Background and context

The devastating impact of Coronavirus Disease 2019 (COVID-19) on human health globally has prompted extensive discussions on how to better prepare for and safeguard against the next pandemic. Zoonotic spillover of pathogens from animals to humans is recognized as the predominant cause of emerging infectious diseases and as the primary cause of recent pandemics [1]. This spillover risk is increased by a range of factors (called drivers) that impact the nature, frequency, and intensity of contact between humans and wild animals. Many of these drivers are related to human impact, for example, deforestation and changes in land use and agricultural practices. While it is clear that the triad of prevention-preparedness-response (P-P-R) is highly relevant, there is much discussion on which of these 3 strategic activities in the field of emerging infectious disease should be prioritized and how to optimally target resources. For this, it is important to understand the scope of the respective activity and the consequences of prioritization.

Already, the World Bank Pandemic Fund and forthcoming global Pandemic instrument [2] negotiated by the World Health Organization (WHO) [3] appear primarily focused on the early detection, and reaction to the appearance of human illnesses, often with explicit focus only on action to be taken once pathogen spillover and spread have occurred. Strategies to reduce the probability of spillover events are under-prioritized and underutilized, as highlighted by recent infectious disease crises such as Ebola and Mpox epidemics, and have been lost in overall preparedness discussions and recovery financing. This “more of the same” focus suggests that it is politically more expedient to allocate financial resources to deal with a problem once it has arisen, rather than taking the steps necessary to reduce the risk of it occurring in the first place. It is often claimed that allocating resources to prevent something from happening is politically difficult as the value of prevention is largely “invisible” (prevention paradox) or it will take a long time to show effects. However, there are now several communications highlighting the economic benefits of prevention of spillover [1,4,5]. If taken, actions to prevent spillover are estimated at $10 to 31 billion per year globally, as a cumulative investment from preventive actions achievable by specific industries. However, addressing the drivers of pathogen spillover through a One Health approach has significant subsequent economic co-benefits; for example, reducing deforestation is estimated to create $4 billion per year in social benefits from reduced greenhouse gas emissions [4]. COVID-19 has demonstrated the immense burden of a pandemic, including significant mortality resulting in economic recession, with the global economy contracting by 4.4 percent in 2020. The expected economic losses from this pandemic are estimated at nearly $14 trillion up to 2024 [6,7]. These losses parallel those incurred by other infectious disease emergencies, including the 2003 SARS pandemic with an estimated economic loss of $52 billion; the Ebola virus disease outbreak in West Africa in 2014 to 2016 with a GDP loss of $2.8 to 32.6 billion and the comprehensive economic and social burden estimated to be $53.19 billion [8]; and the 2015 to 2016 Zika virus disease outbreak with an estimated loss in the United States, Caribbean, and Latin America of $20 billion [9,10]. If invested in, prevention strategies would reduce the likelihood of another pandemic substantially and likely generate sufficient return on investment over time while also having the potential to generate substantial co-benefits [1,10]. Prevention is already valued in other sectors: policymakers and industries have led on prevention in other areas, such as expenditure on counter-terrorism, driving laws and insurance incentives to reduce the frequency of traffic accidents, on the nuclear deterrent, and in some cases on flood prevention and other water management measures, exemplifying a political willingness to spend vast sums of money to preempt a harmful event in certain areas or circumstances, but not on pandemic prevention.

Defining “prevention of spillover’

It is essential to define “prevention of spillover” in the context of preventing outbreaks, endemicity of diseases, epidemics, and pandemics to ensure alignment with prioritization of actions and resources. At present, the term “prevention” is used differently in different contexts. For example, in public health it refers to prevention of human disease from occurring at all (primary prevention) or prevention of small localized disease outbreaks in people from spreading and developing into an epidemic or pandemic (downstream/secondary prevention). Secondary prevention is often achieved by interventions such as early detection, vaccines, improved health systems, drug therapy, health promotion and social and behavior change, and implementation of sanitary measures. Secondary prevention could be better referred to as “containment of infection,” as this clearly describes the objective of these measures while avoiding potential confusion with prevention of spillover.

Prevention of spillover in the context of this paper refers to preventing the critical first step, i.e., preventing a pathogen from transferring from animals to humans. While this paper specifically addresses pandemic prevention in humans, in line with the OHHLEP One Health definition endorsed by the Quadripartite, it is important to note that pathogen spillover from humans to other species or between other species facilitated by human activity (e.g., wildlife trade) can also have devastating impacts on wild and domestic animal populations.

Prevention of spillover can be enacted by addressing drivers of pathogen spillover in a One Health approach at the human–animal–environment interface to minimize the risk of human infection by zoonotic pathogens, including interventions such as vaccines. To be clear on the prioritization of preventing future epidemics that can lead to pandemics, we propose a definition of prevention that focuses on the prevention of zoonotic spillover, i.e., all upstream events that have an impact on pathogen spillover (Box 1, Fig 1, and Table 1), whereas downstream activities are contained within the preparedness and response actions. Prevention of pathogen spread in humans (secondary prevention) specifically involves containment measures that need to be in place after spillover of pathogens to the human population—these measures may be implemented both in the public health sector, in the animal health sector, and in the environment.

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Fig 1. Prevention of zoonotic spillover to humans: Prevention of pathogen spillover from animals to humans; shifting the infectious disease control paradigm from reactive to proactive (primary prevention, upstream).

Prevention includes addressing the drivers of disease emergence, namely ecological, meteorological, and anthropogenic factors and activities that increase spillover risk, in order to reduce the risk of human infection. It is informed by, among other actions, biosurveillance in domestic and wild animals, people and the environment, understanding pathogen infection dynamics, and implementing intervention activities. Exemplary preparedness-response actions (downstream actions) are indicated on the right.

https://doi.org/10.1371/journal.ppat.1011504.g001

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Table 1. Framework for pandemic prevention, preparedness and response (revised from [19]).

https://doi.org/10.1371/journal.ppat.1011504.t001

Scope of prevention of spillover

An important principle is that spillover of pathogens from a natural source only occur after direct or indirect contact between the pathogen (e.g., via an infected host/environment) and people at interfaces between humans, animals, and the environment. Animals and biodiversity do not present an inherent risk per se; risk is created by human behavior that places humans and other species in risky contact that increase chances for spillover. Understanding the presence, diversity, evolution and characteristics, distribution, and infection dynamics of pathogens in the host using a One Health approach can assist in identifying risk factors for spillover, and hence opportunities/critical control points for spillover prevention, although a more generic approach can also be taken in the absence of thorough knowledge of these aspects. Depending on the context and existing evidence, trade-offs of possible interventions, and resource requirements, this can be complex and might require several interventions at different risk interfaces. However, it is possible and has been shown to be more cost-effective than relying on response activities [1,4,5]. Knowledge of the human–animal–environment interface and how this has changed over time (e.g., changes in land use, which species are hunted or farmed, farming methods, food systems, animal trade, infrastructure, and industry developments) are essential to inform approaches for prevention. It is therefore essential to also invest in research and the socioeconomic factors that change these. This also applies for vector-borne diseases, where knowledge on habitat suitability, climate factors, and host abundance can be used for risk assessment. Where available, information on presence, excretion, and pathogenicity of specific pathogens also can inform risk assessment. However, even without that information, knowledge of possible exposure routes across the human–animal–environment interface can be used to identify critical control points, and modification of human behaviors can be introduced to reduce human infection risk in a generic, multi-hazard fashion. Specific factors related to hunting, capturing, farming, and slaughter/preparation of wild animals; intensive/high density livestock farming especially linked to inadequate biosecurity; trade in live animals and animal products; deforestation, extractive industries, and encroachment into wildlife habitat; agricultural expansion and intensification; and urbanization and habitat fragmentation are often important in shaping risk. Overarching drivers, such as climate change, food security, basic animal and human health, animal welfare practices, poverty, and socioeconomic inequalities, should also be considered in the prevention of spillover.

Acknowledgments

We thank the Quadripartite focal points, namely Barbara Haesler, Julian Blanc, Chadia Wannous, and Danny Sheath/Abigail Wright for their continuing input and support to the work of OHHLEP. We express special thanks to Claudia Ciarlantini and Cristiana Giovannini from the Food and Agriculture Organization of the United Nations (FAO) for their efforts and collaboration in developing the figure.