ZMapp

Schematic representation of how monoclonal antibodies are generally made from hybridomas. To make ZMapp, the genes encoding for the antibodies were extracted from the hybridomas, genetically engineered to replace mouse components with human components, and transfected into tobacco plants.

Monoclonal antibodies

ZMapp is an experimental biopharmaceutical drug comprising three chimeric monoclonal antibodies under development as a treatment for Ebola virus disease.

Chemistry

The drug is composed of three monoclonal antibodies (mAbs), initially harvested from mice exposed to Ebola virus proteins, that have been chimerized with human constant regions.

Mechanism of action

Like intravenous immunoglobulin therapy, ZMapp contains a mixture of neutralizing antibodies that confer passive immunity to an individual, enhancing the normal immune response, and is designed to be administered after exposure to the Ebola virus.

History

Two of the drug's three components were originally developed at the Public Health Agency of Canada's National Microbiology Laboratory (NML), and a third at the U.S. Army Medical Research Institute of Infectious Diseases; the cocktail was optimized by Gary Kobinger, then branch chief of the NML, and is undergoing further development by Leaf Biopharmaceutical (LeafBio, Inc.), a San Diego-based arm of Mapp Biopharmaceutical.

Clinical trial

A clinical trial to evaluate the experimental Ebola treatment ZMapp found it to be safe and well-tolerated; however, because of the waning Ebola epidemic, the study enrolled too few people to determine definitively whether it is a better treatment for Ebola virus disease (EVD) than the best available standard of care alone.

Anthony Fauci state on ZMapp

“Importantly, the study establishes that it is feasible to conduct a randomized, controlled trial during a major public health emergency in a scientifically and ethically sound manner.”

—Anthony S. Fauci, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

“Although we do not have definitive evidence that ZMapp is superior to the optimized standard of care, the results of the PREVAIL II trial are promising and provide valuable scientific data,” said Anthony S. Fauci, M.D., director of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. “Importantly, the study establishes that it is feasible to conduct a randomized, controlled trial during a major public health emergency in a scientifically and ethically sound manner.”

ZMapp composition

ZMapp, developed by Mapp Biopharmaceutical, Inc., based in San Diego, is composed of three different laboratory-made proteins called monoclonal antibodies.

Purpose

The treatment is designed to prevent the progression of EVD within the body by targeting the main surface protein of the Ebola virus.

Animal studies

Studies in primates demonstrated that ZMapp had strong antiviral activity and prevented death when administered as late as five days after experimental infection with Zaire ebolavirus.

Study collaboration

The study launched through a collaboration between the Liberian Ministry of Health and NIAID, known as the Partnership for Research on Ebola Virus in Liberia (PREVAIL). It later expanded to include research partners within the countries of Sierra Leone and Guinea and the French medical research organization INSERM.

Principal investigator

The study team was led by co-principal investigators Richard T. Davey, Jr., M.D., deputy clinical director of NIAID's Division of Intramural Research; Moses Massaquoi, M.D., National Chair for Case Management at the Ebola Incident Management System in Monrovia; Foday Sahr, M.D., Brigadier General and First Surgeon General of the Republic of Sierra Leone Armed Forces; and Denis Malvy, M.D., Ph.D., head of the tropical medicine division at the University Hospital of Bordeaux and permanent senior researcher at INSERM.

Study

The trial enrolled 72 participants of any age with confirmed Ebola virus infection from March 2015 through November 2015. The participants came from Sierra Leone (54 patients), Guinea (12 patients), Liberia (five patients) and the United States (one patient, a health care worker evacuated from Sierra Leone).

Average age

The average age of the participants was 24 years, and slightly more than half were women. Investigators closed the study in January 2016 because they could not enroll additional patients, up to the targeted 200, because of the decline in the number of new Ebola cases as the outbreak diminished.

Study end points

The study sought to determine if the experimental drug ZMapp plus the optimized standard of care for treating EVD — providing intravenous fluids, balancing electrolytes needed to maintain bodily functions, and maintaining healthy oxygen and blood pressure levels — was superior to the optimized standard of care alone in reducing deaths caused by EVD.   All participants received the optimized standard of care, and half were randomly assigned to also receive three intravenous infusions of ZMapp administered three days apart. Investigators compared the number of deaths in each group at 28 days after enrollment.

Results

Thirteen deaths (37 percent mortality) were reported in the group of 35 patients who received the optimized standard of care only, while eight deaths (22 percent mortality) occurred in the ZMapp group of 36 patients. One patient left treatment early and was not included in the analysis. Although the difference between the two groups translates to a 40 percent lower risk of death for those who received ZMapp, the difference did not reach statistical significance.

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