U.S. military efforts in biological warfare defense readiness prove themselves with Ebola response.
The 2014-2016 outbreak of Ebola virus disease triggered an unprecedented public health disaster. For the first time since its discovery in 1976, Ebola struck large, crowded and mobile urban populations. It was the largest Ebola outbreak in both numbers of cases and geographic distribution, with more than 28,000 cases, 11,000 deaths, and 10 times the number of all previous Ebola outbreaks combined. The virus spread rapidly through Guinea, Liberia and Sierra Leone, striking Mali, Nigeria, Senegal, Spain, the United Kingdom and the United States as well. In the public health crises over past 100 years, only the 1918 influenza pandemic, the emergence of the human immunodeficiency virus, AIDS in the 1980s and the recent surge in antibiotic-resistant bacterial infections, had greater impacts than Ebola.
Coordinated actions are what ended the Ebola outbreak. The total numbers of cases and deaths ultimately were far below initial projections, in large part because of the use of medical products originally developed by DOD to counter biological warfare threats.
Several lessons can be drawn from this experience to better prepare for future outbreaks. For one, products for biological warfare defense can be used for naturally occurring epidemics. For another, partnerships with other federal, private sector and host-nation stakeholders were key; nevertheless, DOD’s investment to develop medical products for rare but lethal diseases like Ebola was critical. In addition, the response to the Ebola outbreak underscores the difficulty of conducting clinical research during an epidemic and the corresponding need to proactively stage clinical trial sites.
LITTLE NOTICE BEFORE 2014
Because Ebola is a biological warfare threat, DOD’s biological defense program has been developing medical countermeasures for over a decade. As a result, DOD has a portfolio of products and capabilities, unmatched by any other organization in the world, to counter a historically rare tropical disease that, before the 2014-2016 outbreak, had received little in the way of financial investments from civilian investors, or privately funded efforts for medical countermeasure development by the pharmaceutical industry.
An organization within DOD’s Joint Program Executive Office for Chemical and Biological Defense, called the Joint Project Manager for Medical Countermeasure Systems (JPM-MCS), gave crucial support to the U.S. government and international responses to the Ebola outbreak. DOD sponsored the development of vaccines, diagnostic tests and treatments against the Ebola virus as part of its program to counter biological weapons. Thus, DOD was positioned to offer vaccines, diagnostic tests and treatments that only a biological defense program would generate.
The first step in responding to a biological attack—or a naturally occurring epidemic—is to identify the cause. JPM-MCS provided the diagnostic test that confirmed the first cases of Ebola in Sierra Leone, and provided test kits that enabled DOD personnel in seven mobile laboratories to process 4,709 samples during 2014 and 2015. The U.S. Food and Drug Administration (FDA) granted emergency use authorizations to two diagnostic tests that JPM-MCS sponsored for Ebola: EZ-1 and BT-E. EZ-1 was used in Africa, the Ebola treatment centers in the United States and at the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).
In 2014, kits to run more than 20,000 patient tests were placed in DOD medical treatment facilities and the U.S. Centers for Disease Control and Prevention (CDC) Laboratory Response Network. BT-E, as part of JPM-MCS’s Next Generation Diagnostic Systems Increment 1, runs on a device used daily in the clinical labs of military and civilian hospitals to diagnose common infections. It is ready for use at USAMRIID and 16 DOD medical facilities. The EZ-1 inventory available at DOD medical treatment facilities is being phased out by BT-E, which received full FDA clearance for clinical use in February 2017.
VACCINES, READY TO GO
The approach of choice for any disease is prevention. For more than 10 years, JPM-MCS has partnered with the Defense Threat Reduction Agency’s Joint Science and Technology Office (JSTO), the Walter Reed Army Institute of Research, the U.S. Department of Health and Human Services (DHHS), the National Institute for Allergy and Infectious Diseases and the Biomedical Advanced Research and Development Authority (BARDA) and other stakeholders to deliver an Ebola vaccine candidate as an accelerated offshoot of a long-standing project to produce a vaccine to counter three biological warfare threats. (The other two are Sudan and Marburg viruses.) Thanks to 50,000 vaccine doses provided by JPM-MCS, this candidate entered clinical trials in West Africa to evaluate its ability to protect caregivers, case contacts and others at risk, and conferred 100 percent protection 10 or more days after vaccination.
In addition to providing a vaccine candidate to prevent illness, JPM-MCS and JSTO immediately offered three potential therapies to treat patients with the disease, each with unique mechanisms of action.
Favipiravir is a small molecule that inhibits a viral enzyme; TKM silences viral genes; and ZMapp neutralizes the virus through an antibody-mediated action. Favipiravir, TKM-Ebola and ZMapp were used on an emergency basis to treat patients evacuated to the United States and Europe. Favipiravir and TKM-Ebola also were evaluated in Africa by commercial sponsors in collaboration with European and host-nation agencies. However, clinical trials did not confirm the potential suggested by animal testing, perhaps in part because of study design and the severity of disease in patients enrolled in the studies. A U.S. government-sponsored trial of ZMapp gave promising results, but because the study began late in the epidemic, only a small number of patients could be enrolled, limiting the conclusions that could be made. This study is ongoing, along with other studies to identify an Ebola treatment.
Moreover, JPM-MCS plays a key role in operational response. Efforts include collaborations with USAMRIID, DHHS and the World Health Organization to enhance the quality of medical care in developing countries, to prioritize vaccines and therapies for clinical trials, and to establish clinical trial sites in Africa.
Because conducting clinical studies during outbreaks is extremely difficult, an optimal approach would integrate research into outbreak response and would establish teams of host-nation researchers. This approach would designate clinical trial sites and establish study protocols that have clearance from the FDA and host-nation regulatory authorities.
JPM-MCS is sponsoring the Joint Mobile Emerging Disease Intervention Clinical Capability, in partnership with Ugandan medical authorities, to build a research capacity that can deploy to remote treatment units during an outbreak. A study of severe infections in austere settings, expected to begin in August, will provide a baseline activity to enable staff recruitment, training and maintenance of medical and research skills.
Operation Desert Storm and the ongoing civil war in Syria underscore the threats posed by chemical and biological weapons. JPM-MCS delivers products to strengthen medical readiness against the entire spectrum of chemical, biological, radiation and nuclear weapons. Successes include a diagnostic device that identifies six biological weapon agents, an autoinjector to deliver chemical agent antidotes, a smallpox vaccine mass-produced using state-of-the-art methods, and a capability to expand the manufacturing of medical products.
Ongoing projects include four next-generation antidotes for chemical agents and vaccines and treatments for 12 biological weapon threats. Countermeasures for radiation and nuclear threats are coordinated in partnership with BARDA. These enhance the ability of the U.S. military to fight and win in chemical, biological, radioactive and nuclear theaters of operation.
JPM MCS is a defense management organization dedicated to the development of medical products to counter biological warfare threats, producing diagnostic tests, a vaccine candidate and treatments that supported humanitarian relief efforts during a catastrophic disease outbreak. These capabilities would not have been possible without investment in a biological defense program. The response to the Ebola outbreak demonstrates that medical countermeasures for biological warfare defense under field conditions are adaptable to the inevitable and dynamic challenges of naturally occurring epidemics in austere settings.
It also underscores the versatility and value of DOD’s biological defense program and the products it generates. For example, having three treatment options ready to deploy against Ebola, each with a different mechanism of action, was a result of DOD’s balanced portfolio. This is by design, and benefits the global medical community. The coordination of biological defense and public health response is essential to optimize outcomes and ensure efficient use of resources, because the challenges posed by both biological weapons and natural epidemics are open-ended. Though this particular outbreak has ended, continued funding and study will be needed to prevent and manage future outbreaks.
For more information on the DOD response to the Ebola epidemic, go to http://archive.defense.gov/home/features/2014/1014_ebola/.
GEORGE CHRISTOPHER, Lt. Col., USAF, MC (Ret), is the chief medical officer of JPM-MCS. He holds a doctor of medicine degree from the University of Virginia and a B.A. in preprofessional studies from the University of Notre Dame. He is board-certified in internal medicine and infectious diseases, and has supported DOD biological defense programs in provider education, operations and medical countermeasure development since 1996.