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Summaryoforalevidence:DrJohnWoodandDrJames
Robertson,NationalInstituteforBiologicalStandardsand
Control(NIBSC)
27 April 2006

DrJohnWoodandDrJamesRobertsonarePrincipalScientistsintheDivisionofVirologyatNIBSC.DrWood
andDrRobertsonleadtheNIBSC’sinfluenzagroupandtheirresponsibilitiesincludethecontroland
standardisationofinfluenzavaccines.OnbehalfoftheWorldHealthOrganisation(WHO)theNIBSCis
involvedintheserologicaltestingofvaccinetrials;thepreparationanddistributionofinfluenzavirusesto
vaccinemanufacturers;andthecoordinationofEUstrainselectionprocess.

Membersoftheworkinggrouppresentwere:SirJohnSkehel,ProfessorGlynisBreakwell,ProfessorNeil
Ferguson,ProfessorBarryFurr,DrJohnMcCauley,ProfessorAndrewMcMichael,ProfessorKarlNicholson,Dr
GeoffreySchildandRichardStubbins.

Key points

NIBSCisagovernmentfundedagencywhichactsasaninterfacebetweenpublichealthandthevaccine
industrytocontrolandstandardisebiologicalproducts.Reversegeneticstechnologyisusedtomodifyvirulent
strainsbeforetheyaregiventovaccinemanufacturers.TheNIBSCalsosuppliesindustrywithstandardsand
reagentstomeasurevaccinepotencyandisresponsiblefortheofficialtestingofnewvaccines.Insummary,
theNIBSCisinvolvedinmanystagesofthelifecycleofseasonalvaccineproductionandisconstantlylooking
atnewmethodstospeeduppandemicvaccineproduction.

Obtaining sera
DrsRobertsonandWoodtoldthegrouptheyfacenorestrictionsinobtainingsuppliesofseraaftervaccine
manufactureshavecompletedtheirtrialsofseasonalinfluenzavaccines.However,H5N1serahavebeen
morecloselyguarded.TheyhavejustbegunaprojectwithProfessorMariaZambon(HealthProtection
Agency,HPA)toexaminevaccinecrossreactivityinH5N1butthishasjuststartedasithasbeenhardto
obtainthenecessarypermission.Vaccinemanufacturesarereluctanttoreleasetheirseraincaseregulators
requiremoreexperimentsinthefuture.

Pandemic vaccines
DrsRobertsonandWoodconsiderthatpandemicvaccinedevelopmentintheEUhasbeenslowdueto
limitedpublicfunding.ThisisincontrasttothesituationintheUSA.DrWoodtoldthegroupthattheNIBSC
collaboratewiththevaccineindustry,forexampleonanH9N2vaccine.TheEMEAhavehelpedtopersuade
industrytoinvestinpandemicvaccineswiththeintroductionofthemockupfilesandbywaivingthe
regulatoryfeesandseveralpandemicvaccinesarenowinclinicaltrials.However,thisisaslowprocessand
theybelievethatpublicfunding(fromDepartmentofHealth(DH)ortheEU)shouldhavebeenusedtokick
starttheprocessasindustrywouldnotinitiallyreleasefundstodevelopaproductwhichmaynotbe
marketable.



 


Intellectual property (IP)


DrsRobertsonandWoodwereaskedabouttheeffectofIPontheproductionofnovelvaccines.Theyagreed
thatpatentsfortechnology,suchasgenerescuefor(H5N1)virusproductionhavesloweddowntheprocess,
particularlyobtainingmaterialtransferagreements.TheIPholdershavewaivedownershipofthereverse
geneticstechnologyusedinvaccinesintheresearchphase,butwantanagreementwhenthevaccineis
commercialised.ItwasconsideredthatagenericMTAforthetechnologywouldbeuseful,ratherthana
separateoneforeachvirus.ThismaybeanareawhereWHOshouldprovideguidanceandbeinvolvedinthe
negotiations.

Virus production and strain variance
H5N1vaccinesareprovingdifficulttogenerate,achievingacceptableimmunogenicityisachallengeandthe
immunologicalcorrelatesofprotectionarenotwellunderstood.Thewayaheadappearedtobeuseof
functionalserologicaltestssuchasvirusneutralisation,buttheprotectivelevelsofneutralisingantibodyare
currentlynotknown.Thegroupdiscussedtheplasmid-basedsystemusedinreversegenetictechniquesto
produceasafepandemicvirusstrainforthemanufactures.

DrsWoodandRobertsontoldthegroupthatantigenicdriftofH5N1hasbeenseenin2005/6andtwo
distinctgeneticgroupsnowexist,clades1and2.Clade2virusesaregeneticallyheterogeneousand
appeared6monthsago.NIBSCobtainedsamplesofaclade2virusfromTurkeyandtheUSCenterfor
DiseaseControlandProtectionhasobtainedanIndonesianvirus.Vaccinevirusesarenowbeinggeneratedby
reversegenetics.

NIBSChavelookedatcrossprotectionofvaccinesproducedfrom1997,2003and2004H5N1virusesinmice
andhavefoundthatdespiteantigendifferences,theyprotectmiceagainstinfectionwitha2004H5N1virus.

Communication with the Department of Health
DrsWoodandRobertsonwereaskedhowtheirknowledgefeedsintoDHandiftheythinkitisdone
sufficiently.TogetherwithDrStephenInglis(Director,NIBSC),theyaremembersofseveralgovernment
committeesandalsoholdmorecasualmeetingswithDHtotalkthroughissues.Thesemeetingsareeither
arrangedbyNIBSCorDHandincludedabrainstormingmeetingheldabout6monthsagotolookathow
processescanbemadequicker,especiallyforH5N1vaccinedevelopment.Itwashighlightedthattheyoften
provideinformationtoDHbutoftenareuncertainaboutwhatDHdoeswithit.

Research and funding sources
DrsWoodandRobertsonconsideredthatthereisalackofvaccineresearchintheUKcomparedwiththeUS.
TheytoldthegroupthatNIBSChasmadesubmissionstoDHandtotheEUforpandemicvaccine,butthey
havenotbeenfunded.Theywereaskedbythegroupiftheyaregiventhefreedomandresourcestolookat
newapproaches.TheytoldthegroupthattheyhavethefreedomatNIBSCtoinitiatetheirownresearch
programmes,butnottheresources.Theywereunawareifthesituationislikelytoimprovewiththe
forthcomingamalgamationwiththeHPA.

DrRobertson’sresearchworkforthelastthreeyearshasbeenpredominatelydirectedatimprovingthe
reversegeneticstechnology.HisgroupisalsolookingatwaystoimprovethelowviralyieldofH5N1in
vaccinemanufacturing.TheNIBSChashadsomefundingfromtheEUforpandemicvaccineresearch,but
theybothagreedthatfundingresourcesareabigissue.

Facilities for experimental animals
FacilitiesintheUKarenotconsideredasgoodasthoseintheUS.Experimentswithmiceathigh
biocontainmentcanbedoneatNIBSCandHPAfacilitiesatPortonDownarebeingupgradedforferrets,but
 


arecurrentlynotupandrunning.DrMcCauleytoldthegroupthattheInstituteofAnimalHealthhas16-18
roomsavailableforexperimentsusingferrets.

Use of live vaccines
DrsWoodandRobertsonwereaskedtheiropiniononprimingthepopulationforapandemicusinglive
vaccinesandiftheyconsiderittobeagoodidea.Howeverthetimingiscritical;ifliveH5N1vaccinesare
usednowitwouldbeconsideredtoodangerous,butifapandemicisimminenttheriskmaybejustified.A
stockpileoflivevaccine,withthecleavagesiteremoved,couldbeusedtoprimethepopulationinadvanceof
thepandemicreachingtheUK.Evenwithoutanexactmatchinvirusstrain,itispredictedthatthiswould
provideabroadimmunitytothepopulation.

Surge capacity
AprocessevaluationiscurrentlybeingconductedatNIBSCtoidentifyareastoimprovesurgecapacityina
pandemic.ItisanticipatedthattheInstitute’sessentialfunctionswillbepreservedbutsomefunctionswillbe
minimised.

TheNIBSCisnotinvolvedwithdiagnosticsforinfluenza,oranyotherinfectiousdisease.


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