WASHINGTON, Dec. 12, 2014 —
Since 2003, the Defense Threat Reduction Agency has invested more than $300 million to develop medical countermeasures against hemorrhagic fever viruses, and those efforts are paying off today in potential new ways to fight Ebola virus disease.
DTRA’s mission is to protect the United States and its allies from chemical, nuclear, biological and other weapons of mass destruction, and deadly pathogens fall into the WMD category, DTRA Deputy Director Air Force Maj. Gen. John Horner said during a recent interview with DoD News.
“We plan to be in this business for the long term,” he added, “and need to do biosurveillance and strengthen biosecurity worldwide, helping partner countries build their capacity to prevent, treat and monitor the threat of infectious diseases.”
More than 17,290 cases of Ebola virus disease and at least 6,128 deaths have been reported to date in West Africa, according to the World Health Organization and the Centers for Disease Control and Prevention, and the lack of licensed Ebola vaccines and treatments has accelerated efforts, including DTRA’s, to get these medical products into the regulatory approval pipeline.
Ebola Vaccine Candidates
This year, in coordination with DTRA, the Public Health Emergency Medical Countermeasures Enterprise working group chose three lead candidates –- two vaccines and one treatment –- to go forward in the Food and Drug Administration approval pipeline as part of the U.S. Ebola outbreak response.
The vaccine candidates are recombinant VSV-EBOV, from BioProtection Systems/Newlink Genetics, and ChAd-EBOV from GlaxoSmithKline. DTRA is supporting development of the VSV-EBOV vaccine through a contract with BioProtection Systems/Newlink Genetics. NIAID is supporting the ChAd-EBOV vaccine.
The VSV candidate is based on a recombinant, or genetically engineered, virus from an animal disease called vesicular stomatitis. An Ebola virus protein is engineered into a vesicular stomatitis virus, and the new recombinant virus acts as a vector, or carrier, to deliver the Ebola protein into the human body. Genetic engineering is a healthy way to express proteins like Ebola that prompts the body to produce antibodies to lethal Ebola virus disease without the risk of disease from either virus
The other vaccine is a recombinant chimpanzee adenovirus, or cold virus. In this vaccine, an Ebola virus protein is engineered into a chimpanzee adenovirus to deliver the ChAd-EBOV vaccine into people to produce Ebola antibodies.
Human Testing is Underway
Human testing to evaluate the safety of VSV-EBOV is underway at the National Institutes of Health Clinical Center in Bethesda, Maryland and the Walter Reed Army Institute of Research, or WRAIR.
Researchers at the NIH National Institute of Allergy and Infectious Diseases, or NIAID, are conducting an early phase trial to evaluate the VSV-EBOV vaccine for safety and for its ability to generate an immune-system response in healthy adults who receive two injected doses.
At the same time, the WRAIR is testing the VSV-EBOV vaccine as a single dose at its Clinical Trials Center in Silver Spring, Maryland, NIH officials said.
For the ChAd-EBOV vaccine, in early stage clinical trials, again designed to assess vaccine safety and immune response, NIAID will test two versions of ChAd-EBOV.
One is a bivalent, or two-component, version containing genetic material from Ebola Zaire and Ebola Sudan strains. The other is a monovalent, or single-component, version that contains only genetic material from Ebola Zaire, the strain now causing the outbreak in West Africa.
Both vaccines were reviewed by the FDA under an investigational new drug, or IND, application.
Evaluating Vaccine Efficacy
“We should begin to see Phase II and III clinical trials take place in West Africa, probably in the January-February timeframe,” Dr. Ronald K. Hann Jr., director of research and development in DTRA’s Chemical and Biological Technologies Department, said.
He explained that these clinical trial phases evaluate the vaccines’ efficacy, or how well they work.
“We spoke to Doctors Without Borders [recently], and they're helping to map out the Phase II-III clinical trial studies that would be taking place in West Africa,” Hann added, “and they're looking at both the [ChAd-EBOV and VSV-EBOV] vaccine candidates to go into those trials.”
Once either vaccine shows protection, according to a DTRA fact sheet, the trial will stop and the vaccine will be distributed in a mass immunization campaign to help end the Ebola epidemic.
A Promising Ebola Treatment
The lead therapeutic treatment candidate that DTRA and the Public Health Emergency Medical Countermeasures Enterprise working group named to move forward into the FDA pipeline is called ZMapp, from Mapp Biopharmaceutical.
But as early as 2007, DTRA, NIAID and the U.S. Army Medical Research Institute for Infectious Diseases, or USAMRIID, were funding efforts and working hard to show that the monoclonal antibody basis for the experimental drug actually would work.
ZMapp is a cocktail of three different monoclonal, or genetically engineered, Ebola virus disease antibodies that bind to Ebola virus proteins in the body and neutralize the virus, decreasing the amount of virus the patient's immune system has to fight.
Dr. Erin Reichert, chief of the Translational Medical Division of the Chemical and Biological Technologies Department in DTRA’s Research and Development Directorate, describes the road to development for ZMapp.
“Along with our colleagues at USAMRIID and NIAID, we had a small investment in looking at whether or not monoclonal antibodies or antibody-based therapeutics in general would be an appropriate therapeutic countermeasure for Ebola,” she said.
In the scientific community, as early as 2007, researchers debated the value of this so-called passive immunotherapy, or passive transfer, for treating Ebola.
“We funded researchers at USAMRIID, and NIAD had small investments through small-business grants directly to Mapp Biopharmaceutical to determine once and for all if antibodies could be a viable countermeasure”, Reichert said.
Then in the 2012 timeframe, she added, important publications came out of USAMRIID that changed the way researchers viewed antibodies for filovirus infection. Ebola and Marburg viruses both are filoviruses.
“One of those papers was by [Dr. John M. Dye Jr., now chief in USAMRIID’s Viral Immunology Branch],” Reichert said. “He demonstrated for the first time that antibodies from primates exposed to Ebola virus could be transferred to naive primates to protect them from infection. That opened the door for this as far as a viable countermeasure.”
Putting Dollars Against the Product
Also in 2012, she added, DTRA and NIAID “really started putting some dollars against the product and in a very short period of time we were able to accelerate development to a point where, while it is still a [research and development] product, we have a product that could be useful in people.”
ZMapp was developed through a DTRA contract with Mapp Biopharmaceutical and in collaboration with USAMRIID, Defyrus LLC and the Public Health Agency of Canada, according to a DTRA fact sheet.
The ZMapp three-antibody cocktail was discovered in 2014 but the monoclonal antibody research began in 2007.
BARDA is sponsoring the manufacture of ZMapp for Phase I and II clinical studies, which are expected to start in early 2015 at NIAID. Other clinical studies are scheduled to begin in affected African countries in early 2015. ZMapp has been used under an emergency investigational new drug application in Ebola-infected patients in the United States, Africa and elsewhere, according to a White House fact sheet.
Protecting the Force
“We’ve been working very closely with our interagency partners to develop these vaccines and therapeutics to protect the force against a broad range of filoviruses,” Reichert said.
In response to the West Africa Ebola epidemic, development of vaccines and ZMapp has accelerated to focus specifically on delivering something for Zaire, she added.
“Along with our interagency partners -- HHS as well as JPEO have been really critical –- we’ve been able, in a very short period of time, to push those through the regulatory process to get them to a point where they may have an impact on the current epidemic,” Reichert said.
(Follow Cheryl Pellerin on Twitter @PellerinDoDNews)