Sunday, January 4, 2015

DARPA's 7-Day Bio-Defence and the Future of Synthetic Vaccines

US military personnel don special biohazard gear during a training exercise designed to simulate a biological weapon attack. The Department of Defense and other agencies routinely hold training sessions throughout the country as part of a domestic bioterrorism preparedness program. 'The challenge is to integrate these forces to mount an effective response under various attack scenarios," says Prof. Steven Block. Courtsey: US Navy 

Author's note: In 2007, I attended a bio-defence briefing in Washington D.C., delivered by a DARPA scientist. It was as one would expect from DARPA, an incredible presentation on pipeline technologies. Since then I have always thought of DARPA as the 'bugs on the wall folks' and indeed they have successfully produced robotic bugs, but more significantly, in the briefing they discussed advanced bio-defence technologies which we were not allowed to take notes on or photograph the slides of; it was extremely exciting and I left with a sense of awe which DARPA tends to inspire.

Six years later, they have successfully manufactured 10 million doses of H1NI (flu) vaccine within a month. For pharmaceutical companies who invest up too and over a billion per drug and not forgetting the length of time one vaccine can take to bring to market, about ten years, the DARPA/Medicago manufacturing of 10 million doses of H1N1 in one month was a phenomenal feat. Here we are on the threshold of major breakthroughs in vaccine research, development and production, even manufacturing technologies and the future of bio-defence couldn't look brighter. While industry of course continues to work on live attenuated vaccine production is the future a synthetic one?

Current vaccine production based on inactivated  viruses (live attenuated vaccines), has been successful in reducing significant disease burden associated with major epidemics of the 19th and 20th centuries. However, a major draw back has been the lengthy research and development phase, the significant investment costs and the inability to respond rapidly to changing strains. Synthetic vaccines may overcome many of the more traditionally based production obstacles. In 2012 DARPA announced it's Blue Angel Program. On their site they lay out the problem quite concisely with regard to responding to pandemics of the future. Such pandemics may or may not be natural and may or may not be caused by natural pathogens, viruses and toxins. Consider fighting a synthetically produced outbreak. The DARPA site states:

"The 2009 Army Posture Statement, cites a World Health Organization estimate of between 20 annd 50 percent of the world's population being effected if a pandemic were to emerge. WHO forecasts 'it may be six to nine months before a vaccine for a pandemic virus strain becomes available." In a separate report on pandemic influenza, the WHO described several challenges to producing sufficient volumes of vaccine using current, egg based protein-production technology, including the likelihood that two doses per person could be required due to the absence of pre-existing immunity. In short, the potential for a pandemic exists and current technological limitations on defensive measures put the health and readiness of U.S. military forces at risk. A technological solution to increase the speed and adaptability of vaccine production is urgently needed to match the broad biological threat. DARPA's Blue Angel Program seeks to demonstrate a flexible and agile capability for the Department of Defence to rapidly react to and neutralize any natural or intentional pandemic disease. Building on a previous DARPA program, Accelerated Manufacture of Pharmaceuticals, Blue Angel targets new ways of producing large amounts of high quality, vaccine grade protein in less than three months in response to emerging and novel biological threats. One of the research avenues explores plant made proteins for candidate vaccine production. "Vaccinating susceptible populations during the initial stage of a pandemic is critical to containment," said Dr. Alan Magill, DARPA program manager. "We're looking at plant based solutions to vaccine production as a more rapid and efficient alternative to the standard egg-based technologies, and the research is very promising." In a recent milestone development under Blue Angel, researchers at Medicago Inc. produced more than 10 million doses (as defined in an animal model) of an H1N1 influenza vaccine candidate based on virus-like particles (VLP) in one month. Production adhered to Phase 1 appropriate current good manufacturing practices. The work was part of a 'rapid fire' test that ran from March 25, 2012 to April 24, 2012, at a facility in Durham, NC. A third party laboratory tested the production lots to confirm the immunogenicity of the vaccine candidate. Testing confirmed that a single dose of the H1N1 VLP influenza vaccine candidate induced protective levels of hemagglutinin antibodies in an animal model when combined with a standard aluminum adjuvant. The equivalent dose required to protect humans from natural disease can only be determined by future, prospective clinical trials. 

DARPA's 7 Day Bio-Defence 

Photo: DARPA
In May, 2013 Medicago Inc. announced it had successfully produced a VLP vaccine candidate for the H7N9 virus responsible for an influenza outbreak in China. Medicago's future in VLP vaccines couldn't look brighter especially given their success with rapid vaccine production and their work with DARPA. 
An additional, although slightly different project which I believe will make significant strides in bio-defence counter-measures is DARPA's 7-Day Bio-Defence project, again, worth considering in terms of how future vaccines will be manufactured and how investment in this technology could well shift. As stated on their site:

"Military readiness and national security depends on the health and well being of military service members. The Department of Defence's (DoD) cumulative investment in personnel comprises the second largest share of the total defence budget. As such DoD seeks advances in health care to ensure war-fighters can operate at peak performance. Research into natural and synthetic pathogens, and treatments against them is one plank of ensuring military readiness in the face of accidental and offensive biological threats to both war-fighters and the supply chain supporting them. In this context, the 7-Day Biodefence program will seek to develop novel technologies focused on preventing infection by any emerging pathogen, sustaining survival once infected, and building immunity. In recent years, global surveillance networks have determined an increase in the frequency and diversity with which new infectious micro-organisms are emerging. While this increase is due in part to improved reporting, multiple examples demonstrate it is also promulgated by changes in natural systems and possibly human activity. The potential biological threat breaks down into two primary categories: 

1. Exposure to natural pathogens that are the result of: increased human-animal interface; increased population densities and co-location of vulnerable species with pathogen reservoirs; climate change, particularly affecting migration and spread of vectors; and narrowing of genetic diversity among food-animal stocks. 

2. Exposure to synthetic and highly diverse pathogens that have become easier to produce as bio medical and genetic-engineering technologies proliferate internationally; such that pathogens could be used by adversaries for offensive purposes in a direct attack on war-fighters for covert sabotage of the agricultural industry that supports war-fighters. 

Together, these emerging threat agents challenge current medical countermeasures. Today's research and development cycle for countermeasures is ill-equipped for rapid response to emerging biological threats. In response to the unspecified potential threat from emerging pathogens, the goal of the 7-Day Biodefence program is to develop innovative approaches to counter pathogens without regard to their exact nature. The methods being explored do not require prior knowledge of the pathogen and are broadly applicable to multiple, unrelated infectious agents. The program consists of four technical areas investigating novel technologies to: 1. prevent infection; 2. sustain survival; 3. provide transient immunity; and 4. create persistent immunity. See:

Advances in synthetic vaccine manufacturing, VLP's and even 3D bio-printing will significantly change our concept of bio-defence and the manufacturing process of medical counter-measures. The incorporation of these counter-measures will additionally change how we approach threat reduction and possibly remove many of the traditional concerns at the technical level. This could increase interest in areas which have typically been an after thought.

Dr. Jill Bellamy is an internationally recognized expert on biological warfare and defence. She has formerly advised NATO and for the past seventeen years has represented a number of bio-pharmaceutical and government clients working on procurement strategy between NATO MS and Washington DC. Her private government relations consultancy Warfare Technology Analytics is based in the Netherlands. Dr. Bellamy's articles have appeared in the National Review, The Wall Street Journal, The Washington Post, The Sunday Times of London, Le Temps, Le Monde and the Jerusalem Post among other publications. She is a CBRN SME with the U.S. Department of Defence, Chemical, Biological, Radiological and Nuclear Defence Information Analysis Center and CEO of Warfare Technology Analytics.

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