The fingolimod conumdrum…Is it bad for vaccine response or is it RNA virus vaccine

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The surprise of the vaccine responisveness is not that anti-CD20 antibodies blunt the response but it is that fingolimod does not do too well.

I have been thinking about this too. But someone has got there before me.


SARS-CoV-2 antibodies in multiple sclerosis patients depending on the vaccine mode of action?
Rommer PS, Bsteh G, Berger T, Zettl UK.Mult Scler. 2021 Aug 13:13524585211039128. doi: 10.1177/13524585211039128.

The coronavirus disease-2019 (COVID-19) poses major challenges to patients with ongoing immunotherapies. Vaccinations raise the question of adequate protection under immunotherapy. Similarly, it is unclear to which extent those who have already recovered from COVID-19 have protection against re-infection.

van Kempen et al. investigated SARS-CoV-2 antibodies in 546 MS patients including 35 patients with polymerase chain reaction (PCR) confirmed diagnosis of COVID-19. Of those, 88.6% (31/35) developed a positive antibody titre against SARS-CoV-2. The high number of patients developing antibodies (31/35) is impressive. Remarkably, 2/2 (100%) patients on fingolimod displayed antibody titres 8weeks after infection. This is strikingly discrepant to a recent report from an Israeli cohort, where only 1/26 (3.8%) patients treated with fingolimod developed SARSCoV-2 antibodies.2 While COVID-19 seems to elicit a sufficient immune response for seroconversion in patients treated with sphingosine-1-phosphate-receptor (S1PR) modulators, SARS-CoV-2 (mRNA) vaccination does not. There are two explanations as follows:

  • This observation is an outlier explained by small sample size (I think we can say this is not the case as the poor response with fingolimod has been replicated a number of times).
  • There is a difference in immunological response to SARS-CoV-2 infection and vaccination.
    In patients treated with anti-CD20 monoclonal antibodies (mAbs), seroconversion seems to be low after
    infection and comparable to vaccination (16%–23%). While these findings are plausible considering CD20-mAb mode of action, the underwhelming vaccination response under fingolimod is surprising, considering the rates of seroconversion after SARSCoV-2 infection. S1PR-modulators prevent lymphocytes from leaving
    the lymph node. Egress is mainly dependent on proinflammatory cytokines, which are typically released
    in response to viral infections such as SARS-CoV-2 (mainly interleukin (IL)-1b, IL1Ra, IL-6, IL-7, IL-10,
    IP-10 and tumour necrosis factor-alpha).4 S1PR modulation apparently allows for sufficient control of
    SARS-CoV-2 (viral elimination and patient survival)as well as development of humoral defence (i.e. seroconversion) in most cases. However, infection with the original pathogen presents the immune system
    with a broad spectrum of antigens and provides a complex and diverse immune response. Vaccination
    likely causes a narrower response depending on the immunogenicity of the vaccine. It could be hypothesized that mRNA vaccines might not cause sufficient activation of the immune system to mobilize th e lymphocytes under the influence of S1PR modulation, consequently compromising seroconversion. Another hypothesis could be that fingolimod, which is a lipophilic S1P analogue, interacts directly with mRNA nanoparticles, lessening their integrity and the immune response.

  • Thus, the question arises whether different vaccine technologies might have different effects in S1PR
    modulation. While both mRNA and vector vaccines primarily elicit a Th1 response, respective levels of
    secreted cytokines could differ and therefore efficacy on lymphocyte egress could vary.
    Initial data from our cohort indicate this. An interimanalysis of patients treated with S1PR modulators
    shows that seroconversion occurred in 100% (4/4) after SARS-CoV-2 infection, only 55.6% (10/18)
    after mRNA vaccination (which is still considerably higher than in the Israelian cohort) and a remarkable
    83% (5/6) after receiving a vector vaccine. Antibody titres after vector vaccination were higher than after mRNA vaccination but lower than after infection.

  • The extent to which the viral vector could amplify the immune response is speculative. However, optimal
    vaccination strategy in immunocompromised patients is unclear and it is possible that vector vaccines could
    achieve a higher rate of protection in selected patients.

I think this is an interesting one and to add to this debate I have seen cases where 100% of people taking fingolimod made a vaccine response. But it was not to the RNA vaccine nor the viral vector vaccine. We need repeat information on this. In the UK and the USA this vaccine is not approved but if it works then surely a study should be done to see if this is true.

Now the next bit of the equation, we need to see data with siponimod, ponesimod, ozanimod to see what happens.

Surely some people have experience of these. Let us know.

I am hoping that that they will work and them we can bring another idea to the table that can explain the biology and the observations this revolves around the different targets for fingolimod. Fingolimod inhibits S1P1, S1P3, S1P4 and S1P5, but the others only target only S1P1 and S1P5. So effects on S1P3 and S1P4 can be the problem as I may explain at a later date. Time to write another letter.

However it could be worse if you have CAR-T therapy to deplete B cells you may 0% antibody response

Dhakal B, Abedin SM, Fenske TS, Chhabra S, Ledeboer N, Hari P, Hamadani M. Response to SARS-CoV-2 vaccination in patients after hematopoietic cell transplantation and CAR-T cell therapy. Blood. 2021 Aug 2:blood.2021012769. 

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MouseDoctor

6 comments

  • After making a confirmed O antibody response after 2 Pfizer injections I have had third Pfizer shot here in France. I am supposed to be changing from fingolimod to ocrevus in the next few weeks. Out of the frying pan into the fire?

  • After making a confirmed O antibody response after 2 Pfizer injections I have had third Pfizer shot here in France. I am supposed to be changing from fingolimod to ocrevus in the next few weeks. Out of the frying pan into the fire?

  • Well a positive note that a pandemic can possible have an upside of helping us understand more about our immune system and our dmts. Does this give us an insight into the suggestion (not sure if true) that mRNA immunity fades faster?

    What type of vaccine was “ 100% of people taking fingolimod made a vaccine response.”? Novavax? What’s the response to hepB, influenza etc when on fingolimod? Thanks for all your thinking MD.

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