ArticlePDF AvailableLiterature Review
When Pigs Fly: Pandemic influenza enters the
21st century
´dia S. TrovãoID, Martha I. NelsonID*
Fogarty International Center, National Institutes of Health, Bethesda, Maryland, United States of America
Influenza A viruses (IAVs) are one of the most intensively studied pathogens, due to the severe
global mortality and economic disruption associated with influenza pandemics [1]. In addition
to annual epidemics, pandemics sporadically occur when a novel IAV host jumps to humans
from an animal reservoir [2]. Wild waterfowl have long been considered the most important
reservoir host and pandemic risk, but there are indications that mammals are emerging as key
reservoirs. Here, we describe how the modernization of swine production during the last half
century provided new opportunities for IAVs to become established in swine globally [35],
resulting in the first influenza pandemic of swine origin in 2009 [6]. A key lesson is that the
landscape of pandemic risk is not static but continuously shifting in response to demographic
changes in host populations. It is therefore vital to track how transformations in the economy
and global trade impact animal contact rates, disease dynamics, and pandemic risk among
livestock and companion animals.
Pigs fly?
For centuries, domestic pigs (Sus scrofa domesticus) were raised on traditional small-scale
farms that could not sustain IAV transmission. Whereas horses and people traveled frequently
within and between urban areas, causing recurrent influenza outbreaks in both species as far
back as the 13th century [7], influenza was not maintained in any country’s swine population
until 1918, when the Spanish influenza H1N1 pandemic virus was introduced from humans
into swine in the United States [8]. The H1N1 virus circulated in US swine for most of the
20th century without substantially evolving, causing severe disease, or becoming endemic in
swine in other countries.
In the latter decades of the 20th century, the replacement of small-scale swine farms with
larger, more efficient production systems (Fig 1A) had profound effects on disease dynamics.
Enhanced biosecurity improved control of important pathogens, such as hog cholera. But
modern production systems often require pigs to be transported long distances between multi-
ple locations specialized in different growth stages, facilitating the spread of IAV in swine
(IAV-S; commonly known as swine flu) and other pathogens not specifically targeted for erad-
ication. For example, many large breeding operations located in the southern US find it more
efficient to transport fattening pigs to the Midwest “corn belt” than to transport the large vol-
umes of feed back to the south. By the 2000s, trucks were transporting millions of pigs long
distances across North America, facilitating the spread of IAV-S along established “swineways”
In addition, pigs were flying (Fig 1B and 1C). To meet the needs of expanding middle clas-
ses for animal-sourced protein, many countries imported more productive sows (female
PLOS Pathogens | March 19, 2020 1 / 8
Citation: Trovão NS, Nelson MI (2020) When Pigs
Fly: Pandemic influenza enters the 21st century.
PLoS Pathog 16(3): e1008259.
Editor: Katherine R. Spindler, University of
Michigan Medical School, UNITED STATES
Published: March 19, 2020
Copyright: This is an open access article, free of all
copyright, and may be freely reproduced,
distributed, transmitted, modified, built upon, or
otherwise used by anyone for any lawful purpose.
The work is made available under the Creative
Commons CC0 public domain dedication.
Funding: This article was funded by Centers of
Excellence for Influenza Research and Surveillance
(CEIRS), National Institute of Allergy and Infectious
Diseases (NIAID), National Institutes of Health
(NIH), and Department of Health and Human
Services (HHS), under contract number
HHSN272201400008C. The funders had no role in
study design, data collection and analysis, decision
to publish, or preparation of the manuscript.
Competing interests: The authors have declared
that no competing interests exist.
Fig 1. Trends in swine production. (A) Trends in consolidation of swine production in the US, 1964 to 2012 (data available from the US Department of Agriculture
and the National Agricultural Statistics Service Quick Stats Database). (B) Growth of global trade (US$) of live animals between all countries, 1961 to 2017 (data
available from FAOSTAT). (C) The global distribution and density of swine populations (approximately 1 billion animals) is depicted by points shaded along a
gradient from light red (1 to 5 swine per km
) to black (more than 250 swine per km
). Lines with arrows depict the direction and volume of routes of trade (US$) of
PLOS Pathogens | March 19, 2020 2 / 8
breeding pigs) with improved genetics from North America and Europe. Imported swine
must be declared free of certain pathogens, such as African swine fever (ASF) or foot-and-
mouth disease (FMD). However, influenza is not routinely tested for, and many countries do
not quarantine, facilitating the long-distance spread of IAV-S [3,5] (Fig 2A). Using genetic
sequences of IAV-S collected in different countries over time, the direction and timing of viral
movements can be inferred from the evolutionary relationships depicted on phylogenetic
trees. Trees reveal how international trade of live swine in the 1990s and 2000s facilitated the
long-distance dispersal of IAV-S between trade partners, shaping the global spatial distribution
of IAV-S lineages that is observed today. Many countries in Asia import swine from different
continents (Fig 1C), introducing multiple divergent lineages and creating nexuses for genetic
diversity. By the end of the millennium, the high genetic and antigenic diversity of IAV-S
made it one of the most intractable diseases for swine producers in the US and present in most
swine-producing countries [4].
How did the first pandemic virus of swine origin evolve?
It is inherently difficult to predict when and where a pandemic virus will evolve. Pandemic
viruses have a rare combination of properties, including animal-origin surface proteins that
are antigenically divergent from human viruses and thus evade immune detection while
retaining a capacity to replicate and transmit in humans. The evolution of such a variant is
facilitated by a process termed “reassortment,” in which whole segments of the IAV genome
are exchanged between viruses coinfecting a host cell, rapidly repositioning genes into differ-
ent genetic backgrounds (Fig 2B). Reassortant viruses are therefore more likely to evolve in
locations where multiple distinct lineages cocirculate and in hosts with high capacities for reas-
sortment, such as wild birds, poultry, and swine. The pandemic viruses of 1957 (H2N2), 1968
(H3N2), and 2009 (H1N1) were all reassortants with chimeric genomes derived from multiple
lineages. The 2009 pandemic was the first to occur in the genomic era, providing large-scale
sequence data to understand how globalized swine production and long-distance viral migra-
tion contributed to the evolution of a novel reassortant virus.
The 2009 pandemic vividly demonstrated both the promise and persisting limitations of
outbreak investigation in the genomic era. Genetic sequencing of the first H1N1 pandemic
viruses isolated from humans in April 2009 rapidly determined that the reassortant virus was
comprised of three genetic lineages of swine origin (Fig 2B) [6]. However, the country of origin
was unknown, due to geographical gaps in IAV-S surveillance. Many countries did not con-
sider IAV-S an important clinical disease. To their credit, the 2009 pandemic stimulated an
expansion of IAV-S research in many countries, filling gaps in our knowledge of IAV-S diver-
sity and evolution on a global scale [1015]. Expanded surveillance in Mexico revealed how
IAV-S diversity expanded during the 1990s and 2000s, when swine were imported from
Europe and the US, introducing the three IAV-S lineages that reassorted to generate the pan-
demic virus [16]. Going forward, trade flows can identify other countries that import live
swine (and potentially IAV-S) from multiple regions and are at higher risk for generating
novel reassortant viruses with pandemic potential [5].
An outstanding question is the specific circumstances by which the 2009 H1N1 virus trans-
mitted from swine to humans. Both IAV-S sequence data and epidemiological data in humans
support swine-to-human transmission occurring in Central Mexico [16,17]. However, by the
live swine, summarized by region and over the time period 1996 to 2012. Trade data available from United Nations Comtrade Database. Digital layers from GLW
(version 2.01) [38] were downloaded from the publicly available Livestock Geo-Wiki database. FAOSTAT, Food and Agriculture Organization Statistical Database
(United Nations); GLW, Gridded Livestock of the World.
PLOS Pathogens | March 19, 2020 3 / 8
PLOS Pathogens | March 19, 2020 4 / 8
time the first human cases were detected by surveillance, the virus had already diversified
genetically, evidence of transmission in humans for several months [18]. There are multiple
challenges to understanding the human–animal interface for IAVs: (1) There is a need for
coordination between animal health and public health research, (2) the genomics of host
switches are too complex to accurately predict zoonotic potential from genetic sequence alone,
and (3) spillover events can be rare and difficult to detect via traditional modes of virological
surveillance, particularly in developing countries.
Pigs and humans: Who is infecting whom?
It should be noted that the human–animal interface looks quite different from the perspective
of the pig. Only one IAV has successfully transmitted from swine to humans to cause a pan-
demic (2009) [19]. In comparison, swine are continuously experiencing pandemics of human
origin. In the US alone, at least eight genetically distinct IAVs have successfully host jumped
from humans to swine (reverse zoonosis). On a global scale, there have been at least 20 success-
ful human-to-swine transmission events, defined by sustained onward transmission in swine
[20]. This number could be much greater, as many countries do not routinely test for IAV-S.
Tellingly, almost every country’s IAV-S population that has been genetically characterized
includes viruses of human origin. Recently, viruses of human origin were identified in swine
in Australia and Chile that have circulated undetected for decades [21,22].
Notably, as soon as the 2009 H1N1 pandemic virus became established in humans, the
virus disseminated back to swine in at least 30 countries, spanning Africa, Asia, North and
South America, Europe, and Australia [23]. In addition to seeding genetically novel viruses in
swine populations globally, the human-origin viruses frequently reassort with other IAV-S lin-
eages. The proliferation of new reassortants complicates control in swine, introducing new
strains that poorly match those included in commercially available vaccines, and presents new
risks for humans. As a case in point, novel IAV-S reassortants with segments derived from
human-origin pandemic viruses have been associated with over 450 zoonotic infections in the
US since 2011, largely in the context of agricultural fairs [24].
What happened to bird flu?
All three pandemics of the 20th century (1918, 1957, and 1968) were of avian origin, and birds
have been key sources of novel viruses in a range of other mammalian hosts, including swine,
equines, canines, and phocines. For decades, the large numbers of human infections in Asia
with IAVs of the H5N1 subtype and, more recently, H7N9 subtype were considered indica-
tions of impending pandemics, prompting governments to stockpile antivirals and vaccines
targeting H5 and H7 antigens. H5N1 and H7N9 viruses continue to infect humans, but the
absence of sustained human-to-human transmission to date underscores the difficulty of pre-
dicting pandemics, especially as large numbers of human infections and deaths are only one
measure of multifaceted pandemic risk [25].
Fig 2. IAV-S evolution. (A) Inferred spatial movements of the major Eurasian lineage of IAV-S (avian-like Eurasian H1N1) between countries,
inferred from a time-scaled MCC tree of the N1 segment. Lines represent general directions of movement inferred from available genetic data, and
actual paths may differ and include unsampled locations. (B) Genomic reassortment events between the three swine lineages that produced the 2009
H1N1 pandemic virus. Horizontal bars represent the eight individual segments of the IAV genome, ordered from longest (PB2, 2,277 nucleotides) to
shortest (NS, 890 nucleotides). HA, hemagglutinin; IAV, Influenza A virus; IAV-S, IAV of swine; MCC, maximum clade credibility; MP, matrix
protein; NA, neuraminidase; NP, nucleoprotein; NS, nonstructural protein; PA, polymerase acidic protein; PB1, polymerase basic protein 1; PB2,
polymerase basic protein 2.
PLOS Pathogens | March 19, 2020 5 / 8
IAV evolution never follows predictions: What will the next surprise be?
Expanded surveillance in mammalian hosts has yielded several surprises, including divergent
IAVs in bats (H17 and H18) [26], a new genus of Orthomyxovirus (influenza D) in bovines
[27], and the establishment of IAV in canines (CIV) during the 2000s: CIV-H3N8 in the US
[28] and CIV-H3N2 in Asia [29]. An outbreak of H7N2 in felines in New York [30] suggests
that other mammalian species could potentially be capable hosts for IAV transmission at cer-
tain thresholds of animal density and movement. However, IAVs have relatively low reproduc-
tive numbers (R), just above the threshold of 1 required for transmission, and require high
contact rates between susceptible hosts to maintain transmission. For example, CIV in the US
is maintained only in high-turnover animal shelters and dog daycares [31]. In contrast to
swine, whose movements are tracked as livestock commodities and can be directly linked to
disease spread [5,9], efforts to understand and predict emerging threats in companion animals
are impeded by the low availability of public records and virological surveillance. Counterintu-
itively, shifting global attitudes towards dogs as domestic companions has facilitated the emer-
gence of CIV. In the US, CIV-H3N2 appears to be maintained in dog daycares, which have
proliferated and become mainstream. Furthermore, tThe recent introduction of CIV-H3N2
into the US spatial-temporally coincides with efforts by animal rights groups to rescue hun-
dreds of Asian meat dogs for US adoption, although to date no direct link has been established
between any rescue animals and the appearance of CIV-H3N2 in the US [32]. Dogs entering
the US must provide documentation of rabies vaccination but otherwise require no disease
testing or quarantine. The most pronounced change in attitudes towards dogs has been in
China, where pet dogs are surging in popularity in urban areas after being banned for many
decades. High rates of CIV have been observed in pets in Chinese cities [33]. It remains
unclear how populations of meat dogs, strays, and pets interact and collectively contribute to
CIV emergence and transmission. A diversity of swine-origin [33], human-origin [34], and
reassortant IAVs have been isolated from dogs in Asia but with unknown degrees of onward
transmission. High contact rates between canines and humans provides frequent opportunities
for zoonotic transmission, and further research is greatly needed to understand the extent to
which Asia’s rapidly expanding dog populations present a pandemic risk.
Concluding remarks
Transformations in the movement and care of livestock and companion animal populations
have altered animal contact rates, disease dynamics, and pandemic risk. At the same time,
however, technological developments are underway that could enhance pandemic response. A
commitment of resources has mobilized efforts to develop a universal influenza vaccine that
could broadly protect humans against all animal-origin strains [35], as well as technologies to
accelerate production of new vaccines during a pandemic. Harnessing new forms of digital,
social, and medical claims data could detect outbreaks faster, potentially limiting spread [36].
Portable nanopore sequencing technologies are capable of tracking epidemics on location to
guide intervention strategies [37]. Given these advances, it is possible to imagine a future when
pandemic influenza no longer presents a threat to global health and security. However, these
initiatives still face a host of technological, logistical, and market-related challenges. In the race
between human ingenuity and pathogen evolution, influenza can never be underestimated.
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... Since then, pork production has been restructured, with small farms continuously being replaced by large production systems and animals being kept in stocks with ever-increasing population sizes. Pigs are widely transported across Europe and the world, providing connectivity between different swine populations and facilitating the global distribution of swine IAV strains [142]. For instance, the introduction of swine H1N1 into Japanese pig farms could be linked to the import of breeding stocks from North America [143]. ...
... Although it is easier for large and integrated livestock holdings, in comparison to small backyard farms, to be equipped with improved biosecurity or biocontainment measures, an exchange of pathogens with the environment can never be fully prevented [183,184]. The assumption that these large holdings are important to prevent the introduction and release of potentially zoonotic pathogens is challenged: (i) Particularly large and dense populations with genetically similar animals facilitate viral spread between the animals [185,186]; (ii) rolling circle reproduction, especially in large swine holdings, favors the establishment of endemic pathogen circulation through the regular introduction of new susceptible host individuals [6,186]; and (iii) management of large livestock flocks requires huge logistics such as transport of live animals over larger distances which favors (global) pathogen dispersal [10,12,142]. Furthermore, improper ventilation systems and waste disposal could lead to pathogen release, which is especially critical in areas with a high density of animal production facilities [183]. ...
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... This relative scarcity may minimize the opportunities for zoonotic transmission and reduced the priority for assessing their pandemic risk posed to humans at this time. However, relative detection frequency of swine HA clades changes over time and these clades may need to be reassessed in the future given frequent interstate movement of pigs and viruses [28][29][30][31]. Contemporary clade representative isolates from 1A.1.1.3 ...
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... L'intégration croissante des éleveurs à des chaînes de productions complexes et des circuits commerciaux étendus se traduit par l'accroissement des flux intra-et internationaux d'animaux vivants qui accélèrent la diffusion des pathogènes et les possibilités de recombinaison entre virus de différentes lignées (Kilpatrick et al., 2006 ;Trovao et Nelson, 2020). Cette tendance est liée à la spécialisation croissante des élevages dans une étape donnée de la chaîne de production (sélection génétique, reproduction, engraissement) au sein de filières de plus en plus segmentées, ainsi qu'à la concentration de la consommation dans les pôles urbains et la globalisation des échanges. ...
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Le lien supposé entre intensification des productions animales et fréquence grandissante des maladies humaines émergentes à potentiel pandémique est une des controverses majeures qui touchent le système alimentaire mondial. Historiquement, les animaux domestiques ont contribué à l’apparition de maladies humaines majeures et sont le réservoir ou l’hôte intermédiaire de plusieurs zoonoses émergentes. Cependant, l’impact des pratiques associées à l’intensification des productions animales sur la santé humaine reste à déterminer avec objectivité. La concentration des animaux en forte densité dans des structures d’élevage de plus en plus grandes, de même que l’intensité croissante des flux d’animaux vivants aux échelles nationale et internationale constituent des facteurs de risque avérés. Cependant, l’intensification de l’élevage peut aussi conduire à une diminution des risques d’émergence à l’interface faune sauvage–faune domestique–humains, grâce à la généralisation des mesures de biosécurité et à l’encadrement des pratiques d’élevage et des réseaux commerciaux, une évolution très dépendante du contexte socio-économique propre à chaque pays et région.
... Influenza A viruses of the H3 and H1 subtypes currently circulate in birds, humans, swine, dogs, and horses [5][6][7][8][9][10][11]. Human seasonal IAVs infect between 10% and 20% of the human population every year, causing an estimated 290 000 to 650 000 deaths annually [12]. ...
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The Influenza A virus (IAV) hemagglutinin protein (HA) has been studied extensively, but its evolution has not been thoroughly compared among major host species. We compared H3 and H1 evolutionary rates among 49 lineages differentiated by host (avian, canine, equine, human, swine), phylogeny, and geography. Rates of nonsynonymous evolution, relative to synonymous rates, were higher in mammalian than avian hosts. Human seasonal HA and classical swine H1 accumulated 11-13 glycosylation sites, primarily in the antigenically important head domain, whereas lower numbers were maintained in other hosts. Canines had the highest ratio of nonsynonymous to synonymous changes in the more conserved stalk domain. Amino acid changes in canine viruses occurred disproportionately at residues located at protein interfaces. This suggests that they were adaptations affecting the major structural rearrangement of HA, which is critical for cell entry. These findings invite further study of how host ecology and physiology affect natural selection. AUTHOR SUMMARY Influenza virus evolution is of practical importance to health in addition to being an excellent system for the study of parasite/host evolution. Our work explores a largely untapped aspect of influenza evolution: sequence evolution in non-human hosts. This is important in its own right, in terms of both science and domestic animal health. It also puts the evolution of human influenza in a larger, comparative context. Our results also provide evidence concerning the evolution of the hemagglutinin stem domain, which has not been a focus of study but has new importance due to the development of stem-based universal influenza vaccines.
... Bush meat is also linked to the reemergence of Ebola virus in 2015-2016. Since the 1918-1919 Spanish flu, other less severe influenza pandemics have occurred in 1957 (H2N2 Asian Flu), 1968 (N3H2 Hong Kong Flu), and 2009-2010 (H1N1 Swine Flu)(11). Besides, several epidemics caused by novel avian influenza viruses, including the Asian H7N9 virus, and the Asian H5N1 virus, which normally do not infect humans, have occurred after exposure to infected poultry or contaminated environments. Vector-borne diseases are highly sensitive to climate changes(10). ...
... [23][24][25][26] Our last pandemic virus, the 2009 H1N1 swine flu, arose not from some backwater wet market in Asia, but largely from industrial pig operations in the United States. 27,28 Thankfully, it resulted in "only" about a half million deaths. 29 Next time, we might not be so lucky. ...
Over the last few decades, hundreds of human pathogens have emerged at a rate unprecedented in human history. Emerged from where? Mostly from animals. The AIDS virus is blamed on the butchering of primates in the African bushmeat trade, we created mad cow disease when we turned cows into carnivores and cannibals, and SARS and COVID-19 have been traced back to the exotic wild animal trade. Our last pandemic, swine flu in 2009, arose not from some backwater wet market in Asia, however. It was largely made-in-the-USA on pig production operations in the United States. In this new Age of Emerging Diseases, there are now billions of animals overcrowded and intensively confined in filthy factory farms for viruses to incubate and mutate within. Today’s industrial farming practices have given viruses billions more spins at pandemic roulette. How can we stop the emergence of pandemic viruses in the first place? Whenever possible, treat the cause. The largest and oldest association of public health professionals in the world, the American Public Health Association, has called for a moratorium on factory farming for nearly two decades. Indeed, factory farms are a public health menace. In addition to discontinuing the intensive confinement practices of animal agriculture, we should continue to research, develop, and invest in innovative plant-based and cultivated meat technologies to move away from raising billions of feathered and curly-tailed test tubes for viruses with pandemic potential to mutate within.
... The 2009 H1N1 influenza pandemic was of swine origin, highlighting the pathway for zoonotic IAV emergence provided by swine systems [3,5,6]. The 2009 pandemic furthered understanding of how global swine production facilitates the evolution of novel IAVs with zoonotic potential [7][8][9], and how specific human-animal interfaces can be targeted to prevent interspecies spillover events. ...
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Background: Since 2011, influenza A viruses circulating in US swine exhibited at county fairs are associated with over 460 zoonotic infections, presenting an ongoing pandemic risk. Swine 'jackpot shows' that occur before county fairs each summer intermix large numbers of exhibition swine from diverse geographic locations. We investigated the role of jackpot shows in influenza zoonoses. Methods: We collected snout wipe or nasal swab samples from 17,009 pigs attending 350 national, state, and local swine exhibitions across eight states during 2016-2018. Results: Influenza was detected in 13.9% of swine sampled at jackpot shows, and 76.3% of jackpot shows had at least one pig test positive. Jackpot shows had 4.3-fold higher odds of detecting at least one influenza-positive pig compared to county fairs. When influenza was detected at a county fair, almost half of pigs tested positive, clarifying why zoonotic infections occur primarily at county fairs. Conclusions: The earlier timing of jackpot shows and long-distance travel for repeated showing of individual pigs provide a pathway for the introduction of influenza into county fairs. Mitigation strategies aimed at curtailing influenza at jackpot shows are likely to have downstream effects on disease transmission at county fairs and zoonoses.
... Close and regular interactions between swIAV endemic pigs and humans creates an environment that could lead to the emergence of novel strains through bi-directional transmission and subsequent reassortment events [48][49][50]. Furthermore, the limited but present international trade of pigs and global movement of people exacerbates this potential for coinfection with multiple distinct IAV strains [51,52]. ...
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Background Influenza A Viruses (IAV) are endemic pathogens of significant concern in humans and multiple keystone livestock species. Widespread morbidity in swine herds negatively impacts animal welfare standards and economic performance whilst human IAV pandemics have emerged from pigs on multiple occasions. To combat the rising prevalence of swine IAV there must be effective control strategies available. Main body The most basic form of IAV control on swine farms is through good animal husbandry practices and high animal welfare standards. To control inter-herd transmission, biosecurity considerations such as quarantining of pigs and implementing robust health and safety systems for workers help to reduce the likelihood of swine IAV becoming endemic. Closely complementing the physical on-farm practices are IAV surveillance programs. Epidemiological data is critical in understanding regional distribution and variation to assist in determining an appropriate response to outbreaks and understanding the nature of historical swine IAV epidemics and zoonoses. Medical intervention in pigs is restricted to vaccination, a measure fraught with the intrinsic difficulties of mounting an immune response against a highly mutable virus. It is the best available tool for controlling IAV in swine but is far from being a perfect solution due to its unreliable efficacy and association with an enhanced respiratory disease. Because IAV generally has low mortality rates there is a reticence in the uptake of vaccination. Novel genetic technologies could be a complementary strategy for IAV control in pigs that confers broad-acting resistance. Transgenic pigs with IAV resistance are useful as models, however the complexity of these reaching the consumer market limits them to research models. More promising are gene-editing approaches to prevent viral exploitation of host proteins and modern vaccine technologies that surpass those currently available. Conclusion Using the suite of IAV control measures that are available for pigs effectively we can improve the economic productivity of pig farming whilst improving on-farm animal welfare standards and avoid facing the extensive social and financial costs of a pandemic. Fighting ‘Flu in pigs will help mitigate the very real threat of a human pandemic emerging, increase security of the global food system and lead to healthier pigs.
... Still, with high biosecurity measures, the risk of contact between pigs and (wild) birds is probably either absent or low in intensive pig production and risks occur most from pig/human contact. Pigs have experienced influenza outbreaks from human origin, but so far only one case of influenza transmitted from swine to humans has been reported to cause an influenza pandemic in humans (Trovão and Nelson, 2020). ...
Previous influenza A virus (IAV) pandemics have invariably been caused by the introduction of an emergent IAV strain from an animal host into a human population with no or only little pre-existing immunity to the novel strain. Although zoonotic spillover of IAVs into humans can be associated with severe disease and a high fatality rate, these strains are typically poorly adapted to humans and are unable to establish sustained transmission between humans. Given the presumably very high degree of exposure to animal populations with endemic IAV, the number of pandemics remains surprisingly low. In this review, we provide an updated perspective on the molecular mechanisms underlying the adaptation of zoonotic IAV to human hosts, and discuss the implications for future pandemics.
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Global swine populations infected with influenza A viruses pose a persistent pandemic risk. With the exception of a few countries, our understanding of the genetic diversity of swine influenza viruses is limited, hampering control measures and pandemic risk assessment. Here we report the genomic characteristics and evolutionary history of influenza A viruses isolated in Australia from 2012 to 2016 from two geographically isolated swine populations in the states of Queensland and Western Australia. Phylogenetic analysis with an expansive human and swine influenza virus data set comprising > 40,000 sequences sampled globally revealed evidence of the pervasive introduction and long-term establishment of gene segments derived from several human influenza viruses of past seasons, including the H1N1/ 1977, H1N1/1995, H3N2/1968, and H3N2/2003, and the H1N1 2009 pandemic (H1N1pdm09) influenza A viruses, and a genotype that contained gene segments derived from the past three pandemics (1968, reemerged 1977, and 2009). Of the six human-derived gene lineages, only one, comprising two viruses isolated in Queensland during 2012, was closely related to swine viruses detected from other regions, indicating a previously undetected circulation of Australian swine lineages for approximately 3 to 44 years. Although the date of introduction of these lineages into Australian swine populations could not be accurately ascertained, we found evidence of sustained transmission of two lineages in swine from 2012 to 2016. The continued detection of human-origin influenza virus lineages in swine over several decades with little or unpredictable antigenic drift indicates that isolated swine populations can act as antigenic archives of human influenza viruses, raising the risk of reemergence in humans when sufficient susceptible populations arise.
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The capacity of influenza A viruses (IAVs) to host jump from animal reservoir species to humans presents an ongoing pandemic threat. Birds and swine are considered major reservoirs of viral genetic diversity, whereas equines and canines have historically been restricted to one or two stable IAV lineages with no transmission to humans. Here, by sequencing the complete genomes of 16 IAVs obtained from canines in southern China (Guangxi Zhuang Autonomous Region [Guangxi]) in 2013 to 2015, we demonstrate that the evolution of canine influenza viruses (CIVs) in Asian dogs is increasingly complex, presenting a potential threat to humans. First, two reassortant H1N1 virus genotypes were introduced independently from swine into canines in Guangxi, including one genotype associated with a zoonotic infection. The genomes contain segments from three lineages that circulate in swine in China: North American triple reassortant H3N2, Eurasian avian-like H1N1, and pandemic H1N1. Furthermore, the swine-origin H1N1 viruses have transmitted onward in canines and reassorted with the CIV-H3N2 viruses that circulate endemically in Asian dogs, producing three novel reassortant CIV genotypes (H1N1r, H1N2r, and H3N2r [r stands for reassortant]). CIVs from this study were collected primarily from pet dogs presenting with respiratory symptoms at veterinary clinics, but dogs in Guangxi are also raised for meat, and street dogs roam freely, creating a more complex ecosystem for CIV transmission. Further surveillance is greatly needed to understand the full genetic diversity of CIV in southern China, the nature of viral emergence and persistence in the region’s diverse canine populations, and the zoonotic risk as the viruses continue to evolve.
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During December 2016-February 2017, influenza A viruses of the H7N2 subtype infected ≈500 cats in animal shelters in New York, NY, USA, indicating virus transmission among cats. A veterinarian who treated the animals also became infected with feline influenza A(H7N2) virus and experienced respiratory symptoms. To understand the pathogenicity and transmissibility of these feline H7N2 viruses in mammals, we characterized them in vitro and in vivo. Feline H7N2 subtype viruses replicated in the respiratory organs of mice, ferrets, and cats without causing severe lesions. Direct contact transmission of feline H7N2 subtype viruses was detected in ferrets and cats; in cats, exposed animals were also infected via respiratory droplet transmission. These results suggest that the feline H7N2 subtype viruses could spread among cats and also infect humans. Outbreaks of the feline H7N2 viruses could, therefore, pose a risk to public health.
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A canine influenza A(H3N2) virus emerged in the United States in February–March 2015, causing respiratory disease in dogs. The virus had previously been circulating among dogs in Asia, where it originated through the transfer of an avian-origin influenza virus around 2005 and continues to circulate. Sequence analysis suggests the US outbreak was initiated by a single introduction, in Chicago, of an H3N2 canine influenza virus circulating among dogs in South Korea in 2015. Despite local control measures, the virus has continued circulating among dogs in and around Chicago and has spread to several other areas of the country, particularly Georgia and North Carolina, although these secondary outbreaks appear to have ended within a few months. Some genetic variation has accumulated among the US viruses, with the appearance of regional-temporal lineages. The potential for interspecies transmission and zoonotic events involving this newly emerged influenza A virus is currently unknown. © 2017, Centers for Disease Control and Prevention (CDC). All rights reserved.
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Swine influenza presents a substantial disease burden for pig populations worldwide and poses a potential pandemic threat to humans. There is considerable diversity in both H1 and H3 influenza viruses circulating in swine due to the frequent introductions of viruses from humans and birds coupled with geographic segregation of global swine populations. Much of this diversity is characterized genetically but the antigenic diversity of these viruses is poorly understood. Critically, the antigenic diversity shapes the risk profile of swine influenza viruses in terms of their epizootic and pandemic potential. Here, using the most comprehensive set of swine influenza virus antigenic data compiled to date, we quantify the antigenic diversity of swine influenza viruses on a multi-continental scale. The substantial antigenic diversity of recently circulating viruses in different parts of the world adds complexity to the risk profiles for the movement of swine and the potential for swine-derived infections in humans.
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Asia is considered an important source of influenza A virus (IAV) pandemics, owing to large, diverse viral reservoirs in poultry and swine. However, the zoonotic origins of the 2009 A/H1N1 influenza pandemic virus (pdmH1N1) remain unclear, due to conflicting evidence from swine and humans. There is strong evidence that the first human outbreak of pdmH1N1 occurred in Mexico in early 2009. However, no related swine viruses have been detected in Mexico or any part of the Americas, and to date the most closely related ancestor viruses were identified in Asian swine. Here, we use 58 new whole-genome sequences from IAVs collected in Mexican swine to establish that the swine virus responsible for the 2009 pandemic evolved in central Mexico. This finding highlights how the 2009 pandemic arose from a region not considered a pandemic risk, owing to an expansion of IAV diversity in swine resulting from long-distance live swine trade.
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The Ebola virus disease epidemic in West Africa is the largest on record, responsible for over 28,599 cases and more than 11,299 deaths1. Genome sequencing in viral outbreaks is desirable to characterize the infectious agent and determine its evolutionary rate. Genome sequencing also allows the identification of signatures of host adaptation, identification and monitoring of diagnostic targets, and characterization of responses to vaccines and treatments. The Ebola virus (EBOV) genome substitution rate in the Makona strain has been estimated at between 0.87 × 10−3 and 1.42 × 10−3 mutations per site per year. This is equivalent to 16–27 mutations in each genome, meaning that sequences diverge rapidly enough to identify distinct sub-lineages during a prolonged epidemic2, 3, 4, 5, 6, 7. Genome sequencing provides a high-resolution view of pathogen evolution and is increasingly sought after for outbreak surveillance. Sequence data may be used to guide control measures, but only if the results are generated quickly enough to inform interventions8. Genomic surveillance during the epidemic has been sporadic owing to a lack of local sequencing capacity coupled with practical difficulties transporting samples to remote sequencing facilities9. To address this problem, here we devise a genomic surveillance system that utilizes a novel nanopore DNA sequencing instrument. In April 2015 this system was transported in standard airline luggage to Guinea and used for real-time genomic surveillance of the ongoing epidemic. We present sequence data and analysis of 142 EBOV samples collected during the period March to October 2015. We were able to generate results less than 24 h after receiving an Ebola-positive sample, with the sequencing process taking as little as 15–60 min. We show that real-time genomic surveillance is possible in resource-limited settings and can be established rapidly to monitor outbreaks.
A priority for the National Institute of Allergy and Infectious Diseases (NIAID) is development of an influenza vaccine providing durable protection against multiple influenza strains, including those that may cause a pandemic, i.e., a universal influenza vaccine. To invigorate research efforts, NIAID developed a strategic plan focused on knowledge gaps in three major research areas, as well as additional resources required to ensure progress towards a universal influenza vaccine. NIAID will use this plan as a foundation for future investments in influenza research and will support and coordinate a consortium of multidisciplinary scientists focused on accelerating progress towards this goal.
While big data have proven immensely useful in fields such as marketing and earth sciences, public health is still relying on more traditional surveillance systems and awaiting the fruits of a big data revolution. A new generation of big data surveillance systems is needed to achieve rapid, flexible, and local tracking of infectious diseases, especially for emerging pathogens. In this opinion piece, we reflect on the long and distinguished history of disease surveillance and discuss recent developments related to use of big data. We start with a brief review of traditional systems relying on clinical and laboratory reports.We then examine how large-volume medical claims data can, with great spatiotemporal resolution, help elucidate local disease patterns. Finally, we review efforts to develop surveillance systems based on digital and social data streams, including the recent rise and fall of Google Flu Trends. We conclude by advocating for increased use of hybrid systems combining information from traditional surveillance and big data sources, which seems the most promising option moving forward. Throughout the article, we use influenza as an exemplar of an emerging and reemerging infection which has traditionally been considered a model system for surveillance and modeling.