Why does fingolimod affect antibody responses?

W

Barts-MS rose-tinted-odometer:  ★

The Twittersphere is abuzz with the preliminary seroconversion rates in Israelis patients with MS on various DMTs in response to the Pfizer-BionTech COVID-19 vaccine (see below). As expected the antibody seroconversion rates in response to anti-CD20 therapies and S1P modulators are blunted and in most cases inhibited. The backstory or biology around anti-CD20 therapy is well-rehearsed; anti-CD20 therapy depletes B-cells and annihilates germinal centres in lymph nodes and the spleen.

The question I have just been asked is why does fingolimod block antibody responses? To answer this we need to go back to the basics of immunology. 

Fingolimod and other S1P modulators work by internalising the S1P receptor making lymphocytes unresponsive to the S1P signalling or chemotaxis gradient in secondary lymph organs such as lymph nodes. In lay language, this causes lymphocytes to park-up in a long-term car park with a wheel lock-on. Even if you wanted to drive your car out of the car park by starting it up you wouldn’t be able to move it without removing the wheel-lock (fingolimod). By blocking lymphocyte mobility helper T-cells can’t migrate to the so-called germinal centres in the lymph nodes and spleen to help B-cells switch from IgM to IgG antibody production and to then help the B-cells to affinity mature their antibodies, i.e. to make good quality antibodies. Normally these affinity matured B-cells would leave the germinal centre to become memory B-cells or plasmablasts. The plasmablasts then mature to become plasma cells and produce high-quality antibodies, which in the case of anti-spike protein protect you from getting COVID-19 in particular severe COVID-19. Fingolimod and other S1P modulators prevent this normal immunology from happening hence the low or absent anti-COVID-19 antibody response after COVID-19 vaccination.

I like to think of the germinal centres as being the immune system’s university; this is where the immune system sends its primed T-cells to help educate B-cells. After a brutal natural selection process in the germinal centres, a few B-cells survive and graduate with a PhD, i.e. a highly specialised degree or class-switched high-affinity IgG antibodies. This then allows the B-cells to become memory B cells and go into semi-retirement or to set-up their own production company as plasma cells and to produce high-quality antibodies. Anti-CD20 therapies work by blowing up the B-cell university and S1P modulators stop the teachers (T-cells) from educating their students (B-cells). Having no university or no teacher-student interactions have the same effect and result in no educated B-cells and hence no IgG antibody responses.

Please note the above information does not change my personal advice regarding vaccination, whether you are on an anti-CD20 therapy, fingolimod or another S1P modulator (siponimod, ozanimod, ponesimod) #GetVaccinated ASAP; some immunity is better than no immunity. Please note having no anti-SARS-CoV-2 antibodies doesn’t necessarily mean you have no immunity. These antibody studies don’t tell us anything about T-cell responses, which are likely to be as important as antibodies in providing protecttive immunity against SARS-CoV-2.

Han et al. FTY720 suppresses humoral immunity by inhibiting germinal center reaction. Blood. 2004 Dec 15;104(13):4129-33. doi: 10.1182/blood-2004-06-2075. Epub 2004 Aug 19.

FTY720 is a novel immunosuppressant that is highly effective in inhibiting rejection of allografts and autoimmunity in various animal models. It has been shown that the sphingosine 1 phosphate (S1P) receptors are the direct molecular targets of FTY720. However, the mechanisms responsible for inhibiting specific immune responses by FTY720 are not well resolved. In particular, there is no available information on whether or how this compound affects humoral immunity. We have investigated the effect of FTY720 treatment on B-cell response during the immune response to a well-defined T-dependent antigen. Our data demonstrated that germinal center reaction was significantly reduced in peripheral lymphoid tissues of mice treated with FTY720. In addition, FTY720 treatment inhibited the production of high-affinity, class-switched antibodies, but not the production of low-affinity, immunoglobulin M (IgM) antibody. Consistently, FTY720 did not have a significant effect on antibody response to a T-independent antigen. Our results may have important implications in application of FTY720 in immune regulation.

Also see the post by MD from a few days ago. Fingolimod also stops B cells moving within the follciles and and stops them contacting areas where they the B cells are likely to be stimulated.

CoI: multiple

Twitter: @gavinGiovannoni                                              Medium: @gavin_24211

About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

34 comments

  • OK, so this blunted response has been suspected or known for a while. The question now is what happens next?

  • OK so this blunted response has been known or suspected for a long time. The question now is how will you proceed going forward?

    • Just continue as is, i.e. take your fingolimod or anti-CD20 therapy as prescribed. It is clear that pwMS on these treatments do okay if and when they get COVID-19.

      Don’t forget vaccination is not 100% effective and is not really about the individual, but population benefits. If enough people get vaccinated then the pwMS with poor vaccine responses will be protected by herd immunity; they will be ring-fenced by people who are immune and hence can’t spread the virus.

      • Thank you for replying but I assume people with poor vaccine responses are also able to spread the disease?

      • “Don’t forget vaccination is not 100% effective and is not really about the individual, but population benefits.”

        This contradicts so much of what you’ve written previously.

        • Not sure. I have never claimed vaccinations are 100% effective and I have always said vaccination is first and foremost a population health measure.

  • If you had hsct with rituximab 11months prior to vaccine, would this apply? Or would I depend on how recovered bloods were/are?

    • I suspect people with MS in this situation will be okay; 11 months is usually enough time for immune reconstitution post-HSCT. However, a proportion of normal people don’t respond to the vaccine so there will be a proportion of pwMS who don’t respond.

      The message is simple, #GetVaccinatedASAP; some immunity is better than no immunity.

  • Really useful and exhaustive. It might be necessary to break down. 53 sides and sub-slides is quite a big “meal” for some readers, but if on DMT, vitally important reassurance. I’m NEDA and not on any meds: already vaccinated, but I found much to ponder in your Decision Aid. It’s a sort of fast rack information highway. Thank you Prof G.

  • I received Alem almost four years ago and my monthly screening comes back with neutrophils routinely around 1.79 and lymphocytes around 0.73. Consequently I have been cautious during the pandemic about my exposure to the virus.

    I’ve had my initial dose of the Pfizer vaccine and am wondering about a blunted response.

    110% get the logic and sense in being vaccinated, but what I’d appreciate knowing is whether being immunosuppressed and at risk of a blunted response means it would be pertinent to continue to apply a degree of cautious post the second dosage – perhaps most especially those PwMS on anti- CD20 DMTs?

    • People with a normal lymphocyte count may not make an antibody response. There is only one way of knowing is to have a blood test and check if you have seroconverted; these assays are now available via private (e.g. Mayo Clinic), but not NHS, labs.

      The advice from the UK Government is that having the vaccine is not a reason to change your behaviour; social distancing, hygiene and masks are still recommended.

      • Forty years ago a neurologist told me “don’t catch flu”. I asked him how. His response was don’t go near anyone you know that is ill. I washed my hands with soap, cleaned my own desk and telephone, followed the advice. My boss even sent me flowers, as I manned the whole office single handed when my colleagues were all off sick with flu. This happened more than once. Now it seems it was the best advice he could have given me. Sometimes it’s not just the medication we need, it’s what we can do for ourselves however small. Now I keep away from friends that I know that are not sticking to the guidelines.

    • I am not anticipating a problem with alemtuzumab, if you can make an anti-alemtuzumab antibody response (85%)within 1 month of infusion you can make a covid vaccine response aftrer 4 years. In the mices when we deplete their T never return to original levels anr jab hd it is a very artifical view as the cells you have before treatment are not the same you have after treatment. Have you mscovid19ab@qmul.ac.uk. In the israelli study they have 20-30 on alemtuzumab in their cohort.. You can bet Cambridge is doing this as we speak I have heard they are doing ocrelizumab T&B. Not sure what a blunted response means because we dont know how much is enough. The challenge trials in UK should tell us this

      I was horrified that based on antibodies alone it seems that in Israel they stoped vaccinating. Rememebr there is an alternative to no antibodies and that is the AZ anti-COVID antibody.

      Rememebr MScovid19Ab@qmul.ac.uk to get a blood spot card. I do it.

      I will still be cautious after second dose

      • Thanks for both the replies ProfG & MD.

        Did I get my wires crossed – thought signing up to use the blood spot card testing was for Bart’s patients, which I’m not.

  • So for vaccinated people on an anti-CD20 (let’s assume no antibodies were created post vaccination) the next question is: do they have any protection? I am still assuming there is a T cell response to the vaccine, and also assume that the T cell response can keep people in this situation out of the hospital if infected with covid. It doesn’t sound like we have data on this yet, but would you still assume this? Seems like a good question for Professor/Dr. Shane Crotty.

    Trying to assess my personal risk here. I was fully vaccinated about 6 weeks ago with Pfizer and have been operating a bit less worries – I think I would get on an airplane (HEPA filters and ventilation!) and I think I would eat indoors.

    • I’d love to know how you would properly ventilate an airplane. An environment tailor-made to spread an airborne infection you couldn;t better IMO.

      • Airlines claim air flows online a limited amount (mostly vertically) and is then recycled through HEPA filters. There are videos showing that with fog machines even.

        I am not sure I want to try my luck but there are remarkably few reports of infections on planes

        • The medcram guys had a ventilation expert from Harvard on who did some work on it – think airplanes have 20 air changes per hour compared with hospitals targeting 6 per hour. Add in HEPA filters and you start with a decent base. Then looking at the actual airflow, it’s even more contained. There have also been several studies of people with covid on airplanes and checking out how that worked out. One in particular was a 18 hour flight studied in New Zealand – google for it, it’s a pretty interesting read. I’m pretty sure I’d rather be on an airplane vs indoors at a restaurant in the winter.

    • The answer would be yes…we know that most people recover from COVID-19 before there is a significant antibody response….The answer about T cells will arrive in the next couple of weeks/months I suspect some people will make a T cell response and some people wont to complicate it….If Shane Crotty does not have the CD20-treated patients all he can say is what anyone can say and sumise in the absence of data. At some point we have to get back into society, but as ProfG says do it sensibly

      • It is so puzzling…this study talks about roughly 80% seroconversion in cd20 treated cancer patients – which is lower but super high when compared to the recent israeli study?

        https://www.prnewswire.com/news-releases/majority-of-cancer-patients-with-covid-19-have-similar-immune-response-to-people-without-cancer-301251276.html

        The retrospective study involved 261 cancer patients, 77% of whom were diagnosed with solid malignancies and 23% with hematologic (blood) malignancies. Their overall rate of seroconversion (production of antibodies in response to infection) was 92%. However, when patients with solid and blood malignancies were compared, patients with blood cancers
        had a seroconversion rate of only 81.7%—significantly lower than the 94.5% seroconversion rate for patients with solid tumors.

        “The treatments commonly given to patients with blood cancers—anti-CD20 antibody therapy, stem-cell transplants, and steroids—are known to suppress the immune system, which may explain the lower rate of antibodies developed in these patients and their increased risk for severe COVID-19 disease,” said senior author Balazs Halmos, M.D., M.S.,

  • Is it theoretically possible that other SP1 modulators would have a better antibody response?

    I believe a post from the past couple of weeks discussed that the newer drugs don’t impact as many receptors as figolimod. I don’t understand the difference in the receptors to even make a guess.

    • Re: “Is it theoretically possible that other SP1 modulators would have a better antibody response?”

      Yes, I think fingolimod actually depletes lymphocytes, whereas the newer generation of S1P modulators are less depleting.

  • Love the metaphor for the car park and wheel lock 🤓

    Thanks for this post it’s got me off the ceiling of panic and back to feet on the que sera carpet

  • T-cell responses, which are likely to be as important as antibodies in providing protecttive immunity against SARS-CoV-2

    T cell responses are a bit weak, by FTY720…I am afraid

    The role of the S1P–S1P1 axis in immunology continues to
    emerge. S1P1 and S1P4 are highly expressed by T cells, with S1P1
    regulating T cell chemotactic responses11,24, but also impacting resident
    memory commitment25, Treg induction26, and IL-6-dependent
    pathways27,28. S1P1’s chemotactic function has made it a newer
    treatment target for the multiple sclerosis drug fingolimod27,29–31,
    whose aim is forced internalization of the S1P1 receptor on T cells
    to effect their sequestration in SLOs and decrease their transit to
    brain. Ironically, our data suggest that tumors of the intracranialcompartment
    may usurp a previously unrecognized central nervous
    system capacity for eliciting this same phenomenon. Such a capacity
    may play a physiologic role limiting T cell access to the central
    nervous system and contribute to immune privilege.
    Subsets of patients with relapsing remitting multiple sclerosis
    experience a paradoxical exacerbation of multiple sclerosis and
    increase in brain-infiltrating Th17 CD4+ T cells when treated with
    fingolimod. Such patients frequently harbor a phosphorylationdefective
    S1P1, similar to our S1P1-KI mice, which likewise demonstrate
    an increase in TIL numbers27. We do not observe these
    to be Th17 polarized, however, which in the relapsing remitting
    multiple sclerosis patients may instead be a function of strong
    fingolimod agonism and resultant S1P1 signaling through the
    JAK–STAT3–IL17 pathway27,28

    https://www.nature.com/articles/s41591-018-0135-2

  • How comes then that in the covid-DMT studies there is no increased risk with fingolimod? I
    struggle to understand…

  • This result sent me on a bit of a crying jag, because while I was expecting a reduced response, I wasn’t expecting it to be SO reduced (flu vaccine studies have folks on fingolimod generating like 40% of a normal response, also determined with just antibody titer). Was this data a “surprise” to you folks in that sense?

    • Yes it was much worse that I was expecting. We dont know much about this data set. However it wont take long before we know from other studies

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