As you are aware from reading this blog that EBV is strongly associated with MS and some of us believe that there is now enough evidence to accept EBV as the cause of MS. One of the reasons for thinking this is that if you are EBV seronegative, i.e. you have never been infected with the virus your chances of getting MS are close to zero. The latest meta-analysis we did showed that when you use two robust assays to assess EBV seronegativity your risk is in fact zero.
Pakpoor et al.
The risk of developing multiple sclerosis in individuals seronegative for Epstein-Barr virus: a meta-analysis. Mult Scler. 2012 Jun 11.
It is also apparent that you have to be infected with EBV before you develop MS; this is the correct sequence of events to prove causation. As you have gathered causation theory is complex and you need to fulfill many criteria; one of these criteria is experimental evidence. In other words if you stop people becoming infected with EBV you should prevent them from developing MS.
The grand challenge is to develop a vaccine against EBV that prevents wild-type infection and to set-up a study to test this hypothesis, i.e. to take a group of children who are at high risk of developing MS because one or both of their parents have MS, and to vaccinate half of them against EBV and the other half against another virus or with a placebo vaccine, and to then follow them up to see if those vaccinated with the active vaccine have a reduced incidence of MS. The follow-up for this study will have to be for 30-40 years as the average age of onset of MS is 30. To do this experiment we would first need to develop a safe and effective vaccine against EBV. The current vaccines that have been developed are not that effective; they provide some immunity against EBV but not enough to prevent wild-type infection.
Our other grand challenges:
27 Aug 2012
Grand Challenges in MS (4): month of birth effect. Why does the month you are born in affect your risk of MS? I assume you are aware that month of birth is a risk factor for MS. In the Northern hemisphere, if you are born in May …
26 Jul 2012
Grand Challenges in MS (3): changing sex ratio. Why is the incidence of MS increasing amongst woman? To prove that MS is caused by a single factor or the interaction of several factors it has to explain everything we know …
06 Jul 2012
Grand Challenges in MS (2): early aggressive therapy. In response to yesterday’s discussion on whether or not … That is another story, possibly another grand challenge.” “I hope this post in not confusing; if it is I will try and …
02 Jul 2012
Grand Challenges in MS (1): education. It appears that the grandest of all challenges in MS research is education; i.e. getting Researchers and MSers to agree on the unmet needs in the field across all stages of the disease.
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1. Why not give all of them the vaccine. There's surely no placebo effect here2. Why only children at higher risk. I think it will be better to give it to a large number of children in a high-risk area. For example, to all children below 10 in a Scottish town (all whose parents don't object, after checking they are still seronegative)And make it available to those outside the trial if they want it. It's too late for my children but lots of people will jump at it
The general public, in particular parents, and public health officials are nervous about vaccines. They have to be very safe. I assume you are aware of the scares that have happened with MMR and DPT vaccines, not to mention HBV and now the human papilloma viruses. Targeting high-risk children initially is to prove that the strategy works; I think a parent with MS is more likely to take the undefined risks of a vaccine programme to prevent MS than a parent without any personal experience of the disease. I may be wrong? The other issue is getting ethics committees to pass the study protocol.
If a place has a high incidence of MS most parents will have MSers within friends and family. That will be enough personal experience
The anti-vaccine people make a lot of noise, but they are a small minority. Most parents just get all recommended vaccines for their children
Why not develop a drug against EBV in seropositive MSers? If you 'cure' EBV und stop MS surely the causal link would be more than evident?
There are drugs already! Anti-CD20 (Rituximab and ocrelizumab) that deplete B-cells are potent anti-EBV agents and are very effective in MS. The problem is the company that is developing them does not seem to be that interested in finding out if they are working as anti-EBV agents. I think they are. Under the Charcot Project we will be testing two small molecule anti-viral drugs that target EBV. I am really excited by these trials. We have funding in place of one of the trials and are hoping to get funding for the second trial soon. Please watch this space!
A naive question maybe Prof G but why are neuros not prescribing Rituximab or ocrelizumab for MSers? Are they already licensed as MS-drugs or just in trials? I don't know anyone who takes them yet.
Rituximab is available and is used by many MSologists off-license. I have used myself in MSers who fail Natalizumab due to side-effects (anti-natalizumab antibodies. Rituximab is an expensive drug so we have to make a case for using it in MS. Ocrelizumab is currently in clinical trials; we are recruiting for both a PPMS and RRMS trial. The phase 2 results of both rituximab and ocrelizumab are stunning; in the same league as Natalizumab and Alemtuzumab.
I'm not sure I understand what you mean by 'off-license', sorry – you mean another drug with the same ingredients??Anyway, two important questions:1. How would be the dosage of Rituximab (I'll try to get it for my not-confirmed RA.) But how to take it?2. Is a combination of Rituximab and fumarate even better? I'm on fumarate right now.3. Will Rituximab in your opinion be effective for RRSM edging on SPMS as well?THANKS.
Off-license means that the EMA and FDA have not give the drug a license to be used in MS. The neurologist has to take the risk with the MSer to use the drug. I have personally use it very few MSers. As there is no combination data regarding its use with fuamric acid I can't make a statement. I am also not sure about SPMS; there is no SPMS data available that I am aware of; although there is a Rituximab trial been recruited at present by the NIH.
Thank you very much Prof G for your very helpful replies & your patience. Have a nice weekend!
Perhaps the goal should not be to develop a vaccine to prevent EBV but to develop a vaccine that prevents the diseases following an EBV infection.http://stm.sciencemag.org/content/3/107/107fs7.abstract
Post infection may be too late. But we have the Charcot Project, which is nevertheless targeting EBV in MSers with established disease. You have to remember that the risk of MS starts early in life; some risk factors exert their effects in utero!
Unfortunately (and I've seen this before, there is Prog G the academic and Prof G the medic. The former's interest in MS at the population level, the latter is interested in MS at the individual level.Two things which annoyed me about this post: "placebo vaccine" and "the follow-up for this study will have to be for 30-40 years".Surely, there must be a better way. They've been researching the link between MS and EBV for 40 years+. I got glandular fever at 15 (bad case) and MS 20 years later. A colleague got glandular fever at 25 and got MS 5 years later.The evidence is over-whelming and justifies EBV vaccination for all children c.10 years old. This would be justified just to avoid glandular fever (I was bedriden for weeks). I'd like Prog G the medic to run this one i.e. given the weight of evidence get the vaccine rolled out to those who are happy to take it (I'd pay for my children to have it). Placebos and ridiculously long timeframes are purely to keep the MS research industry going and to satisfy academic demands (completely over-engineered). The other side of the coin is to understand why some with EBV develop MS – you hinted that B cells are infeced and there is an immune response (with collateral damage). Alemtuzumab and B cell depleting treatments are possibly knocking out this EBV infected B cells – more evidence of EBV's role. One can't soem bright spark nail this issue for once i.e. two years focused piece of research with a definitive answer at the end (no need to involve mice or EAE – EBV a human disease)? Given the strenght of evidence is almost criminal not to vaccinate kids at high risk of developing MS.
I must play my own Devils Advocate – there is scientific method that we need to follow to be able to affect science and public health policy. There is no place of Bad Science. I want to be remembered as a good scientist.EBV is a virus that has co-evolved with humans and therefore must have a beneficial effect. If not evolution would have jettisoned it from our population. Therefore, preventing EBV infection at a population level may have serious, yet undefined, risk. This is why we need to proceed with this strategy very cautiously and expect side effects of keeping large portions of our population EBV negative. We may reduce the incidence of MS, but increase the incidence of something else. Health, in particular population health, from vaccinations have risk:benefit ratios like any other intervention. We need to know the benefits and risks before we can implement any population health strategy.
It's easy to talk about risk when you haven't got MS (or some other grim disease). As someone who sees MSers on a regular basis you must see how dreadful this disease is – for young people. A 'good scientist' should be proving things and coming up with novel ideas / treatments. The production of peer-reviewed research papers / presentations at conferences should not be the acid test of a good scientist – particularly in medical research. At the end of your career, what would you prefer: to be known as an MS researcher who produced 300 peer reviewed papers and got the Charcot prize, or a doctor who took risks (well thought through risks) so that his patients could have a better quality of life (by stopping the disease, repairing some of the damage, or preventing future generations from geting the disease)? What's sad is that the timescales proposed won't benefit my young children or my future grandchildren. I think there's a lot to learn from the way researchers addressed AIDs. Also, if a plague started rampaging across Europe, it would be amazing how quickly the researchers would develop a solution. The trouble with MS is that no one is dying in the streets and it's not contagious. As a consequence, there is no real urgency to do anything i.e. the 40 year EBV study! We need a new model of MS research where urgency and appropriate risk taking is encouraged / rewarded. I'd hate to think that in 40 years time (I'll be long gone) there is a bunch of MS researchers still looking at genetics, Vit D, EBV etc etc.On the positive side, there is some slow progress. I've reviewed the abstracts for the ECTRIMS 2012 conference. I'm pleases to see that EAE and the injectibles are gettign ahrdly any coverage compared with previous years. Many more abstracts on the new drugs e.g. BG12, Fingolimod etc. Perhaps thigns are changing in MS research (albeit wtill had a tortoise like pace).
Re 'co-evolved with humans and therefore must have a beneficial effect' and 'We may reduce the incidence of MS, but increase the incidence of something else' That is what the cranks say about vaccines and autism!
Believe me I am a risk taker when it comes to doing research, but you still have to work within a ethical framework that protects individuals from rogue scientists. The people that control ethics committees are not into taking risks, so we then have to make the case for doing the trials compelling.
I remember when AIDS started – there was a LOT of talk about how nobody was bothered about it, how the response would have been different if it wasn't the gay community that was affected, etc
In most people EBV does not cause any longterm problems, but it is linked to many rare diseases, for example tumours, in particular lymphomas, various lymphoproliferative disorders and MS and possibly other autoimmune disease. These diseases are not sufficient to select against EBV, in fact the majority of the population become infected with the virus. So what is it doing in these people? It may be doing something good. EBV is one of those viruses that form our metagenome, i.e. the microbes that live with us. I suspect getting rid of EBV from the human genome will have some effect. Don't worry this concern is theoretical and won't stop me pushing for a vaccine trial. At the moment we are trying to define a pre-MS state or the MS endophenotype in people at risk of MS. If we can we can then use this as the study end-point in a vaccine trial and will get a read-out sooner than 30 years.I spend a lot of time thinking about these issues and will share all my thoughts with you in time.
"The phase 2 results of both rituximab and ocrelizumab are stunning; in the same league as Natalizumab and Alemtuzumab. "Were the results stunning for PPMS as well?BTW: The person who used AIDS as a case example of how medical progress was fast tracked: you have to remember that when AIDS hit the gay community 30 years ago, the community itself was a force to be reckoned with. They fought like mad to get to grips with the disease. As gay people work in the feild of science, politics, law, finance, media, etc, they were able to put the disease in the spotlight in a profound way.Unlike AIDS, MS is a fairly uncommon global disease. It doesn't have the attention AIDS and cancer has. Also, considering most MSers give up on work due to health issues, it doesn't have the long term focus.
I suggest you use the search engine on the web-version of the blog to get all our other posts on rituximab and ocrelizumab. The one you are after is:http://multiple-sclerosis-research.blogspot.co.uk/2011/06/study-of-ocrelizumab-in-patients-with.html
Is Alemtuzumab lso considered anti-EBV or is the uniquely a Rituximab property?What clinical indication would point to the use of Ritux over Alem and vice-versa? It seems have to discern the basis upon which one would choose between these (assuming one had the choice!)?Is Ritux considered slightly less aggressive, slightly better safety profile (based on its large scale use in RA) so for less highly active MSers?
Alemtuzumab may also be an anti-EBV agent as it also depletes B-cells, but the B cells rebound very quickly after Alemtuzumab. I want to study this phenomenon, but have had difficulties getting samples. Things may change in the future. Please note that Rituximab has a license to treat EBV-associated lymphoproliferative disease, which is a disease that is caused by EBV directly. No other drug has a license to treat EBV.
Aside from EBV, are you able to answer the second half of my question? I'm really struggling to differentiate between clinical pointers towards one or the other (and I do have the choice being in the US and with a neuro who has a small stockpile of Alem). What indications would tend towards selecting Rituximab versus Alem and vice-versa? Or are they so similar that is it just a straight choice based on an assessment of the results in trials and saftey etc?
Prof G,What about Polio. A virus which can cause disability in humans (mild to severe disability). Thankfully a genius developed a vacine which prevents the disability. I don't believe they needed to do tests for 30-40 years. I don't believe anyone was claiming that the polio virus must have been doing us some good as we've lived with it forever. If only MS could be taken more seriously. There's a notion among many that it's pins and needles and that there are drugs available (injectible). Perhaps you should suggest that members of the ethic committees visit Debbie Purdy or tie up with an MS nurse for a week. Do they no understand that EDSS 10 = death? It's health and safety gone mad.
Polio causes most of its problems in early childhood. Therefore a vaccination programme can be tested very quickly, i.e. with 3 to 5 years. The problem with MS is that it takes 30+ years to develop, not 2-4 years as is the case with polio.
Prof G wrote: Rituximab is available and is used by many MSologists off-license. I have used myself in MSers who fail Natalizumab due to side-effectsWhy only use it on those who fail Natalizumab? It seems to me (especially in light of your stem cell migration post this morning) that the saftey profile of Rituximab is actually better than Natalizumab? Add in the fact that most people will eventually have to stop Natalizumab when PML risk becomes too high and then be at risk of a rebound effect, Rituximab sounds infinitely preferable to Natalizumab? Am I missing something here? (other than the fact Ritux isn't licensed/is expensive).
Ritux. hasn't had phase 3 trials. Ph 2 trial results were good but nobody can be confident about saferty and effectiveness without Ph 3 trialscost-wise it's better than anything else, at least in my part of the world – less than one third that of nartalizumabbut off-licence so it may be dificult to get insurance coverage
I read an article- can't remember where-that said the drug company was not going to go any further with rituximab for MS as it was off patent. Instead, they were developing ocrelizumab as it would be worth it bearing in mind the cost of drug trilas. The only problem was, ocrelizumab wasn't as safe as rituximab.
It was neuroimmunology.wordpress.com- I ggogled rituximab and MS and it was the first article that came up- the shameful story of rituximab