COVID-19 vaccine response in people with multiple sclerosis

[ActiveMSers]

NOTE: THIS IS A PREPRINT AND HAS NOT BEEN PEER REVIEWED. BUT THERE ARE MANY RESPECTED AUTHORS. -D

COVID-19 vaccine response in people with multiple sclerosis

Emma C Tallantyre, Nicola Vickaryous, Valerie Anderson, Aliye Nazli Asardag, David Baker, Jonathan Bestwick, Kat h Bramhall, Randy Chance, Nikos Evangelou, Katila George, Gavin Giovannoni, Leanne Grant, Katharine E Harding, Aimee Hibbert, Gillian Ingram, Meleri J ones, Angray S Kang, Samantha Loveless, Stuart J Moat, Neil P Robertson, Klaus Schmierer, Sita Navin Shah, Jessica Simmons, Matthew Upcott, Mark Willis, Stephen Jolles, Ruth Dobson

doi: https://doi.org/10.1101/2021.07.31.21261326

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

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Abstract

Objective To investigate the effect of disease modifying therapies on serological response to SARS-CoV2 vaccines in people with multiple sclerosis

Methods 473 people with multiple sclerosis from 5 centres provided one or more dried blood spot samples and questionnaires about COVID-19. Information about disease and drug history was extracted from their medical records. Dried blood spots were eluted and tested for antibodies to SARS-CoV2 receptor binding domain. Seropositivity was expressed according to validated cut-off indices. Antibody titers were partitioned into tertiles using data from people on no disease modifying therapy as a reference. We calculated the odds ratio of seroconversion (Univariate logistic regression) and compared quantitative vaccine response (Kruskal Wallis) following SARS-CoV2 vaccine according to disease modifying therapy. We used regression modelling to explore the effect of factors including vaccine timing, treatment duration, age, vaccine type and lymphocyte count on vaccine response.

Results Compared to no disease modifying therapy, the use of anti-CD20 monoclonal antibodies (odds ratio 0.03; 95% confidence interval 0.01-0.06, p<0.001) and fingolimod (odds ratio 0.41; 95% confidence interval 0.01-0.12) were associated with lower seroconversion following SARS-CoV2 vaccine. All other drug groups did not differ significantly from the untreated cohort. Time since last anti-CD20 treatment and total time on treatment were significantly related with response to vaccination. Vaccine type significantly predicted seroconversion, but not in those on anti-CD20 medications.

Interpretation Some disease modifying therapies carry a risk of attenuated response to SARS-CoV2 vaccination in people with MS. We provide recommendations for the practical management of this patient group.

[ActiveMSers]

This is going to be an evolving topic that we need to watch closely. Right now, the anti-CD20 therapies (Ocrevus, Rituxan, Kesimpta) appear to be the biggest problem child. The research is still fuzzy on S1P modulators. They appear to respond well to boosters. Here are some posts by neuros that you'll want to read if you are on any of these medications if you want to make better sense of everything.

More on fingolimod (Gilenya). It is unclear how other similar drugs (Mayzent, Zeposia, Ponvory) work with the vaccines.

https://multiple-sclerosis-research....lures-perhaps/

https://multiple-sclerosis-research....ion-responses/

[ActiveMSers]

5 things a neuroimmunologist wants you to know about COVID-19 vaccines and MS DMTs

https://www.mssociety.org.uk/researc...es-and-ms-dmts

[ActiveMSers]

Here is a summary of neuro Gavin Giovannoni's thoughts on the subject.

https://gavingiovannoni.substack.com...nd-ms/comments

[ActiveMSers]

And the story of S1P modulators (Gilenya, et al) is still unfolding. Maybe it's the type of vaccine that inhibits response?

https://multiple-sclerosis-research....-virus-vaccine

[ActiveMSers]

Ann Rheum Dis
. 2021 Aug 6;annrheumdis-2021-220626.
doi: 10.1136/annrheumdis-2021-220626. Online ahead of print.Humoral and T-cell responses to SARS-CoV-2 vaccination in patients receiving immunosuppression

Maria Prendecki ^{# 1 2}, Candice Clarke ^{# 3 2}, Helena Edwards ^{3 2}, Stacey McIntyre ³, Paige Mortimer ³, Sarah Gleeson ^{3 2}, Paul Martin ^{3 2}, Tina Thomson ², Paul Randell ⁴, Anand Shah ^{5 6}, Aran Singanayagam ^{7 8}, Liz Lightstone ^{3 2}, Alison Cox ⁴, Peter Kelleher ^{4 7}, Michelle Willicombe ^{3 2}, Stephen P McAdoo ^{3 2}
Affiliations expand

• PMID: 34362747
• PMCID: PMC8350975
• DOI: 10.1136/annrheumdis-2021-220626

Free PMC article

Abstract

Objective: There is an urgent need to assess the impact of immunosuppressive therapies on the immunogenicity and efficacy of SARS-CoV-2 vaccination.

Methods: Serological and T-cell ELISpot assays were used to assess the response to first-dose and second-dose SARS-CoV-2 vaccine (with either BNT162b2 mRNA or ChAdOx1 nCoV-19 vaccines) in 140 participants receiving immunosuppression for autoimmune rheumatic and glomerular diseases.

Results: Following first-dose vaccine, 28.6% (34/119) of infection-naïve participants seroconverted and 26.0% (13/50) had detectable T-cell responses to SARS-CoV-2. Immune responses were augmented by second-dose vaccine, increasing seroconversion and T-cell response rates to 59.3% (54/91) and 82.6% (38/46), respectively. B-cell depletion at the time of vaccination was associated with failure to seroconvert, and tacrolimus therapy was associated with diminished T-cell responses. Reassuringly, only 8.7% of infection-naïve patients had neither antibody nor T-cell responses detected following second-dose vaccine. In patients with evidence of prior SARS-CoV-2 infection (19/140), all mounted high-titre antibody responses after first-dose vaccine, regardless of immunosuppressive therapy.

Conclusion: SARS-CoV-2 vaccines are immunogenic in patients receiving immunosuppression, when assessed by a combination of serology and cell-based assays, although the response is impaired compared with healthy individuals. B-cell depletion following rituximab impairs serological responses, but T-cell responses are preserved in this group. We suggest that repeat vaccine doses for serological non-responders should be investigated as means to induce more robust immunological response.

[ActiveMSers]

Timing matters when you last got your Ocrevus or Rituxan. A LOT. -D

Development of humoral and cellular immunological memory against SARS-CoV-2 despite B-cell depleting treatment in multiple sclerosis.

Klara Asplund Högelin1,5 , Nicolas Ruffin1,5, Elisa Pin2 , Anna Månberg2 , Sophia Hober3 , Guro Gafvelin4 , Hans Grönlund4 , Peter Nilsson2 , Mohsen Khademi1 , Tomas Olsson1 , Fredrik Piehl1 , Faiez Al Nimer1,6,* 1 Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine L8:04, 171 76, Stockholm, Sweden 2 Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, 17165, Stockholm, Sweden. 3 Division of Protein Technology, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, 17165, Stockholm, Sweden. 4 Therapeutic Immune Design Unit, Department of Clinical Neuroscience, Karolinska Institutet, Center for Molecular Medicine L8:02, 171 76, Stockholm, Sweden

Summary

B-cell depleting therapies (BCDTs) are widely used as immunomodulating agents for autoimmune diseases such as multiple sclerosis. Their possible impact on development of immunity to SARS-CoV-2 has raised concerns with the COVID-19 pandemic. We here evaluated the frequency of COVID-19-like symptoms and determined immunological responses in participants of an observational trial comprising several multiple sclerosis disease modulatory drugs, (COMBAT-MS; NCT03193866) and in eleven patients after vaccination, with a focus on BCDT. Almost all seropositive and 17.9% of seronegative patients on BCDT, enriched for a history of COVID-19-like symptoms, developed anti-SARS-CoV-2 T-cell memory and T-cells displayed functional similarity to controls producing IFN-γ and TNF. Following vaccination, vaccine-specific humoral memory was impaired, while all patients developed a specific T-cell response. These results indicate that BCDTs do not abrogate SARSCoV-2 cellular memory and provide a possible explanation as to why the majority of patients on BCDTs recover from COVID-19

FULL PAPER: https://www.cell.com/iscience/pdf/S2...showall%3Dtrue
Interestingly, for the patients who had received an infusion within four months before their first dose, only two out of five (40%) had detectable SARS-CoV-2 specific antibodies four weeks after vaccination. The remaining patients with more than 4 months since last infusion, all five out of five (100%) had detectable antibodies four weeks after vaccination. However, regardless of time since last infusion or serology status, all pwMS developed a robust and specific T-cell response (Figure 6C).

FROM BARTS:

This first surfaced many moons ago on SSRN as a preprint when only people taking anti-CD20 who were naturally infected were included. It suggested that most people made an anybody response when infected with SARS-CoV-2 (Only about 25% seroconverted on anti-CD20 (which has been shonw by many others) and not on anti-CD20) and that vaccines were not going to be a problem….How wrong that turned out to be, but the paper now surfaces with vaccine data. Guess what.?…Yep the antibody responses after vaccination is blunted and there is a T cell response so it supports a number of studies by the tortoises…so this is yet another paper saying the same thing. So we can be increasingly confident that this story is correct. What it means is the question I can’t answer.

They show you can make antibodies when there are no B cells in the blood

They also say “When analyzing the percentages of B-cells, all seronegative samples displayed less than 0.2% B-cells of live lymphocytes. Interestingly, among the seropositive pwMS, there were also two samples with less than 0.2% B-cells (Figure 6D), indicating that a virtual absence of B-cells in peripheral blood is not a good predictor of not producing detectable antibodies after vaccination”. However you can see that if you have 1% B cells you are more likely to seroconvert. Those over 6 months delay are more likely to seroconvert 5/5 verse 2/5 less than 6 months

https://multiple-sclerosis-research....-hare-arrives/

[ActiveMSers]

Here's the latest opinion from Bart's out of the UK on the issue of anti-CD20 therapy. Still a bit of limbo, I'm afraid, but the answers appear to be getting clearer. -D

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.

https://multiple-sclerosis-research....dosing-or-not/

[ActiveMSers]

Enlightening. I have a kiw count of B-cells, so no booster for me for at least a few months, when I'll get those levels tested again. Note: this is a preprint. -D

CD19 B cell repopulation after ocrelizumab, alemtuzumab and cladribine: Implications for SARS-CoV-2 vaccinations in multiple sclerosis

David Baker, Amy MacDougall, Angray S. Kang, View ORCID ProfileKlaus Schmierer, Gavin Giovannoni, Ruth Dobson
doi: https://doi.org/10.1101/2021.09.26.21264023

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

Abstract

Background CD20 depletion is a highly-effective treatment for relapsing multiple sclerosis that maintains B cells at low levels through six monthly dosing of 600mg ocrelizumab. This dosing schedule is associated with inhibition of seroconversion following SARS-CoV-2 vaccination, in contrast to the high levels of seroconversion following treatment with alemtuzumab and cladribine tablets. A number of emerging reports suggest that repopulation of 1-3% B cells facilitates seroconversion after CD20-depletion. The frequency of this occurring following repeated ocrelizumab treatment, after other DMT, and after treatment cessation is largely unknown.

Methods Relapse data, lymphocyte and CD19 B cell numbers were extracted from phase II ocrelizumab extension study (NCT00676715) data supplied by the manufacturer via the Vivli Inc, trial data-request portal. Repopulation data of oral cladribine from the phase III CLARITY study (NCT00213135) was supplied by the European Medicines Agency; and the alemtuzumab phase III CARE-MS I (NCT00530348) and CARE-MS II (NCT00548405) trial data were supplied by the manufacturer via the clinicalstudydatarequest.com portal.

Results Only 3-5% of people with MS exhibit 1% B cells at 6 months after the last infusion following 3-4 cycles of ocrelizumab, compared to 50-55% at 9 months, and 85-90% at 12 months. During this time relapses occurred at consistent disease breakthrough rates compared to people during standard therapy. In contrast most people (90-100%) exhibited more than 1% B cells during treatment with either cladribine or alemtuzumab.

Conclusions Few people repopulate peripheral B cells with standard ocrelizumab dosing, however an extending the dosing interval by 3-6 months may allow many more people to potentially seroconvert in the relative absence of excess relapse-activity. Most people demonstrate B cell repletion within 3 months of the last treatment of alemtuzumab and cladribine. This may help protect against severe COVID-19.

Bart's had this to say on the study's results.

B CELL REPOPULATION WITH MS TREATMENTS

So whilst we are on the subject of COVID…sorry Steve:-(…..another T and B cell paper….but this time abit more info on fingolimod or is it both Fingo and Siponimod…..if so what were the two on the bottom (non converters) taking. You can see that even if you make an antibody response on ocrelizumab. the levels are about 10 times less than other DMT and controls….now if you put J&J/AZ into this mix the levels would be ten times less than Pfizer/Moderna, so a reason to try and avoid if you have the options.

MORE: https://multiple-sclerosis-research....-ms-treatments

[ActiveMSers]

Effect of different disease-modifying therapies on humoral response to BNT162b2 vaccine in Sardinian multiple sclerosis patients

Maristella Pitzalis, Maria Laura Idda, Valeria Lodde, Annalisa Loizedda, Moni a Lobina, Magdalena Zoledzwieska, Francesca Virdis , Giuseppe Delogu, Federica Pirinu, Maria Giuseppina Marini, Maura Mingoia, Jessica Frau, Lo rena Lorefice, Maria Fronza, Daniele Carmagini, El isa Carta, Valeria Orrù, Sergio Uzzau, Paolo Solla , Federica Loi, Marcella Devoto, Maristella Steri, Edoardo Fiorillo, Matteo Floris, Ignazio Roberto Zarbo, Eleonora Cocco, Francesco Cucca

doi: https://doi.org/10.1101/2021.09.26.21264067

This article is a preprint and has not been certified by peer review [what does this mean?]. It reports new medical research that has yet to be evaluated and so should not be used to guide clinical practice.

Abstract

Objectives Vaccination against COVID-19 is highly recommended to patients affected by multiple sclerosis (MS); however, the impact of MS disease-modifying therapies (DMTs) on the immune response following vaccination has been only partially investigated. Here, we aimed to elucidate the effect of DMTs on the humoral immune response to mRNA-based anti-SARS-CoV-2 vaccines in MS patients.

Methods We obtained sera from 912 Sardinian MS patients and 63 healthy controls 30 days after the second dose of BNT162b2 vaccine and tested them for SARS-CoV-2 response using anti-Spike (S) protein-based serology. Previous SARS-CoV-2 infection was assessed by anti-Nucleocapsid (N) serology. Patients were either untreated or undergoing treatment with a total of 13 different DMTs. Differences between treatment groups comprised of at least 10 patients were assessed by generalized linear mixed-effects model. Demographic and clinical data and smoking status were analyzed as additional factors potentially influencing humoral immunity from COVID-19 vaccine.

Results MS patients treated with natalizumab, teriflunomide, azathioprine, fingolimod, ocrelizumab, and rituximab showed significantly lower humoral responses compared to untreated patients. We did not observe a statistically significant difference in response between patients treated with the other drugs (dimethyl fumarate, interferon, alemtuzumab and glatiramer acetate) and untreated patients. In addition, older age, male, sex and active smoking were significantly associated with lower antibody titers against SARS-CoV-2. MS patients previously infected with SARS-CoV-2 had significantly higher humoral responses to vaccine than uninfected patients.

Conclusion Humoral response to BNT162b2 is significantly influenced by the specific DMTs followed by patients, as well as by other factors such as previous SARS-CoV-2 infection, age, sex, and smoking status. These results are important to inform targeted strategies to prevent clinically relevant COVID-19 in MS patients.