#MSCOVID19. Way to Make Vaccines Better: A Mousey View and the iMods from COVIDtriMS2021

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What has this got to do with MS..Nothing…..Sort-of

Lab Lessons

Modulation of immunosuppressant drug treatment to improve SARS-CoV-2 vaccine efficacy in mice Paschall, A. V., Ozdilek, A., Briner, S. L., Brindley, M. A., Avci, F.10.1101/2021.09.28.462156 — Posted: 2021-09-30

Significance Statement Immunosuppressant regimens are widely used as therapies for a variety of diseases, including autoimmune, inflammatory, and cancer. However, immunosuppressants can impair critical immune responses to vaccination. The impact of standard immunosuppressant use on the critical, developing SARS-CoV-2 vaccination strategies has not been well-described. In this study, we use a mouse model to determine how different immunosuppressant drugs that act through different mechanisms can impair the antibody response to SARS-CoV-2 spike protein, and how modulating these drug regimens may restore antibody levels and function.

It is work done in Meeces and what it looks are the T and B cell responses to SARS-CoV-2 vaccine in alum (aluminium hydroxide adjuvant) in animals treated with different arthritis drugs. These include leflunomide, which makes teriflunomide, MP methyl prednisolone (steroid), CYC cyclophosphamide (sometimes used in MS) and MM mycophenylate and MTX methotrexate. First I have to say cyclophophamide is a chemical B cell depleter and as you can see the vaccine response is rubbish. Methotrxate is used to block B cell responses. In the test and at the dose used they all drugs tested inhibited the development of an IgG vaccine responses. They were less effective at blocking IgM responses except cyclophosphamide. Furthermore, when they looked in a viral neutralization assay cyclophophamide and methotrxate had a big inhibitory effect and leflunomide didn’t . However, the point is if people took a drug holiday (Halt x 3) around the time of vaccination then methyl prednisolone stopped inhibiting the vaccine responses, methotrexate lesss so and there was no response (ND not detected) with cyclophophamide.

So it says a drug holidays may increase the chances of a vaccine response for some, but not all drugs. A trial is ongoing that will look at drug holidays of methorexate and mycophenylate that should read out in Novemeber.

It doesnt tell us alot for MS but it says there is a way to look.

Maybe this should be done for fingolimod, siponimod, ozanimod and ponesimod. We know fingolimod is a problem child in terms of making B and T responses after vaccination. Would a drug holiday work? I suspect not easy because it hangs around for a long time but am there to be proved wrong. This could be an issue with ozanimod too as its metabolite is active and hangs around for a while. But what about siponimod and ponesimod?

We can go to ECTRIMC2021. As you can imaging it is abit of a COVID-19 fest. Many of the studies have been published on MeDRxiv already so you know what’s happening.

But first to the mousey stuff and ponesimod and a drug holiday may do the trick. I hope the manufacturers are doing a clinical study, they did do the mousey stuff below, so you can be advised what to do. With a drug holiday there was a good vaccine response

ECTRIMS2021. Spiller K et al. P646 – A short pause in ponesimod treatment completely restores the ability to mount post-vaccination antibody titers in mice.Conclusion: The antibody response after vaccination was blunted in mice that were maintained on ponesimod, but not when treatment is temporarily paused. These data suggest that briefly halting ponesimod treatment may help in achieving maximal vaccination effectiveness.

So this says two things. (1) A break to get optimal vaccine response is needed (2) The problem for the vaccine response is to a large part S1P1 mediated. This is bad news for siponimod, and ozanimod (S1P1 & S1P5 modulators) as well as fingolimod (S1P1, 3, 4, 5). Therefore they are all going to have some form of problem, if it is there for ponesimod (S1P1). I can make a case why fingolimod would be the most problematic because immune responses invole S1P4 and possib;y S1P3 which contracts cell function…at least in mice.

What is the supporting data?

Well it seems that fingolimod has the biggest problem vaccine wise as it inhibits vaccine related T and B cell responses. However if that is the case why is fingolimod not associated with worse effect following natural infection. The data is consistent it is not associated with more severe COVID-19 (Simpson-Yap et al 2021 Neurology).

Simpson-Yap et al 098 – Updated results of the COVID-19 in MS global data sharing initiative validate consistent associations of anti-CD20 and other reported risk factors with severe COVID-19 outcomes. Of 5,543 patients in the clinician-reported dataset, 909 with suspected and 4,634 with confirmed COVID-19 were included in the analysis. Previous demographic findings were confirmed: male sex, older age, progressive MS, and higher disability were associated with worse outcomes from SARS-CoV-2 infection. Use of anti-CD20 DMTs (ocrelizumab and rituximab) was associated with worse COVID-19 outcomes…. Associations persisted on restriction to confirmed COVID-19 cases.

Maybe “like for like” is not being assyayed. In non-imod treated individual the blood contains at least 4 main types of T cells but in fingolimod there is one may type left the CD45RA effector cell, these are not what you need for a vaccine response so without purifying the memory cells before the assay the results will be perhaps misleading.

Also there is variation in how poor the serconversion on fingolimod is, there are a number of studies where there is a reasonable or good antibody response. I suspect part of the difference is the assay used to detect response and those against the receptor binding domain, which binds the target often give a lower response than if you measure response to Spike you get more of a response.

In some studies at ECTRIMS2021 there is 100% of a response and 20% of a response in other studies.

What about Siponimod?

Tjalf Ziemssen et al. P810 – Assessing the immune response to SARS-CoV-2 mRNA vaccines in patients with secondary progressive multiple sclerosis treated with siponimod (AMA-VACC clinical trial)

As you can see they are doing a delay study.

They found that half of people (n=14) made anti-SARS-COV2 neutralizing response. Is this better than fingo? Maybe but without head to head it is harder to say but says S1P1 is the important molecule for vaccine response. About 50% made a T cell response and about 67% made a T or B cell response. So maybe a bit better than fingolimod.

There are a few cases of ponesimod appearing the antibody response is blunted also

Can this response be boosted?

Next question is whether even if there is a problem, does it matter because we dont know the consequences of being T or B cell depleted? However in a paper from the Cleveland clinic of the few people getting COVID-19 who where double jabbed all were on anti-CD20 or fingolimod.

Anyway as the main meeting of COVIDTRIMS2021 (there were 171 COVID related presentations) comes to an end today…guess what the Late Breaking News consist of? A Hot-off-the-press clinical trial? No you guessed it…..loads and loads of papers to tell us that CD20 inhibits the COVID19 Vaccine response but there is a T cell response. Fingolimod is not that great either….Maybe something you don’t know:-)

Even I’m bored of it now…So until next year when we hear all about the boosters:-( TTFN……….=Ta Ta For Now

COVID: multiple

General Disclaimer: Please note that the opinions expressed here are those of the author and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.

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MouseDoctor

1 comment

  • Thank you for the update MD1.

    I am not surprised to hear the main focus of the conference was on COVID-19, but it sounds like there was at least a few golden nuggets of knowledge presented this week.

    I do not know your motivations, but I believe they are pure and I must say your dedication to this blog and passion towards MS research in general is very commendable MD1.

    I learned a long time ago…..a true hero does not seek public recognition or monetary rewards…….just a positive outcome for someone else.

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