#MSCOVID19: to delay anti-CD20 dosing or not

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Barts-MS rose-tinted-odometer: ★ (It’s a Black-and-White Friday #000000 & #FFFFFF)

At the beginning of the COVID-19 pandemic, we made the case that B-cells and antibodies against SARS-CoV-2 were not necessary to clear the coronavirus and protecting you from severe disease. However, almost all emerging data challenges this position, therefore I have changed my position.  

It is now clear that cross-reactive immunity from common coronavirus infections provides some protection from COVID-19. IVIG (intravenous immunoglobulin) formulations collected prior to COVID-19 contain neutralizing anti-SARS-CoV-2 antibodies and may have contributed to the survival of agammaglobulinaemic patients who had COVID-19. 

Neutralizing monoclonal anti-SARS-CoV2 antibodies have been shown to be effective against COVID-19 and severe COVID-19 and are now part of our therapeutic armamentarium for treating COVID-19. 

People on anti-CD20 therapy are more likely to get COVID-19, severe COVID-19, are more likely to need ITU and hence more likely to die from COVID-19. 

The study below shows that antibody neutralization levels against SARS-CoV-2 and the observed protection from SARS-CoV-2 infection are clearly related. In other words, anti-SARS-CoV-2 antibodies are important.  

They estimate the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20% of the mean antibody level in convalescent serum from people who have recovered from COVID-19. The estimated neutralization level required for 50% protection from severe infection was significantly lower at 3% of the mean convalescent level. This means you need fewer antibodies to protect you against severe disease. Another interpretation, which I think is more likely,  is that antibodies are a marker of protective T-cell immunity. 

Worryingly the modelled decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained as you need less antibody. Again the latter may be due to T-cell immunity that must be present in the background. Despite this, it is quite clear that antibody neutralization level is highly predictive of immune protection be it via the antibodies themselves or the associated T-cell immunity. 

This study implies that if you don’t have antibodies you won’t be protected. The question that needs to be urgently answered is ‘ is T-cell immunity in the absence of antibody immunity sufficient to protect you against SARS-CoV-2 infection and severe disease?’. Unfortunately, we don’t have real-life data on this at the moment. 

My interpretation of this – based on the observation that people who are on anti-CD20 therapy have a higher risk of severe COVID-19 and hence have on average less cross-reactive anti-SARS-CoV-2 neutralizing antibodies – is that if possible it would be better to have anti-SARS-CoV-2 antibodies than not to have them. The is really important for pwMS on anti-CD20 therapies or S1P modulators who have blunted antibody responses to the COVID-19 vaccines. This is why I have moved my position from getting vaccinated ASAP to let’s time your vaccine to give you the best chance of seroconverting. This means waiting for B-cell reconstitution post-anti-CD20 before vaccinating

An adaptive vaccination/vaccine-booster strategy is logistically challenging for the simple reason that B-cell reconstitution post anti-CD20 therapy is quite variable. This means that after a certain period of time, say 9 months after your last dose of ocrelizumab, 6 months after your last dose of rituximab and 4 months after your last dose of ofatumumab you will have to have monthly B-cell counts to make sure your peripheral B-cell count is above 10 B-cells/mm3 before you can get vaccinated. I also suspect we will then have to check if you seroconvert and if not re-vaccinate you before redosing with the relevant anti-CD20. 

What this strategy won’t answer is even if these patients make an antibody response will the antibody and associated T-cell responses are good enough to protect you from infection or reinfection with the emerging variants? 

So until we have more evidence I am sitting on the fence. It is only fair to tell pwMS about the problem and the uncertainty around this issue and give them the choice to delay or miss their next dose of anti-CD20 therapy. So far some patients are delaying their next course of treatment and others are not on the grounds that they are not prepared to take a chance of undertreating their MS. A lot of the former group of patients are older with more comorbidities and hence are at higher risk of dying from COVID-19. In contrast, the latter group tend to be younger and hence are more willing to take their chances if they get COVID-19. As with all decisions around managing MS during the COVID-19 pandemic, there are no easy black-and-white answers. 

What is clear from this study below is that there is a clear hierarchy when it comes to vaccine potency with the mRNA vaccine, Moderna in particular, being superior to the other vaccines in inducing protective immunity. So if you have a choice I would go with one of the mRNA vaccines when it comes to maximising your antibody levels.

Image from Nature Medicine.

Khoury et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med. 2021 Jul;27(7):1205-1211. 

Predictive models of immune protection from COVID-19 are urgently needed to identify correlates of protection to assist in the future deployment of vaccines. To address this, we analyzed the relationship between in vitro neutralization levels and the observed protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using data from seven current vaccines and from convalescent cohorts. We estimated the neutralization level for 50% protection against detectable SARS-CoV-2 infection to be 20.2% of the mean convalescent level (95% confidence interval (CI) = 14.4-28.4%). The estimated neutralization level required for 50% protection from severe infection was significantly lower (3% of the mean convalescent level; 95% CI = 0.7-13%, P = 0.0004). Modeling of the decay of the neutralization titer over the first 250 d after immunization predicts that a significant loss in protection from SARS-CoV-2 infection will occur, although protection from severe disease should be largely retained. Neutralization titers against some SARS-CoV-2 variants of concern are reduced compared with the vaccine strain, and our model predicts the relationship between neutralization and efficacy against viral variants. Here, we show that neutralization level is highly predictive of immune protection, and provide an evidence-based model of SARS-CoV-2 immune protection that will assist in developing vaccine strategies to control the future trajectory of the pandemic.

Conflicts of Interest

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Preventive Neurology

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni 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. 

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

32 comments

  • Thanks for this. If you were vaccinated prior to being treated with anti-CD20 will that immunity be maintained for as long as it would if you were not on anti-CD20?

    • Not sure, but it will be maintained for years at least. We also know that booster or recall immune responses on anti-CD20 although blunted do happen, which is unlike the response to novel or new antigens. This is why it is important to get vaccinated before starting an anti-CD20 therapy,

  • What is the current theory on anti-CD20 patients that have been infected already? are they any less vulnerable than they were before? yes their t-cell army will have been mobilised but is that all they can hope for. Reinfections rates in genpop are relatively low but my logic says that in the absence of anti-bodies, we are still prone / screwed

    • The immune system is a remarkable thing. So if you have been infected in the past you are likely to have immunological memory that will make the next infection less severe. We now know pwMS on anti-CD20 therapies make T-cell responses.

  • Yeah right. My insurance company pushes back every time my neuro tests my B-cell count, saying it’s not medically necessary. It will take years for them to understand and support a complicated protocol involving multiple antibody and B-cell tests. For me, I think the answer is switching to a different DMT and getting a booster while they figure it out.

  • Dear Prof. G.

    Just wondering.

    When does the Ocrelizumab stop working?
    B-cells are slowly getting back to normal levels, but what does that mean in terms of how Ocrelizumab still does it’s job?

    Im up for my next dose of Ocrelizumab, but within the next few weeks I will be offered my third jab.

    I have already decided months ago that I will try to postpone my Ocrelizumab when im offered the third jab. But Im real scared for my MS.

    • Re: “When does the Ocrelizumab stop working?”

      In patients who have had 3 or 4 courses and then stop being treated the majority >90% are free of relapses and MRI activity at 18 months.

  • I’m looking forward to seeing clinical data on how fully vaccinated anti-cd20 treated patients actually do when infected with covid. At this point it’s all on paper, but how much does the observed T-cell reponse actually matter?
    I’m going to guess that active anti-cd20 + double jab mRNA + no antibody response but robust T-cell response
    will give a relatively decent but blunted protection against severe disease. 50-60% maybe? And very low/no protection against infection.

      • Yes I heard, Prof G., And I’m very sorry. For you, the patient, and for all of us who take anti CD20s, and who now have to question our choice of treatment and lifestyle. At the same time, I have to say that I’m not surprised that someone could pass away while being on an anti-cd20 even if double jabbed. Hopefully, however, this is not going to be too much of a common endpoint – even for these patients.

        On a similar note: Would you consider recommending any of your patients switch treatments? And if so, to which DMTs? Is there any data on pwMS going from cd20s to cladribine?

  • If it’s low B cells that are responsible for not developing antibodies, could this also have implications for pwms with other DMTs whose B cells are chronically lowered (e.g. teriflunomide, DMF,…)? Many of them have their B cells reduced by 50% chronically (although not below levels of 10).
    Would you speculate that this could affect their antibody titers? Or that their titer would drop sooner than the general population?

    • Regarding other DMTs other than the S1P modulators this is not a problem; you seroconvert. You need very few B-cells to make an antibody response.

  • even there is no exact answer – how would you see a female of 37, no comorbities, bmi 20, non smoker, double pfizer with no antibodies but solid t-cell elispot reaction.
    is pregnancy an additional risk factor?

    • Pregnancy is a risk factor for COVID-19 and is on the list for vaccination in the UK with the mRNA vaccines. Outside of this, the risk should be relatively low. I don’t know how reliable the elispot test is in this situation.

  • Excellent information as usual. There is no chance I will get any B cell testing. However, where I live I was notified that I can get a third booster vaccine. In terms of timing I had my last infusion in March 2021. I had my first Covid Vaccine Pfizer in May 2021 and the second in July 2021. I am meant to have my next Ocrevus infusion in October but have told them I am going to delay it until at least 9 months. So my understanding is this means I should get the 3 booster Vaccine at 9 months. The recommendation from our vaccine centre is that my third vaccine should be 2-3 months after the second dose. Which for me means October. Or should I wait until December and then get my next infusion at 10 months. Pretty much left on my own to make these decisions as I attend the only MS clinic in my province. This clinic is tied to a University Hospital. So I really appreciate your insight.

    • I just had my B cells tested at 9 months post-infusion and had zero. In talking with the nurse she said that while there may be zero B cells in the peripheral blood, they may be reappearing in tissues. Of course there is no way to know that. So I will go another month and then get tested again for the B cells. I do not want to get the booster until there is a greater likelihood of having an antibody response. Am an n of 1 so take it as a speck of info in a shore of grains of specks. I have been on Ocrevus since spring of 2017.

      • That is true no B cells in blood does not mean no B cells, Remember to get to lower limit of normal takes between 27 weeks and 175 weeks so there will be many people at 9 months with no peripheral B cells

  • too late for me, I went and had the Ocrevus last week. The MS nurse (rightly I suppose) said not known when booster vaccinations would even start. Maybe if they’d had the stock and not lied about it, they could have been more firm on a date boosters would start?
    As it is, it will now be likely months before B cell start to re-populate so even if I am called for the booster in next few weeks, it really won’t be of any use will it?. I have a child at college (where apparently windows don’t even open) and a hubby who works in a small room, so probaby just a matter of time until I get it?

    30k +cases per day and nigh on 200 deaths, but Sajid Javid says there is a new treatment that when given to immunocompromised after being hospitalised reduces death by a whopping 20%, wow, I can hardly contain my excitement lol

  • Well other` s dont follow your words Professor 🙂

    “Often when determining if a patient mounted a proper response to an mRNA vaccine, we test for the presence of antibodies, but this method neglects an entire arm of a person’s immune response,” said one of the lead authors Sokratis A. Apostolidis, MD, a fellow in the Department of Rheumatology. “Measuring both antibodies and T-cell response gives us a more complete picture of a patient’s immune response, and reveals that patients who can’t generate antibodies as well as a healthy person are actually still protected by the COVID-19 vaccine.”

    Researchers found that patients who had undergone aCD20 treatments had subpopulations of T cells that responded similarly to vaccination as healthy control subjects. Patients who underwent aCD20 therapy generated robust CD4 and CD8 T cell responses to the COVID-19 vaccination. Further, the CD8 T cell response was especially robust among the subgroup of patients with MS who didn’t generate RBD antibodies. This observation reveals that even without circulating B cells, the COVID-19 vaccine effectively primed patients’ immune response to the virus.

    Patients with multiple sclerosis show robust T-cell responses to mRNA COVID-19 vaccines

    https://medicalxpress.com/news/2021-09-patients-multiple-sclerosis-robust-t-cell.html

    • Re: “…are actually still protected by the COVID-19 vaccine.”

      They don’t really know this; showing T-cell responses in a lab is not the same as showing protection from infection, severe infection and death from SARS-CoV-2 in real life. If this was the case explain why we are seeing breakthrough infections in double-vaccinated ocrelizumab patients on anti-CD20 therapies?

      • are the breakthrough cases in cd20 cohort statistically significant vs breakthrough in israel for example? and are there already „a lot“ severe documented cases of cd20 double vaccinated patients?

        would you (still) say risk factors are to be seen like:
        comorbidities>age>high bmi>cd20 double vaccinated (if it was just that simple) or has it become any different recently with cd20 double vaccinated moving to the left?

        thank you very much!

        • I don’t know the answers to these questions these will have to be answered in national registers. Yes, other risk factors will almost certainly play a role. The government knows the vaccines don’t work very well in immunocompromised patients, which is why they are recommending a third dose of the vaccine in this vulnerable group. All I am saying is that if you are B-cell depleted the the thrid dose is not going to make much difference to your antibody responses.

          • so finally through covid we would get tailored treatment strategies for cd20 but the pharma will hate it and most neuros wont do it because of practical reasons…
            but honestly would it not be safe to do a cd19 cell test each 3 month until the 18th month adter last OCR (Dr. Ruth) and thereafter monthly if needed – should be possible no?

  • Interesting that you say most who delay the ocrelizumab are older more co-morbid and that most young people don’t.

    I am young and fit and delayed my infusion by 9 months. I still do feel that every 6/12 is too often for ocrelizumab even without the covid risk.

    New question – positive antibody test post 2 Pfizer’s in December 2020. Had next ocrelizumab in May. I work in NHS so am offered my booster next week which is 4/12 post ocrelizumab. Do you think I should wait a bit longer? Or perhaps because I had antibodies after vaccine it won’t make any difference to wait longer? Dilemmas! Either way I have declined my November dose of anti CD20 I plan to delay it until after the flu NHS season

  • I’m so nervous about being on Ocrevus with this pandemic! I’ve been double vaccinated but not sure that’s enough. Considering changing DMTs , any suggestions? Ocrevus is the only DMT I’ve been on. Thanks

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