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Efficacy and immunogenicity of high-dose influenza vaccine in older adults by age, comorbidities, and frailty

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Vaccine33(2015)4565–4571

ContentslistsavailableatScienceDirect

Vaccine

jo u rn al h om ep a g e :w w w . e l s e v i e r . c o m / l o c a t e / v a c c i n e

Efficacy

and

immunogenicity

of

high-dose

influenza

vaccine

in

older

adults

by

age,

comorbidities,

and

frailty

Carlos

A.

DiazGranados

a,∗

,

Andrew

J.

Dunning

a

,

Corwin

A.

Robertson

a

,

H.

Keipp

Talbot

b

,

Victoria

Landolfi

a

,

David

P.

Greenberg

a,c

aSanofiPasteur,1DiscoveryDrive,Swiftwater,PA18370,UnitedStates

bVanderbiltUniversityMedicalCenter,A2200MCN116121stAveS,Nashville,TN37232,UnitedStates cDepartmentofPediatrics,UniversityofPittsburghSchoolofMedicine,Pittsburgh,PA15261,UnitedStates

a

r

t

i

c

l

e

i

n

f

o

Articlehistory: Received28April2015

Receivedinrevisedform30June2015 Accepted2July2015

Availableonline14July2015 Keywords:

Influenzavaccines,human Vaccines,inactivated Clinicaltrial,phaseIII Aged

Aged,80andover

a

b

s

t

r

a

c

t

Background:Arandomizedtrialdemonstratedthatahigh-doseinactivatedinfluenzavaccine(IIV-HD) was24.2%moreefficaciousthanastandard-dosevaccine(IIV-SD)againstlaboratory-confirmedinfluenza illnessinadults≥65years.ToevaluatetheconsistencyofIIV-HDbenefits,supplementalanalysesexplored efficacyandimmunogenicitybybaselinecharacteristicsofspecialinterest.

Methods:Double-blind,randomized,active-controlled,multicentertrial.Adults≥65yearswere random-ized1:1toreceiveIIV-HDorIIV-SDandfollowedfor6–8monthspostvaccinationfortheoccurrenceof influenza.Onethirdofparticipantswererandomlyselectedtoprovideseraformeasurementof hemag-glutinationinhibitionantibody(HAI)titers.Efficacy(IIV-HDvs.IIV-SD)againstlaboratory-confirmed, protocol-definedinfluenza-likeillness(PD-ILI)andHAIgeometricmeantiter(GMT)ratios (IIV-HD/IIV-SD)wereevaluatedbyage,andnumberofhigh-riskcomorbidandfrailtyconditions.

Results:Efficacy(95%confidenceintervals)ofIIV-HDrelativetoIIV-SDagainstlaboratory-confirmed PD-ILIwas19.7%(0.4%;35.4%)forparticipants65–74years,32.4%(8.1%;50.6%)forthose≥75years,22.1% (3.9%;37.0%)forparticipantswith≥1high-riskcomorbidity,23.6%(−3.2%;43.6%)forthosewith≥2 high-riskcomorbidities,27.5%(0.4%;47.4%)forpersonswith1frailtycondition,23.9%(−9.0%;47.2%)for thosewith2frailtyconditions,and16.0%(−16.3%;39.4%)forthosewith≥3frailtyconditions.Therewas noevidenceofvaccineefficacyheterogeneitywithinage,comorbidity,andfrailtystrata(P-values0.351, 0.875,and0.838,respectively).HAIGMTratiosweresignificantlyhigheramongIIV-HDrecipientsforall strainsandacrossallsubgroups.

Conclusions:EstimatesofrelativeefficacyconsistentlyfavoredIIV-HDoverIIV-SD.Therewasno sig-nificantevidencethatbaselineage,comorbidity,orfrailtymodifiedtheefficacyofIIV-HDrelativeto IIV-SD.IIV-HDsignificantlyimprovedHAIresponsesforallstrainsandinallsubgroups.IIV-HDislikely toprovidebenefitsbeyondIIV-SDforadults≥65years,irrespectiveofageandpresenceofcomorbidor frailtyconditions.

©2015TheAuthors.PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBYlicense (http://creativecommons.org/licenses/by/4.0/).

1. Introduction

Thehighburdenofinfluenzainadults65yearsofageorolder [1,2]persists despitedocumented improvementsinvaccination

Abbreviations: IIV-HD,high-doseinactivatedinfluenzavaccine;HA, hemag-glutinin;IIV-SD,standard-doseinactivatedintramuscularinfluenzavaccine;CI, confidenceinterval;HAI, hemagglutinationinhibition;PD-ILI,protocol-defined influenza-likeillness;NP,nasopharyngeal;PCR,polymerasechainreaction;VE, vac-cineefficacy;GMTs,geometricmeantiters;FAS,fullanalysisset;ACIP,Advisory CommitteeforImmunizationPractices.

∗ Correspondingauthor.Tel.:+15709570745;fax:+15709570934. E-mailaddress:carlos.diazgranados@sanofipasteur.com(C.A.DiazGranados).

rates[3].Ahigh-doseinactivatedinfluenzavaccine(IIV-HD) con-tainingfourtimestheamountofhemagglutinin(HA)antigenper vaccinestraincomparedtostandard-doseinactivated intramuscu-larinfluenzavaccines(IIV-SD)wasdevelopedtoaddresstheneed forimprovedinfluenzaprotectioninthispopulation[4].

Arecentlycompletedtrial(NCT01427309)demonstratedthat IIV-HDwas24.2%(95%confidenceinterval[CI],9.7%;36.5%)more efficacious than an IIV-SD in preventing laboratory-confirmed symptomaticinfluenzainadults65yearsofageandolder[5]. Rela-tiveefficacywashigheragainstvaccine-similarstrains(35.4%[95% CI,12.5%;52.5%]).ThestudyalsodemonstratedthatIIV-HDinduced significantly higher hemagglutination inhibition (HAI) antibody responsescomparedtoIIV-SD.

http://dx.doi.org/10.1016/j.vaccine.2015.07.003

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ToevaluatetheconsistencyofIIV-HDbenefits,weperformed supplementalanalysesoftheoriginalstudydata exploring effi-cacyandimmunogenicityofIIV-HDcomparedtoIIV-SDaccording toparticipants’baselineage,andhigh-riskcomorbidandfrailty conditions.

2. Methods

2.1. Studydesign

Detailsontheoriginalstudydesignareavailableelsewhere[5]. Briefly,the studywasa phase IIIb/IV,multicenter, randomized, double-blind,active-controlledtrialcomparingIIV-HDvs.IIV-SD in adults ≥65 years of ageat 126centers in theUnited States andCanada.Thestudywasapprovedbythreeinstitutionalreview boardsandallparticipantsgavewritteninformedconsentforstudy participation.Enrollmentoccurredduringthefallsof2011(year1) and2012(year2).

2.2. Studyparticipants

The study included medically stable (without moderate or severeacuteillness)adults≥65years.Participantswereexcluded iftheyhad:historyofGuillain–Barrésyndrome,systemic hyper-sensitivity or life-threatening reaction to the study vaccines or their components; received influenza vaccination within 6 monthsprior toenrollment; thrombocytopenia,bleeding disor-der, or received anticoagulants contraindicating intramuscular vaccination;dementia,anycognitivecondition,alcoholabuse,or drugaddiction ata stage that couldinterfere withstudy com-pliance; or were: participating or had participated in another interventionalstudywithin4weeksprecedingenrollment; inves-tigators or their employees or immediate family members; deprived of freedom. Baseline characteristicswere collected at enrollment.

2.3. Vaccines

ThevaccineswereformulatedaccordingtotheU.S.Foodand Drug Administration recommendations. IIV-SD (Fluzone® vac-cine,Sanofi Pasteur,Swiftwater,PA)contained15␮g ofHA per strain.IIV-HD (Fluzone High-Dosevaccine, Sanofi Pasteur) con-tained60␮g ofHA per strain.Both vaccineswere produced in embryonatedchickeneggs, inactivatedwithformaldehyde,split with a nonionic detergent, and contained A/California/7/2009 (H1N1), A/Victoria/210/2009 (H3N2), and B/Brisbane/60/2008 strains for the year 1 season and A/California/7/2009 (H1N1), A/Victoria/361/2011(H3N2), and B/Texas/6/2011 (B/Wisconsin/ 1/2010-likevirus)strainsfortheyear2season.Thevaccineswere providedin0.5-mlprefilledsyringesandadministered intramus-cularlyintothedeltoid.

2.4. Treatmentallocationandassignment

Eachstudyyear,participantswererandomlyassigned 1:1to receiveasingledoseofIIV-HDorIIV-SD.Individualswho partici-patedinbothyearswererandomlyassignedagaintoreceiveone ofthestudyvaccinesduringthesecondyear.Thestudyused con-cealedallocationthroughaninteractivevoiceresponsesystemthat centrallyassignedparticipantsbasedoncomputer-generatedblock randomization.Approximately,1/3ofparticipantswereselected randomlytobeintheimmunogenicitysubset.Participants, inves-tigators,andthesponsor’sstudystaffwereblinded.

2.5. Surveillanceandinfluenzacaseascertainment

Detailsaboutillnesssurveillance,clinicalillnessdefinitions,and influenza laboratorytesting have beenprovided elsewhere[5]. Bothpassiveandactivesurveillanceforrespiratoryillnesseswere utilized.Ifaparticipanthadarespiratoryillness,thestudysitewas tocollectanasopharyngeal(NP)swabwithin5daysofillnessonset. Foreverystudyparticipantreportingarespiratoryillness,the studysiteswereinstructedtocollectinformationontheoccurrence anddurationofrespiratoryandsystemicsymptoms.A protocol-defined influenza-like illness (PD-ILI) was defined as an acute illnesswith≥1ofthefollowingrespiratorysymptoms:sorethroat, cough,sputumproduction,wheezing,ordifficultybreathing; con-current with≥1 of the following systemic signs or symptoms: temperature >37.2◦C (>99.0◦F), chills, tiredness, headaches, or myalgia.

Laboratory confirmation of influenza in NP specimens was definedasapositiveresultontissuecultureand/orpolymerase chainreaction(PCR).AnHAIassayagainstapanelofstandard fer-retantiserawasperformedtodeterminewhethertheidentified straininaculture-positivesamplewasantigenicallysimilartoa vaccinestrain.Asamplewasconsideredantigenicallysimilarto thevaccineiftherewasa≤4-folddifferenceinthetiterofthe clin-icalisolateandthevaccinestrainagainstareferenceantiserum homologoustothevaccine.Positivesamplesbytissuecultureor PCRunderwentgeneticsequencingtodeterminesimilaritytoany vaccinecomponent[5].

2.6. Immunogenicity

BloodsampleswerecollectedformeasurementofHAItitersata visitapproximately28dayspostvaccinationintheimmunogenicity subset.HAItitersagainsteachvaccinestrainweremeasuredusinga standardassay[6]andtestingwasperformedbyasinglelaboratory (FocusDiagnostics,Inc.,Cypress,CA,USA).

2.7. Baselinecharacteristicsevaluatedinsubgroupanalyses EfficacyandimmunogenicityofIIV-HDrelativetoIIV-SDwere evaluatedaccordingtoseveralbaselinecharacteristicsofstudy par-ticipants.

Age.Agestrataweredefinedasparticipants65-–74yearsand those75yearsandolderbasedonageatenrollment.

High-riskcomorbidconditions.Thestudyprotocolprespecified high-riskcomorbidconditionsconsideredtoincreasetheriskof influenzacomplications[2]andincludedthefollowing:asthma, chronicobstructivelung disease,congestive heartfailure, coro-naryarterydisease,valvularheartdisease,atrialfibrillation,sickle celldisease,diabetesmellitus,hypothyroidism,epilepsy,stroke, spinal cordinjury, Parkinson’s disease, chronic kidney disease, chronichepatitis,cirrhosis,HIV/AIDS,cancer,long-termsystemic corticosteroidtherapy,andotherpotentiallyimmunosuppressive therapy. Threestrata were usedfor evaluating vaccine efficacy (VE)homogeneityaccordingtobaselinecomorbidities:no high-riskcomorbidities, onehigh-riskcomorbidity,and two ormore high-riskcomorbidities.Inaddition,VEwassummarizedfor par-ticipantswithoneormoreprespecifiedhigh-riskcomorbidities. Immunogenicitywassummarizedforparticipantswithatleastone prespecifiedhigh-riskcomorbidityandforthosewithatleasttwo prespecifiedhigh-riskcomorbidities.

Frailty-associatedconditions.Thestudyprotocolalso prespeci-fiedseveralfrailty-associatedconditions based onthestudyby Mitnitskietal.[7].Atthetimeofenrollment,thestudysitecollected thepresenceorabsenceofeachofthefollowingconditions,based on participant’s self-report: vision loss, hearing loss, impaired mobility,difficultytoileting,difficultybathing,difficultydressing,

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C.A.DiazGranadosetal./Vaccine33(2015)4565–4571 4567

difficultygrooming, difficultygoing out, skinproblems, resting tremor,changesinsleep,urinarycomplaints,gastrointestinal prob-lems,andhypertension.FourstratawereusedforevaluatingVE homogeneitybasedonbaselinefrailty:nofrailtyconditions,one frailtycondition,twofrailtyconditions,andthreeormorefrailty conditions.Immunogenicitywassummarizedforparticipantswith threeormorefrailty-associatedconditions.

2.8. Statisticalanalysis

Theprimaryendpointoftheoriginalstudywastheoccurrence ofculture-orPCR-confirmedinfluenza≥14dayspostvaccination causedbyanyinfluenzaviraltype/subtype(regardlessofsimilarity tothevaccine)inassociationwithaPD-ILI.EstimatesofrelativeVE inthissupplementaryanalysiswereobtainedforeachofthestrata mentionedaboveforthisendpointandforthefollowingadditional threeendpoints:culture-confirmedinfluenza≥14days postvacci-nationcausedbyanyinfluenzaviraltype/subtypeinassociation withaPD-ILI;culture-orPCR-confirmedinfluenza≥14days post-vaccinationcausedbyaninfluenzastrainsimilartothevaccine componentsinassociationwithaPD-ILI;andculture-confirmed influenza≥14dayspostvaccinationcausedbyaninfluenzastrain similartothevaccinecomponentsinassociationwithaPD-ILI.

Theoriginalstudywaspoweredat80%fortheassessmentofthe primaryobjective[5].

The VE of IIV-HD relative to IIV-SDwas estimated for each subgroupas 1– relative risk.The CIfor efficacyestimateswas calculatedusingtheClopper–Pearsonexactmethodforbinomial proportions[8].

Breslow–Daytests[9]wereusedtoevaluatevaccineefficacy homogeneityacrossthedefinedstrataforeachofthebaseline char-acteristicsofinterest.

Fortheevaluationofimmunogenicity,postvaccinationantibody responsesweresummarizedasHAIgeometricmeantiters(GMTs), GMTratios(IIV-HDtoIIV-SD),andcorresponding95%CIs.TheCIs forGMTsandGMTratioswerecalculated basedonthet distri-butionandtheassumptionthatlog(HAItiter)followedanormal distribution.

StatisticalsignificanceforVEandimmunogenicitywithineach stratumwasdefinedbya95%CIexcludingthenullvalue(0for VEand1for GMTratios).FortheassessmentofVEconsistency betweendefinedstrata,aP-value<0.05fortheBreslow–Daytests wastoindicatesignificantevidenceforrejectingthehomogeneity assumption.

The full analysis set (FAS) comprised all participants who receivedstudyvaccine;subjectsweregroupedbyassigned treat-mentatrandomization(intent-to-treat).Immunogenicityanalyses wereperformedonthoseparticipantsintheFASwhoalsobelonged totheimmunogenicitysubsetandhadapostvaccinationserology result.

AllstatisticalanalyseswereperformedusingSAS® Enterprise Guide5.1(SASInstitute,Cary,NC).

Analysesbysubgroupsdefinedbybaselineageandcomorbid andfrailtyconditionswereprespecifiedinasupplemental statisti-calanalysisplanbeforethestudywasunblinded.

2.9. Roleofthefundingsource

Thestudy’ssponsor,SanofiPasteur,hadprimaryresponsibility forstudydesign,datamanagement,andstatisticalanalyses.The coordinatinginvestigatoroftheoriginalstudy(H.K.T)hada pri-maryroleindatacollectionandinreviewingandapprovingthe originalstudyprotocol.Thedecision topublishthis manuscript wastakeninconsultationbetweenthesponsorandthe coordinat-inginvestigator.Themanuscriptwasdraftedbythecorresponding author(C.A.D)andcriticallyreviewed,edited,andapprovedbyall

Table1

Distributionofbaselinecharacteristicsofinterestbyvaccinegroup.

Baselinecharacteristic IIV-HDn(%)

N=15,990 IIV-SDn(%) N=15,993 Age Age65–74years 10,581(66.2) 10,563(66.0) Age≥75years 5409(33.8) 5430(34.0) High-riskcomorbidities Nohigh-riskcomorbidities 5240(32.8) 5241(32.8) 1high-riskcomorbidity 5365(33.6) 5349(33.4) ≥2high-riskcomorbidities 5385(33.7) 5403(33.8) ≥1high-riskcomorbidity 10,750(67.2) 10,752(67.2) Frailty-associatedconditions Nofrailtyconditions 2129(13.3) 2132(13.3)

Onefrailtycondition 4988(31.2) 4893(30.6)

Twofrailtyconditions 3970(24.8) 4046(25.3)

≥3frailtyconditions 4903(30.7) 4922(30.8)

IIV-HD:high-doseinfluenzavaccine;IIV-SD:standard-doseinfluenzavaccine.

Note:proportionswithlistedcharacteristicsdidnotdiffersignificantlybetween

studygroups.

theauthors.Nopersonsotherthantheauthorsplayedanyrolein writingthemanuscript.

3. Results 3.1. Participants

Atotalof31,989participantswereenrolledwith15,991 ran-domlyassignedtoreceiveIIV-HDand15,998randomlyassigned toreceiveIIV-SD.Ofyear1participants,7645werereenrolledand randomlyassignedagaintoreceiveoneofthestudyvaccinesin year2.Oftheparticipantswhounderwentrandomization,31,983 (>99.9%) receivedstudy vaccineand wereincluded in theFAS: 15,990intheIIV-HDgroupand15,993intheIIV-SDgroup.

Baselineclinicalanddemographiccharacteristicswerewell bal-ancedbetweengroups[5].Inboththegroups,themeanagewas 73.3years, 56%–57% of participants werefemale, and approxi-mately74%hadreceivedinfluenzavaccinationduringtheprevious season.Thefrequenciesoftheprespecifiedbaselinecharacteristics ofinterestwerecloselysimilarforbothvaccinegroups(Table1and SupplementaryTableintheonlineappendix).

3.2. Efficacy

RelativeVEpointestimatesforallsubgroupsofbaseline char-acteristicsofinterestandforallendpointswerepositive,favoring IIV-HDoverIIV-SD(Tables2and3).

Fortheprimaryendpointofculture-orPCR-confirmedinfluenza PD-ILIcausedbyanyinfluenzaviraltype/subtype(regardlessof similaritytothevaccine),IIV-HDwassignificantlymoreeffective thanIIV-SDforbothagestrata(65–74yearsand≥75years),for par-ticipantswithnohigh-riskcomorbiditiesandthosewithatleast one high-riskcomorbidity,and for individualswithone frailty-associatedcondition.RelativeVEpointestimatesfortheendpoint ofculture-confirmedinfluenzaPD-ILIcausedbyanyinfluenzaviral type/subtype(regardlessofsimilaritytothevaccine)were com-parabletothoseoftheprimaryendpoint,butestimateswereless preciseandsignificancewasobservedonlyforthecohortof partic-ipants75yearsofageandolderandforparticipantswithatleast onehigh-riskcomorbidity(Table2).

For 15 of 20 comparisons,relative VE point estimates were higherwhentheanalyseswererestrictedtoinfluenzaisolates clas-sifiedas similartothevaccinecomponents(Table 3).Although CIsfortheestimateswerewider,VEwasstatisticallysignificantly higherforIIV-HDfor6ofthe20comparisons.

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C.A. DiazGranados et al. / Vaccine 33 (2015) 4565–4571 Table2

Efficacyofhigh-doseinfluenzavaccine(IIV-HD)relativetostandard-doseinfluenzavaccine(IIV-SD)againstconfirmedinfluenzacausedbyanyviraltype/subtype(regardlessofsimilaritytothevaccine),associatedwitha protocol-definedinfluenza-likeillness.

Laboratory-ConfirmedInfluenza (PositivePCRand/orCulture)

Culture-ConfirmedInfluenza

BaselineCharacteristic IIV-HD n/N(%) IIV-SD n/N(%) Relative Efficacy% (95%CI) P-Valuea IIV-HD n/N(%) IIV-SD n/N(%) Relative Efficacy% (95%CI) P-Valuea Age Age65–74years 156/10,581(1.47) 194/10,563(1.84) 19.7(0.4;35.4) 0.351 143/10,581(1.35) 174/10,563(1.65) 18.0(−3.0;34.7) 0.313 Age≥75years 72/5409(1.33) 107/5430(1.97) 32.4(8.1;50.6) 63/5409(1.16) 94/5430(1.73) 32.7(6.4;51.9) High-riskcomorbidities Nohigh-riskcomorbidities 66/5240(1.26) 93/5241(1.77) 29.0(1.6;49.0) 0.875 60/5240(1.15) 84/5241(1.60) 28.6(−0.7;49.6) 0.873

Onehigh-riskcomorbidity 82/5365(1.53) 103/5349(1.93) 20.6(−7.1;41.3) 74/5365(1.38) 93/5349(1.74) 20.7(−8.8;42.3)

≥2high-riskcomorbidities 80/5385(1.49) 105/5403(1.94) 23.6(−3.2;43.6) 72/5385(1.34) 91/5403(1.68) 20.6(−9.3;42.5) ... ≥1high-riskcomorbidity 162/10,750(1.51) 208/10,752(1.93) 22.1(3.9;37.0) 146/10,750(1.36) 184/10,752(1.71) 20.6(0.8;36.6) Frailty-associatedconditions Nofrailtyconditions 29/2129(1.36) 44/2132(2.06) 34.0(−7.9;60.2) 0.838 26/2129(1.22) 41/2132(1.92) 36.5(−6.3;62.7) 0.830

Onefrailtycondition 71/4988(1.42) 96/4893(1.96) 27.5(0.4;47.4) 65/4988(1.30) 84/4893(1.72) 24.1(−6.2;45.9)

Twofrailtyconditions 56/3970(1.41) 75/4046(1.85) 23.9(−9.0;47.2) 49/3970(1.23) 64/4046(1.58) 22.0(−15.0;47.3)

≥3frailtyconditions 72/4903(1.47) 86/4922(1.75) 16.0(−16.3;39.4) 66/4903(1.35) 79/4922(1.61) 16.1(−17.8;40.4)

PCR:polymerasechainreaction;CI:confidenceinterval;n:subjectswithspecifiedillness;N:subjectsinthefullanalysisset(intent-to-treat). aP-valueagainsthypothesisofhomogeneityinvaccineefficacyacrossstratadefinedbybaselinecharacteristics,byBreslow–Daytest.

Table3

Efficacyofhigh-doseinfluenzavaccine(IIV-HD)relativetostandard-doseinfluenzavaccine(IIV-SD)againstconfirmedinfluenzacausedbystrainssimilartothevaccinecomponents,associatedwithaprotocol-definedinfluenza-like illness.

Baselinecharacteristic Laboratory-confirmedinfluenzaa (PositivePCRand/orCulture)

Culture-confirmedinfluenzab IIV-HD n/N(%) IIV-SD n/N(%) Relative Efficacy% (95%CI) P-Valuec IIV-HD n/N(%) IIV-SD n/N(%) Relative Efficacy% (95%CI) P-Valuec Age Age65–74years 47/10,581(0.44) 72/10,563(0.68) 34.8(4.6;55.9) 0.940 40/10,581(0.38) 58/10,563(0.55) 31.2(−4.8;55.2) 0.967 Age≥75years 26/5409(0.48) 41/5430(0.76) 36.3(−6.6;62.6) 23/5409(0.43) 34/5430(0.63) 32.1(−18.7;61.8) High-riskcomorbidities Nohigh-riskcomorbidities 22/5240(0.42) 35/5241(0.67) 37.1(−10.2;64.9) 0.357 20/5240(0.38) 30/5241(0.57) 33.3(−21.4;64.1) 0.292

Onehigh-riskcomorbidity 21/5365(0.39) 42/5349(0.79) 50.1(13.9;72.0) 17/5365(0.32) 34/5349(0.64) 50.1(8.3;73.9)

≥2high-riskcomorbidities 30/5385(0.56) 36/5403(0.67) 16.4(−39.6;50.3) 26/5385(0.48) 28/5403(0.52) 6.8(−64.8;47.5) ... ≥1high-riskcomorbidity 51/10,750(0.47) 78/10,752(0.73) 34.6(5.7;55.0) 43/10,750(0.40) 62/10,752(0.58) 30.6(−4.0;54.1) Frailty-associatedconditions Nofrailtyconditions 9/2129(0.42) 22/2132(1.03) 59.0(7.4;83.4) 0.280 8/2129(0.38) 20/2132(0.94) 59.9(5.1;84.7) 0.463

Onefrailtycondition 18/4988(0.36) 35/4893(0.72) 49.6(8.5;73.1) 18/4988(0.36) 26/4893(0.53) 32.1(−28.7;64.9)

Twofrailtyconditions 22/3970(0.55) 25/4046(0.62) 10.3(−65.7;51.8) 18/3970(0.45) 20/4046(0.49) 8.3(−82.6;54.3)

≥3frailtyconditions 24/4903(0.49) 31/4922(0.63) 22.3(−36.8;56.4) 19/4903(0.39) 26/4922(0.53) 26.6(−37.8;61.6)

PCR:polymerasechainreaction;CI:confidenceinterval;n:subjectswithspecifiedillness;N:subjectsinthefullanalysisset(intent-to-treat). aForlaboratory-confirmedinfluenzaassessments,similaritywasdeterminedbyferretantigenicitytestingcomplementedbygeneticsequencing. b Forculture-confirmedinfluenzaassessments,similaritywasdeterminedsolelybytheferretantigenicitytestingmethod.

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C.A.DiazGranadosetal./Vaccine33(2015)4565–4571 4569

Table4

Hemagglutinationinhibition(HAI)geometricmeantiters(GMTs)ofhigh-doseinfluenzavaccine(IIV-HD)andstandard-doseinfluenzavaccine(IIV-SD)againstinfluenza viraltypesandsubtypescontainedinthevaccine.

Vaccinestrain Baselinecharacteristic IIV-HD IIV-SD

N GMT

(95%CI)

N GMT

(95%CI)

A/California/7/2009(H1N1)a,b,c Age65–74years 3540 466.2(448.2;485.0) 3453 263.7(252.5;275.4)

Age≥75years 1714 388.2(366.2;411.5) 1801 216.8(203.5;230.9)

≥1high-riskcomorbidity 3518 451.0(433.1;469.7) 3561 243.6(233.2;254.6)

≥2high-riskcomorbidities 1752 461.6(435.3;489.5) 1776 255.8(240.1;272.5)

≥3frailtyconditions 1601 429.7(405.0;456.0) 1633 241.0(225.9;257.1)

A/Victoria/210/2009(H3N2)a Age65–74years 1609 729.1(685.8;775.1) 1596 349.5(328.4;372.0)

Age≥75years 766 602.3(549.5;660.3) 786 350.6(318.9;385.4)

≥1high-riskcomorbidity 1639 667.4(627.5;709.7) 1646 336.1(315.8;357.6)

≥2high-riskcomorbidities 849 684.3(628.7;744.9) 849 330.8(302.9;361.2)

≥3frailtyconditions 825 649.8(596.8;707.5) 853 338.2(310.2;368.7)

A/Victoria/361/2011(H3N2)b Age65–74years 1931 468.5(444.6;493.7) 1857 269.0(254.4;284.5)

Age≥75years 948 443.1(411.9;476.6) 1015 225.6(209.1;243.4)

≥1high-riskcomorbidity 1879 467.3(443.0;493.0) 1915 245.7(232.4;259.7)

≥2high-riskcomorbidities 903 456.9(423.4;493.1) 927 243.7(224.9;264.2)

≥3frailtyconditions 776 456.2(420.4;495.0) 780 239.9(220.8;260.8)

B/Brisbane/60/2008a Age65–74years 1609 130.3(123.5;137.6) 1596 86.2(81.7;91.0)

Age≥75years 766 155.8(144.8;167.6) 786 125.4(116.0;135.6)

≥1high-riskcomorbidity 1639 138.3(131.2;145.8) 1646 100.8(95.5;106.5)

≥2high-riskcomorbidities 849 146.7(136.3;157.9) 849 110.7(102.8;119.2)

≥3frailtyconditions 825 145.0(134.7;156.1) 853 105.0(97.6;112.9)

B/Texas/6/2011b Age65–74years 1931 97.7(93.2;102.3) 1857 61.6(58.6;64.7)

Age≥75years 948 99.3(92.9;106.2) 1015 62.2(58.4;66.2)

≥1high-riskcomorbidity 1879 104.8(99.9;110.0) 1915 63.3(60.3;66.4)

≥2high-riskcomorbidities 903 113.7(106.1;121.9) 927 66.1(61.7;70.9)

≥3frailtyconditions 776 104.7(96.8;113.2) 780 65.2(60.7;70.1)

CI:confidenceinterval;N:subjectsinthefullanalysissetandtheimmunogenicitysubsetwithatleastoneHAIassayresultfortheyear(s)

aYear1vaccinestrain. bYear2vaccinestrain.

c AstheH1N1vaccinestrainwasthesameforyear1andyear2,thedatawerepooled. Noneofthe12Breslow–Daytests(onetestforeachofthefour endpointsevaluatingthethreebaselinevariables)revealed signif-icantevidenceofheterogeneityoftherelativeVEacrossstratafor eachbaselinecharacteristicofinterest(Tables2and3).

3.3. Immunogenicity

IIV-HDwasassociatedwithsignificantlyhigherGMTsthan IIV-SDforallstrainsandforallsubgroupsofinterest(Table4andFig.1). Overall,postvaccination GMTstendedtobe highestagainstthe H3N2componentofthevaccineinyear1(A/Victoria/210/2009) and lowest against the B component of the vaccine in year 2 (B/Texas/6/2011).

GMTratios(IIV-HD–IIV-SD)rangedbetween1.24and2.09,with allestimatesshowinglowerlimitsoftheCIsabovethenullvalue (Fig.1).GMTratiostendedtobehighestforH3N2vaccine compo-nentsandlowestforBvaccinecomponents.

4. Discussion

Althoughvaccinationcurrentlyrepresentsthemosteffective interventioninpreventinginfluenzaanditscomplications[2,10], antibodyresponseandprotectionelicitedbystandardinfluenza vaccines are lower in persons 65 years of age and older com-paredtoyounger adults [11–13].This isbelieved to berelated to changes associated with aging of the immune system or “immunesenescence”[14,15].Immunesenescenceencompasses notonlyimmunologic deteriorationthat occurswithadvancing chronologicalage,butalsootherage-relatedevents,includingthe developmentandaccumulationofchroniccomorbidillnessesand frailtyconditions.Bothillnessandfunctionalimpairmentincrease withage,butpersonswiththesamechronologicalagemayvary widelyinhealthandfunction[16].

Theresultsofthissupplementaryanalysisprovidereassurance thattheefficacyandimmunogenicitybenefitsofIIV-HDoverIIV-SD thatwereobservedfortheentirestudycohort[5]remainconsistent acrossdifferentsubgroupsofspecialinterest.

Ithasbeenshownthatamongadults65yearsofageandolder, influenza-associated hospitalization rates increase dramatically withincreasingage[1].Studieshavealsoindicatedthat effective-nessofstandardinfluenzavaccinesdecreasesinolderadultsasage increases[12].Bothfactorsplayanimportantroleinthe dispropor-tionateburdenofinfluenzathatisobservedwithincreasingage. Thesupplementaryefficacyanalysisreportedhereinshowedthat IIV-HDprovidedsignificantlybetterprotectionthanIIV-SDagainst laboratory-confirmedPD-ILIinbothagestrataofolderadults.These dataderivedfromarandomized,controlledtrialgreatlyreaffirm theresultsofarecentlypublishedlargeretrospectivecohortstudy thatreportedsimilarestimatesofvaccineeffectivenessinadults 65–74,75–84,and≥85yearsofage[17].

Thedramatic increasein ratesof seriousinfluenza illnessin olderadultsisthoughttobedueinparttotherisingprevalence ofhigh-riskconditionsforinfluenzaillnessanditscomplications inthispopulation[1,14].Apreviousepidemiologicstudyreported that deathrates from influenza and pneumonia in adults ≥65 years ofageincreasedfrom9per100,000populationforthose withnohigh-riskcomorbidityto217per100,000populationfor those with one high-risk comorbidity and to 797 per 100,000 populationfor those withtwo or more high-riskcomorbidities [18]. Prior to recommending universal influenza immunization for individuals 6 months of age and older, the United States Advisory Committee for Immunization Practices (ACIP) recom-mendedinfluenzavaccinationinindividualsconsideredtobeat highriskforinfluenzacomplications,includingthosewithchronic cardiopulmonary,renal,metabolic,hematologic,or immunosup-pressiveconditions[2].Thehigh-riskcomorbidillnessesevaluated

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Vaccine Strain Subgroup GMT rao (95%CI) Forest Plot A/California/7/2009 (H1N1)*^ 65–74 years 1.77 (1.67; 1.87) ≥ 75 years 1.79 (1.64; 1.95) ≥1 high-risk comorbidity 1.85 (1.74; 1.97)

≥2 high-risk comorbidies 1.80 (1.66; 1.97)

≥3 frailty condions 1.78 (1.63; 1.95)

A/Victoria/210/2009 (H3N2)*

65–74 years 2.09 (1.91; 2.28)

≥ 75 years 1.72 (1.51; 1.96)

≥1 high-risk comorbidity 1.99 (1.82; 2.17)

≥2 high-risk comorbidies 2.07 (1.83; 2.34)

≥3 frailty condions 1.92 (1.70; 2.17)

A/Victoria/361/2011 (H3N2)^

65–74 years 1.74 (1.61; 1.88)

≥ 75 years 1.96 (1.77; 2.18)

≥1 high-risk comorbidity 1.90 (1.76; 2.05)

≥2 high-risk comorbidies 1.87 (1.68; 2.09)

≥3 frailty condions 1.90 (1.69; 2.14)

B/Brisbane/60/2008* 65–74 years 1.51 (1.40; 1.63)

≥ 75 years 1.24 (1.12; 1.38)

≥1 high-risk comorbidity 1.37 (1.27; 1.48)

≥2 high-risk comorbidies 1.33 (1.19; 1.47)

≥3 frailty condions 1.38 (1.25; 1.53)

B/Texas/6/2011^ 65–74 years 1.59 (1.48; 1.70)

≥ 75 years 1.60 (1.46; 1.75)

≥1 high-risk comorbidity 1.66 (1.55; 1.77)

≥2 high-risk comorbidies 1.72 (1.56; 1.90)

≥3 frailty condions 1.60 (1.44; 1.78)

GMT Ratio: IIV-HD / IIV-SD

1.0 1.5 2.0 2.5

Fig.1.HAIantibodyGMTratios(IIV-HDtoIIV-SD)forvaccinestrains.

(*)Correspondstoayear1vaccinestrain;(ˆ)correspondstoayear2vaccinestrain.AstheH1N1vaccinestrainwasthesameforyear1andyear2,thedatawerepooled.The plotontherightdepictsGMTratiosforeachsubgroupofinterest;horizontallinesrepresentthe95%confidenceintervalsandsolidsquaresrepresentthepointestimates. Allestimatestotherightofthenullvalueof1favorIIV-HDoverIIV-SD.Estimatesthatdonotintersectwiththenullvaluearestatisticallysignificant.

atbaselineinthisstudycloselycorrespondedtothosethatACIP hastraditionallyconsideredhighriskforinfluenzaandits compli-cations.Previousstudieshavesuggestedthattheeffectivenessof standardinfluenzavaccinesislowerinadultswiththesehigh-risk comorbiditiesthaninthosewithoutthem[19–21].Notably,this supplementaryanalysissuggeststhatthe24.2%improvedefficacy ofIIV-HDover IIV-SDinpreventinglaboratory-confirmedPD-ILI thatwasobservedfortheentirecohort[5]isgenerallymaintained inindividualswithbaselinehigh-riskcomorbidities:therelative efficacyobserved in this supplementaryanalysiswas 22.1% for

individuals withat leastone high-risk comorbid conditionand 23.6%forthosewith2ormorehigh-riskcomorbidities.

Incommunity-dwellingolderadults,frailtyisassociatedwith impairmentofvaccine-inducedantibodyresponseandincreased riskofbreakthroughinfluenzainfection[22].Therefore,ithasbeen suggestedthatevaluatingfrailtystatusintheelderlymayidentify thosewhoarelesslikelytorespondtoinfluenzaimmunizationand beathigherriskforinfluenzaanditscomplications.Ouranalysis ofstrataencompassingone,two,orthreeormorebaselinefrailty conditionsconsistentlyfavoredIIV-HDoverIIV-SD,withrelative

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C.A.DiazGranadosetal./Vaccine33(2015)4565–4571 4571

efficacypointestimatesrangingbetween16.0%and27.5%against anyinfluenzastrain regardlessofsimilarity tothevaccine,and between8.3%and49.6% againstinfluenzastrainssimilartothe vaccinecomponents.

Importantly, our results revealed no significant evidence of vaccineefficacymodificationbyincreasingage,high-risk comor-bidities,orfrailty.

Overall, the supplementary immunogenicity analyses pre-sentedheredemonstratethatIIV-HDsignificantlyimprovedHAI responsesforallstrainsandin allsubgroupsduringbothstudy years.

Thissupplementaryreporthasimportantlimitations.The orig-inal study was not powered to address the objectives of this supplementaryanalysis.Therefore,someestimatespresentedhere forindependentstratadonothavesufficientprecisionto demon-stratestatisticalsignificance.Althoughtheoriginalstudyallowed inclusionof individuals withhigh-risk comorbiditiesand frailty conditions,participantswereexcluded iftheyhadmoderate or severeacute illnesses oriftheywere judgedunable tocomply withstudyprocedures.Extrapolationofstudyresultstosuch indi-vidualsshouldbemadewithcaution.Additionally,thehigh-risk comorbiditiesprespecifiedinthestudyareunlikelytorepresenta homogenouslevelofriskforinfluenzacomplications.Depending onfactorssuchastypeofconditionanditsstage,medical treat-ment,andseverity,theriskmayrangefromminimaltoveryhigh. Accordingly,classifyingindividualsintoasinglegroupwithout tak-ingthesefactorsintoaccountmayhavedecreasedtheabilityto detectdifferencesinsubsetsoflowtohighrisk.Finally,this supple-mentaryanalysisevaluatedseveralassociationswithoutcorrecting formultiplicity.Therefore,evenstatisticallysignificanteffectsneed prudentinterpretations.

Inconclusion,thissupplementaryanalysissuggeststhatIIV-HD islikelytoprovidebenefitsbeyondIIV-SDtoalladults≥65years, irrespectiveofage,presenceofcomorbidities,orfrailty-associated conditions.

ConflictofInterestStatement

ThestudywassponsoredbySanofiPasteur.

C.A.D,A.J.D,C.A.R,V.L,andD.P.GareemployeesofSanofiPasteur. H.K.ThasreceivedresearchfundingfromMedImmune,Sanofi Pasteur,andGilead.

Acknowledgments

Theauthorswouldliketothanktheparticipantsoftheoriginal study,theinvestigatorsfromthe126participatingresearchsites, andthesponsor’sstudyteam.

AppendixA. Supplementarydata

Supplementarydataassociatedwiththisarticlecanbefound,in theonlineversion,athttp://dx.doi.org/10.1016/j.vaccine.2015.07. 003

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