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Long-termE ffectivenessofVaricella Vaccine: A14-Ye ar,

ProspectiveC ohortStudy

WHAT'S KNOWNONTHIS SUBJECT :Varicellavaccineis knownto be highlyeffect ive,withadded benefit fromaseco nddos e. WHATTHIS STUD YADDS:This studydemo nstratesthelasting effectivenessof varicella vaccineandthe benefit ofthe second dose. Breakthroughvaricella occurredsoonaftervaccinatio n, varicellar atesdidnotincrease over14 years,and therewas no increase inzoster inthe cohor t. abstract BACKGROUND:Varicellavaccine waslicensed inthe UnitedStates in

1995 forindividuals $12 monthsof age.A seconddose wasr ecom-

mended inthe UnitedStates inJune 2006.V aricellaincidence and vaccine effectivenesswer eassessedina 14-year prospective study conducted atK aiserPermanenteNor thernCalifornia. METHODS:A totalof 7585childr envaccinated withvaricellavaccinein their secondyear oflife in1995 were followedup prospectively for breakthroughvaricellaand herpeszoster (HZ)thr ough2009. Atotal of 2826of thesechildr enr eceivedaseconddose in2006-2009. Inci- dences ofvaricella andHZ were estimatedand comparedwithpre - vaccine erarates. RESULTS:In thiscohor tofvaccinatedchildr en,the aver ageincidence of varicellawas 15.9per 1000person- years,nine- totenfold lowerthan in thepr evaccineera.V accineeffectivenessatthe endofthestudy period was90%, withno indicationof waningover time.Most cases ofvaricella were mildandoccurred earlyafter vaccination. No childdeveloped varicellaafter asecond dose.HZ caseswer e mild, andr ateswerelower inthecohort ofvaccinated children than inunvaccinated children duringtheprevaccine era (relative risk: 0.61[95% confidence interval:0.43 -0.89]). CONCLUSIONS:This studycon firmed thatvaricella vaccineis effective at preventingchickenpox, withno waningnoted overa 14-year period. One dosepr ovidedexcellentprotection againstmoder atetosevere disease, andmos tcasesoc curredshor tlyafterthecohor twasvac- cinated. Thes tudydataalsosuggestt hatv aricellavaccination mayr educetherisks ofHZ in vaccinatedchildr en.Pediatrics

2013;131:e1389

-e1396

AUTHORS:Roger Baxter,MD,

a

PaulaRay ,MPH,

a

TrungN.

Tran,MD,PhD,

b

Steve Black,MD,

c

Henry R.Shine field, MD,

d

PaulM. Coplan,ScD, MBA,

e

Edwin Lewis,MPH,

a Bruce

Fireman,MA,

a and PatriciaSaddier, MD,PhD b a KaiserP ermanenteVaccineStudy Center,Oakland,California ; b

Epidemiology Department,MerckSharp &Dohme Corp,

Whitehouse Station,New Jersey;

c

Center forGlobal Health,

Cincinnati Children's Hospital,Cincinnat i,Ohio;

d

University of

California SanF ranciscoMedicalCenter,University ofCalifornia,

San Francisco,SanFrancisco ,California; and

e

PurduePharma,

Stamford,Connecticut

KEY WORDS

chicken pox,childre n,effectiveness,vaccine, varicella,zoster

ABBREVIATIONS

CI - confidence interval

HZ - herpes zoster

KPNC - KaiserP ermanenteNorthernCalifornia

PY - person-years

RR - relativerisk

VZV - varicella viruszoster

Dr Baxtersupervised datacollection andanalyses, drafted the initial manuscript,andappr ovedthe final manuscriptas submitted; MsRay designeddata collectioninstruments, coordinatedinterviews anddata collection, performedanalyses, reviewedthe manuscript, andapprovedthe final manuscriptas submitted; DrT ranassistedwithanalysesand themanuscr ipt, critically reviewedthemanuscript ,and approvedthefinal manuscript assubmitted; DrsBlack andShine field assistedwith the originalconcept anddesign, supervisedearly datacollection and analyses,and reviewed andapprovedthe manuscript as submitted; DrCoplan assistedwith originaldesign and statistical plan,and reviewed andapprovedthe manuscriptas submitted; MrL ewisassistedwiththe designand statistical plan, assistedwith analyses,critically reviewed themanuscript , and approvedthefinal manuscriptassubmitted; MrFire man assisted withthe originalconcept anddesign, workedon analyses, criticallyrevi ewedthemanuscript, andappr ovedthe final manuscriptas submitted;and DrSaddier assistedwith analyses andthe manuscript, criticallyreviewedthe manuscript,and approved thefinal manuscriptassubmitt ed. doi:10.1542/peds.2012-3303

Accepted forpublication Jan22, 2013

Addresscorres pondencetoRogerBaxter ,MD, Kaiser Permanente VaccineStudy Center, 1KaiserPlaza, 16B,Floor ,Oakland,CA

94612. E-mail:rog er.baxter@kp.org

PEDIATRICS(ISSN Numbers:Print, 0031-4005;Online, 1098-4275). Copyright© 2013by theAmerican Academyof Pediatrics (Continued onlast page)

PEDIATRICSVolume 131,Number 5,Ma y2013 e1389

ARTICLE

by guest on June 16, 2014pediatrics.aappublications.orgDownloaded from

Varivax(Oka/Mer ckvaricellavaccine

live [MerckSharp& DohmeCorp ,

Whitehouse Station,NJ]), basedon the

OkastraindevelopedbyTakahashietal

inthe1970s, 1 waslicensedintheUnited

Statesin199 5an drecommen dedsoon

afterbythe Advi soryC ommitteeonIm- munizationPractice sforroutinead- ministrationtoallimmun ocom petent children. 2

Beforethatti me,varice llavi-

ruszost er(VZV)inf ectionwasub iqui- tous,with.90%ofpeopleexperiencing infectionbytheageof20years,and resultinginthousa nds ofhospital- izationswith≂100d eathsannually in theUn itedStates. 3-6

Afterintr oduction

ofth evaccin eintheUnited Stat es,dis- easei ncidencefellmarkedl y. 7,8

Efficacyof1doseofvaccinewashighin

clinical trials, 9 and thevaccine 's effec- tiveness wascon firmed inpost - licensurestudies tobe 80%to 94% 10,11 in preventingchickenpox andhighly effectiveinp reve ntingmoderateto severedisea se.However,break- throughdisease wasnoted andout - breaksstill occurred, 12-14 leading toa recommendationby theAdvisory Com- mittee onImmunization Practices in

2006foraseconddoseofthevaccineat

4 to6 yearsof age.

15

Since imple-

mentation ofthe seconddose, studies haver eportedthatvaricellaincidence has declinedfur ther. 11,16

Effectiveness

of the2-dose serieswas calculated to be98% in2 separate studies,a ran- domized, prospectivestudy 11 and a case-controlstudy . 17

The effectof varicellavaccination pro-

gramsontheincidenceofherpeszoster (HZ)inthegeneralpopulationisnotwell known.HZriskwasfoundtobelowerin vaccinated childrenaged,10 years than inunvaccinated children ofthe sameagewithahistoryofvaricella. 18,19

However,concerns arose thatwide-

spreadvaccination ofchildr encould decreaseVZV immune-boostingop- portunitiesand leadto anincre asein

HZ inadults.

20-23

In thecurre ntstudy,we prospectively

followed upa cohort ofchildrenfor 14 yearswhor eceivedvaricellavaccinein their secondyear oflife (in1995) to assess thelong-term effectivenessof the vaccineand theimpact onthe epi- demiology ofvaricella andHZ. We also observedtheimpactoftheseconddose of varicellavaccineintroduced in2006.

This studywas conductedas apost -

licensurecommitment tohealth au- thorities, initiallyin theUnited States and thenworldwide.

METHODS

Study Population

The studywas conductedat multiple

sites inK aiserPermanenteNor thern

California (KPNC),an integrated health

caredeliverysystemserving3.2million members.Themembershipreflectsthe racialand economicdiversity ofthe generalpopulation inthe northern

California region,althoughit under-

representsthelowendoftheeconomic spectrum. 24-26

Members obtainalmost

alltheirmedicalcareatKPNCfacilities.

KPNC databasesstor edetailedin-

formation onall healthcar eencoun- ters, whichar elinkedbyusing the patient's uniquemedical recor dnum- ber.

Parentsor guardians ofchildren12 to

23 monthsof age,who received vari-

cella vaccinebetween Juneand No- vember 1995as apar tof routinecare, werecontacted bytelephone inter- viewers 6months afterr eceiptof the vaccine andasked topar ticipatein along-termfollow-upstudyofvaricella.

Parentsof 7585vaccinated children

consented topar ticipate.

Data Collection

Telephoneinterviews were scheduled

every 6months for14 years,from vaccination through2009.At each contact, parentswere askedaboutthe

occurrenceofvaricellaandzostersincethe lastinterview .Parents werepro-vided atoll-fr eetelephonenumberto

reportnewvaricella intheir childbe- tween interviewsor toask questions.

During eachinterview ,parentswer e

remindedabout theclinical features of varicella andzoster ,andinstructedto callimmediatelyifsignsorsymptomsof either ofthese arose.

Outcomes Definitions

Breakthroughvaricellacaseswer e

basedon parenta lreport;nomed ical confirmationofthe diagn osiswa sre- quired.Pare ntswereaskedwhethe r therewere#50lesions(mild);51to300 lesions(moder ate);or.300l esions (severe).Casesocc urringwi thin6 weeksofv accinat ionwereexcludedto avoidinc ludingvaccine-re latedrash/ varicellaorwild-ty ped iseasethatmay havebeenco ntracte dbeforevaccina- tion.For thedesc riptio nofratesof varicellaafterth eseconddose, only childrenwithco ntinuous KPNCmem- bershipfrom June2006(wh enthe seconddos ewasreco mmended )to

November2009(t heendofthe study)

werein cludedtoensurereli able vac- cinei nformation.CasesofHZrequi red a diagnosisbyamedi calprov ide r,con- firmedby chartr eview,but didnotre- quireanyla borato ryconfirmation.No testingwasdon etodet erminewh ethe r

HZc asesweredu etowild-t ypeo r

vaccine-derivedvirus.

Analyses

Varicella

Wemeasur edtheincidenceof break -

throughvaricella invaccinees every6 months andestimated annualr ates.

The person-timedenominator wasthe

total follow-uptime contributedsince the lastinterview bysubjects who completedtheinterviewforthatphase.

The primaryanalysis wasbasedonthe

first occurrenceofvaricella, and person-timewascensoredatthetimeof thefirst episode,ignoring subsequent e1390BAXTER etal by guest on June 16, 2014pediatrics.aappublications.orgDownloaded from episodes. Wealsomeasur edtotal var- icella incidenceincluding recurr ent cases afterthe first occurrenceof varicellaandalloftheavailableperson- time offollow-up .

Because theentir ecohortwas vacci-

nated, weused historicalvaricella in- cidence ratesasthe comparator to estimate varicellavaccine effective- ness, basedon publishedstudies con- ductedbeforevaccinelicensur e.

5,6,27-30

Twoofth ep ublish edstudieswerepop-

ulationbased,usedparent -repor ted varicella,andprov idedage -specificin- cidencerate sofvaricell ai nchildren. 5,6

Weus edsuscep tibility-adjustedrates,

basedon onlysu sceptible individuals, fromthes epublished studies.

6,30,31

To obtainthea verage historicalvarice lla incidencerateover thedurati onofthe study forcomparison, wecalculated a weighted averagehistoricalincidence rate,assuming allchildr enwer evac- cinated at18 monthsof age(the mid- pointofthesecondyear)andusingthe contribution ofeach agegro upto the total follow-upof thestudy cohort as the weight(T able1). HZ

Tocompar eratesof HZinthestudy

cohortwithratesofHZinunvaccinated children,werev iewedth eliteratureo n thei ncidenceofHZbefore va ccinel i- censure.Weidentifiedonly2population- basedepi demiologicstudiesproviding incidenceratesof physician- diagnose d

HZ inchildr en.

6,32 Wechose HZ referenceratesfromtheonlystudythatrestrictedthe analysisto children whohadex- perienced varicella 6 (Table2).

Statistical Methods

Person-timewas calculatedaccor ding

to interviewcycle. Forvaricella, the relativerisk(RR)wascalculatedasthe ratioof theobserved versusthe pre- vaccine incidencer ates.Vaccineeffec- tivenesswascalculated as1 minusthe

RR. ForHZ,the RRwas ther atioof the

total numberof observedHZ casesin thestudycohortandthetotalnumberof expected casesin unvaccinatedchil- drenof thesame agewith ahistory of naturallyacquir edvaricelladuringthe same periodof time.

This studywas approved bytheKPNC

institutional reviewboard.

RESULTS

Follow-up

Theparents/guardiansof9316children

12through23monthsofage,vaccinated

between Juneand November1995, wereinvitedtoparticipateinthisstudy.

Overall,9.9% couldnot ber eachedby

telephone, 6.2%r efusedtoparticipate, and2.5%wereineligiblebecauseofage orlanguagebarriers,yieldinganinitial cohortof7585(81.4%)patientsenrolled byDecember1995.Fourteenyearslater, at theend ofNovember 2009,a totalof

7386 enrollees(97.4%of theorigi-

nal cohort)were stillbeingcontacted and interviewedby studystaff .A totalof 103098person-years (PY)offollow- up datawer ecollected.

Giventhehighretentionrateofthestudy

cohort,the racial/ethnicd istribution remainedessentiallythesa meafter 14 years offollow-up .Inourfinal roundof interviews, 51%of part icipantswere male; 6.5%wer eblackor African

American,12%wereAsian,15%wer e

Hispanic, 43%wer ewhite,23%wer e

multiracial,and 0.4%wer ecategorized as other.

Breakthrough Varicella(>6Weeks

After Vaccination)

A totalof1505breakthr oughcases of

varicella werereported inthe14 years aftervaricellavaccination.Allcaseswere reportedaftert hefirst doseof vaccine; no casesw erereporteda fterdose2.Of allbreakthroughcases,includingrepeat episodes, 356(24%of1505) re port ed51 to 300lesions (moder atecases)and30 (2%)r eported.300l esions(severe cases). Ofth e1505reports,8 0c ases (5.3%)werer eporte dasrepeatcasesof varicella. Thei ncidencerates offirst episode ofbr eakthroughvaricellaare presentedi nTable3.

The averageincidencerate ofbr eak-

throughvaricella overthe 14years of follow-up was15.9 per1000 PY (95% confidence interval[CI]: 15.1-16.7) for varicella episodeswith anynumber of lesions. Consideringall episodes(in- cluding recurrences),theaverage in- cidence rateofbr eakthrough varicella was 14.6per 1000P Y(95% CI:13.9-

15.4)foranysymptoms,3.7per1000PY

(95% CI:3.4 -4.1) for.50 lesions,and

0.3 per1000 PY (95%CI:0.2-0.5) for

.300 lesions(data notshown).

Annual breakthroughratesof varicella

werestable at≂26per1000 PY inthe first 4years aftervaccination. They decreasedto,20per1000PYafterthe fourthyear ,to≂9 per1000 PY atthe end of11 yearsof follow-up, thento

2 per1000 in2009, thelast yearof

follow-up.A totalof 28first-incident TABLE1 AverageHistoricalIncidence Ratesof Varicella Fro mPublished Population-basedStudies of UnvaccinatedChildren (Prevaccine Era)per1000 PY

Age GroupNHIS

1

Kentucky

2

Unadjusted

RateSusceptibility-

adjustedRate a

Unadjusted

RateSusceptibility-

adjustedRate a

1-4 y82.1 9799.4 120

5-9 y90.3 19780.7 231

10-15 y17.5 11613.5 117

Weightedaveragehistoricalrate

b

140.1158.9

NHIS, NationalHe althInterviewSurvey.

a

FromV esseyetal,2001.

30
b

Historical incidencer ateofvaricella expectedto beobservedinthe studycohor tat theend ofthe 14-yearfollow-up.

ARTICLE

PEDIATRICSVolume 131,Number 5,Ma y2013 e1391

by guest on June 16, 2014pediatrics.aappublications.orgDownloaded from breakthroughvaricellacases with .300 lesionswer ereported overthe

14 yearsof follow-up, including13in

thefirst 4years aftervaccination.

Overall,ther edidnotseem tobe an

increasein theseverity ofbr eak- throughvaricella casesover timein vaccinated children(Fig1).

Comparison WithHistorical

Incidence Ratesof Varicella

Based onsusceptibility-adjusted his-

toricalratesofvaricellaforchildren1to

15 yearsold inthe 2r eference studies,

the expectedave ragevaricellain- cidence ratesinthe cohort children, had theyr emainedunvaccinated,were

140.1 and158.9 per1000 PY (Table 1).

Theobservedincidencerateof15.9per

1000 PYinthe 1-to 15-year-old vacci-nated childreninthe studywas there- fore9 to10 timeslower thanthe historical ratesinchildr enof thesame

age inthe prevaccine era.Theover all vaccineeffectivenessattheendof the studywas8 9%to 90%depending on ther eferencestudyused.Annual vaccineeff ectivenessrangedfrom

73% to80% in19 96

-1997( thefirst 2 yearso fthestudy) to80%to 90%in

2000-2009 (thela st10yearso ft he

study).

Racial Differencesin Breakthrough

VaricellaRates

The averageincidencerate ofr eported

breakthroughvaricellawas slightly lowerinAsian(12.4per1000PY[95%CI:

10.6-14.5]) andAfrican-American (11.5

[95% CI:14.8 -17.2]). ForHispanicchil- dren,the rate was13.0per1000 PY (95% CI:11.3 -15.0), andfor multiracial participants,it was15.1 per1000 PY (95% CI:13.6 -16.8).

Breakthrough VaricellainStudy

ParticipantsWhoReceived

a SecondDose

Amongthestudyparticipantswhowere

still activein thelast surveyyear ,4546 (62%) werecontinuousKPNC health plan membersf romJune2006to

November2009.Ofthese,2829children

(62% [or38.3% ofthe studycohor t]) receiveda seconddose ofvaricella vaccine. Nobr eakthroughvaricella cases wererepor tedafterreceiptof a seconddose. TABLE2 Incidence ofHZ Accordingto AgeGroup andCompared WithHistorical Rates

Age Group

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