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1.  Risk factors and characteristics of H5N1 Highly Pathogenic Avian Influenza (HPAI) post-vaccination outbreaks 
Veterinary Research  2008;40(3):15.
Highly pathogenic avian influenza (HPAI) virus H5N1 is now endemic in South-East Asia but HPAI control methods differ between countries. A widespread HPAI vaccination campaign that started at the end of 2005 in Viet Nam resulted in the cessation of poultry and human cases, but in 2006/2007 severe HPAI outbreaks re-emerged. In this study we investigated the pattern of this first post-vaccination epidemic in southern Viet Nam identifying a spatio-temporal cluster of outbreak occurrence and estimating spatially smoothed incidence rates of HPAI. Spatial risk factors associated with HPAI occurrence were identified. Medium-level poultry density resulted in an increased outbreak risk (Odds ratio (OR) = 5.4, 95% confidence interval (CI): 1.6–18.9) but also climate-vegetation factors played an important role: medium-level normalised difference vegetation indices during the rainy season from May to October were associated with higher risk of HPAI outbreaks (OR = 3.7, 95% CI: 1.7–8.1), probably because temporal flooding might have provided suitable conditions for the re-emergence of HPAI by expanding the virus distribution in the environment and by enlarging areas of possible contacts between domestic waterfowl and wild birds. On the other hand, several agricultural production factors, such as sweet potatoes yield, increased buffalo density, as well as increased electricity supply were associated with decreased risk of HPAI outbreaks. This illustrates that preventive control measures for HPAI should include a promotion of low-risk agricultural management practices as well as improvement of the infrastructure in village households. Improved HPAI vaccination efforts and coverage should focus on medium poultry density areas and on the pre-monsoon time period.
doi:10.1051/vetres:2008053
PMCID: PMC2695038  PMID: 19081006
avian influenza; H5N1; poultry; risk factor; HPAI outbreak
2.  Flying Over an Infected Landscape: Distribution of Highly Pathogenic Avian Influenza H5N1 Risk in South Asia and Satellite Tracking of Wild Waterfowl 
Ecohealth  2011;7(4):448-458.
Highly pathogenic avian influenza (HPAI) H5N1 virus persists in Asia, posing a threat to poultry, wild birds, and humans. Previous work in Southeast Asia demonstrated that HPAI H5N1 risk is related to domestic ducks and people. Other studies discussed the role of migratory birds in the long distance spread of HPAI H5N1. However, the interplay between local persistence and long-distance dispersal has never been studied. We expand previous geospatial risk analysis to include South and Southeast Asia, and integrate the analysis with migration data of satellite-tracked wild waterfowl along the Central Asia flyway. We find that the population of domestic duck is the main factor delineating areas at risk of HPAI H5N1 spread in domestic poultry in South Asia, and that other risk factors, such as human population and chicken density, are associated with HPAI H5N1 risk within those areas. We also find that satellite tracked birds (Ruddy Shelduck and two Bar-headed Geese) reveal a direct spatio-temporal link between the HPAI H5N1 hot-spots identified in India and Bangladesh through our risk model, and the wild bird outbreaks in May–June–July 2009 in China (Qinghai Lake), Mongolia, and Russia. This suggests that the continental-scale dynamics of HPAI H5N1 are structured as a number of persistence areas delineated by domestic ducks, connected by rare transmission through migratory waterfowl.
Electronic supplementary material
The online version of this article (doi:10.1007/s10393-010-0672-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s10393-010-0672-8
PMCID: PMC3166606  PMID: 21267626
avian influenza; epidemiology; disease ecology; migration
3.  Risk factor modelling of the spatio-temporal patterns of highly pathogenic avian influenza (HPAIV) H5N1: a review 
Highly pathogenic avian influenza virus (HPAIV) H5N1 continues to impact on smallholder livelihoods, to constrain development of the poultry production sector, and to cause occasional human fatalities. HPAI H5N1 outbreaks have occurred in a variety of ecological systems with economic, agricultural and environmental differences. This review aimed to identify common risk factors amongst spatial modelling studies conducted in these different agro-ecological systems, and to identify gaps in our understanding of the disease’s spatial epidemiology. Three types of variables with similar statistical association with HPAI H5N1 presence across studies and regions were identified: domestic waterfowl, several anthropogenic variables (human population density, distance to roads) and indicators of water presence. Variables on socio-economic conditions, poultry trade, wild bird distribution and movements were comparatively rarely considered. Few studies have analysed the HPAI H5N1 distribution in countries such as Egypt and Indonesia, where HPAIV H5N1 continues to circulate extensively.
doi:10.1016/j.sste.2012.01.002
PMCID: PMC3389348  PMID: 22749203
Spatial epidemiology; avian influenza; H5N1
4.  Evidence of Infection by H5N2 Highly Pathogenic Avian Influenza Viruses in Healthy Wild Waterfowl 
PLoS Pathogens  2008;4(8):e1000127.
The potential existence of a wild bird reservoir for highly pathogenic avian influenza (HPAI) has been recently questioned by the spread and the persisting circulation of H5N1 HPAI viruses, responsible for concurrent outbreaks in migratory and domestic birds over Asia, Europe, and Africa. During a large-scale surveillance programme over Eastern Europe, the Middle East, and Africa, we detected avian influenza viruses of H5N2 subtype with a highly pathogenic (HP) viral genotype in healthy birds of two wild waterfowl species sampled in Nigeria. We monitored the survival and regional movements of one of the infected birds through satellite telemetry, providing a rare evidence of a non-lethal natural infection by an HP viral genotype in wild birds. Phylogenetic analysis of the H5N2 viruses revealed close genetic relationships with H5 viruses of low pathogenicity circulating in Eurasian wild and domestic ducks. In addition, genetic analysis did not reveal known gallinaceous poultry adaptive mutations, suggesting that the emergence of HP strains could have taken place in either wild or domestic ducks or in non-gallinaceous species. The presence of coexisting but genetically distinguishable avian influenza viruses with an HP viral genotype in two cohabiting species of wild waterfowl, with evidence of non-lethal infection at least in one species and without evidence of prior extensive circulation of the virus in domestic poultry, suggest that some strains with a potential high pathogenicity for poultry could be maintained in a community of wild waterfowl.
Author Summary
Until recently, the highly pathogenic avian influenza (HPAI) viruses responsible for high mortality in some domestic poultry were considered not to have a wild bird reservoir, but to emerge in domestic poultry populations from low pathogenic viruses perpetuated in wild waterbirds. The rapid spread of H5N1 HPAI virus in 2005–2006, with concurrent outbreaks reported in both domestic and wild birds over Asia, Europe, and Africa, has raised concerns about the potential role of migratory birds in the epidemiology of the HPAI infection. Wild birds were sampled in Africa and tested by molecular and virological methods in an attempt to trace the circulation of HPAI viruses. In addition, some of these wild birds were equipped with satellite transmitters to track their local and migratory movements in relation to the potential spread of avian diseases. Avian influenza viruses (H5N2) were detected in wild waterfowl in Nigeria, and were subsequently characterized as highly pathogenic by molecular sequencing (HPAI viral genotype). Movements of one infected bird tracked by satellite telemetry revealed that it survived infection by an HP viral genotype. This result constitutes a rare finding of infection by an AIV with an HPAI viral genotype in healthy wild birds.
doi:10.1371/journal.ppat.1000127
PMCID: PMC2503949  PMID: 18704172
5.  Persistence of Highly Pathogenic Avian Influenza H5N1 Virus Defined by Agro-Ecological Niche 
Ecohealth  2010;7(2):213-225.
The highly pathogenic avian influenza (HPAI) H5N1 virus has spread across Eurasia and into Africa. Its persistence in a number of countries continues to disrupt poultry production, impairs smallholder livelihoods, and raises the risk a genotype adapted to human-to-human transmission may emerge. While previous studies identified domestic duck reservoirs as a primary risk factor associated with HPAI H5N1 persistence in poultry in Southeast Asia, little is known of such factors in countries with different agro-ecological conditions, and no study has investigated the impact of such conditions on HPAI H5N1 epidemiology at the global scale. This study explores the patterns of HPAI H5N1 persistence worldwide, and for China, Indonesia, and India includes individual provinces that have reported HPAI H5N1 presence during the 2004–2008 period. Multivariate analysis of a set of 14 agricultural, environmental, climatic, and socio-economic factors demonstrates in quantitative terms that a combination of six variables discriminates the areas with human cases and persistence: agricultural population density, duck density, duck by chicken density, chicken density, the product of agricultural population density and chicken output/input ratio, and purchasing power per capita. The analysis identifies five agro-ecological clusters, or niches, representing varying degrees of disease persistence. The agro-ecological distances of all study areas to the medoid of the niche with the greatest number of human cases are used to map HPAI H5N1 risk globally. The results indicate that few countries remain where HPAI H5N1 would likely persist should it be introduced.
Electronic supplementary material
The online version of this article (doi:10.1007/s10393-010-0324-z) contains supplementary material, which is available to authorized users.
doi:10.1007/s10393-010-0324-z
PMCID: PMC3005111  PMID: 20585972
global ecology; highly pathogenic avian influenza; agro-ecology; epidemiology
6.  Environmental Factors Contributing to the Spread of H5N1 Avian Influenza in Mainland China 
PLoS ONE  2008;3(5):e2268.
Background
Since late 2003, highly pathogenic avian influenza (HPAI) outbreaks caused by infection with H5N1 virus has led to the deaths of millions of poultry and more than 10 thousands of wild birds, and as of 18-March 2008, at least 373 laboratory-confirmed human infections with 236 fatalities, have occurred. The unrestrained worldwide spread of this disease has caused great anxiety about the potential of another global pandemic. However, the effect of environmental factors influencing the spread of HPAI H5N1 virus is unclear.
Methodology/Principal Findings
A database including incident dates and locations was developed for 128 confirmed HPAI H5N1 outbreaks in poultry and wild birds, as well as 21 human cases in mainland China during 2004–2006. These data, together with information on wild bird migration, poultry densities, and environmental variables (water bodies, wetlands, transportation routes, main cities, precipitation and elevation), were integrated into a Geographical Information System (GIS). A case-control design was used to identify the environmental factors associated with the incidence of the disease. Multivariate logistic regression analysis indicated that minimal distance to the nearest national highway, annual precipitation and the interaction between minimal distance to the nearest lake and wetland, were important predictive environmental variables for the risk of HPAI. A risk map was constructed based on these factors.
Conclusions/Significance
Our study indicates that environmental factors contribute to the spread of the disease. The risk map can be used to target countermeasures to stop further spread of the HPAI H5N1 at its source.
doi:10.1371/journal.pone.0002268
PMCID: PMC2386237  PMID: 18509468
7.  Improving Risk Models for Avian Influenza: The Role of Intensive Poultry Farming and Flooded Land during the 2004 Thailand Epidemic 
PLoS ONE  2012;7(11):e49528.
Since 1996 when Highly Pathogenic Avian Influenza type H5N1 first emerged in southern China, numerous studies sought risk factors and produced risk maps based on environmental and anthropogenic predictors. However little attention has been paid to the link between the level of intensification of poultry production and the risk of outbreak. This study revised H5N1 risk mapping in Central and Western Thailand during the second wave of the 2004 epidemic. Production structure was quantified using a disaggregation methodology based on the number of poultry per holding. Population densities of extensively- and intensively-raised ducks and chickens were derived both at the sub-district and at the village levels. LandSat images were used to derive another previously neglected potential predictor of HPAI H5N1 risk: the proportion of water in the landscape resulting from floods. We used Monte Carlo simulation of Boosted Regression Trees models of predictor variables to characterize the risk of HPAI H5N1. Maps of mean risk and uncertainty were derived both at the sub-district and the village levels. The overall accuracy of Boosted Regression Trees models was comparable to that of logistic regression approaches. The proportion of area flooded made the highest contribution to predicting the risk of outbreak, followed by the densities of intensively-raised ducks, extensively-raised ducks and human population. Our results showed that as little as 15% of flooded land in villages is sufficient to reach the maximum level of risk associated with this variable. The spatial pattern of predicted risk is similar to previous work: areas at risk are mainly located along the flood plain of the Chao Phraya river and to the south-east of Bangkok. Using high-resolution village-level poultry census data, rather than sub-district data, the spatial accuracy of predictions was enhanced to highlight local variations in risk. Such maps provide useful information to guide intervention.
doi:10.1371/journal.pone.0049528
PMCID: PMC3501506  PMID: 23185352
8.  Movements of Wild Ruddy Shelducks in the Central Asian Flyway and Their Spatial Relationship to Outbreaks of Highly Pathogenic Avian Influenza H5N1 
Viruses  2013;5(9):2129-2152.
Highly pathogenic avian influenza H5N1 remains a serious concern for both poultry and human health. Wild waterfowl are considered to be the reservoir for low pathogenic avian influenza viruses; however, relatively little is known about their movement ecology in regions where HPAI H5N1 outbreaks regularly occur. We studied movements of the ruddy shelduck (Tadorna ferruginea), a wild migratory waterfowl species that was infected in the 2005 Qinghai Lake outbreak. We defined their migration with Brownian Bridge utilization distribution models and their breeding and wintering grounds with fixed kernel home ranges. We correlated their movements with HPAI H5N1 outbreaks, poultry density, land cover, and latitude in the Central Asian Flyway. Our Akaike Information Criterion analysis indicated that outbreaks were correlated with land cover, latitude, and poultry density. Although shelduck movements were included in the top two models, they were not a top parameter selected in AICc stepwise regression results. However, timing of outbreaks suggested that outbreaks in the flyway began during the winter in poultry with spillover to wild birds during the spring migration. Thus, studies of the movement ecology of wild birds in areas with persistent HPAI H5N1 outbreaks may contribute to understanding their role in transmission of this disease.
doi:10.3390/v5092129
PMCID: PMC3798894  PMID: 24022072
Brahminy duck; movement ecology; Tadorna ferruginea; avian influenza
9.  Avian influenza, domestic ducks and rice agriculture in Thailand 
Highly pathogenic avian influenza (HPAI) caused by H5N1 viruses has become a global scale problem which first emerged in southern China and from there spread to other countries in Southeast and East Asia, where it was first confirmed in end 2003. In previous work, geospatial analyses demonstrated that free grazing ducks played critical role in the epidemiology of the disease in Thailand in the winter 2004/2005, both in terms of HPAI emergence and spread. This study explored the geographic association between free grazing duck census counts and current statistics on the spatial distribution of rice crops in Thailand, in particular the crop calendar of rice production. The analysis was carried out using both district level rice statistics and rice distribution data predicted with the aid of remote sensing, using a rice-detection algorithm. The results indicated a strong association between the number of free grazing ducks and the number of months during which second-crop rice harvest takes place, as well as with the rice crop intensity as predicted by remote sensing. These results confirmed that free grazing duck husbandry was strongly driven by agricultural land use and rice crop intensity, and that this later variable can be readily predicted using remote sensing. Analysis of rice cropping patterns may provide an indication of the location of populations of free grazing ducks in other countries with similar mixed duck and rice production systems and less detailed duck census data. Apart from free ranging ducks and rice cropping, the role of hydrology and seasonality of wetlands and water bodies in the HPAI risk analysis is also discussed in relation to the presumed dry season aggregation of wild waterfowl and aquatic poultry offering much scope for virus transmission.
doi:10.1016/j.agee.2006.09.001
PMCID: PMC2311503  PMID: 18418464
Highly pathogenic avian influenza; Domestic ducks; Remote sensing; Agriculture intensification; Rice paddy production
10.  Avian influenza vaccination in Egypt: Limitations of the current strategy 
Vaccination of domestic poultry against avian influenza (AI) has been used on a large-scale in South East Asia since 2003 and in Egypt since 2006 to fight H5N1 highly-pathogenic avian influenza (HPAI) epidemics. The decision to use mass vaccination against HPAI in Egypt was taken as an emergency measure based on positive impact of such control measures in Vietnam and the People's Republic of China. However, three years on, the impact on disease control of AI vaccination in Egypt has been very limited. Despite the continuous vaccination of poultry against HPAI, poultry outbreaks and human cases are reported regularly. A recent assessment study highlighted substantial weaknesses in the current immunisation programme and its lack of positive impact on the spread of infection or the maintenance of public health safety. The shortcomings of the vaccination strategy may be attributed in part to a lack of sufficient support in terms of funding and communication, the absence of an efficient monitoring system, and inadequate training of field technicians. The difficulties of blanket vaccinations in semi-commercial farms and household poultry sectors are well known, however, improvements in the industrial sector should be possible though better government controls and greater collaboration with the private sector. AI vaccination should be regarded as just one control tool within a broader disease control program integrating surveillance, outbreak investigation, disease management systems, and the rigorous implementation of bio-security measures. If incorrectly implemented, AI vaccination has a limited impact as a disease control measure. Moreover, without strict bio-security precautions undertaken during its application, farm visits to vaccinate poultry could facilitate the spread of the virus and therefore become a risk factor with important implications on the maintenance of the virus and potential risk for human exposure.
PMCID: PMC2805840  PMID: 20076791
Avian influenza; disease control; vaccination strategy; public health risk; Egypt
11.  Antigenic Variation of Clade 2.1 H5N1 Virus Is Determined by a Few Amino Acid Substitutions Immediately Adjacent to the Receptor Binding Site 
mBio  2014;5(3):e01070-14.
ABSTRACT
Highly pathogenic avian influenza (HPAI) viruses of the H5N1 subtype are genetically highly variable and have diversified into multiple phylogenetic clades over the past decade. Antigenic drift is a well-studied phenomenon for seasonal human influenza viruses, but much less is known about the antigenic evolution of HPAI H5N1 viruses that circulate in poultry. In this study, we focused on HPAI H5N1 viruses that are enzootic to Indonesia. We selected representative viruses from genetically distinct lineages that are currently circulating and determined their antigenic properties by hemagglutination inhibition assays. At least six antigenic variants have circulated between 2003, when H5N1 clade 2.1 viruses were first detected in Indonesia, and 2011. During this period, multiple antigenic variants cocirculated in the same geographic regions. Mutant viruses were constructed by site-directed mutagenesis to represent each of the circulating antigenic variants, revealing that antigenic differences between clade 2.1 viruses were due to only one or very few amino acid substitutions immediately adjacent to the receptor binding site. Antigenic variants of H5N1 virus evaded recognition by both ferret and chicken antibodies. The molecular basis for antigenic change in clade 2.1 viruses closely resembled that of seasonal human influenza viruses, indicating that the hemagglutinin of influenza viruses from different hosts and subtypes may be similarly restricted to evade antibody recognition.
IMPORTANCE
Highly pathogenic avian influenza (HPAI) H5N1 viruses are responsible for severe outbreaks in both commercial and backyard poultry, causing considerable economic losses and regular zoonotic transmissions to humans. Vaccination is used increasingly to reduce the burden of HPAI H5N1 virus in poultry. Influenza viruses can escape from recognition by antibodies induced upon vaccination or infection through genetic changes in the hemagglutinin protein. The evolutionary patterns and molecular basis of antigenic change in HPAI H5N1 viruses are poorly understood, hampering formulation of optimal vaccination strategies. We have shown here that HPAI H5N1 viruses in Indonesia diversified into multiple antigenic variants, that antigenic differences were due to one or a very few substitutions near the receptor binding site, and that the molecular basis for antigenic change was remarkably similar to that for seasonal human influenza viruses. These findings have consequences for future vaccination and surveillance considerations and contribute to the understanding of the antigenic evolution of influenza viruses.
doi:10.1128/mBio.01070-14
PMCID: PMC4056550  PMID: 24917596
12.  Pathobiological features of a novel, highly pathogenic avian influenza A(H5N8) virus 
The endemicity of highly pathogenic avian influenza (HPAI) A(H5N1) viruses in Asia has led to the generation of reassortant H5 strains with novel gene constellations. A newly emerged HPAI A(H5N8) virus caused poultry outbreaks in the Republic of Korea in 2014. Because newly emerging high-pathogenicity H5 viruses continue to pose public health risks, it is imperative that their pathobiological properties be examined. Here, we characterized A/mallard duck/Korea/W452/2014 (MDk/W452(H5N8)), a representative virus, and evaluated its pathogenic and pandemic potential in various animal models. We found that MDk/W452(H5N8), which originated from the reassortment of wild bird viruses harbored by migratory waterfowl in eastern China, replicated systemically and was lethal in chickens, but appeared to be attenuated, albeit efficiently transmitted, in ducks. Despite predominant attachment to avian-like virus receptors, MDk/W452(H5N8) also exhibited detectable human virus-like receptor binding and replicated in human respiratory tract tissues. In mice, MDk/W452(H5N8) was moderately pathogenic and had limited tissue tropism relative to previous HPAI A(H5N1) viruses. It also induced moderate nasal wash titers in inoculated ferrets; additionally, it was recovered in extrapulmonary tissues and one of three direct-contact ferrets seroconverted without shedding. Moreover, domesticated cats appeared to be more susceptible than dogs to virus infection. With their potential to become established in ducks, continued circulation of A(H5N8) viruses could alter the genetic evolution of pre-existing avian poultry strains. Overall, detailed virological investigation remains a necessity given the capacity of H5 viruses to evolve to cause human illness with few changes in the viral genome.
doi:10.1038/emi.2014.75
PMCID: PMC4217095
avian influenza virus; genetic evolution; HPAI A(H5N8); migratory waterfowl; reassortment
13.  Spatial and Temporal Association of Outbreaks of H5N1 Influenza Virus Infection in Wild Birds with the 0°C Isotherm 
PLoS Pathogens  2010;6(4):e1000854.
Wild bird movements and aggregations following spells of cold weather may have resulted in the spread of highly pathogenic avian influenza virus (HPAIV) H5N1 in Europe during the winter of 2005–2006. Waterbirds are constrained in winter to areas where bodies of water remain unfrozen in order to feed. On the one hand, waterbirds may choose to winter as close as possible to their breeding grounds in order to conserve energy for subsequent reproduction, and may be displaced by cold fronts. On the other hand, waterbirds may choose to winter in regions where adverse weather conditions are rare, and may be slowed by cold fronts upon their journey back to the breeding grounds, which typically starts before the end of winter. Waterbirds will thus tend to aggregate along cold fronts close to the 0°C isotherm during winter, creating conditions that favour HPAIV H5N1 transmission and spread. We determined that the occurrence of outbreaks of HPAIV H5N1 infection in waterbirds in Europe during the winter of 2005–2006 was associated with temperatures close to 0°C. The analysis suggests a significant spatial and temporal association of outbreaks caused by HPAIV H5N1 in wild birds with maximum surface air temperatures of 0°C–2°C on the day of the outbreaks and the two preceding days. At locations where waterbird census data have been collected since 1990, maximum mallard counts occurred when average and maximum surface air temperatures were 0°C and 3°C, respectively. Overall, the abundance of mallards (Anas platyrhynchos) and common pochards (Aythya ferina) was highest when surface air temperatures were lower than the mean temperatures of the region investigated. The analysis implies that waterbird movements associated with cold weather, and congregation of waterbirds along the 0°C isotherm likely contributed to the spread and geographical distribution of outbreaks of HPAIV H5N1 infection in wild birds in Europe during the winter of 2005–2006.
Author Summary
Highly pathogenic avian influenza virus of the H5N1 subtype emerged more than a decade ago in poultry in South-East Asia. In 2005, it spread outside Asia infecting both poultry and wild birds in the Middle East, Europe and Africa. Both trade of poultry and movements of wild birds were likely implicated in the spread of the infection; however, the ability of wild birds to carry the virus to novel geographical areas is still highly debated and remains obscure. In Europe, the virus mainly infected wild birds, and emergence coincided with a spell of cold weather, which is known to result in massive movements of wild waterbirds. In this paper, we demonstrate that movements of wild waterbirds associated with cold weather contributed to the spread and geographical distribution of outbreaks in Europe during the winter of 2005–2006. Higher density of wild waterbirds on bodies of water that remain unfrozen ahead of the freezing line likely favoured transmission of the virus and resulted in distinctive distribution of outbreaks at locations where surface air temperatures were 0°C–2°C. This has important implications for surveillance, which should target areas where temperatures are close to freezing in winter, especially in poultry-dense regions close to areas where waterfowl aggregate.
doi:10.1371/journal.ppat.1000854
PMCID: PMC2851735  PMID: 20386716
14.  Free-grazing Ducks and Highly Pathogenic Avian Influenza, Thailand 
Emerging Infectious Diseases  2006;12(2):227-234.
Free-grazing ducks in rice paddies are a critical factor in the spread and persistence of avian influenza.
Thailand has recently had 3 epidemic waves of highly pathogenic avian influenza (HPAI); virus was again detected in July 2005. Risk factors need to be identified to better understand disease ecology and assist HPAI surveillance and detection. This study analyzed the spatial distribution of HPAI outbreaks in relation to poultry, land use, and other anthropogenic variables from the start of the second epidemic wave (July 2004–May 2005). Results demonstrate a strong association between H5N1 virus in Thailand and abundance of free-grazing ducks and, to a lesser extent, native chickens, cocks, wetlands, and humans. Wetlands used for double-crop rice production, where free-grazing duck feed year round in rice paddies, appear to be a critical factor in HPAI persistence and spread. This finding could be important for other duck-producing regions in eastern and southeastern Asian countries affected by HPAI.
doi:10.3201/eid1202.050640
PMCID: PMC3373083  PMID: 16494747
Avian influenza; epidemiology; spatial analysis; Thailand; animal husbandry; research
15.  Model-Based Evaluation of Highly and Low Pathogenic Avian Influenza Dynamics in Wild Birds 
PLoS ONE  2010;5(6):e10997.
There is growing interest in avian influenza (AI) epidemiology to predict disease risk in wild and domestic birds, and prevent transmission to humans. However, understanding the epidemic dynamics of highly pathogenic (HPAI) viruses remains challenging because they have rarely been detected in wild birds. We used modeling to integrate available scientific information from laboratory and field studies, evaluate AI dynamics in individual hosts and waterfowl populations, and identify key areas for future research. We developed a Susceptible-Exposed-Infectious-Recovered (SEIR) model and used published laboratory challenge studies to estimate epidemiological parameters (rate of infection, latency period, recovery and mortality rates), considering the importance of age classes, and virus pathogenicity. Infectious contact leads to infection and virus shedding within 1–2 days, followed by relatively slower period for recovery or mortality. We found a shorter infectious period for HPAI than low pathogenic (LP) AI, which may explain that HPAI has been much harder to detect than LPAI during surveillance programs. Our model predicted a rapid LPAI epidemic curve, with a median duration of infection of 50–60 days and no fatalities. In contrast, HPAI dynamics had lower prevalence and higher mortality, especially in young birds. Based on field data from LPAI studies, our model suggests to increase surveillance for HPAI in post-breeding areas, because the presence of immunologically naïve young birds is predicted to cause higher HPAI prevalence and bird losses during this season. Our results indicate a better understanding of the transmission, infection, and immunity-related processes is required to refine predictions of AI risk and spread, improve surveillance for HPAI in wild birds, and develop disease control strategies to reduce potential transmission to domestic birds and/or humans.
doi:10.1371/journal.pone.0010997
PMCID: PMC2890401  PMID: 20585637
16.  Evolutionary and Transmission Dynamics of Reassortant H5N1 Influenza Virus in Indonesia 
PLoS Pathogens  2008;4(8):e1000130.
H5N1 highly pathogenic avian influenza (HPAI) viruses have seriously affected the Asian poultry industry since their recurrence in 2003. The viruses pose a threat of emergence of a global pandemic influenza through point mutation or reassortment leading to a strain that can effectively transmit among humans. In this study, we present phylogenetic evidences for the interlineage reassortment among H5N1 HPAI viruses isolated from humans, cats, and birds in Indonesia, and identify the potential genetic parents of the reassorted genome segments. Parsimony analyses of viral phylogeography suggest that the reassortant viruses may have originated from greater Jakarta and surroundings, and subsequently spread to other regions in the West Java province. In addition, Bayesian methods were used to elucidate the genetic diversity dynamics of the reassortant strain and one of its genetic parents, which revealed a more rapid initial growth of genetic diversity in the reassortant viruses relative to their genetic parent. These results demonstrate that interlineage exchange of genetic information may play a pivotal role in determining viral genetic diversity in a focal population. Moreover, our study also revealed significantly stronger diversifying selection on the M1 and PB2 genes in the lineages preceding and subsequent to the emergence of the reassortant viruses, respectively. We discuss how the corresponding mutations might drive the adaptation and onward transmission of the newly formed reassortant viruses.
Author Summary
H5N1 highly pathogenic avian influenza (HPAI) virus emerged in China in 1996, and has spread beyond Asia since 2003. Following the first outbreak reported in Indonesian poultry farms in December 2003, the virus spilled over to 27 Indonesian provinces by June 2006, and became endemic in the country. In the following years, repeated sporadic human infections in Indonesia had been attributed to H5N1 HPAI viruses. Nonetheless, the viral evolution and transmission have not been fully understood. Here, we report phylogenetic evidence of a group of interlineage reassortant viruses isolated from human and cats in Java. Our comparative study of the reassortant viruses and one group of genetic parents found that although their rates of evolution were similar and both of their phylogenies were not geographically structured within mainland Java, the growths of genetic diversity were different. We also detected significant positive selection on the viral matrix and polymerase genes preceding and subsequent to the emergence of the reassortant viruses, which might correspond to viral adaptation. Based on our findings, we discuss the possibility of host switching in facilitating the emergence of the reassortant strain, and call for more extensive viral surveillances in the non-avian population in Indonesia.
doi:10.1371/journal.ppat.1000130
PMCID: PMC2515348  PMID: 18725937
17.  Different Environmental Drivers of Highly Pathogenic Avian Influenza H5N1 Outbreaks in Poultry and Wild Birds 
PLoS ONE  2013;8(1):e53362.
A large number of highly pathogenic avian influenza (HPAI) H5N1 outbreaks in poultry and wild birds have been reported in Europe since 2005. Distinct spatial patterns in poultry and wild birds suggest that different environmental drivers and potentially different spread mechanisms are operating. However, previous studies found no difference between these two outbreak types when only the effect of physical environmental factors was analysed. The influence of physical and anthropogenic environmental variables and interactions between the two has only been investigated for wild bird outbreaks. We therefore tested the effect of these environmental factors on HPAI H5N1 outbreaks in poultry, and the potential spread mechanism, and discussed how these differ from those observed in wild birds. Logistic regression analyses were used to quantify the relationship between HPAI H5N1 outbreaks in poultry and environmental factors. Poultry outbreaks increased with an increasing human population density combined with close proximity to lakes or wetlands, increased temperatures and reduced precipitation during the cold season. A risk map was generated based on the identified key factors. In wild birds, outbreaks were strongly associated with an increased Normalized Difference Vegetation Index (NDVI) and lower elevation, though they were similarly affected by climatic conditions as poultry outbreaks. This is the first study that analyses the differences in environmental drivers and spread mechanisms between poultry and wild bird outbreaks. Outbreaks in poultry mostly occurred in areas where the location of farms or trade areas overlapped with habitats for wild birds, whereas outbreaks in wild birds were mainly found in areas where food and shelters are available. The different environmental drivers suggest that different spread mechanisms might be involved: HPAI H5N1 spread to poultry via both poultry and wild birds, whereas contact with wild birds alone seems to drive the outbreaks in wild birds.
doi:10.1371/journal.pone.0053362
PMCID: PMC3538778  PMID: 23308201
18.  Avian influenza surveillance reveals presence of low pathogenic avian influenza viruses in poultry during 2009-2011 in the West Bengal State, India 
Virology Journal  2012;9:151.
Introduction
More than 70 outbreaks of the highly pathogenic avian influenza (HPAI) H5N1 have been reported in poultry in the western and north-eastern parts of India. Therefore, in view of the recent HPAI H5N1 outbreaks in poultry, active AI surveillance encompassing wild, resident, migratory birds and poultry was undertaken during 2009–2011 in the State of West Bengal.
Methods
A total of 5722 samples were collected from West Bengal; 3522 samples (2906 fecal droppings + 616 other environmental samples) were from migratory birds and 2200 samples [1604 tracheal, cloacal swabs, environmental samples, tissue samples + 596 blood (serum)] were from domestic ducks and poultry. All tracheal, cloacal and environmental samples were processed for virus isolation. Virus isolates were detected using hemagglutination assay and identified using hemagglutination inhibition (HI) and reverse transcriptase polymerase chain reaction (RT-PCR) assays. Sequencing and phylogenetic analysis of partial region of the hemagglutinin and neuraminidase genes was done. Intravenous pathogenicity index assays were performed in chickens to assess pathogenicity of AI virus isolates. Serum samples were tested for detection of antibodies against AI viruses using HI assay.
Results
A total of 57 AI H9N2, 15 AI H4N6 and 15 Newcastle Disease (NDV) viruses were isolated from chickens, from both backyard and wet poultry markets; AI H4N6 viruses were isolated from backyard chickens and domestic ducks. Characterization of AI H9N2 and H4N6 viruses revealed that they were of low pathogenicity. Domestic ducks were positive for antibodies against H5 and H7 viruses while chickens were positive for presence of antibodies against AI H9N2 and NDV.
Conclusions
In the current scenario of HPAI H5N1 outbreaks in West Bengal, this report shows presence of low pathogenic AI H9N2 and H4N6 viruses in chickens and domestic ducks during the period 2009–2011. This is the first report of isolation of H4N6 from India. Antibodies against AI H5 and H7 in ducks highlight the probable role of domestic ducks in the transmission of AI viruses. Human infections of H9N2 have been reported from China and Hong Kong. This necessitates implementation of prevention and control measures to limit the spread of AI viruses.
doi:10.1186/1743-422X-9-151
PMCID: PMC3488339  PMID: 22867041
Avian influenza surveillance; H9N2 virus; H4N6 virus; NDV; Poultry; India
19.  Characterizing wild bird contact and seropositivity to highly pathogenic avian influenza A (H5N1) virus in Alaskan residents 
Background
Highly pathogenic avian influenza A (HPAI) H5N1 viruses have infected poultry and wild birds on three continents with more than 600 reported human cases (59% mortality) since 2003. Wild aquatic birds are the natural reservoir for avian influenza A viruses, and migratory birds have been documented with HPAI H5N1 virus infection. Since 2005, clade 2.2 HPAI H5N1 viruses have spread from Asia to many countries.
Objectives
We conducted a cross-sectional seroepidemiological survey in Anchorage and western Alaska to identify possible behaviors associated with migratory bird exposure and measure seropositivity to HPAI H5N1.
Methods
We enrolled rural subsistence bird hunters and their families, urban sport hunters, wildlife biologists, and a comparison group without bird contact. We interviewed participants regarding their exposures to wild birds and collected blood to perform serologic testing for antibodies against a clade 2.2 HPAI H5N1 virus strain.
Results
Hunters and wildlife biologists reported exposures to wild migratory birds that may confer risk of infection with avian influenza A viruses, although none of the 916 participants had evidence of seropositivity to HPAI H5N1.
Conclusions
We characterized wild bird contact among Alaskans and behaviors that may influence risk of infection with avian influenza A viruses. Such knowledge can inform surveillance and risk communication surrounding HPAI H5N1 and other influenza viruses in a population with exposure to wild birds at a crossroads of intercontinental migratory flyways.
doi:10.1111/irv.12253
PMCID: PMC4181814  PMID: 24828535
Alaska; H5N1; influenza
20.  Evolutionary Dynamics and Emergence of Panzootic H5N1 Influenza Viruses 
PLoS Pathogens  2008;4(9):e1000161.
The highly pathogenic avian influenza (HPAI) H5N1 virus lineage has undergone extensive genetic reassortment with viruses from different sources to produce numerous H5N1 genotypes, and also developed into multiple genetically distinct sublineages in China. From there, the virus has spread to over 60 countries. The ecological success of this virus in diverse species of both poultry and wild birds with frequent introduction to humans suggests that it is a likely source of the next human pandemic. Therefore, the evolutionary and ecological characteristics of its emergence from wild birds into poultry are of considerable interest. Here, we apply the latest analytical techniques to infer the early evolutionary dynamics of H5N1 virus in the population from which it emerged (wild birds and domestic poultry). By estimating the time of most recent common ancestors of each gene segment, we show that the H5N1 prototype virus was likely introduced from wild birds into poultry as a non-reassortant low pathogenic avian influenza H5N1 virus and was not generated by reassortment in poultry. In contrast, more recent H5N1 genotypes were generated locally in aquatic poultry after the prototype virus (A/goose/Guangdong/1/96) introduction occurred, i.e., they were not a result of additional emergence from wild birds. We show that the H5N1 virus was introduced into Indonesia and Vietnam 3–6 months prior to detection of the first outbreaks in those countries. Population dynamics analyses revealed a rapid increase in the genetic diversity of A/goose/Guangdong/1/96 lineage viruses from mid-1999 to early 2000. Our results suggest that the transmission of reassortant viruses through the mixed poultry population in farms and markets in China has selected HPAI H5N1 viruses that are well adapted to multiple hosts and reduced the interspecies transmission barrier of those viruses.
Author Summary
H5N1 influenza virus has been responsible for poultry outbreaks over the last 12 years—the longest recorded example of highly pathogenic avian influenza (HPAI) circulation in poultry. The ecological success of this virus in diverse species of both poultry and wild birds with sporadic introduction to humans suggests that it is a likely source of the next human pandemic. Genome sequences of H5N1 viruses reveal extensive genetic reassortment (mixing) with other influenza subtypes to produce many H5N1 genotypes that have developed into multiple genetically distinct clades, some of which have spread to affect over 60 countries. Here, we analyze all available sequence data of avian influenza viruses from Eurasia and show that the original HPAI H5N1 virus (referred to as A/goose/Guangdong/1/96) was likely introduced directly into poultry as an intact virus particle from wild aquatic birds. In contrast, H5N1 genotypes were generated in aquatic poultry populations after the introduction of A/goose/Guangdong/1/96 virus. Our results suggest that the transmission of reassortant viruses through the diverse poultry populations in farms and markets in China has selected H5N1 viruses that are well-adapted to multiple hosts and reduced the interspecies transmission barrier of those viruses.
doi:10.1371/journal.ppat.1000161
PMCID: PMC2533123  PMID: 18818732
21.  Associations between attributes of live poultry trade and HPAI H5N1 outbreaks: a descriptive and network analysis study in northern Vietnam 
Background
The structure of contact between individuals plays an important role in the incursion and spread of contagious diseases in both human and animal populations. In the case of avian influenza, the movement of live birds is a well known risk factor for the geographic dissemination of the virus among poultry flocks. Live bird markets (LBM's) contribute to the epidemiology of avian influenza due to their demographic characteristics and the presence of HPAI H5N1 virus lineages. The relationship between poultry producers and live poultry traders (LPT's) that operate in LBM's has not been adequately documented in HPAI H5N1-affected SE Asian countries. The aims of this study were to document and study the flow of live poultry in a poultry trade network in northern Vietnam, and explore its potential role in the risk for HPAI H5N1 during 2003 to 2006.
Results
Our results indicate that LPT's trading for less than a year and operating at retail markets are more likely to source poultry from flocks located in communes with a past history of HPAI H5N1 outbreaks during 2003 to 2006 than LPT's trading longer than a year and operating at wholesale markets. The results of the network analysis indicate that LPT's tend to link communes of similar infection status.
Conclusions
Our study provides evidence which can be used for informing policies aimed at encouraging more biosecure practices of LPT's operating at authorised LBM's. The results suggest that LPT's play a role in HPAI H5N1 transmission and may contribute to perpetuating HPAI H5N1 virus circulation amongst certain groups of communes. The impact of current disease prevention and control interventions could be enhanced by disseminating information about outbreak risk and the implementation of a formal data recording scheme at LBM's for all incoming and outgoing LPT's.
doi:10.1186/1746-6148-6-10
PMCID: PMC2837645  PMID: 20175881
22.  Anthropogenic factors and the risk of highly pathogenic avian influenza H5N1: prospects from a spatial-based model 
Veterinary Research  2009;41(3):28.
Beginning in 2003, highly pathogenic avian influenza (HPAI) H5N1 virus spread across Southeast Asia, causing unprecedented epidemics. Thailand was massively infected in 2004 and 2005 and continues today to experience sporadic outbreaks. While research findings suggest that the spread of HPAI H5N1 is influenced primarily by trade patterns, identifying the anthropogenic risk factors involved remains a challenge. In this study, we investigated which anthropogenic factors played a role in the risk of HPAI in Thailand using outbreak data from the “second wave” of the epidemic (3 July 2004 to 5 May 2005) in the country. We first performed a spatial analysis of the relative risk of HPAI H5N1 at the subdistrict level based on a hierarchical Bayesian model. We observed a strong spatial heterogeneity of the relative risk. We then tested a set of potential risk factors in a multivariable linear model. The results confirmed the role of free-grazing ducks and rice-cropping intensity but showed a weak association with fighting cock density. The results also revealed a set of anthropogenic factors significantly linked with the risk of HPAI. High risk was associated strongly with densely populated areas, short distances to a highway junction, and short distances to large cities. These findings highlight a new explanatory pattern for the risk of HPAI and indicate that, in addition to agro-environmental factors, anthropogenic factors play an important role in the spread of H5N1. To limit the spread of future outbreaks, efforts to control the movement of poultry products must be sustained.
doi:10.1051/vetres/2009076
PMCID: PMC2821766  PMID: 20003910
avian influenza; epidemiology; poultry farming; spatial analysis; Thailand
23.  Highly Pathogenic Avian Influenza Virus among Wild Birds in Mongolia 
PLoS ONE  2012;7(9):e44097.
Mongolia combines a near absence of domestic poultry, with an abundance of migratory waterbirds, to create an ideal location to study the epidemiology of highly pathogenic avian influenza virus (HPAIV) in a purely wild bird system. Here we present the findings of active and passive surveillance for HPAIV subtype H5N1 in Mongolia from 2005–2011, together with the results of five outbreak investigations. In total eight HPAIV outbreaks were confirmed in Mongolia during this period. Of these, one was detected during active surveillance employed by this project, three by active surveillance performed by Mongolian government agencies, and four through passive surveillance. A further three outbreaks were recorded in the neighbouring Tyva Republic of Russia on a lake that bisects the international border. No HPAIV was isolated (cultured) from 7,855 environmental fecal samples (primarily from ducks), or from 2,765 live, clinically healthy birds captured during active surveillance (primarily shelducks, geese and swans), while four HPAIVs were isolated from 141 clinically ill or dead birds located through active surveillance. Two low pathogenic avian influenza viruses (LPAIV) were cultured from ill or dead birds during active surveillance, while environmental feces and live healthy birds yielded 56 and 1 LPAIV respectively. All Mongolian outbreaks occurred in 2005 and 2006 (clade 2.2), or 2009 and 2010 (clade 2.3.2.1); all years in which spring HPAIV outbreaks were reported in Tibet and/or Qinghai provinces in China. The occurrence of outbreaks in areas deficient in domestic poultry is strong evidence that wild birds can carry HPAIV over at least moderate distances. However, failure to detect further outbreaks of clade 2.2 after June 2006, and clade 2.3.2.1 after June 2010 suggests that wild birds migrating to and from Mongolia may not be competent as indefinite reservoirs of HPAIV, or that HPAIV did not reach susceptible populations during our study.
doi:10.1371/journal.pone.0044097
PMCID: PMC3439473  PMID: 22984464
24.  Homo- and Heterosubtypic Low Pathogenic Avian Influenza Exposure on H5N1 Highly Pathogenic Avian Influenza Virus Infection in Wood Ducks (Aix sponsa) 
PLoS ONE  2011;6(1):e15987.
Wild birds in the Orders Anseriformes and Charadriiformes are the natural reservoirs for avian influenza (AI) viruses. Although they are often infected with multiple AI viruses, the significance and extent of acquired immunity in these populations is not understood. Pre-existing immunity to AI virus has been shown to modulate the outcome of a highly pathogenic avian influenza (HPAI) virus infection in multiple domestic avian species, but few studies have addressed this effect in wild birds. In this study, the effect of pre-exposure to homosubtypic (homologous hemagglutinin) and heterosubtypic (heterologous hemagglutinin) low pathogenic avian influenza (LPAI) viruses on the outcome of a H5N1 HPAI virus infection in wood ducks (Aix sponsa) was evaluated. Pre-exposure of wood ducks to different LPAI viruses did not prevent infection with H5N1 HPAI virus, but did increase survival associated with H5N1 HPAI virus infection. The magnitude of this effect on the outcome of the H5N1 HPAI virus infection varied between different LPAI viruses, and was associated both with efficiency of LPAI viral replication in wood ducks and the development of a detectable humoral immune response. These observations suggest that in naturally occurring outbreaks of H5N1 HPAI, birds with pre-existing immunity to homologous hemagglutinin or neuraminidase subtypes of AI virus may either survive H5N1 HPAI virus infection or live longer than naïve birds and, consequently, could pose a greater risk for contributing to viral transmission and dissemination. The mechanisms responsible for this protection and/or the duration of this immunity remain unknown. The results of this study are important for surveillance efforts and help clarify epidemiological data from outbreaks of H5N1 HPAI virus in wild bird populations.
doi:10.1371/journal.pone.0015987
PMCID: PMC3017094  PMID: 21253608
25.  Evaluating the Impact of Environmental Temperature on Global Highly Pathogenic Avian Influenza (HPAI) H5N1 Outbreaks in Domestic Poultry 
The emergence and spread of highly pathogenic avian influenza (HPAI) A virus subtype H5N1 in Asia, Europe and Africa has had an enormously socioeconomic impact and presents an important threat to human health because of its efficient animal-to-human transmission. Many factors contribute to the occurrence and transmission of HPAI H5N1 virus, but the role of environmental temperature remains poorly understood. Based on an approach of integrating a Bayesian Cox proportional hazards model and a Besag-York-Mollié (BYM) model, we examined the specific impact of environmental temperature on HPAI H5N1 outbreaks in domestic poultry around the globe during the period from 1 December 2003 to 31 December 2009. The results showed that higher environmental temperature was a significant risk factor for earlier occurrence of HPAI H5N1 outbreaks in domestic poultry, especially for a temperature of 25 °C. Its impact varied with epidemic waves (EWs), and the magnitude of the impact tended to increase over EWs.
doi:10.3390/ijerph110606388
PMCID: PMC4078585  PMID: 24950061
avian influenza; highly pathogenic avian influenza; H5N1; environmental temperature; spatial analysis; Bayesian statistics

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