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Researchers identify structure of Ebola virus-neutralizing antibody
LA JOLLA, Calif.—An academic-government research team is taking aim at a deadly human pathogen and possible bioterrorism threat: Ebola virus disease (EVD). Working in tandem against this viral threat, scientists from the Scripps Research Institute and the U.S. Army's Medical Research Institute have isolated and analyzed the structure of an antibody that neutralizes the Sudan virus, one of several species of EVD and the type responsible for most of the virus' outbreaks among humans.
These viral hemorrhagic fevers are highly infectious, but not very contagious. As an outbreak progresses, bodily fluids from diarrhea, vomiting and bleeding represent a hazard. The virus kills 50 to 90 percent of infected patients.
Large-scale epidemics have occurred mostly Africa, in poor, isolated areas that lack proper medical equipment or well-educated medical staff. The potential for widespread EVD epidemics is considered low due to high fatality rates and the remote areas where infections usually occur, but in recent years, the virus has come to be classified as a bioterrorism threat due to its ability to cause disease, resistance to currently available medicines and its increased ability to be spread into the environment.
Currently, there are no U.S. Food and Drug Administration (FDA)-approved vaccines for prevention of EVD. This is due to the complications posed by five different characterized species: Zaire ebolavirus (ZEBOV), Reston ebolavirus (REBOV), Côte d'Ivoire ebolavirus (CIEBOV), Bundibugyo ebolavirus and Sudan ebolavirus (SEBOV).
U.S. government researchers recently demonstrated that an experimental vaccine containing proteins from Ebola and Sudan viruses provides monkeys with some protection against those viruses—but researchers still do not understand how the vaccine works, and it has never been tested in humans.
"It's important to understand the difference between the five different ebola viruses that are circulating," says Scripps Research Associate Prof. Erica Ollmann Saphire, "because antibodies that target one are not effective against the others. Of these five viruses, Sudan is responsible for half of the outbreaks among humans, and there are no known antibodies. That is why we wanted to better understand the structure of Sudan's surface and how to develop antibodies against it."
Ollman Saphire and her Scripps colleagues then teamed up with U.S. Army virologist John M. Dye to isolate and analyze an antibody that neutralizes the Sudan virus. Their efforts were published Nov. 20 in an advance online edition of Nature Structural & Molecular Biology.
To find the antibody, the researchers injected lab mice with an engineered virus that makes copies of the Sudan virus coat protein. This protein caused the mice's immune B cells to make various antibodies against it, which the team harvested and cultured in the lab. Testing each type of antibody for its ability to block the infection of cells with the Sudan virus, the researchers found one good candidate, antibody 16F6, which not only neutralized the virus in the lab dish, but also significantly delayed the deaths of infected mice.
From there, 16F6 was sent to Ollmann Saphire 's lab at Scripps in California, where researchers used X-ray crystallography and related techniques to visualize the atomic-scale details of the viruses bound by antibodies. They observed that 16F6 attaches to the Sudan virus in a way that links two segments of the viral coat protein. The virus is known to use one of these segments, GP1, to grab hold of a host cell. When this happens, the cell automatically brings the virus inside, encapsulated within a bubble-like chamber known as an endosome.
Normally, the cell would destroy the contents of such an endosome, but the researchers observed that the Sudan virus employs its other viral coat-protein segment, GP2, to fuse to the wall of the endosome so that it and the rest of the virus escape into the doomed cell's interior. Antibody 16F6 seems to prevent this fusion process from happening by keeping GP2 bound to GP1, according to the Scripps team.
According to Ollman Saphire, 16F6's protein-linking strategy is the best one that antibodies have against EVD. Notably, the antibody's binding site on the Sudan virus coat protein is virtually the same as the binding site of an Ebola Zaire-neutralizing antibody known as KZ52, which Ollmann Saphire and Scripps Research colleague Prof. Dennis Burton found and analyzed three years ago.
"We think it's not just a coincidence that these two different antibodies, evoked in two different host species by two different ebolaviruses, use the same strategy of linking GP1 and GP2," Ollmann Saphire says.
The researchers are now working to obtain structural data on several other EVD-neutralizing antibodies, and at least one of these may also work by linking GP1 to GP2, says Ollman Saphire.
These findings "help us to understand more precisely what an ebolavirus vaccine or immunotherapy ought to do," she says, adding that the protein-linking strategy identified in this study may help guide further development of vaccines and immunotherapies.
"It is economically impractical to vaccinate every man, woman and child for something as rare as EVD, but it would be nice to have a stockpile to whip out if an emergency outbreak happens," she says. "In addition to that, you never know when a lab worker is going to stick themselves, or a when a tourist will visit the wrong cave. It's nice to have a vaccine that is going to give you immunity a month from now, but there are times you also need something immediately, and delivering an antibody is the only way to ensure immunity."
The study, "A shared structural solution for neutralizing ebolaviruses," was funded in part by the U.S. National Institutes of Health and the Defense Threat Reduction Agency. Co-authors of the paper included João M. Dias, a research associate in the Ollmann Saphire lab who is now a senior scientist at Heptares Therapeutics in England, and Ana I. Kuehne, a researcher in Dye's laboratory at Fort Detrick.