My prediction is that we will prevent multiple sclerosis (MS) by accident, i.e. as a secondary outcome to a broader public health intervention.
Many stakeholders think we can run a randomised controlled EBV vaccination trial in a high-risk cohort to prevent MS. This is not feasible. Firstly, the incidence of MS is relatively low; therefore, you would need a large study (approximately 10,000 EBV-negative subjects) to capture enough events, i.e. people developing MS, in a relatively short period (<10 years) to show that an EBV vaccine is effective. This also assumes that a sterilising or non-sterilising vaccine will have a similar effect, which may not be the case. A sterilising vaccine prevents wild-type EBV infection, whereas a non-sterilising vaccine doesn’t prevent wild-type infection but reduces the severity of the primary infection. For example, GSK’s monovalent GP350 (single antigen) vaccine was abandoned when it was shown to prevent infectious mononucleosis (IM) but did not prevent wild-type EBV infection.
People at high risk of MS
Polygenic risk scores and other biomarkers of MS risk are not sensitive and specific enough to enrich clinical trials. A pragmatic way to identify a high-risk cohort is to recruit first and second-degree relatives who are approximately 10 times more likely to develop MS than the general population. However, these high-risk subjects would need to be recruited early, that is, as infants, before EBV exposure to maximise the power of the trials. We have shown that by 10 years of age, over three-quarters of children in the UK are already EBV seropostive. In addition, the average onset of MS is close to 30 years of age, with less than 3% of people developing MS before the age of 16, the age of consent for clinical trials. Therefore, an EBV vaccine trial in a high-risk cohort will take decades. I will be long gone, i.e. deceased, by the time this sort of trial reads out. I want to see MS prevented in my lifetime.
Similar arguments can be made for other delayed EBV-associated diseases. These include other autoimmune diseases (systemic lupus erythematosus or SLE, rheumatoid arthritis, Sjogren’s syndrome, primary biliary cirrhosis, and inflammatory bowel disease) and EBV-associated cancers (Hodgkin, diffuse B-cell, Burkitt, CNS and other lymphomas, nasopharyngeal carcinoma and gastric cancer). Dare I suggest we design a basket study to catch all these diseases?
Targeting infectious mononucleosis
Years ago, I realised that we need to get an EBV vaccine licensed to prevent infectious mononucleosis (IM), which needs to be adopted as a public health intervention at a population level. We can then collect real-world data via a registry to see what happens to the incidence of a basket of diseases in people who have been vaccinated and those who choose not to. To address safety concerns, we have suggested doing this study on 12 to 13-year-old adolescents before the peak in the incidence of IM. This occurs at 12-13 in girls and 15-17 in boys. This three-year gap in the peal of IM between girls and boys is because girls mature earlier than boys and start kissing earlier. EBV is mainly transmitted via saliva; hence, it is called the kissing disease. The target age of 12-13 is the same age that HPV vaccination is given; therefore, it will be easier to implement an EBV vaccine nationally by piggybacking the EBV vaccine onto the HPV vaccine. Once an EBV vaccine is shown to be relatively safe in adolescents, it could be moved to an earlier age group to try and vaccinate the majority of children before EBV exposure.
I am aware that about 80% of adolescents aged 12-13 are already EBV seropositive and hence may not need the vaccine. However, as latent-lytic cycling of EBV may underlie the pathogenesis of MS, boosting immunity to EBV with a vaccine may reduce lytic infection and hence reduce the incidence of MS or EBV-associated diseases. A good analogy here is Shingrex, a varicella-zoster virus vaccine given to adults likely to be VZV seropositive to minimise the risk of getting shingles.
Did you know that recent data has shown that adults who have had the Shingrex vaccine may be at lower risk of developing dementia? The mechanism behind this is unknown, but if this finding is causal, i.e., if Shingrex reduces the incidence of Alzheimer’s disease (AZD), it will tell us something about the pathogenesis and cause of AZD. There is a literature linking herpes viral infection to AZD.
The good news is that a gold rush is happening with several big pharma companies developing EBV vaccines to prevent IM. Let us assume one of the companies can get regulatory approval and marketing authorisation for their EBV vaccine to reduce the incidence and potential severity of IM. Will public health officials and governments adopt the vaccine nationally, find the resources to pay for the vaccine, and set up real-world registry studies to see if downstream diseases such as MS, SLE and Hodgkin's disease are prevented? I am not sure. Vaccine uptake by governments is generally slow and, potentially, even slower considering the backlash after the rapid rollout of the COVID-19 vaccine, the rise in the influence of the anti-vaccine lobby and the recent problems with the respiratory syncytial virus (RSV) and rotavirus vaccines.
Governments and individuals, in particular parents, will need convincing. We should start by challenging the medical dogma that IM is a benign self-limiting disease. IM is an unpleasant disease associated with significant short and long-term morbidity and mortality. Using NHS hospital statistics for England, the incidence of acute IM needing admission is estimated to be 108 per 100,000 of the population annually. In other words, over 60,000 patients with acute IM are admitted to NHS hospitals in England each year and spend, on average, 3-4 days in the hospital. Assuming this applies to the UK, we estimate that IM consumes over 250,000 NHS inpatient days annually. This is likely underestimated, as IM follows a latitudinal gradient and is more common in Scotland and Northern Ireland than in England. Hence, extrapolating English figures to the country's north will underestimate NHS admission rates.
Complicated IM
People with IM are typically admitted with complications, in particular, throat and upper airway obstruction, difficulty swallowing and dehydration. Then, there are the acute complications associated with IM that often need admission. These include meningoencephalitis, haemolytic anaemia, thrombocytopaenia, neutropaenia, haemophagocytic syndrome, myocarditis, hepatitis, pancreatitis, pericarditis, pneumonitis, conjunctivitis, splenic rupture, Guillain-Barre syndrome, cranial neuritis, transverse myelitis, brachial neuritis and chronic fatigue syndrome (CFS). Yes, about 3-5% of patients diagnosed with CFS have had recent IM.
Schoolchildren typically lose 1-4 weeks of schooling due to IM and its sequelae. Up to 30% of University students get IM, and about 1 in 8 must re-do a year of studies. A similar story plays out in the military. Between 2002 and 2018, there were 23,861 cases of IM in the US military, which is an incidence of 104.2/1,000 patient-years. This worked out to 44,606 total medical encounters, 4,189 hospital bed days and 2,797 weeks/yr of lost duty time. Military recruits who have IM are forbidden from doing any physical exercise for 8 weeks to prevent splenic rupture. In some countries, this period of inactivity is increased to 12 weeks. Then, there are the elite athletes who can’t compete for months and rarely years after IM. Outbreaks of IM amongst athletes often occur in sports camps. I hope you understand that IM is not a pleasant disease.
The case for an EBV vaccine to prevent IM is a no-brainer. Do you agree? However, the vaccine needs to be shown to be cost-effective, and the rub is herein. A national EBV vaccine programme is particularly compelling if it may reduce the long-term sequelae of EBV. I anticipate big pharma companies trying to price the latter into their products. The price based on a cost-benefit analysis to prevent IM alone will be relatively low compared to a vaccine that prevents MS, other autoimmune diseases, and potentially several cancers.
United Kingdom and the NHS
The UK should take the lead on this. Despite having the NHS and its record-keeping systems to do these studies, we are not large enough as a country. Some preliminary power calculations suggest we need between 210,000 and 300,000 EBV-negative adolescents to answer the question on MS prevention. If only 20% of adolescents are EBV-negative, then we will need 1.0-1.5 million adolescents to be enrolled in the study to answer the question in 5-7 years. This is why MS prevention is so hard; it needs to be a global effort.
What needs to be done? We need to hold a multi-disease stakeholder meeting around EBV-associated disease prevention, not just MS prevention but all of the potential diseases I have mentioned above. Let us assume we get a vaccine licensed to prevent IM. What needs to be done to get public health officials to adopt the vaccine as a public health intervention? Do we need a preemptive policy initiative, including economic modelling, to convince public health officials to adopt an EBV vaccine? How do we get a licensed EBV vaccine rolled out nationally and collect high-quality data to show that the vaccine is reducing the incidence of a basket of EBV-associated cancers and autoimmune diseases? In addition, an effective EBV vaccine may reduce the incidence of post-transplant and immunosuppressive lymphoproliferative diseases. Is there a national register for these diseases? Can we use the same registries or reporting structures that are in place for cancer surveillance for autoimmune diseases? Or can we clone these cancer surveillance systems for autoimmune diseases? What funding do we need? Who will fund such a meeting? I estimate that it will cost about £40,000 to hold this meeting. Is anyone willing to fund or part-fund this meeting?
In addition to preparing for the post-licensing studies, many other fundamental questions concerning EBV and its role in human biology need to be answered. These will need to be done in parallel. For example, what will the impact of remaining EBV-negative be as we get older? Will an adolescent EBV vaccine create an older population that is susceptible to IM as vaccine immunity wanes? EBV is one of the viruses that has co-evolved with humans and may play an essential role in human biology. Will eliminating EBV from the human population have adverse effects? As you can see, ‘I have many miles to go before I sleep’.
Attitudes to an EBV vaccine
I would like to know how many people with MS would let their children be vaccinated with a new EBV vaccine. When I asked my patients this question, they overwhelmingly said no. They would only agree to vaccinate their children if the EBV vaccine was shown to be relatively safe for adults and adolescents. This attitude toward new vaccines is not unique to emerging EBV vaccines but has been noted with other vaccines and explains why the COVID-19 vaccine was never given to infants and young children.
To explore your attitude toward an EBV vaccine, please spare two minutes to complete this survey. Would you allow your children, grandchildren, or other young relatives to be vaccinated, and at what age do you think they should be vaccinated?
Thank you for your participation.
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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 Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.
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