In the 1970s, Hank Balfour, a virologist at the University of Minnesota Medical School, was studying the long-term survival prospects of kidney transplant patients when he noticed that a small proportion of them went on to develop a rare form of cancer known as post-transplant proliferative disorder. He was particularly intrigued when he discovered that almost all of these patients had been infected with a virus called Epstein-Barr or EBV, a curious pathogen that has captivated and puzzled virus-hunters for decades. “EBV can maintain latency within human cells,” says Balfour. “When we began studying it, it seemed that certain people were more prone to difficulties managing the virus immunologically, perhaps due to their genetic makeup, which allows the virus to put a damaging footprint on the immune system, causing long-term problems.” For while “hit-and-run” viruses such as Ebola or Sars-CoV-2 – which invade organs, wreaking havoc in their wake, before leaving the body – tend to make headlines in the virology world, EBV is a classic example of a “hit-and-stay” virus. These infections silently assimilate within the body’s tissues, in such a way that it is nigh on impossible for the immune system to get rid of them; they remain with us for the rest of our lives. Exactly what they do and how they affect our health has long been a mystery, but over the past 40 years, there has been mounting evidence that EBV is not as benign as it may seem. EBV has evolved to coexist with humanity for millions of years, long before the advent of modern humans. It has become adept in hiding in a type of immune cell called B cells, where it stays for decades. Because most of us catch EBV in childhood – more than half of children in England have contracted EBV by the age of 12 – we do not even realise we have it. The only noticeable time when EBV rears its head is when teenagers or young adults become infected or immune-suppressed and develop mononucleosis or glandular fever, an illness associated with extreme fatigue and swollen glands. However, the presence of the virus in our bodies has also been associated with about 200,000 cases of cancer worldwide every year, which develop years after infection. Associations have been made between EBV and Hodgkin lymphoma, as well as cancers of the head, neck and stomach. In particular, it is estimated that about 40% of Hodgkin lymphoma cases in the UK are related to EBV infection, with those who have previously had glandular fever being at a higher risk. EBV has also been associated with a range of autoimmune disorders, from lupus to chronic fatigue syndrome. But while the medical world has known about these links for some time, most doctors have been nonplussed as to what to do about it. The main problem is that EBV infection is ubiquitous – most estimates suggest that the virus is inside 95% of the world’s population. And because EBV-related cancers are relatively rare – fewer than one in 300 cancer cases in the UK, and about 1.5% of cancers globally, are connected to the virus – modern medicine has largely taken the approach of pretending that the problem does not exist. “The problem with EBV is that clinicians don’t want to deal with it, because they don’t really know what to do with it,” says Balfour. “And academic researchers, for some reason, have shied away from EBV, perhaps because of its complexity.” However, this may be about to change. In January, Science published a landmark study that showed overwhelmingly that EBV is implicated in multiple sclerosis (MS), an incurable autoimmune disease that affects the central nervous system. Scientists, led by Alberto Ascherio from the Harvard TH Chan School of Public Health, examined more than 10m blood samples from US military personnel collected over 20 years and identified that those who became infected with EBV were 32 times more likely to later develop MS. Perhaps tellingly, the levels of a protein called neurofilament light chain – a marker in the blood that indicates nerve degeneration is occurring – increased only after EBV infection. Ascherio explains that it was possible to prove this association for the first time only because of the sheer number of people involved in the study. “The high prevalence of EBV in the general population has been a huge obstacle in demonstrating a causal link in the past,” he says. “This study shows that EBV is the leading cause of MS, but there are clearly other factors involved such as genetics and vitamin D deficiency among EBV-positive individuals. To provide an analogy, most smokers will never develop lung cancer, and similarly, most EBV-infected individuals will not develop MS.” What determines vulnerability to EBV? So why is it that most of us can coexist unknowingly with EBV and never develop either EBV-related cancers or MS, but yet for some, the infection becomes a pathway to chronic illness? The answer lies in the delicate balance between the virus and the body’s immune system. Hiding out in the body’s B-cells, EBV emerges now and then to replicate and avoid getting eradicated altogether by immune defenders called T-cells. But if it is allowed to replicate too much because the host’s T-cells are not functioning properly or they are immune-suppressed in some way, the virus can move into other tissues, causing damage. A recent example of this is in some cases of long Covid where the symptoms have been linked to reactivation of EBV, a mechanism that has also been proposed as a cause of chronic fatigue syndrome. “It seems clear that EBV reactivation could play a role in long-term consequences of Sars-CoV-2 infection,” says Jeff Gold, a researcher at the World Organisation, which studies long Covid. “The family of symptoms for some long Covid patients is identical to those we would expect from the virus reactivating.” In the case of MS, Ascherio suggests the inability of the body to keep the virus in check means that EBV ends up in nerve cells. “EBV-infected B-cells could be more prone to invade the central nervous system and cause damage,” says Ascherio. He believes that the presence of the virus within the central nervous system induces an autoimmune reaction, because of coincidental similarities between EBV proteins and the myelin sheaths that form a protective layer around nerves in the brain and spinal cords. This causes the body to attack its own cells, leading to progressive degeneration. The factors that cause EBV-infected individuals to develop various forms of cancer are an even more complex mixture of genetics and immune dysfunction. It appears that EBV can suppress the normal dying process of infected cells, and if these cells happen to possess other aberrant mutations, they can then grow and develop into a tumour. But it is thought that the chances of this happening can be heightened by certain lifestyle factors. For example, chemicals such as tobacco smoke, pesticides and food additives might be able to interact with EBV and either amplify its genome within B cells, or alter the way it interacts with the immune system in some malignant fashion. “The chances of an EBV-infected person developing an EBV-positive tumour are very, very low,” says Alan Rickinson, a cancer researcher at the University of Birmingham, who has studied EBV for the past 50 years. “But of course there are predisposing factors that can increase the risk.” Rickinson points to the example of nasopharyngeal cancer (NPC), one of the cancers that has been linked to EBV. While people of southern Chinese ethnicity have been shown to be more genetically prone to getting NPC, this is not the whole story. In reality, the likelihood of someone developing NPC or not comes down to a combination of genetic susceptibility, EBV exposure and lifestyle factors. “Studies from Hong Kong in particular have highlighted the practice of weaning infants on salted fish, a concoction known to contain potential carcinogens,” Rickinson says. “This is one example of a lifestyle factor that may increase the chances of NPC developing later in life.” Can we vaccinate against EBV? When the connection between EBV and certain cancers began to emerge in the 1980s, Balfour set his sights on developing a vaccine to prevent people from becoming infected with the virus. Over the next 30 years, his efforts would repeatedly be knocked back as pharmaceutical companies stalled and mulled over whether such a jab would be economical. But the advent of cheaper messenger RNA (mRNA) vaccine technology over the past two years, and the discovery that EBV appears to be the main cause of MS, has added new impetus for bringing such a vaccine to market. As Balfour puts it: “I think the evidence is now very, very strong that EBV is necessary for MS. And if you take EBV away, you don’t get MS.” After years of little progress, there are now three EBV vaccines in the pipeline. Moderna has turned its attention towards the virus, and is conducting phase 1 clinical trials of an mRNA vaccine for EBV at 15 centres across the US, while research teams at the US National Institute of Allergy and Infectious Diseases and Balfour’s own lab are working on their own jabs. Moderna’s clinical trial is targeting people in the 18-30 age range, but given that so many people contract EBV as children, the ultimate aim is to administer the vaccine to infants. However, there remain many challenges and questions ahead. “One obstacle is that it will take a very large study of long duration to demonstrate that an EBV vaccine prevents MS, so most likely experimental studies will need to rely on intermediate outcomes, such as whether the vaccine prevents EBV infection and mononucleosis,” says Ascherio. The other question is whether the vaccine will need to provide what scientists call sterilising immunity – preventing the virus from binding at all to human cells – in order to prevent cancers and MS, or whether simply limiting the severity of the infection will be sufficient. “There are few vaccines that induce sterilising immunity,” says Katherine Luzuriaga, a professor of molecular medicine at UMass Chan Medical School, who is leading Moderna’s clinical trial. “However, it is possible that an effective EBV vaccine could limit the dissemination of the virus, prevent aberrant immune reactivity, and reduce viral load at the initiation of infection, all factors that may play a role in downstream disease pathogenesis not only in MS but EBV-related cancers as well.” Researchers are also interested in whether antiviral drugs that directly target EBV could provide ways of halting the progression of the disease in patients who already have MS. But while scientists have identified a number of candidates that can stop EBV replicating in a test tube, finding a drug that can clear the virus from the body remains a challenge. But for Balfour, there is a sense of encouragement that progress is finally being made in an area that has been greatly neglected for so long. “The Science paper has been a gamechanger and a sort of vindication of something that I believed in,” he says. “For a long time, there’s been this known association between EBV and MS, but when I would apply for grants, people would still say that EBV has little if anything to do with MS. But now people are rethinking the value of an EBV vaccine, as we’ve seen that it’s much better not to get infected at all.”