Boosters in seroconversion-negative CD20-depleted individuals remain largely negative


Longitudinal analysis of antibody trajectories and humoral responses to a third dose of mRNA vaccines against SARS-CoV-2 in patients with a history of anti-CD20 therapy (RituxiVac 2.0)Sidler, D., Born, A., Schietzel, S., Horn, M. P., Aeberli, D., Amsler, J., Moeller, B., Njue, L. M., Medri, C., Angelillo-Scherrer, A., Borradori, L., Seyed Jafari, S. M., Radonjic-Hoesli, S., Chan, A., Hoepner, R., Bacher, U., Mani, L.-Y., Iype, J. M., Suter-Riniker, F., Staehelin, C., Nagler, M., Hirzel, C., Maurer, B., Moor, M. B.

Background Morbidity and mortality of COVID-19 is increased in patients with B-cell depleting therapies, the majority of which also show compromised vaccination-induced immune responses. Herein, we report on the trajectories of anti-SARS-CoV-2 antibodies in patients from the original RituxiVac study compared to healthy volunteers and investigate the immunogenicity of a third vaccination in previously non-responding patients. Methods A follow-up evaluation was performed in volunteers and patients from the RituxiVac Study (NCT04877496), which investigated the humoral and cell-mediated immune response after SARS-CoV-2 mRNA vaccination in patients with a history with anti-CD20 depleting therapies (rituximab or ocrelizumab). The current population included 33 patients and 26 healthy volunteers with initial humoral vaccine response and 32 non-responding patients. Primary outcome was anti-SARS-CoV-2 antibody trajectories in vaccine responders 4.3 months (median; interquartile range [IQR]: 3.6-4.8 months) after first evaluation and humoral responses after a third vaccine dose in previous non-responders. Antibody decay rates were compared using analysis of covariance in linear regression. Results In patients with detectable anti-spike IgG antibodies after two-dose vaccination, circulating anti-spike IgG persisted in 88% (29/33) of patients 5.6 months after the second vaccination (median; IQR: 5.1-6.7) compared to 92% (24/26) of healthy volunteers 6.8 months after the second dose (IQR: 6.0-7.1) (p=0.7). Antibody decay rates were comparable between patients and controls with -0.54 signal/cut-off (s/c) units per month (IQR -0.72 to -0.45) and -0.60 s/c units per month (IQR: -0.88 to -0.44), p=0.70. Two-dose responders with loss of circulating antibodies at follow-up (n=4/33, 12%) had lower initial antibody concentrations (p<0.01). Biomarkers for immunocompetence, including CD3, CD4 or CD19 cell count at baseline did not predict anti-spike IgG persistence. In two-dose non-responders, a third dose of mRNA vaccine against SARS-CoV-2 elicited humoral response with detectable anti-spike IgG antibodies in 19% (6/32) participants. No clinical parameters nor biomarkers of immunocompetence predicted humoral response after a third vaccine dose. Conclusion The present study reveals comparable antibody reduction rates between patients with CD20-depleting treatment history and healthy volunteers, but inefficient humoral responses to a third dose of SARS-CoV-2 mRNA vaccines in the majority of two-dose non-responders. There is a need for individually tailored vaccination strategies in immunocompromised patients that could be stratified by B cell counts and initial level of antibody titers. (Funded by Bern University Hospital, number, NCT04877496)

In this study they look at anti-Spike response and it is remarkably high at 88% compared to some studies. This is in part due to the assay target used but one also imagines there are other explanations. It as to be said that the people taking anti-CD20 had a variety of conditions including transplantation, cancer and autoimmune diseases, many of which was not MS. Also the interval between vaccine and CD20 dosing was years and B cell numbers were above a few cells. However the important element of this study was that when people who had not converted after two doses 26/32 remained negative after a third booster the 6/32 (19%) that were positive had their vaccine some time (> 1-2 year) after CD20 depletion. So this suggests to me that many of the anti_CD20 antibody treated MSersthat did not make a vaccine response after two doses are unlikely to make an antibody response atfer a booster if they stuck to the standard 6 monthly dosing schedule.

I suspect that this will apply to many of you as you will already of had your boosters without any delay in your dosing schedule.

This probably means that without the antibdy response you defence against infection is reduced, We hope that you T cells can do the job of clearing the virus and remember there now a number of anti-viral options available if you do get infected.

Maybe people will read and assimilate the information out there to help people to make an antibody response. If you are not taking anti-CD20, it appears that antibody levels after boosters will be enhanced (see below)

Antibody titers before and after booster doses of SARS-CoV-2 mRNA vaccines in healthy adults Demonbreun, A. R., Sancillo, A., Vaught, L. A., Reiser, N. L., Pesce, L., McNally, E. M., McDade, T. W. MedRXIv 10.1101/2021.11.19.21266555

Two-dose messenger RNA vaccines (BNT162b2/Pfizer and mRNA-1273/Moderna) against
SARS-CoV-2 were rolled out in the US in December 2020, and provide protection against
hospitalization and death from COVID-19 for at least six months. Breakthrough infections have
increased with waning immunity and the spread of the B.1.617.2 (Delta) variant in summer
2021, prompting approval of boosters
(for all adults over 18 in the US and currently over 40 in UK). We measured anti-receptor binding domain (RBD) IgG and surrogate virus neutralization of the interaction between SARS-CoV-2 spike protein and the human angiotensin-converting enzyme (ACE2) receptor, before and after
boosters in N=33 healthy adults. We document large antibody responses 6-10 days after
booster, with antibody levels that exceed levels documented after natural infection with COVID19, after two doses of vaccine, or after both natural infection and vaccination.
Surrogate neutralization of B.1.617.2 is high but reduced in comparison with wild-type SARS-CoV-2. These data support the use of boosters to prevent breakthrough infections and suggest that antibody-mediated immunity may last longer than after the second vaccine dose.

How much antibody do you need to give protection. It seems it can be assessed

Protective characteristics of COVID-19 convalescent and post-vaccination IgG antibodiesKlegerman, M. E., Peng, T., Seferovich, I., Rahbar, M. H., Hessabi, M., Tahanan, A., Wanger, A., Grimes, C. Z., Ostrosky-Zeichner, L. Z., Koster, K., Cirillo, J. D., Abeydeera, D., De Lira, S., McPherson, D. D.10.1101/2021.11.19.21266547 

“a protective Ab level of 7.5 µg/ml was determined, based on 95% of the normal distribution of the post-vaccination population”

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  • MD, thanks for the ongoing data. I have asked this question a few times but havent yet had a conclusive response. After 2 doses and contracting covid, what is the risk level for this patient? they would still not make an antibody response without bcells. Does this mean that they could actually catch covid again very soon after? if not, why not? Thanks

    • Not sure anything can be conclusive COVIDwise. If you have caught COVID and survived why would you do this agai. Your T cell response is now in such a better place because they respond to different bits to theantibodies and therefore you get more immunity to more proteins that will help protect against the next variant.I think if antibody levels drop you could catch this again and again. We saw this in Brazil already. I think herd immunity is not going to will be like a cold you catch it and then your immune system gets rid of it, as you get older and have more morbidities the risk of a worse course may develop, but with the more open natural of Society you may get infected when you antibody levels are high not get infected and boost your immune system.

    • This is my position at the moment. I caught covid at the start of august and didn’t have a bad time with it. Despite being on Ocrelizumab for almost 1 year now. Strangely the free NHS antibody test you can get post a positive PCR confirmed antibodies 3 weeks after initial infection, but doesn’t tell you the levels of antibodies. I did a private test out of curiosity a few weeks later which said I had no antibodies.

      • If that is your picture then you are a young amn and as such should blast off the virus no problem now as to the NHS test if it is PCR it is looking for virus and not antibody so it would come back postivie or negative and being PCR positive 3 weeks after intitial infection doses occur and may have been abit slow because of ocrelizumab. Howerver as to antibodies if the thresold is 0.8 then 0.9 is positive but a few weeks later it could drop, but you may need 20 or 100 to deal with infection but I suspect you were antibody negative because the two tests were picking up different things.

    • I think you cannot isolate for ever…you have to be careful. The data will energe soon on anti-CD20 vaccinated getting COVID

  • Dear MD, pwMS who seroconverted after two doses (because they postponed anti CD20) and then got the infusion and > 5 months later have a low ab level: Should they postpone the next infusion again and wait for some B cells before they get the third jab? (No apparent disease activity.)

    • If you have made an Ab response on two the chances for a boost on third is good in the example here when you look at the seroconverters after two with the boost most make a response but some do not and my guess that if you have B cells present it is in your favour to do so again, if you have no B cells then there is a chance for no response. This my concern and therefore it has to be your choice if you are willing to delay

  • Hi MD,
    thank you for the post – just got my third dose of pfizer (being non antibody responder due to OCR treatment). guess wont have antibody reaction because did nit happen last time with same timing (6m post OCR) but doc said get the „training“ now for the winter wave. you would agree?
    found this research that kind of confirms that? (i did an ELISPOT t-cell test with „reactive“ result)
    ……spike-specific memory B and T cells were still detectable, forming the basis for a quick recall response. As expected, the faded humoral immune response was vigorously elevated to 66.8 AU/ml by 7.2 folds 1 week after the third dose along with abundant spike-specific circulating follicular helper T cells in parallel. Meanwhile, spike-specific CD4+ and CD8+ T cells were also robustly elevated by 5.9 and 2.7 folds respectively…….

    • I have more or less stopped posting on the T cell responses in CD20-depleted indviduals…it is clear that the vast majority of people make a CD4 and CD8 T cell response and indeed some people make an even bigger CD8 response than the controls.

      As to “doc said get the „training“ now for the winter wave. you would agree?” …Sort of we have been having wave after wave in this third wave…Yet get training maybe that is what ProfG has been telling me, save two hours a day from bloggin and get out getting ready for COVID-19

  • Had neuro appt. today and have a question. I had 2 doses of Moderna and no antibodies. Have been off of Ocrevus for just over 11 months. Doc recommended getting a third Moderna full dose. I had a recent CD19 test that shows still no B cells. Question is that Doc said that the CD19 test only measures peripheral B cells and they make up only 2% of the B cells overall. So, with a zero CD19 serum count, is this third Moderna jab going to to do any good?

    • Your neuro is correct and a third jab will boost your T cells and you may get an antibody response, it is clear that people with no peripheral blood B cells do make antibody responses. Having B cells in the blood increases probabilities. I think full dose is good if you have no previus response

  • Interesting, thanks MD. Wondering about what happens for Fingolimod. I’m guessing most also won’t convert later if they didn’t make any ab earlier. What about if fingolimod had been ceased- is there any indication how long you need to be off fingolimod before you might start to make ‘normal’ responses? Is there still lingering effects on blunting antibody response say 6months after ceasing fingo?

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