Can we optimize CD20 for COVID protection?


The answer one suggests is Yes but will it happen? I don’t know. Or should I say I don’t know how much it will occur in the UK.

It is a rapidly changing environment

Here are two papers one with alot of references and speculation galore (Long hand)  and one with the data without to much commentary (short hand) for you to decide. Also looking at the data from a what causes MS sort of view I can’t see that the reappearence of memory B cells associates with a return of disease activity (but i suspect it is a subset that is important and that they can be depleted by active drugs is the important issue, However, it sort of fits with what others are saying and I guess what comes back is not the same.

Anyway sit back and have a read

David BakerAmy MacDougallAngray S KangKlaus SchmiererGavin GiovannoniRuth Dobson Clinical and Experimental Immunology, uxab015,

Although there is an ever-increasing number of disease-modifying treatments for relapsing multiple sclerosis (MS), few appear to influence COVID-19 severity. There is concern about the use of anti-CD20-depleting monoclonal antibodies, due to the apparent increased risk of severe disease following 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. However, it is evident that poor-seroconversion occurs in the majority of individuals following initial and booster COVID-19 vaccinations, based on standard 6-monthly dosing intervals. Seroconversion may be optimized in the anti-CD20-treated population by vaccinating prior to treatment-onset or using extended/delayed interval dosing (3-6 month extension to dosing interval) in those established on therapy, with B cell monitoring until (1-3%) B cell repopulation occurs prior to vaccination. Some people will take more than a year to replete and therefore protection may depend on either the vaccine-induced T cell responses that typically occur or may require prophylactic, or rapid post-infection therapeutic, antibody or small molecule anti-viral treatment 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.

The above described the current state of knowledge when it was written and explains the available science behind the opinion.

However the data that helped to inform that opinion is now available here.

The original message from the MedXRiV version ( is less muted, but changes are made during Peer-review. The important point is there is data that can help inform your decision. It is sad to say that we have been behind the curve when it comes to vaccination advice and disease modifying treatments to optimise success. I hope we learn enough from the third dose to better inform the forth (booster) dose. I know some centres are suggesting delays. But the landscape is changing especially as antivirals occur

David BakerAmy MacDougallAngray S KangKlaus SchmiererGavin GiovannoniRuth Dobson Baker D, CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis Mult Sclerosis and related disorders, 2021. Published:December 04, 2021 DOI:


  • Clinical trial data was interrogated to determine the frequency of 1-3% B cell repopulation over 12-18 months
  • Few people repopulate after standard 6 monthly ocrelizumab dosing, but an extended dosing interval could allow many more people to repopulate B cells.
  • CD19+ B cells rapidly repopulated after cladribine and alemtuzumab treatment.


Background: Ocrelizumab maintains B-cell depletion via six-monthly dosing. Whilst this controls relapsing multiple sclerosis, it also inhibits seroconversion following SARS-CoV-2 vaccination unlike that seen following alemtuzumab and cladribine treatment. Emerging reports suggest that 1-3% B-cell repopulation facilitates seroconversion after CD20-depletion.Objective: To determine the frequency of B-cell repopulation levels during and after ocrelizumab treatment.Methods: Relapse data, lymphocyte and CD19 B-cell numbers were obtained following requests to clinical trial data-repositories. Information was extracted from the phase II ocrelizumab extension (NCT00676715) trial and the phase III cladribine tablet (NCT00213135) and alemtuzumab (NCT00530348/NCT00548405) trials obtained clinical trial data requestsResults: 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. Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. However, few people repopulate peripheral B-cells with standard ocrelizumab dosing. Controlled studies are warranted to examine a view that delaying the dosing interval by 3-6 months may allow more people to potentially seroconvert after vaccination.

This is not rocket science or a unique view

Longitudinal humoral response after SARS-CoV-2 vaccination in ocrelizumab treated MS patients: To wait and repopulate?van Kempen ZLE, Wieske L, Stalman EW, Kummer LYL, van Dam PJ, Volkers AG, Boekel L, Toorop AA, Strijbis EMM, Tas SW, Wolbink GJ, Löwenberg M, van Sandt C, Ten Brinke A, Verstegen NJM, Steenhuis M, Kuijpers TW, van Ham SM, Rispens T, Eftimov F, Killestein J; immunity against SARS-CoV-2 study group.Mult Scler Relat Disord. 2021 Nov 23;57:103416.

Objective: The objective of this study was to measure humoral responses after SARS-CoV-2 vaccination in MS patients treated with ocrelizumab (OCR) compared to MS patients without disease modifying therapies (DMTs) in relation to timing of vaccination and B-cell count.

Methods: OCR treated patients were divided into an early and a late group (cut-off time 12 weeks (3 months) between infusion and first vaccination). Patients were vaccinated with mRNA-1273 (Moderna). B-cells were measured at baseline (time of first vaccination) and SARS-CoV-2 antibodies were measured at baseline, day 28, 42, 52 and 70. (10 weeks)

Results: 87 patients were included (62 OCR patients, 29 patients without DMTs). At day 70, seroconversion occurred in 39.3% of OCR patients compared to 100% of MS patients without DMTs. In OCR patients, seroconversion varied between 26% (early group) to 50% (late group) and between 27% (low B-cells) to 56% (at least 1 detectable B-cell/µL).

Conclusions: Low B-cell counts prior to vaccination and shorter time between OCR infusion and vaccination may negatively influence humoral response but does not preclude seroconversion. We advise OCR treated patients to get their first vaccination as soon as possible. In case of an additional booster vaccination, timing of vaccination based on B-cell count and time after last infusion may be considered.

And another

Conte WL B-cell depleters attenuate the humoral response to SARS-CoV-2 vaccines in multiple sclerosis patients: A case-control study. Mult Scler Rel Disorders 2021.DOOI:


Methods: This is a case-control study looking at the odds of developing antibodies to three SARS-CoV-2 vaccines (Pfizer-BioNTech, Moderna, and Johnson & Johnson) in patients treated with B-cell depleters or S1P modulators versus other disease modifying therapies.  Patients were recruited who did not have a prior COVID-19 infection and received one of the three vaccines were tested for antibodies against the SARS-CoV-2 spike protein (Labcorp, semi-quantitative total antibody) at least two weeks following the final dose of the vaccine. Groups (B-cell, S1P modulators, other DMT, and no DMT) were compared on antibody level. The main outcome was whether or not a humoral response was detected by antibody testing.

Results: Sixty-seven patients were enrolled in the study, with 17 on OCR, 3 on OFA, 12 on S1P modulators, 29 on other DMT, and 6 not currently on any DMT. Patients who received OCR or OFA had decreased odds of forming antibodies (OR 0.031, p < 0.001, 95% CI (0.003–0.268)). Patients who received S1P modulators did not have decreased odds of forming antibodies (OR 0.413, p = 0.413, 95% CI (0.28–21.7). However, when analyzing the antibody response as a continuous variable, patients on S1P modulators showed lower absolute levels of antibodies (p = 0.024).

Conclusions: Patients who received B-cell depleters within the prior 6 months of SARS-CoV-2 vaccination had decreased odds of developing antibodies compared with other DMTs.  In line with other similar research, this suggests that B-cell depleters attenuate the antibody response to SARS-CoV-2 vaccines.  Although S1P modulators had an attenuation of the absolute antibody level, the odds of being negative did not differ from those on other DMTs

So here there was poor seroconversion with B cell depleters and most Sphingosine -1-phopshate modulators made a response but not most were siponimod and not fingolmod so is there a difference…maybe., People who have previously had COVID-19 could become reinfected more easily with Omicron.

However, we are entering a new COVID era. Whilst in South Africa a low number have been vaccinated, but many have been infected. It seems that people are getting re-infected and the rate is over three times that of delta. So be careful. At present there is not enough information on the consequences of infection,

Lake et al, Third COVID-19 Vaccine Dose Boosts Neutralising Antibodies in Poor Responders MedRXiv doi:

Objective: To determine if poor responders to COVID19 RNA vaccines (<50% neutralisation) after two doses would remain poor responders, or if a third dose could elicit high levels of NAbs.

Participants: 269 healthy individuals ranging in age from 19 to 80 (Average age: 51; 165 females and 104 males) who received either BNT162b2 (Pfizer) or mRNA1273 (Moderna) vaccines. Main Outcome Measures NAb levels were measured: i) 2 to4 weeks after a second vaccine dose, ii) 2 to 4 months after the second dose, iii) within 1 to 2 weeks prior to a third dose and iv) 2 to 4 weeks after a third RNA vaccine dose.Results: In 269 study participants, percent neutralisation ranged from 0% to 99% 2 to 4 weeks after a second vaccine dose. The majority of vaccine recipients (154/269, 57%) demonstrated NAb levels at greater than 75% 2 to 4 weeks after their second dose. Our study also revealed that 25% of vaccine recipients did not neutralise above 50% (Median neutralisation: 21%, titers <1:80) within a month after their second dose. We called these individuals Vaccine Poor Responders (VPRs). Twenty-three VPRs ranging in age from 31 to 79 (10 males, 13 females, average age: 62.5) independently obtained a third dose of either BNT162b2 or mRNA1273 vaccine 1 to 8 months (average: 5 months) after their second dose. Within a month after their third dose, poor responders showed an average 20 fold increase in NAb levels (range 46% to 99%). Conclusions The results suggest that poor responders are not permanently poor responders; they can generate high NAb levels with an additional vaccine dose independent of mRNA vaccine manufacturer. It is possible that poor responders are a source of breakthrough infections. Although it is not known what levels of NAbs protect from infection or disease, many vaccine recipients in high risk professions may wish to keep peripheral NAb levels high, limiting infection, asymptomatic viral replication, and potential transmission.

Remember this is in healthy individuls. Some give a poor response and give a better response after a boost. This is immunology 101 and one expects that you will make a stronger response after a boost. But if higher antibodies levels protect you then boosters should be beneficial,

COI Multiple

Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.. This is be read to offer clinical advice,which will come from your local neurology team

About the author



  • Are you aware of any studies on Ocrelizumab or Rituxan with more than 4 doses?? Based on when Ocrevus was approved in the US, some (many?) of us are closer to 10 doses…and Rituxan was used a lot in Europe before that. Am I on a fool’s errand hoping a 12 month pause will make a difference? (That’s meant as a rhetorical question, unless you have any thoughts!)

    • The scandnavian seems to be if you are stable then is is safer to break but i dont know of the repopulation curve after more doses and as you say it could be longer because with every 6 month dose there are fewer B cells to clear out.

  • Thanks for this MD. 1 year from last Ocrevus and still no B cells. My question is whether 1-3% of B cell repopulation reflects “low-normal” and, if so, can one expect that if you indeed seroconvert it very well may result in low antibodies? In other words, would waiting for a normal B cell count result in a higher quantity of amtibodies?

  • Thanks alot for the updates, MD. I know some people are tired of the covid-papers, but i want you to know that i really appreciate them. To some of us, what you’re sharing is really important knowledge.
    Do you think the remdesivir, casirivimab / imdevimab, molnupiravir etc. Will have reduced effectiveness against the new Omicron-variant? Do you think there is hope that the Omicron variant will be a very infectious but low virulence strain?

    • Omnicron is very infectious based on reports coming out of South Africa as for virulence this will take a couple of weeks to show itself…although it is siad to mildish remember many people in South Africa have been infected with Beta variant which has immune escape but is not particularly virulent. So people may have some protection. We will here about the anti-virals soon but they target , I think it has already been reported that some of the antibodies are not that effective, some are

      • I read that the Regeneron monoclonal antibody cocktail may be less effective to Om and they are hopefully working on a fix. However, a different company (Lilly?) said lab results show their Mab neutrlaizes Omecron in lab study. Let’s hope so. Anti-viral pill apparently work still as they don’t target spike but it is early days. For the anti-viral pills I don’t understand why there has not been an explanation as to why the anti-viral pills are not studied in combination in light of risk of potential resistance down the road.

        • From South Africa they are finding of omicron in hospitalised people who are hospitalised for other reasons supporting a mild effect. This is good news

  • Nice works
    Mouse 🙂


    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”

    I am a bit confused

    Memory b cell are the “bad guys” they must be clear to control ms

    But they also produce antibodies for us to combat injection (virus bacteria,etc)

    So anti cd 20 theraphy clear most memory b cell so basically you became more and more without antibodies and more prone to infections

    The precursors for antibody responses are the memory b cells(into plasma cells) …Right?

    Differentiation of memory B cells into plasma cells is far faster than differentiation by naïve B cells, which allows memory B cells to produce a more efficient secondary immune response.[4] The efficiency and accumulation of the memory B cell response is the foundation for vaccines and booster shots.[4][3]

    • Yes memory can be good and bad guys the MS drugs are like hammers and remove all, what we need are better tools. We know the memory cell is a mixture of different cell types and the bad ones are within one of those types. However once you make plasma cells that make the antibodies then removal of memory B cells does not remove the responsee as shown in monkies over ten years treated with anti-CD20. However I suspect there will be loss as you see loss of serum immunoglobulin levels so there is some impact whether this in on new antibody responses I dont know but we have the perfect opportunity to test this with COVID-19

  • Thank you for publishing this MouseDoctor. It’s a great start, we need to be thinking more like this. How can we “de-risk” anti-CD 20 treatment in the covid era. There are starting to be some solutions on the horizon and this is more of what we need to be looking for! Many thanks for publishing this.

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