Pandemic InfluenzaOctober 27, 2008Death rates from major infectiousdiseases in the United States: 1900-1965Death rates from ALL CAUSESin the United States: 1900-1994Armstrong et al., 1999, JAMA 281: 611918 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 citiesInfluenza 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 α 2,3 linkage togalactose, humans mostly α2,6linkageNeuraminidase cleaves sialicacid links; required for viralshedding (target of Tamiflu)Virus also encodes an RNA-dependent RNA polymeraseGenome 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 typeCurrently 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 vaccineDrug 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 derivativesCan we predict which strains willemerge? Positive selection?Bush et al., 1999, Science 286: 1921The next pandemic…When, not if. How bad will it be?Why was 1918 so bad?Can we predict the next source of majorantigenic shift or species crossing?1918 death rate unusually high inmales and people ages 20-40Noymer and Garenne, 2000,Pop. Dev. Rev. 26: 5651918 flu recovered from US Army pathology samplesand one person buried in the Alaska permafrostRecombinant expression strategy:Hoffmann et al., 2000, PNAS 97:6108Properties of the reconstructed1918 virus in mouse infectionsa: regular influenzab-f: recombinant 1918Microarray analysis for inflammation-associated gene expressionDeath receptor Interleukin 6Interferon Toll-like receptorG2/M checkpoint glutathioneKash et al., 2006, Nature 443: 578Only 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?Taubenberger et al., 2005, Nature 437: 889QuestionsCan 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 humans(except maybe sometimes)H5N1 - 1997 H9N2 - 1999 H7N2 - 2002H7N7 - 2003 H7N3 - 2004 H10N7 - 2005H5N1 returns most yearsCumulative laboratory-confirmed cases throughSeptember 2008: 387Cumulative deaths: 245www.who.intH5N1 spread - October 200822-40 weeks to an H5N1 vaccineHow is H5N1 (or HPAI)different from normalhuman influenza?Human, normally SA-α-2,6-GalAvian, normally SA-α-2,3-GalFixed H5N1 binds to alveolar macrophagsand type II pneumocytes; consistent withsevere alveolar damage in humanpatientsNote ferrets and cats are better models forhuman infection than micevan Riel et al., 2006, Science 312: 399Shinya et al., 2006, Nature 440: 435Wednesday papers:Paper 1: Stevens J, Blixt O, Chen LM, Donis RO,Paulson JC, Wilson IA. “Recent avian H5N1 virusesexhibit increased propensity for acquiring humanreceptor specificity.” J Mol Biol. 2008 Sep19;381(5):1382-94Paper 2: Morens DM, Taubenberger JK, Fauci AS.“Predominant role of bacterial pneumonia as a cause ofdeath in pandemic influenza: implications for pandemicinfluenza preparedness.” J Infect Dis. 2008
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