Researchers from Fred Hutchinson Cancer Research Center and the University of Washington have discovered a human antibody that in laboratory tests blocks infection by the Epstein-Barr virus, or EBV.
The finding of the antibody — along with the site it targets — opens a new path to developing an effective vaccine against a virus best known in the United States for causing mononucleosis, or mono, but which is globally associated with about 200,000 cancer cases a year, including some Burkitt and Hodgkin lymphomas, non-Hodgkin lymphoma, and stomach and nasopharyngeal cancers. EBV infection also may activate genes associated with autoimmune diseases such as lupus and multiple sclerosis.
Dr. Andrew McGuire of Fred Hutch’s Vaccine and Infectious Disease Division is the senior author of the paper published today in the journal Immunity. He initiated the study after working on human antibodies against HIV and deciding to apply some of what has been learned there to a different virus. The antibody he found, known as AMM01, is the first human antibody shown to block EBV infection in cells in the lab. Prior to this study, only mouse antibodies had been identified against the virus.
“The idea was to apply some of the approaches that have revolutionized the HIV vaccine development field in the past 10 years,” McGuire said, including discovering the antibodies people make to HIV and studying them in the lab to see how they interact with the virus.
And then, McGuire added, “you think about how you can use that information to design better vaccines.”
There is no licensed vaccine against EBV. There are preventive vaccines against other cancer-causing viruses, including hepatitis B, which can cause liver cancer, and human papillomavirus, or HPV, which causes cervical cancer as well as some cancers of the penis, anus, vagina, vulva, mouth and throat. Research led by Fred Hutch’s Dr. Denise Galloway and colleagues laid the groundwork for the creation of the HPV vaccine.
EBV was the first virus shown to cause cancer in humans. Its discovery in 1964 led to a growing recognition that viruses and other pathogens are associated, directly or indirectly, with up to 20 percent of all cancers around the world. Eliminating that burden is the goal of Fred Hutch’s recently formed Pathogen-Associated Malignancies Integrated Research Center, which is led by Galloway and brings together infectious disease researchers like McGuire and experts in cancer biology, global oncology, immunotherapy and other specialties to better understand, treat and prevent cancers linked to infectious agents.
The British researcher Dr. Anthony Epstein first identified the virus that bears his name in tumor samples sent to him by Dr. Denis Burkitt, an Irish surgeon and missionary working in Uganda in the 1950s. The samples came from a rapidly fatal cancer of the immune system first described by Burkitt in 1958. Burkitt lymphoma remains the most common cause of childhood cancer deaths in sub-Saharan Africa.
EBV is now known to be one of the most common human viruses, infecting about nine out of 10 people worldwide at some point in their lives. Most commonly spread through saliva (there’s a reason mono is called the "kissing disease"), it is a member of the herpesvirus family. Like other herpesviruses, infection is lifelong, with latent, or inactive, stages. But with EBV, most people have no symptoms, not even mono.
Researchers are still trying to understand why the virus causes no or only mild symptoms in most people but is linked to cancer in others. Age of infection, genetic susceptibility, environmental factors and interactions with other pathogens are all potentially part of the mix, said Dr. Edus H. “Hootie” Warren, head of Fred Hutch Global Oncology. The program has a research partnership with the Uganda Cancer Institute and research ties in China.
In Uganda, almost all children are infected with EBV before they are 2 years old, but the most common (though still rare) cancer linked to the virus, endemic Burkitt lymphoma, also seems to be associated with malaria, said Warren, who was not involved in McGuire’s research. In China, EBV infection occurs in older children and in the U.S., in adolescents and teenagers.
EBV causes the most cancer cases and cancer deaths in southern China and Southeast Asia, Warren said. About 10 percent of gastric cancers and almost 100 percent of nasopharyngeal carcinomas — a type of head and neck cancer — are linked to EBV. Sun Yat-Sen University Cancer Center in Guangzhou, China, for example, sees almost 5,000 cases of nasopharyngeal carcinoma a year. Treating the tumors, which grow deep inside the nasopharynx (the upper part of the throat, behind the nose) requires intensive radiation and often chemotherapy.
“The question out there is could we prevent these cancers with universal EBV vaccinations?” said Warren. “It’s definitely something that would make sense in China because EBV causes a lot of morbidity and mortality there. In China, a vaccine would make an enormous difference.”
Previously, scientists had identified a small number of antibodies to EBV, but they all came from EBV-infected mice, not humans. The mouse antibody that best blocks infection targets a molecule on the surface of EBV called glycoprotein 350, or gp350, which helps the virus attach to B cells, a type of immune cell that is infected by EBV. Although the only human clinical trial of an experimental gp350-targeted EBV vaccine conducted to date showed a clinical benefit — fewer people developed infectious mononucleosis — the vaccine did not prevent EBV infection itself.
Drawing on what has been learned from research on the immune response in people infected with HIV, McGuire and his team searched for and found antibodies to EBV in the blood serum of infected humans. Of five antibodies isolated, one — named AMM01 — completely blocked infection in cells in the lab and did so at a different site of vulnerability than the mouse experiments found, an EBV protein called gH/gL. Moreover, it blocked infection in both of the two different cells that EBV infects — B cells and epithelial cells — rather than just in B cells.
“Because this antibody binds to a different viral protein and we show that it can neutralize both cell types, you could argue that that will make a better vaccine or complement the gp350 one that’s been tested and showed some efficacy,” McGuire said.
McGuire just started his own lab last July, after moving from postdoc to an assistant faculty appointment, but he began this work under a VIDD Faculty Initiative Grant awarded in 2015. He and his colleagues isolated the antibodies the following year and, working with UW’s Dr. David Veesler and Hutch researcher Dr. Marie Pancera — who recently co-authored a paper on a new malaria antibody and its target — they were able to describe the structure of the binding site soon afterward.
The next step will be testing the antibody in an animal model; McGuire is applying for funding for that project now. Besides holding out promise for a vaccine, which would work by teaching the body to make such an antibody, another potential use of these results would be to directly administer the antibody intravenously, as is now being tested for an antibody against HIV in a global clinical trial called the AMP Study, short for "antibody-mediated protection." With an EBV antibody, such an approach could be used to protect patients undergoing stem cell or organ transplants who may be EBV-negative with an EBV-positive donor or whose own latent EBV infection may reactivate when their immune system is depressed.
And down the road, there is the possibility that lessons learned from finding antibodies for HIV, malaria and now EBV could be applied to additional viruses.
“This approach made such a huge impact on the HIV-vaccine field that more and more people are starting to do this with other pathogens now,” McGuire said.
Fred Hutch’s Vaccine and Infectious Disease Division, the National Institutes of Health, a Pew Biomedical Scholars Award, the Netherlands Organization for Scientific Research and the European Molecular Biology Organisation funded the study.
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Mary Engel is a former staff writer at Fred Hutchinson Cancer Research Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.