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Zoonoses 3
Prediction and prevention of the next pandemic zoonosis
Stephen S Morse, Jonna A K Mazet, Mark Woolhouse, Colin R Parrish, Dennis Carroll, William B Karesh, Carlos Zambrana-Torrelio,
W Ian Lipkin, Peter Daszak

Lancet 2012; 380: 1956–65 Most pandemics—eg, HIV/AIDS, severe acute respiratory syndrome, pandemic influenza—originate in animals,
See Comment pages 1883 are caused by viruses, and are driven to emerge by ecological, behavioural, or socioeconomic changes. Despite their
and 1884 substantial effects on global public health and growing understanding of the process by which they emerge, no
This is the third in a Series of pandemic has been predicted before infecting human beings. We review what is known about the pathogens that
three papers about zoonoses
emerge, the hosts that they originate in, and the factors that drive their emergence. We discuss challenges to their
Mailman School of Public control and new efforts to predict pandemics, target surveillance to the most crucial interfaces, and identify
Health (Prof S S Morse PhD),
and Center for Infection and
prevention strategies. New mathematical modelling, diagnostic, communications, and informatics technologies can
Immunity (Prof W I Lipkin MD); identify and report hitherto unknown microbes in other species, and thus new risk assessment approaches are
Columbia University, needed to identify microbes most likely to cause human disease. We lay out a series of research and surveillance
New York, NY, USA; One Health opportunities and goals that could help to overcome these challenges and move the global pandemic strategy from
Institute, School of Veterinary
Medicine, University of
response to pre-emption.
California, Davis, CA, USA
(Prof J A K Mazet PhD, Introduction roughly 400 emerging infectious diseases that have been
Prof S S Morse); Centre for identified since 1940 are zoonotic,3 and these pathogens
The emergence of novel infectious diseases such as
Immunity, Infection and
Evolution, University of HIV/AIDS, severe acute respiratory syndrome (SARS), are the focus of particular public health interest.4,5
Edinburgh, Edinburgh, UK and pandemic influenza has shown the vulnerability of Similarly, specific geographical regions or interfaces
(Prof M Woolhouse PhD); human beings to new zoonotic health threats. The between people, wildlife, livestock, and the environment
College of Veterinary Medicine,
mortality and morbidity associated with HIV/AIDS have have been identified as the origins of recent emerging
Cornell University, Ithaca, NY,
USA (Prof C R Parrish PhD); US devastated communities in some countries and led to infectious diseases, and thus are targets for intense
Agency for International global changes in public health. The rapid pandemic surveillance.3,5–7 Analysis of previous emergence events
Development, Washington, spread of SARS coronavirus in 2003 and a new triple- has led to a better understanding of the causes (so-called
DC, USA (D Carroll PhD);
reassortant H1N1 influenza in 2009 both resulted in drivers) of emergence.6,8 These advances, coupled with a
EcoHealth Alliance, New York,
NY, USA (W B Karesh DVM, substantial economic loss as the pathogens exploited— better understanding of the dynamics of pathogen
C Zambrana-Torrelio MSc, and in some instances closed down—global travel and transmission, ecology, and evolution as they emerge and
P Daszak PhD); and IUCN trade networks.1 These vulnerabilities emphasise the spread, promise the possibility to predict pandemics.
Species Survival Commission
need for a systematic, pre-emptive approach that aims to Here we review these findings and the most promising
Wildlife Health Specialist
Group, Gland, Switzerland prevent the spread, or even the initial emergence, strategies to improve anticipation, prediction, and pre-
(W B Karesh) of pandemics. emption of the next pandemic zoonosis at the source.
Correspondence to: The emergence of novel pandemic agents often seems
Dr Peter Daszak, EcoHealth to be inherently unpredictable.2 Indeed, no pathogens
Alliance, 460 West 34th Street,
have been predicted before their first appearance. How- Search strategy and selection criteria
New York, NY 10001, USA.
[email protected] ever, patterns in the origins and spread of new pathogens We searched PubMed and ISI Web of Knowledge with the
can be noted and are an intrinsic, albeit ad-hoc, part of terms “emerging infectio*”, “zoonos*”, or “pathogen
surveillance strategy. For example, more than 60% of the discovery” in combination with the terms “modeling”,
“prediction”, “surveillance”, “evolution”, “ecology”, or
“methodology” for papers published in any language before
Key messages
Sept 25, 2012. We did our searches when we began to
• Most recent pandemics, such as HIV/AIDS, severe acute respiratory syndrome, and develop and write the paper and again before submission of
pandemic influenza, are caused by zoonotic pathogens (ie, pathogens harboured by the revised, final version. Some coauthors provided
non-human animals), are viral diseases, and originated in wildlife references that they deemed of particular importance. We
• Such infections are usually driven to emerge by ecological, behavioural, or largely selected publications from the past 5 years, but did
socioeconomic changes not exclude commonly referenced and highly regarded older
• Technological advances in mathematical modelling, diagnostics, communication, publications. We also searched the reference lists of articles
and informatics enable targeted global surveillance of emerging and previously identified by our searches and selected those judged
unknown infections in both human beings and other species relevant. Reviews and book chapters are cited to provide
• New risk-assessment approaches show promise for the use of these capabilities to readers with more detailed information and references than
predict and pre-empt potential pandemics at their source (eg, in wildlife or other is possible in the space allowed. Our reference list was
animals), and need to be further developed modified on the basis of comments from peer reviewers.

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Origins and dynamics of pandemic zoonoses

When the origins of emerging infectious diseases are
traced back to first emergence in the human population,
some distinctive patterns are revealed that could be
used in disease control.3,6 First, the frequency with which
new pathogens emerge is increasing, even when the
increased surveillance globally is taken into account,3
suggesting that efforts to coordinate the global strategy to
fight pandemics are timely and of growing importance.9,10
Second, the emergence of all major groups of emerging High risk
infectious diseases correlates strongly with human popu- Moderate risk
Low risk
lation density, supporting the hypothesis that disease
emergence is driven by largely anthropogenic changes,
Figure 1: Global hotspots for emerging infectious diseases that originate in wildlife
such as the expansion of agriculture, travel routes, and A database of all known emerging infectious diseases3 since 1940 was used to identify the most likely origins of
trade, and changes in land use.11 Finally, the emergence each separate emergence event. Presence or absence of infections emerging from wildlife was analysed with
of zoonotic pathogens of wildlife origin (which have logistic regression against a series of known drivers, including human population density, change in human
population density, and wildlife diversity (mammalian species richness), gridded at 1 km² resolution. The global
dominated the pandemics of the past 100 years) correlates distribution of model outputs gives a measure of the likelihood of a region to generate a new zoonotic emerging
strongly with both human density and the global infectious disease that originates in wildlife. Because previous pandemics have mainly originated in wildlife, these
distribution of wildlife biodiversity.3,8 Spatially explicit maps identify hotspots where the next pandemic is most likely to originate.
models can be used to identify the regions most likely to
produce the next emerging zoonoses (so-called hotspots reported.17,19 Pathogens can transfer from human beings
of emerging infectious disease).3 These hotspots are to animals and between different animal species before
regions where human activities take place against a being transferred back to people, allowing remixing
background of high wildlife biodiversity, with concomitant and evolution with spill-back and potentially enhanced
microbial biodiversity (figure 1). Targeting of surveillance pathogenicity (eg, influenza).20,21
to such regions provides a rationale for better allocation Human pathogens from all taxa contain zoonotic
of global resources to prevent emerging infectious disease species. Roughly 80% of viruses, 50% of bacteria, 40% of
or rapidly deal with outbreaks.3 fungi, 70% of protozoa, and 95% of helminths that infect
The process through which pandemic zoonoses human beings are zoonotic.18 Most of the identified
emerge can be analysed to identify the crucial control reservoirs are mammalian (roughly 80%) or, to a lesser
points and specific research challenges (panel 1, extent, avian,18,22 although people share some pathogens
figure 2). The model we adopt here (developed by with invertebrates, which act as vectors23 or intermediate
Daszak) to assess pandemic potential has three stages— hosts. Identification of the key taxonomic groups that are
no human infection (stage 1), localised human infection sources for the emergence of zoonotic disease could help
(spillover; stage 2), and widespread transmission and to improve targeting of surveillance and interventions.
global dissemination (stage 3). The frequency at which Ungulates are the mammalian taxa with which human
stages 1 and 2 occur is unknown but probably high. beings share the most pathogens17—perhaps not surprising
That human populations are continually exposed to a because, as major food sources, these animals are often in
wide variety of non-human-animal pathogens, many of close proximity to people, and their diseases have been
which infect human beings, seems reasonable to studied extensively. Rodents, carnivores, and primates are
assume. To assess the role of pathogen biology in also well represented. Although pathogens deemed emerg-
emergence, investigators need to know how many ing or re-emerging are disproportionately likely to be
pathogens people are exposed to and how many zoonotic,18 their reservoirs are much the same as those of
successfully cross the species barrier. A complete non-emerging zoonoses.22
inventory of spillovers is not available, but researchers The situation, however, is substantially different for
have a good working knowledge of pathogens of pathogens that have reached stage 3. A disproportionate
domestic livestock and pets (species in frequent contact number of these pathogens are viruses, suggesting that
with human beings). Almost 50% of the roughly viruses have the potential to evolve more rapidly than do
1000 species of pathogens that are noted in livestock other kinds of pathogen. However, this finding could be
and pets are zoonotic,17 implying that any barriers due to ascertainment bias. Less complete knowledge is
between these hosts and human beings are routinely available about the diversity of viruses than that of other
breached by many different pathogens. More than 50% pathogens, and researchers might still be missing many
of the recognised pathogens of human beings can at stages 1 and 2.24 Although a lot of stage 3 pathogens that
infect other vertebrate hosts.18 Many non-human infect only people don’t strictly have reservoirs (eg,
pathogens can infect several hosts, and clear examples HIV-1), many are thought to have had zoonotic origins,
of viruses transferring between different animal hosts including in non-human primates, which contrasts
to cause outbreaks in other species have been strongly with the minor contribution of primates as

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Panel 1: Stages in disease emergence Stage 3 Pandemic emergence

International travel and trade
Several researchers have separated the process of emergence into distinct steps or • HIV/AIDS
stages. Morse originally divided the process into two steps, introduction (into a new • Severe acute respiratory syndrome

species, such as human beings) and establishment/dissemination.6,12 Wolfe and

colleagues13 subsequently developed a model with five stages—a so-called pathogen
pyramid—to represent successively greater pathogen adaptation to successful human
infection and transmission, from inability to infect human beings (stage 1) to exclusively
human disease (stage 5).
Figure 2 shows an alternative depiction of the stages of emergence, which emphasises the
Stage 2 Localised emergence
dynamics of infection rather than pathogen properties. The frequency of these events
Expansion of the wildlife–human being interface
probably diminishes from stage 1 to stage 2, and the final stage, true pandemic • Nipah virus
emergence (ie, intercontinental spread of a pathogen in human beings), is far rarer than • Ebola virus
the initial localised emergence events.
Stage 1 (pre-emergence): the putative pandemic pathogen is still in its natural reservoir.
Ecological, social, or socioeconomic changes (eg, change in land use) alter the dynamics of
pathogen transmission within the host or between hosts and allow the pathogen to
expand within its host population, spread to a new region, or be transmitted to another
non-human host population or species. Each of these changes increases the likelihood of
Stage 1 Pre-emergence
the pathogen making contact with and spilling over into human beings (and thus
progressing to stage 2).1,6,7 The drivers that cause stage 1 emergence tend to be large-scale Encroachment into wildlife habitat
Change in land use
environmental, agricultural, or demographic shifts—eg, moving of livestock to a region
for the first time, or transportation of wildlife from a region for food. Such events
happened before the emergence of Nipah virus in Malaysia in 1997, after intensively
managed pig farms and fruit orchards were built in a region frequented by fruit bats (the
natural reservoir). These bats began to feed on fruit trees around pigsties, enabling viral
transmission to pigs and stage 1 emergence.14 Similarly, change in land use in Africa has
brought livestock, people, and wildlife into the same habitat, leading to multidirectional
pathogen transmission between livestock and non-human primates (stage 1), and some
spillover into people (stage 2).15
Figure 2: Emergence of pandemic zoonotic disease
Stage 2 (localised emergence): initial spillover of a wildlife or livestock pathogen to Stage 1 is a pre-emergence state, in which naturally occurring microbes are
people. Causes range from handling of butchered wildlife to exposure to fomites in transmitted between their animal reservoirs. Disturbances to the ecology of these
wildlife markets or livestock farms, or in the wild. Outcomes vary widely, from small populations (eg, due to changes in land use) change the dynamics of microbial
clusters of human cases (eg, Menangle virus)16 to large outbreaks, some with limited transmission and can lead to a heightened risk of pathogen spillover to other
non-human wildlife or livestock hosts (but not people). Stage 2 is localised
person-to-person transmission (eg, Ebola virus) and some without (eg, Hendra virus). emergence, either through self-limiting spillover events (green peaks and troughs,
Stage 3 (full pandemic emergence): sustained person-to-person transmission and representing the rise and fall in numbers of infected people with time) or
large- scale spillover (red peaks, representing spikes in the number of infected
large-scale spread, often aided by global air travel (eg, HIV/AIDS, severe acute respiratory
people with time), that leads to person-to-person transmission for a few
syndrome) or the international movement of reservoir hosts or vectors through trade pathogen generations. In stage 3, some spillover events might lead to indefinitely
(eg, West Nile virus). Stage 3 pandemics are rare because even pathogens capable of sustained person-to-person outbreaks, international or global spread, and the
some person-to-person transmission might not be able to maintain long enough chains emergence of a true pandemic. The size, spread, and potential effect of events
increase from stage 1 to stage 3, but the frequency falls so that full stage 3
of transmission to spread (eg, Nipah virus in Bangladesh). pandemics are quite rare. By dissecting this process and analysing the interactions
of the underlying drivers with the risk of spillover and spread, development of a
more structured approach to pandemic prevention is possible. The ultimate goal
of successful pandemic prevention is to move the control point to stage 1.
reservoirs for zoonoses in general. If risk is a function of
contact frequency and probability of successful adap-
tation to human beings, pathogens acquired from other 2003 and was due to hunting and trading of bats for
primates might already be better adapted to successful food.27 In the wildlife markets of southern China these bat
transmission than those from other mammals (exposure viruses seemed to become stage 1 pathogens, which
from rodents, bats,25 and other common vertebrates are spilled over to civets before being transmitted to people
the most frequent). and achieving stage 2.28 SARS coronavirus then under-
Many pandemic zoonoses (ie, those that reach stage 3), went repeated cycles of transmission in people, and
such as HIV/AIDS,26 have achieved sustained person-to- spread nationally and then globally (ie, reached stage 3),
person transmission without the need for a non-human including 251 cases as far away as Toronto. Non-human
reservoir. For example, SARS, which originated from the hosts can have a role in the maintenance and transmission
SARS-like coronaviruses of bats, emerged in China in of some stage 3 pathogens (eg, influenza A virus).20,21 Of

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the 400 or so known emerging pathogens, roughly A successful pathogen needs to possess the molecular
100 occur only as human pathogens—ie, such special- machinery to infect people, invade human cells or
isation is rare.29 Some of the seemingly specialist human tissues, replicate, and access tissues from which it can
pathogens are thought to have had zoonotic origins much exit the host and transmit (directly or indirectly) to other
further back in evolutionary time (eg, Plasmodium people.38,43 Historical examples are few, and thus to
falciparum).30 This pattern could be the norm, but the quantify the relative contribution of exposure frequency
origins of most specialist human pathogens are un- versus phylogenetic relatedness to the risk of successful
known.13 Much more is known about the dynamics of infection is difficult. Analysis of host–pathogen data-
pandemic pathogens once they can be transmitted among bases of primates shows that closely related sympatric
people. Transmission rates are often higher in dense than host species are more likely to share parasite species than
in sparse populations, and spread is often greatly are distantly related sympatric host species.44 Although
enhanced by air travel or human migration. The any pathogen from a mammalian (or avian) host is a
mathematics of these spreading events is well known, potential threat, that exposure of people to novel
and a sophisticated array of computational models have pathogens from our closest animal relatives poses the
been used to back-predict such events accurately—eg, the greater risk to public health is at least plausible.
first case clusters of SARS31 and the subsequent global Microbes often evolve substantially during emergence
spread, including the country-by-country distribution of (eg, SIVcpz evolved into HIV-1), and the role of evo-
human cases.32 Models based on air travel, realistic lutionary adaptation in enabling pathogen establish-
human contact networks, and individual countries’ ment in human populations is a subject of active
capacities to deal with outbreaks can now produce research.45,46 Alternatively, some pathogens can spread
reasonably accurate predictions of future pandemic between human beings without evolutionary change
spread (particularly for influenza).33–35 However, less is from the genotypes present in the wildlife host
known about the factors that enable pathogens to move (eg, Ebola virus), and thus can enter the human popu-
from stage 2 to stage 3 and ultimately achieve pandemic lation at stage 2. Phylodynamics, which combines a
status. During this process, stuttering chains of novel modelling framework for host, epidemiological, and
human transmission (as with human monkeypox in molecular data,47,48 especially for RNA viruses, shows
Africa, for example36,37) can become self-sustaining (which particular promise for understanding of patterns of
monkeypox has still not achieved in people36). The viral evolution during epidemics.48,49
distribution and behaviour of human beings, reservoir Testing of the relative importance of exposure and host
hosts, and vectors are crucial for emergence, and human relatedness in stage 2 emergence is an important
demographics and behaviour often establish capacity for challenge. For plant pathogens, experimental infection of
person-to-person transmission. closely or distantly related plants with a range of fungal
Differential host physiology, especially age and immuno- pathogens has shown that host relatedness is a key factor
competence, affect susceptibility to infection.38,39 The surge in the ability of a pathogen to infect a novel host.50 Such a
in immunocompromised patients during the HIV/AIDS study would be logistically and ethically challenging in
pandemic was associated with an upsurge in other mammals, but experimental work with several model
emerging pathogens.7,9 Host factors often receive less systems and various other organisms is underway, and
research focus than does pathogen virulence, but systematic studies of host–parasite databases might
improved knowledge of host responses is essential to provide an alternative. These studies might provide new
understand the species barrier and why some zoonotic surveillance opportunities by allowing improved
pathogens are benign in their natural hosts but lethal targeting of the key wildlife species most likely to harbour
when introduced to other species.38,39 the next emerging zoonosis.
In view of the importance of human activities in
emergence, integration of social sciences research— Pathogen discovery
particularly that focused on human behaviour and demo- Identification of zoonotic pathogens has been substan-
graphics—into models of infectious disease emergence tially improved by advances in molecular diagnostics,
and evolution is essential to understand pandemics.40,41 which make possible the identification of hitherto
The importance of human exposure throughout the unknown pathogens in nature (so-called pathogen
emergence process also suggests that simple behavioural discovery).51,52 This process also includes differential
precautions could greatly reduce risk. Risks to hunters, diagnosis of infectious disease and surveillance for known
food handlers, and livestock workers from occupational or novel microbes that are normally benign in natural
exposure could be reduced in hotspots of emerging hosts but have the potential to become pathogenic in other
infectious diseases though routine sanitation and bio- hosts. Traditionally, microbe hunters used many tech-
safety precautions, as has been tried with H5N1 in niques, including in-vitro and in-vivo culture, immuno-
agricultural settings.42 Nosocomial spread could be histochemistry, electron microscopy, and serology.
prevented by stringent adherence to infection control Immunohistochemistry of clinical samples was used
practices—eg, use of sterile injection equipment. successfully in several cases. Molecular techniques were

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used to first identify sin nombre virus, Nipah virus, West potential human pathogens in other species. The goal of
Nile virus, SARS coronavirus, and Lujo virus, among such studies is to characterise novel microbes and assess
others. With the advent of unbiased molecular methods, probable virulence and transmissibility in people. How-
the use of visualisation techniques has already begun to ever, crucial challenges exist in prediction of the effects of
shift from discovery to provision of evidence of causal these new microbes, especially for viruses.53 In some cases
relations between an infectious agent and disease, by (eg, coronaviruses54), host range can at least partially be
locating evidence of the agent at sites of pathological predicted by receptor specificity and other factors.24,54 When
changes, including in both chronic and acute disease.51 virulence factors are known (as for many bacteria38), meta-
Rapid, cost-effective molecular techniques allow broad- genomic analysis for these factors can be very useful.52
scale screening of samples, and pathogen discovery could Such analysis is more challenging with viruses than with
be a strategy in wildlife to pre-empt pandemic zoonotic other microbes,19,43,55 although the experimental develop-
disease emergence through early identification. This ment of mutations in H5N1 that increase transmissibility
strategy might be particularly effective when enhanced by in a ferret model has allowed targeted surveillance for
hotspot modelling, which allows targeting of specific isolates that are most likely to become efficient human
regions with the highest spillover risks. Historically, most pathogens.56 However, even when putative human patho-
surveillance efforts have been designed to detect individual gens can infect human-cell cultures, they are often unable
pathogens in natural reservoirs, vectors, or at-risk human to infect people. Genetically humanised murine models
or animal populations through use of individual (so-called have been developed for SARS57 and hepatitis C virus
singleplex) PCR assays or serology. However, the costs (which usually can infect only human beings and
for multiplex PCR, microarrays, and high-throughput chimpanzees).58 Humanised mice,59 or other model
sequencing continue to fall, and thus these assays are systems, could perhaps be adapted to screen for the ability
increasingly used as primary techniques for syndromic of newly discovered microbes from wildlife reservoirs to
surveillance and studies of microbial diversity and infect people. Workers at the Rockefeller Foundation Virus
discovery.51,52 The challenge with any of these technologies Program in the mid-20th century used a low-tech version
is determination of the relevance of a microbial signature. of the strategy—intracerebral inoculation—on suckling
5000 species of mammals and 10 000 species of birds are mice, which are susceptible to many infections by this
known, each of which probably has at least several unique route.60 However, screening in humanised mice is not yet
endemic viruses. Therefore the total number of new widely available. In most cases, prediction of human
pathogens awaiting discovery is probably far higher than virulence or transmissibility from molecular or phylo-
the 2000 to 3000 characterised. When other vertebrate- genetic data alone is still not feasible (another crucial
associated microbes are also considered, clearly the unmet need), although promising work has been done
unfocused application of high-throughput screening could with in-vitro tests to assess ability to induce a hyper-
rapidly exhaust resources without substantively reducing inflammatory cytokine response in human cells as a
pandemic risk. Therefore, discovery efforts need to be predictor of virulence.61,62 Molecular data will be of
directed toward reservoirs and vectors where human increasing predictive value as the global genomic data-
being–animal interfaces6 and hotspot modelling3 or other base expands, thereby allowing wider comparisons and
information suggest an increased risk of transmission. In identification of commonalities. The predictive value will
the past few years, the abundance and availability of increase further if these molecular data are correlated with
molecular sequence data have made possible the identifi- epidemiological and clinical data, and as our understanding
cation of unknown microbes in nature based on of host requisites for transmission and barriers to cross-
similarities to the sequences of known organisms, even in species transfer improves. As programmes for pathogen
crude nucleic acid extracts (so-called metagenomics).51,52 discovery in wildlife expand rapidly, the development of
This approach has clear value during the early stages of risk assessment criteria for the importance of these
emergence. However, sequence data became available microbes is crucial. In our opinion, crucial questions
while an epidemic was still in progress for the first time remain and further research could substantially improve
only during the West Nile outbreak in 1999, and then again our understanding and our capacity to prevent pandemics
during the 2003 SARS outbreak and the 2009 influenza before they emerge (panel 2).
H1N1 pandemic. This information was invaluable for These research questions are part of a much-needed
rapid development of diagnostics, identification of the basic research programme to investigate prediction of
source of the infection, and pathogen discovery. However, pandemics. However, previous evidence of pathogen
the rapid sequencing and identification of new pathogens spillover is a simple predictor of possible future emer-
before large-scale spread remain a substantial challenge. gence, and an active interface between human beings and
other species is an obvious sine qua non. The capacity of
Prediction of pandemic potential in novel a novel virus to transmit to people, and especially to cause
microbes illness, is a clue that the virus can replicate well in human
Advances in meta-genomic technology have led to efforts beings, and thus could gain the properties that allow
in which molecular data are prospectively used to identify onward transmission. Spillover infections just below the

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Panel 2: Prediction of pandemic potential

Programmes for pathogen discovery (including within wildlife interactions for commonly expressed receptors (eg, sialic
populations) are expanding rapidly, and development of risk acids or heparan sulfate proteoglycans) or ease of adaptation
assessment and prioritisation criteria for these microbes is of the virus to a new host receptor.24 However, the cell
crucial. Several lines of inquiry could substantially increase receptor is still unknown for more than 50% of human
capacity to prevent pandemics before emergence. viruses. Highly host-specific receptor structures are a barrier to
• Research about the relative importance of host relatedness infection of a new host. Receptor binding is a necessary (but
versus contact frequency: evidence shows that pathogens not sufficient) condition to enable viral entry to a cell and
from closely related host species might be better able to successful replication. Changing of receptor affinity (from
spill over from one to the other.63 Emerging pathogens in avian-type to mammalian-type) was the first step in the
people have originated in both closely related host species adaption of H5N1 avian influenza virus to mammalian
(eg, HIV-1 from chimpanzees26) and distantly related hosts transmission, but other mutations were also needed.68,69
with which human beings have had close recent contact Intracellular barriers and host resistance factors also exist for
(eg, severe acute respiratory syndrome from bats and many viruses.43,55,70,71 Viral genes that interfere with these
civets,27 Nipah virus from bats and pigs,14 influenza from functions might be identified on the basis of signatures or
pigs and birds20,64). similarity to known genes.
• Analysis of viral relatedness as a predictor of emergence: • Capacity to exploit new routes of transmission: widespread
wildlife viruses that are more closely related to known human outbreaks are often correlated with high transmission
pathogens are often assumed to be more likely to infect efficiency, which might be partly related to the route or
people than are those not similar to human pathogens. frequency of spread.72 Human behaviour is an important
However, with the possible exception of the component that should be integrated into any predictive
orthomyxoviruses and paramyxoviruses, the viral families model,41 but the aspects of behaviour that matter are
that caused the most important recent zoonoses in human established by the pathogen’s mode of transmission.
beings (ie, lentiviruses and coronaviruses) were recognised to • Prediction of virulence in human beings: along with
have the potential for emergence only after they had already prediction of human transmissibility, perhaps the biggest
done so. Analysis of viral traits and phylogenetic relations, and challenge is to assess the likelihood that a wildlife or
how these correlate with pathogenicity after a virus spills over, livestock virus will cause noteworthy disease if the virus
will be crucial.65,66 does infect people. True risk to human beings is related to
• Host range and plasticity: emerging pathogens often have a both the transmissibility of a pathogen and the severity of
broad host range. Pathogens that are more able to undergo the disease that results, and many zoonotic viruses that
successful transmission between different host taxa are also infect people cause no disease (eg, simian foamy viruses73)
more likely to infect human beings than are those less able or mild symptoms (eg, Menangle virus16). Why some
to transmit between different host taxa.22 These viruses that are benign in their natural hosts induce a
mechanisms should be elucidated and predictive severe or lethal hyperinflammatory response in a new host
correlations made. (eg, Ebola virus, sin nombre virus) is not well understood,
• Estimates of a virus’s ability to evolve: the factors that allow but the causative pathogen components or structures
a pathogen to successfully jump species are poorly known, should be identified and the mechanisms of species
but might include high mutability and an absence of specificity further elucidated.
proofreading to correct mutations, which are thought to • Patterns of host–virus coevolution: coevolutionary
explain the high proportion of negative-stranded RNA relationships in a group of related viruses and their wildlife
viruses in emerging pathogens.19,29 So-called evolvability67 hosts can be assessed easily by analysing genetic sequences.74
might help to explain why some pathogens have a high Strong patterns of coevolution during recent evolutionary
propensity for host jumps.19 time suggest stable long-term interactions with little
• Research about host–receptor interactions: receptor binding is host-switching, but pathogens that have frequently moved
an essential first step in cell infection and has been associated from one host to another have poorly aligned coevolutionary
with changes in host and tissue tropism.19,24,45 Prediction of trees. Improved understanding of the pathogen’s
receptor binding necessitates understanding of the opportunities for transfer are needed for prediction.

threshold for self-sustainment in people (ie, infections endemic countries is crucial for prediction of if and when
with a basic reproduction number slightly <1) have been this pathogen moves from stage 2 to 3. Additionally,
suggested as the prime epidemics-in-waiting,75,76 although because pandemic zoonoses are such a large threat to
they are difficult to identify in advance. Thus, spillover global public health, to understand the ecological,
events of any magnitude should be carefully monitored. virological, and social rules governing their emergence
For H5N1, intensive monitoring of each spillover case in seems important. A concerted, interdisciplinary research

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focus on the process of disease emergence is urgently project initiated in 2009 by the US Agency for International
needed, and should include all sectors of the medical Development. The programme is a suite of capacity-
sciences, ecologists, social scientists, and wildlife building investments designed to rapidly identify (and
biologists, among others. eventually predict) the emergence of new public health
threats and increase country-level capacities to mitigate the
Global strategy for surveillance and prevention potential effects of these threats.85 It draws heavily from
For emerging infections, strengthening of public health efforts to address the H5N1 threat, and emphasises a
surveillance worldwide to provide early warning has been strategic approach that builds on the understanding that
the primary recommendation of expert groups for the the health and wellbeing of people, animals, and the
past two decades.4,5,10,77,78 Although greatly improved, environment are inextricably linked; promotes a One
public health surveillance capabilities remain restricted Health approach that spans the animal health, public
and fragmented, and have uneven global coverage.20,64,79 health, environmental, and conservation communities;86
For the ProMED website see ProMED and the ProMED-mail e-mail LISTSERV and targets promotion of policies and capacities to identify and
http://www.promedmail.org website were developed in the 1990s to improve early- minimise the risk of emergence of new disease; and uses a
warning capacity.77 This notion has expanded substan- risk-based approach to target investments where the likeli-
tially, with a series of new initiatives such as WHO’s hood of disease emergence is greatest.
Global Outbreak Alert and Response Network;80 a The Emerging Pandemic Threats programme, through
tripartite One Health initiative involving WHO, the Food its PREDICT component, has developed an approach in
and Agriculture Organization of the UN, and the World which predictive modelling is used to identify the regions,
For HealthMap see http://www. Organisation for Animal Health; HealthMap.org (and wildlife hosts, and human being–animal interfaces most
healthmap.org/en/ similarly Canada’s Global Public Health Intelligence likely to propagate the next emerging zoonosis. The
Network), a system that does high-capacity searching and approach brings together experts from specialties, includ-
filtering of internet feeds to identify novel pathogen ing wildlife ecology, epidemiology, genetics, virology,
outbreaks as rapidly as possible;81 and, in the USA, the informatics, and veterinary medicine, all focused on
Centers for Disease Control and Prevention’s Global building of a global early warning system for emerging
Disease Detection programme, the Department of De- diseases that move between wildlife and people. The
fense’s Global Emerging Infections Surveillance and programme’s first goal is to obtain timely and reliable data
Response System, and other initiatives. These initiatives for zoonotic threats, through internet surveillance of
have been assisted by regional coordination and the reports of unusual events in hotspot countries, analyses of
formation of, for example, the European Centre for the capacity of pathogens to emerge and then spread
Disease Prevention and Control, and subregional net- under different social systems in hotspots, and in-depth
works such as the Mekong Basin Disease Surveillance sample collection from the wildlife hosts most likely to
Network.82,83 The adoption of the revised International harbour zoonoses. Samples are analysed to identify
Health Regulations, which have a target of establishment known zoonotic pathogens and new, closely related
of minimum core capacities, or specific plans, by mid- viruses, and then those deemed most likely to infect and
2012, by the 194 member states of WHO was a noteworthy cause illness in people are more fully characterised.
advance.84 The revised Regulations incorporate a broad PREDICT is active in 20 developing countries in
definition of outbreaks of public health concern, which emerging infectious disease hotspots and focuses on
include outbreaks in non-human animals, and provides surveillance at human being–animal interfaces where
an incentive for low-income countries to build capacity cross-species transmission is most likely. Infection in the
for pandemic surveillance and prevention. Although natural or reservoir hosts is often asymptomatic,20 and
implementation will probably be delayed because many thus testing of seemingly healthy animals is essential, but
countries have so far been unable to achieve minimum might be resource intensive, and unproductive if done
core capacity goals, the adoption of the Regulations randomly. To avoid this issue, PREDICT uses a combin-
should greatly improve standards for surveillance, ation of risk modelling to target locations, interfaces, and
reporting, and response.82 host taxa, and computerised data collection and analysis
Efforts to reduce or prevent pandemic zoonoses before and active wildlife field sampling at high-risk sites to
they emerge in people have also begun, and might form collect and identify viruses that might transfer from
the template for a new, globally coordinated pandemic wildlife and cause disease. The programme partners with
prevention strategy. For influenza, these efforts have been national and local governments, in-country scientists,
focused on animal surveillance as a strategy to identify and other local specialists who are active in outbreak
periods when the risk of spillover to people is high.64 Wider reporting, microbial characterisation, and pathogen
surveillance in wildlife to include targeted pathogen discovery, in collaboration with other US Agency for
discovery has been called for.3,5,7,64 However, few coordinated International Development Emerging Pandemic Threats
efforts have been implemented to pre-empt zoonotic projects as appropriate. These partnerships are intended
disease emergence with wildlife surveillance. The to ensure the longevity of the programme by building
Emerging Pandemic Threats programme is a noteworthy capacity in the most in-need regions. The programme’s

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scale gives some indication of how feasible this type of new human coronavirus respiratory disease from Saudi
approach is for identification of the many thousands of Arabia89 and a novel haemorrhagic fever virus in central
novel pathogens that are probably in wildlife globally. In Africa90 are examples of the great improvement in
the first two years of the programme, around surveillance capabilities.
100 000 samples from 20 000 animals (mainly bats, Understanding of the process of emergence and spread
rodents, and non-human primates) in 20 countries have has moved from anecdotal through analytical to poten-
yielded 150 novel viruses from families known to harbour tially predictive. Researchers are positioned to move
zoonoses. These data will be used to further refine global from a paucity of data to a wealth of information on
hotspot mapping and modelling strategies and test potential pathogens in nature. The challenge is to develop
hypotheses about zoonotic transmission. They will also the basic research agenda to allow potential pathogens to
be shared as open source information, after the be distinguished from harmless microbes by use of
appropriate country clearances, through an interactive molecular sequence data only (the most commonly
application at HealthMap.org. In selected high-risk collected information), or information that can be
regions, the associations between viral diversity, biological deduced from these data—eg, structures of key proteins.
diversity, patterns of human contact with wildlife and Political will for countries to act together to strengthen
livestock, and changes in land use are being explored to global networks against pandemic emergence also seems
decipher the rules that govern disease emergence. to have become positive. This new approach to pandemic
The ultimate goal of the Emerging Pandemic Threats prevention is shown by the handling of the discovery, in
programme is to develop a strategy to prevent future 1997, of a highly pathogenic influenza A (H5N1) of avian
pandemics at the source before they infect human origin that infects people (precursor of the now widespread
beings—an ambitious goal that requires more than H5N1 avian influenza).91 Since then, and despite the
building of health-care capacity or surveillance and virus’s continued inability to transmit effectively between
diagnostic programmes. The challenge to true pandemic people, the public health community has recognised that
prevention (and pre-emption) is how to address the a lethal virus circulating only in wildlife and domestic
underlying drivers that are essentially ecological (eg, animals creates extraordinary opportunities to mitigate
juxtaposition of livestock production and wildlife future risk.64 The response to H5N1 has implicated not
populations) or occur on large spatial scales because of only clinical, diagnostic, and therapeutic advances, but
economic activity (eg, change in land use related to also better understanding of avian ecology, the economics
development of tropical forests).1 In the case of both of poultry production in low-income countries, and the
Nipah virus14 and H5N1,87,88 economic development ecology of the virus across the virus’s broad host range.
resulted in changes to animal production that led to the For perhaps the first time, the response to a zoonotic
opening of a new niche for a pathogen. Could the pandemic has included development agencies improving
seemingly opposing forces of economic development and individual countries’ abilities to identify new zoonoses
public health have been reconciled before rather than early and mitigate quickly any new health threats arising
after these outbreaks occurred? Expansion of so-called within their borders.
health impact assessments is a possible approach.12 The challenge is to establish whether and how re-
Incentives for industries with roles in activities that searchers can intervene before a pathogen reaches the
propagate pandemics could be linked to development human population and develop appropriate triggers for
initiatives. For example, concessions in development of action. Zoonotic diseases, by definition, should be a key
logging or mining could include better food supply chains mission of human-health agencies, agricultural author-
as an alternative to bushmeat hunting, better clinics for ities and producers, and natural resource managers,
migrant workers than are available, and more intensive all working cooperatively. Substantial investments in each
surveillance of livestock at these crucial interfaces. of these challenges are essential because the ecological
Similarly, efforts to curtail the wildlife trade for food and and social changes worldwide that allow the emergence
pets in hotspot and other countries could include creation of infectious diseases are increasing at an unprecedented
of incentives for consumers that lead to certification of rate. Integration of efforts and coordination of budgetary
industries promoting healthy practices. resources for prevention and control is clearly a challenge
that governments, both local and national, need to
Conclusion confront, and building of capacity to sustain these efforts
The basis on which to build a global pandemic preven- might be the greatest challenge of all.
tion strategy has changed substantially over the past few Contributors
decades. A newly revised global reporting system of SSM and PD selected the topics for review, wrote portions of the paper,
outbreaks and new molecular methods for pathogen and coordinated and edited the contributions of all other authors. SSM
did the searches of scientific literature, with contributions from the
identification and discovery are available, and advances other authors. CZ-T analysed the underlying data and produced the
in communications technology—eg, access to mobile hotspot map; all other authors contributed sections of the Series paper,
phones and the Internet, even in remote areas—have provided references, and contributed to revisions. All authors reviewed
enabled improved reporting. The early identification of a the paper.

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Conflicts of interest 21 Dawood FS, Jain S, Finelli L, et al. Emergence of a novel

We declare that we have no conflicts of interest. swine-origin influenza A (H1N1) virus in humans. N Engl J Med
2009; 360: 2605–15.
Acknowledgments
22 Woolhouse MEJ, Gowtage-Sequeria S. Host range and emerging
This research was funded by the US Agency for International and re-emerging pathogens. Emerg Infect Dis 2005; 11: 1842–47.
Development (USAID) Emerging Pandemic Threats PREDICT project
23 Kilpatrick AM, Randolph SE. Drivers, dynamics, and control of
(USAID cooperative agreement GHN-A-009-00010-00). WIL is supported emerging vector-borne zoonotic diseases. Lancet 2012;
by grants from the National Institutes of Health (AI079231, AI57158), and 380: 1946–55.
the Defense Threat Reduction Agency. PD is supported by an Ecology and 24 Woolhouse MEJ, Scott F, Hudson Z, Howey R, Chase-Topping M.
Evolution of Infectious Diseases award from the Fogarty International Human viruses: discovery and emergence. Phil Trans R Soc B 2012;
Center of the National Institutes of Health (2R01-TW005869) and the 367: 2864–71.
National Science Foundation Human and Social Dynamics programme 25 Calisher CH, Childs JE, Field HE, Holmes KV, Schountz T. Bats:
(BCS-0826779). MW receives support from the Wellcome-Trust-funded important reservoir hosts of emerging viruses. Clin Microbiol Rev
VIZIONS project, and SSM is supported by the Arts and Letters 2006; 19: 531–45.
Foundation. We thank Murray Trostle for his invaluable insights and 26 Keele BF, Van Heuverswyn F, Li YY, et al. Chimpanzee reservoirs of
Aleksei A Chmura (EcoHealth Alliance) for figure 2. The contents are the pandemic and nonpandemic HIV-1. Science 2006; 313: 523–26.
responsibility of the authors and do not necessarily reflect the views of 27 Li WD, Shi ZL, Yu M, et al. Bats are natural reservoirs of SARS-like
USAID or the United States Government. This paper is dedicated to the coronaviruses. Science 2005; 310: 676–79.
memory of Prof Joshua Lederberg (1925–2008). 28 Guan Y, Zheng BJ, He YQ, et al. Isolation and characterization of
viruses related to the SARS coronavirus from animals in Southern
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