FAO-OIE-WHO Joint Technical Consultation on Avian Influenza at ...

DOI: 10.1111/j.1750-2659.2009.00114.xwww.influenzajournal.comOriginal Article<strong>FAO</strong>-<strong>OIE</strong>-<strong>WHO</strong> <strong>Joint</strong> <strong>Technical</strong> <strong>Consultation</strong> on AvianInfluenza at the Human-Animal Interface<strong>Joint</strong> <strong>Technical</strong> <strong>Consultation</strong> Writing Committee: Tara Anderson, Ilaria Capua, Gwenaëlle Dauphin, Ruben Donis, Ron Fouchier, ElizabethMumford, Malik Peiris, David Swayne, and Alex ThiermannContributors: Peter ben Embarek, Sylvie Briand, Ian Brown, Christianne Bruscke, Joseph Domenech, Pierre Formenty, Keiji Fukuda, KeithHamilton, Alan Hay, Lonnie King, Juan Lubroth, Gina Samaan, Les Sims, Jan Slingenbergh, Derek Smith, Gavin Smith, and Bernard VallatAcknowledgements: Support for this meeting was provided by the European Commission, US Centers for Disease Control, Canadian InternationalDevelopment Agency, EU-funded project FluTrain, the Government of Italy, and the Comune of Verona. This publication contains the collectiveviews of an international group of experts and does not necessarily represent the decisions or the stated policy of the World Health Organization.Correspondence: Elizabeth MumfordE-mail: mumforde@who.intAccepted 30 March 2009.For the past 10 years, animal health experts and human healthexperts have been gaining experience in the technical aspects ofavian influenza in mostly separate fora. More recently, in 2006, ina meeting of the small <strong>WHO</strong> Working Group on InfluenzaResearch at the Human Animal Interface (Meeting report availablefrom: http://www.who.int/csr/resources/publications/influenza/<strong>WHO</strong>_CDS_EPR_GIP_2006_3/en/index.html) in Geneva allowedinfluenza experts from the animal and public health sectors todiscuss together the most recent avian influenza research. Ad hocbilateral discussions on specific technical issues as well as formalmeetings such as the <strong>Technical</strong> Meeting on HPAI and HumanH5N1 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 theunderstanding of the topics of concern to each sector. The sectorshave also recently come together at the broad global level, andhave developed a joint strategy document for working together onzoonotic diseases (<strong>Joint</strong> strategy available from: ftp://ftp.fao.org/docrep/fao/011/ajl37e/ajl37e00.pdf). The 2008 <strong>FAO</strong>-<strong>OIE</strong>-<strong>WHO</strong><strong>Joint</strong> <strong>Technical</strong> <strong>Consultation</strong> on Avian Influenza at the HumanAnimal Interface described here was the first opportunity for alarge group of influenza experts from the animal and publichealth sectors to gather and discuss purely technical topics of jointinterest 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) evaluatethe factors affecting evolution and emergence of a pandemicinfluenza strain and identify existing monitoring systems, and (3)identify modes of transmission and exposure sources for humanzoonotic influenza infection (including discussion of specificexposure risks by affected countries). A final session was held todiscuss broadening the use of tools and systems to other emergingzoonotic diseases. The meeting was structured as short technicalpresentations with substantial time available for facilitateddiscussion, to take advantage of the vast influenza knowledge andexperience available from the invited expert participants.Particularly important was the identification of gaps in knowledgethat have not yet been filled by either sector. <strong>Technical</strong> discussionsfocused on H5N1, but included other potentially zoonotic avianand animal influenza viruses whenever possible.During the consultation, the significant threat posed by subtypesother than H5N1 was continually emphasized in a variety ofcontexts. It was stressed that epidemiological and virologicalsurveillance for these other viruses should be broadening andstrengthened. The important role of live bird markets (LBMs) inamplifying and sustaining AIVs in some countries was also arecurring topic, and the need for better understanding of the role ofLBMs in human zoonotic exposure and infection was noted. Muchis understood about the contribution of various virus mutationsand gene combinations to transmissibility, infectivity, andpathogenicity, although it was agreed that the specific constellationof gene types and mutations that would characterize a potentiallypandemic virus remains unclear.The question of why only certain humans have become infectedwith H5N1 in the face of massive exposure in some communitieswas frequently raised during discussion of human exposure risks. Itwas suggested that individual-level factors may play a role. Moreresearch is needed to address this as well as questions of mode oftransmission, behaviors associated with increased risk, virologicaland ecological aspects, and viral persistence in the environment inorder to better elucidate specific human exposure risks.It became clear that great strides have been made in recent yearsin collaboration between the animal health and public healthsectors, especially at the global level. In some countries outbreaksof H5N1 are being investigated jointly. Even greater transparency,cooperation, and information and materials exchange would allowª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29 1

<strong>FAO</strong>-<strong>OIE</strong>-<strong>WHO</strong> <strong>Joint</strong> <strong>Technical</strong> <strong>Consultation</strong> on Avian Influenza at the Human-Animal Interfacework regarding its prevention and control, and identify keyareas for future technical collaboration between the animaland public health sectors. It was emphasized that both sectorsare jointly responsible for overcoming any barriers tosuch collaboration.It was noted that the ongoing H5N1 HPAI crisis has presentedboth challenges and opportunities to the global community,and has resulted in an unprecedented response, bothon the national and international levels. International organizationssuch as <strong>FAO</strong>, <strong>OIE</strong>, and <strong>WHO</strong> have established andimproved tools and developed global strategies to respondbetter to these challenges, have supported countries andregions, and have strengthened links with each other. Membercountries have increased their internal and regional collaborations,initiating integrated national preparedness programs,joint task forces, and interministerial committees. Achievementsin AI prevention and control were noted, includingimproved disease awareness, elimination of outbreaks in mostaffected countries and control of the disease in many others,as well as better understanding of the importance of controllingpathogens at their source, of political commitment, ofstrong veterinary and public health systems, of multidisciplinaryand multisectoral involvement, of public–private partnerships,of socio-economic analysis and advocacy, and ofeffective communication among all stakeholders.Given the international realities of globalization, climatechange, and other converging factors, it was further notedthat the risk of infectious disease outbreaks will alwaysremain and that the strategies and lessons learned from AIshould serve as the foundation of systems designed to preventand control other zoonotic diseases. It was stressedthat we must invest in the improvement of general toolsand methodologies related to early detection, active andpassive surveillance, preparedness, emergency response,communication, and collaboration, including the fundingof collaborative activities to study infectious diseases at thehuman–animal interface. It was also emphasized that stepsalready taken by animal health and public health organizationsin confronting H5N1 in a collaborative and integratedmanner must be made self-sustaining, so that progress cancontinue even after short term funding flows cease or areredirected to other areas of zoonotic disease.2 Virological characteristics of influenzaviruses (Session 1)The objective of this session was to identify virologicalcharacteristics important for zoonotic and pandemic disease.Speakers presented data on the distribution and phylogenyof H5N1 and other zoonotic AIVs; the effects ofsingle mutations and virus-level factors on influenza transmissibility,infectivity, and pathogenicity in humans; receptorsand host specificity; the zoonotic potential of otherAIVs; which specific virus characteristics are of interest forpublic health; and the occurrence of these characteristics incirculating animal viruses.2.1 Epidemiology, distribution, and phylogeny ofcurrently circulating animal influenza virusesH5N1 avian influenza in poultry and humansThe currently circulating H5N1 AIV was first identified inanimals in 1996 and first caused disease in humans in1997. Since 2003, it has caused widespread animal outbreaksand associated human cases, as it has spread inpoultry and wild birds across Asia, Africa, and Europe andaffected domestic poultry, wild birds, and several mammalianspecies in more than 60 nations. The virus is nowendemic in poultry in several countries. The disease can beeffectively controlled in poultry when appropriate measuresare correctly applied, 2 but such application requires astrong veterinary infrastructure, investment of significantresources, and cooperation among all stakeholders.Introduction of H5N1 into a country may occur throughimportation of captive birds, movement of infected poultryand products, indirect mechanical transmission via contaminatedequipment and materials, and ⁄ or movement ofwild birds. It was generally agreed that in developed countries,legal movement of poultry (e.g., eggs and day oldchicks) poses negligible risk due to extensive industry regulation,but illegal movement of poultry poses great risks.While the role of wild birds has remained controversial, itwas agreed that wild bird migration has been responsiblefor some instances of long distance virus spread (e.g., intosome European countries) but that the maintenance ofvirus in poultry in many endemic regions is the result oflocal poultry trade rather than re-introduction of virusesvia wild birds. It was agreed that the exact method of specificintroductions into individual countries generallyremains undetermined.From 2003 through October, 2008, 387 human cases ofH5N1 have been confirmed in 15 countries in Asia, Africa,and Europe. Of these, 245 were fatal, giving a case fatalityrate (CFR) that ranges from 44 to 81% depending on thecountry. Human CFR is likely influenced by time to presentationat a health care facility, appropriateness of clinicalmanagement, surveillance bias in case detection, and populationcharacteristics. Most human H5N1 cases haveoccurred where the disease is entrenched in the poultrypopulations, and exposures have been to avian (rather thanhuman) virus sources, re-emphasizing the importance ofdisease control in the avian reservoir. To date, virus clades2 Guidelines are available from <strong>OIE</strong>(http://www.oie.int/eng/normes/mcode/en_sommaire.htm) and <strong>FAO</strong>(http://www.fao.org/avianflu/en/animalhealthdocs.html)ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29 3

<strong>Joint</strong> Writing Committeeidentified in human cases reflect those circulating locally inanimals.Participants discussed the likelihood that all human casesare being detected. Clearly, some human cases have likelygone unrecognized because of logistical and diagnostic constraintsand limited access to health care, as well as differencesin surveillance systems (i.e., influenza like illness ⁄ ILIsurveillance versus pneumonia surveillance), outbreakinvestigation capabilities, and political willingness to investigateand report suspects. In some cases, H5N1 infectionmay not be considered a differential diagnosis due to lackof clinical experience or because no poultry exposure wasreported. It was mentioned that the number of ‘‘official’’<strong>WHO</strong>-reported cases is likely low for the above reasons,and because samples from some true cases (especially subclinical,mild, or acutely fatal cases) may not be submittedfor laboratory confirmation at a <strong>WHO</strong>-approved laboratory.3 It is unknown what proportion of H5N1 cases maybe subclinical or mild. Some seroprevalence studies haveindicated that these cases do occur but at a low frequency(see section 4.2 exposure).The public health sector is frequently asked whether thepandemic risk is increasing or decreasing, especially giventhe decreased number of reported human H5N1 cases since2006. To date, the H5N1 virus genes are entirely of avianorigin, human cases are sporadic, and there is no evidenceof sustained human-to-human transmission. The manypossible reasons for the decreasing number of reportedhuman cases were discussed, but there was general consensusthat the animal and public health sectors must remainvigilant, because whenever AIVs (H5N1 or other subtypes)are circulating and evolving, and whenever humans arepotentially exposed, a pandemic threat will remain.Risks from other subtypes and co- circulationNumerically, the majority of human infections with AIVssince 1959 have been caused by the H5N1 subtype (due tothe current outbreak). It was noted that AIVs such asH9N2 and H7 viruses have also infected humans, and itwas agreed that it is likely that both animal and humaninfections with AIVs are underreported (for humans, particularlythose causing milder infections such as H9N2 andH7). As a variety of AIVs are both animal and publichealth threats, knowledge of where these viruses are circulatingis critical to minimizing risk. However, very little isknown about the overall circulation of AIVs globally. Toincrease data on the geographic distribution and prevalenceof other subtypes, it was discussed that H9, and possiblyadditional AI subtypes, be made <strong>OIE</strong>-notifiable for animals3 List of <strong>WHO</strong> approved laboratories for human H5 diagnosis isavailable at: http://www.who.int/csr/disease/avian_influenza/guidelines/h5_labs/en/index.html(as H5 and H7 AIVs are currently). However, it must beconsidered that a lack of surveillance mechanisms for suchviruses in many countries could penalize those exportingcountries with good surveillance systems.Whether different clades within a subtype or different AIsubtypes can outcompete each other was discussed. It wasnoted that multiple viruses within the same subtype generallydo not co-circulate in poultry. It is unclear whetherthis is due to competition between different viruses of thesame subtype or because viruses have not been introducedin poultry populations at the time when another virus ofthe same subtype is circulating. It was agreed that themechanisms underlying the generation of clade diversityand clade replacement within subtypes are not well understood.It was further suggested that the identification of multiplesubtypes in live bird markets (LBMs), some poultrypopulations, and wild birds may indicate that virus subtypescirculate in separate compartments within these populations,rather than indicating true co-circulation. It wascommented that viruses will circulate most efficiently inspecies to which they are adapted, and such adaptationcould affect host range and therefore limit spread. Theeffects of immunity among clades within a subtype andamong subtypes on circulation and co-circulation in thefield were also discussed, but these effects, including theeffects of other mechanisms on virus circulation, requirefurther investigation. It was noted that, overall, there isinsufficient data to make conclusions on co-circulation ofAIVs in poultry.2.2 Viral determinants of zoonotic infectivity andpathogenicity in humansEffects of virus mutationsThe four critical steps of the viral life cycle for influenzaviruses are (i) virus binding, fusion, and entry (mediatedby the hemagglutinin ⁄ HA protein), (ii) transcription andreplication (mediated by the PB1, PB2, PA, and NP proteins);(iii) modulation of innate immune responses (mediatedby the NS1 protein); and (iv) virus particle release(mediated by the neuraminidase ⁄ NA protein) and transmission.Changes to these proteins therefore affect theinfectivity, pathogenicity, and transmissibility of AIVs inanimals and people. Although extensive and detailed dataexist describing specific genomic mutations and proteinchanges which influence characteristics of avian and humaninfluenza viruses, it is currently not possible to predictwhat specific combination or ‘‘constellation’’ of mutationswould be required to transform an AIV into a pandemicvirus. It is also not possible to predict whether H5N1would retain its high mortality if it were to become easilytransmissible among humans.4 ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29

<strong>Joint</strong> Writing Committeedata from humans and identifying the appropriate animalmodel for addressing different research questions wasstressed (see also section 4.1, models, below).The complicated epidemiology of swine influenza waspresented. Currently, H1N1, H3N2, and H1N2 subtypesare endemic in some regions, and swine influenza viruses(SIVs) in North America differ from those in Europe.Modern SIVs are usually derived through reassortment ofhuman, avian, and swine viruses. Swine influenza viruseshave occasionally transmitted to humans, with at least 40documented cases representing all SIV subtypes. The mainrisk factor for humans is exposure to infected pigs, withlittle evidence of human-to-human transmission, thoughthe total number of human SIV cases is small given thenumber of swine workers worldwide. Many SIV infectionsin people likely go undetected; however, it is difficult todetermine seroprevalence due to cross-reactivity betweenhuman and swine viruses in the hemagglutination inhibition(HI) assay and the fact that recent human seasonalinfluenza exposure or vaccination can boost antibody titersto SIVs.3 Evolution and emergence of a pandemicvirus strain (Session 2)The objective of session 2 was to evaluate the factors affectingevolution and emergence of a pandemic strain and discussmonitoring systems. The speakers presented data onthe evolution of human pandemic viruses; the evolution ofH5N1 in birds; characteristics of H5N1 influencing mutationand reassortment; <strong>WHO</strong> and OFFLU monitoringactivities; and the role of antigenic cartography. Much discussionfocused on surveillance, thus a separate surveillancesection was added to this summary.3.1 Viral determinants and ecological conditionsaffecting mutation rate and probability ofreassortmentEmergence of a pandemic strainTo date, only influenza subtypes H1, H2, and H3 have metthe three requirements for causing human pandemics,namely, they (i) contained an HA to which the humanpopulation was immunologically naïve, (ii) were able toreplicate and cause disease in humans, and (iii) were ableto efficiently transmit between people. The role of pigs inthe past three pandemics is unclear and may have beenoverestimated and that of domestic poultry underestimated.However, no precursor avian ⁄ animal viruses to the previousH1, H2, and H3 pandemic strains are available, thuswe do not know the series of mutations that occurred duringtheir emergence and so can not learn from the past topredict the course of emergence of the next pandemic.However, it is likely that once AIVs have mutated sufficientlyto circulate widely in humans, they will no longercirculate in poultry. They may, however, transmit to andcirculate in pigs.In discussion, it was noted that the last three pandemicsubtypes arose from AIVs that had low pathogenicity inpoultry, thus the next pandemic virus may evolve fromeither a low or high pathogenicity AIV. It also may evolvefrom an influenza subtype other than H5N1. The currentconcern about H5N1 reflects primarily the potential severityof an H5N1 pandemic, because even if acquisition ofpandemicity is associated with some loss of virulence forhumans, the multifactorial virulence properties of H5N1suggest that it would likely still remain a formidable causeof human morbidity and mortality.Co-circulation of viruses was discussed again in the contextof influenza pandemics (it was previously discussed inthe Risks from other subtypes and co-circulation subsectionof section 2.1). It was suggested that more influenza circulationin human populations leads to more cross-protectionand increased overall immunity (perhaps through internalgenes) and reduces the risk for a pandemic. However, competitionamong subtypes in humans was seen as unlikely todecrease risk of emergence of a pandemic strain, as twoseasonal influenza A subtypes (H1 and H3) already co-circulatein humans on an ongoing basis.There was much discussion on how to prioritize potentiallypandemic subtypes and strains. The question of therisk of avian H1s and H3s was raised, as both avian H1and H3 viruses are circulating in avian populations, especiallyin LBMs. Current avian H3s are still cross-reactingantigenically to some extent with human seasonal strains,so that seasonal influenza infection and vaccination mayhave boosted immunity to avian H3s in people. Thus, participantsagreed that H3 may be a minimal threat. However,seasonal H1s may not be boosting immunity to avianH1 strains, as avian and human H1s are antigenically distinct.Both H1 and H3 diversity in avian populations andtheir antigenic cross-reactivity should be further assessedusing neutralization and HI test serology studies of humansera from different sub populations against avian strains toevaluate the risk from these subtypes. As H2s are notincluded in human seasonal vaccines and those born after1968 have no immunological memory to these viruses, andbecause this subtype has proven pandemic potential, it wassuggested that H2 viruses still pose a pandemic risk. H9N2viruses and H7 viruses have repeatedly infected humansand H9N2 viruses in particular are geographically widespread.Thus, they both remain pandemic candidates. Itwas suggested that organizations prepare a repository ofvaccine seed strains for a variety of different subtypes,based on viral surveillance in animal populations and zoonoticrisk.6 ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29

<strong>FAO</strong>-<strong>OIE</strong>-<strong>WHO</strong> <strong>Joint</strong> <strong>Technical</strong> <strong>Consultation</strong> on Avian Influenza at the Human-Animal InterfaceMutation and reassortmentThe original low pathogenic virus progenitor of the currentlycirculating H5N1 is thought to have emerged fromthe natural gene pool in wild ducks, then started to circulatein domestic ducks and geese, then moved to otherdomestic poultry. The current virus emerged when reassortantviruses were generated locally in domestic ducks (dueto the frequent gene flow from the wild bird reservoir),and then, in 1997, spread through domestic ducks andother poultry in farms and LBMs. Rapid HA evolutionoccurred in 1999–2000, when most clades were generated,perhaps due to circulation of virus among large, immunologicallynaïve populations of diverse species. This mayhave allowed selection of H5N1 viruses adapted to multiplehosts, accounting for the ecological success of this virusstrain.In general, populations of influenza viruses are highlydiverse, and evolve rapidly. Substitution rates are generallyhigh for all influenza viruses (including this H5N1 andhuman viruses) regardless of their host. The rates are significantlyhigher in HA and NA genes compared withinternal genes, and there is negative selection for mutationin genes other than HA and NA. Selection forces aresite-specific within the HA, generally affecting antigenicreceptor binding and glycosylation sites. Mechanisms forevolution include neutral and selection-driven mutation,reassortment, and possibly compensatory mutations thatmaintain fitness of reassortant viruses. Forces that influencethe direction of viral evolution were discussed; the diversitycurrently seen in H5 viruses in birds is probably due tospatial heterogeneity and adaptation to a variety of avianhosts.Many inherent virus characteristics predispose influenzaviruses to mutation and reassortment. The influenza RNApolymerase is not capable of proofreading the progenygenomic RNA and therefore, nucleotide substitutions occurwith high frequency. The short viral generation time furtherexpands the supply of substitution mutants availablefor selection. Genome partitioning into eight RNA moleculesallows easy reassortment, as demonstrated by frequentfield isolations of reassortant AIVs. In addition, avian–human reassortant viruses have already emerged andcurrently circulate in swine. The 16 HA and 9 NA AIVsubtypes currently known offers a broad array of hostrange, viral tropism, viral shedding, and immune evasionphenotypic characteristics that may confer selective advantagesunder a variety of pressures. Reassortant genotypesshow that certain gene linkages do seem to occur based onfunctional interactions, but these are not yet well understood.Because influenza viruses are established in multipleavian and mammalian hosts, including humans, dual infectionsare possible and can allow reassortment in a coinfectedindividual, especially species expressing both SA2,3and SA2,6 receptors in the upper airway (e.g., swine).Influenza viruses cause a mucosal infection therefore limitedimmunologic memory favors immune evasion,repeated infections, co-infection, reassortment, and mutation.These characteristics contribute to the plasticity andoverall evolutionary success of influenza viruses.Interestingly, in contrast to human and avian viruses,there was almost no antigenic change in classical SIVstrains between the time of their introduction at the beginningof the previous century until the emergence ofhuman-avian-swine triple reassortant H3N2 viruses in thelate 1990s.3.2 Monitoring for important viral changesMonitoring by <strong>WHO</strong> and OFFLUThe <strong>WHO</strong> Global Influenza Surveillance Network (GISN)was established in 1952 to monitor antigenic and geneticevolution and mutations and spread of human seasonalinfluenza virus variants, to decide on the composition ofhuman influenza virus vaccines. Resistance to antiviralpharmaceuticals is also monitored. This information isimportant for biannually recommending virus strains forhuman seasonal and H5 vaccines, and for assessing changesinfluencing the reliability of current diagnostic reagents,increasing human zoonotic or pandemic risk, changingclinical outcomes, or resulting in drug resistance. Some laboratoriesin the network are monitoring swine and avianviruses as well.The <strong>OIE</strong> ⁄ <strong>FAO</strong> Network of Expertise on Avian Influenza(OFFLU; now entitled ‘<strong>OIE</strong>/<strong>FAO</strong> Network of Expertise onAnimal Influenza’) was created in 2005 to facilitateexchange of scientific data and biological materials, offertechnical advice and expertise, collaborate with the <strong>WHO</strong>influenza network, and support AI research. Active collectionand analysis of AIV strains allows the OFFLU networkto share information and material in support of global AIprevention and control. <strong>Technical</strong> activities address gaps ininfluenza diagnostic and epidemiological knowledge.OFFLU and <strong>WHO</strong> are working to formalize communicationsand build upon current collaborations includinginformation sharing and technical projects. Activities toimprove virological and epidemiological monitoring andjoint analysis will be crucial to early detection and riskassessment of public health-relevant AIVs circulating inanimal populations.The example of Africa and the Middle East was used todemonstrate how animal sector virological surveillancemight be used to identify public health-relevant viral mutations.In these regions, H5N1 has been identified in bothpoultry and wild birds since 2006, and the sequence datafrom many isolated viruses has been made available to thescientific community. The data (which suggest multipleª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29 7

<strong>Joint</strong> Writing Committeeintroductions in some areas and ongoing circulation in others)can be used to inform specific animal sector preventionand control measures. As well, data can be used to informpublic health risk assessment. For example, mutations associatedwith previous human pandemic isolates have beenidentified in these viruses, and adamantane resistance hasalso been identified. These findings were communicated tothe international public health sector immediately afterdetermination. Improved two-way communication betweenthe animal and public health sectors regarding which specificmutations are of public health interest, and which ofthose mutations are circulating in animal populations,would optimize early detection of emerging viruses withincreased zoonotic or pandemic potential.The importance of systematic monitoring of AIVs forantiviral resistance was stressed. When current antiviralsare no longer useful against circulating strains, new antiviralsneed to be developed. Laboratories need to investigatenew resistance mutations by genotypic and phenotypicscreening, flag resistant viruses for tracking, and communicatethese findings readily between the animal and publichealth sectors.Development of a standard H5N1 nomenclature by thejoint <strong>WHO</strong> ⁄ <strong>OIE</strong> ⁄ <strong>FAO</strong> H5N1 evolution working group hasprovided both the animal and public health sectors with aphylogenetic classification system based on the HA gene. 5This system improves interpretation of sequence data fromdifferent laboratories, removes subjective geographical references,allows for expansion as new clades emerge, andprovides a basis for a more extensive system including antigenicvariation and genotyping. Expansion of the system toH9 and SIVs is being planned. It was mentioned that theunified nomenclature further strengthens pandemic preparednessactivities related to vaccine, antiviral, and diagnostictest development and stockpiling by focusing effortson the most relevant emerging viruses.5 http://www.who.int/csr/disease/avian_influenza/guidelines ⁄ nomenclature/en/index.htmlAntigenic cartographyAntigenic cartography provides a way to visualize the antigenicevolution of influenza viruses using HI assay data. Inantigenic maps, antigenically similar viruses appear closertogether, allowing visualization of antigenic changesthrough time and geographical space. The technique wasfirst applied to human H3 virus evolution, using ferretserumgenerated HI data from human seasonal viruses, andsince 2004 has been effectively used by <strong>WHO</strong> for selectionof human influenza vaccine strains. H5 antigenic cartographyis in the early stages of development for human vaccinestrain selection, but is also being used for evaluatingavian viruses for animal health sector use. Different patternsare being seen using the animal health sector HI data,which may be due to creation of HI sera in chickens(rather than ferrets) or to using sera raised with adjuvanted(rather than non-adjuvanted) antigens. It was suggestedthat, ideally, the antigenic analyses of circulating strains bythe animal health and public health sectors should be integrated.Epidemiological and virological surveillance and informationsharingIn discussion, the importance of strengthening global virologicaland epidemiological surveillance for H5N1 and otheranimal influenza viruses to ensure early detection of bothdisease and virological changes was strongly emphasized.It was agreed that both the animal and public heath sectorswould benefit from improved knowledge of the propertiesof H5N1 (or other AIVs) that are circulating inanimals to adequately assess which strains should be recommendedfor veterinary and human vaccines and toupdate diagnostic reagents according to genetic and antigenicevolution. Having a full and broad picture of the distributionand prevalence of viruses and disease globallywould allow better assessments of animal and public healthrisks, as well as the identification of mutations of publichealth significance.Surveillance in poultry and wild birds in Europe,North America, Hong Kong, and other selected locationsis intensive, but in many areas of AI risk, surveillance isweak or lacking and needs to be supported andimproved in a sustainable way. It was noted that inEurope, existing surveillance has led to early detection ofH5N1 on several occasions. Currently, the extensiveEuropean data is maintained in the DG-SANCO database,6 and partly (for wild bird isolates) in theEU-funded research project New-Flubird. 7 A commonglobal platform and linking of surveillance systems wouldbe ideal, with one constraint being the differences intypes of surveillance among countries. Improved communicationbetween existing platforms would already be apositive step forward.It was recognized that when effective passive and activesurveillance leads to early disease detection, then diseasecontrol is improved. However, effective animal sector surveillancerequires a complete and functional veterinaryinfrastructure and supporting diagnostic laboratory capacity.As well, effective use of resources requires appropriatetargeting (e.g., by species, sector) and implementationaccording to differing disease patterns (e.g., for sporadicversus endemic disease situations). It was recognized that6 DG Sanco data available at http://ec.europa.eu/food/animal/diseases/controlmeasures/avian/eu_resp_surveillance_en.htm7 New Flubird data available at http: ⁄⁄www.new-flubird.eu ⁄8 ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29

<strong>FAO</strong>-<strong>OIE</strong>-<strong>WHO</strong> <strong>Joint</strong> <strong>Technical</strong> <strong>Consultation</strong> on Avian Influenza at the Human-Animal Interfacesurveillance may not be implemented properly, even if thesystem is appropriately written in the national legislation.Surveillance systems in humans should also vary by the diseasesituation. For example, where AIVs are endemic andsporadic human cases are occurring, it was suggested thatit would be most efficient to focus on the early identificationof clusters of human cases.The social aspects of surveillance were discussed, forexample that passive surveillance fails when people feelthreatened by the consequences or when tools and systemsare impractical for the targeted community (e.g., broadcase definitions for AI in areas where poultry deaths arecommon), and thus, that surveillance should be community-basedand customized for each setting. The use ofcommunity-level incentives and disincentives was discussed,and it was agreed that the differences between what may byconsidered incentives and disincentives by the key playersin the human and animal health sectors may not be appreciated.It was agreed that overall, surveillance in human andanimal populations should be better coordinated. Coordinationis working well in Indonesia, where there is activehuman surveillance in areas of animal outbreaks and viceversa. This has, for example, reduced average time tohuman antiviral treatment from 4 to 2 days. It was suggestedthat it would be more sustainable to coordinate AIsurveillance with surveillance for other zoonotic diseases.It was agreed that any coordination requires good communicationbetween the animal and public health sectors,which may vary on the local level and may be influencedpolitically.There was a generalized call for <strong>OIE</strong>, <strong>FAO</strong>, and <strong>WHO</strong>to formalize the sharing of virus samples and associatedinformation for all AIVs. The importance of whole genomesequencing of an appropriate virus subset and ensuringtimely availability of information was also stressed.The problem of information sharing with and amongcountries who may have technological difficulties in ‘‘connecting’’was discussed (as these are often the countries atrisk). It was noted that timely information sharing canalso allow individual countries to decrease their risk ofexposure.4 Human transmission risks and exposuresource (Session 3)The objective of session three was to identify likely modesof transmission and exposure sources for zoonotic infectionwith AIVs. During this session, speakers presented data onpossible modes of seasonal and zoonotic influenza transmission;sources of exposure for human cases of H5N1(including the potential roles of exposure to poultry productsand by-products, of culturally relevant poultry ⁄ humaninteractions, of poultry management systems, of LBMs andof contaminated environments); food safety issues; andevidence to explain the low incidence of H5N1 cases inhumans. The country representatives briefly outlined whatthey considered the successes and challenges of theirnational H5N1 experience, which are also summarizedhere.4.1 Modes of transmission for human infectionwith avian influenza virusesModes of transmissionThe modes of human seasonal influenza transmission havenot been completely elucidated. People shed influenza virusfrom the respiratory tract, and potential modes of transmissioninclude contact spread, aerosol spread, and dropletexposure. Influenza virus survives on hands for 5 minutesbut on other surfaces for 12–48 hours. It was suggestedthat hand hygiene is important to decreasing risk. Viabilityof virus in aerosols depends on initial concentration, temperature,and humidity. Inhalable particles account for

<strong>Joint</strong> Writing CommitteeFerret studies suggest that contact and droplet transmissionof H5N1 and other AIVs to mammals are generallyinefficient, although H5N1 has been transmitted to ferretshoused in a room where asymptomatic infected chickenswere slaughtered. Overall, studies show that transmission(as well as pathogenicity and virulence) depend not onlyon animal host species but also on virus subtype and virusstrain, dose, and exposure route.4.2 Exposure risk for human infection with avianinfluenza virusesExposure data on human casesSpecific exposure risks for AI H5N1 infection in humansare not well understood, and likely differ greatly by country.Along with direct contact with sick or infected poultry,indirect contact with poultry, environmental contamination,and contact with healthy infected poultry are alsolikely to be risks. Most humans infected to date were notin ‘‘traditional’’ occupational risk groups, while subpopulationssuch as children and housewives seem to be at greaterrisk in some countries. As well, the risks posed by differenttypes of poultry, and household animals such as cats, arenot yet understood. It was agreed that it is not currentlypossible to globally disentangle data and determine specificrisk activities, and that epidemiological data collection andanalysis should be improved. It was suggested that ecologicalaspects, the species of birds or other animals, the vaccinationstatus of domestic poultry, and the type of poultryproduction system 8 associated with human cases shouldalso be recorded and considered in analysis. It was stressedthat, although it is clear that control of AI in poultry is themost important step in reducing zoonotic risk and pandemicthreat, understanding specific zoonotic risks isimportant to enable development of practical risk reductionmeasures for humans.Representatives from affected countries reported thathuman cases are usually located in areas of poultry cases, andthat exposure history has included household poultry raising(especially poultry living inside the house), poor poultry vaccinationcoverage, exposure to sick or dead poultry, lack ofan indoor water source, visiting LBMs, having an underlyingmedical condition, and in some cases occupational poultryexposure. In many cases, a specific exposure was inconclusiveor unknown despite in-depth investigation.The question of why human H5N1 cases seem to beoccurring only in certain countries and communities wasdiscussed. It was agreed that this reflects primarily the presenceof infected poultry and the amount of virus present,8 Poultry production sectors described in: <strong>FAO</strong> Recommendations onthe Prevention, Control and Eradication of Highly Pathogenic AvianInfluenza in Asia, Sept. 2004, available at http://www.fao.org/docs/eims/upload/165186/<strong>FAO</strong>recommendationsonHPAI.pdfbut might also reflect the surveillance system or other asyet unidentified local ecologic, cultural, genetic, virological,or management factors.Most studies have indicated a very low seroprevalence ofantibodies to AIVs among people in high risk occupations,such as poultry cullers and LBM workers, in affected countries.The many difficulties with the serological tests werementioned, and it was noted that more sensitive and discriminatingsubtype-specific tests need to be developed. Itwas agreed that more seroprevalence studies for AIVs inhumans need to be done and the results from completedstudies need to be shared with the wider scientific communityin a more timely manner. It was noted that solutionsmust be found to improve timely publishing and sharingof study results with the animal and public health communities,to improve the availability of seroprevalence, casecontrol and attack rate data for zoonotic AIVs.Consumption and inactivationAvian influenza is not generally considered a food safetyissue, as complete cooking inactivates the virus and the riskof infection from foods cross contaminated with virus isnegligible.Virus is contained in meat, viscera, blood and eggs frompoultry infected with highly pathogenic AIVs. Consumptionstudies of raw infected chicken meat in ferret and pigmodels suggest that H5N1 viruses initiate infection via thetonsil or pharynx with spread to the upper and lower respiratorytract. However, experimental data in pigs and ferretssuggest that foodborne infection by consumption of rawinfected meat would require higher viral doses than wouldinfection through respiratory tract exposure. Thus, riskreduction measures for humans include pasteurization orthorough cooking of meat and eggs, basic kitchen hygiene,and consuming products derived from vaccinated poultry(as poultry vaccination prevents viremia and localization ofvirus in muscle tissue).Freezing at )70°C preserves the virus, while inactivationat )20°C is inconsistent and unpredictable, and refrigeration(4°C) allows slow virus inactivation in meat due todecreasing pH and enzymatic action. Infectious virus hasbeen detected in frozen raw poultry stored in a householdfreezer.Risk from live bird markets and virus in the environmentMultiple AIV subtypes, including H5N1, H9N2 and H6N1,have been obtained from birds in LBMs in Asia. Interestingly,H7 subtype viruses are not commonly found inLBMs. Isolation rates and virus subtypes differ by speciesof poultry and location, with more frequent virus recoveryfrom aquatic poultry (ducks and geese) than chickens, andhigher isolation rates during the winter. Studies show thatLBMs can maintain, amplify, and allow dissemination of10 ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29

<strong>FAO</strong>-<strong>OIE</strong>-<strong>WHO</strong> <strong>Joint</strong> <strong>Technical</strong> <strong>Consultation</strong> on Avian Influenza at the Human-Animal InterfaceAIVs to farms and are a source for human infection, andare therefore a useful site for targeted surveillance. It wasnoted that, in an affected country, virus concentration isgenerally low at the farm or household level, increases atwholesale markets, and is further amplified and sustainedat LBMs from where virus may be disseminated back tofarms and households.Data from different countries was presented. Risk factorsfor LBM contamination included housing of unsold poultryovernight, presence of Muscovy ducks, presence of a largeduck population, and slaughtering in multipurpose areasand in stalls. Human risk at LBMs was associated with thepresence of restaurants and food stalls in markets, havingfamily members in the market, and the use of traditionalslaughtering processes. Viral burden in LBMs was shown tobe decreased by implementing a rest day, removal of particularspecies (e.g., quail), improving market hygiene, andnot allowing live poultry to remain overnight. However,LBMs must be specifically assessed as they vary greatlyamong and within countries and therefore do not all havethe same risk factors.It was discussed that in many countries LBMs play animportant role in people’s cultural and economic lives, andthus appropriate and culturally sensitive ways to decreaseassociated AI risks must be sought. Specific targeted assessmentsof LBMs would allow understanding of the environmentalcontamination of different areas within LBMs andamong LBMs in different settings, communities, and countries.Having decisive political support would allow the animaland public health sectors to develop appropriatestrategies, regulatory frameworks and guidance. Measuresto decrease risks could then be integrated into national systemsto improve the general hygiene of LBMs and reducerisks for AIV and other animal and zoonotic pathogens.Contamination of environments can be heavy duringpoultry outbreaks, with virus being isolated from households,wet feces, pond water, mud under animal cages, soil(including that beneath houses on stilts), in poultry rangingplaces, and on the feathers of dead poultry. In environments,AIVs survive in water, in feces, and on surfaces.Temperature, porosity of the surface and water salinity allaffect survival time. More recent H5N1 viruses have beenshown to survive longer in chicken feces than those virusesfrom 1997, but studies suggest this is due to longer decaytimes because of higher virus titers within feces and is notan intrinsic resistance of the virus strains to inactivation.Cultural practices associated with riskSome key cultural practices may increase risk to humans.For example, traditional poultry production and peoplesharing their living areas with poultry put humans in closeand prolonged contact with infected animals and contaminatedenvironments, and cock fighting involves direct contactwith avian blood and respiratory secretions. Oftenthese practices are linked with economics (household poultryturning household waste into inexpensive protein, duckfarmers paying rice farmers to allow ducks to feed on leftover rice); practicality (food stalls and family membershelping in LBMs; eggs and poultry available in householdor village); necessity (LBM and household slaughterrequired when no available cold chain; workers staying inpoultry house to protect poultry); cultures and beliefs(entertainment and prestige of cock fighting; believing inbad luck or karma as cause of outbreaks). It was suggestedthat extensive public awareness campaigns and communicationmay improve public knowledge but not changepractices due to the considerations described above. It wasemphasized that cultural issues are complicated and taketime to change, requiring an integrated package of interventions,education, and work within the community.Poultry systems and management practices associated withriskMuch more is known about risk of spread of the virus inanimal populations than is known about human zoonoticrisk. Because exposure of humans mainly occurs directly orindirectly through infected poultry, it is important tounderstand the risk posed by different poultry populations.As well, poultry raising and marketing systems differamong countries and therefore pose different risks. In general,risk of spread among birds is increased in countriesthat have large poultry populations, and that produce avariety of avian species in all four <strong>FAO</strong>-defined poultry sectors,8 especially when much of the production is in smallscale farms or in households. The H5N1 endemic countriestend to have large domestic waterfowl and wild bird populations,although the limited available field data on the roleof wild birds in virus spread is difficult to interpret in thecontext of reservoirs and infection dynamics. The diseaseoften has seasonal occurrence, with outbreaks generallyoccurring in the winter, due to many factors including riceharvests and holiday festivals as well as weather.Risk of incursion onto a farm is determined by theamount of outside contact and whether it involves possiblyinfected or contaminated material, the local level of infection,and biosecurity measures taken. It was noted thateven in endemic countries most poultry and locations willnot be infected or contaminated (with the exception ofsome LBMs), though each flock will have its own risk profilebased on multiple factors, especially biosecurity level.Increasing human populations, food prices, and concernsabout ethical rearing could lead to more poultry raisedoutdoors, which would increase risk for exposure and virusspread.There was some discussion on the effects of naturallyacquired influenza immunity on infection dynamics inª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29 11

<strong>Joint</strong> Writing Committeepoultry and wild birds. Some birds probably have immunityto a variety of AIV strains, and this may influencewhat subtypes are seen in the populations season to season.Public health aspects of poultry vaccinationThe topic of poultry vaccination in was raised severaltimes during the meeting, and the national vaccinationprograms of China, Egypt, Indonesia, and Viet Nam weredescribed by representatives of the respective Ministries ofAgriculture. Countries consider vaccination of poultryimportant for protecting public health as well as animalhealth. The vaccination coverage varies among countries,among locations in a country, and among poultry sectorsand avian species. Constraints to effective implementationmay include inability to achieve adequate coverage oflarge, dispersed poultry populations, insufficient manpower,inadequate post-vaccination monitoring, use ofdifferent vaccines, variable vaccine quality and lack ofquality assurance, as well as weak regulatory support andinsufficient infrastructure of veterinary services in somecases. Strategically targeting vaccination by species or sectormay increase efficiency of national programs. It wasrecognized that comprehensive recommendations for effectivepoultry vaccination are already available from <strong>OIE</strong>and <strong>FAO</strong>. 9The possibility of harmonizing the selection of virusstrains for avian and human vaccines was raised, as theupdating processes are currently different. However, theneeds, processes, and vaccine development systems are alsodifferent. Given the importance of poultry vaccination forthe protection of animal and public health, the need forcontinued vaccine research was stressed, including workingtowards developing a poultry vaccination platform thatelicits neutralizing antibody, works in multiple species, canbe given orally or is otherwise easy to administer, and providesgood duration of protection. Monitoring of AIVstrains in the field, especially in the commercial productionsectors, is also important.Other variables affecting risk of human diseaseDiscussions of human risk variables invariably raises thequestion of why the number of human cases is relativelysmall given the massive potential exposure of humans inareas where H5N1 is circulating. It was suggested that thereare likely other inherent virus-related or individual hostrelatedvariables that influence transmission to and infectionof humans.Virus-specific factors (described in depth in previous sections)do not seem to explain the observed pattern of9 HPAI Manual chapter, HPAI code chapter, output from Vaccinationmeeting 2007 (http://www.oie.int/eng/info_ev/Other%20Files/A_Guidelines%20on%20AI%20vaccination.pdf)human infections. Differences in virus dose and exposureintensity also do not explain the infection pattern, becausethere are very few cases in cullers and others potentiallyexposed to very large virus doses and 25% of negative controlsreport high levels of exposure to poultry, while 25–30% of H5N1 cases do not report any poultry exposure.The mode of transmission also does not explain theobserved epidemiology as case control studies have notidentified unusual exposures (like swimming in rivers andlakes, or eating raw duck blood) as explanations for themajority of cases. It was therefore suggested that increasedrisk must be associated with host factors, including immunityor genetic or phenotypic susceptibility. Evidence forsome clustering of cases among blood relatives supportsthe potential role of genetic susceptibility, although sharedenvironmental exposures must also be considered wheninvestigating human clusters.How to evaluate these factors was discussed. It wasagreed that a more full assessment of the potential individualvariables (e.g., analyses of ILI ⁄ health history, coinfectionwith other influenza viruses, assessment of antibodyand cell mediated immunity (CMI), glycan arraysfor receptors, genetic evaluation, epidemiological studiesof families where some individuals are highly exposedand some are not), as well as more extensive and consistentdata on exposures as described above (e.g., behavioralfactors, seasonality, climate, links with poultryoutbreaks, gender, age, occupation; behaviors ⁄ activitiesincluding level of skill, species of animals present, virusclade, and cultural aspects) would provide not only cluesto the true exposure risks but practical information formore effective surveillance and monitoring and fordevelopment of more effective control and preventionstrategies.National-level successes and challenges:Invited representatives of selected Ministries of Health andMinistries of Agriculture identified their national successesand challenges regarding H5N1 at the human-poultryinterface, including:Successes:• Increased political commitment and coordination withlocal authorities• Increased cooperation between animal health and publichealth sectors• Increased collaboration with international reference laboratories,and with international partners (<strong>FAO</strong> ⁄ <strong>OIE</strong> ⁄<strong>WHO</strong>) and funding agencies• Increased public and professional awareness and availabilityof community-based information, education, andcommunication activities• Vaccination campaigns preventing disease spread amongpoultry and reducing viral load12 ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29

<strong>FAO</strong>-<strong>OIE</strong>-<strong>WHO</strong> <strong>Joint</strong> <strong>Technical</strong> <strong>Consultation</strong> on Avian Influenza at the Human-Animal Interface• Implementation of government compensation promotingrapid disease reporting and transparency• Upgraded national laboratory diagnostic capacity andinfrastructureChallenges:• Inadequate virological and epidemiological surveillancein domestic poultry including waterfowl, and in wildbirds• Understanding the linkage between poultry outbreaksand disease in humans, including understanding occurrenceof human cases where no cases were reported inpoultry• Risks from extensive backyard, household, and rooftoppoultry production• Risks from LBMs• Large populations of poultry to vaccinate and risks posedby unvaccinated poultry in LBMs and household flocks• Cultural practices such as cock fighting• Ineffective (or unfunded) compensation programs forculled poultry during outbreak control• Ongoing tensions between levels of governments andamong sectors5 Broadening the use of tools andsystems (Session 5)During this session speakers briefly discussed emerginginfectious diseases (EIDs) at the human–animal interface,tools and methods used to evaluate emergence of otherzoonotic diseases, and the <strong>OIE</strong> ⁄ <strong>FAO</strong> ⁄ <strong>WHO</strong> Global EarlyWarning System for transboundary animal diseases(GLEWS). There was recognition that some tools and systemswere developed for, or strengthened by, the H5N1 situationover the past 10 years, but that these systems havealso been used effectively to address many other zoonoticor emerging diseases.Presenters emphasized that EIDs are the ‘‘new reality’’ asup to 34 new EIDs are expected worldwide by 2015, andnoted that 61% of EIDs are zoonoses. Speakers reviewed thefactors influencing emergence including genetic, biological,physical, environmental, ecological, social, political, and economicfactors, as well as the role of animal and public healthsystems. Changes in host–pathogen ecology were consideredthe most important single driver for emergence. The convergenceof these human, animal, and environmental health factorsrequires working collaboratively, in a multidisciplinaryway, and at local, national, and global levels to attain optimalhealth of humans, animals, and the environment. In discussion,it became clear that this concept was not new, howeverthe roles and strategies of all the players globally are not fullyunderstood nor effectively integrated.‘‘Wicked problems’’ (those that have no solution throughtraditional processes) were discussed in the context of EIDs,and it was noted that managing these problems requireslinking together separate problem-solving activities into integratedstrategies and systems. For example, all countries havea stake in everyone else’s disease surveillance, however it isnot necessarily in a country’s best interest to share surveillanceinformation with their neighbors or the internationalcommunity. Managing such dilemmas requires workingacross disciplines, professions, and animal and public healthcommunities and factoring in social, economical, and politicalforces, as well as ensuring political will, prioritizingresearch to support evidence-based policies and decisions,adding value gained from avian influenza H5N1 experienceby applying it to other zoonoses, determining the potentialapplication of ‘‘big science’’ (e.g., global technology and bioinformatics)and creating concurrent planning scenarios ofimproving what exists and creating what doesn’t.The animal and public health sectors have vast experiencein addressing EIDs, and recognize the importance of rapidresponse, global collaboration, and multidisciplinary teams.In the past, these activities have consistently been done separately,but now the continuum between animal and humanpathogens, the need for integrated (meaning linked not necessarilysingle) strategies, and the need for improved animaland public health infrastructures is increasingly apparent.Health is now recognized as an outcome shaped by a broadrange of social, economic, natural, ecological and politicalenvironments that form an ever-changing dynamic. Thus,new ways of working together need to be identified thatreflect this reality. Our work on avian influenza H5N1 hasgiven us valuable experience in how to effectively do riskcommunication and messaging, and how to evaluate socialand cultural determinants of disease; however, we must buildon these experiences and become even better as we appreciatethe need to incorporate the social sciences into our strategiesto confront new emerging zoonoses.Today’s technologies can help to better detect, manage,and contain the international spread of EIDs. There havebeen great improvements in global tools and systems, suchas surveillance and forecasting of emerging diseases throughintersectoral (animal, human, and environment) collaborationsuch as GLEWS, formal collaboration with wildlife diseaseexperts, support of EID vectorborne network, and<strong>WHO</strong> global outbreak alert and response network(GOARN), global public health information network(GPHIN), and connection of different laboratory networks.Technology and successful collaborations have allowed riskmapping, forecasting and early detection of EID events[e.g., Rift valley fever (RVF) and Ebola]. Working togetheron each of the steps from forecasting through response atthe country-level builds trust, and therefore facilitates amore efficient and coordinated response and improved preventionand control. It was noted that standardization ofrisk analysis and forecasting needs to be addressed, includ-ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29 13

<strong>Joint</strong> Writing Committeeing identifying standard procedures, methodologies, and ⁄ orplatforms and training personnel in their use. It was furtheremphasized that animal and public health authoritiesshould have a common and coordinated strategy to forecast,detect, and control EID outbreaks, as well as commonStandard operating procedure (SOPs) for district surveillanceofficers and veterinarians to control selected EIDsusing an <strong>FAO</strong> ⁄ <strong>OIE</strong> ⁄ <strong>WHO</strong> agreed strategy, as well as preparednessand occupational health guidelines.Issues around early detection of EIDs were discussed.The current and future activities of the GLEWS early warningsystem were reviewed, and include bringing togetheranimal and public health systems to share information onzoonotic disease outbreaks, conduct epidemiological andrisk analyses, and to deliver early warning messages to theinternational community. The goal is to develop holisticapproaches to pathogen and disease understanding whichinclude ecological and socioeconomic factors, pursue outbreakprobability modeling, and examine disease presenceor absence in relation to a variety of external factors. It isalso planned to expand the use of this system to sharemany kinds of data (e.g., laboratory diagnostic capacities ofcountries or regions, veterinary infrastructure, and trainingavailable) and to provide a common platform for othercollaborative work (such as identifying risk factors forendemic diseases). It was suggested that international agenciescould place interns in countries to conduct GLEWSsurveillance and build internal commitment for programs.It was noted that to ensure early detection, surveillanceneeds to be improved in wildlife, especially in situationswhere wildlife come into contact with humans (e.g., via thepet trade, bush-meat or live game markets), as well as indomestic livestock. However, experience with the <strong>WHO</strong>event management system has shown that, with increasedsurveillance, it becomes challenging to determine whichidentified events require a response. Work is ongoing toboost the real signals against the background, look at morereliable sources of information, and develop a gold standardfor a positive predictive value of information. It was mentionedthat another large area of work is to link other toolsfor information gathering and analysis (e.g., Google). Using‘‘big science’’ technologies to solve the surveillance questionwas discussed, such as using deep amplicon sequencing topick up subclinical pathogens. Broad geographical samplingwould also decrease concerns about transparency by ‘‘eveningout the playing field.’’ It was mentioned that, in 2008, wehave the technology to not be surprised by every new outbreak,and should be applying it more appropriately.6 General conclusionsThe world faces continued threats from avian influenzaand other zoonotic diseases, which can only be effectivelyminimized through new strategies of collaboration focusedat the human–animal interface.Collaboration and coordinationMuch has been learned about controlling avian influenza inanimals and people, and the world is better prepared to confrontinfluenza threats. However, important gaps remainboth in scientific knowledge (e.g., modes of transmission,occupational risk, baseline exposure rates, role of live birdmarkets) and in the rational and sustainable implementationof control measures. The animal and public health sectorsneed to coordinate and complement their research as well astheir disease control and prevention activities in a more formalizedmanner and to the fullest extent possible.Surveillance and use of dataThe circulation and continuous evolution of potentiallyzoonotic animal influenza viruses in birds, humans, andother hosts poses an ongoing public and animal healththreat. Along with H5N1, other animal influenza virusesalso have or could develop the characteristics necessary toinfect humans and potentially become a pandemic strain.The prevalence and distribution of all animal influenzaviruses have been insufficiently characterized on a globallevel, and is likely to be underestimated. Some systems andtools for virological and epidemiological surveillance andmonitoring of animal influenza viruses in animal andhuman populations exist. However, influenza surveillanceneeds to be expanded to integrate other relevant privateand public institutions so that circulation, evolution,dynamics, and risks can be fully understood and analyzed,sustainably and in real time.Transdisciplinary research on zoonotic riskControlling avian influenza in poultry is the primarymethod to reduce human risk from zoonotic infections.Understanding the measures aimed at preventing and controllingHPAI H5N1 in poultry has improved greatly overthe past 4 years. In many countries measures have beeneffectively applied, decreasing the number of human casesbeing reported. However, the specific human activities andbehaviors, as well as host, virus and ecologic and countrylevelfactors (e.g., the role of live bird markets), associatedwith human zoonotic influenza have not been identifiedsufficiently to support strategies to eliminate public healthrisk. Further data collection, analysis, and research bothwithin and between the human and animal health sectorsare critical to fully understand the scientific basis for zoonoticrisk.Sharing of information and technical toolsThere has been a dramatic improvement over the past fewyears in both the collaboration between the animal and14 ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29

<strong>FAO</strong>-<strong>OIE</strong>-<strong>WHO</strong> <strong>Joint</strong> <strong>Technical</strong> <strong>Consultation</strong> on Avian Influenza at the Human-Animal Interfacepublic health sectors and the availability of technical toolsfor monitoring and understanding influenza (e.g., antigeniccartography, shared databases). However, mechanisms forfacilitating broad and timely access to information andtools are not adequately developed to ensure early detectionof, rapid assessment of, and response to threats from influenzaviruses. The implementation of more effective preventionand control tools and strategies can only be achievedthrough a more effective and timely exchange of genetic,antigenic, and epidemiological data on these viruses.Moving towards sustainabilityEnsuring sustainability is crucial to maintaining infrastructureand capacity development and development of toolsand systems for assessment and response. One way fortools and systems built or planned to address AI to becomemore sustainable would be to make them applicable for abroader array of existing and emerging diseases.Addressing other emerging zoonosesIt is clear that avian influenza H5N1 is just one of a numberof emerging zoonoses, and that experience with H5N1at the human–animal interface can be enormously instructiveand insightful in meeting the challenges of futureemerging diseases. The development of effective best practices,tools, and systems to control and prevent H5N1 canbe leveraged and applied to other zoonoses.Conflict of interestThe authors and contributors have not declared any conflictsof interest.ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29 15

<strong>Joint</strong> Writing CommitteeAppendix A: Recommended short tomedium term actionsCollaboration and coordination1. Promote and strengthen ongoing collaboration (e.g.,joint evolution working group, technical exchange ofscientific information, national coordination of sectors)and identify novel areas for additional technical collaboration.2. Identify new strategic partners to better address gaps inknowledge at the human–animal interface.Surveillance and use of data1. Broaden the timely collection of both HPAI and LPAIinfluenza viruses and associated epidemiological data toensure that the full scope of hosts, ecologies, and geographicareas are represented (e.g., including environmentalmonitoring in markets, rice paddies, households,and other areas of increased risk).2. Expand partnerships with the private sector andimprove capacity where necessary to ensure adequateinfluenza surveillance.3. Support research on diagnostic tests for influenza inpoultry and humans aimed at improving consistency,sensitivity, rapidity, and cost-effectiveness.4. Use virological surveillance data to inform continual reassessmentof diagnostic reagents and vaccines, monitorvirus evolution and antiviral resistance, and assess risks ofemergence of potential zoonotic and pandemic strains.Transdisciplinary research on zoonotic risk1. Increase and improve data on zoonotic influenza inhumans through standardized data collection, and additionalcase control and serological studies in the field.2. Develop tools and conduct integrated analysis of zoonoticrisks from animal influenza viruses, and translatetechnical knowledge gained into practical strategies andrecommendations at the interface.3. Determine the public health risks from live poultry marketsand assess the impact of interventions at differentlevels of the market chain.4. Improve understanding of the pathogenesis and modesof intra- and inter- species transmission of zoonoticinfluenza viruses through more detailed studies inhumans and better animal models, including improvingunderstanding of the tissue distributions of virus receptorsand their role as barriers to transmission, and useknowledge to enhance animal and public health riskmitigation strategies.5. Improve understanding of the factors that drive the evolutionof animal influenza viruses in poultry, otherbirds, and mammals.6. Promote full genome sequencing of isolates and ensurecontinual updating of information on all relevant influenzavirus mutations and reassortments.7. Determine the zoonotic potential of swine and otheranimal influenza viruses of various subtypes.8. Develop and validate more sensitive and specific testsfor detecting antibodies to avian influenza viruses inavian and non-avian species including humans.9. Incorporate experts in social sciences and communicationto ensure that interventions and recommendationsto decrease public health risks take into account culturaland socioeconomic aspects that will improve theefficacy of implementation.10. Monitor the impact on public health of measuresto reduce infections in poultry, such as poultry vaccination,and strive to continually improve such measures.Sharing of technical tools and information1. Continue to strengthen and improve existing mechanismsand systems for information collection, sharing,and analysis maintained by <strong>OIE</strong> and <strong>FAO</strong> (includingOFFLU) and <strong>WHO</strong> (such as GLEWS) and facilitateand promote interagency collaboration wherever possible.2. Establish real-time communication systems towidely share and discuss technical information amongall global, regional, and national partners and stakeholders.3. Find innovative solutions to improve technical collaborationand effective information and material sharing.Actions for broadening1. Promote a more holistic and collaborative approach toimprove both human and animal health and build moreeffective teams and partnerships, especially throughstrengthening of existing institutions.2. Promote study of the ecology of emerging zoonoses andconstruct new interventions and prevention strategiesbased on scientific understanding of the effects of ecologyon diseases at the interface.3. Encourage the further expansion and refinement of theGLEWS system and the GLEWS platform for sharinginformation among the organizations (e.g., considerincluding laboratory and outbreak investigation teamtraining and developing internships).4. Move towards coordinated development of diagnosticsand reagents for use across animal and publichealth laboratories wherever appropriate, to ensureimproved standardization, comparability, and accuracyof results.16 ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29

<strong>FAO</strong>-<strong>OIE</strong>-<strong>WHO</strong> <strong>Joint</strong> <strong>Technical</strong> <strong>Consultation</strong> on Avian Influenza at the Human-Animal Interface5. Recognizing the fact that many infectious diseases ofhumans have emerged from previously unrecognizedpathogens in wildlife, leverage the concept of ‘‘Big Science’’by using novel approaches to pathogen discovery,the use of new informatics tools, and open sharingof information.6. Devise and apply tools to monitor the efficacy of implementedstrategies towards a better response capabilityfor emerging diseases of importance.ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29 17

<strong>Joint</strong> Writing CommitteeAppendix B: Gaps at the human–animalinterfaceSurveillance1. Enhanced and sustainable epidemiological and virologicalsurveillance in animals and humans (withimproved scope and quality of data collected) forH5N1, H9N2, and H7 viruses as well as otherpotentially zoonotic animal influenza viruses, includingswine influenza viruses (leading to closer estimatesof the global prevalence and distribution of theseviruses).2. Solution to achieve better reporting of potentially zoonoticnon-H5 and H7 subtypes.3. Enhanced surveillance specifically among ducks, othersilent reservoirs of avian influenza, and wild birds toevaluate prevalence and persistence.4. Improved surveillance in human populations potentiallyexposed to animal influenza viruses, including sero-surveillanceand serological studies.5. Increased support of virological surveillance, especiallythe use of screening tests, with confirmatory testing andmore frequent and representative genetic characterization,antigenic characterization, and full genomesequencing of selected strains.Virology1. Phylogenetic information on other potentially zoonoticinfluenza subtypes.2. Understanding the contribution of avian virus reassortmentto host range expansion, virulence, and transmissibility.3. Understanding determinants of fitness, and of the fitnessloss ⁄ gain by reassortment among influenza viruses.4. Efficient and reliable methods for virus isolation fromenvironmental samples, including air.5. Understanding of factors affecting cross-protection ofpoultry and human vaccines.6. Understanding of the effect of vaccination on influenzavirus evolution.Epidemiology1. Expanded and consistent capture of epidemiological dataon human zoonotic influenza infections (including useof standard data collection tools and standard definitions).2. Estimate of the baseline level of potential risk variablesfor populations in general.3. Estimate of the true incidence and numbers exposedfor H5N1 and other potentially zoonotic influenza subtypesin humans (e.g., by systematic review and metaanalysis).4. Valid baseline data, including serosurvey data, forexposure to H5N1 and other potentially zoonoticinfluenza subtypes, including serological investigationof people living near poultry outbreaks, working inhigh risk populations, and in contact with confirmedhuman cases.5. Determination of risk factors for human zoonotic influenzainfections within and among countries, includingvirus, host, and ecological factors (including understandingof risk associated with indirect contact withpoultry and contaminated environments and posed bydifferent avian and mammalian species).6. Further investigations of the link between poultry outbreaksand human cases (especially when no apparentlink exists), including joint investigations and analysisof national ⁄ community level factors contributing torisk.7. Understanding which production and slaughter practicesor procedures have increased risk for humanexposure and infection.8. Analysis of role of case definition (e.g., contact withsick and poultry) in identification of human cases.9. Comparative analysis of the epidemiology of differentzoonotic influenza viruses in humans.10. Expanded knowledge of host range of animal influenzasubtypes and strains.11. Understanding of competition among and within circulatingvirus subtypes.12. Understanding of viral persistence in the environment.13. Availability of rationales for developing practical publichealth measures and messages to optimize impact.Live bird markets1. Understanding of virus prevalence and transmission inLBMs, including impact of market interventions onvirus circulation.2. Understanding LBMs as a risk factor for human disease.Virus transmission ⁄ infectivity ⁄ pathogenesis1. Understanding of receptor structural diversity, distribution,and binding, including virus, host species and individualbinding differences, using new technologies suchas glycan arrays and virus histochemistry, and includinghypothesis testing using virus infectivity studies in variousspecies.2. Understanding of the HA mutations required to changethe binding affinity of H5N1 and other potentially zoonoticanimal influenza viruses to allow the virus to passmore easily to ⁄ among humans, and of selection forcesaffecting binding affinity.3. Understanding of the species barrier, including determinantsof species barriers strength for different viruses.18 ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29

<strong>FAO</strong>-<strong>OIE</strong>-<strong>WHO</strong> <strong>Joint</strong> <strong>Technical</strong> <strong>Consultation</strong> on Avian Influenza at the Human-Animal Interface4. Understanding the transmission ⁄ infectivity ⁄ pathogenesisof human seasonal and potentially zoonotic animalinfluenza viruses in various animal species, as well ashumans, including understanding of viral determinantsof these characteristics and identification of appropriateanimal models for associated research.5. Comparison of characteristics of avian viruses thatremain in the avian reservoir to those that spill over tothe mammalian host.6. Understanding of host-specific factors that affect thepolymerase complex, and therefore replication.7. Understanding homosubtypic and heterosubtypic immunityto human seasonal and potentially zoonotic animalinfluenza viruses and its effect on transmission ⁄ infectivity⁄ pathogenesis and serological responses, includingunderstanding of non-HA gene immunity.8. Better understanding of role of heterogeneity in sheddingand thus transmission from infected hosts.9. Additional assessment of the impacts of virus genotypeon phenotype.Analysis and sharing1. Mechanisms for timely and open sharing of information,viruses, reagents, sequence information, technology, andtools within and among sectors.2. Mechanisms for joint data collection and analysis amongsectors.3. Mechanisms for timely sharing of information frominternational or regional epidemiological and virologicalanalyses back to countries from which the data cameand neighboring countries at risk.4. More complete analysis on available virus isolates (e.g.,genetic, antigenic, and genotypic).5. Better understanding of antiviral resistance, includinghow it is acquired, and its effects on fitness.6. Solutions to maximize use of the available information.7. Expanded use of new technologies (e.g., antigenic cartography)to analyze other virus subtypes.Pandemic potential1. Determination of the pandemic potential of variousinfluenza subtypes and strains, including receptor repertoire,geographical distribution, and human exposure⁄ seroprevalence ⁄ immunity.2. Model to assess human infection ⁄ transmission potentialof viruses.3. Understanding of pathways if virus adaptation tohumans, including investigations using reverse adaptationof human strains.4. System to track mutations and evolution to ensureunderstanding of development of a pandemic strain(retrospectively, if necessary).Behavior change and assessment1. Determination of costs and benefits of household, village,and community poultry management practices,including cultural relevance.2. Behavior change communication that is targeted atstakeholders at each critical point along the chain.3. Risk reduction measures focused at the communitylevel, and implemented by the community.4. Impact assessments for proposed and implemented measures.5. Focus on biosecurity at all levels of the human–animalinterface.Diagnostics1. Standardization ⁄ harmonization of laboratory testing⁄ diagnostic procedures with respect to reference antigensand antisera for human sera, poultry sera, wildbird sera, and reference materials.2. Antigen detection tests that are as sensitive and specificbut not as expensive as RT-PCR.3. Serological tests that show significant difference betweenhomologous and heterologous local strain antigens, anda better understanding of what is the protective HI titer.4. Sensitive and specific serologic tests to identify previoushuman infection with AIVs.5. Updated best-practice assay manuals, implementation ofproficiency testing in laboratories, and training of diagnosticiansand epidemiologists.Optimizing the human health–animal health interface1. Optimized, coordinated surveillance and disease reportingsystem for influenza and other zoonotic diseases.2. <strong>Joint</strong> meta-leadership training and skill development.3. Better understanding of the difference between incentivesand disincentives of animal and public health tocreate win–win situations and build trust and respectbetween sectors.4. Shift from capacity building to capacity effectivenessand sustainability.5. Optimized roles and responsibilities of PPP and Nongovernmentalorganization (NGOs).6. Research and development centers to work holisticallyand ecologically for emerging zoonoses, beginning withH5N1.7. Participation of business communities as effective andequitable players in controlling, responding, and preventingEIDs.8. An integrated collaborative mindset and action plan tobetter understand infectious disease ecology and ensureapplicability for other zoonotic diseases.9. Global agenda for action.ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29 19

<strong>Joint</strong> Writing Committee10. More surveillance of animal outbreaks that precedehuman cases in collaboration with Ministries of Agriculture,Veterinary Services, and NGOs working inconservation.11. Improved technologies for forecasting and outbreakprediction.12. More ecological studies.13. Mechanism for joint analysis of gaps and research priorities.20 ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29

<strong>FAO</strong>-<strong>OIE</strong>-<strong>WHO</strong> <strong>Joint</strong> <strong>Technical</strong> <strong>Consultation</strong> on Avian Influenza at the Human-Animal InterfaceAppendix C: Abbreviations and acronymsAIAIVARDSCFRDG-SANCOECEUEID<strong>FAO</strong>GISGLEWSHAHIILIHPAIIZSVeLBMLPAIMODSNANGONS<strong>OIE</strong>OFFLURVFSASARSSIVSOP<strong>WHO</strong>Avian influenzaAvian influenza virusAcute respiratory distress syndromeCase fatality rateEU Directorate General for Health and Consumer AffairsEuropean CommissionEuropean UnionEmerging infectious diseaseFood and Agriculture OrganizationGeographic information systemGlobal Early Warning SystemHemagglutinin (gene or protein)Hemagglutinin-inhibition testingInfluenza-like illnessHighly pathogenic avian influenzaIstituto Zooprofilattico Sperimentale delle VenezieLive bird marketLow pathogenic avian influenzaMultiple organ dysfunction syndromeNeuraminidase (gene or protein)Non-governmental organizationNon-structural (gene or protein)World Organization for Animal HealthThe <strong>OIE</strong> ⁄ <strong>FAO</strong> Network of Expertise on Avian Influenza*Rift valley feverSialic acidSevere acute respiratory syndromeSwine influenza virusStandard operating procedureWorld Health Organization*OFFLU has recently changed its name to The <strong>OIE</strong>/<strong>FAO</strong> Network of Expertise on Animal Influenza to reflect its broader scope.ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29 21

<strong>Joint</strong> Writing CommitteeAppendix D: Agenda22 ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29

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<strong>Joint</strong> Writing CommitteeAppendix E: Participants26 ª 2010 <strong>FAO</strong>, <strong>OIE</strong> and <strong>WHO</strong>, Influenza and Other Respiratory Viruses, 4 (Suppl. 1), 1–29

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