#MSCOVID19 B cell repopulation with MS treatments


You have seen the data but you can now read the full paper

We have been examining the B cell repopulation potential from a trial data set, where access was provided by Roche. Thanks for that

If it is the case that a certain level of B cell numbers are associated with a COVID-19 related antibody response after vaccination. we asked how many people on standard ocrelizumab dosing would reach that level at 6 after dosing and then what would happen at 9, 12, 15, and 18 months after the last dose, if there was a drug holiday, remembering the 6 monthly dosing keeps the B cells inhibited.

CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis

David Baker, Amy MacDougall, Angray S Kang, Klaus Schmierer, Gavin Giovannoni, Ruth Dobson

MedRXiv doi: https://doi.org/10.1101/2021.09.26.21264023

BACKGROUND: CD20 depletion is a highly-effective treatment for relapsing multiple sclerosis that maintains B cells at low levels through six monthly dosing of 600mg ocrelizumab. This dosing schedule is associated with inhibition of seroconversion following SARS-CoV-2 vaccination, in contrast to the high levels of seroconversion following treatment with alemtuzumab and cladribine tablets. A number of emerging reports suggest that repopulation of 1-3% B cells facilitates seroconversion after CD20-depletion. The frequency of this occurring following repeated ocrelizumab treatment, after other DMT, and after treatment cessation is largely unknown.

METHODS: Relapse data, lymphocyte and CD19 B cell numbers were extracted from phase II ocrelizumab extension study (NCT00676715) data supplied by the manufacturer via the Vivli Inc, trial data-request portal. Repopulation data of oral cladribine from the phase III CLARITY study (NCT00213135) was supplied by the European Medicines Agency; and the alemtuzumab phase III CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405) trial data were supplied by the manufacturer via the clinicalstudydatarequest.com portal.

RESULTS: Only 3-5% of people with MS exhibit 1% B cells at 6 months after the last infusion following 3-4 cycles of ocrelizumab, compared to 50-55% at 9 months, and 85-90% at 12 months. During this time relapses occurred at consistent disease breakthrough rates compared to people during standard therapy. In contrast most people (90-100%) exhibited more than 1% B cells during treatment with either cladribine or alemtuzumab.

CONCLUSIONS. Few people repopulate peripheral B cells with standard ocrelizumab dosing, however an extending the dosing interval by 3-6 months may allow many more people to potentially seroconvert in the relative absence of excess relapse-activity. Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. This may help protect against severe COVID-19.

This paper may help you to decide what you are going to do. Remember it is an un-peer-reviewed paper. It has been submitted for such review

If you want more details and references then you can have a read of this paper too. This has been submitted but as it is a review you cannot add to MedRXiv. The journal has moved publishers and they don’t have a pre-print site, so I thought why not cut out the middle man.

David Baker, Amy MacDougall, Angray S Kang, Klaus Schmierer, Gavin Giovannoni, Ruth Dobson Seroconversion following COVID-19 vaccination: Can we optimize protective response in CD20-treated individuals? Submitted for publication

Although there is an ever-increasing number of disease-modifying treatments for relapsing multiple sclerosis (MS), few appear to influence the severity of COVID-19. There has been increasing concern about the use of anti-CD20-depleting monoclonal antibodies, due to the apparent increased risk of severe disease following natural SARS-CoV-2 infection and inhibition of protective anti-COVID-19 vaccine responses. These antibodies are given as maintenance infusions/injections and cause persistent depletion of CD20+ B cells, notably memory B cell populations that may be instrumental in the control of relapsing MS. However, they also continuously deplete immature and mature/naïve B cells that form the precursors for infection-protective antibody responses, thus blunting vaccine responses. Seroconversion and maintained SARS-CoV-2 neutralizing antibody levels provide protection from COVID-19. This may be optimized in the anti-CD20-treated population by vaccinating prior to treatment onset or extended-interval/delayed dosing in those established on therapy, with monitoring of B cell numbers until B cell repopulation occurs prior to vaccination. Some people will take more than a year to replete and therefore protection may require exogenously supplied antibodies or prophylactic antiviral agents to optimise protection against COVID-19. Further studies are warranted to demonstrate the safety and efficacy of such approaches and whether or not immunity wanes prematurely as has been observed in the other populations.

So whilst we are on the subject of COVID…sorry Steve:-(…..another T and B cell paper….but this time abit more info on fingolimod or is it both Fingo and Siponimod…..if so what were the two on the bottom (non converters) taking. You can see that even if you make an antibody response on ocrelizumab. the levels are about 10 times less than other DMT and controls….now if you put J&J/AZ into this mix the levels would be ten times less than Pfizer/Moderna, so a reason to try and avoid if you have the options

Sabatino JJ, Mittl K, Rowles W, Mcpolin K, Rajan JV, Zamecnik CR, Dandekar R, Alvarenga BD, Loudermilk RP, Gerungan C, Spencer CM, Sagan SA, Augusto DG, Alexander J, Hollenbach JA, Wilson MR, Zamvil SS, Bove R. Impact of multiple sclerosis disease-modifying therapies on SARS-CoV-2 vaccine-induced antibody and T cell immunity. medRxiv [Preprint]. 2021 Sep 20:2021.09.10.21262933.

Vaccine-elicited adaptive immunity is an essential prerequisite for effective prevention and control of coronavirus 19 (COVID-19). Treatment of multiple sclerosis (MS) involves a diverse array of disease-modifying therapies (DMTs) that target antibody and cell-mediated immunity, yet a comprehensive understanding of how MS DMTs impact SARS-CoV-2 vaccine responses is lacking. We completed a detailed analysis of SARS-CoV-2 vaccine-elicited spike antigen-specific IgG and T cell responses in a cohort of healthy controls and MS participants in six different treatment categories. Two specific DMT types, sphingosine-1-phosphate (S1P) receptor modulators and anti-CD20 monoclonal antibodies (mAb), resulted in significantly reduced spike-specific IgG responses. Longer duration of anti-CD20 mAb treatment prior to SARS-CoV-2 vaccination were associated with absent antibody responses. Except for reduced CD4+ T cell responses in S1P-treated patients, spike-specific CD4+ and CD8+ T cell reactivity remained robust across all MS treatment types. These findings have important implications for clinical practice guidelines and vaccination recommendations in MS patients and other immunosuppressed populations.

There were only 7 people treated with S1P1 modulator. This is another example where if you test for anti-Spike you are more positive than if you do anti receptor binding domain….Nothing new there really.

General Disclaimer: Please note that the opinions expressed here are those of 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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  • My wife is on rituxamab(last infusion 9 months ago) mycophenolate ,azathioprine and prednisolone. She had her vaccination 8 weeks after her rituxamab infusion and then the second dose 11 weeks later. We tested for antibodies which came back negative, what is the likelihood she produced a T-Cell response with the medication she takes?
    She has just had her 3rd primary dose even though she is still B-Cell depleted as she needs her rituxamab infusion in 4 weeks, she did stop her mycophenolate this time ,2 weeks prior to her 3rd dose(wasn’t told to stop during original vaccination) if she never made a T-Cell response the first time do you think it’s likely she will make one this time?
    We have been stuck in our house for the last 20 months due to not knowing if she has any protection at all, and it’s now really starting to have an effect on both of us.

    • Rituximab depletes the B cells and would let the T cells go and at 9 months the chances of a B cell response may be better but you add into the mix mycophenylate and this is getting rid of B cell responses and T cells responses and is one of the drugs of concern for stopping COVID vaccine responses and your chances of vaccine response must be low. There is a study looking at boosters in mycophenylate to read out in novemeber. Next in you add azathioprine as another whammay and top off with a dose of steroid, so I think the chances of B or T cell response will be very low. I havent been following the mycophenylate literature enough to know what the drug holiday does but not sure if there would be much of a T cell response to boost.

      In terms of protection you are best to be cautious, but I understand shielding for so long isnt a great answer. I would think a case could be made for protective anti SARS-COV-2 antibody (but I.m not a doctor), but I dont think it is approved for such prophylactic treatments

      • So I’m essence, the likelihood my wife has made any response to her original vaccination and 3rd primary dose is essentially zero, looks like another 12-18 months locked away for us.
        Thank you for getting back to me so quickly with an answer.

        • there might be some hope…:

          Merck & Co.’s Covid-19 antiviral drug,
          molnupiravir, appears to inhibit several major variants of the
          virus, including the highly contagious delta strain, according
          to early stage data presented by the company at an infectious
          disease conference early Wednesday.
          The findings came out of laboratory research pitting the
          experimental drug against the variants in cell culture. Further
          research may be needed to confirm the results in human testing.
          “It’s a really nice observation because it gives us
          confidence that it will work the same across the variants that
          are already out there, and potentially against any new variants
          that may emerge,” said Jay Grobler, the lead author and
          executive director of biology discovery at Merck.
          Molnupiravir, which could be taken as a pill, is being
          tested in a phase 3 trial expected to conclude in November. It
          is being developed for use in non-hospitalized Covid-19 patients
          who have had symptoms for five or fewer days and are at risk for
          a severe infection.
          The new research presented Wednesday also found that the
          prevalence of variants seen in Merck’s molnupiravir trials was
          similar to the representation of those strains around the world
          at the time, between October 2020 and January 2021.
          The company will continue to look at the experimental
          drug’s clinical activity against variants, Grobler said.

  • “Except for reduced CD4+ T cell responses in S1P-treated patients, spike-specific CD4+ and CD8+ T cell reactivity remained robust across all MS treatment types.”

    So this is good, bad or neutral for us, fingolimod users?

  • Last Ocrevus infusion in December, 2020. Still no B cells. Hope T cell response is present – and robust. Waiting for repopulation and then will re-vax. Extraordinarily frustrating and nerve-wracking. If exposed or infected will make a straight line, without haste, to the site providing covid monoclonal antibody treatment cocktail. Incredibly grateful to the work done, and promptly communicated, by the entire Barts team, especially Mousedoc, et al.

  • Hello MD. Thanks for this very informative study. I was looking at the paper and I see that there is about 10% of risk of relapses during each year after stopping ocrelizumab treatment. To me this looks a bit counter intuitive as I would have expected that relapses would increase with distance from last infusion. Duo you have an hypothesis for this? Did I get the tables and charts wrong?
    Also in figure 25 there are pwMS that kept relapsing despite a very low level of CD19 and memory b cells. An idea to explain that? Figures don’t seem so reassuring.
    Also figure 25 does not show an increase in memory b cells… is it the scale too wide to be visible? It is difficult to correlate memory with relapses. Thanks a lot again

    • It is a fact that even if you continually take ocrelizumab people relapse on treatment so if you look at the phase II on drug for 4 years the relapse rate is 0.1. which is the same as being off it for 18 months. So it seems there may not be excess relapses by stopping. However that is the risk people will have to way up, that is why I put the individual data plots there for people to see. Im not deciding what to do you guys are. However, looking at the figures some of those people relapsing should probably have been switched onto something else as you can see quite a few people were very active on drug and continued to relapse off drug. I asked prof Peihl how long he would be confident on a drug holiday and he suggests if the person was stable on treatment…18 months more concern is for people who have just started ocrelizumab and may be more active like the people you see.

      I put the graphs there so it is evident that people relapse when menory B are rock bottom and there is not a surge before people relapse, dang but it is what it is. It says the peripheral blood is not the place and perhaps the capacity to deplete memory cells in blood is a biomarker for treatment potential but levels are not a biomarker of activity.. I aslo thing the bloods were not done frequently enough.

      • Another great paper and analysis MD (and team)! Let’s hope it does not get blocked by the T-cell referees.

        “…It says the peripheral blood is not the place and perhaps the capacity to deplete memory cells in blood is a biomarker for treatment potential but levels are not a biomarker of activity”…….I agree, but who wants to get a LP more than once. Not fun. Maybe a small molecule DMT is better at getting into the bone marrow and CNS to attack more B-cells.

        I wanted to get your thoughts on the following Q&A from a major US based university hospital/MS center. The following is the first major source I could find on what to do past year 2 of Cladridine. It would appear “someone” has obtained authorization to re-treat if breakthrough activity is detected. I would normally provide a link, but I did not think it was appropriate. A quick google search for the Q&A language below and it can be found. Wonder why this information is not more widely known, if it is correct, which given the reputation of the hospital, I would assume it is correct and feasible. Why hasn’t the drug manufacturer updated the Prescribing Information!!

        Q: What can be done if patients on cladribine have breakthrough activity?

        A: All patients who have a relapse either during or following treatment can be treated with systemic corticosteroids. Switching to an alternative therapy may be considered in patients with breakthrough activity before the second course of cladribine or within a year of completing their second course. In patients who exhibit activity a year beyond the second course, can be considered either for re-dosing with 1.75 mg/kg per year or a switch to an alternative therapy. Prior to starting another disease modifying therapy, lymphocyte counts and contraindications should be reviewed.

        • This is bonkers a relapse and a switch when alemtuzumab is a retreatment. Over 50percent of alemtuzumab were not NEDA and need a third course those three doses sort out 75percent of people. It is obvious that people Fail cladribine who knows it may be one relapse rather than two, I think profKs first person on cladrine had disease breakthrough after six years so 5 years drug free.

          The prblem is because Merck canned their trial there is no supportive data.

      • Thanks for your reply, very clear. Do you think it is possible that there are b cells in the brain that are not being hit by ocrelizumab? If so, would there be a way to push them to leave the CNS like something that locally stimulates the immune system and attracts b cells to go where the stimulation is generated and then get them killed by ocrelizumab? On the other hand, if there is no b cell in the CNS this would have interesting implications on the disease.
        I would like to read what ProfG would do for those highly active people: switch to overall higher efficacy treatment (alemtuzumab or AHSCT) or to a brain penetrant treatment (cladribine)?

        • Yes 100percent that is why anti CD20 does not get rid of oligoclonal bands. Push them out I think the approach is get in there and kill them….Strike that thought… BTK inhibitors will manage them

  • ”however an extending the dosing interval by 3-6 months may allow many more people to potentially seroconvert in the relative absence of excess relapse-activity.”
    What about disability progression? Should one abandon the double dose trial?

    • No it should not be abandoned but what is means is that people will be depleted for months longer because a double dose means it hangs around longer and so repopulation will be slower.

  • After reassurance it was available in my locality, I booked my third dose today but the confirmation nhs text states booster, can you advise if the 3rd dose and booster inoculations are the same thing?

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