InfluenzaVaccinesinolderpersons65+

PaulVanBuynderProfessor,GriffithUniversityChairman,ImmunisationCoalition

Outline

1.  Influenzainolderpersons2.  Vaccineeffectivenessinthe

elderlyincludingdurationofprotection

3.  Desirableattributesininfluenzavaccinesforolderpersons

4.  aTIV5.  hdTIV6.  Recommendations

Outline

1.  Influenzainolderpersons2.  Vaccineeffectivenessintheelderlyincludingdurationofprotection

3.  Desirableattributesininfluenzavaccinesforolderpersons

4.  aTIV

5.  hdTIV

6.  Recommendations

Burdenofinfluenzaintheelderly

§ Influenzaisaseriousinfectiousdiseaseandplacesasignificantdiseaseburdenontheelderly

§  Theincidenceofinfluenza-relatedhospitalizationsishighestintheelderly

§  Age-relatedimmunevulnerabilitymayresultinseriouscomplicationsassociatedwithinfluenzaintheelderly

§  Influenzaintheelderlyisassociatedwithsignificantdirectandindirectmedicalcost

AnnualInfluenzaImpactVariesbyAgeGroup

2010-11 2011-12 2012-13 2013-14 2014-15

Cases

Hospita

lizations

Reedetal.PLOSOne10(3):e0118369 http://www.cdc.gov/flu/about/disease/2014-15.htm

2014-15H3N2DriftSeason:Over700KHospitalizationsOver34MCases

…andthereareotherimpacts

•  Influenzacausesaninflammatoryresponsewhichincreasesthechancesofheartattackandstrokefollowinginfection

•  Manyinfectionsanddeathsgounrecognisedasworseningofco-morbidcardiacneurologicalandrespiratorydiseases

Outline1.  Influenzaintheelderly

2.  Vaccineeffectivenessinolderpersonsincludingdurationofprotection3.  Desirableattributesinolderperson’influenzavaccines

4.  aTIV

5.  hdTIV

6.  Recommendations

Thegoalofvaccinationisnotonlytopreventdiseasebuttoinfluencethetrajectoryofintrinsiccapacity…dealingwiththeimpactsonfrailty

important

Immunosenescence

§ Increase in exhausted memory T cells

§ Decrease in naïve T cells § Decrease CD8 cell population § CD8/CD4 ratio <1 § Decreased telomerase § Telomere shortening

§ … Decreased response to all vaccines

EffectofImmunosenescence

•  Effectofseriousoutcomesincreases– 90%ofdeathsinelderly– 3-4hospitalisationsperdeath

•  Responsetovaccinationsdecreases– Efficacyabout60%inhealthyadults– Efficacy27-40%inelderly

•  ..butarestillcostsavingsoamarginforimprovement

2016-17USdata

•  VEallages 42%•  VE6/12to8years 61%•  VE65yrs+ 25%

•  Overall30%againsthospitalisationsallages•  Overall37%againsthospitalisations65years+•  “Yougottheflubutyouweren’thospitalisedandyoudidn’tdie”

Durationofprotection

•  TwonewCDCstudieslasttwelvemonths– Onein<50years– Oneinallages

•  VEdeclinesprogressivelyacrosstheinfluenzaseasonandthismaybeasmuchas8%permonth

•  Inelderlyvaccinemayhavenoeffectafter3-4months

•  Influenzaimmunizationoccursearlyinautumn•  Periodofinfluenzacirculationvariesyearly•  Mayleavelargetimeperiodbetweenimmunizationandexposure

ImportanceofPersistence

ImportanceofBreadthofResponse

1.MMWR,2013;CDC2015;2.MMWR2014;CDC2015;3.MMWR2015.

SeasonalYear

VaccineEffectiveness

(%)

o  Bridgesetal.JAMA2000(VEinadults1998-1999[matched]=86%,VE1997-1998inadults[mismatched]=50%)

o  OhmitetalNEJM2006(VE[matched]=83%,VE[mismatched]=69%)

o  CDCVE201419%in>65+

Patients≥65yearshighestinfluenza

associatedhospitalization

Conclusions

§  Influenzaisakeycontributortomorbidityandmortalityintheelderly

§  Increasesincoveragelikelymighthavemodestgains;however,improvementinVEwouldhavegreatestimpact

§  EvenatlowVE,vaccinationcanbecost-effectivein65+

AvertedHospitalizationsforIncrementalVEImprovements2011-15InfluenzaSeasons,U.S.

Biggerstaffetal.CDCunpublisheddata.2016

§  Forthe2014-15driftH3season,animprovementof+5%averts86Khospitalizations,+10%averts108K,and+40%averts232K

§  EvenatlowVE,influenzamorbidityin65+maybereducedwithincrementalVEincreases

Hospita

lizations

DesirableCharacteristicsofanenhancedfluvaccineforolderpersons§ Influenzavaccinesarelesseffectiveintheelderlyduetoimmunesenescence

§ Influenzavaccinesareevenmoreineffectiveintheelderlyduringseasonswhenthereisastrainmismatch

§ Influenzavaccineeffectivenesswanessignificantlyduringtheseason

§ Improvedinfluenzavaccinesneedto:

§  Enhanceimmuneresponsesinsusceptiblepopulations§  Providebroadercross-protectionwhenvaccinestrainmismatchoccurs

§  Improvethedurationofprotectionduringthefluseason

§  Offerimprovedclinicaloutcomesagainstinfluenza

VaccineProductsforOlderAdults

19

ProductType(abbreviation)

ProductType

TIV trivalentinfluenzavaccine

QIV quadrivalentinfluenzavaccine

aTIV(>30countries)

MF59-adjuvantedtrivalentinfluenzavaccine

hdTIV(availableinUSAandCanada)

trivalentinfluenzavaccine,highdose

Enhancedvaccinesforolderadults

Outline

1.  Influenzainolderpersons2.  Vaccineeffectivenessintheelderlyincludingdurationof

protection

3.  Desirableattributesininfluenzavaccinesforolderpersons

4.  aTIV5.  hdTIV

6.  Recommendations

AdjuvantedTrivalentInfluenzaVaccine

TheMF59®adjuvantcontainedinaTIVisanoil-in-wateremulsioncomposedofsqualeneastheoilphase,stabilizedwiththesurfactantspolysorbate80andsorbitantrioleate,incitratebuffer

21

ProposedMF59ModeofActionatInjectionSite

InjectionSite1.MF59recruitsimmunecells

Vaccine-specificResponsesT-cell

activationB-cell

activationAntibodyrelease

2.Differentiatesrecruitedimmunecellsintoantigenpresentingcells(APCs)

Neutralizingfluspecificantibodies

3.T-cellactivationandB-cellexpansion

LymphNode

MF59

Antigen

Macrophages

Chemoattractants

ReleaseRecruit

Monocytes&Neutrophils

Increasedantigenreuptake

APCs IncreasedAPCmigration

Seubert et al., J Immumol, 2008; Schultze et al., Vaccine, 2008. Khurana et al., Sci Transl Med, 2010. Calabro et al., Vaccine, 2011. Vono et al., Proc Natl Acad Sci USA, 2013.

Timeline of aTIV Experience

ApprovedinItaly(≥65years) Approvedin

Canada(≥65years)

ApprovedinCanada

(6to<24mos)

FirstClinicalTrialInitiated

1997 20152011 20141992 2012

SeqirusDataonFile

PivotalPIII

ComparativeEffectivenessStudy

(Canada)

ProspectiveEffectiveness(Italy)

2011 2012 2015 2016 2017

ApprovedintheUK

(≥65years)

ApprovedinUS(>65years)

ClusterRCTinchildrenYR1of3(Canada)

ClusterRCTinLTCF(US)

H3N2 aTIV:TIV

Day22 1.42 (1.11-1.81)

Day181 1.35 (1.06-1.71)

Day366 1.3 (1.01-1.67)

PersistenceofResults:HigherGMTsAgainstHomologousH3N2Strain

Risk ratio (95% CI)

2.0 1.5 1.0 0.67

Non-inferiority Bound

Favors aTIV Favors TIV

HigherantibodytitersforH3N2upto12monthspost-vaccinationFreySE,etal.Vaccine.2014;32:5027-5034.

aTIVExpandsSerologicCoverageof14/15NHH3N2Mismatch–Microneutralisation

•  VaccinationpoliciespreferentiallyrecommendaTIVtohigh-riskpatientsinItaly•  Thus,patientsreceivingaTIVweregenerallyolder,hadmorefunctionallimitationsand

higherratesofcomorbidities.Thesepatientsmaythereforehavehadmorebaselinehospitalizations

LowerInfluenza-relatedHospitalizationRiskforaTIVAdjustedriskratioforpneumoniaorinfluenzahospitalization*

•  (Hospitalizationsoccurringduringpeakofseason)

•  VaccinationwithaTIVsignificantlyreducedtheriskofhospitalizationsvsTIV

•  RR=0.75(95%CI=0.57,0.98)

25%reductioninriskforhospitalization†post-vaccinationwithaTIV

•  (Hospitalizationsoccurringbeforeinfluenzaseason)

•  Priortoflu-season,subjectsintheaTIVgroupwereatgreaterriskofhospitalizationsthanthoseintheTIVgroup

•  RR=1.17(95%CI=0.96,1.43)

17%higherriskforhospitalization†atbaseline

*Riskratioswereadjustedtoaccountforconfoundingfactors.†Riskforinfluenzaorpneumonia-relatedhospitalization.aTIV=adjuvantedtrivalentinactivatedinfluenzavaccine;CI=confidenceinterval;RR=relativerisk;TIV=trivalentinactivatedinfluenzavaccine.ManninoS,etal.AmJEpidemiol.2012;176:527-533.

ProtectionAgainstLaboratoryConfirmed

Influenza

OddsRatio(VE)

95%CIforOddsRatio SignificanceLower Upper

OverallaTIV(n=282) 0.65(35%) 0.34 1.25 <0.194

OverallTIV 1.12(0) 0.52 2.38 0.774

OverallaTIV(corrected) 0.42(58%) 0.19 0.95 0.038

OverallTIV(corrected) 1.02(0) 0.32 2.39 0.970

CommunitydwellingaTIV 0.27(72%) 0.08 0.86 0.030

ComparativeaTIVoverTIV 0.37(63%) 0.14 0.96 0.040

VanBuynderetal.,Vaccine,2013.

ComparativeInfluenzaVaccineEffectiveness2011-12aTIVvsTIV

•  Amongthevaccinatedstudypopulation(n=227),therelativevaccineefficacywas63%(4-86%,p=0.04)whencomparingaTIVtoTIVdirectly.

•  TheabsolutevaccineefficacyforaTIVwas58%(5-82%,p=0.04)overalland72%(2-93%,p=0.047)fornon-longtermcareresidents.

•  aTIVappearedtoprovideasignificantimprovementontheprotectionavailableagainsttheknownhospitalizationsanddeathinthisgroup.

27

VEagainstinfluenzahospitalisationsinpatients65yearsandolderinSOS

network,2011-2014

28

All Vaccines Non-Adjuvanted Adjuvanted

McNeilS,etal.2016.http://cic-cci.ca/wp-content/uploads/2016/11/CIC16_Abstract-Book.pdf

JointCommitteeonVaccinationandImmunisation

https://app.box.com/s/iddfb4ppwkmtjusir2tc/file/247634612957

•  Available evidence indicated better immunogenicity and effectiveness for aTIV in comparison with IIV in the elderly –  The MHRA also indicated there were no

concerns about its safety.

•  aTIV, under quite conservative estimates of effectiveness, would be highly cost-effective in both the 65-74 and 75 and over age groups

Outline

1.  Influenzainolderpersons2.  Vaccineeffectivenessintheelderlyincludingdurationof

protection

3.  Desirableattributesininfluenzavaccinesforolderpersons

4.  aTIV

5.  hdTIV6.  Recommendations

IIV3-High-DoseVaccine:Timeline

•  1999: ConceptproposedbyWendyKeitel,MD(BaylorU.)and FredRuben,MD(SanofiPasteur)

•  2000-2003: Developmentalworkanddose-ranging(PhaseI)studies1

•  2005-2006: PhaseIIstudy2

•  2006-2007: PhaseIIIstudy3

•  2009: Licensurepluscommitmenttopost-licensureefficacystudy

•  2009-2010: FIM07EfficacyTrial4

•  2011-2013: FIM12EfficacyTrial5

•  2014: PublicationofFIM12EfficacyResults5 AdditionofEfficacyDatatoPrescribingInformation

1.KeitelWA,etal.ArchInternMed.2006;166(10):1121-1127.2.CouchRB,etal.Vaccine.2007;25(44):7656-7663.3.FalseyA,etal.JInfectDis.2009;200(2):172-180.4.DiazGranadosC,etal.Vaccine.2013;31(6):861-866.5.DiazGranadosCA,etal.NEnglJMed.2014;371(7):635-645.

hdTIVEfficacyandSafety

•  PhaseIIItrials:higherantibodyresponseandreducedlaboratory-confirmedinfluenzaversusstandardTIV

•  Enhancedprotectionagainstserious,life-threateningpneumoniaassociatedwithinfluenza.

•  Thesafetyprofileofhigh-doseTIVissimilartothatofstandardTIV

hdTIVSuccessinOlderAdults

•  Retrospectivecohortstudyofover2.5millionpeopleintheUS:significantlymoreeffectivethanstandard-dosevaccineinpreventionofinfluenza-relatedhospitaladmissions–  22%moreeffectivethanthestandardTIV–  22%moreeffectiveforpreventionofinfluenzahospitaladmissions

IzurietaHS,etal.NEnglJMed.2000;342(4):232-239.

PrimaryOutcome:Everhospitalized

•  StatisticallysignificanteffectofhighdosevaccineforNHresidents•  NoevidenceofeffectforprovidingfreevaccinetoNHstaff.

OddsRatio* LCL UCL p-value

Treatments

Highdosevs.standarddosevaccine 0.930 0.875 0.988 0.0195

Freestaffvaccinevs.usualstaffcare 1.018 0.958 1.081 0.572 *AdjustedforprioryearNHhospitalizationrate,ageofresident,meanageofresidentsinNH,individualADLscore,meanADLscoreinNH,CognitiveFunctionScore(CFS),MeanCFSinNH,historyofCHFrisk-group,prevalenceofCHFrisk-groupinNH

Multivariablelogisticregression

hdTIVSuccessinOlderAdults

•  ClusternursinghomestudybyGravenstein2017LancetrespMed

–  12.5%decreaseinanyhospitalizationwithhdTIV

•  Realworldstudies:significantlymoreeffectivethanstandardTIVinthepreventionofinfluenza-relatedmedicalencounters,hospitalisations,anddeath

IzurietaHS,etal.NEnglJMed.2000;342(4):232-239.

Outline

1.  Influenzainolderpersons2.  Vaccineeffectivenessintheelderlyincludingdurationof

protection

3.  Desirableattributesininfluenzavaccinesforolderpersons

4.  aTIV

5.  hdTIV

6.  Recommendations

So

•  Magnitudeofbenefitfromenhancedvaccineswillvarywithseasonmatchandcirculatingstrains

•  Appearstobeoftheorderof25%•  Datainsufficienttorecommendoneoverother

•  Mustuseoneoftheminelderly

The Study

1028 pregnant women in 2017 85% had a pertussis vaccine 35% had an influenza vaccine 3 Major factors

Belief in vaccine Physician Season

2018

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