1Pandemic InfluenzaOctober 9, 20061918 influenza epidemic: realizationof a worst-case scenarioFirst case: Albert Mitchell, Camp Funston, KS, March 11, 1918Up to 20% of all humans infected20-50 million deaths worldwide, 650,000 in the US2.5% average case mortality rate; up to 16% in some cities21918 death rate unusually high inmales and people ages 20-40Noymer and Garenne, 2000,Pop. Dev. Rev. 26: 565Damage due to overzealous immune response?Kash et al., 2006 Nature epub ahead of print doi:10.1038/nature05181 Influenza APleiomorphic enveloped virus,80-120 nmOrthomyxoviridae family,isolated from ferrets in 1933Endemic in water birds (ducks,gulls, shorebirds)Invasion mediated by HAprotein (hemagglutinin)binding to sialic acidBirds mostly α2,3 linkage togalactose, humans mostly α2,6linkageNeuraminidase cleaves sialicacid links; required for viralshedding (target of Tamiflu)Virus also encodes an RNA-dependent RNA polymerase3Genome has 8 RNA segmentsEach viral RNA segment ispackaged by the nucleoprotein NPwith a polymerase heterotrimer(PA, PB1, PB2) ready to goSegments reassort when distinctviruses infect the same cellMajor antigenicdeterminants are HA(hemagglutinin) and NA(neuraminidase)16 HA types and 9 NAtypes found in waterfowlAntigenic SHIFT is due toa new HA or NA typeAntigenic DRIFT is due topoint mutations in HAand NAPANDEMICS arise whenhuman populations areimmunologically naïvefor a new type4Currently H3N2 and H1N1 causemost of the yearly infectious cyclewww.cdc.govNote that influenza and pneumonia USUALLY cause ~8% of allreported deaths during the winter monthsInfluenza vaccine productionCurrently grown in embryonated chicken eggsLive virus inactivated by formaldehyde treatment~ 3 eggs per dose; availability would be severelycompromised with avian influenza epidemicLag time from seed strain choice to large-scaleavailability is 28 weeksCell-based vaccine culture methods are underdevelopmentPublic confidence in vaccines is generally lowSwine flu - 1976Compare public response to MMR vaccine5Drug treatments for influenzaAmantidine and RimantidineApproved by FDA in 1976Active only against influenza AInhibitors of M2; virus cannot escape envelopeWidespread resistance; no longer recommendedOseltamivir (Tamiflu) and Zanamivir (Relenza)Approved by FDA in 1999Active against both influenza A and influenza BInhibitors of neuraminidase; prevent viral sheddingfrom cell surfaceOseltamivir delivered orally as an ethyl ester pro-drugFound by screening sialic acid derivativesWednesday papers:Paper 1: Tumpey TM, Basler CF, Aguilar PV, ZengH, Solorzano A, Swayne DE, Cox NJ, Katz JM,Taubenberger JK, Palese P, Garcia-Sastre A.(2005). "Characterization of the reconstructed 1918Spanish influenza pandemic virus" Science 310:77-80.Paper 2: de Jong MD, Tran TT, Truong HK, Vo MH,Smith GJ, Nguyen VC, Bach VC, Phan TQ, Do QH,Guan Y, Peiris JS, Tran TH, Farrar J. (2005)."Oseltamivir resistance during treatment ofinfluenza A (H5N1) infection". N Engl J Med.353(25):2667-72.61918 flu recovered from US Army pathology samplesand one person buried in the Alaska permafrostRecombinant expression strategy:Hoffmann et al., 2000, PNAS 97:6108Only 10 aa changes in polymerase subunitsconsistently distinguish human from avianPB2: 5 changes, found rarely in avian lineages but occasionally in high pathogenicityavian strains (HPAI) H5N1, H7N7, or H9N2 that infected humansPB2: Lys627 crucial for high pathogenicityPB1: replaced by reassortment in both 1957 and 1968; replicative advantage?PB1: Asn375 to Ser found in swine and equine as well as human isolatesTradeoffs between function and antigenicity?7QuestionsCan this work help us to predict the next pandemic?What else do we need to know?Pandemics require virulence plus transmissibility;how can we study transmissibility?What are the dangers of this project?Should this project have been approved by theNSABB? Should the sequences have beenpublished?How should we be preparing for the next influenzapandemic?H5N1: The next big thing?Highly pathogenic avian influenza (HPAI):communicated directly from birds to humans butnot (so far) communicated among humansH5N1 - 1997 H9N2 - 1999 H7N2 - 2002H7N7 - 2003 H7N3 - 2004 H10N7 - 2005H5N1 returns most yearsCumulative laboratory-confirmed cases throughOctober 2006: 242Cumulative deaths: 148www.who.int8H5N1 spread - October
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