2

Pathogen Introduction into Humans

Cristina Cassetti, National Institutes of Health, opened the first session by noting that there has been major investment by various funding entities to understand the ecology of infectious diseases and the mechanisms by which pathogens and viruses jump species and start adapting to new hosts. These investments are made under the assumption that preventing a pathogen spillover event can prevent downstream infections and epidemics. However, she noted a need to understand how prevention efforts can be improved, as lessons from recent outbreaks have not succeeded in preventing spillover events. The opening session addressed potential mechanisms of pathogen emergence and introduction into humans.

PATHOGEN EXPOSURE FROM WILDLIFE

Raina Plowright, Cornell University, provided an overview of pathogen spillover from animals with an example of her work on the spread of Hendra virus in Australia. This virus is transmitted from bats (flying foxes or fruit bats) to horses, and from horses it can then spread to humans. It is a highly fatal disease, and cases tend to occur in clusters, explained Plowright. Her team’s investigation of Hendra virus transmission included the case of a domesticated horse that died in a citrus orchard (Plowright et al., 2015). Examination of the orchard revealed a population of bats was roosting in the orchard, likely a result of splintering and dispersal of native bat populations in the local area into smaller groups as they attempt to find alternative food in farmlands after their native food sources were depleted. Plowright’s team collected urine samples from the bats in the orchard using plastic sheets placed under the roost and tested them for pathogens. Approximately half of the urine samples were positive for Hendra virus, ultimately leading to the conclusion that the horse was likely exposed to the virus when consuming grass contaminated by bat urine containing Hendra virus.

Plowright presented a conceptional framework that illustrates factors that need to be present and in alignment for spillover to occur.

These factors include:

• source host distribution and density,
• source host infection prevalence and shedding,
• source host infection intensity,
• virus survival,
• target host exposure to pathogen (source host and target host behavior), and
• target host susceptibility.

Many of these factors are dynamic, Plowright said, but when all factors align, it creates a “perfect storm” condition for a spillover event to occur.

Additionally, a spillover is the first component of a pandemic for many pathogens from wildlife, she explained, but the ability to infect humans varies by pathogen. Many viruses do not spread effectively in humans, and some require many mutations to become efficiently transmitted among humans. Other viruses can directly transmit from animals to people and lead to outbreaks in humans. When there is a need for mutations to facilitate human transmission, long chains of transmission and bridging hosts can be very important for viral evolution and adaptation, Plowright noted. Understanding these components of the spillover process offers opportunities for interventions to stop the spread of the pathogen from animals to humans.

Plowright framed the spillover process through a complex systems approach to assess the various and interconnected factors that can drive the outcome (Vora et al., 2024). Each driver can be seen as changing the permeability of each layer, making it easier for the virus to get through from one layer to another. In the example of the horse infected with Hendra virus, one of the drivers of the event was the geographical shift of the bat population owing to food restrictions in their original habitat, which were caused by drought attributable to climate change and deforestation for agriculture intensification. Plowright highlighted the need to understand this complexity to identify potential points of intervention, which, in this case, range from the types of trees planted on the farm to policies on land use. Pandemic prevention is often framed as an issue that requires biomedical solutions. While Plowright acknowledged this point, she also noted that pandemics often originate in ecological systems—systems-based solutions are therefore a critical component for effective disease prevention.

Plowright further outlined four reasons for why preventative action is often not taken (Fineberg, 2013). First there is bias against action, as people are often more afraid of any potential harm caused by preventive actions than the harm caused by inaction, as demonstrated by the lack of horse vaccination against Hendra virus. Second, the benefits from prevention are invisible, as the outcome of successful preventive actions is that no disease outbreaks happen. Third, when a disease outbreak is prevented, there is no crisis to rally around and no emotional impact throughout society. And fourth, there are misaligned incentives. For example, governments of lower-income countries may be inclined to allocate resources toward more pressing health care issues with immediate needs instead of to pandemic surveillance and prevention measures for a crisis that has yet to happen. Importantly, investment by the lower-income countries toward pandemic prevention results in benefits for other countries, including higher-income nations, but potentially come with the cost of not addressing ongoing endemic diseases in the lower-income countries.

Plowright emphasized that outbreak prevention is possible. The conditions that led to Hendra virus outbreaks in 2017 were replicated in 2020, but outbreaks did not recur in 2020. Research later revealed that this was likely because up to 75 percent of one of the virus-carrying bat species had moved to a patch of flowering habitat instead of to agricultural habitats that put them in close contact with horses and humans. This revealed that replanting some of those winter flowering trees to establish this habitat, alongside preventative measures like vaccines, could be a comprehensive strategy to prevention (Plowright et al., 2024). Plowright encouraged the audience to rethink the concept of prevention and to consider the cost of inaction as part of the narrative of the importance of prevention.

PATHOGEN EXPOSURES FROM FARMING AND AGRICULTURE

Charles Bebay, from the Food and Agriculture Organization (FAO) of the United Nations, discussed the risk of pathogen exposure in farming and agriculture, noting that there are many pathways of pathogen exposure in agriculture. These include

• the close animal–human interaction during management (e.g., brooding, feeding, handling);
• high-density livestock farming and overcrowding;
• processing (e.g., slaughtering) and movement of livestock without preinspection;
• poor biosecurity practices in farms, processing facilities, or transportation;
• deforestation and habitat conversion for agriculture;
• encroachment into wildlife habitats for livestock grazing;
• overuse of antibiotics;
• indiscriminate disposal of agricultural byproducts; and
• consumption of raw or poorly processed animal products.

Bebay noted several challenges to improving, preventing, and mitigating pathogen spillover. These include

• rising incomes increase the demand for livestock-based foods;
• accelerated land use increases contact between people, domesticated animals, and wildlife;
• unregulated wildlife trade, including the lack of understanding of wildlife disease ecology;
• limited diagnostic capacity in many low- or middle-income countries (LMICs);

• rapid virus mutation requiring constant updates to detection methods; and
• complex early warning systems requiring multiple data sources.

Bebay addressed the need to integrate social, cultural, political, and economic factors in prevention to a greater degree while acknowledging that these factors are hard to address, as regulations are poorly enforced and resources to achieve best practices may be lacking. For example, in farm communities with limited resources, incentivizing uptake of biosecurity measures can be challenging. Delays in reporting of initial cases of infection—patient zero—could be mitigated by having effective local mechanisms to quickly share information on the incident. Therefore, Bebay suggested it is important to look at early warning systems involving the local community participation, though government restrictions and unwillingness to share information also delay reports. Finally, government restrictions, weak private-sector vaccine supply chains, and misinformation on animal health are all factors that limit the prevention and mitigation of spillovers from agriculture.

Bebay then described strategies in use by FAO for mitigating pathogen exposure in farm settings. First, he said, it is important to have a collaborative approach that engages all stakeholders (e.g., the local community, farmers, transporters, and food processors) to foster interdisciplinary planning and cocreation of disease surveillance. Second, FAO promotes prevention and control measures, which encompass sociobehavioral changes in animal–human interactions, support of biosecurity measures, vaccination, and veterinary training, as well as limits on antimicrobial use and enhanced surveillance for resistant pathogens. Third, FAO outlines strategies for the regulation of food systems components, including the improvement of farm and processing surveillance systems, the regulation of wildlife trade and reduction of wildlife–human interface incursions, the implementation of integrated pest and pathogen management, and the control of water and waste. Finally, FAO encourages research studies on disease-resistant animal varieties. FAO supports mitigation by working with governments and communities, he said, and providing technical support, projects, and programs.

Bebay concluded that demographic, climatic, and economic trends will continue to increase the risk of pathogen exposure and spillover in agricultural settings, especially in LMICs. Spillovers in agricultural contexts display a diverse set of behaviors, and limiting exposure and transmission is complex. FAO has strived to embrace bottom-up, community-focused and community-led interventions; the implementation of multicountry collaborative training programs and strengthening of cross-border surveillance; and the adaptation of a holistic One Health approach to develop effective surveillance, strategies, and evaluation tools (Box 2-1).

He ended with a call to action to strengthen partnerships, invest in research, and commit to fostering resilient food systems globally.

PATHOGEN EXPOSURE FROM LABORATORY SETTINGS

Luis Ochoa Carrera, Michigan State University, discussed the prevention of pathogen exposure in laboratory settings. Laboratories are hubs of scientific innovation and discovery and are uniquely positioned at the forefront of efforts to understand, diagnose, and address infectious diseases, Ochoa stated. However, he said, these are also environments where unintentional pathogen exposure can pose risks for the laboratory personnel, the surrounding communities, and beyond.

Ochoa explained that laboratory-acquired infections or exposures to infectious agents have been recognized as occupational hazards since the twentieth century. Exposures have been linked to various sources, such as accidental spills, needle sticks or other injuries, aerosolization of pathogens, and inadequate use of personal protective equipment. Over time,

advancement in safety practices, technology, and biosafety guidelines have significantly reduced the frequency and severity of laboratory exposures, Ochoa said. Exposures occur through human error, including lapses in concentration, procedural noncompliance, or lack of experience and inadequate training, he said. Many institutes provide theoretical training but insufficient hands-on experience with biosafety protocols. Further, he said, resource restraints, particularly in resource-limited settings, outdated equipment, and inadequate infrastructure can exacerbate the risks. An increase in research demands, with the rapid pace of scientific discovery, especially during a public health crisis, can also lead to pressure that compromises safety.

Consequences of laboratory exposures to the affected individuals include acute illness, long-term health complications, or even fatalities in rare cases. The laboratories involved also experience operational disruptions, as they may need to pause operations for decontamination and investigations. Beyond the laboratories and personnel, there are also public health risks if an incident leads to uncontrolled exposures and broader outbreaks, Ochoa said. He noted that the sectors most affected by biosafety issues are diagnostic laboratories, given their work with high volumes of potentially infectious specimens that require rapid turnover, as well as research institutions and academic laboratories that are handling high-consequence pathogens or engage in dual-use research of concern—research that, based on current understanding, is intended for beneficial purposes but can reasonably be anticipated to be misused for harmful purposes. The variability in training and resources among the different institutions and laboratories often results in inconsistent adherence to biosafety standards.

Ochoa described the most common routes of exposure to pathogens in laboratory settings, which include the inhalation of aerosols and direct contact by accidental spills, splashes, and handling of contaminated surfaces. In laboratories that work with nonhuman primates or other animal models, bites or scratches present other potential exposure sources. Incidents may go underreported owing to fear of punishment, lack of mandatory reporting systems, or unawareness of exposure, Ochoa explained. There is a lack of data on low-dose or subclinical exposures, which may not manifest with immediate symptoms but can have longer-term health implications, and there is limited understanding on how behavioral factors such as stress, training, fatigue, and workplace culture affect adherence to safety protocols. Despite advancements in biosafety practices, Ochoa said that gaps in understanding remain on the global incidence rate of laboratory exposures, pathogen-specific risks, and factors that contribute to underreporting such as cultural, institutional, and regulatory barriers.

When exposure occurs, laboratories often follow established protocols, including immediate containment measures to ensure the affected

area is isolated and thoroughly disinfected to prevent further exposure. Incident reporting to internal biosafety officers, institutional safety committees, and where required, public health authorities, is the next step. Further, postexposure prophylaxis (e.g., vaccines, antivirals) can be provided, depending on the pathogen involved, and a root cause analysis may be performed to identify procedural training or systemic failures that led to the exposure. These actions often align with institutional biosafety policies and international guidelines but can vary widely across facilities, Ochoa said.

Some critical areas where current practices fall short include comprehensive reporting, Ochoa stated. The fear of reputational damage or punitive measures can lead to underreporting or incomplete documentation of incidents. There is no centralized global database that compiles lessons learned from laboratory exposures, impairing the ability to share best practices that lead to improvements. Further, he noted, laboratories can fail to adapt risk assessments to evolving research activities or emerging pathogens, leaving gaps in prevention strategies. The ripple effects of laboratory exposures can be profound, Ochoa said, leading not only to delays in research, but also to shutdowns and remediation efforts. Further, high-profile incidents may erode public confidence in scientific research and institutions. Finally, incidents may lead to heightened scrutiny, potentially resulting in burdensome regulations that limit innovation, he added.

To prevent exposures, Ochoa said there is a need to invest in training and certification, particularly improving access to practical scenario-based biosafety and biosecurity training based on local needs. Further, investments in infrastructure are essential to ensure that laboratories meet or exceed global biosafety standards, particularly in regions with emerging research capacities, he added. It is also essential to address the shortage of skilled biosafety professionals, particularly in newly established laboratories. Finally, Ochoa said that adaptation and use of the global harmonization of guidelines, such as the World Health Organization’s Laboratory Biosafety Manual and the International Organization for Standardization’s biological risk management system, can reduce risks. To enhance risk assessment, artificial intelligence (AI) and data analytics can be used to track incidents and establish training efficacy. The rapid expansion of laboratory networks globally, often in countries with limited experience, underscores the urgency of these efforts, he said. He reiterated that global collaboration and stakeholder enforcement is required to prevent laboratory exposures, which not only protects personnel, but also safeguards the surrounded communities, maintains public trust, and ensures that scientific advancements progress through collaboration, investments, and a commitment to biosafety and biosecurity.

INTENTIONAL RELEASE AND BIOSECURITY

Paul Friedrichs, White House Office of Pandemic Preparedness and Response Policy, opened by reflecting that the ultimate purpose of meeting to discuss disease prevention is to address and alleviate human suffering. Friedrichs said that early discussions at the start of the COVID-19 pandemic centered on public health but later included other important expertise areas such as ecology, economy, and education. One notable challenge, he said, arose from miscommunication when experts from different disciplines use similar language to reflect different concepts related to their respective fields. This is one reflection of the complexity of One Health, an intellectual approach that integrates perspectives at the intersection of human, animal, plant, and environmental health.

Friedrichs highlighted the potential misuse of biomedical technologies and knowledge for nefarious purposes, such as gaining power or inflicting suffering on others, and the importance of considering national security factors in this discussion on preventing patient zero. Fredrich argued that society is on the cusp of an inflection point in medical history given the confluence of AI and machine learning tools, the rapid increase in computational capabilities and capacity, and the revolution in biotechnology.

Biomedical breakthroughs and emerging technologies can directly affect human health, as per the recent Food and Drug Administration approval of the first gene therapy treatment for sickle cell anemia. Across the product pipelines of pharmaceutical companies, encouraging and exciting innovations are working their way through clinical trials because of this confluence of technologies, he said. Drug development is premised on large amounts of information and the design of algorithms. Friedrichs cautioned that the same information could be enticing for those who seek to do harm. Friedrichs said there should be consideration for establishing global norms on acceptable use of emerging technologies. He pointed out that other industries, such as aviation and nuclear research, have risk guidelines in place. When working with the most promising but also potentially threatening technologies known to mankind, establishing clear guardrails that biomedical researchers should follow is imperative, Friedrichs argued.

Friedrichs acknowledged the need for continuous improvement on processes and structures, especially in the field of pandemic prevention. He highlighted the importance of acknowledging the reality that humans are fallible, and that technology can be misused, while committing to ensure that those risks are mitigated in an effort to minimize human suffering.

DISCUSSION

Misalignment of Incentives

Plowright noted that one of the hurdles for prevention of disease spillover is misalignment of incentives. In some communities with multiple local public health threats, such as high incidence of tuberculosis or HIV/AIDS, investment in pandemic preparedness may not be a priority issue. Therefore, she argued, there is a need to ensure that disease surveillance benefits communities with fewer resources. For example, researchers could explore how pandemic disease surveillance could also benefit endemic disease prevention and support public health infrastructure. Collaboration with local communities is therefore key for successful action.

Bebay added that when organizations consider community-based interventions for pandemic disease surveillance, they often apply a public health lens, which may not align with priorities of farmers or local communities. He added that applying social sciences to better understand the priorities, capacity, and practices of a community would help better determine appropriate interventions. Friedrichs said that when looking back at past outbreaks, what stands out is how difficult it is to understand what truly motivates people and what little research is done to determine modern rational incentives. He noted that this struggle to understand motives and identify appropriate incentives is ubiquitous.

Considering One Health Approaches

An attendee raised the issue that the concept of risk is subjective and asked how to prioritize risk and understand it in context, without paralyzing research. Friedrichs said that there is a need for interdisciplinary health researchers and practitioners to speak with one voice. He noted the need for multilateral perspectives from global partners to collectively identify priorities and opportunities to reallocate resources to lesser-studied pathogens. Ochoa added that there are diverse risks in the context of laboratory exposures, including health, economic, and reputational risks. There is a need to consider all of these possibilities, how they can affect research operations and biosafety measures, and what needs to be done to mitigate those risks, he said.

A participant asked the panel how groups can act as one team and build synergies to measure progress, especially across changes in leadership. Friedrichs answered that activities like this National Academies workshop bring together diverse voices and expert communities that influence strategies for addressing this problem. He said that the health community should continue to revisit its shared purpose of preventing disease emergence and

transmission. There is a need to communicate risk in a clearer way to help inform resourcing decisions and individual decisions, he added, noting that there is a lack of knowledge on how to bridge this decision making with the ecological and environmental communities.

Preventing the next pandemic requires a holistic approach that addresses the health of plants, animals, and humans, while assessing health together with economic and reputational risks and indemnification, said Friedrichs. Plowright added that metrics are important for accountability but noted that not everything can easily be measured. Building a comprehensive system of metrics would facilitate a better multidisciplinary approach to reduce risk, she said.

Online participants asked whether medical anthropology could be used to help include the lived realities and the diverse needs of different communities. Cassetti answered that the importance of social sciences to understand the context of outbreaks is becoming more and more clear. It is not possible to find a one-size-fits-all solution for prevention, she said; solutions must be tailored to the needs of the local community, which requires understanding what drives the community’s decisions and behavior. She suggested that this should also be discussed more with funders as well. Plowright reflected on the negative outcomes that follow spillover identification on a farm, such as financial loss and trade restrictions. She said that bringing in social sciences can systematically inform how to incentivize the detection and the reporting of pathogens in ways that will protect the broader community’s health but also protect the interests of the individual who makes the report.

Erik Karlsson, Institut Pasteur du Cambodge, also reflected on potential negative downstream effects and disincentives from his experience working in an LMIC. He recalled the earlier point that one challenge of taking preventative action is that if the effort is successful and spillover is prevented, nothing happens. This is not an output that policy makers can work with, as it cannot be quantified. Bebay responded that there is a critical need to provide evidence that is based on social sciences work. Further, he added, livestock owners are critical stakeholders, and engagement of the private sector will be important to inform policy and build an evidence base.

An attendee noted that when it comes to the funding of different sectors, generally the human side is considered primary, the animal side is secondary, and ecosystem and plants are tertiary, and that set of priorities is reflected in how much investment and funding goes to each sector. The idea of sharing one voice implies that all voices will have the same level of influence, but she noted that this is not reflected in practice. She wondered whether there is a willingness to elevate perspectives that have been marginalized. Plowright agreed that unequal weight of importance is assigned to these different knowledge areas, and that social and environmental sciences are also often left out of strategic or funding conversations. She noted that

this work should be highly integrative, but there is limited funding, and funding agencies are also often not set up with the appropriate expertise to review transdisciplinary project proposals.

Detection of Patient 0, 1, or 50 in Various Regions

An audience member proposed that in LMICs where immediately identifying an initial spillover is not feasible, a successful strategy may be to identify patients relatively early in an outbreak and work backwards to identify patient 0. He asked for the panel’s thoughts on how to identify a feasible starting point for detecting the first case. Plowright answered that it is very important to understand the context within which pathogens are circulating and how each local or regional community is operating. Whether setting the goal for preventing patient 50 or patient 0 will depend on two factors, she said. If it involves a highly infectious pathogen, there is little time to intervene before the outbreak spreads beyond control. Therefore, it is important to intervene as upstream as possible in the outbreak dynamic for such a pathogen. She also noted that there is a lack of metadata on environmental conditions and other factors influencing pathogen spillover, particularly in Africa and Southeast Asia, making these very difficult systems to study. Collecting this data will require significant time and investment, she said, but doing so will facilitate the ability to detect and respond to infections earlier in the outbreak cycle.

Evidence Collection

Jonathan Sleeman, U.S. Geological Survey, reflected on the expressed need for more evidence and increasing the data collection to understand these systems, but he wondered whether current knowledge is sufficient and the concepts generalizable enough to start taking action now, given how high the risks are. Cassetti answered that in some cases there is enough knowledge, but there is a lack of political will to invest in implementing the solutions. Plowright added that there are significant actions that can be taken now with the current knowledge about the risks of inaction and the benefits of solutions. For example, building resilient ecosystems also has benefits for clean water and air, climate mitigation, and biodiversity conservation, but the political will to invest in prevention is also necessary to commit to these initiatives, she said. A participant commented that it is a challenge to receive funding that encompasses a true One Health approach, holistically assessing human, environmental, and animal health.