This essay was written for a recent application, so excuse the academic-y style writing. 

The emergence of novel pathogens, whether through natural spillover events, accidental releases, or deliberate actions, remains a significant global health concern. Early detection of these threats is crucial, enabling timely responses ranging from targeted containment measures to rapid medical countermeasure development. However, our current surveillance systems, primarily designed to detect known pathogens, face limitations in identifying novel threats, particularly those with extended incubation periods.

Traditionally, the discovery of new human pathogens has relied on astute clinicians identifying unusual case clusters (Dawood et al., 2009; Drosten et al., 2003; Zhu Na et al., 2020). This approach is inherently reactive, delays detection, and may miss pathogens that spread asymptomatically at first. Recognizing these constraints, there has been growing interest in pathogen-agnostic surveillance methods, with metagenomic sequencing (MGS) emerging as a particularly promising technology.

MGS allows for the detection and characterization of all genetic material in a sample, including that of unknown pathogens, without requiring prior knowledge of their specific sequences. This capability has garnered attention in recent national biosecurity strategies and public health recommendations as a potential cornerstone of more robust early warning systems (Department of Defense, 2023; Dubin et al., 2022; UK Cabinet Office, 2023).

Currently, MGS is primarily confined to academic research and a relatively niche clinical market. While some groups and government programs are working to implement routine untargeted MGS in wastewater surveillance, the United States still lacks a comprehensive MGS-based biosurveillance system.

This essay outlines several concrete strategies for implementing effective pathogen-agnostic biosurveillance in the United States. The proposed strategies are designed to provide broad pathogen and population coverage with a relatively small number of samples, improving cost-effectiveness. Importantly, these strategies are not mutually exclusive; eventually, we should implement a layered approach designed to maximize coverage and sensitivity across different pathogen types and transmission routes.

1. National Wastewater Surveillance System (NWSS): The NWSS, a CDC initiative established during the COVID-19 pandemic, has demonstrated its utility in cost-effectively tracking disease spread across large populations (Kirby et al., 2021). Currently focused on targeted detection of SARS-CoV-2, influenza A, RSV, and Mpox (CDC, 2024b), the system could be expanded to include deep untargeted MGS in select major cities and travel hubs alongside continued, more spatially resolute targeted testing.
2. Traveler-based Genomic Surveillance (TGS) program: The TGS program, led by CDC’s Travelers’ Health Branch, is a public-private partnership that collects samples from international travelers at major U.S. airports (CDC, 2024a). The program currently operates at eight major U.S. international airports, collecting nasal swabs from volunteers (Bart et al., 2023) and analyzing wastewater from aircraft and airport triturators (Morfino et al., 2023). It has already proven valuable for early detection, identifying multiple Omicron variants weeks before their detection elsewhere in the US and demonstrating strong correlations between traveler positivity rates and community prevalence (Smith et al., 2024). It could be expanded to include untargeted MGS.
3. Air sampling: Metagenomic sequencing of air samples can detect a wide range of respiratory and skin pathogens from many people in a single sample (Justen et al., 2024). While the Department of Homeland Security’s BioWatch air sampling program faced challenges with false positives and cost-effectiveness (GAO, 2021), a revamped version could leverage recent technological advancements to efficiently sample and sequence bioaerosols in high-traffic areas such as airports and public transit stations. Air sampling could also be integrated with existing building maintenance procedures, including analysis of vacuum dust from cleaning crews or HVAC filters.
4. US blood and plasma supply: The United States maintains an extensive infrastructure for collecting and testing blood and plasma donations, with over 20 million contributors in 2021 (Bhasin & Justen, 2024). Currently, samples are only tested for known, blood-transmissible pathogens. Leftover samples from routine testing could be pooled and subjected to MGS, enabling detection of novel pathogens.
5. Laboratory discards: Major diagnostic companies like LabCorp and Quest Diagnostics process millions of clinical samples annually, ranging from routine samples like nasal swabs to highly specialized samples like lymph node biopsies. After fulfilling their primary diagnostic purpose, these samples could be pooled and sequenced to detect the spread of novel pathogens.
6. National pathogen survey: Implementing a national swab sampling program could provide comprehensive data on pathogen prevalence and incidence, and enable detection of emerging pathogens. This approach, modeled after the UK’s COVID-19 infection survey (Pouwels et al., 2021), would involve randomly selecting households to regularly provide swab samples. These samples would then be couriered to designated laboratories for MGS and analysis. Such a program could offer a more accurate picture of disease burden than current symptom-based reporting systems, capturing both symptomatic and asymptomatic cases.
7. Clinical metagenomic sequencing: Expanding the use of MGS in clinical settings could significantly enhance our ability to diagnose and monitor infectious diseases, including identifying novel pathogens. Currently limited in scope, clinical MGS faces challenges such as regulatory hurdles around using MGS data for diagnostics (NIST, 2016) and patient privacy concerns (BARDA, 2023). Addressing these concerns would allow for the aggregation of anonymized genomic data or results across patient samples, enabling the detection of novel pathogens at a population level.

The United States has the potential to build a more robust biosurveillance capability that can both alert us to the emergence of novel pathogens and effectively track known threats. This essay has outlined several concrete approaches, many of which leverage existing infrastructure and systems. In some cases, implementing these strategies primarily requires building the capacity to perform MGS on samples and analyze the resulting data. In others, new partnerships and regulatory guidance are needed.

As we move towards implementing pathogen-agnostic detection systems, it will be crucial to conduct more thorough cost-effectiveness analyses of different approaches (D’Souza & Schmitt, 2024), considering various criteria for effective biosurveillance (Bradshaw & Grimm, 2024). Outstanding challenges include developing improved tools for MGS data analysis and novel pathogen detection (Kaufman, 2023), further reducing sequencing costs, and implementing robust privacy-preserving measures. With sustained effort and investment, the United States can establish a robust biosurveillance system this decade that significantly enhances our ability to detect and respond to emerging biological threats, ultimately safeguarding public health and national security.

References

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