Learning from other B cell deficiencies. It says what we think we know about MS
mRNA vaccine boosting enhances antibody responses against SARS-CoV-2 Omicron variant in patients with antibody deficiency syndromes Zimmerman, O., Altman Doss, A. M., Kaplonek, P., VanBlargan, L. A., Liang, C.-Y., Chen, R. E., Monroy, J. M., Wedner, H. J., Kulczycki, A., Mantia, T. L., O’Shaughnessy, C. C., Davis-Adams, H. G., Bertera, H. L., Adams, L. J., Raju, S., Zhao, F. R., Rigell, C. J., Biason Dy, T., Kau, A. L., Ren, Z., Turner, J., O’Halloran, J. A., Presti, R., Fremont, D. H., Kendall, P. L., Ellebedy, A. H., Alter, G., Diamond, M. S. MedRXiv 10.1101/2022.01.26.22269848
Patients with primary antibody deficiency syndromes (PAD) have poor humoral immune responses requiring immunoglobulin replacement therapy. [So this is not MS but it may be relevant to people on long-term deletion of B cells who have low levels of antibody and are therefore at increased risk from infection. To counter this you get given immunoglobulin (antibody), which has been taken from many people and is often called intravenous immunoglobulin]. Immunoglobulin replacement products had low anti-spike and receptor binding domain (RBD) titers and neutralizing activity [So there is probably not along in the intravenous immunoglobulin for stopping you catching COVID-19 if you are infected]. In COVID-19-naive PAD patients, anti-spike and RBD titers increased after mRNA vaccination but decreased to pre-immunization levels by 90 days [So just like with anti-CD20 some people make a response but it is a low level response and this wanes rapidly] . Patients vaccinated after SARS-CoV-2 infection developed higher responses comparable to healthy donors [So if you have been naturally infected there is a better chance of making an antibody response]. Most vaccinated PAD patients had serum neutralizing antibody titers above an estimated correlate of protection against ancestral SARS-CoV-2 and Delta virus but not against Omicron virus [So even if vaccinated without a booster you are susceptible to omicron infection and this is the case for most people irrespective if you are taking MS treatments], although this was improved by boosting [So with a boost it increases the chance of a better response]. Thus, currently used immunoglobulin replacement products likely have limited protective activity [Intravenous immunoglobulin is not going to give you much protection although stuff collected post-vacination is likely to do that], and immunization and boosting of PAD patients with mRNA vaccines should confer at least short-term immunity against SARS-CoV-2 variants, including Omicron.
But what does this actually say about MS?
I think it says what we think we know about MS
SARS-CoV-2 third vaccine immune response in MS patients treated with ocrelizumab Brill, L., Raposo, C., Rechtman, A., Zveik, O., Levin, N., Djian, E., Wolf, D., Vaknin-Dembinsky, A.10.1101/2022.01.26.22269876 — Posted: 2022-01-28
The introduction of a third dose vaccination along with new variants of concerns raises questions regarding serology and T-cell responses in patients with MS (pwMS) treated with B-cell depletion who develop attenuated humoral response to vaccines. The aim of this study is to longitudinally evaluate humoral and cellular response to SARS-CoV-2 mRNA vaccine in ocrelizumab-treated pwMS before and following third vaccine dose. Following the third vaccine dose, patients who are low or non-responders following initial vaccination did not increase antibody titers. [So this is consistent with what we have seen before] In healthy controls and ocrelizumab-treated pwMS, cellular response decreased 6 months following initial vaccination and increased significantly after the third booster. [So this is consistent with what we have seen before].
What are the thoughts?
Well it seems that it depends on the neuro……Before omicron came along and the cases were low, one could perhaps consider a delay between dose and vaccine as it seemed evident that time was needed to optimise an antibody response, so some people are looking at extended interval dosing. However, as omicron loomed large the advice seemed to be jab, jab, jab again. There is no clear cut answer what is best and each persons situation and risks are different.
As we can see here and was evident a few months ago, many people on anti-CD20 will not make a response after the third doses. Furthermore even if you do make a response, you may not make a particularly good response. So a thought was jab, jab , jab to get a T cell response from the third jab and then there are the anti-virals.
So what was seen here…Antibody levels “and response rate post-third dose were significantly lower in pwMS treated with ocrelizumab compared to healthy controls (p<0.001; 9/27 33.3% vs 30/30 100%, for ocrelizumab versus health controls, respectively)”. All patients with increased antibody levels after the third dose were initially vaccinated ≥5 (great or equal to five) months after the last ocrelizumab infusion. Moreover, patients who were vaccinated with third dose ≥5 months following the last ocrelizumab infusion had a significantly increased likelihood for a positive serologic (antibody) response (8 of 9 [88.9%] verses 6 of 17 [35.5%]; P = .04).
Therefore, the longer the interval the more chance of an antibody response. However is five months enough and I suspect for many people it will not be. So we have to rely on the T cell responses. Some people suggests the booster boosts the response.
However, based on the data presented here, seems to suggest that the T cell response seems to be largely formed by the second jab and the third jab does not seem to make a big impact, although it revives a flagging response.
Now we need to explain what is being measured the antibody levels are detecting the product of the immune response from the memory cells, but the T cell response measures what can be stimulated by the memory T cells. So the antibody response if high, stops infection, but T cells will target infected cells and it will take them a day or two to get going. When they do they make more of themselves and then once they get rid of infection they probably die off.
I personally think the companies have been a bit slow in investigating this and for many agents there is limited information about what to expect after one and two jabs let alone three or four. I wonder what will happen with the forth doses…I suspect nothing different?
Persistently reduced humoral and cellular immune response following third SARS-CoV-2 mRNA vaccination in anti-CD20-treated multiple sclerosis patientsHamza Mahmood Bajwa, Frederik Novak, Anna Christine Nilsson, Christian Nielsen, Dorte K. Holm, Kamilla Østergaard, Agnes Hauschultz Witt, Keld-Erik Byg, Isik S. Johansen, Kristen Mittl, William Rowles, Scott S. Zamvil, Riley Bove, Joseph J. Sabatino Jr., Tobias SejbaekmedRxiv 2022.01.27.22269944; doi: https://doi.org/10.1101/2022.01.27.22269944
Objective To examine humoral and cellular response in multiple sclerosis patients on anti-CD20 therapy after third BNT162b2 mRNA SARS-CoV-2 vaccination.
Results We found that 14.0%, 37.7%, and 33.3% were seropositive after first, second and third vaccination. The median Ab-levels were 74.2 BAU/mL (range: 8.5-2427), 43.7 BAU/ml (range: 7.8-366.1) and 31.3 BAU/mL (range: 7.9-507.0) after first, second and third vaccination, respectively. No difference was found in levels after second and third vaccination (p=0.1475). Seropositivity dropped to 25.0% of participants before the third vaccination, a relative reduction of 33.3% (p=0.0020). No difference was found between frequencies of spike reactive CD4+ and CD8+ T-cells after second (0.65 ± 0.08% and 0.95 ± 0.20%, respectively) and third vaccination (0.99 ± 0.22% and 1.3 ± 0.34%), respectively.
Conclusion In this longitudinal cohort we found no significant increased humoral or cellular response with administration of a third SARS-CoV-2 mRNA vaccination. These findings suggest the need for clinical strategies to include allowance of B cell reconstitution before repeat vaccination and/or provision of pre-exposure prophylactic monoclonal antibodies.
So again the data shows that people do not seroconvert with the booster and importantly the T cell response is similar to that found after two doses so Jab. Jab, Jab does not seem to make much of a change and therefore one suspects that many people treated with ocrelizumab/rituximab will be susceptible to omicron. The data will surface soon .no doubt.
But what does MS actually say about MS?
I think says what we think we know about MS
Moser T, Otto F, O’Sullivan C, Hitzl W, Pilz G, Harrer A, Trinka E, Wipfler P. Recall response to COVID-19 antigen is preserved in people with multiple sclerosis on anti-CD20 medications – A pilot study. Mult Scler Relat Disord. 2022 Jan 24;59:103560. doi: 10.1016/j.msard.2022.103560.
Background: Antibody responses to SARS-CoV-2 vaccination are impaired in people with multiple sclerosis (MS) under anti-CD20 therapies. It is however unclear, whether patients who received the basic immunization prior to anti-B cell medication start respond to the COVID-19 booster dose, once B cells are depleted.
Aim: To investigate the humoral response to recall antigen by COVID-19 booster vaccines in people with MS (pwMS), who recently started an anti-CD20 therapy compared to people with long-term B cell depletion.
Methods: We enrolled 15 pwMS who had received booster vaccination on anti-CD20 therapy. Of these, 11 had established anti-CD20 medications and were therefore vaccinated during a continuous state of B cell depletion (CD20-vaccine cohort). Four pwMS had received the basic immunization prior to anti-CD20 therapy commencement and only the booster dose (vaccine-CD20-vaccine cohort) under conditions of B cell depletion. We assessed SARS-CoV-2 specific antibody responses after booster vaccination among both groups and evaluated accompanying B cell numbers and proportions from the peripheral circulation.
Results: The booster dose of SARS-CoV-2 vaccination elicited measurable antibody responses in 18% of individuals from the CD20-vaccine cohort compared to 100% from the vaccine-CD20-vaccine cohort. Antibody-levels were significantly higher among patients from the vaccine-CD20-vaccine cohort compared to the CD20-vaccine cohort (mean 951.25 ± 1137.96 BAU/ml, vs mean 12.36 ± 11.94 BAU/ml; mean difference 938 BAU/ml (95% CI: 249-1629 BAU/ml), p <0.0001). Among the vaccine-CD20-vaccine cohort, the booster immunization led to augmentation of spike antibody levels in 75% despite concomitant B cell depletion, and values increased by 3.8 – 9.4-fold compared to basic immunization. We observed no correlation of B cell kinetics and SARS-CoV-2 antibody levels.
Conclusion: Our study suggests that antibody production to recall COVID-19 antigens is preserved in pwMS despite concomitant anti-CD20 therapy. If corroborated in bigger cohorts, this could have implications in the management of individuals about to start B cell medications.
So it says you can keep the response if you generate before you deplete your B cells so get vaccinated before you start ocrelizumab/ofatumumab if you can,
MS tells us that we need antibodies to prevent infection
So we know that CD20-depletion and fingolimod inhibit antibody responses but only fingolimod inhibits T cells responses and guess what? Yep ocrelizumab and fingolimod are associated with more infections than other MS disease modifying treatments. So antibodies are important to protect against infection. This was before the arrival of omicron when two doses of vaccine were protective. We know that protection against omicron is poor from two doses even without disease modifying treatment. However, there is an odd one out and that is rituximab. Why isn’t it associated with increased infections, like ocrelizumab?
I am not convinced the biology rituximab and ocrelizumab is different, Perhaps the rituximab data holds the key. Maybe it has something to do with B cell repopulation and the people taking rituximab were able to repopulate their B cells and gave an antibody response, like in a past paper of the same group (red dots). If true it may tell us how to improve vaccine response for the booster. However, sorry to say, it is probably too late as many people will have had their booster already.
Sormani et al.EbiomedicineOpen https://doi.org/10.1016/j.ebiom.2021.103581
However, I am wrong I have written and heard back from Prof Sormani and she thinks that it is probably just an issue that the gorup sizes were not big enough for rituximab, because as you can see there is an overlap of the confidence intervals (the red line) and with one more infection the rate would approach the rate seen in fingolimmod and ocrelizumab. So I’m thinking too much.
Breakthrough SARS-CoV-2 infections in MS patients on disease modifying therapies Irene Schiavetti et al. MedRxiv 2022.01.22.22269630; doi: https://doi.org/10.1101/2022.01.22.22269630
Background. Patients with Multiple Sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to SARS-CoV-2 vaccines. In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in pwMS on different Disease Modifying Therapy (DMT). Methods. Data on number of vaccinated patients and of patients with a breakthrough infection were retrospectively collected in 27 Italian MS centers. We estimated the rate of breakthrough infections and of infection requiring hospitalization per DMT. Findings. 19,641 vaccinated pwMS were included in the database. After a median follow-up of 8 months, we observed 137 breakthrough infections. As compared to the other DMTs, the rate of breakthrough infections was significantly higher on ocrelizumab (0.57% vs 2.00%, RR=3.55,95%CI=2.74-4.58, p<0.001) and fingolimod (0.58% vs 1.62%, RR=2.65,95%CI=1.75-4.00, p<0.001), while there were no significant differences in any other DMT group. In the ocrelizumab group the hospitalization rate was 16.7% vs 19.4% in the pre-vaccination era (RR=0.86,p=0.74) and it was 3.9% in all the other DMT groups vs 11.9% in the pre-vaccination period (RR=0.33,p=0.02). Interpretation. The risk of breakthrough SARS-CoV-2 infections is higher in patients treated with ocrelizumab and fingolimod, and the rate of severe infections was significantly reduced in all the DMTs excluding ocrelizumab.
If interested also have a look at : https://doi.org/10.1101/2021.12.23.21268177; th
COI: Non relevant
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Title: COVID Vaccine responses and ocrelizumab
Sourced From: multiple-sclerosis-research.org/2022/02/covid-vaccine-responses-and-ocrelizumab/?utm_source=rss&utm_medium=rss&utm_campaign=covid-vaccine-responses-and-ocrelizumab
Published Date: Thu, 03 Feb 2022 13:00:00 +0000