March 8, 2016

Experimental Ebola antibody protects monkeys

At a Glance

  • A monoclonal antibody derived from a person who survived Ebola virus disease protected non-human primates when given as late as 5 days after Ebola infection.
  • The antibody can now advance to testing in humans as a potential treatment for Ebola virus disease.
Ebola virus bound by antibodies The Ebola virus surface glycoprotein (blue) is shown bound by protective antibodies mAb114 (pink/white) and mAb100 (purple/white). NIAID

The Ebola virus causes acute disease that can lead to severe illness and death. It typically affects multiple organs in the body. Symptoms usually appear 2 to 21 days after exposure. Infection can cause fever, headache, body aches, weakness, stomach pain, and lack of appetite. Later symptoms include vomiting, diarrhea, and internal and external hemorrhage (bleeding).

There are currently no licensed treatments for Ebola virus infection. The 2014-2015 outbreak in West Africa, which caused more than 11,000 deaths, highlighted the need for effective therapies.

One experimental drug cocktail called ZMapp is now being evaluated in human trials. Developed by Mapp Biopharmaceutical Inc., ZMapp is composed of 3 different monoclonal antibodies (mAbs). These are made by immunizing mice and “cloning” the cells that produce the most effective antibodies.

A team of scientists led by Dr. Nancy J. Sullivan of NIH’s National Institute of Allergy and Infectious Diseases (NIAID) set out to develop a simplified treatment with fewer antibodies by generating mAbs from human survivors of Ebola virus disease. Results appeared online in 2 papers on February 25, 2016, in Science.

The researchers obtained blood samples from a survivor of the 1995 Ebola outbreak in Kikwit, Democratic Republic of the Congo. Tests showed that, more than a decade after infection, the survivor retained antibodies against Ebola. Collaborators from the Institute for Research in Biomedicine in Switzerland then cloned antibody-producing B cells from the survivor to make mAbs for potential use as a therapeutic for Ebola infection.

The NIAID researchers found that 2 of the mAbs (mAb110 and mAb114) had unique properties and were the most potent against Ebola virus.

Collaborators from the U.S. Army Medical Research Institute of Infectious Diseases administered a lethal dose of Zaire ebolavirus to 4 rhesus macaques, then treated 3 of the animals, beginning a day later, with a mixture of the mAbs for 3 consecutive days. The untreated control macaque developed Ebola virus disease and succumbed to the virus, but the treated animals survived and remained free of Ebola symptoms.

Since mAb114 was the most potent mAb, the researchers tested it alone. They found that even when treatment began 5 days after virus exposure—a delay common in an outbreak setting—the treated animals survived and remained free of Ebola symptoms.

The NIAID team and Dartmouth College colleagues also performed a structural analysis, described in the second paper, of how mAb110 and mAb114 prevent the Ebola virus from entering target cells. Most notably, they found that mAb114 binds to a novel site of vulnerability on the Ebola virus that was previously thought to be unreachable by antibodies.

“The antibody mAb114 is the first to demonstrate the ability to neutralize the virus by this mechanism,” Sullivan says. “Together the evidence shows a single antibody could prove to be an effective therapy against Ebola virus disease and warrants further exploration in clinical trials.”

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Reference: Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, Ploquin A, Doria-Rose NA, Staupe RP, Bailey M, Shi W, Choe M, Marcus H, Thompson EA, Cagigi A, Silacci C, Fernandez-Rodriguez B, Perez L, Sallusto F, Vanzetta F, Agatic G, Cameroni E, Kisalu N, Gordon I, Ledgerwood JE, Mascola JR, Graham BS, Muyembe-Tamfun JJ, Trefry JC, Lanzavecchia A, Sullivan NJ. Science. 2016 Feb 25. pii: aad5224. [Epub ahead of print]. PMID: 26917593.
Structural and molecular basis for Ebola virus neutralization by protective human antibodies. Misasi J, Gilman MS, Kanekiyo M, Gui M, Cagigi A, Mulangu S, Corti D, Ledgerwood JE, Lanzavecchia A, Cunningham J, Muyembe-Tamfun JJ, Baxa U, Graham BS, Xiang Y, Sullivan NJ, McLellan JS. Science. 2016 Feb 25. pii: aad6117. [Epub ahead of print]. PMID: 26917592.

Funding: NIH’s National Institute of Allergy and Infectious Diseases (NIAID).