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#053: EBV Insights. Shedding Light on Its Impact on MS with Prof. Dr. Christian Münz

EBV, the Epstein-Barr virus, and its influence and impact on multiple sclerosis has long been a subject of interest to Dr. Christian Münz. As Professor of Viral Immunobiology at the Institute of Experimental Immunology at the University of Zurich, he has contributed to the latest studies and research findings that show a strong link between EBV infection and the subsequent development of MS. We talk about how certain the theory is, what mechanisms of action are suspected and what future treatment strategies could result from it. After all, EBV is extremely widespread and only a small proportion of the population suffers from MS.

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[00:00:00] Nele Handwerker: Hello Christian, it’s such a pleasure to have you on the show, and I send a hello to Zürich in Switzerland.

[00:00:07] Christian Münz: Hello Nele, how are you?

[00:00:09] Nele Handwerker: Good, how are you? Before we start with the interview, it would be lovely if you could introduce yourself to the audience, so they know who is with me on the podcast today.

Introduction – Who is Prof. Dr. Christian Münz?

[00:00:19] Christian Münz: Yes, for sure. My name is Christian Münz, I’m co-director of the Institute of Experimental Immunology at the University of Zürich. I studied originally biochemistry in Tübingen and then did a long period of research in New York at The Rockefeller University before, in 2008, I returned to Europe to my current position in Zürich. And I’m married, I have two children and a cat. And my hobbies are sailing and anything outdoors that Switzerland offers.

[00:00:54] Nele Handwerker: Okay, nice. So, you’re sailing on Lake Zürich.

[00:01:01] Christian Münz: Whenever there is wind, which is the main limiting factor of the Zürich Lake.

[00:01:06] Nele Handwerker: Yes, but you can go probably somewhere for vacation and do a bit longer trips.

Personal motivation for your career choice?

[00:01:16] Christian Münz: I’m fascinated by the plasticity of the immune system. How our body is able to reject all kinds of foreign substances. And this immune system has obviously developed in the context of mostly infectious diseases, so viral and bacterial challenges. Therefore, my lab study is primarily indeed exactly this interaction of our very versatile immune system to one particular virus, mostly the Epstein-Barr virus.

[00:01:48] Nele Handwerker: Okay. And before we dive deeper into the Epstein-Barr virus and its mechanisms and correlation with MS, I would like to talk a little bit more about this virus.

EBV and its significance

What is the Epstein-Barr virus (EBV) and how prevalent is it in the population worldwide?

[00:02:06] Christian Münz: Yes. The Epstein-Barr virus is a very successful pathogen in humans. It infects more than 90 percent of the human adult population. In many geographical regions in the world, it infects very early. For example, in Africa infection is usually widespread, so more than 90 percent already after a few months after birth. While here in Europe and the U.S. a third of individuals have a delayed primary infection, so experience the infection later in life, usually between ten and 20 years of age. 

And once Epstein-Barr virus infects it establishes a persistent latent infection, so we carry it for life. But even though it’s a virus that might initially seem a little bit threatening, our immune system, during co-evolution with this pathogen that is around, probably due to or during all human evolution, immune system has learned to control it to near perfection. Most of us will not realize even that they originally got infected and most of us will not realize that we constantly carry it with us.

[00:03:18] Nele Handwerker: Yes, unfortunately, I had a typical Mononucleosis when I was 14. But not as bad as my sister and my sister doesn’t have MS luckily, it’s a complicated story.

What are the health implications of an EBV infection in people?

[00:03:36] Christian Münz: Unfortunately, EBV causes quite severe diseases in a subset of infected individuals. It was the first human tumor virus discovered. It was 1964 discovered in a disease called Burkitt lymphoma which is very prevalent in Sub-Saharan Africa, in children five to nine years of age. So even in this region it affects very few of the infected individuals.

But in the context of other environmental factors, in the context of the individual genetic makeup that each one of us carries, it can cause quite severe disease. And it causes basically these tumors, of which Burkitt lymphoma is one example, but it also causes immune pathologies, when the immune system overshoots in response to the Epstein-Barr virus. One transient disease is indeed Infectious Mononucleosis. And then there’s also diseases like Chronic Active EBV and HLH. So hyperactivations of the immune system that can be life-threatening.

[00:04:46] Nele Handwerker: And if I remember a German interview with Henri-Jacques Delecluse correctly, I think it’s like two percent of all cancer infections are caused by EBV. It’s quite severe in, or quite important as well, in the cancer research.

[00:05:07] Christian Münz: Definitely.

[00:05:08] Nele Handwerker: Okay, so…

[00:05:09] Christian Münz: And particularly, EBV can enter cells that we are not that clear how it enters. It causes a lot of Nasopharyngeal carcinoma and gastric carcinoma, especially in Asian populations. And there EBV causes quite sizeable numbers. Around two-thirds to three-quarters of all EBV-associated tumors fall in this category.

[00:05:34] Nele Handwerker: Oh, wow. Okay. So that’s a lot. Let’s talk a little bit more about the relationship between EBV and MS.

Relationship between EBV and MS

What is the connection between EBV and multiple sclerosis (MS)?

[00:05:46] Christian Münz: It seems like, even though this connection is still under investigation, but it seems like that Epstein-Barr virus, under certain environmental factors and under certain genetic predispositions, can actually kick off a preclinical phase of autoimmunity in the central nervous system. This preclinical phase, seems from epidemiological studies, lasts several years. So, it can last five to ten years before then the disease manifests clinically. It could very well be the trigger that is absolutely required for the development of MS, but fortunately still it triggers this disease in a small subset of infected individuals.

[00:06:41] Nele Handwerker: Yes, that’s good.

Are there indications of a direct dependency between EBV and MS?

[00:06:53] Christian Münz: Right. Indeed, in longitudinal studies it was suggested that, or was found, that every individual that develops MS gets infected by EBV with exactly this time period of five to seven years on average before onset of MS. And in EBV negative individuals, even though these are obviously very rare because more than 90 percent of the population carries EBV, MS disease is virtually absent, suggesting that one of the factors that needs to fall in place for MS development is indeed an EBV infection. 

These longitudinal studies I think are the strongest evidence for this connection. And then there are maybe more difficult to interpret factors, so that the EBV-specific immune response is altered in MS patients. We see also that certain parameters of the EBV-specific immune response fluctuate with disease and relapsing remitting MS. And it was even suggested that EBV infection might spread to organs including the central nervous system and that might be associated with MS.

[00:08:22] Nele Handwerker: Okay, now you have talked about the arguments that support dependency. But there are probably still some arguments that are against that theory.

What arguments support such a dependency, and what arguments are against it?

[00:08:33] Christian Münz: Yes. I mean the argument that one hears most is, you know, indeed what we discussed beforehand, how can it be that such a widespread infection would cause a fairly rare, still very prevalent but fairly rare autoimmune disease? And this argument I think is the strongest argument against Epstein-Barr virus being such a prevalent or widely distributed pathogen in the human population.

[00:09:03] Nele Handwerker: Okay.

What are the remaining open questions

[00:09:10] Christian Münz: Yes, so, the main question obviously, that especially patients probably would like to know, if indeed EBV is one of the triggers and does it help us to know that? Is it still important at the time when the disease clinically manifests itself? What are the mechanisms by which EBV would contribute to the disease? And can we do something against it? Can we learn something from this connection that could be therapeutically useful? 

Because in other EBV-associated diseases we have unfortunately seen that for example in Hodgkin’s lymphoma 50 percent are EBV-associated. But the treatment of EBV negative Hodgkin and EBV positive Hodgkin is the very same. Then the knowledge that EBV is in a subset of the tumors does not really help. And hopefully, there’s a method that will be different. But we have to first see what the mechanisms exactly are and how therapeutically we can intervene.

[00:10:21] Nele Handwerker: Okay, so let’s come to that interesting topic of treatment strategies and progress.

Treatment strategies and progress

What treatment strategies emerge from research for MS concerning EBV?

[00:10:32] Christian Münz: Yes. There are two main hypotheses how this virus could be connected to MS. One is that EBV infection triggers an immune response, and this immune response cross-reacts on antigens or parts of the brain. And therefore, EBV infection would trigger a pathogenic process, a pathogenic immune response that would then go on and develop the disease. 

In this instance or if that is the case then tolerogenic approaches either, you know, targeting specifically this cross-reactive immune response could be helpful. The other hypothesis is that EBV infection allows the immune system to continuously stimulate autoimmunity by virtue of the infection being less well controlled. So that one could think of the infection causing inflammation in the central nervous system, maybe even some EBV infected cells go directly into the brain. If that would be the case, then targeting these infected cells and eliminating their both inflammatory potential but also how they in general drive forward an autoimmune response would be the therapeutic strategy. 

What is a little bit attractive about the second hypothesis is that indeed therapies that deplete the main host cell of Epstein-Barr virus, the human B-cell, are, have proven in the past, quite successful in multiple sclerosis. One hope could be that we learn through this connection with EBV infection to characterize this B-cell compartment or these B-cells in more detail and then just delete those pathogenic B-cells that EBV infection drives and therefore do not have to eliminate a large part of the immune system in general.

How advanced are the developments in measures to prevent EBV or limit its effects in the body?

[00:12:47] Christian Münz: Yes. An EBV vaccine seems to be indeed maybe around the corner. There are several centers and companies that work on it. There’s a large program at the National Institute of Health in the United States. Moderna has also dedicated quite a bit of resources to Epstein-Barr virus vaccination. And in both of these center’s phase one clinical trials have been started and in part even completed, and phase two clinical trials are started. So, these vaccines will probably become available within the next years and then we’ll have to see if that is actually the type of manipulation that would indeed be beneficial to prevent MS generation.

Which groups of people would benefit most from such measures?

[00:13:52] Christian Münz: That is a very good question. And I mean the initial trials will be in individuals that have at late age not experienced Epstein-Barr virus infection yet. Because they have a very high frequency past, you know, the second half or the second decade of life, so past 50, and often these frequencies are between 30 and 50 percent. 

Prevention of Infectious Mononucleosis will probably be the first target. And then, once these vaccines prove sufficiently powerful enough to achieve that goal, then one can think of extending that to other patient populations. And if indeed the lack of immune control of EBV that drives or continues to drive maybe inflammation and immune system stimulation is a mechanism by which EBV contributes to MS, then one could also think that even therapeutically such vaccines could help because they could then strengthen the EBV-specific immune control.

How long would it likely take to see significant progress in treating EBV?

[00:15:03] Christian Münz: Yes, so if these vaccines… The good thing about EBV is a little bit, we have quite a bit of tools to actually treat EBV. So, the very first treatment against for example these EBV-associated tumors were indeed T-cell lines. Parts of the immune system that were stimulated and then given back to the tumor patients. For example, a patient that had received a transplant and because of that they were immune suppressed and couldn’t control Epstein-Barr virus very well, so that they also got these T-cell lines. 

We have this knowledge how these EBV-specific T-cell lines can be used. Now we start to have knowledge how vaccine formulations might trigger EBV-specific immune responses. So, we will have I think within a few years quite an extensive set of tools how to manipulate EBV infection. And the challenge is more to figure out which of these manipulations would be best for MS patients, what is exactly the mechanism by which EBV leads to that CNS autoimmunity and therefore choose the right intervention to take.

What potential risks are associated with measures against EBV?

[00:16:25] Christian Münz: Yes, so, the biggest risk maybe is indeed that if this first hypothesis that I mentioned, so basically this cross-reactive immune response, would be the main mechanism by which EBV contributes to multiple sclerosis. Then one needs to avoid stimulating with any immunomodulatory treatments this cross-reactive response. 

Because in the worst case it would make the disease more severe. Therefore, unfortunately, we’ll probably still have to define in detail the immune response that could be harmful versus the immune response that could be beneficial to treat EBV. These studies have already started, so it’s pretty clear that maybe a particular portion of an EBV antigen could be avoided or maybe should be also avoided in those vaccination trials. But maybe more information or most likely more information along these lines is needed.

[00:17:35] Nele Handwerker: Well then, let’s talk a little bit more about research and the challenges that come with it.

Research and challenges

How challenging is it to develop effective countermeasures against EBV, and why?

Nele Handwerker: Because from that earlier German interview I remember Professor Henri-Jacques Delecluse said that they are doing research since, I think it was 40 years for finding an EBV vaccination and at least the last 40 years they weren’t successful.

[00:18:06] Christian Münz: Right. Yes, so, the challenge comes with that it’s a pathogen that only infects humans. There are viruses that are somewhat related and close in evolution in monkeys but unfortunately nothing similar beforehand other than smaller mammals. Therefore, the challenge with pathogens like EBV is always that what do we take as a model system where we can vaccinate and then see that the vaccine-induced immune response that we have elicited leads to protection from EBV infection or leads to protection from EBV-associated pathologies. 

And with that we still struggle. We’ve gotten a little bit better. So, we know that experimental systems where we actually put some human immune cells into mice and then vaccinate those or transfer the immune response that we have elicited with a vaccine in other mice, influences an EBV infection. But it’s models that are quite labor-intensive. Maybe also in immunology we have not developed them as rapidly as other preclinical systems. But this is a challenge. Because upon vaccination one can easily measure, as we know from the COVID pandemic, antibody, and T-cell responses. But we need sort of some system that gives us confidence that these responses are strong enough to withstand the virus and allow the virus not to develop any pathologies.

 

[00:19:48] Nele Handwerker: Okay. And let’s go a step back.

What role do environmental factors play in the spread of EBV and MS?

[00:19:58] Christian Münz: Environmental factors are probably still a large contributor to how EBV infection is perceived by our immune system. Because genetic contribution to MS is probably rather on the 20 to 30 percent range. These are studies basically in mono-psychotic twins, where fortunately for the twin, it is not that frequent that both develop the disease. When one thinks of, you know, that the twins have usually grown up in the same environment, at least during the first years of life, the contribution of the genetic makeup might even be less than these 20 to 30 percent. 

Then there’s a large contribution of environmental factors. And EBV seems to synergize with genetic risk factors. But probably synergies in the same way with this large, maybe a little bit black box of other environmental factors. And it is indeed the challenge to figure out what are the synergies that EBV then piggybacks on to develop this disease. Our immune system is a little bit an imprint of our history, right? Basically, it’s an imprint of our ancestral history, so the genes. 

But it’s also an imprint of all the environmental challenges, other infections that we have seen over time. And we know for some diseases, like this Burkitt lymphoma in which EBV was originally discovered, that it only occurs in holoendemic malaria regions. Coinfection with malaria, this one parasite that causes malaria, is quite important for the disease to develop. Similarly, other environmental factors are probably responsible for that EBV then causes, in a small subset of affected individuals, the disease. And deciphering them would obviously be very, very helpful. But maybe if you have a fairly safe EBV vaccine, that is not even necessary. 

So, then we would give the safe EBV vaccine rather to a larger proportion of the population and then allow protection from MS. We know that there’s an age distribution or age dependency on Infectious Mononucleosis, it’s a disease of overshooting immune response that occurs only later in life. Unfortunately, even though we study EBV since 64, 1964, we still don’t know what the reason is for why Infectious Mononucleosis affects all the individuals.

People have argued, okay, it’s other immune responses that have developed beforehand and they just get re-stimulated by the infection, therefore they go berserk. Or it could be that the infectious dose is different. So, there are many hypotheses, but again this suffers a little bit from the fact that EBV is a human-tropic virus, so only infects humans, and therefore modelling Infectious Mononucleosis has not been easy.

[00:23:21] Nele Handwerker: Yes, and I remember when we had it in the multiple sclerosis management master’s program that I think if you have really radical Mononucleosis it’s like 50 percent of all your spreading immune cells are trying to control EBV infections, so really extreme reaction.

[00:23:45] Christian Münz: Yes. Yes, in humans I would even say it is the pathogen that triggers the strongest T-cell response. Exactly for that… I mean based on the expansions that one sees in Infectious Mononucleosis. And all the secondary lymphoid tissues like the tonsil, the spleen swell up. In the sort of peak phase of IM often the recommendation is also to not do any sports because any hit to the spleen could cause trauma and then rupture and severe side effects. For us in Switzerland the example for that is always Roger Federer. Because Roger Federer had to pause at one point in his tennis-career because he had Infectious Mononucleosis and was recommended not to play.

[00:24:31] Nele Handwerker: Okay, yes. Yes, as I said, my sister was shortly before going into hospital. She was 18 and I had it with 14. For me it was not as bad. I just had a little bit swollen lymph nodes but not as bad. Yes. An ugly virus.

What hopes and challenges do you see for the future of research on EBV and MS?

[00:25:00] Christian Münz: The hope is indeed that this knowledge how EBV is connected to MS allows us to refine or maybe even newly develop therapies. I think especially building on our knowledge already on the B-cell depleting therapies and then maybe identifying a subset of B-cells that is driven by EBV infection, either through direct infection of these cells by EBV or as a part of the immune response against EBV. 

We hope that knowing this sort of cross-section between these two phenomena, the EBV infection and the successful therapy, we might be able to very efficiently just go after this small subpopulation of B-cells that might be pathogenic. And if that would be the case then we could indeed allow the immune systems of MS patients to be less compromised by the treatment and maybe be still as efficient as with the B-cell depleting therapies.

[00:26:06] Nele Handwerker: That would be lovely.

Quickfire Q&A Session

Complete the sentence: "For me, multiple sclerosis is...."

[00:26:15] Christian Münz: A rare complication of Epstein-Barr virus infection.

[00:26:20] Nele Handwerker: From your point of view, yes, I totally understand that one. And at ECTRIMS they were very, let’s say, I’m coming from marketing side, and I think it was very marketing style talking about the second hit. First hit is Epstein-Barr virus, but what is the second hit? And if we could find out or get rid of the first hit, then probably we could get rid of MS at all. Would be lovely.

What development would you like to see in the field of multiple sclerosis in the next 5 years?

[00:26:52] Christian Münz: A refinement of the therapies and maybe also then if this refinement just targets a smaller subset of immune cells, a deeper depletion or deeper elimination of that subset. Because I think we are struggling a little bit with the fact that there’s still somewhat underlying progressive disease, not relapsing remitting fortunately anymore, but still some progression. And from other autoimmune diseases one could think that a more efficient elimination of the pathogenic process, maybe a deeper depletion of the pathogenic process could be very beneficial. So yes, more refined, but then in the refined targeting maybe more efficient.

[00:27:48] Nele Handwerker: Sounds good.

Farewell

Finally, what message of hope or encouragement would you like to share with the listeners?

[00:27:58] Christian Münz: As one has seen in the past years or decade, there are more and more treatments that were developed against multiple sclerosis. This has shown that indeed it is a disease that disease modifying treatments can be developed. And the better we understand that the more we identify the factors that are involved in the disease, that will allow to develop new therapies. So, I think the message of hope is that indeed we might be able to be a little bit more specific in our treatments and more refined in our treatments so that quality of life stays high, but suppression of disease is still quite efficient.

[00:28:53] Nele Handwerker: Sounds good.

How and where can interested people follow your research activities?

[00:29:06] Christian Münz: Yes, so mostly on the website of our institute. Unfortunately, I’m not that much into LinkedIn and Instagram, so therefore I have to point towards mostly the website of our institute where we publish our new findings and have links more or less to our new research studies.

Christian Münz on PubMed

[00:29:27] Nele Handwerker: Fantastic. And of course, I will place that link in the show notes and the blog article, and of course a link to PubMed for the ones that want to dive really deep into research topics. Yes, Christian, thank you very much for that interesting interview about Epstein-Barr virus and let’s hope, fingers crossed, there will be soon positive outcomes and that at least for the next generation there will be less prevalence of Epstein-Barr virus and MS. And maybe even for us, a better understanding for the ones that already live with the disease would be lovely. Thank you very much.

[00:30:12] Christian Münz: Yes, thank you very much, Nele.

[00:30:13] Nele Handwerker: Bye-bye.

[00:30:14] Christian Münz: Bye-bye.

See you soon and try to make the best out of your life,
Nele

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