#MSCOVID19 Anti-CD20. Can an COVID-19 antibody response be made..Maybe

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The data is surfacing and it tells us that people taking ocrelizumab: (a) Make an anti-viral T cell response and (b) make a blunted antibody response.

Apostolidis et al 2021,https://www.medrxiv.org/content/10.1101/2021.06.23.21259389v1.full

Coppola N et al. Preliminary evidence of blunted humoral response to SARS-CoV-2 mRNA vaccine in multiple sclerosis patients treated with ocrelizumab. Neurol Sci. 2021 Jun 15:1–4. doi: 10.1007/s10072-021-05397-7.

Is there a guarentee that you will make an antibody response when you get the jab……….Answer = No

If you want a postive response COVID19 antibody test get yourself an anti-Spike test, An anti-receptor binding domain of spike test is less likely to be as positive. If you want an irrelevant test… get a nucleocapsid test…Yep quite a few people have done this and is no use for many vaccines as they are all based on Spike.

Why do this?

Look at the data below if you do anti-Spike the majority of people are positive using 1ug/ml cut off and the 10microcgramme/ml cutoffs (line). Receptor binding domain is only a small fraction of Spike so it makes sense you have more to whole Spike. However the antibodies to receptor binding domain stop the virus attaching to your cells to prevent infection. The higher the level, the better chance you have to block the virus from infecting and this is important with the Greek letter named variants of concern, as they need more antibody to stop them infecting.

T1 is the baseline before starting vaccine this is where the baseline is measured Apostolidis et al. 2021. Grey dots controls, orange dots MS

Do people make an antibody response it they seemingly have no B cells in the Blood?: YES sometimes. Therefore lack of B cells in your blood before vaccination does not say you won’t make a vaccine response, but on the flip side if you have B cells in your blood you are probably more likely will make a vaccine response. You could measure this and if you have B cells…green light…vaccinate you will probably make an antibody response.

Do you make an antibody response if you have more than 2% B cells: Possibly Yes?

Do you make an antibody response if you have more than 0.1% B cells: Possibly Yes? However this level is at the bottom of the pile, therefore, if you have a blood test before you are vaccinated and you have say above 0.2% B cells (need more data) or 1% B cells then you are likely going to make a B cell response to the COVID vaccine. https://www.medrxiv.org/content/10.1101/2021.06.23.21259389v1.full

However already I have to say be warned!!. There will be exceptions and we saw this (doi: 10.1007/s00415-021-10663-x.) last week. Lymphocyte level 1.22 x 10*9/L and 1% CD19 B cells and no antibody response detected with an interval of 5 months.

How do you guarentee you will have B cells…you can’t because people repopulate their B cells at very different rates. Some get back to lower limit of normal quickly (around 6 months) some take (three or more) years. So in this example essentailly no one had 1% B cells less than 6 months after infusion….This is why they do it every 6 months. Therefore to increase the chance of B cells above 0.2% you would probably have to delay your next dose of ocrelizumab. However what is the risk that disease reactivates?

What is 1% of lymphocyte level? This is where it is not good science because it should be based on absolute numbers not percentages. In healthly individuals the lymphocyte range is about 1000-4000cells/microlitre at 1% this is 10 to 40 cells/microlitre. So point 0.1% is 1 cell/ul so perhaps if you are 2 cells/ul that could be enough.

However, be warned again

Based on the phase II extension data at 6 months after dosing there are still people with 0 CD19 cells/uL counts and at 9 months there are still people at 0, but at 12 months there people at 2 cells and therefore the question is what are the risks of disease reactivation if you do this. Exactly how many I will have a look at the data. It may not be worth the effort

I have drawn a line at about 10 cells (1%) per microlitre so as you can see by 9 months (i.e. 96 weeks) after the last dose (triangle) over 50% of people had reached this level. From Baker et al. 2020 MSARD. Please not bloods were only looked at about every 3-6 months so pay not attention to the line between the dots. The slope may be very different

During the pandemic ProfG has suggested some immunity is better than no immunity, but as fears ease and boosters arrive or you live in a area with little virus, Do you try and optimise your chances of an antibody response or plough on regardless? The answer is based on Opinion Only..We don’t have the data

Are you convinced the level of antibody is enough? I will say that of the antibody reponses in CD20-treated individuals that are positive, they are generally lower than occurs in people who have not had anti-CD20.

There has already been data on the influence of rituximab and the influence of relapse.

Maarouf A, Rico A, Boutiere C, Perriguey M, Demortiere S, Pelletier J, Audoin B; Under the aegis of OFSEP. Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond? Neurol Neuroimmunol Neuroinflamm. 2020 Jun 25;7(5):e825.

Maroouf et al. 2020

We can look at rituximab data where dosing was stopped because of the COVID-19 pandemic. 33 people were stopped and not one relapse developed despite stopping for 8-31 months and there are at least 7 people without B cells at 9 months but with only 5 with B cells definately above B cells at 1%.

Barun B, Gabelić T, Adamec I, Babić A, Lalić H, Batinić D, Krbot Skorić M, Habek M. Influence of delaying ocrelizumab dosing in multiple sclerosis due to COVID-19 pandemics on clinical and laboratory effectiveness. Mult Scler Relat Disord. 2021 Feb;48:102704.

Figure 2
Barun et al. 2020

The mean time between two ocrelizumab infusion during the lockdown was 7.72±0.64 (range 6.07 to 8.92) months. The mean time between last ocrelizumab infusion and the lymphocyte sampling prior to post COVID infusion was 6.59±0.95 (range 5.18 to 8.49) months. In this period, none of the studied patients had a relapse.

Tazza F, Lapucci C, Cellerino M, Boffa G, Novi G, Poire I, Mancuso E, Bruschi N, Sbragia E, Laroni A, Capello E, Inglese M. Personalizing ocrelizumab treatment in Multiple Sclerosis: What can we learn from Sars-Cov2 pandemic? J Neurol Sci. 2021 May 20;427:117501. doi: 10.1016/j.jns.2021.117501.  During SARS-CoV-2 pandemic, we adopted a personalized delayed protocol for ocrelizumab infusions in Relapsing Remitting Multiple Sclerosis (RRMS) patients according to the national recommendations. Out of the 83 RRMS patients whose infusion was scheduled between March and December 2020, 56 patients experienced a delay in treatment based on MS severity and SARS-CoV2 infection risk profile. In most cases, the immunophenotype was performed monthly to guide re-infusions. Specifically, B CD19 + cells repopulation rate was monitored. Mean infusion delay was 103.1 [SD 40.6] days, and none of the patients presented relapses or active disease at MRI at the end of the observation period. Treatment naïve status and the interval between immunophenotyping and the last ocrelizumab infusion were predictors of earlier B CD19 + cells repopulation……Our findings suggest that a personalized treatment with a delayed infusion schedule does not compromise ocrelizumab short-term efficacy and may help to lengthen the therapeutic window for an effective response to SARS-CoV2 vaccine.

There are UK studies in the pipeline when people stopped dosing ocrelizumab last March, which address this. There will be more anti-CD20 data following vaccination. As these surface it will start to answer the risks of a delay and help determine whether it is deemed necessary. It may not be and maybe unwise

However, you will not know this until vaccinated individuals get infected. Lets hope it doesnt happen

The rate of re-infection is about 1:1000% so it will happen but this information will be a trickle. I am sure most, if not all people will do OK as the T cell response and your, weight (BMI), sex and age, if you have this demographic, will protect you.

SARS-CoV-2 vaccine breakthrough infections are asymptomatic or mildly symptomatic and are infrequently transmitted.Rovida, F., Cassaniti, I., Paolucci, S., Percivalle, E., Sarasini, A., Piralla, A., Giardina, F., Sammartino, J. C., Ferrari, A., Bergami, F., Muzzi, A., Novelli, V., Meloni, A., Grugnetti, A. M., Grugnetti, G., Rona, C., Daglio, M., Marena, C., Triarico, A., Lilleri, D., Baldanti, F.10.1101/2021.06.29.21259500 — Posted: 2021-07-03

Vaccine breakthrough SARS-CoV-2 infection was monitored in 3694 healthcare workers receiving 2 doses of BNT162b2. SARS-CoV2 infection was detected in 33 subjects, with a 3-months cumulative incidence of 0.90% and 0.42% in SARS-CoV-2-naïve and experienced subjects, respectively. Vaccine protection was 87% in naïve and 94% in experienced subjects when compared with a pre-vaccination control group. The infection was mildly symptomatic in 16 (48%) and asymptomatic in 17 (52%) subjects. Virus isolation was positive in 7/13 (54%) symptomatic and 4/8 (50%) asymptomatic subjects tested, and B.1.1.7 lineage was detected in all subjects. Antibody and T-cell responses were not reduced in subjects with breakthrough infection. Evidence of virus transmission, determined by contact tracing, was observed in two (6.1%) cases.This real-world data confirm the protective effect of BNT162b2 vaccine. A triple antigenic exposure, as occurring in experienced subjects, may confer a higher protection. Virus transmission from vaccinated subjects is infrequent. As a possible recipient of a death sentence if I caught covid, I have been cautious. But I would also want to know the safety of any decision made.

Should a pilot be done? Maybe there will soon be enough data to make a call. I expect the argument will be “T cells are enough” and they will test antibodies against Spike. However, this is not just about ocrelizumab and MS, but rituximab and other conditions and ofatumumab too. I sure there there will always people who do not give a good vaccine response. Can you optimise this?

Interferon-gamma release assay testing to assess COVID-19 vaccination response in a SARS-CoV-2 seronegative patient on rituximab: a case report. Int J Infect Dis. 2021 Jun 30:S1201-9712(21)00542-7. doi: 10.1016/j.ijid.2021.06.054

I am not making any recomendations …..More data will surface

General Disclaimer: Please note that the opinions expressed here are those of author and do not necessarily reflect the positions of BartsMS or 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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18 comments

  • I got my first BNT jab 5 month after the previous OCR cycle -> 3 weeks for the second jab (this Friday!!) -> 3 weeks for the next OCR infusion. Keep worrying about OCR wiping out little guys trying to remember anything meaningful… If I were to do this all over again, what would be the best timing and intervals of jabs and OCR infusions? Thank you!

    • To be honest we dont really know, there is not enough granularity in the data, there are clearly people who convert with an interval of less than 5 months and there are those that don’t for a lot more than 5 months. So the solution is probably not a “do this and it is a magic solution”. It is clear to me most people if not all people are getting some form of immunity from current practice and hopefuly this is enough to stop people being hospitalised and dying. I know there are more papers soon to surface and each one adds vital information

      At the moment in the UK, it is a balance of no-immunity verses some-immunity, it looks like the case numbers are soaring. I think the discussion centres on moving forward once we have the population done and boosters are considered, there are some people with low-antibody responses due to ocrelizumab usage.

      We have to get our data out and others have to do the same too. Different vaccines may give different results and all we have seen in the literature is about pfizer. I saw some nice data from South America using a differnt vaccine to that used in UK and the result on fingolimod looked pretty good….fluke or is it telling us something?

      • Thank you MD! Looking at my B-cell counts right now (still at 0.1) I was thinking it probably doesn’t make too much a difference now and few month earlier..

      • Hi MD, if this different vaccine also makes the same spike protein, what could be the point of difference triggering different part of immunity? Different adjuvant? Or was it an inactivated vaccine you are referring? Thank you!

        • Different methods of getting there, adenovirus making spike protein, mRNA, inactivated Coronavirus or virus protein but all willl make the same spike protein identified and published back in Jan 2020.

  • Is there any data on what level of immunity pwMs maintain after Ocrevus if they were vaccinated prior to starting therapy? Can we assume they retain full immunity (or as much as they would have without Ocrevus) or will the benefit be blunted? I note previous case reports of losing varicella immunity after starting Ocrevus treatment.

    • I believe it will be retained at least for some time assuming you do not get hypogammaglobulineamia as there is literature from other vaccinations remember plasma cells cells that make antibody do not get deleted by anti CD20

  • Re: “… not one relapse developed despite stopping for 8-31 months and there are at least 7 people without B cells at 9 months but with only 5 with B cells definitely above B cells at 1%.”

    Are relapses the right metric? People with PPMS don’t have relapses, but they get worse. Isn’t low dose or very intermittent anti-CD20 therapy simply converting people with relapsing MS into PPMS? This is the critical question we have to answer. We know from deductive reasoning that relapses and MRI activity are not MS, so what is happening to the real MS in these patients, i.e. their brain volumes and neurological functioning?

  • Thank you for this MD and thank you for continuing to bring us up to date information I really appreciate it.

    Two questions (one for Prof G!)

    To MD – is the spike protein antibody test the good one ie the one we need? I assume so but I got slightly confused by the above. You already know that I had a positive spike antibody test post double vaccination on ocrelizumab (but delayed my dose)

    Prof G – you said that intermittent or low dose anti CD20 is potentially converting RRMS to PPMS. I may be misunderstood but I thought that high dose induction therapy followed by lower dose or different dosing was one of the treatment protocols you were researching for the future? (Sorry my understanding could well be low level here!!)

    • Re: “high dose induction therapy followed by lower dose or different dosing was one of the treatment protocols you were researching for the future?”

      Yes. this is called the ADIOS trial. The outcome is NEDA-2 (relapse and MRI activity) so won’t directly address the question around CNS penetration and smouldering MS. However, we can potentially get to that with BVL and other MRI metrics.

  • Very interesting post! Thank you. I asked my Neuro to wait for b cells to go at least at 2 mcl before getting vaccine and monitor lymphocytes every month after 6 months from last ocrelizumab dose. Happy to see it matches with data that are surfacing and that no relapse occurred after dispensation of Anti-CD20. How can we know if T cell response will be enough and last for a long time?

  • Well I’ve given up. After 2 covid jabs and being on Ocrevus I am taking it for granted that I am as protected as someone who hasn’t had the vaccine.

    And Boris letting it rip yesterday with facemasks, nightclubs, no social distancing and being quite prepared to accept 100,000 cases per day (what about Long Covid???????)was the final nail, I am back self isolating.

    Due Ocrevus in September, probably the next time I will leave the house.

    • 32,500 cases today and rising, what could possibly go wrong?
      Johnson (don’t call him Boris, it humanises him) is a gambler by nature, yet going by his record he’s on the mother and father of a losing streak.

    • I hear what you are saying. Ignoring data of long covid and recent study showing loss of brain tissue with even mild covid? Another “shredder?” Is this strategy a tacit (or overt) acknowledgment that chasing the variants, in light of recent Israeli data, is a no-win situation so therefore adopt the pursuit of herd immunity and hope natural immunity saves the day? Needless to say I don’t agree with such a strategy.

  • Therefore lack of B cells in your blood before vaccination does not say you won’t make a vaccine response

    I like this bit ….Meaning blood is not a good measure for tissue infiltrating lymphocites

    • Yep but you know this already. Likewise you can relapse with essential no B cells in blood

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