The B cell repopulation holds the key to successful vaccine responses after CD20


If you are taking a CD20 depleting antibody and want an antibody response then it seems increasingly clear to me that you have to have sufficent B cells to make a response.

In the blood there are 4 main cell types and to give a simplified view these are circulating (1) immature B cells you may hear these called transitional B cells or regulatory B cells These then become (2) mature B cells which we are also called naive B cells. These give rise to new antibody responses and following stimulation can form cells in the lymph glands that exit into the blood as (3) plasmablasts (a short lived antibody producing cells) that gives rise to plasma cells that usually live in the bone marrow. The other main cell type are (4) memory B cells these are generated from naive B cells and can make more memory B cells or can form plasma blasts.

The memory B cells in the blood make up about 20-30% of the CD19 B cell population. The remainder are largely naive B cells. The immature B cells are a small fraction of the B cells in the blood but after depletion these cells flood out of the bone marrow to fill the space and they make IL_10, which is a T cell inhibitor, which is why they are called regulatory cells. However, IL-10 is a B cell growth factor, which is probably why they make IL-10.

So it would not be a surprise that if you have to make a COVID-19 response, you have to make naive B cells and this is what I have said before.

Based on what we have seen before I have suggested that you need around 1-3% CD19 B cells. I think this is roughly 10 cells per microlitre, so 70% of 10 is 7 so says you may need around 7 naive B cells if my estimates are correct and this new paper says that you need about 6 naive B cells per microlitre (a thousandth of a litre) to make an antibody response.

However, based on what we have read at 6 months after ocrelizumab only 30% of people have 1% CD19 B cells.This says that if you stick to the standard 6 monthly dosing schedule then 70% of people won’t have 1% B cells and won’t make an antibody response after COVID 19 vaccination.

So the choice will be :

(1) Plough on regardless at a 6 monthly dosing cycle and hope that you are one of the 20-30% making Spike receptor binding domain antibodies that neutralise the covid-19 virus

(2) Plough on regardless at a 6 monthly dosing cycle and hope that T cell responses are enough for protection

(3) Measure your B cell levels and then decide to (a) plough on regardless or (b) risk delaying the infusion

(4) Measure your B cell levels until they reach the magic figure and then vaccinate and hope you make a response before MS potentially returns.

(5) Wait for a certain time and hope that your B cells have returned.

However, how long would you have to wait and that is the issue. For some people this will be more than a year.

So we have to see how B cells repopulate when you stop drug. The only problem is in the real world you don’t stop dosing. This data is in the early stage trials but it is not always published nor measured. E.g. Do we know what happens with Ublituximab/Ofatumumab …I don’t do you?

As you can see (dots on the bottom line) there are still some people that do not make an antibody response even though they have more than 6 naive cells per microlitre. So there are no guarentees.

Association of Naive B Cells with Humoral Response to SARS-CoV-2 VaccinationSchulz, E., Hodl, I., Forstner, P., Hatzl, S., Sareban, N., Moritz, M., Fessler, J., Dreo, B., Uhl, B., Url, C., Grisold, A., Khalil, M., Kleinhappl, B., Enzinger, C., Stradner, M. H., Greinix, H., Schlenke, P., Steinmetz, I.10.1101/2021.08.11.21261898 — Posted: 2021-08-13

Objectives Immunocompromised patients are at risk of severe coronavirus disease 2019 and are considered a high priority for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. Humoral vaccination response is impaired in these patients when circulating B cells are lacking. We aimed to analyze B-cell subsets at the time of vaccination to identify potential predictors of humoral vaccination response. Methods Patients (n=120) receiving B-cell-depleting therapy (n=41), those suffering from inborn errors of immunity (n=25) and hematologic malignancies (n=56), and healthy controls (n=79) were vaccinated twice with BNT162b2 or mRNA 1273. B-cell subsets were analyzed prior to vaccination. Two independent anti-SARS-CoV-2 S immunoassays targeting the receptor-binding domain (RBD) or trimeric S protein (TSP) were performed three to four weeks after the second vaccination. Results Seroconversion occurred in 100% of the healthy controls, in contrast to 67% (RBD) and 82% (TSP) of the patients, while only 32% (RBD) and 22% (TSP) achieved antibody levels comparable to those of healthy controls. The number of circulating naive B cell was strongly associated with antibody levels (r=0.761, P<0.001) across all immunosuppressive treatments or conditions. In multivariable analysis, the number of naive B cells was an independent predictor for achieving antibody levels comparable to healthy controls, and receiver operating characteristic analysis predicted that at least six naive B cells per microL were required. Conclusions Assessing the abundance of naive B cells in immunocompromised patients could be useful in predicting the optimal vaccination response.

How long to wait

Gurion R, Rozovski U, Itchaki G, Gafter-Gvili A, Leibovitch C, Raanani P, Ben-Zvi H, Szwarcwort M, Taylor-Abigadol M, Dann EJ, Horesh N, Inbar T, Tzoran I, Lavi N, Fineman R, Ringelstein-Harlev S, Horowitz NA. Humoral serologic response to the BNT162b2 vaccine is abrogated in lymphoma patients within the first 12 months following treatment with anti-CD2O antibodies. Haematologica. 2021 Jul 29. doi: 10.3324/haematol.2021.279216.

In this study in people with cancer on anti-CD20 to get a vaccine response you had to wait over a year.

Interestingly, the rate of seropositivity increased according to the time between anti-CD20 administration and vaccine, from 3% within 45 days, to 22% between 45 days and one year and to 80% after one year. Remarkably, the latter percentage was equal to that of patients never exposed to anti-CD20.

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  • very interesting. So as always, our choices are rubbish. There’s never a good/bad choice with anything to do with MS is there?

    Maybe someone could point out this to the neuros/MS staff across the country cos believe you me, they ain’t singing from the same hymn sheet with regards to corona. This isn’t a joke, how do different parts of the NHS find out these things, is it left to individual neuros to be reading these papers/research as they come out?

    • At the moment there probably isn’t any choice. I am framing it this way so maybe people who can have influence will think about it. I think the studies need to be be done small scale before messing it up opportnities for the masses…To me it is obvious that they are some special cases that need invesitgating asap.

      As for information.
      You are getting the information as quick as the rest of the world. The neuros may be getting it here too as they are probably not reading this preprint stuff. They wait until it is reviewed and this maybe a few weeks to many months away, they will know wht you know. Here you get the news and my biased view of this information

  • If the anti-CD20 DMT infusion is delayed, and labs do not demonstrate sufficient CD19 at 6 mos., when should the CD19 be rechecked? (Assuming continue to hold DMT)

    And if no antibody response is seen after a 2 shot initial series, should you receive a 1 shot booster or repeat the series of 2 shots after adequate repopulation?

    • How often should B cells be looked at…I dont know I am guess every month. I will have to look at the rituximab data to see if it can inform on this

      The booster protocols are decided the JCVI but I would say the boosters will be a single injection.

  • Dear MD,

    I received my first jab at 41 weeks when cd20 was 0.054, while 0.080 is the lowlevel of normal.

    These are the numbers I know. I am having a hard time to translate it to your numbers above.

    Does my 0.054 fit in your numbers above?

    • 54 cells per microlitre = 0.054 x 10*9 cells/Litre….therefore you should have made some response, so an experiment in action you can tell us after the second jab. If you can have it measured rememeber anyone from Barts can email

  • Hello MD and thank you for the continuous update on Anti-CD20. At the moment, I am going for scenario 3b or 4. Since I was not vaccinated for pneumococcal vaccine, I wanted to have get it with the covid one. I was also considering to get a tetanus vaccine booster dose. Will combining all these vaccines in a narrow window influence the B cell response for each of them? I was wondering that with low level of B cells most of them will be used to make response to the first vaccine I get and therefore the response to the subsequent vaccines will be dampened because of lower number of available naive B cells. Does this make sense? What would be your advice from immunology point of view? Thanks a lot

  • Mouse doctor.
    I love your posts. You’re hilarious and smart. But how the f**k is this an “easy read”. I’m a physician and I understand about 10-20% of what you wrote here.

    • This is a tough read for you being a doctor? I am far from being a MD, but this is far from being a tough read.
      Regardless, I think that any person with strong scientific background should have basic analytical and reading comprehension skills.

    • In short dose at 6 monthly cycles and 70percent of people don’t make a neutralising antibody response. Alternatively to get anti body response will mean a delay in dosing and you need to repopulate your B cells

  • Re“…says that you need about 6 naive B cells per microlitre (a thousandth of a litre) to make an antibody response”. Sorry to nit pick but it is a millionth of a liter. Milli- = 10 minus 3

  • Any thoughts on whether there is a link between length of time someone has been in an anti-CD20 and B-cell replete on rate? I’ve been on one 5 years / 10 doses and assumed it would take forever to replete, but maybe that’s not a valid assumption? I may have to look into testing my levels before my next dose.

    • Hi. You might not. It varies. I’ve been on Ocrevus for 4 years. I had two infusions delayed due to COVID – the first was 6 weeks late and the second was 8 weeks late. I got my levels tested right before each delayed infusion, and my B cells had already started repopulating – I was at 4% when I was two months late. Sadly, vaccines weren’t available yet.

      When I’m right at the 6 month mark, my B cells remain <1%.

      So, in other words, it's possible not to have to wait forever. I just can't seem to get my timing right.

        • 65 yo with Susac, dx Feb 2109- treated with ivig, steroids and rituximab. Off steroids Nov 2020, last dose rituximab March 2020. So 18 mo after last dose and still <1% B cell pop. Have you seen anyone go this long without repopulating? Had Moderna 2/2021 and 3/2021- Just got 3rd dose Sept 2021 and anti s ab (Roche elecsys) showed 46 U/ml just prior to 3rd dose 6 mo after second dose. ~ Roche equivalent to BAU/ml 1:1. Will repeat ab level 30 d after 3rd dose. bTW + activation of Cd4 and Cd8 by research study.

  • Boosters have become available to immunocompromised people in the US. If someone on Ocrevus got two mRNA shots between infusions and didn’t make detectable antibodies, is there any value in getting a booster before B cells repopulate? That is, can you somehow boost your T cell protection?

    • No I dont think it is that quite that quick for most people but they divide rapidly and one they start they repopulate

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