Are you still waiting to hear if and how we can get a COVID-19 response on sphingosine-1-phophate modulators.

A

If you are being vaccinated the identified problems within the drug family are spngosine-1-phophospahte, modulators because although CD20-depleting antibodies get a bad mark for inhibiting antibody responses, there is always the T cell response to come to the rescue. However it has been consistently reported that there is a defect in the B and T cell response with sphingosine-1-phosphate response. Whilst the issue will be these agents stop T and B cell migration, can you get a response? The problem has also befallen mycophenylate an immunosuppressive drug. In the study below they delay treament for a few days whilst the vaccination is done and they find a response.

Eva Schrezenmeier et al Temporary hold of mycophenolate boosts SARS-CoV-2 vaccination-specific humoral and cellular immunity in kidney transplant recipients. doi: https://doi.org/10.1101/2022.01.05.21268478

We applied a fourth dose of SARS-CoV-2 vaccine during temporary myophenaloic acid hold to 29 kidney transplant recipients, who had not mounted a humoral immune-response to previous vaccinations. Seroconversion after vaccination was observed in 76% of patients, associated with acquisition of virus neutralizing capacity. Whereas overall proportions of spike-reactive CD4+ T cells remained unaltered after the fourth dose, In summary, MPA hold was safe and augmented all arms of immunity during booster vaccination, suggesting its implementation in vaccination protocols for clinically stable transplant recipient

This approach has been found to be efficacious with methotrexate in arthritis

Arumahandi de Silva et al Pausing methotrexate improves immunogenicity of COVID-19 vaccination in patients with rheumatic diseases medRxiv 2021.11.17.21266441;  doi: https://doi.org/10.1101/2021.11.17.21266441

When will we see the data for the sphongosine-1-phospate modulators?

At ACTRIMS2022?

P133. Evaluating Humoral Immune Response to mRNA COVID-19 Vaccines in Siponimod-treated Patients with Advancing Forms of Relapsing Multiple Sclerosis: A COVID-19 Vaccine Sub-study of Phase 3b EXCHANGE Trial A. Bar-Or, Y. Mao-Draayer, S. R. Delgado, R. J. Fox, L. Cruz, X. Meng, G. Mavrikis Cox, S. Cohan;

Background: Siponimod is approved in the USA for treatment of adults with RMS. Given the ongoing COVID-19 global pandemic, it is important to assess if patients can mount an anti-viral humoral immune response to COVID-19 vaccines while receiving siponimod.
Objectives: To assess humoral immune response to non-live COVID-19 mRNA vaccines (Pfizer/Moderna) in a subset of patients enrolled in EXCHANGE (NCT03623243), a 6-month, open-label, single-arm trial of conversion to siponimod in patients with advancing forms of RMS.
Methods: This is a single-arm pilot sub-study in siponimod-treated patients currently participating in the core EXCHANGE study who have received a full course (2 doses) of mRNA COVID-19 vaccine. EXCHANGE enrolled patients aged 18-65 years with advancing forms of RMS, EDSS score 2.0-6.5, and on continuous oral/injectable/infusion DMTs for ≥3 months at time of consent. Patients with known prior COVID-19 diagnosis will be excluded from the sub-study and evaluation of IgG response to SARS-CoV-2 nucleocapsid protein will be assessed on study. Patients in the sub-study will continue taking siponimod as per the EXCHANGE study protocol. The sub-study will evaluate the number of patients achieving positive IgG response to SARS-CoV-2 spike protein ≥14 days after full course vaccination. Exploratory endpoints include rate of seroconversion and evaluation of magnitude of humoral response to COVID-19 vaccination.
Results: This sub-study plans to enroll up to 20 patients from the EXCHANGE core study. An interim analysis will be performed following collection of sub-study assessments. The following data will be presented together with the detailed sub-study design: sub-study patient demographics including MS history, number of patients achieving vaccination response via the presence of serum SARS-CoV-2 spike IgG antibodies, as well as quantitative humoral response to COVID-19 vaccine.
Conclusions: This sub-study will contribute to a better understanding of humoral immune responses that occur in siponimod-treated patients with advancing forms of RMS after COVID-19 mRNA vaccination.

So we dont know if there is a poblem and if there is the solution, but for fingolimod a solution could be helpful

ACTRIMS 2022 P128. COVID-19 Antibody Response after Third mRNA Vaccine in MS Patients Treated with B cell-depleting and S1P Receptor-Targeting Therapies Compared to Controls: Interim Analysis. S. Conway, M. Houtchens, B. Glanz, T. J. Saraceno, M. Polgar-Turcsanyi, G. Bose, S. Saxena, A. Paul, R. Bakshi, S. Bhattacharyya, K. Galetta, T. Kaplan, C. Severson, T. Singhal, L. Stazzone, J. Zurawski, B. Healy, H. Weiner, T. Chitnis;

Background: Immunosuppressed patients may not mount an adequate immune response to SARS-CoV2 (COVID-19) mRNA vaccines and are eligible to receive a third dose. There is limited knowledge about third dose vaccine response in multiple sclerosis (MS) patients.
Objectives: Assess the SARS-CoV2 Spike antibody response in MS patients on high efficacy immunotherapies who received a third dose of mRNA vaccine.
Methods: This is an extension of a study of patients with MS, aged 18-65, on fingolimod, siponimod, ofatumumab, or ocrelizumab for at least 3 months prior to first mRNA SARS-CoV-2 vaccine (Pfizer® or Moderna®). A cohort of healthy controls (HC) who received the mRNA vaccines were also enrolled. Blood samples for the SARS-CoV-2 Spike antibody (Anti-SARS-CoV-2 S, Roche-Elecsys) were collected 2-3 months after the second mRNA vaccine. Some patients received a third mRNA vaccine and had additional blood samples collected 1-2 months later. The proportion who seroconverted (antibody>0.4 U/ml) and SARS-CoV-2 Spike antibody levels were assessed.
Results: 21 MS patients (9 fingolimod, 12 ocrelizumab) who received a third dose of vaccine were included in this interim analysis and were compared to 32 HC who received two doses of vaccine. 33% (4/12) of patients on ocrelizumab seroconverted, compared to 7/9 (77.8%) in the fingolimod group, and 32/32 (100%) in the HC group (p=0.081 comparison of ocrelizumab to fingolimod group, p=2.8*10-6 comparison of ocrelizumab group to HC, p=0.044 comparison of fingolimod group to HC). The median Spike antibody level after a third vaccine was 0.51 U/mL in the MS group, <0.4 U/mL in the ocrelizumab group, 4.57 U/ml in the fingolimod group, which was significantly different compared to the HC group who had a median Spike antibody level of 1,744U/mL (p= 8.0*10-10 comparison of MS to HC; p=3.4*10-7 comparison of ocrelizumab group to HC; p= 4.7*10-6 comparison of fingolimod group to HC). Of the 11 MS patients who had spike antibodies measured after both the second and third vaccines, 3/11 (27.3%) seroconverted after the second, and 5/11 (45.4%) seroconverted after the third (p=0.625). Of the 3 fingolimod patients who had spike antibodies measured after both their second and third vaccines, 1/3 seroconverted after the second, and 2/3 seroconverted after the third. Of the 8 ocrelizumab patients who had spike antibodies measured after both the second and third vaccines, 2/8 seroconverted after the second compared to 3/8 after the third. When comparing median level of Spike antibodies between second and third vaccines in MS patients, the median level was <0.4 U/mL prior to third vaccine and 0.4 U/mL after third vaccine.
Conclusions: MS patients on ocrelizumab and fingolimod have significantly lower rates of seroconversion, and lower median spike antibody levels in response to a series of three mRNA SARS-CoV-2 vaccines compared to HC who received only two vaccine doses. Data on additional patients will be available at the time of presentation.

How the good news may be shown in monkey experiments and that says you may not need T or B cells to get rid ofthe virus as we hypothesized about 2 years ago. Most MS drugs do not target the innate immune response

Mild SARS-CoV-2 infection in rhesus macaques is associated with viral control prior to antigen-specific T cell responses in tissuesNelson, C. E., Namasivayam, S., Foreman, T. W., Kauffman, K. D., Sakai, S., Dorosky, D. E., Lora, N. E., NIAID/DIR Tuberculosis Imaging Program, , Brooks, K., Potter, E. L., Roederer, M., Sher, A., Weiskopf, D., Sette, A., de Wit, E., Hickman, H. D., Brenchley, J. M., Via, L. E., Barber, D. L.10.1101/2022.01.06.475282 — Posted: 2022-01-07

“SARS-CoV-2 replication wanes in the lungs prior to T cell responses, and in the nasal and oral mucosa despite the apparent lack of Ag-specific T cells, suggesting that innate immunity efficiently restricts viral replication during mild COVID-19”.

SARS-CoV-2 mRNA Vaccination in People with Multiple Sclerosis Treated with Fingolimod: Protective Humoral Immune Responses May Develop after the Preferred Third Shot. Achtnichts L, Ovchinnikov A, Jakopp B, Oberle M, Nedeltchev K, Fux CA, Sellner J, Findling O.Vaccines (Basel). 2022; 10(2):341. doi: 10.3390/vaccines1002034

Evidence suggests limited development of protective IgG responses to mRNA-based vaccines in sphingosine-1-phosphate receptor (S1PR)-modulator treated individuals with multiple sclerosis (MS). We studied the extent of the humoral immune response after the preferred third mRNA SARS-CoV-2 vaccine in S1PR-modulator treated people with MS (pwMS) and insufficient IgG responses after the standard immunization scheme. Eight pwMS that were treated with fingolimod received a third homologous SARS-CoV-2 mRNA vaccine dose, either the Moderna’s mRNA-1273 or Pfizer-BioNTech’s BNT162b2 vaccine. We quantified the serum levels of IgG antibodies against the receptor-binding domain of SARS-CoV-2 four weeks later. An antibody titer of 100 AU/mL or more was considered protective. After the third vaccination, we found clinically relevant IgG titers in four out of eight individuals (50%). We conclude that the humoral immune response may reach protective levels after the third preferred dose of the homologous SARS-CoV-2 mRNA vaccine. Vaccine shots in S1PR-modulator treated pwMS ahead of schedule may be a strategy to overcome insufficient humoral immune responses following the standard vaccination scheme.

Disclaimer This is the view of the author and does not represent an Institution. This is not clinical advice and should not be viewed as such

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6 comments

  • Is there any data regarding Pfizer Vs Moderna mRNA vaccines for SIP treated patients?

    Personally (Fingolimod, 5+ years) received 3 doses Pfizer with no antibody response, however 4th booster (half dose) Moderna has now created a moderate response, ~750 U/ml.

  • Last night there was a seminar on covid-19 and MS-patients held by Haukeland – the hospital of Bergen, Norway. They concluded that patients on anti-cd20 should now live normally and like everyone else, because their experience is that there are very few cases of severe covid-19 infection in these patients if they’ve been triple jabbed. In other words, T-cell responses and the relative decrease of risk that comes with omicron (as compared to other strains) are considered to be ”safe enough” to not recommend any isolation or social-distance measures for anti-cd20 patients who do not have several other risk factors. It’s also worth mentioning that I consider this especially significant since Remdesivir is the only available anti-viral in Norway now. No mAbs are currently used.

    Thoughts on this, MD?

    • I am sure this is the current UK view also….it is go back to normal and we can deal the infections. I have opinions on this but essentially all restrictions are gone

  • Definitely waiting here in Chicago. On fingolimod and 4x vaxx’ed. Negative for antibodies following the third shot – not sure if I developed anything after the fourth. Lack of guidance from my med team/the world is very, very,very frustrating and isolating. My partner and I have put our lives on hold to try to stay safe.

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