Epstein-Barr virus, a common microbe that has its fingerprints on a range of deadly cancers in Asia and Africa, often gets a pass from disease researchers in the United States, who know it primarily as the cause of infectious mononucleosis, or mono — “the kissing disease.”
But for years, EBV has been a target of Dr. Andrew McGuire and his team at Seattle’s Fred Hutchinson Cancer Research Center. In 2017, they announced the discovery of an antibody, dubbed AMMO1, isolated from the blood of infected humans. In laboratory cell cultures, this tiny immune protein blocked the virus, which is also known as human herpesvirus 4, or HHV-4.
Today in the journal Cell Reports Medicine, McGuire’s team describes a significant advance in that research. The AMMO1 antibody has successfully blocked infection in two animal models, preclinical evidence that could pave the way to tests of a vaccine for humans.
“This was a very straightforward experiment that no one has been able to do before,” McGuire said.
“There has been skepticism in the research community what an EBV vaccine could achieve. Here we show at least that this antibody can protect from infection. My hope is that it will help convince the naysayers that a vaccine could be protective.”
The study offers encouraging news for people living in Uganda, where young children carrying both malaria and EBV are susceptible to Burkitt lymphoma, a potentially deadly, disfiguring disease related to non-Hodgkin lymphoma. The virus attacks B cells, the immune cells in the blood that operate like factories for the production of antibodies of all kinds, and certain epithelial cells that line internal surfaces of organs in the body.
In Burkitt lymphoma, these mutated B cells proliferate, causing severe swelling of lymph nodes in the neck, and it is rapidly fatal without chemotherapy.
Research on both the cancer and the virus is historically intertwined. British researchers Drs. Anthony Epstein and Yvonne Barr discovered the virus that bears their names in 1964, three years after hearing a lecture by Dr. Denis Burkitt on his research on the childhood cancer named after him. Burkitt lymphoma is the first human cancer proven to be caused by a virus, a finding that led to a string of discoveries of additional virus-cancer links.
A successful vaccine might prevent significant morbidity and death throughout the world. Today roughly 20% of cancers diagnosed globally are linked to infectious agents, as are at least 31% of cancers in Africa. In China and Southeast Asia, EBV is associated with deadly gastric and nasopharyngeal cancers, and it is suspected in a range of autoimmune diseases in western nations, including rheumatoid arthritis and multiple sclerosis.
“There is massive interest in the prevention of EBV outside of North America,” McGuire said.
AMMO1 was discovered using techniques first developed to search for antibodies against HIV, a disease unique it its ability to elude antibody defenses through rapid mutation of its surface proteins, the typical targets of antibodies.
Since his lab was able to isolate AMMO1, McGuire has been testing it in laboratory mice that were genetically engineered to carry human B cells. In the most recent experiment, AMMO1 protected 100% of the mice from a challenge of a high dose of EBV. The same antibody was also cross-reactive: It was effective against a similar virus that attacks another animal species.
Previous attempts to develop an EBV vaccine for humans have focused on a target on the surface the virus called gp350, which it uses to lock onto the surface of B cells. However, there is no similar target on the surface of epithelial cells, which could explain why gp350 vaccines were not effective.
AMMO1, on the other hand, appears to protect against EBV in both B cells and epithelial cells. This may be because it blocks a different protein that the virus may need to break into either cell type. Known as the gH/gL complex, this versatile molecular gadget, part of the break-in toolkit of Epstein-Barr virus, could turn out to be its weakness.
With these results in hand, McGuire and his team are continuing to work toward development of a vaccine that could teach the body’s B cells to make AMMO1 whenever a vaccinated person is exposed to the virus. Years of research lie ahead, and history shows that what looks promising in preclinical work may never make it into human arms.
Yet a great deal hangs on the success of such efforts. Given the broad range of lethal mischief EBV wreaks on humanity, an injection that blocks this virus would take a place among immunizations against hepatitis B and human papillomavirus as the first truly effective anticancer vaccines.
Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs.
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