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Prediction and Prevention of The Next Pandemic Zoonosis
Prediction and Prevention of The Next Pandemic Zoonosis
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.
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
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
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
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
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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