ZMapp Trial Gives Hope for Ebola Treatment and Emergency Response

Author:  Joshua Smith-Sreen

Institution:  Boston University

The recent Ebola epidemic killed more than 11,000 people and infected more than 28,000 between 2014 and 2016 (1). The outbreak began in the early spring of 2014, when a new variant of the Ebola virus emerged in Guinea and rapidly spread throughout West Africa (2). This crisis prompted an immediate response from the scientific community to try to develop an effective therapy for the diversity of symptoms, from fever and weakness to bleeding from the eyes (2), which characterize the viral disease.  Fortunately, a drug was recently found to have the potential to treat the Ebola Virus Disease, according to findings from the clinical trial PREVAIL II in the New England Journal of Medicine on October 13.

A model of the Ebola Virus with the embedded glycoproteins that are targeted by ZMapp

A model of the Ebola Virus with the embedded glycoproteins that are targeted by ZMapp

The drug, ZMapp, was proven to be safe and tolerable for patients in this randomized, controlled trial. The purpose of the trial was to compare the drug to the most effective treatment now, known as the optimized standard of care, in which patients are provided with intravenous fluids, balancing electrolytes and sufficient oxygen levels (4). However, ZMapp’s benefit when compared to optimized standard care alone could not be definitively determined, due primarily to the low number of enrolled patients, which only reached 72 (4).

ZMapp is a protein-based drug developed by San Diego-based Mapp Biopharmaceutical Incorporated. The drug is a cocktail of three different laboratory-synthesized proteins called monoclonal antibodies. Essentially, the drug functions by targeting a major membrane glycoprotein of the virus responsible for host cell infection (5). The three monoclonal antibodies function in conjunction to neutralize this glycoprotein, through a mechanism not fully understood by researchers, inhibiting the reproduction of the virus in a host (5).

More than anything, this clinical trial demonstrated the ability for a controlled test of a drug during a dire public health emergency such as the recent outbreak of the Ebola Virus Disease (EVD).

“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.” said Anthony S. Fauci, the director of the National Institute of Allergy and Infectious Diseases, or NIAID (4).

This study was launched in February of 2015 (6) as a collaborative effort between NIAID and the Liberian Ministry of Health, labelled as the Partnership for Research on Ebola Virus in Liberia (PREVAIL). The project later involved partners based in Sierre Leone and Guinea, as well as a French national research institution, INSERM (4).

Prior to the launch of the clinical trial, ZMapp had been used to treat several patients in early 2015, but its efficacy could not be scientifically proven in humans. Earlier studies showed successful reversion of advanced-stage EVD using ZMapp in nonhuman primates (2), and so a study of the drug on humans was certainly warranted.

PREVAIL II enrolled 72 patients of all ages, originating from Sierra Leone, Guinea, Liberia and the United States. Investigators were forced to close the study preemptively in January as they were unable to obtain new participants due to the diminishing number of Ebola cases as the outbreak subsided. They had aimed for 200 participants. All of the patients were provided with the optimized standard of care, and half additionally received three intravenous doses of ZMapp three days apart (3).

The survival rates between the groups was compared after 28 days of the trial. There were thirteen deaths in the group of 35 that received only the optimized standard of care - a 37% mortality rate (3). There were eight deaths in the group of 36 that received both the optimized standard of care and the ZMapp treatment - a 22% mortality rate (3). Although these results seem to indicate a lower risk of death with ZMapp treatment, statistical significance could not be reached (p < 0.05) and so the trial was ultimately inconclusive (3).

Should another outbreak occur or the spread experience a resurgence, Mapp Biopharmaceuticals is permitted under an Expanded Access Protocol to offer ZMapp to patients in the four countries in which the trial took place. The US Biomedical Advanced Research and Development Authority will fund this future implementation. 

Some may take these results to mean that “ZMapp might not be a game-changer” in the world of Ebola treatment as CNN’s Jen Christensen put it (1).

However, PREVAIL II brought more than inconclusive data. It was the first clinical trial of its kind, held in a controlled, scientific environment amidst the chaos of a public health crisis, and provided hope for a more successful response to future Ebola outbreaks.