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.