influenza vaccines in older persons 65+ · 2018. 2. 16. · 1. influenza in older persons 2....
TRANSCRIPT
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
Dedicated bi level marketing Extended shelf life