Researchers identify structure of Ebola virus-neutralizing antibody

Findings help in understanding more precisely what an Ebolavirus vaccine or immunotherapy ought to do, which may help guide further development of vaccines and immunotherapies

Amy Swinderman
LA JOLLA, Calif.—An academic-government research team istaking aim at a deadly human pathogen and possible bioterrorism threat: Ebolavirus disease (EVD). Working in tandem against this viral threat, scientistsfrom the Scripps Research Institute and the U.S. Army's Medical ResearchInstitute have isolated and analyzed the structure of an antibody thatneutralizes the Sudan virus, one of several species of EVD and the typeresponsible for most of the virus' outbreaks among humans.
These viral hemorrhagic fevers are highly infectious, butnot very contagious. As an outbreak progresses, bodily fluids from diarrhea,vomiting and bleeding represent a hazard. The virus kills 50 to 90 percent ofinfected patients.
Large-scale epidemics have occurred mostly Africa, in poor,isolated areas that lack proper medical equipment or well-educated medicalstaff. The potential for widespread EVD epidemics is considered low due to highfatality rates and the remote areas where infections usually occur, but inrecent years, the virus has come to be classified as a bioterrorism threat dueto its ability to cause disease, resistance to currently available medicinesand 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 complicationsposed by five different characterized species: Zaire ebolavirus (ZEBOV), Reston ebolavirus (REBOV), Côted'Ivoire ebolavirus (CIEBOV), Bundibugyo ebolavirus and Sudan ebolavirus(SEBOV).
U.S. government researchers recently demonstrated that anexperimental vaccine containing proteins from Ebola and Sudan viruses providesmonkeys with some protection against those viruses—but researchers still do notunderstand how the vaccine works, and it has never been tested in humans.
"It's important to understand the difference between thefive different ebola viruses that are circulating," says Scripps ResearchAssociate Prof. Erica Ollmann Saphire, "because antibodies that target one arenot effective against the others. Of these five viruses, Sudan is responsiblefor half of the outbreaks among humans, and there are no known antibodies. Thatis why we wanted to better understand the structure of Sudan's surface and howto develop antibodies against it."
Ollman Saphire and her Scripps colleagues then teamed upwith U.S. Army virologist John M. Dye to isolate and analyze an antibody thatneutralizes the Sudan virus. Their efforts were published Nov. 20 in an advanceonline edition of Nature Structural &Molecular Biology.
To find the antibody, the researchers injected lab mice withan engineered virus that makes copies of the Sudan virus coat protein. Thisprotein 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 antibodyfor its ability to block the infection of cells with the Sudan virus, theresearchers found one good candidate, antibody 16F6, which not only neutralizedthe virus in the lab dish, but also significantly delayed the deaths ofinfected mice.
From there, 16F6 was sent to Ollmann Saphire's lab atScripps in California, where researchers used X-ray crystallography and relatedtechniques to visualize the atomic-scale details of the viruses bound byantibodies. They observed that 16F6 attaches to the Sudan virus in a way thatlinks two segments of the viral coat protein. The virus is known to use one ofthese segments, GP1, to grab hold of a host cell. When this happens, the cellautomatically brings the virus inside, encapsulated within a bubble-likechamber known as an endosome.
Normally, the cell would destroy the contents of such anendosome, but the researchers observed that the Sudan virus employs its otherviral coat-protein segment, GP2, to fuse to the wall of the endosome so that itand the rest of the virus escape into the doomed cell's interior. Antibody 16F6seems to prevent this fusion process from happening by keeping GP2 bound toGP1, according to the Scripps team.
According to Ollman Saphire, 16F6's protein-linking strategyis the best one that antibodies have against EVD. Notably, the antibody'sbinding site on the Sudan virus coat protein is virtually the same as thebinding site of an Ebola Zaire-neutralizing antibody known as KZ52, whichOllmann Saphire and Scripps Research colleague Prof. Dennis Burton found andanalyzed three years ago.
"We think it's not just a coincidence that these twodifferent antibodies, evoked in two different host species by two differentebolaviruses, use the same strategy of linking GP1 and GP2," Ollmann Saphiresays.
The researchers are now working to obtain structural data onseveral other EVD-neutralizing antibodies, and at least one of these may alsowork by linking GP1 to GP2, says Ollman Saphire. 
These findings "help us to understand more precisely what anebolavirus vaccine or immunotherapy ought to do," she says, adding that theprotein-linking strategy identified in this study may help guide furtherdevelopment 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 astockpile to whip out if an emergency outbreak happens," she says. "In additionto that, you never know when a lab worker is going to stick themselves, or awhen a tourist will visit the wrong cave. It's nice to have a vaccine that isgoing to give you immunity a month from now, but there are times you also needsomething immediately, and delivering an antibody is the only way to ensureimmunity."
The study, "A shared structural solution for neutralizingebolaviruses," was funded in part by the U.S. National Institutes of Health andthe 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 seniorscientist at Heptares Therapeutics in England, and Ana I. Kuehne, a researcherin Dye's laboratory at Fort Detrick. 

Amy Swinderman

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