By Jason Gale

Jeff Cohen was 17 and living in Baltimore when mononucleosis knocked him off his feet. He thinks he got it from his high school girlfriend — now his wife — who once he got sick would ring the doorbell, drop off his homework and run away before he could get to the door. “She was afraid I might give her something,” said Cohen, who was laid low for a week with a fever, sore throat and swollen glands. “I’m certain it actually came from her.”

That teenage case of mono, also known as glandular fever, would make a lasting impression. Five decades later, Cohen is now chief of the Laboratory of Infectious Diseases inside the National Institutes of Health, where he’s leading efforts to create a vaccine for Epstein-Barr virus, or EBV, which causes mono.

EBV was for years dismissed as a mild rite of passage — a virus that most people get and recover from, even though it stays in the body for life. But that view has been changing rapidly since a 2022 study provided strong evidence that EBV is a trigger for multiple sclerosis, a chronic progressive disease that affects the central nervous system. Researchers also believe EBV plays a role in a wide range of serious conditions — from lupus and certain cancers to rheumatoid arthritis — and may trigger some cases of chronic fatigue syndrome. Some suspect it could be a hidden driver of long Covid.

That breadth has made EBV a kind of Rosetta Stone for understanding how persistent viral infections can quietly undermine human health. And Cohen’s decades-long pursuit of a vaccine, carried out inside the publicly funded NIH, underscores why the slow, methodical science that government institutions support matters — especially when the payoff may be decades away.

“It was a very quiet field I was working in with little competition,” Cohen said. “Then the multiple sclerosis paper came out, and suddenly people got very, very interested.”

Moderna Inc. had already begun testing an EBV vaccine in late 2021 and has since expanded its program. Merck & Co. is also developing a candidate. But Cohen’s group, working through the NIH’s National Institute of Allergy and Infectious Diseases in collaboration with the Vaccine Research Center, had been laying the groundwork for years — long before the commercial race began.

Even as EBV draws wider scientific scrutiny, political headwinds may now complicate progress. Federal funding for biomedical research is under pressure, and the NIH is laying off staff ahead of budget cuts expected under the Trump administration. Vaccine research is still moving forward, but the outlook has grown less certain amid shifting political and financial dynamics.

Cohen didn’t set out to make EBV his life’s work. After his medical residency in the late 1980s, he trained in Boston with virologist Elliott Kieff, whose research revealed how EBV usurps control over cell growth. There, Cohen worked on understanding how the virus drives infected immune cells to become cancerous.

When he joined NIH in 1990, he shifted focus. “I wanted to try to figure out a way to prevent EBV infection if we could,” Cohen said.

EBV was named after Anthony Epstein and Yvonne Barr, who discovered the virus in 1964 along with Bert Achong. Like other herpesviruses, it is typically acquired early in life. It first infects the throat and then hides in B cells — the immune cells involved in antibody production. There the virus lies largely dormant, expressing few or no proteins that would alert the immune system, allowing it to evade detection.

The NIH team’s first vaccine candidate is designed to train the immune system to recognize a crucial part of the virus that allows it to attach to B cells. The goal is to prevent EBV from establishing a lifelong presence in the body, said clinical immunologist Jessica Durkee-Shock, who joined Cohen’s team four years ago and is leading the clinical trials. An initial trial, focused on safety, showed promising results that she expects to announce in the fall.

A study on a second vaccine candidate will test whether it can block the virus from infecting not only B cells, but also the cells that line the throat, potentially preventing transmission through saliva.

Vaccinating against EBV poses unique challenges, in part because protection may need to be concentrated at the virus’s point of entry: typically the mouth and throat, lined with mucous membranes. “It has to induce effective, robust immune responses in children — and hopefully at the mucosal surfaces, because a lot of these transmissions occur through mucosal contact,” said Akiko Iwasaki, Sterling professor of immunobiology at Yale School of Medicine.

In their own work on herpes simplex virus — the common herpesvirus that causes cold sores and genital herpes — Iwasaki’s team has found that building up immune defenses right where the virus enters the body, such as the mouth or genitals, can be key to stopping infection. It’s a similar idea to what NIH researchers are exploring with their EBV vaccine.

Durkee-Shock, a pediatrician and immunologist, treats children with genetic immune disorders who are especially vulnerable to viruses. “They really get the most extreme manifestations of EBV-related disease,” she said. “They can develop cancers, or they can have overactive immune responses that become life-threatening.”

One of the most famous cases was David Vetter, the so-called bubble boy, born in Texas in 1971 with a rare genetic disorder that left him without a functioning immune system. He underwent a bone marrow transplant in the hope of rebuilding his immune defenses. But with his immunity still severely compromised, he was infected with EBV, likely through a kiss, and died within months from an aggressive lymphoma caused by the virus.

Vaccination may not work for such immune-compromised patients. But if fewer people in the general population carry the virus, those children could be protected through herd immunity. “If EBV stopped circulating, they wouldn’t be exposed in the first place,” Durkee-Shock said.

EBV doesn’t usually cause cancer on its own, Cohen said, but it can act as a contributing factor. In Burkitt lymphoma, for example, it works in combination with a genetic mutation. In transplant patients with weakened immune systems, EBV alone may be enough to trigger lymphoma.

Multiple sclerosis may work the same way. Scientists suspect EBV subtly alters the immune system over time, increasing the risk of misdirected immune attacks on the brain and spinal cord years later. A vaccine could be valuable even if it doesn’t completely prevent infection. By lowering the amount of virus in the body or delaying infection, it may reduce the risk of long-term complications.

Cohen and Durkee-Shock believe EBV may have an even broader impact. Studies suggest a connection to chronic fatigue syndrome (myalgic encephalomyelitis), and researchers are now exploring possible links to dementia.

Scientists are also reassessing the effects of other herpesviruses. Recent studies suggest that people who receive the shingles vaccine — designed to prevent reactivation of the varicella-zoster virus — have a lower risk of developing dementia and heart disease. Some researchers believe the harm may stem not just from the virus itself, but from the chronic inflammation triggered when it reactivates, potentially damaging blood vessels or the brain.

Other work has linked the cold sore virus to Alzheimer’s disease. The possibility that herpesviruses might play a role in driving common and devastating chronic diseases has made it all the more important to stop their spread.

Cohen remembers meeting Epstein when the late virologist was 89 years old. “He came up to me and said, ‘Professor Cohen, I have one question: What adjuvant are you using?’” Cohen said, referring to the substances added to vaccines to enhance their effect. “He was still incredibly sharp.”

These days, Cohen keeps a photo from that meeting on his desk — a reminder of how far the field has come since Epstein’s early discoveries. But it’s also a testament to something else: how crucial long-term public investment in science can be. The vaccine Cohen is testing today is the product of decades of work, much of it undertaken before anyone grasped the full consequences of EBV. In many ways, the virus has served as a key to unlocking the hidden roots of immune-driven illnesses.

Iwasaki, who has known Cohen since she was a postdoctoral fellow at NIH 26 years ago, said his career illustrates the value of long-term public investment in science. She said the stable environment traditionally provided by the NIH for tackling difficult problems over many years was becoming harder to find.

“This kind of sustained effort may or may not be possible elsewhere,” she said.

Such scientific work — slow, uncertain and ahead of its time — rarely begins with a clear commercial incentive. It shows the importance of institutions that are willing to ask big questions long before they seem profitable or urgent.