On post-viral sequelae
January 25, 2022 12:29 PM   Subscribe

Results of a 20-year study have established a causal link between the Epstein-Barr virus and Multiple Sclerosis.

Multiple Sclerosis (MS) is a debilitating progressive autoimmune disease of unknown etiology, in which myelin, the insulation sheath that is crucial to nervous system function, degrades. While viral triggers have been previously suspected, a link had not yet been established.

The core problem was this:

Epidemiologists: "Epstein-Barr infection is so common, and MS relatively rare, so we'd need to monitor millions of people for decades to see if there's an association."

Funding agencies: "Not feasible"

Military: "Hold my beer"


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Active-duty members are screened for HIV during military service, and residual serum from these tests (>62 million serum samples) is archived by the Department of Defense. From those, Bjornevik et al. identified 5.3% as negative for antibodies to the Epstein-Barr virus (EBV), yielding in a cohort of hundreds of thousands of EBV-negative young adults.

The meat of the study focused on 801 from that cohort who were diagnosed with MS during their period of service. Only one of the 801 MS cases occurred in an individual who was EBV-negative. Compared to a control cohort, this represents a 32x increase in risk for development of MS. Median time from the first EBV-positive sample to MS onset was 5 years. The same comparison run for cytomegalovirus returned no additional risk for MS, and no other confounding factor, including a gene mutation linked to a 3-fold increased risk, came close.

Risk of MS was not increased after infection with other viruses, including the similarly transmitted cytomegalovirus. No other virus needed: the occurrence in MS cases was much higher for EB than 13 other viral controls clearly stood out, both prior to and after MS onset. Serum levels of neurofilament light chain, a biomarker of neuroaxonal degeneration, increased only after EBV seroconversion. These findings cannot be explained by any known risk factor for MS, and establish EBV as the leading cause of MS.

The paper, from Bjornevik, Cortese, Healy, Kuhle, Mina, Leng, Elledge, Niebuhr, Scher, Munger and Ascherio, appeared in Science, 13 Jan 2022. Also see the Perspective, from Robinson and Steinman.

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Aside from the catch-all post viral syndrome, other well-known post-viral sequelae include shingles (chickenpox), the "sleeping sickness" encephalitis lethargica (Spanish flu), atypical polio (diptheria), post-polio syndrome (polio), and subacute sclerosing panencephalitis (measles). A viral cause remains a strong possibility for chronic fatigue syndrome.

And now there's Long Covid.
posted by Dashy (41 comments total) 42 users marked this as a favorite
 
Epstein-Barr is the virus behind the common disease mononucleosis. It's estimated that 90% of Americans are infected with it by age 35.
posted by Dashy at 12:35 PM on January 25 [12 favorites]




It's great to see the long term effects of viral infections getting more research. It's bizarre how we've gone from polio (which is incontrovertibly a long-term illness due to a viral infection) to pretending that you either get better or die, with no in between, over the last 60 years. I hope this helps push forward research on long Covid, Lyme, ME/CFS and all the other post-infectious diseases.

I'm not convinced that EBV is a leading cause of MS. Seems you could equally say that EBV is a necessary condition for developing MS, because clearly the overwhelming majority of people who get EBV don't develop MS.
posted by ssg at 12:48 PM on January 25 [16 favorites]


An mRNA vaccine for Epstein-Barr has entered its phase one trial, building on the success of Moderna's vaccines against COVID.

So, I suppose, if one good thing comes out of this mess.. maybe we'll see a vaccine for this thing in our lifetimes.
posted by fight or flight at 12:50 PM on January 25 [23 favorites]


I really enjoyed your write up Dashy. Thanks for the added context.
posted by now i'm piste at 12:58 PM on January 25 [13 favorites]


When I did a search for Epstein-Barr and MS, I was surprised that it was another study from the last couple of days that came up first: Clonally Expanded B Cells in Multiple Sclerosis Bind EBV EBNA1 and GlialCAM. In normal words, Study Explains How Epstein-Barr Virus Infection Could Cause MS.
posted by clawsoon at 1:17 PM on January 25 [3 favorites]


Actually the link they found is not causal, it is correlational. And it is not a perfect correlation. One person in the study group contracted MS without EBV infection.
posted by storybored at 1:27 PM on January 25 [8 favorites]


We don't know they didn't get an EBV infection until after their blood sample was taken - following that up on that one case and seeing if they now test positive would be an interesting thing
posted by mbo at 1:33 PM on January 25


EBV seems to cause a little bit of everything, doesn’t it?
posted by atoxyl at 2:02 PM on January 25 [1 favorite]


Actually the link they found is not causal, it is correlational. And it is not a perfect correlation. One person in the study group contracted MS without EBV infection.

The study addresses that like so:
One MS case was EBV-negative in the last sample, obtained 3 months before MS onset, which could suggest that EBV was not the cause of disease in this patient. This individual could have been infected with EBV after the last blood collection, could have failed to seroconvert in response to infection (an uncommon but nevertheless regular phenomenon seen after infections and vaccines), or could have been misdiagnosed. Another explanation is related to etiological diversity, which is common for any clinically defined disease. For example, all cases of paralytic poliomyelitis are by definition caused by poliovirus, but rare cases of acute flaccid paralysis, clinically indistinguishable from poliomyelitis, can be caused by other enteroviruses (34). The extremely low MS risk in EBV-negative individuals suggests that by far most MS cases are caused by EBV and could thus potentially be prevented by a suitable vaccine.
posted by BungaDunga at 2:07 PM on January 25 [21 favorites]


This is really interesting! Like storybored, I hope we see more research on what makes the difference between folks who are diagnosed with MS (global prevalence estimated in 2020 at 35.9 per 100,000 population*) and the other 99.96% of people who live their entire adult lives infected with EBV (estimated at 90% worldwide).

EBV is implicated in other disorders as well, though also at very low rates: "It has been estimated that less than 1 percent of persons infected with Epstein-Barr virus (EBV) have central nervous system complications. These complications include encephalitis, Guillain-Barré syndrome, aseptic meningitis, facial palsy, transverse myelitis and Bell's palsy."

Clawsoon, I appreciate the possibility raised by that B Cells Bind GlialCAM study - the mechanism seems plausible and its discovery is cool! But the actual causal link isn't super clear-cut: both MS and non-MS patients had antibodies that target GlialCAM, and it's not made clear whether anti-GlialCAM antibodies were present in patients that did NOT have EBV antibodies. I look forward to learning more about this line of inquiry.

*I feel sure that the global prevalence estimate for MS is low! If non-EBV pathways to MS exist, that doesn't mean we shouldn't work on the EBV ones! Working on treatments for widely-prevalent pathologies which may contribute to rare but awful outcomes is great! Maybe eradicating EBV will be the great medical success of the 21st century.

I still feel nervy and hope medical and pharma researchers are keeping in mind the human history of acting against Unmitigated Bads or for Unmitigated Goods in ways that we're now coming to question - the intense use of internal and external antibiotics, e.g., to get rid of "germs". This example is not to say that antibiotics aren't a major leap forward for human (and, in some cases, non-human) flourishing! But that uncritical and overenthusiastic use of them contributes to building resistant strains of bacteria that are dangerous to us, and can damage healthy fellow-travelers in our bodily biomes and ecosystems.
posted by rrrrrrrrrt at 2:12 PM on January 25


As ssg says it looks like EBV is necessary but not sufficient for inducing MS. We probably still need to look for genetic predisposition. Like pretty much ALL European narcoleptics have the MHC variant DRB5*0101-DRB1*1501-DQA1*0102-DQB1*0602 (known to its friends as DQ0602) but so do 15% of the normal population so this immune variant is necessary but not sufficient. Mutations in the gene NRCLP1 which makes Orexin are also involved - banjaxed NRCLP1 means no orexin which is known to be the main mediator of sleep and arousal. An epidemic was triggered by by the Pandemrix 'flu vaccine in 2009/10 but only in a few people because the disease needs at least three rare-enough ducks in a row.
Back to MS, though: the highest rates epidemiologically are found in The Orkneys, Old Scotland and . . . Nova Scotia. Is that a genetic connection ?
posted by BobTheScientist at 2:14 PM on January 25 [5 favorites]


We probably still need to look for genetic predisposition.

If they develop a really good EBV vaccine it may not actually matter what the genetic basis is though, right? Once you've identified a necessary cause and build a mechanism to prevent it, that's game over for MS whether you know the whole picture in-between.

Obviously it would likely be useful to know the answer, but much less urgent than developing an EBV vaccine and following up for however long you'd need to make sure that it really does prevent MS.
posted by BungaDunga at 2:24 PM on January 25 [2 favorites]


Well if they can also link it to ALS it might sweeten the pot.
posted by Oyéah at 2:27 PM on January 25


A good EBV vaccine would be wonderful in and of itself. High school and college students who have mono often fail their classes and lose months of their lives to being sick.
posted by hydropsyche at 2:36 PM on January 25 [9 favorites]


And if I can squeeze myself into a green jersey, I'll mention that EBV was isolated from samples sent to Tony Epstein's London lab by Denis Burkitt, an evangelical Christian from Enniskillen who was doing missionary doctoring in Uganda after WWII. He noticed that the incidence of a disfiguring childhood cancer [Burkitt's Lymphoma] correlated with the rainfall pattern and suspected that mosquitos were transmitting a virus. Several batches of sample revealed no viruses until one shipment was delayed by fog and Yvonne Barr, the effective graduate student in Epstein's lab saw the tell tale signs of infection. She married soon after, emigrated to Australia and left science. But was alive to videolink for a 50 year retrospective in 2013. She died in 2016, but 2 years later, it turned out that she had been born in Carlow in 1931 about 1 km from the Tech where I was then working. We are campaigning to get the new science building named for her, rather than yet another Victorian patriarch.
posted by BobTheScientist at 2:41 PM on January 25 [34 favorites]


So.... ehm... given the ease of creating new mDNA vaccins (thank you, covid), and this... is it really a big ask to get a research project going as a long term project started with, well, you know...
posted by DreamerFi at 2:50 PM on January 25


...the highest rates epidemiologically are found in The Orkneys, Old Scotland and . . . Nova Scotia. Is that a genetic connection ?

"Nova Scotia" means New Scotland and the dominant genetic ancestry there is Scottish.
posted by 100kb at 3:00 PM on January 25 [2 favorites]


is it really a big ask to get a research project going as a long term project started with, well, you know...
. . . BITCOIN?!
posted by slater at 3:16 PM on January 25 [1 favorite]


So, I suppose, if one good thing comes out of this mess.. maybe we'll see a vaccine for this thing in our lifetimes.


EBV, HIV, Lyme disease.. the floodgates are open now.
posted by ocschwar at 3:18 PM on January 25 [4 favorites]


So.... ehm... given the ease of creating new mDNA vaccins (thank you, covid), and this... is it really a big ask to get a research project going as a long term project started with, well, you know...

Unclear what you want to vaccinate, but mRNA based HIV vax testing is already underway.
posted by pwnguin at 3:47 PM on January 25 [5 favorites]


An mRNA vaccine for Epstein-Barr has entered its phase one trial, building on the success of Moderna's vaccines against COVID.

EBV, HIV, Lyme disease.. the floodgates are open now.


We've been working on an HIV vaccine for 40 years now with no luck. None of the approaches worked. By contrast with Covid, many approaches work. It turns out to be a relatively easy thing to vaccinate against.

Whether mRNA can demonstrate it will help with the hard-to-develop vaccines is at best unproven. Not my field but I seriously doubt the Covid approach ("take the most obvious protein on the virus and use that as an antigen") would work with HIV, because variations have that is what we'd have been testing with the non-mRNA trials.

(There are other mRNA approaches and we should try them--but I wouldn't be surprised by years more of failed trials before we get a success--if we get a success.)
posted by mark k at 4:06 PM on January 25 [5 favorites]


The best connection being seen right now between a virus and ALS is Chronic Lymes. This would involve believing in Chronic Lymes which many folks do not.
But I am hopeful that with Long COVID we start to have more acceptance of the possibility of a viruses causing long term injury and debilitiation, even after it is undetectable, and then better research on it.
posted by mutt.cyberspace at 4:21 PM on January 25


Lyme disease is bacterial, no?
posted by mark k at 4:25 PM on January 25 [3 favorites]


Michael Mina (one of the authors above) just reminded Twitter of another sequelae of measles: immune system reset., where up to 80% of existing antibodies are erased, leading to an increased mortality rate in the years following infection.
posted by Dashy at 4:27 PM on January 25 [8 favorites]


This is really interesting, and I hope the vaccine is effective.
posted by Dip Flash at 4:28 PM on January 25


If they develop a really good EBV vaccine it may not actually matter what the genetic basis is though, right?

Well, if the vaccine is sterilizing so that you can actually stop a significant number of people from getting infected and you can convince enough people to get it (which might be possible in some parts of the world, but would be unlikely in, for example, the US or Central Europe), then maybe.

If it works only as well as our current Covid mRNA vaccines, then most people are still going to get infected. Then it all depends if someone who is vaccinated and then gets an EBV infection is equally as susceptible to MS as an unvaccinated person. Research to figure that out would take a couple decades, as you'd need to vaccinate kids and then follow them into at least their 20s to see if they get MS.

Probably a good idea to vaccinate everyone against EBV if the vaccine works anyways (even if it doesn't prevent infection that well, maybe it prevents serious mono and other post-infectious illnesses), but things would have to line up right even with a reasonably good EBV vaccine to prevent MS. I sure hope we have research that will tell us the causative factors faster than 20 years though!

People are still getting long Covid even with mRNA vaccines (some data shows prevalence might be lower for vaccinated people, but it's far from conclusive).
posted by ssg at 4:44 PM on January 25 [3 favorites]


Somewhat importantly, EBV isn’t nearly as infectious as something like COVID. 10% of adults manage not to get it.

A vaccine – even a thoroughly-mediocre one – could do a lot of good.
posted by schmod at 5:12 PM on January 25 [4 favorites]


I'm also very interested in a Lyme vaccine, as I live in Lyme country and I'm an outdoorsy sort.

We've already been working on shot ourselves in the foot over a Lyme vaccine. The short of a long story is that it was killed in the (previous) height of anti-vaxx fever.

There's presently a collaboration between Valneva (French biotech) and Pfizer for a Lyme vaxx, which has shown promising results in Phase 2 trials and could be available in 2025. Here is your reminder that vaccines *usually* take a while and we were insanely lucky with the current Covid vaxxes.

MassBiologics’ Lyme PrEP shot might be ready for FDA approval by 2024.
posted by Dashy at 5:15 PM on January 25 [13 favorites]


Lyme disease is bacterial, no?


mRNA vaccines are anti-anything.

The idea with mRNA vaccines is to figure out what's worth attacking with antibodies, encode it in mRNA, trick your body to produce some, and watch you make antibodies. They were testing the tech against cancers and Lyme disease for her a decade now, but without emergency use authorization, it was a slooooow process to get studies approved and launched. This method is good for anything where the body for whatever reason doesn't know what to attack and needs a cheat sheet.
posted by ocschwar at 5:23 PM on January 25 [7 favorites]


Good lord, I forgot another one. Cervical cancer is the result of HPV. Still blows my little mind that we can prevent cancer with a vaccine.

(also still blows my mind that some parents refuse it because it means confronting fact that their Precious might have sex someday).
posted by Dashy at 5:28 PM on January 25 [9 favorites]


Dashy, we also treat (though not prevent) some oral melanomas in dogs with vaccines.

I haven't kept up with the DFTD folks but bet they're still doing interesting work with trying to vaccinate Devils for DFTD too.

Transmissible cancer in Tasmanian devils: localized lineage replacement and host population response and Use of Oncept melanoma vaccine in 69 canine oral malignant melanomas in the UK
posted by esoteric things at 5:46 PM on January 25 [4 favorites]


I had no idea - how very cool!
posted by Dashy at 5:48 PM on January 25


The short of a long story is that it was killed in the (previous) height of anti-vaxx fever.

I just finished reading The Doctor Who Fooled The World, a ripping yarn I can heartily recommend to anybody interested in understanding the epidemiology of that particular fever.
posted by flabdablet at 6:49 PM on January 25 [1 favorite]


mRNA vaccines are anti-anything.

I was responding to a comment that I thought was saying it was viral, not saying it ruled out vaccination.

This method is good for anything where the body for whatever reason doesn't know what to attack and needs a cheat sheet.

It's not clear it's better than other techniques, though. If you can identify a crucial epitope you could presumably do it by recombinant protein too. It's possible (probable even) it'll be more effective in some cases, less effective in others.

I know the companies selling the technology make broad claims for easier development, but it's not like there are a lot of proven case studies--or how costs will work out.
posted by mark k at 6:51 PM on January 25 [2 favorites]


Somewhat importantly, EBV isn’t nearly as infectious as something like COVID. 10% of adults manage not to get it.

It definitely isn't, but in this study 98% of their (military) population has EBV antibodies by the end of the study. Maybe you're more likely to get EBV in the military, but no matter how you look at it there are very few people who manage to avoid EBV by the time they get to 40 or so (and even fewer if some people are infected but don't produce antibodies). So being able to significantly reduce the proportion of people infected would definitely depend on vaccine effectiveness against infection and transmission, how many people are willing to take it, etc. Any vaccine would have to be highly effective and provide durable protection to work.
posted by ssg at 7:26 PM on January 25 [1 favorite]


The NYTimes just published an article about the risk factors that may lead to long covid, and according to the study, EBV is one of them:

A third factor is the reactivation of Epstein-Barr virus, a virus that infects most people, often when they are young, and then usually becomes dormant.
posted by Dip Flash at 6:54 AM on January 26 [3 favorites]


My mom died of MS a few months ago, 40 years after she was diagnosed. I wouldn't wish this disease on my worst enemy. I remember hearing about the correlation between EBV and MS at a conference maybe 15 years ago; it's heartening to see that there is hope for a vaccine to save people from slowly degrading like my mom.

My dad got Parkinson's a few years after they divorced. He always suspected that there was a virus that she transmitted that gave it to him, since his identical twin brother doesn't have it. I wonder how many more neurological diseases are going to be found to be caused by viruses. My dad died about 5 years ago of the Parkinson's. I'm personally very scared that I'll get something similar to what my parents had.
posted by little king trashmouth at 7:10 AM on January 26 [6 favorites]


Yes - I woke up this morning with that very rememberance- hey, remember Lymes is a bacteria (a spirochete like Syphilis which are hard to kill). However... my larger comment stands. There is real potential to look at how vectors (virus, bacteria, maybe fungi, etc OR multiple vectors together) can cause long term damage that become debilitiating to a person later in life. I remain hopeful about that.
posted by mutt.cyberspace at 7:14 AM on January 26 [1 favorite]


Oncept is also used to treat melanoma in gray horses (melanoma is very common in gray horses and I don't know if horses of other colors get it at all)
posted by sepviva at 4:24 PM on January 26




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