If you are a regular MS-Selfie reader, you will know that I am a proponent of the Epstein-Barr virus (EBV) theory of multiple sclerosis (MS). I am convinced that EBV is the cause of MS. EBV is necessary but insufficient for the development of MS. Put simply, people who are EBV negative don’t get MS. This observation underlies the hypothesis that an EBV vaccine can prevent MS. I am happy to report that several vaccine companies are developing EBV vaccines, so this question about primary MS prevention will hopefully be answered in the next 10-20 years.

It is now time for the next experiment on the EBV-related prevention strategy.

As you know, I have taken partial retirement to focus on MS prevention. The second hypothesis is based on the observation that a history of symptomatic EBV infection or infectious mononucleosis (mono) is a more substantial risk factor for MS than asymptomatic EBV infection. People with a history of mono have, on average, double the risk of getting MS compared to people without a history of mono. This is why we need to focus on what is happening to the immune system during mono to determine which changes lead to MS.

Please note the case for targeting mono with a vaccine goes beyond MS prevention.

Mono is often described in medical texts as a benign, self-limiting viral infection. However, as with most infections, mono can be severe and associated with significant morbidity and mortality in addition to the potential delayed complication of developing. A minority of people with acute mono have to be admitted to a hospital with complications. These include pharyngeal and/or upper airway obstruction, difficulty swallowing and dehydration. Other complications include meningoencephalitis, haemolytic anaemia, thrombocytopaenia, neutropaenia, haemophagocytic syndrome, myocarditis, hepatitis, pancreatitis, pericarditis, pneumonitis, conjunctivitis, splenic rupture, Guillain-Barré syndrome, cranial neuritis, transverse myelitis, brachial neuritis and chronic fatigue syndrome (CFS). Approximately 3-5% of patients diagnosed with chronic fatigue syndrome have a history of recent mono, and about 10% of patients with documented mono develop CFS.

Children typically miss 1 to 3 weeks of school due to mono and its sequelae. Most children are too ill to attend school during the first week of mono. They begin to feel better in the second week and may be able to return to school with some restrictions; however, they remain contagious and should avoid close contact with other students for the first two weeks. By the third week, most school children are no longer infectious and can return to school without restrictions. However, many children experience lingering fatigue for several weeks or months after the initial infection, which impacts school performance. Participation in contact sports is not recommended for at least three weeks after mono due to the potential risk of splenic rupture. Approximately 30% of university students experience mono, and about 1 in 8 must retake a year of studies. Persistent fatigue after mono impacts university performance.

The risk of splenic rupture post-mono prevents students and athletes from playing contact sports and military recruits from participating in physical training. In the U.S. military, mono has been shown to reduce operational readiness, as each patient with mono is unable to perform duties for at least 2 weeks following infection.

Therefore, from a medical and socioeconomic perspective, it could be argued that preventing or treating acute mono represents an unmet medical need. Preventing mono with a vaccine or treating it with effective antivirals to reduce the duration and severity of mono would reduce the acute and chronic complications of mono itself and, potentially, EBV-associated autoimmunity and malignancy.

Immunologists currently favour molecular mimicry to explain how EBV may cause MS. Arguably, the most well-documented infectious agent to trigger autoimmunity is group A beta-haemolytic streptococcus (strep) or Streptococcus pyogenes. It is the established cause of acute rheumatic fever (acute rheumatic fever), Sydenham’s chorea, glomerulonephritis, arthritis and vasculitis. We therefore hypothesise that EBV drives MS disease activity, as strep infection drives attacks of acute rheumatic fever.

The first attack of MS is asymptomatic in the majority of people who develop MS and is likely to occur relatively soon after primary EBV exposure. MS manifests later, when a subsequent attack or lesion forms in a pathway that results in neurological symptoms. This explains why most people who develop MS have pre-existing old white matter lesions on their brain MRI when presenting with their first clinical attack. EBV differs from strep because it establishes a latent infection that reactivates intermittently. This intermittent asymptomatic reactivation of EBV (latent-lytic cycling) likely drives MS disease activity.

In contrast, strep tends to cause repeated symptomatic infections. However, asymptomatic colonisation with strep is associated with elevated anti-streptolysin (ASO) titres (antibodies against a strep protein) and other serological markers of strep infection. Similarly, people with MS have increased titres and responsiveness to a broader array of EBV epitopes in their antibody and T-cell repertoires compared to healthy controls, supporting the latent-lytic cycling hypothesis as the driver of MS disease activity. It is the latent-lytic cycle that acts as a booster, increasing antibody levels and the number and diversity of T cells.

The emergence of antibiotics to treat strep pharyngitis or tonsillitis was associated with a rapid decline in the incidence of acute rheumatic fever. Observational data, rather than randomised controlled trial data, demonstrated the primary link between strep infection and acute rheumatic fever. Randomised controlled trials were only conducted much later to prove that secondary antibiotic prophylaxis in patients with a prior episode of acute rheumatic fever could prevent recurrent attacks and the chronic sequelae of rheumatic fever.

If EBV infection triggers MS attacks in a similar way to how strep causes attacks of acute rheumatic fever, then treating acute mono with effective antiviral therapies may prevent MS and other EBV-associated conditions. An effective antiviral treatment for mono would be considered a primary prevention measure. With acute rheumatic fever as the analogy, this concept could be further extended to the treatment of established MS. Treating patients with MS continuously or prophylactically with EBV antivirals over the long term may prevent further attacks and the chronic sequelae of MS, i.e., EBV antivirals could be used as a secondary prevention measure. Arguably, this is how currently licensed MS disease-modifying therapies and some experimental therapies work, by targeting memory B-cells where latent EBV resides.

We hypothesise that treating mono with an effective antiviral will reduce EBV viral loads and the aberrant immune response induced by EBV during mono. This may prevent the immunological events that lead to MS, analogous to treating pharyngitis due to strep with penicillin or other antibiotics to prevent acute rheumatic fever.

To test the EBV-mono/MS hypothesis, we need to develop effective treatments for mono. Once antiviral therapies are licensed for treating mono, and they are widely adopted in clinical practice, we could use population registries to track the impact of this treatment intervention on the incidence of MS and other EBV-related disorders.

Studying mono is proving more difficult than I thought. This is based on changes to medical practice induced by COVID. Many people presenting with a sore throat are not seen face-to-face by doctors, and very few receive tests to diagnose the specific cause. Many patients are now managed remotely, and many see their local pharmacist. This means that many people who have mono are not being treated appropriately; they are inappropriately prescribed antibiotics to cover strep. Antibiotics are prescribed to cover strep and prevent the development of post-streptococcal-associated autoimmune disease. The good news is that we will change this practice and have put in place a pathway to diagnose both strep sore throats and mono, in the hope of studying them to see if we can find an immunological signature associated with autoimmunity, and then try to prevent this signature with an antiviral that targets EBV.

If this study is successful, we hope to secure funding for a large, multicentre randomised controlled trial to develop a treatment for mono. If anyone from the pharma industry is reading this newsletter, can I urge you to consider creating new antiviral drugs to target EBV? There is a large market, and there is a good chance that such a treatment will profoundly impact post-mono autoimmunity. If such a therapy gets licensed, it will provide a reason for primary care HCPs to diagnose and treat mono. If our hypothesis is correct, we would then see a gradual decline in the incidence of new cases of MS and other EBV-associated autoimmune diseases. Wouldn’t that be amazing?

Now that we have the diagnostic pathway set up for strep sore throats and acute mono, we would be interested in whether you would be willing to participate in the studies we propose. If you have time, we would greatly appreciate it if you could watch this short video that explains our studies and then complete a brief online survey. This would take about 2-3 minutes to complete. The survey results will then be used to support our ethics application for the proposed studies. Thank you for being so supportive; we would be able to do this kind of...