By Dr. Christopher G. Earnhart
“As the threat space has grown less predictable, it has become evident that preparedness must expand beyond a specific pathogen focus to include a response strategy for emerging, unanticipated, and potentially engineered threat agents,” writes Dr. Christopher G. Earnhart.
Whether it be poisoned arrows and bullets, wells contaminated with corpses, or plague-ridden bodies catapulted over city walls, the use of biological weapons goes back centuries. With the introduction of the “germ theory” that diseases are caused by microscopic organisms, the 19th century ushered in a new understanding of the mechanisms of biological agents, thus enabling their deliberate use in warfare.
In the 20th century, trained scientists in state-level programs weaponized pathogens and toxins, however the difficulty of creating functional bioweapons led to a relatively stable and finite (though not short) list that included weaponized smallpox, anthrax, botulinum toxin, and plague, among others. In response, there have been significant efforts by the U.S. Department of Defense and interagency partners to develop and procure medical countermeasures (MCMs) such as vaccines, antibodies, and antivirals to protect the warfighter and the nation.
In the 21st century, rapid advances in biotechnology have created a dynamic and increasingly unpredictable threat environment. Molecular biology tools and methods are both increasingly sophisticated and broadly accessible. With easily acquired commercial kits and internet-published methods, altering an organism’s DNA no longer requires doctoral training and expensive infrastructure. This has substantially lowered entry barriers for bioweapons development. Technical advances can also improve the efficiency of state-level programs in discovering new agents or modifying existing ones to subvert MCMs. These advances may fuel a less predictable era of biowarfare, and biodefense must adapt to this evolving reality.
To maintain preparedness in an evolving threat space, a series of strategic pivots were initiated and have been matured over the past decade. These strategies have been tuned by lessons learned during the COVID-19 response, creating a much more mature and integrated approach to both preemptive and reactive preparedness. These pivots included leveraging MCM platforms already used and matured by industry, operationalizing a highly integrated capabilities-based preparedness posture, and improving and employing computational approaches for MCM development.
Pivot 1: Medical Countermeasure Platforms
The JPEO-CBRND Platforms for Rapid Integrated Solutions for MCMs (PRISM) office implemented what was at the time a novel concept: platform-based approaches to streamline development of MCM candidates. A platform is typically a product class that has broad utility, similarity in structure and mechanism of action, and standardized development, manufacturing, and regulatory approaches. As an analogy, if the Department of Defense developed a single truck chassis to use as a flat-bed, box truck, and ambulance, it could simplify development, testing and evaluation, supply chain, and production of all vehicle types using that platform chassis.
For MCMs, monoclonal antibodies (mAbs) are a platform where an antibody ‘chassis’ can be adapted to neutralize a broad range of biological threat agents and can be developed using processes already matured by industry and are similar for all mAbs. There are over 120 fully licensed mAbs, thus the U.S. Food and Drug Administration is very familiar with their production, safety profile, and mechanisms of action. These platform characteristics have enabled mAb MCMs to be developed in a shorter timeframe, at lower cost, and with reduced developmental risk. Due in part to these efficiencies, mAbs are now a prominent product type for many biodefense indications, saving time and money across the portfolio.
Pivot 2: Create and Integrate a Capabilities-based Preparedness Posture
It became apparent that the efficiencies of platform approaches could enable a rapid response to an unanticipated threat, but only when coupled with the appropriate development, manufacturing, and testing capabilities. The JPEO-CBRND Enabling Biotechnologies office was assigned to develop a system-of-systems by assembling, maturing, integrating and stabilizing the capabilities required for a rapid response to an unanticipated pathogen. Lessons learned during the COVID-19 response have enabled a focus on approaches that significantly reduce developmental durations and stabilize emergency access to key performers.
Critical to a response is the ongoing understanding of the appropriate developmental risk tolerance needed to balance rapidity of development with product safety and efficacy while limiting technical failures during a critical biodefense response. This evolving system is methodically reducing timelines to enable what was previously seen as an impossible goal – medical rapid response. Many of these response enablers and concepts are now at the forefront of Department of Defense and national biodefense strategies.
Pivot 3: Computational Biology to Enable Response
Despite the responsiveness and developmental risk reduction made possible by use of platforms and capabilities-based approaches, the fundamental properties of biological systems eventually create a limit to the speed of traditional experiment-driven drug development, necessitating highly innovative approaches to further reduce timelines. Long contemplated, a transition from experimental to computational drug design was only recently seen as a real possibility, enabled by massive innovation in high performance computing and computational biology.
In addition to time savings, the high risk of failure in MCM development can be significantly reduced if critical quality attributes such as efficacy, safety, and manufacturability are simultaneously computationally optimized prior to an MCM ever being physically made. The Emerging Biotechnologies office, in collaboration with the Department of Energy, has recently launched the Generative Unconstrained Intelligent Drug Engineering (GUIDE) program to develop computational MCM discovery and design approaches leveraging the latest methods in artificial intelligence, large language models, machine learning and molecular simulation.
Even during the foundational stage of the program, GUIDE is discovering specific countermeasures against known threats to enable preemptive preparedness. Within the Emerging Biotechnologies technical portfolio, GUIDE establishes and maintains superiority in rapid response MCM development over adversaries that may use computational methods for bioweapons design.
Christopher G. Earnhart, PhD, is the Chief Technology Officer in the Enabling Biotechnologies office at the Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense (JPEO-CBRND) of the US Department of Defense. This essay is based on his experiences in his current role and as Joint Product Lead of the Platforms for Rapid Integrated Solutions for Medical Countermeasures office.
