EBV: is it time to pluck the black swan?

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SEPSEPIEN a commentator this morning said: “Would have been more rewarding to find a DMT that successfully addresses the causes of MS”. I agree and I really think we have found the cause of MS. It is Epstein Bar Virus (EBV). The epidemiology is pretty convincing that EBV acts in the MS causal pathway and all of our effective i.e. licensed DMTs work on memory B-cell where the latent EBV virus resides. 

The piece on my #1 ECTRIMS-2021 highlight, i.e. the MRI changes in relation to treatment with Atara Bio’s anti-EBNA1 allogeneic CTLs (cytotoxic T-cells), has resulted in at least ten emails from business analysts wanting to speak to me about the product. I think it is my reference to a ‘Black Swan’ that piqued their interest. What they don’t realise is that when you pluck a black swan it looks just like a plucked white swan.

So if Atara Bio gets their product to market they will get pipped by the simple repositioning of the licensed DMTs as anti-EBV agents. What do I mean? 

Rituximab (anti-CD20) is licensed to treat EBV-associated lymphoproliferative disorders. Peripheral EBV viral loads plummet when you administer anti-CD20 therapies. In other words, anti-CD20 therapies are anti-EBV drugs so why would you need to use an expensive cellular therapy? To get into the CNS. Step up the CNS penetrant BTK inhibitors.

Ibrutinib the first licensed BTKi is a potent anti-EBV drug and works very well against EBV-associated lymphomas including CNS lymphomas. EBV in fact uses BTK as a signalling molecule to bypass B-cell receptor-mediated cell cervical signals.  

MD produced a wonderful and very influential review showing all of our DMTs in MS work via memory B-cell reducing their levels in the periphery with the exception of natalizumab that blocks trafficking of memory B-cells into the CNS. 

So all it will take for Big Pharma to pluck Atara Bios black swan is for them to produce data showing how their DMTs impact EBV viral infection in the periphery and potentially in the CNS. The frustrating thing for me is I have been trying to get Pharma to do these studies for decades. Just maybe with a black swan soaring up above they may start to listen. I suspect some of the companies have data on this already.

The good thing that Atara Bio has done is to move EBV centre stage. So maybe now we will get some momentum behind our EBV vaccination study off the ground. 

For those of you who have progressive MS please note how much improvement occurred in the study subject in the Atara Bio phase 1 study. It is almost too good to be true, which is why I referred to it as the Lazarus effect

A plucked swan; was it a black or white swan?

Baker et al. Memory B Cells are Major Targets for Effective Immunotherapy in Relapsing Multiple Sclerosis. EBioMedicine. 2017 Feb;16:41-50. 

Although multiple sclerosis (MS) is considered to be a CD4, Th17-mediated autoimmune disease, supportive evidence is perhaps circumstantial, often based on animal studies, and is questioned by the perceived failure of CD4-depleting antibodies to control relapsing MS. Therefore, it was interestingly to find that current MS-treatments, believed to act via T cell inhibition, including: beta-interferons, glatiramer acetate, cytostatic agents, dimethyl fumarate, fingolimod, cladribine, daclizumab, rituximab/ocrelizumab physically, or functionally in the case of natalizumab, also depleted CD19+, CD27+ memory B cells. This depletion was substantial and long-term following CD52 and CD20-depletion, and both also induced long-term inhibition of MS with few treatment cycles, indicating induction-therapy activity. Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS. This creates a unifying concept centered on memory B cells that is consistent with therapeutic, histopathological and etiological aspects of MS.

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General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni 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. 

60 thoughts on “EBV: is it time to pluck the black swan?”

  1. What will best impact on EBV in the CNS – Atara Bio’s anti-EBNA1 allogeneic CTLs, BTK inhibitors or EBV vaccination? Where are we with the EBV vaccination study and how can we support it?

    1. Why would vaccination matter to MSers?

      Perhaps to the future generation, but the pressing need is treating the sick.

      I am more interested in anti-viral of some sort. Remember how HIV+ MSers do very well and could be MS free.

  2. Nassim Taleb is a family friend and a distant cousin of my mother. I am reasonably familiar with his work on tail risk events.
    Not sure he would have qualified an anti-EBV agent as a Black Swan.

    What happened to that Swiss firm working on that other agent?

      1. A somehow related question since you are still awake and responding: since Natalizumab keeps B cells out of the blood brain barrier and does not destroy them, what would happen to a patient who has been on natalizumab for a very long time and then switch immediately to alemtuzumab?
        Would lemtrada take care of all those EBV-carrying barbarians at the gates?

  3. Why would pharma slaughter the cash cow that keeps giving? If the cause of MS was virus, then why doesn’t barts run the trail, vaccinate all family member of MS patients against ebv then compare to unvacinated families ms patients
    Total cost 3 million. Then blackmail pharma you will release the results and get billions to finance nerve repair strategies. Sometimes you have to spend money to make. Forget pointless trails like chariot that slow MS and concentrate on curing ms

    1. Tackling EBV will make a small fortune. Maintaining the status quo will make many times that for many drug companies. We may want to destroy MS, but big pharma need to avoid that for business continuity. Look at the rate of development of Psiolocybin (magic) mushrooms and compare to SSRIs. The mushrooms ‘cure’ depression and have been around for longer than dinosaurs. SSRIs are a non-curative treatment which drug companies sell over and over again, profiting each time. You don’t need a medical degree to see why drug companies don’t deliberately develop cures.

      1. The SSRI are all off patent, very little money to be made there.

        Pharma does not sit on a known MS cure out of greediness – whoever finds this stands to make 10s, possibly 100s of billions. There is plenty wrong with pharma incentives but *this* is not it.

      2. Fully agreed, but human nature favours us to think conspiratorially rather than admitting ignorance of a complex subject.
        It is the lowest hanging fruit in terms of intellectual traps, binding the masses to fight a common pseudo-fictional enemy (most often a system).

      3. Yes your right

        Yeah it was a sarcastic question. They will possibly never tackle EBV as its tied to so many diseases and it’s a money earner, just like anti depressants

        Orrrrr they don’t have the knowledge to tackle it

      4. There is clearly an element of hype surrounding psychedelics that seems similar to the former hype around cannabis… Let’s remember that most of the cannabis trials ended up failing and, most significantly all the ones related to treating neurological diseases.

    2. Have you ever considered it is because it is a hard virus to treat/vaccinate against. The vaccines/treatments of EBV are being developed to avoid cancers and lymphomas not MS, because a causal link to a range of cancers has been proved. You will notice they created vaccines to HPV, but it takes time. However, the vaccines will not help us who have EBV as it is already hidden in our cells.

  4. Why would vaccination matter to MSers?

    Perhaps to the future generation, but the pressing need is treating the sick.

    I am more interested in anti-viral of some sort. Remember how HIV+ MSers do very well and could be MS free.

  5. “For those of you who have progressive MS please note how much improvement occurred in the study subject in the Atara Bio phase 1 study.”

    But the anti-CD pharma companies can’t show such improvements can they? If not, why haven’t they already done so.

  6. I suspect EBV vaccination isn’t going to work for pwMS because we’re already infected and our immune response is inadequate at clearing the latent infection. The Atara Bio’s anti-EBNA1 allogeneic CTLs bypass this deficiency. The vaccination may help the next generations wipe out the causative EBV, but only by introducing it into the routine childhood vaccination programme across the world, so that MS, some lymphomas, some nasopharyngeal carcinoma and Burkitt’s lymphoma are spoken about like Smallpox (an historical illness). Maybe we will need to give it before birth like pertussis/whooping cough. We need a definitive study on BTK inhibitors and to expedite work on Atara Bio’s anti-EBNA1 allogeneic CTLs first.

    1. Not necessarily, there is a therapeutic EBV vaccine being developed.

      It’s many years away and may or may not work, however it’s in early stage development

      Plus long covid treatments will possibly target EBV so it’s an interesting time, just years away if successful

  7. Why would you select something like ibrutinib over adoptive/cellular immunotherapy?? Hasn’t it become evident B cell depletion is less than ideal in a pandemic? I prefer resources be focused on ATA188 and it’s updated versions. It will prove to be much less costly and life consuming than traditional current or proposed MS meds.

  8. How come Ataras treatment praised from a phase 1 trail?

    And a phase 3 Mastitinab for progressive MS, showed positive results at significantly slowing MS and gets zero praise and big scepticism over the results on this blog?

    Strange

    1. Sorry please tell me where the lack of praise and big scepticism

      https://multiple-sclerosis-research.org/2020/09/mastinib-sclerosis-and-covid-19/

      https://multiple-sclerosis-research.org/2020/09/progressive-ms-masitinib-another-duck-lines-up-at-msvirtual2020/ Their words in 2020 where “Efficacy results from the MAS high-dose parallel group (titrated 6.0 mg/kg/d) were inconclusive and no new safety signal was observed”.

      Had a look at ectrims 2021 and nothing on mastinib it was presented in 2020 and no paper has surfaced yet. The trial in ALS was suspended. Why? hear t conditions the trial has started again

      1. You’ve commented before that you suspect the positive phase 3 results maybe down to the manufacturer wanting to sell the rights to a bigger drug manufacturer

  9. ?

    I feel so stupid reading and re-reading this quote

    “Importantly, memory B cells were augmented by B cell activating factor (atacicept) and tumor necrosis factor (infliximab) blockade that are known to worsen MS.”

    Does that mean that all of the meds mentioned actually worsen MS by doing that?

      1. So it’s T cells dying off that worsen ms symptoms, but B cells dying off doesn’t? I’m sorry for being so confused by this.
        JCV levels forced me off Tysabri. I did better on that than others I’ve used since then. I failed Ocrevus horribly, took almost 2 years for me to have enough B cells for my neurologist to “feel comfortable” prescribing anything else.
        I’m going to start Lemtrada really soon. From what I understand, it’s going to kill off both B and T cells.
        Thanks for all that you do!

  10. EBV – that old chestnut. Like a bad penny it comes round again. This is from the Blog from January 2010! Nearly 12 years ago. It’s the elephant in the room. Everyone knows it’s the culprit, but nobody does anything about it. Is this another blog post on EBV which fizzles out and reappears in 6 or 12 months time.

    https://multiple-sclerosis-research.org/2010/01/primary-ebv-infection-and-ms/

    COI I have MS and don’t want to see myself continuing to climb up the EDSS. I have received no compensation from any pharma company. MS gives a good living to neuros / MS researchers / pharma, but took away my living. I had a bad case of mono (EBV) at 14.

    1. Anon whoever you are;-) a duck hunter? You continue to shoot the messenger killing the swan and not the duck…. Everyone knows it the cause….except the people in charge of the purse strings;-(. The establishment doesn’t like the idea…if they dont like the idea. Nobody is going to fund the studies. They are much happier pouring dosh in other places…maybe EBV will form part of the gut microbiota:-) Then we can get interested.

      1. “The establishment doesn’t like the idea…if they dont like the idea….”

        This has made me even angrier! I thought science was evidence based! Who are the establishment? I wouldn’t mind if MS was the equivalent of an ingrowing toenail, but it’s the biggest cause of disability in young people. So we keep on funding the same bloody projects rather than tackle the root cause. I wouldn’t just shoot the messenger, I’d shoot the whole bloody lot of you. 50 years of fannying around on EAE and DMTs that don’t address the cause. You’ve ruined my enjoyment of the Antiques Roadshow – so I’m even angrier now.

      2. Who are the establishment?..Your mates? I wonder…The gong collectors?

        Antiques Roadshow..Now, Now….I know you are jesting. You may be having a sneeky peek at the Mating game…who can resist abit of Panda and albatross porn and after strictly and Dr Who….What a trilogy?…Never mind you can catch up on Antiques Roadshow when your blood pressure is down. Maybe a quick trip to “Anger Management can help. Maybe you can compare notes with SID…I am sure you would get on like a house on fire. Like-minds and all that. Maybe you should meet up, but beware sadly you are probably being hunted down by the FBI/Po-lice to stop you going on a shooting-fest.

        PS. I am not sure you can blame EAE for this one.. nor the DMT for that matter. The establishment does not give you DMT, DMT are made by Pharma

      3. To be fair I think TBI actually causes more disability in young people than MS and treatment for TBI is basically non-existent. Really MS has the best treatment options of any neurological disease.

      4. There is no establishment at work here only people, and I have never met a person who takes the idea they are wrong in a positive light. This is true for flat-earthers, anti-vaxxers, scientists, engineers, politicians and people who post on blogs and websites.

  11. I remember MD writing Atara data were good but not enough. What would be good enough?
    People infected by EBV have anti EBNA1 antibody, why natural antibodies are not sufficient to keep EBV at bay therefore requiring a vaccine or a CTL treatment?
    The new generation of BTK inhibitors is non depleting so they should not target EBV directly. Will they?
    Why is remyelination occurring in people with CTL treatment? EBV is on b cells not on neurons…

    1. Virus develop immune escaping mechanisms, vaccines/Car-T could bypass these mechanisms and build immunity to certain proteins without knowing who the end target is. Latent EBVs could come out of memory B-cells and find there are cops everywhere looking for everyone has that exact hand.

  12. These posts generate a lot of interest / comments / hope. However, what would be very useful is to understand the timescales with which some of these treatments will actually be available (BTKs, Atara etc). I expect that I am not alone in using the information on the blog to develop my treatment strategy. Right now that involves weighing up the risk of HSCT against that of smouldering for a few years on anti CD20 whilst a more effective therapy emerges

    1. Atare has phase 2/3 trials to do you are talking 5-6 years for a phase III, 1-2 years to get the regulator package together 1-2 years for NICE to approve and if it is a phase II it is 2-3 years. I they are done one after the other it takes 10-15 years to develop an MS drug

  13. Why will Atara “get pipped by the simple repositioning of the licensed DMTs as anti-EBV agents.”?
    The current DMTs have not shown any Lazarus effect in Progressive MS

  14. I will be first in line for an EBV vax.

    I understand that EBV is causal. HOWEVER I am anecdotal evidence that an immune system trying to keep EBV in check is responsible for progression as well.

    I was in good shape early 2018 then had a long slow decline – by the fall, was looking at wheelchairs. Balance, gait (both legs) and fatigue. I was not sick, per se.

    My gp and ND put their heads together with my permission and sent me for 15 vials of blood work. I was diagnosed with reactivated EBV and put on acyclovir (although not the best option, it has worked okay for me). I identified two previous “relapses” that may have been reactivations as well. I had no idea.

    Within 2 weeks my mobility was back. I experimented going off a few times .. and boom down I went.

    I’ve just completed year 2 of Mavenclad. I came off near end of year 1 and did seem to worsen, however I had multiple things going on. Because Mav doesn’t clear out ALL B mem cells, I’m really hoping it was enough to get me off antivirals. I’m tapering down now.

    In my opinion, based on an n=1 experiment lol, this vaccine will help those who are progressive as well. Any infection takes us down, and EBV has made MS here way worse than it needed to be. We HAVE to be fighting EBV, because EBV unchecked is also responsible for some cancers.

    I would LOVE to be part of a trial. But as I said – first in line. Hope it doesn’t take too long!

  15. MD produced a wonderful and very influential review showing all of our DMTs in MS work via memory B-cell reducing their levels in the periphery
    2 questions
    Atara engineered cytotoxic t cells are programed to kill memory b cells (carrying ebv) they dont touch resident plasma ,nor the anti cd 20 dmts
    1:If “all of our DMTs in MS work via memory B-cell reducing their levels in the periphery” Including Atara drug
    Why them are you doing a trial of anti plasma cells (ixazomib)?
    if plasma cells is this culprid them Atara drug should not work they do not kill plasma cells
    2: Why did they do only progressive disease trial ? Are they planing to do Rrms
    Agradecido

  16. I am still thinking about all this and was just reading about transverse myelitis.
    Do we think that EBV association of MS could result from the infection itself or from the response to it?
    And if most of us are infected with EBV in our childhood, why is the median age for CIS symptoms around 29 ?

    1. Interesting question… I had Mono at age 12, and my first symptoms of MS were at age 18. I had Mono again at age 28. I know everyone’s MS is their own, but even with these EBV events, RRMS journey was pretty quiet until I reached my mid-late 40s. I did’t take a DMD until I was 50! Now at age 63, I’m still on Tysabri. My MS has slowed significantly, though I have symptoms every single GDamned day.
      I know…your mileage may vary…

  17. True. Mind you the Shingrix vaccine also keeps me from getting shingles – which I’d had twice already.

    I’m definitely willing to give it a try (should the Mav experiment not be successful).

  18. The reluctance of Big Pharma to do causal research on MS is one of the reasons I started the Mystery Solved project (with support from ECF and incentive from Gavin). The aim is to obtain active MS tissue (via rare biopsy material and autopsy) and to perform multi-Omics on it, in order to find out more about the role of EBV.
    With the knowledge that Natalizumab keeps the bad guys out of the CNS, we may indeed have to look much more peripherally. Supported by the findings of the Prof. John Harley group in Cincinnati that EBNA2 (EBV latency III) binds to >50% of the transcription factors of risk genes for MS (and other AID such as rheuma, IBS, Lupus, DM1), this suggests that there are MS specific EBV infected memory B cells circulating that trigger CD8 cells to attack the CNS. As other AID also occur in flare-ups, these specific B cells may be only intermittently present. If this can be found, it would be an ideal therapeutic target!

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