No. 21 - April 2006 - eswi

April 2006, No. 21EDITORIALAnimals are the source of nearly all newlyemerging infections. This has been demonstratedby the emergence of the West Nilevirus, found in wild birds and mosquitoes, theSARS virus, found in pteropid bats, and ofcourse the influenza A virus, found andspread primarily by free-living ducks. Indeed,all influenza A subtypes, divided on the basisof HA (to date 1–16) and NA (to date 1–9)antigens, have been found in migratory birds.Due to rapidly changing human behaviourand animal ecology, infections are spreadingfaster and farther. Currently, an H5N1 avianinfluenza pandemic is looming over Europeand although human-to-human transmissionhas not yet been reported, the disease’s burdenon public and animal health is alreadyenormous. Not only does the H5N1 AI virushave a death rate of over 50% in humans, millionsof poultry, livestock and migratory birdsare likely to die or be culled. In addition,poor coordination between different disciplinesin response to influenza outbreaks islimiting our ability to deal adequately with thethreat they pose to human and animal health.To limit the effects of influenza on publichealth and livestock production, integratedand effective action from all the disciplinesinvolved is urgently required. At ESWI’sSecond European Influenza Conference,11–14 September 2005, Malta, the entireinfluenza stakeholder community was representedand were given ample opportunity toexchange information. The main outcomewas indeed the acute need for a EuropeanInfluenza Task Force: a well-structured collaborationamong health experts, specialistsin the fields of virology, epidemiology, pathology,ecology and agriculture, as well as policymakers, the European authorities and communicationexperts.The duties of the task force would be to:• Gain insight into the European picture ofinfluenza, taking into account temporaland geographical variation of influenzaviruses in Europe and in those areas thatmay pose a direct threat to Europe.Besides human influenza viruses, those ofseveral animal species like wild birds,poultry, pigs, horses and cats should betaken into account• Prioritise research and integrateknowledge of different disciplines onhuman and animal influenza• Advance early warning systems andintervention strategies for influenzaoutbreaks in humans and animals.Participation of industrial partners in thisarea is crucial• Translate knowledge into policy advice,emphasising the integration of humanand animal health strategies• Increase the annual influenza vaccinationrate to one-third of the human populationin all European Union (EU) memberstates• Create public–private partnershipsbetween European authorities andvaccine manufacturers for research anddevelopment of pandemic influenzavaccine candidates and antivirals• Establish adequate stockpiles of antiviralcompounds for pandemic influenzapreparedness in all EU member states.The task force must be able to respond rapidlyand effectively, therefore emergent datamust be exchanged and integrated quickly.When the need occurs, outbreak managementteams can be formed, consisting of taskforce representatives as well as local expertsand policy makers from the affected countries.They would focus on geographical distributionand the species involved, and gaindetailed knowledge of the different aspects ofthe viruses and their interactions with hosts,assessing the risk of spread, and advising onthe best options for intervention. During theSARS outbreak, the viability of this approachwas shown by the World Health Organizationteams formed to deal with this threat.In line with its policy plan, ESWI intends tomeet the stakeholders’ needs. Currently, weare facilitating the formation of a EuropeanInfluenza Task Force by helping to identify therespective participants and representatives,stimulating communication among them, andhelping to create the political will and therequired funding possibilities for this initiative.The following weeks will be crucial tothe success of ESWI’s initiative.A. OSTERHAUSChair, ESWICONTENTSPAGE 1 – EditorialPAGE 2 – Influenza H5N1, updatePAGE 3 – Evolution of H3N2influenza A viruses inhumans and the effect onsialic acid bindingPAGE 4 – A new avian influenza virusreassortant H5N7 sharesgenes with highlypathogenic strainsPAGE 6 – International meetings onpandemic preparednessand controlPAGE 8 – Calendar of events1

INFLUENZA H5N1, UPDATEIntroductionDuring outbreaks of highly pathogenic avianinfluenza (HPAI) in China and Hong Kong in1997, human cases of infection with avianinfluenza A viruses of the H5N1 subtype werereported for the first time. Out of 18 confirmedcases, six were fatal. The culling ofinfected animals at live bird markets inDecember 1997 stopped the occurrence ofnew transmissions from birds to humans.However, during new outbreaks of HPAI inFebruary 2003, two more fatal cases in aHong Kong family with a travel history toChina were reported.Since December 2003, influenza A viruses ofthe H5N1 subtype again have caused massiveoutbreaks of HPAI in numerous Asian countriesand again transmissions from infectedbirds to humans were reported. In China,Vietnam, Thailand, Cambodia, Indonesia andTurkey, and more recently in Iraq, a total of170 confirmed human cases of H5N1 infectionshave been reported, of which 92 werefatal [1].These events and the recent further spread ofhighly pathogenic influenza A viruses is ofgreat concern considering the threat of newoutbreaks of HPAI in poultry and the risk ofthe emergence of viruses with pandemicpotential.Host rangeIn addition to the transmission of avianinfluenza viruses from infected poultry tohumans, the infection of various field speciessuch as tigers and leopards, has beenreported. In most of these cases the animalswere fed carcases of H5N1 virus-infectedchickens. Horizontal transmission of thevirus was also observed; in a tiger-breedingunit in Thailand, 147 out of 441 tigers died orhad to be euthanised as a result of the consumptionof infected chicken carcases.In order to better understand the pathogenesisof the virus and confirm its horizontaltransmission, we have infected catsexperimentally with a highly pathogenicH5N1 influenza virus [2]. As expected, thecats were very sensitive to infection withinfluenza virus A/Vietnam/1194/04 (H5N1).In addition, two sentinel cats that were placedtogether with cats that were infected by theintratracheal route 2 days earlier alsobecame infected. All cats developed clinicalsigns such as fever, and the disease was characterisedas necrotising interstitial pneumoniaby histopathology. In addition, withvirus isolation and immunohistochemistry,virus replication was detected in variousorgans including liver, kidney, heart, brainand the submucosal and myenteric plexi ofthe intestines. Presence of the virus in nervoustissue of the gastrointestinal tract wasonly observed in cats that had been fedinfected chickens. This raises the possibilitythat, via the lumen of the intestine, the viruscan find a new portal of entry and disseminateto other organs. In all cases the presenceof infected cells was associated with localinflammation and necrotic lesions.The virus was not only excreted from the respiratorytract, but also found in the faeces ofinfected cats. This has also been the case inhumans, which suggests that the virus can betransmitted via the faeco-oral route.The observation that influenza A/H5N1viruses currently circulating in Asia can infectcats, has a number of important implications:• Cats are at risk during outbreaks of H5N1for disease and mortality• Cats not only could play a role in thespread of the virus within or betweenfarms, but also in the transmission frombirds to humans• The infection of cats could provide thevirus with the opportunity to adapt toefficient replication and transmission in amammalian host, which could increasethe risk of the emergence of a pandemicvirus.Clinical presentationMost human cases of H5N1 infection concernindividuals that have had close contact withinfected poultry. Probable human-to-humantransmission has been reported in isolatedfamily clusters [3]. After an incubation timethat can vary from 2 to 8 days, most patientsdevelop high fever and an influenza-like illnesswith lower respiratory tract symptoms.In a number of cases, diarrhoea was alsoobserved and patients have been describedwith diarrhoea and encephalopathies withoutrespiratory tract symptoms [3]. These findingscorrelate with the pathological changeswe have observed in H5N1 virus-infected cats.It therefore cannot be excluded that inhumans, viral replication in the central nervoussystem and the intestines is the cause ofthese symptoms. In any case, this atypicalclinical presentation should be taken intoaccount. Ultimately, viral pneumonia can leadto acute respiratory distress syndrome(ARDS) and multi-organ failure involving theheart and kidneys, resulting in death. As indicatedabove, the case-fatality rate is high(about 50%), however, the incidence of caseswith milder illness is not known.Geographic spreadInitially the spread of highly pathogenicinfluenza A/H5N1 viruses was restricted tocountries in South-East Asia. From April2005, wild birds, including geese at QinghaiLake in central China, were infected with avirus variant that caused the death of thousandsof birds. In July and August 2005, thevirus spread further westwards causing outbreaksin poultry or wild birds in WesternSiberia, Kazakhstan and Mongolia.In October 2005, influenza A/H5N1 outbreakswere reported in poultry in Romaniaand Turkey, and in wild swans in Croatia. InDecember 2005, the Ukraine reported thefirst influenza A/H5N1 outbreak.By February 2006, a rapid geographicalspread of influenza A/H5N1 viruses had beenobserved. The virus was detected in poultry inIraq, Egypt, India and Nigeria. In nine othercountries – Azerbaijan, Bulgaria, Greece,Italy, Slovenia, Iran, Austria, Germany andFrance – the virus was detected in wild birds,especially swans [4].The virus could have been spread by thetransport of infected poultry or poultry products.It is also possible that wild birds wereresponsible for the further spread of H5N1viruses into the European continent, althoughthis has yet to be confirmed. Chances are thatinfluenza H5N1 outbreaks will further2

increase in those affected areas. During thewinter months, wild birds with differentReferencesmigratory routes can come into contact witheach other in African countries or the Middle1. World Health Organization report. Accessed online athttp://www.who.int/csr/disease/avian_influenza/country/cases_table_2006_02_20/en/index.html.2. Rimmelzwaan GF, van Riel D, van Amerongen G, et al. Influenza A virus (H5N1) infection in domestic catscauses systemic disease with possible novel routes of virus spread within and between hosts. Am J Pathol2006;168:176–83.3. Current Concepts: Avian Influenza A (H5N1) Infection in Humans. The Writing Committee of the WorldHealth Organization (WHO) Consultation on Human Influenza A/H5. N Engl J Med 2005;353:374–85.4. World Health Organization report. Accessed online athttp://www.who.int/csr/disease/avian_influenza/en/index.html.East, where transmission of the virus betweeninfected flocks and uninfected flocks can takeplace. There is a chance therefore, that duringspring migration birds flying northwardsinto Europe have come into contact withinfected birds. Alternative modes of virusspread include legal and illegal import ofbirds or bird products from endemic areas,as was reported in Belgium, the UK andTaiwan.G. RIMMELZWAAN, T. KUIKEN, R. FOUCHIER,A. OSTERHAUSDepartment of VirologyErasmus MCRotterdam, The NetherlandsEVOLUTION OF H3N2 INFLUENZA A VIRUSESIN HUMANS AND THE EFFECT ON SIALICACID BINDINGWinters in Europe are associated with thespread of influenza. In recent years, however,data from UK surveillance schemes such asthe Royal College of General PractitionersWeekly Returns Service, suggest a decline inthe severity of seasonal influenza indicated byfewer reports of influenza-like illness (ILI) [1].Over the past 5 years, winters with less influenzadisease have become the norm in England.The human respiratory tract presents a formidablechallenge to the influenza virus. Cilialining the airway epithelium sweep foreignparticles back up the mucociliary escalatorand the glycocalyx – a complex web of glycosylatedproteins and lipids – forms a barrierprotecting the respiratory epithelium. Mucusis laden with decoy receptors in the form ofsialyloligosaccharide-containing mucins, andinnate defence molecules such as the collectinsmannose-binding lectin (MBL) andsurfactant protein-D (SP-D) bind to foreignglycoproteins as part of the antiviral hostdefence. In addition to immune surveillance,interactions between the virus and glycosylatedreceptors in the respiratory tract maydrive evolution of the virus as it adapts tohumans. Despite these factors, the influenzaA H3N2 subtype has circulated continuouslyin the human population for almost 40 years,demonstrating the capacity of the virus forevolutionary adaptation.In the mid-to-late 1990s, many influenza referencelaboratories found that clinicalinfluenza isolates could no longer agglutinatechicken erythrocytes routinely used inhaemagglutination inhibition (HI) tests. Ashaemagglutinin relies on the interactionbetween viral haemagglutinin (HA) and sialicacid displayed on the surface of erythrocytes,this phenomenon suggested the receptorbindingcharacteristics of the circulatinghaemagglutinin must have changed in someway. To investigate this, we assembled a panelof viruses from the archives at the HealthProtection Agency Centre for Infections,London, UK. This panel, which formed thebasis for much subsequent work, comprisedH3N2 isolates ranging from the pandemic-eraof 1968–1969 through to modern times, andincluded representatives from many of theantigenic subtypes that circulated during thistime. Isolates were carefully selected to avoidthe influence of egg-adapted mutations in HAand therefore, only cell-grown material wasincluded to preserve the receptor-bindingproperties of the original clinical isolate.Haemagglutinin assays with the virusesrevealed a clear decline in ability to agglutinatechicken erythrocytes over time, possiblydue to loss of affinity for α-2,3-linkedsialic acid found on these cells [2]. The exactnature of the observed receptor-bindingchanges was investigated using glycopolymersdisplaying α-2,3 (3’SL) and α-2,6-linked(6’SL; 6’SLN) sialic acid synthesised in theUniversity of Reading Chemistry Department,Reading, UK. Specifically, HA-binding affinityfor 3’SL declined over time. Affinity for 6’SLNwas more variable but recent viruses also hada low affinity for this receptor analogue.When these data were related to the molecularchanges that occurred during evolution ofthe virus, it was clear to see that reducedbinding to 3’SL and 6’SLN was accompaniedby an increase in the number of potential glycosylationsites on HA from seven to 11 or 12.During antigenic drift, HA has becomeincreasingly glycosylated to shield antigenicsites from the immune system. However,these bulky sugar chains added in the vicinityof the receptor-binding pocket might interferewith the HA–sialic acid interaction.Interestingly, using reverse genetics we foundthat deletion of a potential glycosylation siteon HA changed the pattern of erythrocytebinding such that the virus regained theability to agglutinate chicken erythrocytes.The development of primary cell cultures ofhuman airway epithelium (HAE) is an excitinginnovation that has recently been used tostudy virus pathogenesis and cellular interactionsof diverse respiratory viral pathogensincluding influenza virus, RSV, PIV3 and3

SARS [3]. HAE accurately recapitulate humanairway cellular morphology and the highlycomplex glycocalyx layer consisting of tetheredand soluble mucins, many terminatingin sialic acid. HAE developed at the UNCCystic Fibrosis Center at the University ofNorth Carolina, USA, were used to investigatethe biological consequences of the receptorbindingchanges that we had observed. Sialicacid receptors for human influenza (α-2,6-linked sialic acid) are widespread on the tracheobronchialepithelium and found on bothciliated and non-ciliated cells in HAE [3].Accordingly, human strains of influenza Acould efficiently infect HAE and cause widespreaddestruction of the ciliated epithelium.Surprisingly, the avian virus receptor (α-2,3-linked sialic acid) was found on ciliated cellsin HAF, and these cells were infectable withavian strains of influenza, although the infectionwas limited compared with humanviruses. Moreover, the most recently isolatedhuman viruses infected a greater proportionof non-ciliated cells compared with those isolatedin 1969 shortly after the introduction ofH3 surface antigen from an avian source. Thisperhaps reflects the decreased receptorbindingcapacity of recent viruses for α-2,3-linked sialic acid found on ciliated cells, asdemonstrated in haemagglutinin and syntheticsialic acid binding studies. The consequencesfor the virus of losing affinity forsialic acid and infecting a minor populationof airway cells could be decreased virulencedue to less efficient replication or reducedtransmission.Whether these properties of modern virusestranslate to decreased virulence and lesssevere disease in humans is an interestingquestion. Highly glycosylated viruses areindeed less virulent in a mouse model comparedto earlier less glycosylated viruses [4].Furthermore, these highly glycosylatedviruses showed increased susceptibility toneutralisation by the lung collectins MBLand SP-D, suggesting that reduced virulencemay be due to enhanced recognition andclearance by sugar recognition molecules ofthe innate immune system.Recent surveillance in the UK indicates adecline in reported ILI in the community [1],and it is interesting to speculate whetherthis is due to reduced transmissibility orReferencesdiminished virulence – the consequencesof decreased receptor-binding affinity andincreased HA glycosylation. Of course theseepidemiological findings could also be drivenby widespread immunity to H3 and greaterimpact of vaccination programmes. However,after such a prolonged circulation, the questionis whether there is further capacity forH3 evolution? Furthermore, it remains to beseen whether the apparent decline of H3N2leaves the door open for a new pandemicvirus to emerge [5].C. THOMPSONSchool of Biological SciencesThe University of ReadingReading, UK1. Goddard NL, Kyncl J, Watson JM. Appropriateness of thresholds currently used to describe influenzaactivity in England. Commun Dis Public Health 2003;6:238–45.2. Thompson CI, Barclay WS, Zambon MC. Changes in in vitro susceptibility of influenza A H3N2 viruses to aneuraminidase inhibitor drug during evolution in the human host. J Antimicrob Chemother2004;53:759–65.3. Zhang L, Bukreyev A, Thompson CI, et al. Infection of ciliated cells by human parainfluenza virus type 3 inan in vitro model of human airway epithelium J Virol 2005;79:1113–24.4. Reading PC, Morey LS, Crouch EC, et al. Collectin-mediated antiviral host defense of the lung: evidencefrom influenza virus infection of mice. J Virol 1997;71:8204–12.5. Whittaker RG, Underwood PA. A mechanism for influenza subtype disappearance. Med Hypotheses1980;6:997–1008.A NEW AVIAN INFLUENZA VIRUSREASSORTANT H5N7 SHARES GENES WITHHIGHLY PATHOGENIC STRAINSIn September 2003, H5 influenza A infectionwas detected for the first time in Denmark inan outdoor-bred commercial flock of 12,000mallards that had shown increased mortalityfor some time. Reverse transcriptionpolymerasechain reaction (RT-PCR)with sequencing identified the strain as a previouslyundescribed subtype combination,H5N7. The strain was isolated from pools ofrespiratory tissues, brain and internal organs.Full genome characterisation of H5N7revealed a possible reassorted strain of bothlow pathogenic and highly pathogenic avianinfluenza virus.Identification of H5N7Characterisation of the haemagglutinin (HA)gene revealed a 95.6% nucleotide sequenceidentity with a highly pathogenic (HP) H5N2strain from Italy (A/Chicken/Italy/312/97)and the neuraminidase (NA) gene showed96.8% nucleotide sequence identity with aHP H7N7 strain from The Netherlands(A/Chicken/Netherlands/01/03). The H5N7HA sequence showed highest sequence identityto HP H5; however, the HA1/HA2 cleavagesite sequence K-E-T-R, was without the multibasicresidues typical for HP strains [1]. TheH5N7 strain showed a 98.1% HA nucleotide4

sequence identity with two low pathogenic(LP) isolates of H5N2 avian influenza virus(AIV) (A/Duck/Denmark/65047-P8 and–p13/04) found in faecal samples from wildducks in Denmark in 2004. Based on thefinding of AIV H5, all 12,000 ducks wereculled in order to eliminate the possibility ofvirus spread to commercial poultry with theadditional risk of drifting into a HP type. Noevidence of human AIV infection was demonstratedamong the people handling the ducks.The H5N7 subtype combination had not previouslybeen reported and the possibility ofreassortment in the internal proteins with HPAIV strains had to be addressed. The H5N7strain possessed sequence characteristics ofa LP virus strain and the chicken intravenouspathogenicity index value was 0.00; however,the H5N7 virus was isolated from multipleorgan tissue cultures, a characteristic for HPAIV. Moreover, the combination of HA and theinternal proteins might have unpredictableinfluence on the virulence and pathogenicityof a virus [2]. Therefore, it was necessary tocharacterise the full genome of the new H5N7strain.H5N7 possesses internalproteins of highlypathogenic originIt is believed that all 16 subtypes of HA andnine of NA are perpetuated in the wild waterfowlpopulation and reassort at highfrequency. We full-length sequenced thegenome of the H5N7 strain and madecomparisons with HA and NA sequencehomologues closest to H5N7, the LPA/Duck/Denmark/65047/04 (H5N2) and theHP A/Chicken/Netherlands/1/2003/(H7N7),respectively, and in relation to representativesof known genetic lineages of influenza A inthe GenBank.Although it is difficult to assign subtype originof AIV internal genes, we found that the H5N7strain most probably was a reassortantbetween a H5N2, H7N7 and possibly a H6subtype virus (Figure). The basic polymerasegene 2 (PB2) of H5N7 was common to bothH5N2 and H7N7 strains with a nucleotideidentity of 97.2%. The nucleotide sequence ofthe PB1 gene was about 95% identical to bothof its closest relatives H5N2 and H7N7. Theacidic polymerase protein (PA) gene showed98% identity to the PA gene of H5N2. Thenucleoprotein (NP) gene showed highestidentity to a H6 subtype (A/Duck/HongKong/3096/99 [H6N2]) (96.9%), andgrouped phylogenetically with the NP genes ofA/Teal/Hong Kong/W31/97 (H6N1) andA/Quail/Hong Kong/G1/97 (H9N2), believedto have contributed to the internal genes ofthe 1997 HP H5N1 strains from Hong Kong(not shown). The matix gene (M) had 98.1%identity to H5N2 but the closest isolate inGenBank was that of a H6 subtype (98.6%)(A/WDK/ST/1737/2000 [H6N8]). The nonstructuralgene (NS) had greatest nucleotidesequence identity to the human fatal case isolateA/Netherlands/219/03 (H7N7) (98.4%).The NS gene of the H5N7 isolate belongs tothe NS phylogenetic subgroup A as does theH7N7 strain, while the NS gene of the H5N2strain belongs in subgroup B (not shown).The NS gene was the only one closely relatedto genes of the current HP H5N1 Z genotype.Determination ofpathogenicity andinhibitory drug resistanceThe A/Netherlands/219/032 (H7N7) isolatedfrom the human fatal case in The Netherlandsin 2003 differed by 14 substitutions in the HA,HANAPB2PB1PANPMNSH7N7HANAPB2PB1PANPMNSH5N7NA, PB2, PA and NS proteins from otherhuman and avian infectious H7N7 virus at thattime [3]. Some of these substitutions werealso found in segments of the new H5N7genome, namely PB2 V297I, PA F666L, NAP458S and NS V137I. It is not known if any ofthese substitutions influence host infection,virulence or the multi-organ tissue tropismobserved for the H5N7 strain. No sequenceindications of HP were found in the internalproteins, e.g. substitution PB2 E627K or NS1D92E. Host-specific amino acid residues inthe H5N7 genome were all of avian origin andthe HA protein possessed the amino acid HAQ226 and G228 indicating preferential bindingto the avian-like NeuAca2,3-Gal receptor.Our results suggest that the H5N7 strain is LPand is not adapted to a mammalian host. TheH5N7 strain did not have any sequence indicatorsof resistance to matrix or neuraminidaseinhibitory drugs. The presence ofthe virus in the brain and internal organ poolmay be explained by weakness due to systemicbacterial infection in the sick mallards.LP H5 AIV might be precursors for HP strains.Therefore, if a newly reassorted AIV virus,HANAPB2PB1PANPMNSH5N2Common genes ofH5N2 and H7N7Genes of possible H6 originH7N7H5N2Figure. Simplified illustration of thepossible origin of the H5N7 genome.5

like the new H5N7 with segments of HP avianorigin, is allowed to circulate in the poultryor wild bird breeding colonies, it has thepotential to develop into a HP strain. Theexperience with the 1918 Spanish flu virushas shown that pathogenicity to humans is notsolely dependent on a multibasic cleavage siteor multi-organ tropism, but likely the combinationof genes, especially the HA and polymerasegenes, is essential for high virulence[2]. Our results emphasise the need for fullgenome surveillance for LP AIV strains inorder to be prepared for drifted or reassortedstrains.K. BRAGSTAD, A. FOMSGAARDDepartment of VirologyStatens Serum InstitutCopenhagen, DenmarkP.H. JØRGENSEN, K.J. HANDBERGAvian VirologyDanish Institute for Food and VeterinaryResearchReferencesDepartment of Poultry, Fish and FurAnimalsMinistry of Food, Agriculture and FisheriesDenmark1. Bragstad K, Jorgensen PH, Handberg KJ, et al. New avian influenza A virus subtype combination H5N7identified in Danish mallard ducks. Virus Res 2005;109:181–90.2. Tumpey TM, Basler PV, Aguilar H, et al. Characterization of the reconstructed 1918 Spanish influenzapandemic virus. Science 2005;310:77–80.3. Fouchier RA, Schneeberger PM, Rozendaal FW, et al. Avian influenza A virus (H7N7) associated withhuman conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci2004;101:1356–61.INTERNATIONAL MEETINGS ON PANDEMICPREPAREDNESS AND CONTROLDue to the continuing spread of the highlypathogenic H5N1 influenza virus, a universalsense of urgency developed in 2005 toincrease pandemic preparedness planning.Demonstrating this sense of urgency, aunique meeting was organised in November2005 at the World Health Organization’s(WHO) headquarters in Geneva [1]. Thismeeting was co-sponsored by four internationalagencies: WHO, the World Food andAgriculture Organization (FAO), the WorldOrganization for Animal Health (OIE), andthe World Bank. The meeting was attended bymore than 600 experts from over 100 countries.The aim of the meeting was to establishprecise needs and priorities, and the bestways in which to meet these. There was clearconsensus that as no virus of the H5 subtypehad ever circulated widely among humans,vulnerability to a pandemic caused by such avirus would be universal. Many participantsagreed that pandemic influenza is a threat tothe scientific, technical, political, social, economic,agricultural and health sectors ofsociety, and also has implications for bothnational and global security. Indeed, the SARSepidemic some years ago provided an indicationof how a future outbreak of pandemicinfluenza might have major social, politicaland economic consequences, as well as aheavy toll on human health in a closely interconnectedand interdependent world. It wasestimated that based on the scenario of a mildpandemic, mortality could range from 2 millionto 7.4 million deaths worldwide andglobal economic losses of around US$800billion within 1 year.So far, the virus has established its strongestfoothold in small backyard flocks in rural andperi-urban areas, where control is most difficultand opportunities for human exposurethe greatest.Apart from the health issues and strategies topre-empt and/or control the consequences ofa future pandemic, the meeting clearly recognisedthe need for pandemic preparednessplans to also include strategies for ensuringbusiness and societal continuity.To date, in many affected countries, managementhas been driven by the crisis at handrather than by results-based planning. Publicinformation, particularly that concerning riskcommunication, has not succeeded in achievingan adequate public understanding of theissues in line with the level of risk. This haseither resulted in panicked over-reaction orthe perpetuation of high-risk behaviours. Theparticular vulnerability of parts of Africa toavian influenza emerged as a matter of greatconcern during the meeting. This continenthas an estimated 1.1 billion chickens, mostlyproduced in backyard farming systems; massculling would be extremely difficult to accomplishand the resources to compensatefarmers or pay for animal vaccines are notavailable. Traditional practices and ruralpoverty favours the home slaughter and consumptionof birds when signs of illnessappear in a flock, as has been demonstratedin a recent outbreak in Nigeria. The incidenceof human cases is sometimes linked to behaviourthat can be avoided.Overall, the WHO has identified five priorityactions for the international community:• Reduce human exposure to the H5N1virus• Strengthen early warning systems• Intensify rapid containment operations• Provide real-time information about theevolution of a pandemic to ensure thatresources, which will be strainedeverywhere, will be invested in measureshaving the greatest likelihood of success• Coordinate global research, including theaccelerated development of pandemicvaccines and expanded productioncapacity.6

In January 2006, a follow-up meeting to theNovember meeting was held in Beijing, China.During this pledging conference, an amountof US$1.9 billion was raised by donor countriesto support the priority activities forglobal, regional and national pandemicpreparedness [2].Apart from general measures, the availabilityof adequate volumes of antiviral agents andpandemic vaccines will be of key importanceto contain the impact of a future pandemic.During a meeting held in Geneva, Switzerlandon 7–9 November 2005, the WHO’s DirectorGeneral Dr Lee Jong-Wook summarised thecentral points raised about vaccines: “A universalnon-specific pandemic vaccine may bethe ultimate protective solution for humaninfluenza. ‘Smart’ solutions are being investigated.Issues of technology transfer, resolutionof licensing and regulatory obstacles,sustained use of GMP and prequalificationare under discussion. Predictable, increasedorders for seasonal flu vaccine will supportgreater manufacturing capacity, including indeveloping countries.” He recommended thefollowing action: “Map out a global strategyand work plan for coordinating antiviral andinfluenza vaccine research and development,and for increasing production capacity andequitable access.”Vaccine production capacity and equitabledistribution are clearly very inter-related.Global pandemic vaccine production capacityclearly also depends on the unit dose anddose regimen needed for protection.Preceding the above meeting, the WHO hadorganised a meeting on development andevaluation of influenza pandemic vaccines on2–3 November 2005. During this, vaccinemanufacturers presented their progress withtheir respective developments of candidatepandemic vaccine formulations [3]. Themeeting revealed that significant progress forthe development of candidate pandemic vaccineshas been made. Eight influenza vaccinemanufacturers are already involved or areabout to start clinical trials in 2006. Onemock-up dossier has been filed according tothe European Medicine Evaluation Agency(EMEA) [4] in 2005 and four more suchdossiers are expected to be filed in 2006.Recent clinical studies with nonadjuvantedcandidate pandemic vaccines have shownthat unrealistically high doses are required toconfer protection based on serological findings.Today, various prototype vaccine formulationswith different strains and adjuvantsare being investigated. Because of the vastclinical experience with aluminium compoundsas adjuvants in vaccines, ‘alum’ iscurrently the most used adjuvant for pandemicvaccine formulations. MF59 – anothercommon adjuvant – has also been safetytested and is used in an existing influenzavaccine formulation in many Europeancountries.Overall, current evidence from clinical trialswith recent candidate pandemic vaccinesindicate that the total antigen contentrequired for a vaccine to be effective may bea limiting factor for the production of adequatevolumes of vaccines when they areneeded. Reasonable progress has been madetowards the development and potential registrationof candidate pandemic vaccines in2005. However, research efforts should beincreased with a high priority to furtherreduce the necessary antigenic content ofpandemic vaccines so that available and newproduction facilities can produce the maximumnumber of effective vaccine doses. Thisis of key importance to achieve the ultimategoal of equitable accessibility of pandemicvaccines for the world population.B. PALACHEGlobal Medical Affairs Director InfluenzaVaccinesSolvay PharmaceuticalsThe NetherlandsReferences1. World Health Organization. Meeting on avianinfluenza and human pandemic influenza.7–9 November 2005, Geneva, Switzerland.2. World Health Organization. InternationalPledging Conference on Avian and HumanInfluenza. 17–18 January 2006, Beijing,China.3. World Health Organization. Meeting ondevelopment and evaluation of influenzapandemic vaccines. 2–3 November 2005,Geneva, Switzerland.4. European Agency for the Evaluation ofMedicinal Products. Guidelines onsubmission of Marketing AuthorizationApplication for Pandemic Influenza Vaccinesthrough the centralized procedure. London,5 April 2004,www.emea.eu.int/pdfs/human/vwp/498603en.pdf.7

CALENDAR OF EVENTSDate/Venue Title Organiser/Secretariat3–5 May 2006 24th Annual Meeting of the Kenes International/ESPID 2006Basel, Switzerland European Society for Paediatric 17 Rue du Cendrier, PO Box 1726Infectious Diseases CH-1211 Geneva 1SwitzerlandTel: +41 22 908 0488Fax: +41 22 732 2850E-mail: espid@kenes.com7–11 May 2006 19th International Conference Courtesy AssociatesSan Juan, Puerto Rico on Antiviral Research Tel: +1 800 202-973-8790/+1 800-453-1357E-mail: ISAR@courtesyassoc.com8–10 May 2006 Ninth Annual Conference on National Foundation for InfectiousBaltimore, Maryland, Vaccine Research DiseasesUSA 4733 Bethesda Avenue, Suite 750Bethesda, Maryland 20814-5278USATel: +1 301 656 0003 x19Fax: +1 301 907 0878E-mail: info@nfid.org3–5 July 2006 7th Congress of the International Nelda RousseauStellenbosch Federation of Infection Control Unistel Consultus (PTy) LtdSouth Africa PO Box 19063, Tygerberg, 7505,South Africa27–30 August 2006 12th Conference of the European Viale Matteotti, 7Florence, Italy Society of General Practice/Family 50121 Firenze, ItalyMedicine Tel: +39 055 50351Fax: +39 055 50019123–6 September 2006 9th Annual Meeting of the E-mail: paul.klapper@escv2006.co.ukBirmingham, UK European Society for Clinical sue.skidmore@escv2006.co.ukVirology18–20 October 2006 The Second International IVW 2006 SecretariatVienna, Austria Conference on Influenza Vaccines Meetings Managementfor the WorldThe Barn, Rake MeadowStation Lane, MilfordSurrey, GU8 5ADUKTel: +44 (0) 1483 427770Fax: +44 (0) 1483 428516INFLUENZA BULLETINThe Influenza bulletin is published for the European Scientific Working group onInfluenza by Thomson Gardiner-Caldwell Communications. The opinions expressed in thispublication should not be construed as those of the publisher or sponsors.Consult full prescribing information on any drugs or devices discussed.© 2006 Thomson Gardiner-Caldwell Communications. All rights reserved.Victoria Mill, Windmill Street, Macclesfield, Cheshire SK11 7HQ, UKThe organisations supporting ESWI include:Baxter Vaccines, Berna Biotech, Chiron Vaccines,F. Hoffmann-La Roche, MedImmune, Sanofi Pasteur MSD,Solvay Pharmaceuticals, Nobilon International, Crucell.ESWI MEMBERSDr L. BrydakPolandDr T. HeikkinenFinlandProfessor A.D.M.E. OsterhausThe NetherlandsDr D.J. SmithUnited KingdomDr R. SnackenBelgiumProfessor T. SzucsSwitzerlandProfessor S. van der WerfFranceDr G.A. van EssenThe NetherlandsADVISERSDr J. McElhaneyUSADr W. HaasGermanyDr A.M. PalacheThe NetherlandsProfessor C. HannounFranceDr A. LindeSwedenINFLUENZA BULLETINIf you want to be put on the mailinglist, please contact:ESWI MANAGEMENTDavid De Pooter, c/o Link Inc,Tolstraat 9, 2000 Antwerp, BelgiumTel: + 32 32 32 93 42Fax: + 32 32 32 17 04E-mail: info@linkinc.beESWI website: www.eswi.org8