EBV: is it time to pluck the black swan?

Barts-MS rose-tinted-odometer: ★★★★★
London Gray & Raining #666677 #C4D3DF

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.

Conflicts of Interest

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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. 

#MSCOVID19 info wars

It is one thing calling for scientists to turbocharge the development of a coronavirus vaccine but quite another to get the population to have the vaccine. The anti-vaxxers are organising rapidly and have started circulating content with false information to achieve their aims. The movie plandemic is one example and is covered in a very good article in the New York Times today.  

The primary reason I started this blog was to counteract anti-science movements and to provide people with MS and their families a rational interpretation of MS-related research. It is interesting to note that there is now good data science to show how anti-science movements, despite having very few initial supporters, get their message across and sow enough confusion to get undecided people to support their movement. 

What I find fascinating, albeit scary, is how dynamic and multifaceted the anti-vaccination campaigns are, which explains their explosive growth in recent times (see figure and paper below). It also shows how gullible people are in general. The study below highlights why we scientists need to fight back using the same tactics. Simply sitting in our ivory towers using traditional media and unidirectional channels will not be good enough to fight the anti-vaccination and other anti-science movements. 

I have a vested interest in this. One of our lines of research is to use an anti-EBV vaccine to prevent MS. If people don’t want vaccines how are we going to get this prevention strategy adopted by funders, ethics committees and more importantly the general population? 

Can you help? Yes, please help fight fake news, by reporting it and calling it out for what it is. And don’t believe the fabricated conspiracy theories that are peddled to support these anti-science movements. The vast majority of conspiracy theories are wrong.

Image from Johnson et al. The online competition between pro- and anti-vaccination views. Nature published: 13 May 2020.

Johnson et al. The online competition between pro- and anti-vaccination views. Nature published: 13 May 2020

Distrust in scientific expertise is dangerous. Opposition to vaccination with a future vaccine against SARS-CoV-2, the causal agent of COVID-19, for example, could amplify outbreaks, as happened for measles in 2019. Homemade remedies and falsehoods are being shared widely on the Internet, as well as dismissals of expert advice. There is a lack of understanding about how this distrust evolves at the system level. Here we provide a map of the contention surrounding vaccines that has emerged from the global pool of around three billion Facebook users. Its core reveals a multi-sided landscape of unprecedented intricacy that involves nearly 100 million individuals partitioned into highly dynamic, interconnected clusters across cities, countries, continents and languages. Although smaller in overall size, anti-vaccination clusters manage to become highly entangled with undecided clusters in the main online network, whereas pro-vaccination clusters are more peripheral. Our theoretical framework reproduces the recent explosive growth in anti-vaccination views, and predicts that these views will dominate in a decade. Insights provided by this framework can inform new policies and approaches to interrupt this shift to negative views. Our results challenge the conventional thinking about undecided individuals in issues of contention surrounding health, shed light on other issues of contention such as climate change, and highlight the key role of network cluster dynamics in multi-species ecologies.

CoI: we are planning to do an anti-EBV vaccine study to prevent MS

Pathways to Cures

Barts-MS rose-tinted-odometer ★★★★★ 

I am en route to a ‘Pathways to Cures’ meeting in Washington DC hosted by the National MS Society. The aim of the meeting is to refine the ‘Stop, Restore, and End Pathways’ for MS and to develop an international consensus on what an MS cure looks like. I am honoured to be invited to participate in this meeting and would like to thank the NMSS for inviting me. 

As always I feel like an imposter; a neurologist who dares to dream about being a public health doctor hoping to someday be in a position to say we have prevented MS, at least in a proportion of people. 

Only yesterday I read a very inspiring essay in the New England Journal of Medicine by Sonia Vallabhm who carries a rare genetic disease that at some stage of her life will strike her down and result in her dying of fatal brain disease at a relatively young age. Instead of accepting her fate her and her husband have retrained as scientists to study her disease so as to prevent its consequences. 

So many of the messages in her essay resonate with what we are trying to do in MS I, therefore, took a writer’s liberty of paraphrasing her essay from an MS perspective. Apologies about the blatant plagiarism; I hope Sonia and the NEJM will forgive me! 

If you have time please read her essay before reading my ‘fictional’ take on her messages. Sonia’s writing skills are clearly superior to mine, but the issues she raises are very clear. If you are at risk of a preventable disease that destroys the brain, why wouldn’t you want to know about being at risk of acquiring the disease in question and why wouldn’t you want to prevent the disease? 

Sonia Vallabh. The Patient-Scientist’s Mandate. N Engl J Med 2020; 382:107-109.

Eight years ago, at the age of 24, I learned that I had a 1 in 4 chance of developing multiple sclerosis. In response, I left my fledgeling career in law to retrain in biomedicine. Starting in night classes and entry-level laboratory jobs, I earned a PhD in biomedical research in the spring of 2018. I now have an established research group focused on the prevention of MS.

There is a proud tradition of activated patients driving science. Fellow travellers of this path may be familiar with the kinds of questions I fielded from day one, in particular, whether it was appropriate for patients, or potential patients, to work on their own disease. 

My goal is prevention: to preserve at-risk brains, including mine, in full health. MS is a silent disease advancing slowly: the average patient with MS is unemployed 10 years after diagnosis, in a wheelchair by 20 years and has their life expectancy clipped by about 8 years. To the best of my knowledge, there have been no prevention trials. Previous clinical trials targeting so-called prevention have focused on preventing the second clinical attack, i.e. the conversion from clinically-isolated syndrome (CIS) to clinically definite MS (second attack), have generally confirmed the known efficacy of licensed disease-modifying therapies. However, predictive or at-risk testing provides an opportunity, and arguably a mandate, to aim for a higher goal: preservation of brain function and ultimately the full quality of life. This is important as a lot of brain tissue and cognitive reserve is lost prior to the first clinical attack in MS. This is why I want to prevent developing MS. 

Because at-risk people have no clinical symptoms testing drugs as a primary prevention strategy based on an MS risk score will require testing drugs in normal people. This realization has defined my priorities for the past 5 years leading me to focus on EBV the likely cause of MS; in particular, EBV vaccination and the treatment of infectious mononucleosis. These treatment targets require a biomarker that can reflect vaccine and drug activity without a definite MS phenotype. My research programme has highlighted many other issues, for example, the need for validated tools for quantifying MS risk in the general population; appropriate recruitment infrastructure (high-risk and population-based registers); defining the presymptomatic natural history of MS; and proactive engagement with funders, public health officials and regulatory agencies. As this list suggests, redefining the aims of drug and vaccine development to encompass MS prevention leads to many new research goals and widens the relevant stakeholders we need to engage with. 

In the area of MS prevention, it will take more than a  patient-scientist partnership to drive this shift. Perhaps there is something peculiarly clarifying about defining success by honestly answering the question “What would you want for your own brain?”.

My assessment of plausibly relevant approaches was guided by my bottom line: Which approach would face the smoothest path to a first-in-human trial in healthy people at high risk of developing MS?

Guided by practicality, in 2017 we hosted a task-force to develop an MS prevention strategy (see PDF below). The potential for EBV vaccination to prevent MS was endorsed by all participants. Three years on, the building blocks of this program are advancing towards a clinical trial. The progress is slow, very slow, but we will get there. 

On the patient side, an emerging task is to rally people who are at risk of developing MS. Currently, very few of those at known risk of developing MS is seeking prevention strategies. Many are counselled against seeking this information because an unlucky result is not actionable at present. I understand this argument, but there’s more to actionability than meets the eye. To succeed in the clinic, we will need to rally supporters behind a counternarrative, one that honours the opportunity that at-risk individuals have to contribute to rewriting the collective future of people with MS. This reframing will not persuade everyone at risk, but it will resonate with some. And, especially when dealing with an uncommon disease, every person matters; every voice matters.

For me, the journey from patient to scientist continues to reaffirm that pursuing at-risk testing was the right choice for me and my family — a decision that continues to empower me in new ways as the years unfold. 

I still occasionally encounter the concern that there is a conflict of interest inherent in researching your own potential disease. But far from seeing a conflict of interest, I see an exquisite alignment of interests as I work with mentors and allies toward a trial testing a vaccine and/or drug I hope to take myself, to prevent the disease that threatens my and my families future.

CoI: multiple

To B or not to B

Is targeting the B-cell sufficient to get on top of MS or do we need something extra?

I spoke at the MS Nurses’ MS@TheLimits2019 meeting at the Royal College of Physicians yesterday. My brief was to cover the role of B-cells in the pathogenesis of MS and to review the converging evidence that supports B-cells being the central player in the pathogenesis of MS.

It is clear that depleting B-cell therapies are very effective in controlling relapses and MRI activity. With a very favourable safety profile and relatively low treatment and monitoring burden, B cell therapies are likely to become one of the most widely prescribed classes of DMT. However, B-cell therapies don’t match HSCT, alemtuzumab and natalizumab when it comes to downstream end-organ damage markers, in particular, brain volume loss. Why? I wish I knew. But if I knew the answer to this question I would have a pretty good idea about the cause of MS.

A clue may be in the ‘Field Hypothesis‘. It is clear to me that relapses and focal MRI activity are not the primary events in MS. Focal inflammation is not MS. Focal inflammation is in response to what is causing MS and the cause is likely to be something in the CNS. Focal changes occur in the white matter weeks to months before you get a Gd-enhancing lesion. When you stop natalizumab and allow re-trafficking of lymphocytes you get rebound disease activity way and above what one would expect from pre-treatment baseline levels of disease activity. What is happening in the brain, or field, of these patients to trigger such a vigorous inflammatory response? Could it be a virus? Importantly, B-cells appear to be needed for the rebound response. Rituximab, and I suspect ocrelizumab, are very effective in preventing rebound. However, as both these agents target a small subset of T-cells you can’t claim categorically that the rebound is only driven by B-cells.

The difference between HSCT, alemtuzumab and natalizumab and the anti-B cell therapies (rituximab, ocrelizumab and possibly cladribine) is the former take out or inhibit trafficking of both T & B cells. As HSCT and Alemtuzumab have the best data in relation to long-term remission, or potential cures, you have to conclude that you need to target both B cell and T cells (substantial peripheral depletion) if this is your treatment aim.

Please note that I classify cladribine as a B-cell depelter and not a dual B and T cell depelter. The level of T-cell depletion with cladribine is modest at the licensed dose (~50%) which is not sufficient to put it into the same class as alemtuzumab and HSCT. This is one of the reasons why I refer to cladribine as being a SIRT (selective immune reconstitution therapy) and the others as NIRTs (non-selective immune reconstitution therapies).

I have always made the point that to treat MS you need much more than an anti-inflammatory and that you also have to have neuroprotective therapies and potentially remyelinating agents on board as well. If you have disabilities we need to be thinking about neurorestorative therapies and finally you need to target lifestyle and wellness to tackle the issue of comorbidities and ageing.

So in short, targeting B-cells is important, but not sufficient to get on top of the shredder.

You will see that a large part of my talk was covering the link between EBV, B–cells and MS. The B-cell hypothesis at least strengthens the case for EBV being the cause of MS and the need for an EBV vaccine for MS prevention trials. Please don’t forget that EBV lives inside memory B cells and hijacks the B cell’s biology in many ways that have potential relevance to MS and other autoimmune diseases.

My talk will be available online in a few weeks to help you interpret my presentation. In the interim you can download my talk from my slide sharing site.

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