Are you ready for an EBV vaccine to prevent MS?

"Professor Giovannoni, you tell me that my daughter has a 1 in 40 chance of developing multiple sclerosis and that MS has reached epidemic proportions in parts of the world? Is there anything I can do to reduce her chances of getting MS? Is there anything we can do to stop other people from getting MS?"

Although multiple sclerosis (MS) is a complex disease due to the interaction of genetic and environmental factors data on the occurrence of MS at the population level (epidemiology) supports the Epstein Barr Virus (EBV) as being necessary, but not sufficient, for someone to develop MS. In other words, EBV is probably the cause of MS.

Of all the putative causative agents that have been proposed to be associated with MS, EBV is the only one where the risk of getting MS if you are EBV negative is close to zero or zero if you limit the analyses to those studies which use a technique called immunofluorescence microscopy as the gold-standard assay to detect anti-EBV antibodies.

EBV arguably fulfils eight of nine of the so-called Bradford-Hill criteria for causation. The ninth and final Bradford-Hill criterium that would be necessary to prove EBV is the cause of MS is experimental proof.

The ultimate experiment to prove EBV is the cause of MS is to do an EBV vaccine study; if preventing EBV infection prevents or substantially reduces the number of new cases of MS you have proved EBV is the cause of MS. This experiment is easier said than done. Firstly, we need a vaccine; should the vaccine be a non-live component vaccine or should we use a live attenuated vaccine? Because infectious mononucleosis due to EBV, which typically occurs in adolescence or early adulthood, seems to be the main risk factor for MS, some commentators have suggested early wild-type EBV infection or attenuated EBV infection in childhood would be sufficient. The latter approach is analogous to so-called chickenpox parties that were the vogue when I was growing up, i.e. it is better to get chickenpox when you are very young as it tends to be mild compared to late VZV infection that tends to be more severe. Other examples of this approach are cowpox to prevent smallpox and live oral polio vaccines.

As far as component vaccine goes should it be bivalent (two proteins), trivalent (three proteins) or polyvalent (many proteins)? We know that the monovalent (single protein) vaccine targeting the gp350 protein (GSK / Medimmune), although effective in preventing IM, failed to protect people against wildtype EBV infection. To the best of my knowledge, the monovalent gp350 vaccine has not been taken forward. This is a pity as it looked safe and preventing IM may be sufficient to prevent MS. One hypothesis is that it is the aberrant immune response to EBV infection, which occurs during IM is the trigger for autoimmunity and not necessarily the EBV infection itself.

At this juncture, most people are of the opinion that to test the EBV hypothesis we need a sterilizing vaccine, i.e one that prevents you from being infected with wildtype EBV. This is why most vaccines in development (NIH and Moderna) are targeting EBV proteins required for viral entry into B-cells (gp350, gH/gL/gp42), epithelial cells (gH/gL) and other cells (gB). One of the potential downsides of sterilizing vaccines is that as immunity wanes over time it will potentially leave an older population at risk of late wild-type infection. To overcome this any vaccine strategy may need to include booster doses.

With the population being risk-averse when it comes to vaccines do we design a trial that targets the general population or only people at high risk of developing MS, i.e. first- and second-degree family members? I favour the general population and using IM as the intermediate phenotype or signal that your vaccine actually works and then follow people up for decades to see if the vaccine prevents MS and other EBV-associated diseases. An IM trial can be done over months to years, but an MS prevention study will take decades to read-out; the lag time between EBV infection and the development of MS is on average 10 to 20 years. An analogy for using an intermediate phenotype is the HPV vaccine programme to prevent cervical cancer; the primary outcome of the trials was CIN (cervical intraepithelial neoplasia) an intermediate phenotype that can go on to become cervical cancer in a proportion of subjects.

The biggest debate is what age group do we target? Do we go early in childhood, adolescents or later? I think we need to go early in childhood before the majority of subjects are infected with EBV. The longer you wait the fewer people will be protected against EBV infection. This is also a balancing act between getting the general population to support the vaccine and potential adverse events. This is why the early consensus has been to piggy-back the EBV vaccine onto the HPV vaccine by giving the two vaccines together at age 12-13 with the main selling point being the prevention of IM. Most people in the general population know that IM is not such a benign disease and can result in major complications and even death in a small number of very unfortunate people. There is also the problem of chronic fatigue syndrome post-IM, which is very similar to long-COVID that occurs in about 1 in 10 people who have had COVID-19. Most people I speak to about IM know someone who has had post-viral fatigue after IM and its debilitating effects.

As with all trials of medicinal products or vaccines do you compare it to a placebo, an active comparator, a population not vaccinated or historical data? For example, the Oxford-AstraZenca COVID-19 vaccine was compared to the meningococcal vaccine, whilst other COVID-19 vaccines were compared against a placebo. I don’t really have strong views on this, but my inclination would be to go with a placebo-controlled study as this seems the most pragmatic option. I am not sure there is a good comparator at hand; maybe the VZV vaccine?

If the primary outcome is IM, which in my opinion is the only way we are going to get a pharma company interested in developing, testing and marketing an EBV vaccine then how do we show that the vaccine is preventing MS or other EBV-associated diseases? The only way this can be done is with good registry studies that track the incidence of EBV-associated diseases (MS, lupus, rheumatoid arthritis, lymphoma, etc.) and use a comparator disease that is not associated with EBV that you hope will stay constant in terms of incidence. This strategy may require the setting-up of new registers or simply using the Nordic countries, in particular Sweden, which have such registries in place already to track autoimmune disease and lymphomas. The Nordic countries, however, may not be suitable however to test the ability of an EBV-vaccine to prevent EBV-associated nasopharyngeal cancer and Burkitt’s lymphoma that are common in Asia and Africa, respectively.

The elephant in the room with a population EBV vaccination programme is getting public health officials, politicians and the general public to support an EBV vaccine programme. One way is to raise awareness around the morbidity and mortality of IM; i.e. its impact on school pupils, university students and military recruits. About 30% of university freshman and military recruits develop IM in their first year of entry and this impacts negatively on their studies and training. In the military, once someone is diagnosed with IM they are not allowed to do physical training for 3 months because of the risk of causing a ruptured spleen. Although a ruptured spleen is a relatively rare complication of IM it can be precipitated by abdominal trauma and is life-threatening.

We also need to sharpen up our diagnosis and definition of IM. An audit done at our hospital a few years ago showed that ~50% of IM was misdiagnosed at point-of-care. This is clearly a problem if we want to use IM as the primary outcome for a vaccine trial. We have some ideas on how to upgrade the diagnosis of IM so fewer cases will be misdiagnosed or missed. The latter will require us to engage with primary care clinicians and other healthcare providers.

Finally, we need to address the potential negative consequences of an EBV vaccine at a population level. As EBV is one of the viruses that has co-evolved with humans over many millions of years evolutionary biologists argue it must have a positive role to play in human biology. One theory states that as EBV immortalises B-cells it may play a role in extending B-cell memory. The only way to test this hypothesis is to do the vaccine study and build in sub-studies to see what the impact of being EBV-negative has on human biology. There have been several studies looking at the immune system in EBV negative adults and there doesn’t appear to be anything wrong with their immunity. However, 4-5% of EBV negative adults may be protected from infections by the 95-96% of EBV infected people around them. Things may be very different when the majority of the population remain EBV negative.

So where do we go from here? What we need is an international consortium to do the leg work mentioned above including pharmaceutical companies and the NIH. I think we need a policy initiative targeting the general population, public health officials, the WHO, educationalists and the military on the morbidity and mortality associated with IM. This will lay the foundations for EBV vaccine trials. In addition, we need funding agencies to come to the table with grants to improve the diagnosis of IM and to fund the creation of population registers to track EBV-associated diseases. I think we need to pre-identify a vaccine ready EBV-negative cohort of people at high risk of getting MS in the event the population-based vaccine studies being delayed due to vaccine-hesitancy or other reasons. I am sure people with MS will be more willing to put forward their siblings and children for an MS prevention trial than people with no family history of MS. Having skin-in-the-game changes things.

So you can see the MS Preventive Neurology team have a lot of work to do. Exciting? You bet.

You may be interested to read our report on EBV and MS prevention.

CoI: multiple

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