Influenza: prospect for prevention and control

Influenza is an emerging and re-emerging disease. Since the late 1930s influenza viruses have been isolated yearly from different parts of the world during epidemics and pandemics. The "epidemiologic success" of influenza is due largely to rapid and unpredictable antigenic changes (antigenic drift) among human influenza viruses, and the emergence of new subtypes (antigenic shift), mostly from reassortment between human and avian influenza viruses. Antigenic shifts were attributed to the global pandemic viruses of 1957 (H2N2 Asian flu) and 1968 (H3N2 Hong Kong flu). Concern over possible new pandemics has been heightened by recent reports of human infection in Asia in 1997 with avian viruses (H5N1) and in 1999 (H9N2) and isolation of human-avian reassorted viruses from pigs and humans in Europe. Influenza has a high rate of inapparent infection, short incubation and high infectivity; epidemics usually start abruptly and spread rapidly to neighboring communities and countries. Isolation and quarantine are often unsuccessful in preventing the spread of the infection. Although not perfect, immunization and chemoprophylaxis are highly effective at minimizing the spread of influenza and reducing morbidity and mortality, social disruption and economic loss. Plans for future influenza epidemics and pandemics require national and international programs to be in place for the monitoring of influenza activity, the dissemination and exchange of information and the provision and delivery of sufficient quantities of vaccines and antiviral agents. This paper reviews and discusses the antigenic variations of the influenza virus, potential influenza pandemics, protective efficacy of inactivated vaccines and antiviral agents and preparation for control of future epidemics and pandemics.     

New and emerging infectious diseases.

New emerging infectious diseases include "severe acute respiratory distress syndrome" (SARS) and avian influenza A H5N1. First cases of SARS, induced by a new strain of coronavirus, were described in China in 2002 and by May 2003 8360 cases and 764 deaths were reported by the World Health Organization. The disease can be transmitted from person to person and at the onset is characterized by nonspecific symptoms such as a fever of > 38 degrees C, dry cough, myalgia, and dyspnea. Adults can develop severe hypoxemia requiring intubation, whereas the course of the disease is generally benign in children. Avian influenza A H5N1 is another emerging infectious disease transmitted from avian species to humans, without clear evidence of transmission from human to human. The widespread outbreaks of H5N1 avian influenza in 2003-2004 have caused major problems for the poultry industry in many Asian countries. On January 2004 the disease crossed over to humans, for the first time in Vietnam, causing 74 deaths to date (mortality rate of 50%) in southeastern countries. Unlike SARS, the avian flu occurs in rural areas, where people live in intimate contact with birds, and many of the victims are children < 5 years of age. As for SARS, the World Health Organization has adopted a global action plan to control avian influenza among chickens and ducks and at the same time to limit the threat of a human flu pandemic.     

Avian influenza A (H5N1) infectious in both birds and humans in South-Eastern Asian countries

Avian influenza affects most types of birds and occurs in epidemics on poultry farms. The fatal disease is named "highly pathogenic avian influenza" and is caused by influenza A virus subtypes H5 and H7. The natural reservoir is the migratory waterfowl that occasionally infects domestic poultry. In 1997 in Hong Kong, 18 persons were infected and 6 of them died. At the end of 2003 and the beginning of 2004, avian influenza H5N1 infected numerous farms in several South-Eastern Asian countries. The virus was transmitted to humans in close contact with infected birds. A total of 34 persons were infected and 23 of them died. There is currently a considerable concern about the H5N1 avian influenza that has infected humans: the high virulence, evolution rate, the possibility of recombination with other influenza viruses, how H5N1 variants that infect humans or different approaches to the development of influenza vaccines.     

Avian influenza and human health

Natural infections with influenza A viruses have been reported in a variety of animal species including humans, pigs, horses, sea mammals, mustelids and birds. Occasionally devastating pandemics occur in humans. Although viruses of relatively few HA and NA subtype combinations have been isolated from mammalian species, all 15 HA subtypes and all 9 NA subtypes, in most combinations, have been isolated from birds.In the 20th century the sudden emergence of antigenically different strains transmissible in humans, termed antigenic shift, has occurred on four occasions, 1918 (H1N1), 1957 (H2N2), 1968 (H3N2) and 1977 (H1N1), each time resulting in a pandemic. Genetic analysis of the isolates demonstrated that 'new' strains most certainly emerged after reassortment of genes of viruses of avian and human origin in a permissive host. The leading theory is that the pig represents the 'mixing vessel' where this genetic reassortment may occur.In 1996, an H7N7 influenza virus of avian origin was isolated from a woman with a self-limiting conjunctivitis. During 1997 in Hong Kong, an H5N1 avian influenza virus was recognised as the cause of death of 6 of 18 infected patients. Genetic analysis revealed these human isolates of H5N1 subtype to be indistinguishable from a highly pathogenic avian influenza virus that was endemic in the local poultry population. More recently, in March 1999, two independent isolations of influenza virus subtype H9N2 were made from girls aged one to four who recovered from flu-like illnesses in Hong Kong. Subsequently, five isolations of H9N2 virus from humans on mainland China in August 1998 were reported. H9N2 viruses were known to be widespread in poultry in China and other Asian countries.In all these cases there was no evidence of human to human spread except with the H5N1 infections where there was evidence of very limited spread. This is in keeping with the finding that all these viruses possessed all eight genes of avian origin. It may well be that infection of humans with avian influenza viruses occurs much more frequently than originally assumed, but due to their limited effect go unrecognised.For the human population as a whole the main danger of direct infection with avian influenza viruses appears to be if people infected with an 'avian' virus are infected simultaneously with a 'human' influenza virus. In such circumstances reassortment could occur with the potential emergence of a virus fully capable of spread in the human population, but with antigenic characteristics for which the human population was immunologically naive. Presumably this represents a very rare coincidence, but one which could result in a true influenza pandemic.     

Is avian influenza a risk for humans?

Avian influenza is an infectious disease of birds, caused by type A strains of the influenza virus. The disease, which was first identified in Italy more than 100 years ago, occurs worldwide. Avian influenza viruses are mainly distributed by migratory birds. Different mammals like swine, horse and finally humans are susceptible for avian influenza viruses. The high possibility of genomic changes like gene shift and drift is caused by the segmented RNA genome. During the avian flu outbreak in East Asia at the end of 2003 the virus also killed several humans in Vietnam and Thailand. That avian influenza could also infect humans has been known since 1997. The H5N1 flu outbreak seemed successfully controlled, but currently new cases in poultry and humans in Vietnam, Thailand, China and Indonesia are recognized. Also another avian influenza A strain type H9N2 was prevalent in chickens of local markets in Hong Kong. Because of the natural virus reservoir like wild and/ or domesticated ducks and others, actually there is little chance of eradicating avian influenza. Furthermore the virus could mutate and jump to humans with the threat of a global influenza pandemic.     

Influenza, an existing public health problem

Seasonal influenza is an acute and recurring respiratory disease known since ancient times, occuring, in particular, during winter months and having an elevated effect on public health worldwide.The disease has high morbidity rates for people of all ages and particularly high mortality rates for children, adults over 60 years old, patients with chronic illnesses and pregnant women. Prevention control strategies include vaccination using inactivated, subunit or genetically modified virus vaccines. Influenza in humans is caused by two subtypes of influenza virus A and one of influenza virus B. The influenza virus A that affects humans mutates easily, thereby often causing new antigenic variants of each subtype to emerge, requiring the inclusion of such variants in annual vaccines in order to assure proper immunization of the population.The influenza pandemic refers to the introduction and later worldwide spread of a new influenza virus in the human population, which occurs sporadically. Due to the lack of immunity in humans against the new virus, serious epidemics can be provoked resulting in high morbidity and mortality rates. Historically, influenza pandemics are a result of the transmission of the virus from birds to humans, or the transfer of such genes to seasonal influenza. Wild waterfowl--both migratory and shore birds--carry a large diversity of influenza virus subtypes, which are eventually transmitted to domestic birds. Some of those viruses cross the species barrier and infect mammals, including humans.The adaptation process of the avian virus to mammal hosts requires time. Therefore, the presentation of these cases can take several years. Since December 2003, in several Southeast Asian countries a large proportion of domestic birds have been affected by an avian influenza epidemic (subtype H5N1). By Februrary 2006, the epidemic had already affected countries in Europe and Africa, having a significant economic impact on commercial poultry due to the more than 180 million birds that were sacrificed. Some strains of this avian influenza virus have directly, although incipiently, infected the human population.The virus has not yet acquired with complete efficiency person-to-person infection and transmission, which has limited its spread among humans. Since the mortality rate in infected individuals is greater than 50%, the World Health Organization (WHO) called on their member countries to establish preparation and emergency plans against the threat of a possible pandemic associated with H5N1 virus, or another virus related to common influenza.These actions are intended to prevent or reduce the impact of the threat, as experienced in previous pandemics, such as in 1918 when roughly 40 million people died worldwide.The prevention and control plans include, among other strategies, vaccination and antiviral medications. Nevertheless, to date there are no vaccines to be administered to the population in the case of a new influenza pandemic emergency and it is possible that countries that produce the annual seasonal influenza vaccine lack the capacity to produce the pandemic virus vaccine in a short period of time. In addition, recent studies have identified the existence of influenza virus strains resistant to common antiviral agents. The purpose of this review is to update the basic concepts of influenza in order to strengthen epidemiological surveillance of the disease and reinitiate prevention and control actions in the event of a pandemic.     

Avian influenza infections in birds – a moving target

Avian influenza (AI) is a complex infection of birds, of which the ecology and epidemiology have undergone substantial changes over the last decade. Avian influenza viruses infecting poultry can be divided into two groups. The very virulent viruses cause highly pathogenic avian influenza (HPAI), with flock mortality as high as 100%. These viruses have been restricted to subtypes H5 and H7, although not all H5 and H7 viruses cause HPAI. All other viruses cause a milder, primarily respiratory, disease (low pathogenic avian influenza, LPAI), unless exacerbated by other infections or environmental conditions. Until recently, HPAI viruses were rarely isolated from wild birds, but for LPAI viruses extremely high isolation rates have been recorded in surveillance studies, particularly in feral waterfowl. In recent years, there have been costly outbreaks of HPAI in poultry in Italy, the Netherlands and Canada and in each of these countries millions of birds were slaughtered to bring the outbreaks under control. However, these outbreaks tend to have been overshadowed by the H5N1 HPAI virus, initially isolated in China, that has now spread in poultry and/or wild birds throughout Asia and into Europe and Africa, resulting in the death or culling of hundreds of millions of poultry and posing a significant zoonosis threat. Since the 1990s, AI infections due to two subtypes, LPAI H9N2 and HPAI H5N1, have been widespread in poultry across large areas of the world, resulting in a modified eco‐epidemiology and a zoonotic potential. An extraordinary effort is required to manage these epidemics from both the human and animal health perspectives.     

Genetic strategy to prevent influenza virus infections in animals

The natural reservoirs of influenza viruses are aquatic birds. After adaptation, avian viruses can acquire the ability to infect humans and cause severe disease. Because domestic poultry serves as a key link between the natural reservoir of influenza viruses and epidemics and pandemics in human populations, an effective measure to control influenza would be to eliminate or reduce influenza virus infection in domestic poultry. The development and distribution of influenza-resistant poultry represents a proactive strategy for controlling the origin of influenza epidemics and pandemics in both poultry and human populations. Recent developments in RNA interference and transgenesis in birds should facilitate the development of influenza-resistant poultry.     

Characterization of H9N2 Avian Influenza Viruses Isolated from Poultry Products in a Mouse Model

Low pathogenic H9N2 avian influenza viruses have spread in wild birds and poultry worldwide. Recently, the number of human cases of H9N2 virus infection has increased in China and other countries, heightening pandemic concerns. In Japan, H9N2 viruses are not yet enzootic; however, avian influenza viruses, including H5N1, H7N9, H5N6, and H9N2, have been repeatedly detected in raw poultry meat carried by international flight passengers from Asian countries to Japan. Although H9N2 virus-contaminated poultry products intercepted by the animal quarantine service at the Japan border have been characterized in chickens and ducks, the biological properties of those H9N2 viruses in mammals remain unclear. Here, we characterized the biological features of two H9N2 virus isolates [A/chicken/Japan/AQ-HE28-50/2016 (Ck/HE28-50) and A/chicken/Japan/AQ-HE28-57/2016 (Ck/HE28-57)] in a mouse model. We found that these H9N2 viruses replicate well in the respiratory tract of infected mice without adaptation, and that Ck/HE28-57 caused body weight loss in the infected mice. Our results indicate that H9N2 avian influenza viruses isolated from raw chicken meat products illegally brought to Japan can potentially infect and cause disease in mammals.     

Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model

Avian influenza A H5N1 viruses continue to spread globally among birds, resulting in occasional transmission of virus from infected poultry to humans. Probable human-to-human transmission has been documented rarely, but H5N1 viruses have not yet acquired the ability to transmit efficiently among humans, an essential property of a pandemic virus. The pandemics of 1957 and 1968 were caused by avian-human reassortant influenza viruses that had acquired human virus-like receptor binding properties. However, the relative contribution of human internal protein genes or other molecular changes to the efficient transmission of influenza viruses among humans remains poorly understood. Here, we report on a comparative ferret model that parallels the efficient transmission of H3N2 human viruses and the poor transmission of H5N1 avian viruses in humans. In this model, an H3N2 reassortant virus with avian virus internal protein genes exhibited efficient replication but inefficient transmission, whereas H5N1 reassortant viruses with four or six human virus internal protein genes exhibited reduced replication and no transmission. These findings indicate that the human virus H3N2 surface protein genes alone did not confer efficient transmissibility and that acquisition of human virus internal protein genes alone was insufficient for this 1997 H5N1 virus to develop pandemic capabilities, even after serial passages in a mammalian host. These results highlight the complexity of the genetic basis of influenza virus transmissibility and suggest that H5N1 viruses may require further adaptation to acquire this essential pandemic trait.     

Avian-to-human transmission of H9N2 subtype influenza A viruses: relationship between H9N2 and H5N1 human isolates

In 1997, 18 cases of influenza in Hong Kong (bird flu) caused by a novel H5N1 (chicken) virus resulted in the deaths of six individuals and once again raised the specter of a potentially devastating influenza pandemic. Slaughter of the poultry in the live bird markets removed the source of infection and no further human cases of H5N1 infection have occurred. In March 1999, however, a new pandemic threat appeared when influenza A H9N2 viruses infected two children in Hong Kong. These two virus isolates are similar to an H9N2 virus isolated from a quail in Hong Kong in late 1997. Although differing in their surface hemagglutinin and neuraminidase components, a notable feature of these H9N2 viruses is that the six genes encoding the internal components of the virus are similar to those of the 1997 H5N1 human and avian isolates. This common feature emphasizes the apparent propensity of avian viruses with this genetic complement to infect humans and highlights the potential for the emergence of a novel human pathogen.     

Viral and Host Factors Required for Avian H5N1 Influenza A Virus Replication in Mammalian Cells

Following the initial and sporadic emergence into humans of highly pathogenic avian H5N1 influenza A viruses in Hong Kong in 1997, we have come to realize the potential for avian influenza A viruses to be transmitted directly from birds to humans. Understanding the basic viral and cellular mechanisms that contribute to infection of mammalian species with avian influenza viruses is essential for developing prevention and control measures against possible future human pandemics. Multiple physical and functional cellular barriers can restrict influenza A virus infection in a new host species, including the cell membrane, the nuclear envelope, the nuclear environment, and innate antiviral responses. In this review, we summarize current knowledge on viral and host factors required for avian H5N1 influenza A viruses to successfully establish infections in mammalian cells. We focus on the molecular mechanisms underpinning mammalian host restrictions, as well as the adaptive mutations that are necessary for an avian influenza virus to overcome them. It is likely that many more viral and host determinants remain to be discovered, and future research in this area should provide novel and translational insights into the biology of influenza virus-host interactions.     

Genetic Characterization and Pathogenesis of Avian Influenza Virus H7N3 Isolated from Spot-Billed Ducks in South Korea,Early 2019

Low-pathogenicity avian influenza viruses (LPAIV) introduced by migratory birds circulate in wild birds and can be transmitted to poultry. These viruses can mutate to become highly pathogenic avian influenza viruses causing severe disease and death in poultry. In March 2019, an H7N3 avian influenza virus—A/Spot-billed duck/South Korea/WKU2019-1/2019 (H7N3)—was isolated from spot-billed ducks in South Korea. This study aimed to evaluate the phylogenetic and mutational analysis of this isolate. Molecular analysis revealed that the genes for HA (hemagglutinin) and NA (neuraminidase) of this strain belonged to the Central Asian lineage, whereas genes for other internal proteins such as polymerase basic protein 1 (PB1), PB2, nucleoprotein, polymerase acidic protein, matrix protein, and non-structural protein belonged to that of the Korean lineage. In addition, a monobasic amino acid (PQIEPR/GLF) at the HA cleavage site, and the non-deletion of the stalk region in the NA gene indicated that this isolate was a typical LPAIV. Nucleotide sequence similarity analysis of HA revealed that the highest homology (99.51%) of this isolate is to that of A/common teal/Shanghai/CM1216/2017 (H7N7), and amino acid sequence of NA (99.48%) was closely related to that of A/teal/Egypt/MB-D-487OP/2016 (H7N3). An in vitro propagation of the A/Spot-billed duck/South Korea/WKU2019-1/2019 (H7N3) virus showed highest (7.38 Log₁₀ TCID₅₀/mL) virus titer at 60 h post-infection, and in experimental mouse lungs, the virus was detected at six days’ post-infection. Our study characterizes genetic mutations, as well as pathogenesis in both in vitro and in vivo model of a new Korea H7N3 viruses in 2019, carrying multiple potential mutations to become highly pathogenic and develop an ability to infect humans; thus, emphasizing the need for routine surveillance of avian influenza viruses in wild birds.     

Molecular Characterization of Closely Related H6N2 Avian Influenza Viruses Isolated from Turkey,Egypt, and Uganda

Genetic analysis of circulating avian influenza viruses (AIVs) in wild birds at different geographical regions during the same period could improve our knowledge about virus transmission dynamics in natural hosts, virus evolution as well as zoonotic potential. Here, we report the genetic and molecular characterization of H6N2 influenza viruses isolated from migratory birds in Turkey, Egypt, and Uganda during 2017–2018. The Egyptian and Turkish isolates were genetically closer to each other than they were to the virus isolated from Uganda. Our results also suggest that multiple reassortment events were involved in the genesis of the isolated viruses. All viruses contained molecular markers previously associated with increased replication and/or pathogenicity in mammals. The results of this study indicate that H6N2 viruses carried by migratory birds on the West Asian/East African and Mediterranean/Black Sea flyways have the potential to transmit to mammals including humans. Additionally, adaptation markers in these viruses indicate the potential risk for poultry, which also increases the possibility of human exposure to these viruses.     

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.     

Influenza viruses and the evolution of avian influenza virus H5N1.

Although small in size and simple in structure, influenza viruses are sophisticated organisms with highly mutagenic genomes and wide antigenic diversity. They are species-specific organisms. Mutation and reassortment have resulted in newer viruses such as H5N1, with new resistance against anti-viral medications, and this might lead to the emergence of a fully transmissible strain, as occurred in the 1957 and 1968 pandemics. Influenza viruses are no longer just a cause of self-limited upper respiratory tract infections; the H5N1 avian influenza virus can cause severe human infection with a mortality rate exceeding 50%. The case death rate of H5N1 avian influenza infection is 20 times higher than that of the 1918 infection (50% versus 2.5%), which killed 675000 people in the USA and almost 40 million people worldwide. While the clock is still ticking towards what seems to be inevitable pandemic influenza, on April 17, 2007 the U.S. Food and Drug Administration (FDA) approved the first vaccine against the avian influenza virus H5N1 for humans at high risk. However, more research is needed to develop a more effective and affordable vaccine that can be given at lower doses.     

A clinical approach to the threat of emerging influenza viruses in the Asia‐Pacific region

Seasonal influenza epidemics and periodic pandemics are important causes of morbidity and mortality. Patients with chronic co‐morbid illness, those at the extremes of age and pregnant women are at higher risks of complications requiring hospitalization, whereas young adults and obese individuals were also at increased risk during the A(H1N1) pandemic in 2009. Avian influenza A(H5N1) and A(H7N9) viruses have continued to circulate widely in some poultry populations and infect humans sporadically since 1997 and 2013, respectively. The recent upsurge in human cases of A(H7N9) infections in Mainland China is of great concern. Sporadic human cases of avian A(H5N6), A(H10N8) and A(H6N1) have also emerged in recent years while there are also widespread poultry outbreaks due to A(H5N8) in many countries. Observational studies have shown that treatment with a neuraminidase inhibitor (NAI) for adults hospitalized with severe influenza is associated with lower mortality and better clinical outcomes, especially when administered early in the course of illness. Whether higher than standard doses of NAI would provide greater antiviral effects in such patients will require further investigation. High‐dose systemic corticosteroids were associated with worse outcomes in patients with severe influenza. There is an urgent need for developing more effective antiviral therapies for treatment of influenza infections.     

From the Cover: Dating the emergence of pandemic influenza viruses

Pandemic influenza viruses cause significant mortality in humans. In the 20th century, 3 influenza viruses caused major pandemics: the 1918 H1N1 virus, the 1957 H2N2 virus, and the 1968 H3N2 virus. These pandemics were initiated by the introduction and successful adaptation of a novel hemagglutinin subtype to humans from an animal source, resulting in antigenic shift. Despite global concern regarding a new pandemic influenza, the emergence pathway of pandemic strains remains unknown. Here we estimated the evolutionary history and inferred date of introduction to humans of each of the genes for all 20th century pandemic influenza strains. Our results indicate that genetic components of the 1918 H1N1 pandemic virus circulated in mammalian hosts, i.e., swine and humans, as early as 1911 and was not likely to be a recently introduced avian virus. Phylogenetic relationships suggest that the A/Brevig Mission/1/1918 virus (BM/1918) was generated by reassortment between mammalian viruses and a previously circulating human strain, either in swine or, possibly, in humans. Furthermore, seasonal and classic swine H1N1 viruses were not derived directly from BM/1918, but their precursors co-circulated during the pandemic. Mean estimates of the time of most recent common ancestor also suggest that the H2N2 and H3N2 pandemic strains may have been generated through reassortment events in unknown mammalian hosts and involved multiple avian viruses preceding pandemic recognition. The possible generation of pandemic strains through a series of reassortment events in mammals over a period of years before pandemic recognition suggests that appropriate surveillance strategies for detection of precursor viruses may abort future pandemics.     

Influenza pandemic--current crisis

In most cases, influenza is not fatal, even without treatment. Moreover, vaccination and antivirals have reduced influenza-related mortality in recent years. However, the direct transmission of avian influenza viruses to humans with lethal outcomes in Hong Kong in 1997 was a potent reminder of the devastating potential of the disease. Currently, H5N1 avian influenza viruses are circulating in many Asian countries, and the human death toll continues to rise as the virus spreads to European countries as well. Since the beginning of the outbreak in Asia, more than 120 cases have been confirmed and the mortality rate has been no less than 50%. Current vaccines for H3N2 and H1N1 viruses, of course, have no effect on infection by H5N1 viruses. In addition, H5N1 viruses that are resistant to the antiviral drugs amantadine and oseltamivir have emerged. Fortunately, a virus that is capable of efficient transmission among humans has not emerged. However, it is not a matter of if, but when, such a virus will appear. Here, we review the current situation of avian influenza and pandemic preparedness.     

Phylodynamics of Highly Pathogenic Avian Influenza A(H5N1) Virus Circulating in Indonesian Poultry

After its first detection in 1996, the highly pathogenic avian influenza A(H5Nx) virus has spread extensively worldwide. HPAIv A(H5N1) was first detected in Indonesia in 2003 and has been endemic in poultry in this country ever since. However, Indonesia has limited information related to the phylodynamics of HPAIv A(H5N1) in poultry. The present study aimed to increase the understanding of the evolution and temporal dynamics of HPAIv H5N1 in Indonesian poultry between 2003 and 2016. To this end, HPAIv A(H5N1) hemagglutinin sequences of viruses collected from 2003 to 2016 were analyzed using Bayesian evolutionary analysis sampling trees. Results indicated that the common ancestor of Indonesian poultry HPAIv H5N1 arose approximately five years after the common ancestor worldwide of HPAI A(H5Nx). In addition, this study indicated that only two introductions of HPAIv A(H5N1) occurred, after which these viruses continued to evolve due to extensive spread among poultry. Furthermore, this study revealed the divergence of H5N1 clade 2.3.2.1c from H5N1 clade 2.3.2.1b. Both clades 2.3.2.1c and 2.3.2.1b share a common ancestor, clade 1, suggesting that clade 2.3.2.1 originated and diverged from China and other Asian countries. Since there was limited sequence and surveillance data for the HPAIv A(H5N1) from wild birds in Indonesia, the exact role of wild birds in the spread of HPAIv in Indonesia is currently unknown. The evolutionary dynamics of the Indonesian HPAIv A(H5N1) highlight the importance of continuing and improved genomic surveillance and adequate control measures in the different regions of both the poultry and wild birds. Spatial genomic surveillance is useful to take adequate control measures. Therefore, it will help to prevent the future evolution of HPAI A(H5N1) and pandemic threats.