Abstract
Introduction
In the fourth year of a global pandemic, we have had sufficient time to assess the effects of COVID-19 on US national security and public health. In terms of national security, the outbreak on the USS Theodore Roosevelt serves as a critical example of how a disease event can drastically affect force readiness. 1 On the public health side, beleaguered healthcare workers continue to be stretched thin and are working to provide care in an increasingly politicized environment—a situation that is ongoing and unlikely to be fixed immediately due to continued low wages and a demoralized public health community that is continually harassed. 2 Meanwhile, stakeholders continue to be stymied on how to address misinformation and shifting guidelines on managing disease events, which has left the general public confused and frustrated. 3
Unfortunately, experts predict that disease outbreaks reaching epidemic and pandemic levels will happen more frequently without substantial intervention. This is due to anthropogenic effects such as climate change and activities that increase interactions between humans, animals, and insects in novel ways.4-6
Stakeholders prioritize biological threats through lists of known pathogens and biologically derived toxins, which has helped allocate scarce resources toward detecting, preventing, and preparing for known pathogens assessed on metrics such as lethality and infectivity. However, this list-based approach accounts for only the known realm of biological threats. 7 Further, the pathogens that are prioritized are either associated with past biological weapons programs or recent outbreaks. 8
Fortunately, advances in the life sciences, combined with emerging and evolving technical capabilities and big data, are empowering biodefense and public health stakeholders to scrutinize the unknown realm of biological threats. These advances are ushering in a potential age of threat agnostic approaches in the biospace that do not rely on identifying the specific agent or pathogen causing a biological event.
Detect, Prevent, and Prepare
The United States currently addresses biological threats in biodefense and public health using the detect, prevent, and prepare approach.
Detect
Detection is critical to addressing biological threats because it allows for the rapid deployment of resources and prevents events from spreading beyond control. To prevent emerging biological events from growing larger, US local, state, federal, and tribal territories use detection capabilities that can track circulating pathogens of interest in the immediate environment or identify outbreaks by aggregating reported cases. Even if such detection methods fail to prevent disease events entirely, advanced knowledge enables the United States to blunt the impact of these events by accelerating the research and development of diagnostics and therapeutics, as well as activating policies and implementation plans to respond to and recover from an event. 9
Currently, the US government applies its list-based approach across a number of programs and initiatives. Key interagency partners across the US government determine this list.10,11 Some examples of these programs and initiatives include the Centers for Disease Control and Prevention (CDC) Center for Forecasting and Outbreak Analytics (CFA), syndromic surveillance programs, such as BioSense, and efforts within the Department of Defense (DOD) Chemical and Biological Defense Program (CBDP).
Center for Forecasting and Outbreak Analytics
In 2022, the CDC created the CFA to “generate forecasts and analyses to support outbreak preparedness and response.” 12 The center also focuses on building collaboration and engaging in performance assessments to empower decisionmakers to improve outbreak responses. Recent calls for CFA funding applications included partnering with the CFA to strengthen this area by updating disease modeling and analytics at the local and regional levels. 13
The CFA has shown achievements even in its nascent stages. For example, the CFA was involved in the 2022 mpox outbreak within the United States, as well as during the early days of the COVID-19 Omicron variant surge. Although these examples were disease-specific, the CFA's work on building virtual analyst platforms and engaging industry partners can enable a more pathogen agnostic approach to forecasting.
The CFA's current approach is pathogen-specific, which has been successful in response to diseases like polio and COVID-19. However, in response to concerns that we also need to be prepared for unknown pathogens and toxins, the CFA is moving toward operating in a more agnostic-friendly manner. However, because each infectious disease is unique, a fully agnostic approach to biological threats within the CFA would also require supplementation through traditional methods such as syndromic surveillance. More recently, the CFA announced a new cooperative agreement opportunity to scale resources and strengthen resilience across academic, public, and private partnerships, with an emphasis on innovation and increasing decisionmaking support for jurisdictions during public health emergencies. 13 Such funding opportunities and calls for collaboration point to a growing shift toward agnostic public health readiness.
BioSense
Syndromic surveillance is a crucial component of early warning programs that is frequently used to identify an influx of potentially infectious patients within healthcare emergency departments. Tracking symptoms, versus directly identifying a pathogen, is an agnostic approach that can more quickly identify trends and initiate response measures. Such strategies have been used for infectious diseases, such as influenza, which proved helpful across several states in the analysis of 9 diagnostic codes and identification of influenza risk factors to prompt earlier observation of increasing numbers of cases despite inconsistent testing. The National Syndromic Surveillance Program (NSSP) is a collaborative effort across the CDC, federal partners, state and local health departments, academic partners, and healthcare facilities. 14 This program runs data through the BioSense Platform, which collects, analyzes, and shares “electronic patient encounter data received from emergency departments, urgent and ambulatory care centers, inpatient healthcare settings, and laboratories.” 15 This BioSense Platform was developed in response to congressional mandates within the Public Health Security and Bioterrorism Preparedness and Response Act of 2002, 16 which sought to bolster public health readiness through syndromic surveillance.
The NSSP and, thus, the BioSense Platform, is partnered with 6,200 healthcare facilities across the United States and has a 24-hour throughput from the point a patient visits a healthcare facility to the timeframe in which data are collected and analyzed. Currently, the BioSense Platform receives 6 million electronic health messages per day from emergency departments that represent 73% of the US healthcare infrastructure. The NSSP supports state and local health department utilization of syndromic surveillance, like that of Arizona, which uses key terms and codes within the electronic medical record system, such as chief complaint and discharge diagnosis, to establish a dashboard for hospital COVID-19 and influenza-like illness.15,17 Through this data collection, sharing, and analysis, public health officials have a stronger capacity to identify early signs of an outbreak.
Syndromic surveillance programs like that of the BioSense Platform, allow for a more synergistic relationship between healthcare facilities and public health authorities. Once this relationship is established, little resource investment is required from the data supplier. The NSSP harnesses a threat agnostic approach to early warning through data metrics that are based on symptoms rather than laboratory results. Deidentified data, such as chief complaint and diagnosis codes, can include specific phrases that may be pathogen-specific, but syndromic surveillance is designed to monitor general health events based on aggregate indicators. In its truest sense, syndromic surveillance is pathogen agnostic in that it focuses on broader indicators of potential outbreaks rather than disease-specific indicators. While keywords and diagnoses such as “influenza” may be utilized, a threat agnostic strategy allows for a more agile approach to threat awareness and disease surveillance. There are limitations, however, in that a broader approach to surveillance lacks specificity and is dependent upon widespread utilization and data sharing to ensure efficacy. 18 Engagement with the BioSense Platform among healthcare facilities varies and requires integrating with the Meaningful Use program within the Centers for Medicare and Medicaid Services, which provides incentives for hospitals to accelerate their use of electronic medical records. 19
Syndromic surveillance efforts, such as the NSSP and its BioSense Platform, play a critical role in enhancing national readiness for not only biological events, but also for tracking the large-scale health impacts of disasters, such as hurricanes or oil spills. Syndromic surveillance is pathogen agnostic at its foundation because it focuses on generalized signs and symptoms of illness that may suggest larger public health impacts. Researchers can adapt syndromic surveillance tools built on its pathogen agnostic and threat detection characteristics, but these tools also require greater recognition of their utility across detecting and monitoring biological threats. Ultimately, syndromic surveillance can be an effective tool in threat agnostic strategies, but challenges exist in ensuring that end users, such as hospitals, are aware of its potential applications and benefits. This disconnect represents a broader issue within public health and biodefense efforts, in which there is a diffusion of innovation failure and the tools do not reflect the needs of the user.
Chemical and Biological Defense Program
Housed within the DOD, CBDP addresses biodefense and chemical defense needs for service members across multiple operational environments. This program works toward 4 strategic goals, as laid out by the 2020 CBDP Enterprise Strategy: (1) to plan for the future fight, (2) to deliver at speed, (3) drive innovation, and (4) optimize the enterprise. 20
One way CBDP works to address these needs is through researching, developing, testing, and deploying chemical and biological agent detection capabilities. Some of these are pathogen-specific, including tools such as pathogen-specific sensors, diagnostics, and medical countermeasures. In the modern servicemember context, CBDP is testing more agnostic approaches, which includes deploying a variety of sensors, including wearable technology for individual service members, establishing/standing environmental capabilities for situational awareness of known and unknown agents, and finding robust ways to aggregate these different data entry pathways. Such aggregation efforts can provide early detection of an attack or natural disease event to either thwart or mitigate its effects. For example, CBDP worked with the Logistics Management Institute to develop a prototype capability with multiple data inputs that could lead to an integrated early warning system. This capability, which uses the select agents and toxins list as a guide to leverage agent-specific sensors, buys service members the critical seconds needed to use personal protective gear or other means to thwart an attack.21-24
Prevent
The second critical component of addressing biological threats to the United States is prevention. Prevention can fall under 2 general umbrellas of activity: (1) ensuring that biological events are thwarted through adequate detection and other capabilities; and (2) ensuring that knowledge, equipment, expertise, and access to dangerous pathogens are leveraged exclusively for legitimate purposes. 25
To this end, the US government applies its list-based approach across a number of programs and initiatives. This list-based approach prioritizes activities that are meant to prevent specific pathogens and biological toxins from causing disease or other negative health outcomes for US citizens. These include the Strategic National Stockpile and the Hospital Preparedness Program, focused on their National Special Pathogen System.
Strategic National Stockpile
The Strategic National Stockpile (SNS) stores critical medical countermeasures, supplies, medicines, and devices for lifesaving care during a health threat within the United States. Started as the National Pharmaceutical Stockpile, the SNS was established in direct response to bioterrorism concerns from nonstate actors in 1999. While initially housed under the CDC, the US Department of Homeland Security now oversees the SNS following its rapid expansion in 2003 in partnership with the US Department of Health and Human Services (HHS) Administration for Strategic Preparedness and Response (ASPR).26,27
Priorities for what should be housed within the SNS are informed by the Department of Homeland Security's biennial Biological Threat Risk Assessment: a classified risk assessment based on known factors associated with perceived changes in biological risk. These factors include a prioritized list of known pathogens, what is likely to occur given traditional scenarios and historical agents used, and how changes in pathogen traits (such as antibiotic resistance) may affect the risk assessment outcome. 28 However, given the limitations of this current approach, many have seen pathogen agnostic approaches as a way to move away from the current “1 bug, 1 drug” system to a “many bugs, 1 drug” approach: a benefit that, if it occurs, can make the SNS significantly more effective.29,30
Hospital Preparedness Program and National Special Pathogens System
The Hospital Preparedness Program (HPP), housed within ASPR, works to bridge preparedness and readiness gaps across healthcare facilities that act independently of each other but constitute a critical infrastructure. Federal funding for healthcare preparedness and response is primarily provided by the HPP, which has provided US$6.6 billion since 2002, across 326 healthcare coalition networks and within all 50 states. 31 Support is provided by ASPR through TRACIE (Technical Resources, Assistance Center, and Information Exchange), which includes regionally based officers and resources. Prior to the COVID-19 pandemic, the HPP administered US$376 million for pandemic and influenza preparedness, as well as for H1N1 and Ebola response. During the COVID-19 pandemic, the HPP provided an additional US$390 million of emergency supplemental funding to support collaboration between healthcare facilities and other entities. Overall, the HPP works to ensure that healthcare facilities have the capacity and resources to prepare for, detect, and respond to a variety of events, which are efforts supported through programs such as the Regional Disaster Health Response System and the National Special Pathogens System (NSPS).
The NSPS was established to build on the Regional Treatment Network for Ebola and Other Special Pathogens Network, which was established in 2014 at the behest of Congress to better respond to the 2014 Ebola virus disease outbreak. This network and the subsequent NSPS sought to enhance special pathogen readiness through a series of specialized readiness centers built within existing healthcare facilities. The current NSPS focuses on 4 tiers of healthcare facilities: all healthcare facilities, assessment centers, treatment centers, and specialized care facilities. Currently, there are 10 Regional Emerging and Other Special Pathogens Treatment Centers (RESPTCs) as specialized care facilities and 55 state-designated Special Pathogens Treatment Centers. Funding has been inconsistent over the years; however, with a surge of funding during the COVID-19 pandemic, US$21 million was awarded to 13 healthcare facilities to serve as RESPTCs, including 3 new facilities.32,33 A consortium of academic medical centers, the National Emerging Special Pathogens Training and Education Center (NETEC), serves as a hub for resources and educational materials as well as research.
While the initial NSPS focus was on Ebola and special pathogens, such as avian influenza and Marburg virus, it has expanded to include a wide variety of readiness and resilience tools addressing the full needs of healthcare facilities, including engineering controls, ethics, cleaning and disinfecting, and infection prevention resources beyond high-consequence diseases. The amount of resources to improve healthcare response to infectious diseases has grown to evolve general readiness in a more agnostic approach, but many resources are still inherently pathogen-specific. The goal of the NSPS is focused on special pathogens, but since the COVID-19 pandemic, it has become clear that specialized care is critical and must include broader capacity to respond to novel and emerging infectious diseases. Patient care and healthcare biopreparedness should embrace pathogen agnostic approaches as a way to build all-hazards efforts that can be translated across a larger spectrum of roles and potential scenarios. The ability of specialized centers, such as RESPTCs, to provide a larger contribution to infectious disease readiness is evolving but ultimately lacks a home within US healthcare preparedness. 34
The HPP offers a wide range of healthcare readiness and biopreparedness resources and funding, focused on building a more robust healthcare infrastructure that uses an all-hazards approach. As the Ebola outbreak in 2014 and COVID-19 pandemic shed light on infectious disease vulnerabilities within healthcare, the NSPS, NETEC, and RESPTCs were developed to respond to an acute pathogen crisis. Since these events, however, such programs have been broadened to provide a more holistic, pathogen agnostic approach to healthcare readiness. Healthcare biopreparedness and bioresponse programs, such as those within HPP and NETEC, began with a focus on pathogens for detailed response plans but have since evolved to include resources that are increasingly focused on transmission dynamics of diseases, such as respiratory diseases or viral hemorrhagic pathogens. While diagnostics and patient care will require pathogen-specific protocols, the healthcare response to infectious diseases is moving toward more strategic processes that focus on agnostic and broadly applicable efforts that can serve a larger purpose.
Prepare
Preparation is a third critical component of addressing biological threats. As numerous biological events have shown us, even modern detection and prevention methods cannot guarantee that such events will not occur. Therefore, countries like the United States should incorporate Pareto optimal solutions, such as implementing preparedness efforts into efforts to address biological threats. *
The US government applies its list-based and recent events prioritization approach across a number of programs and initiatives to prepare for biological events. This approach enables and prioritizes research and development of protocols and products to address specific pathogens and biological toxins as determined by key interagency partners within the US government.10,11 These partners include designated Ebola Treatment Centers, the HHS Coordination Operations and Response Element (H-CORE), and efforts within CBDP.
HHS Coordination Operations and Response Element
H-CORE is a permanent organizing entity that ensures synchronization of medical countermeasure efforts across the federal government. H-CORE, housed within ASPR, was created following the successful interagency partnership between DOD and HHS via Operation Warp Speed, the federal effort that accelerated vaccine development to historically unprecedented timelines by supporting multiple COVID-19 vaccine candidates.35-37
H-CORE continues to address COVID-19, which includes working with the CDC to roll out and distribute COVID-19 vaccines, monoclonal antibodies, and oral antivirals to states, regions, and localities. 37 This narrow lane for H-CORE is reinforced because it is funded directly through COVID-19 appropriations. 38
Chemical and Biological Defense Program
CBDP plays an important role for military preparations against chemical and biological threats. Part of this role is to function as a preventive measure by signaling to US adversaries that they should not use biological and chemical threats against US troops because of the ability to detect and prophylactically address such threats, which renders attacks useless. 39
If a biological event affects servicemembers, CBDP's mission is to ensure advance preparations to mitigate the impact and treat affected individuals. Historically, CBDP protected military personnel from weaponized pathogens or natural disease threats in the field, such as those from Ebola, anthrax, and botulinum toxin; these pathogens were prioritized based on internal DOD assessments determined to be known threats for service members in specific environments and regions. This mission has expanded to the research and development of countermeasures of biological threat events of historic significance, such as the 2009 influenza A virus (H1N1) and the 2014-2016 Ebola outbreak.23,40
Key CBDP activities deal with select agents, as these are considered particularly challenging pathogens and toxins in military operations. For example, in fiscal year 2016, CBDP transitioned a cocktail of 3 monoclonal antibodies to clinical development at HHS: a cocktail that showed efficacy against the Ebola virus. In the same year, CBDP also conducted a study that showed how moxifloxacin provides significant protection against death from inhalational anthrax. 41 CBDP even conducted studies that have been critical toward the development of recombinant botulinum and plague vaccines. 41
Threat Agnostic Approaches – An Overview
There will always be a need to understand and address known threats. However, stakeholders have also started exploring ways to understand and identify unknown pathogens, which can serve as a potentially powerful approach that increases the lead time from when a disease event may spill over into animal or human populations compared with list-based methods.
Three major changes are driving these emergent approaches, known as threat agnostic approaches. First, advances in environmental and sample sequencing technologies allow researchers to identify genetic material across not only known pathogens in a sample, but potentially unknown or previously unidentified pathogens. Second, advances in biotechnology and computational biology are enabling full-genome sequencing; this capability offers significant insights into the genetic information of an organism compared with historic, slower methods that used cell and animal studies to grow and observe pathogen characteristics. Third, capabilities that allow deeper understanding and inspection of common elements in pathogen progression, growth, and distribution in the body (such as a better understanding of complex host response mechanisms) provide opportunities to target host response mechanisms, as well as disease transmission dynamics, that help enhance readiness and response. 7
Rather than explicitly focusing on the genome of the pathogen itself, threat agnostic approaches focus on emergent capabilities to measure, analyze, and identify patterns of disease and infection that are observed from human and animal hosts. Identifying these patterns can indicate signals of infection, known as bioagent agnostic signatures, at a cellular level; this capability can be leveraged by scientists to develop diagnostic and surveillance tools and medical countermeasures without even knowing, identifying, or characterizing the pathogen directly. 42
The US government and other governmental and nongovernmental entities have focused on efforts, both domestically and internationally, to make this vision a reality. The US Department of Energy's Pacific Northwest National Laboratory, including key stakeholders such as former director of the National Biodefense Analysis and Countermeasures Center, Dr. George Korch, has taken the lead on identifying key research areas to advance emergent capabilities in threat agnostic approaches. Further, the Pacific Northwest National Laboratory has served as a coordinating body that connects technical researchers and experts with the wider biorisk and national security communities to build consensus on the opportunities, challenges, and directions such approaches should take. 43
Threat Agnostic Approaches for Addressing Biological Risks
If the vision of threat agnostic approaches is fulfilled in the coming years, the United States and the global community will have a new suite of capabilities that can complement existing efforts that use list-based approaches. 44 Of critical importance is how threat agnostic approaches open the door to address novel pathogens even without direct characterization of their properties—this agile capability can be applied in a complementary fashion across ongoing detection, prevention, and response activities in the biodefense and public health sectors. This capability is increasingly important as the landscape of biological threats from natural, accidental, and deliberate sources are significantly different from those of even a few decades ago. † 45-48
The promise of threat agnostic approaches is easiest to see in the area of detection. Understanding how previously uncharacterized pathogens affect the general public or servicemembers based on bioagent agnostic signatures can significantly enhance the ability of both public health organizations and biodefense programs. For example, the CFA or CBDP could increase the accuracy of outbreak models and ensure that servicemembers can operate in environments where biological threats pose a very real threat toward mission completion. Further, such an approach would address existing gaps with list-based detection methods that may either create false alarms or even create false confidence. For example, as of mid-2021, the US Department of Homeland Security's BioWatch system detects only small and very specific DNA signatures for 6 commonly known biological agents, which include the causative agents of anthrax, smallpox, plague, and tularemia.48-50 However, as COVID-19 shows, such specific capabilities would not detect high-impact disease outbreaks—a gap that threat agnostic approaches could fill.
Threat agnostic approaches also have clear applications in preventing both the emergence and spread of health events from the local to the global scale. If potential cases are detected earlier, stakeholders can take swifter action to prevent local events from turning to outbreaks and epidemics. 51 For example, stocking the Strategic National Stockpile with a balance of medical countermeasures that address specific pathogens and novel pathogens that exhibit particular types of threat agnostic signatures can better prepare the United States for novel pathogens from natural, accidental, and deliberate sources. 52 In the public health context, healthcare readiness programs like those within HPP are increasingly integrating pathogen agnostic approaches into existing frameworks through “all-hazards” initiatives. Public health programs, including biosurveillance, are collectively working to ensure pathogen agnostic efforts build prevention and response capabilities in a complementary fashion that works in tandem and not as a replacement of those that are specific to certain pathogens. These strategies all collectively build on foundational preparedness and response efforts.
Even if a disease outbreak takes root with a novel pathogen, a threat agnostic approach can offer significant contributions in the response to such a biological event. As more information is collected to simultaneously characterize a pathogen and its unique threat agnostic signatures, researchers can leverage these 2 pathways—effectively a hybrid approach that is more holistic than traditional approaches—to accelerate research and development toward improved diagnostics, medical countermeasures, and other tools to contain and accelerate the end of the event. On the defense side, these types of efforts can be catalyzed through programs such as CBDP, which already conducts this work, but with an added benefit—with better characterization of host immune responses, there may even be potential to accelerate clinical trials for promising treatments. Such acceleration can also have positive knock-on effects for programs such as H-CORE.
Challenges in Leveraging Threat Agnostic Approaches
Current challenges to fully leveraging threat agnostic approaches can be divided into 3 categories: technical, resource, and institutional challenges. While none are insurmountable, stakeholders must be clear-eyed about both the potential opportunities and the challenges ahead in order to make effective and reality-based policies that increase the ability of the United States and other countries to achieve the promise of threat agnostic approaches.
While stakeholders have built a strong vision for threat agnostic approaches to address biological threats, more research must be conducted to make significant gains in this space. Each of the areas discussed previously about what capabilities are catalyzing threat agnostic approaches have unique basic science challenges associated with them. In the case of next-generation environmental and sample sequencing technologies, such as next-generation metagenomic sequencing, researchers have been able to identify and characterize novel organisms in a sample more quickly and cheaply than ever before. This capability, combined with existing knowledge on gene expression and cell morphology, enables researchers to predict and infer what a novel sample may or may not be capable of. This capability also highlights our relative lack of understanding about how microbes are related on a genetic level—an issue that has been raised, particularly in the national security context, concerning the case of how certain Bacillus anthracis-like pathogens present with anthrax symptoms. 53 To this end, there is a huge shift occurring, reliant on building new microbial trees of life, to understand how pathogens and microbes are related to each other. As relationships are redrawn and further research is conducted to characterize pathogen relationships at the genetic level, stakeholders will need to plan for and understand the implications of these relational changes, as well as their implications to both threat agnostic approaches and list-based approaches to addressing biological threats.
Whole genome sequencing capabilities enable researchers to obtain deep and accurate reads of the entire genome of a pathogen more quickly and cheaply than ever before. This is further combined with increased capabilities in bioinformatics to infer how genetic sequences translate into morphology. However, inference does not translate to incontrovertible fact. Even with multiple deep reads of a whole genome sequence, accuracy issues and the need to verify inferences through laboratory tests still represent significant challenges and bottlenecks to leveraging threat agnostic approaches as an agile alternative to existing methods. While these issues will likely be slowly overcome, stakeholders should be aware of these challenges to ensure adequate resources are devoted to navigating them.
Threat agnostic capabilities, such as those that focus on pathogen–host interactions, are particularly promising in that they effectively shrink the near-infinite landscape of biological threats to specific relationships between hosts and pathogens. These relationships include how pathogens enter into specific host cells, take over the host cell's machinery, replicate within the cell, and escape from the cell to propagate further. However, researchers will need to conduct further research to gain a better understanding of various complex systems and interactions, such as those of the immune system and the evolving landscape of pathogens that individuals are, or will potentially be, exposed to. This is an enormously difficult task given the differences that exist between individuals around the world.
Resource limitations are an ongoing challenge for those working in biorisk management. The COVID-19 pandemic highlights the “feast or famine” cycle that stakeholders have experienced for decades. 54 In the defense sector, this has meant inconsistent resources to fund critical programs, such as CBDP, in realizing its full potential, as well as competition across agencies for scarce resources. In the public health sector, the pandemic has drawn attention to inherent vulnerabilities that are created when public health is systemically weakened by inconsistent funding and support. Preparedness efforts are also not immune to partisanship, which has been observed within topics such as virus discovery work and investigations into COVID-19 origins, which often impacts funding. For example, the US Agency for International Development canceled the DEEP VZN (Discovery & Exploration of Emerging Pathogens – Viral Zoonoses) program prematurely. 55 Beyond such resource and partisan hurdles that threat agnostic strategies face, there are also institutional limitations and biases that may come with categorizing efforts as “biodefense” rather than “public health” or “pandemic preparedness.” Preparedness and response efforts for biological events, regardless of origin, occur across multiple sectors and often build upon partnerships; therefore, funding streams and leadership designations should reinforce cooperation and collaborative efforts across key stakeholders. The Biden administration has consistently signaled that addressing biological threats is a high priority, which will be necessary to ensure sustainable funding and prioritization to address these systemic issues across multiple administrations. 56
Finally, institutional limitations must be explored, understood, and addressed. The COVID-19 pandemic and its continued effects have corresponded with social erosion in public institutions and activities, including a loss of faith in government and lack of trust in science. These challenges have grave implications as stakeholders try to stem the tide of the accelerated emergence of biological events. For example, current pathogen-specific efforts require consideration and identification of novel diseases, which is a critical component of understanding what threats may be circulating through human, animal, and insect populations. However, the alternative narratives associated with the origins of COVID-19 have made such efforts less attractive and politically unviable in certain circumstances—this is a crucial issue that stakeholders must address to be better prepared to respond to novel biological threats. Further, preparedness efforts, such as diagnostics and medical countermeasures, are only effective if people are willing to use them. A key lesson from the COVID-19 pandemic was that although novel mRNA vaccines were developed, large segments of the population refused them for a variety of reasons. In January 2023, Secretary Austin rescinded the mandate that required the US Armed Forces under the Department of Defense to be vaccinated against COVID-19 because it posed a problem in terms of continuity of defense operations. 57
Conclusion
Biodefense and public health approaches based on lists of known pathogens and biologically derived toxins have served the United States and the global community well in prioritizing and addressing threats from well-characterized and known pathogens, and they should continue to be used as appropriate. However, current global trends in geopolitics, advances in the life sciences and their applications, and anthropogenic effects, such as climate change, are highlighting the limitations of list-based approaches in a critical area: addressing pathogens that are unknown and uncharacterized.
Addressing this gap will be critical to stemming the tide when it comes to disease events, particularly in human populations. Threat agnostic approaches, which focus on understanding signatures of disease, are viewed by researchers and other stakeholders as a way to fill this critical gap.
While there is a strong vision for threat agnostic approaches, stakeholders still need to overcome 3 major hurdles to fully enable this capability to be used in tandem with list-based approaches and leverage the best of both. First, significant technical barriers exist, including the ability to obtain greater granularity on how complex systems, such as the immune system, work across multiple communities. Second, such research and efforts need to be consistently funded and prioritized, rather than the feast or famine approach to funding resources and interests. Finally, stakeholders must explore ways to understand how public faith in institutions, such as government and science, have eroded, and they must take concrete steps to reverse this trend. Threat agnostic strategies have the potential to address key vulnerabilities in current efforts and increasingly complex biological threats, but it is critical they are seen as complementary to pathogen-specific programs rather than replacements in order to successfully integrate, implement, and unlock threat agnostic activities to the best extent possible.