilst maintaining the pathogenic MS B cells at a low level and keeping your MS in check.

Thereforefore, there may be a time window to open the vaccine window but with ocrelizumab you may have to miss two dosing cycles (rituximab one to two), if and only if, the level of protection cannot be achieved whilst on treatment. Read the paper above and this figure should make sense.

Therefore let’s hope that a low level of antibodies is important for protection and so it doesn’t matter if the response is blunted.

COI:Multiple

About the author

MouseDoctor

26 comments

  • An article again assuming COVID-19 is something that is just going to get worse in a linear fashion and we should all be immunized. Nothing in the natural history of the world has ever worked that way, more especially a virus otherwise the human race would have been wiped out long ago. Why don’t you get on with trying to cure MS and stop obsessing about an illness that is just another virus. There are far more, about 9.5 million people, who die every year from cancer per year for instance compared to this virus of fewer than 500,000 deaths worldwide. About 645,000 die of heart attacks annually. We do not hear about that every day over and over again, as if the world will end unless we don’t do something. In comparison, this virus is overly exaggerated for the sole purpose of terrorizing people into complying with his vaccination agenda. How many people were apparently going to die according to the now discredited ‘scientist’ Neil Fergusson in the first six months in the UK alone, half a million wasn’t it? I could go on about how many false claims have been peddled as fact by the scientific community over the past six months, but suffice to say that that the real threat that those who have interest in this blog have is MS. The obsession in the medical community with covid will lead to far more suffering and death than this virus ever will. This blog is becoming irrelevant for MS sufferers who want to find out about the latest research into curing and treating MS.

    • “An article again assuming COVID-19 is something that is just going to get worse in a linear fashion and we should all be immunized” I suggest you have another read and stop spouting nonsense.

      “This blog is becoming irrelevant for MS sufferers who want to find out about the latest research into curing and treating MS”

      If you read the blog, most people with MS do not like being labelled as an “MS Sufferer”

      There were people with MS saying on this blog tha they are going to stop ocrelizumab whilst waiting for a vaccine and therefore the content is relevant.

      “the latest research into curing and treating MS”….In case you haven’t realised MS research has to some extent been put on hold. The funding bodies have shut up shop for 2020

      “Why don’t you get on with trying to cure MS”….surely providing more evidence of which cells to target is doing that….Why don’t you…

      • I couldn’t agree more with anon above. I’ve posted several times on this. Covid 19 is just giving frustrated neuro-immunologists a chance to show off how clever they are. Lots of pretty graphics showing T cells snd B cells. Thousands of pointless papers on Covid 19 which are of no interest or use to those with MS. On 4th July take team G to the boozer and let me know which one so I can buy the first round (I’ll call the landlord and pay). When you are there work out how to resurrect your MS research activities so those with MS can have some hope of treatments to stop progression and encourage repair. MS research has been in the doldrums for years and Covid 19 has been a complete overblown distraction. I’m not David Icke, but even I can see that this “pandemic” has been manipulated to take away our most basic freedoms. Mr Gates will dictate healthcare for the world rather than elected governments. I’d add an MSlivesmatter (they don’t evidenced by the lack of progress to address the real disease) but I’ll be shot for offending someone.

        • “I’ve posted several times on this.”
          And you still can’t choose an identity you’re comfortable with 😉 but let’s save the conspiracy guff, it’s an unnecesssary distraction. Don’t worry we’ll probably all be sacked soon to save the university from bankruptcy and you’ll have to take your glass half-full optimism off to another blog, where you might find more deserving targets for your ire.

          • “Don’t worry we’ll probably all be sacked soon to save the university from bankruptcy” After 11 years following this blog I won’t lose any sleep over this. Plenty of time to unpick the disease and identify effective therapies to stop progression. But nothing has materialised and it’s still the old B cell v T cell debates and jam tomorrow stuff. I’d say thanks, but then I think, for what?

        • Dear Sid,
          I am sure you could be David Icke is you wanted to be…it’s just a name after all. If we shot you…you would no doubt be ressurrected maybe it could be David Icke. However, you do not seem to understand that B cells have been our research activity for some time. We can’t all work on the same thing. Maybe I’ld do a post on progression but that won’t make you happier. Maybe I should do a post on metformin and COVID-19, because if the MS research is right and metformin rejuvenates macrophages to be young, then diabetics on metformin should do better than diabetics not on metformin….Is there a difference? If not, then perhaps the 3 planned trials on metformin in MS have failed before they start.

    • A figure of 500,000 was arrived at assuming thwere were going to be no mitigation measures and people just went on as normal and there being absolutely no natural immunity in the population. 1-2% mortality in general population of 66 million gives you a simple back ofan envelope prediction of 500,000 deaths. Ferguson’s resignation after his leg-over infractions does nothing to discredit the science behind the epidemiology, his left-wing political views probably sealed his fate compared to the chief scientist Dominic Cummings.
      If you don’t like the blog, there are many others available.

  • I respectfully disagree completely with Anon and Mike.

    As a pwMS, MD is exactly right in saying that this could not be more relevant right now. I am considering stopping ocrelizumab due to COVID-19 because not only does it affect my health it affects my job significantly.

    In the middle of a global pandemic when much research and trials have been put on hold, I have no idea how you can say research into the novel disease is not relevant. I think you are just using this opportunity to have a good old vent at someone else’s expense…

    Thanks to the blog writers for keeping us up to date. I find this post incredibly helpful actually. Was it modified since the anti CD20 posts of the last week or so? Because it feels much more reassuring to me.

    • Disrespectfully disagreeing is fine too Rebekah, glad you find the blog useful and ignore the curmudgeons 😉

  • The anti-pandemic, racist, flat earthers most likely represet less than 1% of readers on this blog and they probably only read the title of each post and see #MSCOVID-19 and go right to the comments section to post their hate and distain. If these individuals actually took the time to read the amazing work being done by this team, they would realize how this research around COVID and DMTs, particularly Ocrevus, is advancing patient care and challenging big pharma…..all to the benefit of pwms. The research around extended dosing of Ocrevus and anti-drug anti-bodies will have such a POSTIVE impact on pwms.

    Ocrevus all most killed me at my last infusion, which was the fourth cycle. I experienced infusion related reactions and post infusion reactions. I had no breakthrough activity or new lesions while on Ocrevus, so it did slow the progression of my disease. However, the adverse reactions to the drug have left me with more problems. I was told I am allergic to Ocrevus, which is BS. In reality, I am probably part on the unlucky 1% that develops anti-drug antibodies, but neither the drug company nor my Neuro doctors (at one of the best MS centers in the U.S.) would even consider this hypothesis.

    This blog has been my life line to emerging, relevant, and unbias research! Keep up the good work and just shake your head and laugh at the haters who take the time to post hateful comments without reading the content of your work!

    • Thanks “I was told I am allergic to Ocrevus”,….this means you have anti-drug antibodies (and T cells), typically allergic is IgE but not always

    • “This blog has been my life line to emerging, relevant, and unbias research! Keep up the good work and just shake your head and laugh at the haters who take the time to post hateful comments without reading the content of your work!”

      Thank you for expressing my thoughts in your eloquent comment! Over the years my wife and I have tremendously benefited healthwise from research and information distilled on this blog. In truth, I actually was chuckling at the miserable attitude demonstrated in comments above.

      C’mon folks, this post is totally relevant to those of us taking ocrelizumab or similar. How many people would that be? Multiple thousands. Not every post is relevant for each person. Take time to express gratitude for those posts which are important to you and please have the common sense to just shut the fuck up if your critique is nothing more than bitching. Don’t ruin the blog for others who are gaining years of life and quality of life in those years from this blog, especially those in my household.

      Rollo

  • I for one would like to thank you for your continued commitment to pwMS. I’m on Rituximab. I understand what you are saying but I’ve probably just had a very mild relapse. For me delaying the Ritux to make me vaccine ready is far risking than having my next course In three weeks. A personal thought through choice.
    Back in March I think I had Covid, I say I think because testing wasn’t readIly available so will never know for sure.
    Tomorrow I am having a COVID 19 antibody test. Results will be interesting!

    • With rituximab you repopulate twice as fast as with ocrelizumab and if you are having relapses you may be a quick repopulator. Therefore, if.you monitor B cells it will help inform. However as I have said vaccine readiness depends on having a vaccine and the vaccine being useful and also the level that protects is unknown it may be very low,and we could be worrying.over nothing.

  • I’d love for the optimal dosing of anti-CD20s to be known and specifically I’d love to know that less is more (or at least enough). But what about the DODO trial where Prof G was thinking that a double dose of Ocrevus would be better at targeting the intrathecal B cells? Plus I remember a post where you said that the smaller a person was, the better Ocrevus was at reducing the risk of progression, which to me suggests that more is more, in terms of dosing (since everybody gets the same amount of drug)!

    • You are correct. Yes there is data that in terms of ocrelizumab and the influence of progression size matters. The smaller you are the more depletion you have and the beter the effect on slowing progression. For relapsing disease it doesnt seem to matter. I think the DODO trial was on the cards, but if you double the dose then it will double the time taken for B cells to recover. Will this mean more lymophopenia, more hypogamma globulinemia and more infections.

      • I’m from Houston area in USA and echo Rollo that this blog has been my lifeline to cogent info extremely relevant to me and helps me have a background understanding to make better informed decisions about managing my MS. Such info is scarce here in the States despite the significant impact on my quality of life. I can’t thank you enough for explaining the facts and clarifying ideas that are scientific theory, hypotheses, or speculative ruminations. It has made feel more confident in my own decision making with my neurologist and given me more of a sense of control during this crazy time. I am not alone in these feelings : many MSers in the States follow this blog as a main source of info about Covid. P.S. a shill will give themselves away every time by the words they choose.

  • Thank you.
    Given that IFN beta is showing promise as a theraputic, has anyone assessed Lemtrada’s activity?

By MouseDoctor

Translate

Categories

Recent Posts

Recent Comments

Archives