Animal influenza research needs: protecting humans, animals, food, and economies.

For the past 10 years, animal health experts and human health experts have been gaining experience in the technical aspects of avian influenza in mostly separate fora. More recently, in 2006, in a meeting of the small WHO Working Group on Influenza Research at the Human Animal Interface (Meeting report available from: http://www.who.int/csr/resources/publications/influenza/WHO_CDS_EPR_GIP_2006_3/en/index.html) in Geneva allowed influenza experts from the animal and public health sectors to discuss together the most recent avian influenza research. Ad hoc bilateral discussions on specific technical issues as well as formal meetings such as the Technical Meeting on HPAI and Human H5N1 Infection (Rome, June, 2007; information available from: http://www.fao.org/avianflu/en/conferences/june2007/index.html) have increasingly brought the sectors together and broadened the understanding of the topics of concern to each sector. The sectors have also recently come together at the broad global level, and have developed a joint strategy document for working together on zoonotic diseases (Joint strategy available from: ftp://ftp.fao.org/docrep/fao/011/ajl37e/ajl37e00.pdf). The 2008 FAO-OIE-WHO Joint Technical Consultation on Avian Influenza at the Human Animal Interface described here was the first opportunity for a large group of influenza experts from the animal and public health sectors to gather and discuss purely technical topics of joint interest that exist at the human-animal interface. During the consultation, three influenza-specific sessions aimed to (1) identify virological characteristics of avian influenza viruses (AIVs) important for zoonotic and pandemic disease, (2) evaluate the factors affecting evolution and emergence of a pandemic influenza strain and identify existing monitoring systems, and (3) identify modes of transmission and exposure sources for human zoonotic influenza infection (including discussion of specific exposure risks by affected countries). A final session was held to discuss broadening the use of tools and systems to other emerging zoonotic diseases. The meeting was structured as short technical presentations with substantial time available for facilitated discussion, to take advantage of the vast influenza knowledge and experience available from the invited expert participants. Particularly important was the identification of gaps in knowledge that have not yet been filled by either sector. Technical discussions focused on H5N1, but included other potentially zoonotic avian and animal influenza viruses whenever possible. During the consultation, the significant threat posed by subtypes other than H5N1 was continually emphasized in a variety of contexts. It was stressed that epidemiological and virological surveillance for these other viruses should be broadening and strengthened. The important role of live bird markets (LBMs) in amplifying and sustaining AIVs in some countries was also a recurring topic, and the need for better understanding of the role of LBMs in human zoonotic exposure and infection was noted. Much is understood about the contribution of various virus mutations and gene combinations to transmissibility, infectivity, and pathogenicity, although it was agreed that the specific constellation of gene types and mutations that would characterize a potentially pandemic virus remains unclear. The question of why only certain humans have become infected with H5N1 in the face of massive exposure in some communities was frequently raised during discussion of human exposure risks. It was suggested that individual-level factors may play a role. More research is needed to address this as well as questions of mode of transmission, behaviors associated with increased risk, virological and ecological aspects, and viral persistence in the environment in order to better elucidate specific human exposure risks. It became clear that great strides have been made in recent years in collaboration between the animal health and public health sectors, especially at the global level. In some countries outbreaks of H5N1 are being investigated jointly. Even greater transparency, cooperation, and information and materials exchange would allow more timely and effective responses in emergency situations, as well as in assessment and planning phases. Ensuring sustainability was also frequently emphasized, e.g. in infrastructure and capacity development and in development of tools and systems for surveillance, assessment and response. It was suggested that one way for tools and systems built or planned to address avian influenza to become more sustainable would be to make them applicable for a broader array of existing and emerging zoonotic diseases.

Well before the 31 influenza outbreaks recorded since the first pandemic was described in 1580, pandemic-like events were reported as early as the fifth century BC by the Greek physician Hippocrates. In the last century, the "Spanish flu" pandemic of 1918-19 killed 20-40 million people, while the "Asian flu" pandemic in 1957 and "Hong Kong flu" in 1968 each caused an estimated 1-4 million deaths. Pandemics originate with the emergence of a new subtype of influenza virus able to cause disease, replicate in humans, and spread efficiently from one person to another. An avian influenza virus can improve its transmissibility in humans by adaptive mutation or genetic reassortment (the mixing of animal and human influenza viruses). Recent studies confirm that the 1918-19 pandemic probably originated from the reassortment of avian and human viruses (1). Reports of human infections and deaths caused by avian influenza virus A(H5N1) in Hong Kong Special Administrative Region in 1997 (2) and 2003, and in Viet Nam and Thailand in 2004 are stark reminders of the threat of pandemic influenza. Outbreaks of avian influenza are increasingly frequent, probably as a result of intensive agricultural practices, high virus transmissibility and the presence of natural reservoirs in migratory birds. The ability of three of the 15 known subtypes of avian influenza viruses (H5N1, H7N7 and H9N2) occasionally to infect human beings makes them one of the most likely candidates to become the next pandemic virus. The current influenza outbreaks in poultry are unprecedented in their scale, geographical spread and adverse economic effects among affected populations. Containment will requite the mobilization of significant resources over several months, leading to continued exposure of many individuals to H5N1. In addition, resistance in current strains to one of the two classes of available antiviral drugs has been demonstrated in vitro. Because of its high pathogenicity in humans, there are growing concerns that if H5N1 were to become transmissible in humans, the heavy toll of the 1918-19 "Spanish flu" pandemic could be repeated (3). Most experts believe that future influenza pandemics are inevitable and may be imminent (4). Nobody can be sure when a pandemic will happen, how quickly it will spread, and what morbidity, mortality and economic impact it will cause. Forecasting models predict a major disease burden, with 25-30% of the population filling ill and potentially enormous economic costs worldwide, especially in the poorest countries where resources for surveillance and health care are limited and population health and nutritional status are poor. A comprehensive public health approach to influenza pandemics must include at least four key activity areas: Limiting the circulation of avian and other animal influenza viruses. The main strategy for preventing the emergence of a pandemic virus is to reduce the opportunities for human exposure to animal viruses with demonstrated human pathogenicity. Human infections with avian influenza viruses and mutations leading to efficient human-to-human transmission are both rare events. However, large outbreaks in poultry magnify the possibility of human infection. …

This report is produced each month by the APHA Surveillance Intelligence Unit and the six Species Expert Groups (livestock and wildlife). The international horizon-scanning summaries are produced by the Defra/APHA International Disease Monitoring (IDM) team, notifiable disease reports by the APHA Veterinary Exotic and Notifiable Disease Unit (VENDU), and threat analysis by the cross-agency Veterinary Risk Group (VRG). The report is drawn from scanning surveillance information, data and reports produced by the APHA Veterinary Investigation Centres and non-APHA partner postmortem examination providers contributing to the Veterinary Investigation Diagnosis Analysis (VIDA) database and complying with standardised diagnostic and laboratory testing criteria. Other livestock and wildlife scanning surveillance reports may also be found at www.gov.

Viral Tropism and the Pathogenesis of Influenza in the Mammalian Host

With cases documented in more than 170 countries, the global swine flu pandemic that erupted in spring 2009 remains a serious public health problem. Caused by a strain of H1N1 influenza virus, which is normally found in pigs, the flu now known as novel H1N1 has so far been less severe than regular seasonal flu in terms of deaths and hospitalizations. Yet given its remarkable capacity for human-to-human transmission and a widespread lack of immunity among potentially exposed people, it’s likely the number of cases will rise during the flu season later this fall and winter, according to many public health experts. Given that possibility, enormous resources are being mobilized to address novel H1N1, with an emphasis on vaccine development, education, and efforts to its limit its movements among human communities. Yet one potential source of the original outbreak—factory swine farming in concentrated animal feeding operations (CAFOs)—has received comparatively little attention by public health officials. CAFOs house animals by the thousands in crowded indoor facilities. But the same economy-of-scale efficiencies that allow CAFOs to produce affordable meat for so many consumers also facilitate the mutation of viral pathogens into novel strains that can be passed on to farm workers and veterinarians, according to Gregory Gray, director of the Center for Emerging Infectious Diseases at the University of Iowa College of Public Health. “When respiratory viruses get into these confinement facilities, they have continual opportunity to replicate, mutate, reassort, and recombine into novel strains,” Gray explains. “The best surrogates we can find in the human population are prisons, military bases, ships, or schools. But respiratory viruses can run quickly through these [human] populations and then burn out, whereas in CAFOs—which often have continual introductions of [unexposed] animals—there’s a much greater potential for the viruses to spread and become endemic.” Gray says workers exposed routinely to livestock can pass these zoonotic infections—which transmit readily among humans and animals—on to the wider public. However, public health agencies that monitor risks from zoonotic infections routinely overlook CAFO workers, according to Ellen Silbergeld, a professor at the Johns Hopkins Bloomberg School of Public Health. And animal disease sampling data collected by the food animal industry typically are not shared publicly, according to Gray, although such data could reveal how novel pathogens evolve in CAFOs and how they might move among animals, workers, and the broader community. Experts believe that without these data, society has a diminished capacity to detect and respond to new zoonotic threats before they become more widespread.

Avian Influenza Virus Infections in Humans

Increasing incidences of emerging and re-emerging diseases that are mostly zoonotic (e.g. severe acute respiratory syndrome, avian influenza H5N1, pandemic influenza) has led to the need for a multidisciplinary approach to tackling these threats to public and animal health. Accordingly, a global movement of 'One-Health/One-Medicine' has been launched to foster collaborative efforts amongst animal and human health officials and researchers to address these problems. Historical evidence points to the fact that pandemics caused by influenza A viruses remain a major zoonotic threat to mankind. Recently, a range of mathematical and computer simulation modelling methods and tools have increasingly been applied to improve our understanding of disease transmission dynamics, contingency planning and to support policy decisions on disease outbreak management. This review provides an overview of methods, approaches and software used for modelling the spread of zoonotic influenza viruses in animals and humans, particularly those related to the animal-human interface. Modelling parameters used in these studies are summarized to provide references for future work. This review highlights the limited application of modelling research to influenza in animals and at the animal-human interface, in marked contrast to the large volume of its research in human populations. Although swine are widely recognized as a potential host for generating novel influenza viruses, and that some of these viruses, including pandemic influenza A/H1N1 2009, have been shown to be readily transmissible between humans and swine, only one study was found related to the modelling of influenza spread at the swine-human interface. Significant gaps in the knowledge of frequency of novel viral strains evolution in pigs, farm-level natural history of influenza infection, incidences of influenza transmission between farms and between swine and humans are clearly evident. Therefore, there is a need to direct additional research to the study of influenza transmission dynamics in animals and at the animal-human interface.

Since 1997 the community has witnessed a strain of highly pathogenic H5N1 avian influenza virus emerge and spread at an unprecedented rate. It has had devastating consequences for domestic poultry, wild avian species, and humans on 3 continents; 240 human cases have occurred with 141 deaths. From 1999 to 2003, poultry outbreak control measures in the European Union alone resulted in the depopulation of 50 million birds at a substantial cost to the global economy. Because of the ongoing human and animal infections, the public health and veterinary communities have recognized the urgent need for an ongoing collaborative and participatory approach to prevention and control of highly pathogenic avian influenza (HPAI). This monograph contains the proceedings of the International Scientific Conference on Avian Influenza held in Paris, France, in April 2005. The conference was sponsored by the World Organization for Animal Health (OIE) and the Food and Agriculture Organization (FAO), in collaboration with the World Health Organization (WHO). To address the emerging animal health crisis and mitigate risks to human health, at the outset of the HPAI H5N1 outbreaks in Southeast Asia in early 2004, these organizations held joint meetings in Rome (February 2004), followed by 2 regional meetings in Bangkok (February 2004) and Ho Chi Minh City (February 2005) to issue guidelines and recommendations for prevention and control. Because it appears that this HPAI H5N1 epizootic will persist for some time, the Paris 2005 meeting was held to achieve consensus on the most current strategies for long-term prevention and control, including poultry vaccination when appropriate. Bernard Vallat, the director general of the OIE, opened the meeting and urged scientists and regulators to consider strengthening farm biosecurity measures; to assess the role of ducks as a reservoir for avian influenza; to evaluate animal vaccination strategies; and to promote strengthening of veterinary services to enable better detection, surveillance, and response as an international public good. This meeting marked the official launching of the OIE/FAO Network (OFFLU), a network of avian influenza reference laboratories created to promote research on avian influenza, provide technical assistance to developing countries on diagnosis and management, and serve as a mechanism to interface with the WHO Influenza Network to obtain virus isolates from animals that can be used to produce vaccines to prevent a human pandemic. Opening remarks were made by Ilaria Capua, director of OIE and the National Reference Laboratory for Newcastle Disease and Avian Influenza in Padua, Italy. Dr. Capua called on the veterinary scientific community to take the following actions to limit the spread of the outbreaks: 1) expand understanding of the role of waterfowl and other nongallinaceous birds in the ecoepidemiology of HPAI, 2) further define the role of poultry vaccination in reducing the spread of infection and promoting animal welfare, 3) educate workers about prevention of exposure to avian influenza, and 4) conduct studies to address food safety concerns. More than 300 internationally renowned scientists with expertise in avian influenza attended the meeting, which featured sessions on ecology and epidemiology, pathogenesis, human health implications, diagnostics, control strategies including vaccination, and improvement of management tools. Highlights of the scientific recommendations generated include an emphasis on global sharing of viral isolates, research on epidemiology of wild birds, research on mechanisms of transfer between wild and domestic avian species, and research on pathogenesis in other farmed birds to clarify their role as intermediate hosts. The scientists concluded that the following elements were critical for achieving long-term control of HPAI infections in animals and humans: monitoring viruses for antigenic changes in virulence, performing surveillance of H9N2 viruses with the potential to infect mammals, and conducting epidemiologic studies at the human-animal interface by the OIE/FAO and the WHO networks of reference laboratories. This monograph contains the full text of the introductory speeches and manuscripts upon which the invited talks and abstracts of the poster sessions were based. It is an excellent reference for anyone interested in understanding the challenges the public health and veterinary community are facing due to the rapid emergence and complex ecoepidemiology of a viral pathogen that represents a major threat to public health and animal well-being.

Consequences and global risks of highly pathogenic avian influenza outbreaks in poultry in the United Kingdom

Swine influenza virus A (H3N2) infection in human, Kansas, USA, 2009.

The introduction of swine or avian influenza (AI) viruses in the human population can set the stage for a pandemic, and many fear that the Asian H5N1 AI virus will become the next pandemic virus. This article first compares the pathogenesis of avian, swine and human influenza viruses in their natural hosts. The major aim was to evaluate the zoonotic potential of swine and avian viruses, and the possible role of pigs in the transmission of AI viruses to humans. Cross-species transfers of swine and avian influenza to humans have been documented on several occasions, but all these viruses lacked the critical capacity to spread from human-to-human. The extreme virulence of H5N1 in humans has been associated with excessive virus replication in the lungs and a prolonged overproduction of cytokines by the host, but there remain many questions about the exact viral cell and tissue tropism. Though pigs are susceptible to several AI subtypes, including H5N1, there is clearly a serious barrier to infection of pigs with such viruses. AI viruses frequently undergo reassortment in pigs, but there is no proof for a role of pigs in the generation of the 1957 or 1968 pandemic reassortants, or in the transmission of H5N1 or other wholly avian viruses to humans. The major conclusion is that cross-species transmission of influenza viruses per se is insufficient to start a human influenza pandemic and that animal influenza viruses must undergo dramatic but largely unknown genetic changes to become established in the human population.

Avian influenza (AI) has had great impacts on global health and socioeconomics in the past two decades. Among many newly emerged influenza viruses, avian influenza viruses (AIVs) have played either indirect or direct role in human infections. The continuous evolvement of AIVs through antigenic drift and genetic reassortment has led to emerging diversities of local virus strains or variants. These dynamic changes of AIVs, even low pathogenic avian influenza (LPAI) viruses, have not only affected poultry health but also resulted in severe and fatal human cases. Moreover, the persistence of these viruses at a population level may lead to outbreaks of AI occurring year after year in a vicious cycle, if they are not completely eradicated. In light of the emergence of novel H7N9 and other subtypes of AIVs in China in recent years, residents of Taiwan who live closely to this neighboring country must be well prepared in case these viruses are imported. Furthermore, the potential for interspecies transmission to humans from either of the two subtypes of avian H5N2 and H6N1 viruses increases the risk assessment of potential public health threats coming from continuous viral mutations. These two AIV subtypes are relevant in chickens and have been endemic in Taiwan for many years, and the newly emerged novel three subtypes (H5N2, H5N3, and H5N8 clade 2.3.4.4) of AIVs that have spread island-wide since January of 2015 must be expeditiously assessed for public health risks. In summary, this article discusses the history, virology, and epidemiology of avian influenza in humans. We believe that fully understanding virological and epidemiological characteristics of avian influenza viruses and the history of past pandemics or major epidemics will help strengthen the effectiveness of prevention and control measures.

Avian influenza (AI) virus detections occurred frequently in 2022 and continue to pose a health, economic, and food security risk. The most recent global analysis of official reports of animal outbreaks and human infections with all reportable AI viruses was published almost a decade ago. Increased or renewed reports of AI viruses, especially high pathogenicity H5N8 and H5N1 in birds and H5N1, H5N8, and H5N6 in humans globally, have established the need for a comprehensive review of current global AI virus surveillance data to assess the pandemic risk of AI viruses. This study aims to provide an analysis of global AI animal outbreak and human case surveillance information from the last decade by describing the circulating virus subtypes, regions and temporal trends in reporting, and country characteristics associated with AI virus outbreak reporting in animals; surveillance and reporting gaps for animals and humans are identified. We analyzed AI virus infection reports among animals and humans submitted to animal and public health authorities from January 2013 to June 2022 and compared them with reports from January 2005 to December 2012. A multivariable regression analysis was used to evaluate associations between variables of interest and reported AI virus animal outbreaks. From 2013 to 2022, 52.2% (95/182) of World Organisation for Animal Health (WOAH) Member Countries identified 34 AI virus subtypes during 21,249 outbreaks. The most frequently reported subtypes were high pathogenicity AI H5N1 (10,079/21,249, 47.43%) and H5N8 (6722/21,249, 31.63%). A total of 10 high pathogenicity AI and 6 low pathogenicity AI virus subtypes were reported to the WOAH for the first time during 2013-2022. AI outbreaks in animals occurred in 26 more Member Countries than reported in the previous 8 years. Decreasing World Bank income classification was significantly associated with decreases in reported AI outbreaks (P<.001-.02). Between January 2013 and June 2022, 17/194 (8.8%) World Health Organization (WHO) Member States reported 2000 human AI virus infections of 10 virus subtypes. H7N9 (1568/2000, 78.40%) and H5N1 (254/2000, 12.70%) viruses accounted for the most human infections. As many as 8 of these 17 Member States did not report a human case prior to 2013. Of 1953 human cases with available information, 74.81% (n=1461) had a known animal exposure before onset of illness. The median time from illness onset to the notification posted on the WHO event information site was 15 days (IQR 9-30 days; mean 24 days). Seasonality patterns of animal outbreaks and human infections with AI viruses were very similar, occurred year-round, and peaked during November through May. Our analysis suggests that AI outbreaks are more frequently reported and geographically widespread than in the past. Global surveillance gaps include inconsistent reporting from all regions and human infection reporting delays. Continued monitoring for AI virus outbreaks in animals and human infections with AI viruses is crucial for pandemic preparedness.

The World Organisation for Animal Health (OIE)/United Nations Food and Agriculture Organization (FAO) joint network of expertise on animal influenza (OFFLU) includes all ten OIE/FAO reference laboratories and collaborating centers for avian influenza, other diagnostic laboratories, research and academic institutions, and experts in the fields of virology, epidemiology, vaccinology, and molecular biology. OFFLU has made significant progress in improving its infrastructure, in identifying and addressing technical gaps, and in establishing associations among leading veterinary institutions. Interaction with the World Health Organization (WHO) Global Influenza Program is also critical, and mechanisms for permanent interaction are being developed. OFFLU played a key role in the WHO/OIE/FAO Joint Technical Consultation held in Verona (October 7-9, 2008), which provided an opportunity to highlight and share knowledge and identify potential gaps regarding issues at the human-animal interface for avian influenza. OFFLU experts also contributed to the working group for the Unified Nomenclature System for H5N1 influenza viruses based on hemagglutinin gene phylogeny (WHO/OIE/FAO, H5N1 Evolution Working Group, Towards a unified nomenclature system for highly pathogenic avian influenza virus (H5N1) in Emerging Infectious Diseases 14:el, 2008). OFFLU technical activities, led by expert scientists from OIE/FAO reference institutions and coordinated by OIE and FAO focal points, have been prioritized to include commercial diagnostic kit evaluation, applied epidemiology, biosafety, vaccination, proficiency testing, development of standardized reference materials for sera and RNA, and issues at the human-animal interface. The progress to date and future plans for these groups will be presented. OFFLU is also involved in two national projects implemented by FAO in Indonesia and Egypt that seek to establish sustainable mechanisms for monitoring virus circulation, including viral characterization, and for streamlining the process to update poultry vaccines for avian influenza.

Cross-sectoral assessment of health risks arising or existing at the human-animal interface is crucial to identifying and implementing effective national disease control measures. This requires availability of information from 4 functional information 'streams' - epidemiological, laboratory, animal, and human health. The Food and Agriculture Organization of the United Nations (FAO)/ World Organisation for Animal Health (OIE)/ World Health Organization (WHO) Four-Way Linking (4WL) project promotes the establishing of a national-level joint framework for data sharing, risk assessment, and risk communication, in order to both improve communications within and among governmental public health and animal health influenza laboratories, epidemiology offices, national partners, with the aim of strengthening the national capacity to detect, report and assess risks arising from emerging influenza viruses. The project is currently being implemented in countries where H5N1 avian influenza is endemic and where human cases have been reported. The project is comprised of two main activities at country level: a 'review mission', which is the project launch in the country and has the objective to assess the existing situation; and a 'scenario based workshop', with the scope to bring together key national partners and build relationships among people working in the 4 information streams and to improve understanding of national strengths and gaps. During the workshop the delegates engaged in interactive sessions on basic risk assessment and devoted to specify the needs and roles of the 4 different streams. The participants work through a mock influenza outbreak scenario, which practically illustrates how risk assessment and communication of an emergency at the animal-human interface is more effective when there is linking of the 4 streams, collaboration, communication, and coordinated action. In 2010, Egypt was the first country where the project was successfully implemented, followed by Vietnam and Indonesia.