The effectiveness of the national hepatitis B vaccination program 25 years after its introduction in Iran: a historical cohort study

w w w . e l s e v i e r . c o m / l o c a t e / b j i d

The

Brazilian

Journal

of

INFECTIOUS

DISEASES

Original

article

The

effectiveness

of

the

national

hepatitis

B

vaccination

program

25

years

after

its

introduction

in

Iran:

a

historical

cohort

study

Mohsen

Moghadami

_,

_Nazanin

_Dadashpour

_,

_Ali

_Mohammad

_Mokhtari

_,

Mostafa

Ebrahimi

_,

_Alireza

_{Mirahmadizadeh}

a_{ShirazUniversityofMedicalSciences,ClinicalMicrobiologyResearchCenter,Shiraz,Iran}

b_{ShirazUniversityofMedicalSciences,SchoolofMedicine,DepartmentofInternalMedicine,Shiraz,Iran} c_{ShirazUniversityofMedicalSciences,StudentResearchCommittee,Shiraz,Iran}

d_{ShirazUniversityofMedicalSciences,DepartmentofHealth,Shiraz,Iran}

e_{ShirazUniversityofMedicalSciences,Non-communicablediseasesresearchcenter,Shiraz,Iran}

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o

Articlehistory:

Received21June2019 Accepted6October2019

Availableonline1November2019

Keywords:

HepatitisB Vaccination

Effectivenessresearch

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b

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Introduction:HepatitisBvirus(HBV)isresponsibleforoneofthemostcommonhumanviral infections.Anestimated257millionpeoplearelivingwithchronicHBVinfection world-wide,andmortalityhasreached900,000deathsinrecentyears.In2001,theWorldHealth OrganizationreportedaprevalenceofchronichepatitisBinfectioninIranbetween2–7%.

Objective:ToassesstheeffectofthenationalHBVmassvaccinationprogramafter25years.

Methods:Aretrospectivecohortstudywasconductedinvaccinatedandunvaccinatedpeople accordingtotheyearofbirth.Bloodsampleswereobtainedfromeachenrolledpersonand dataaboutdemographicvariables,andmedicalandvaccinationhistorywerecollectedusing astandardizedquestionnaire.Personswereconsidereduninfectediftheywerenegativefor bothHBsAgandanti-HBc.Also,Vaccineeffectivenesswasmeasuredbycalculatingtherisk ofdiseaseamongvaccinatedandunvaccinatedpersonsanddefiningthepercentagerisk reductionofinfectioninthevaccinatedgroup.

Results:Atotalof2720personswereinterviewed.TherateofHBVbreakthroughinfection amongthevaccinatedgroupwassignificantlylowerthaninunvaccinatedgroup.One hun-dredninety-fourcaseswithpositiveHBVmarkersofinfectionwereidentified.Therisk ratioofHBVinfectionwas0.71,95%CI:0.54–0.94(vaccinated/unvaccinated).Theestimated vaccinationeffectivenessagainstHepatitisBinfectionwas29%(95%CI:6%–46%).

Conclusions: IranhassuccessfullycombinedhepatitisBvaccinationintoregular immuniza-tionprograms. TheWHOgoalofreducingHBsAgprevalencetoanequivalentof1%by

∗ _{Correspondingauthor.}

E-mailaddresses:[email protected](M.Moghadami),[email protected](N.Dadashpour),

[email protected](A.M.Mokhtari),[email protected](M.Ebrahimi),[email protected](A.Mirahmadizadeh).

https://doi.org/10.1016/j.bjid.2019.10.001

1413-8670/©2019SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.ThisisanopenaccessarticleundertheCC BY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/4.0/).

hasbeenreached.Withrespecttovaccinationeffectivenessandlowprevalenceofthe dis-easeinthecountry,catch-uphepatitisBvaccinationprogramsforadolescentscanguarantee theimmunityofthepopulation.

©2019SociedadeBrasileiradeInfectologia.PublishedbyElsevierEspa ˜na,S.L.U.Thisis anopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).

Introduction

Hepatitis Bvirus (HBV) isresponsible forone of the most criticalhumanviral infections.Thevirusisresponsible for acuteandchronicliverdiseases,rangingfromahealthy car-rierstate to cirrhosis and finallyhepatocellular carcinoma (HCC).1 _{According to the latest World Health Organization}

(WHO)report,257millionpeopleareestimatedtolivewith chronicHBVinfectionworldwide,andmortalityhasreached to900,000deathsinrecentyears,mostlyfromcomplications suchasHCCorcirrhosis.2

TheoverallprevalenceofHBVinfectionintheworldwas estimatedat 3.6%, but it dependson the geographic area. Theprevalenceofchronic HBV (positive HBV surface anti-genorHBsAg)rangesfromlessthan2%insomeareaswith a low-prevalence situation (e.g. Western Europe) to 2–7% inintermediate-prevalenceregions(eg,Mediterranean coun-tries,andtheMiddleEast)tomorethan8%inhigh-prevalence areas(e.g.WesternAfrica).3–5

AccordingtothereportsofWHOin2001andofthe Cen-ters forDisease Controland Prevention(CDC) in 2005,the prevalenceofchronichepatitisBinfectionamongIranian pop-ulationrangesbetween2–7%.6,7_{Thiswiderangeofprevalence}

isduetothedifferentgeographicalareasinthecountrywith variablecustomsandcultures.8–11

TheimportantpointinthemanagementofHBVinfection isthatitemergesregardlessofavailabletherapeutic modal-itiessuchasinterferonand antiviraltherapies.There isno definitecureforHBVinfection.12_{Ontheotherhand,the}

pres-enceofantibodytohepatitisBsurfaceantigen(anti-HBs)was associatedwithresistancetoreinfection,includingdiffering serologically-definedsubtypesorserotypes.13_{Thisraisedthe}

possibilitythataneutralizingantibodyeitherfromanimmune globulinorvaccine-inducedmightprotectagainstHBV infec-tion,sincethehepatitisBvaccinewasshowntopreventHBV infectioneffectively.14_{Thus,strategiessuchasneonatal}

vac-cinationagainsthepatitisB,particularlythose borntoHBV infectedmothersisthe mosteffectivestrategytodiminish thespreadofHBVinthecommunity.15

InJuly2016,the WHOannounceditsnew ¨GlobalHealth SectorStrategyonViralHepatitis,2016-2021outliningaplan toreducetransmissionofallhepatitisvirusesandtheir dis-easeburden.16_{Thegoalsfor2020are30%declininginnew}

HBV infections, and alsoan HBsAg prevalence in children ofno morethan 1.0%and,by 2030,a 90% declinein new infections with a prevalence in children of no more than 0.1%.Thespecificgoalforthepreventionofmother-to-child transmissionisto improvedelivery ofabirthdose of vac-cinefromthe2015worldwidebaselineof39%to50%by2020 and 90% by2030 withHBV testing in all pregnant women

and development of new interventions based on antiviral treatment.16

TheepidemiologyofHBVhasbeenextensivelystudiedin the pre-vaccine era, but after introducing the vaccine, few studieshaveaddressedthisissue.Ontheotherhand,these studieshavehaddifferentresultsandreportedthe effective-nessofhepatitisBvaccinationfromlowtohigh.17

IntheIslamicRepublicofIran,massvaccinationagainst HBV infection started in 1993. Thisprogram has launched a new era of hepatitis B control and was one of the first large-scaleHBVprogramsintheregion.Itwasmandatoryfor neonatesbornafterthistimetobevaccinatedusinga recom-binant HBV surface antigenwith classic three consecutive doses.Inthissurvey,weassessedtheimpactofthenational HBVmassvaccinationprogramonthechroniccarriageofHBV andtherateofHBVacquisitionintheIranianpopulation25 yearsafterimplementationofthenationalvaccination pro-gram.

Materials

and

methods

StudyDesign:retrospectiveorhistoricalcohortstudyforthe evaluationofHBVvaccinationimpact.

NationwidehepatitisBvaccinationprogram

TheMinistry ofHealthand MedicalEducationinIranheld thespecificprogramofimmunizationagainsthepatitisBfor thosebornafter1993throughthenationalhealthsystem net-work forurbanandruralareaswithcoverageofmorethan 95%.18 _{Infantsweregivenintramuscular dosesofHBV}

vac-cineat birth,twoand six monthsofage. Thegovernment hascoveredallthe expensesoftheprogram.InIran,since theintroductionofthenationalimmunizationprogram, var-iousHBVvaccineshavebeenused,includingvaccinesmade inCuba,Korea,India,andIran.

Studypopulationandsetting

IntheIslamicRepublicofIran,whichhasapopulationof80 million,publichealthservicesaredeliveredthrougha nation-widenetwork.Thepublicsectoroffersprimary,secondary,and tertiaryhealthservicesforthewholecountrypopulation.The focusofthegovernmentonprimaryhealthcareoverthelast threedecadeshasmadethepublicsectorthemainprovider ofprimaryhealthcareservicesthroughoutthecountry.Some primaryhealthcareservicessuchasprenatalcareand vacci-nationprogramsareprovidedfreeofchargeinpublichealth caresystems.ShirazisthecapitalofFarsprovincein south-ernIranwithapopulationof1,400,000,intheurbanareaand

650,000,inruralparts.Intheurbanarea,nearly100%ofthe populationhasbeenimmunizedwithpreciseregistriesof vac-cinationdata.19

ConcerningtheyearofintroductionofthenationalHBV vaccination program of all infants in Iran (1993), a ret-rospective cohort study was conducted in vaccinated and unvaccinatedcohortsaccordingtothebirthyear.The unvacci-natedcohortwasdefinedaspersonsbornin1992andearlier. Thevaccinatedcohortwasdefinedaspersonsbornin1994 andinthefollowingyears.Thecohortbornin1993wasnot included.

Inclusionandexclusioncriteria

Inclusion criterion inthe vaccinated group was the age of 17–24years,and intheunvaccinated groupit wasthe age rangeof26–50years.Exclusioncriteriawerelackofconsent forparticipating,havinganon-Iraniannationality,orlackof documentationforHBVvaccinationsuchasvaccinationcard orelectronicdocumentinthoseaged17–24years.Also,inthe unvaccinatedgroup,thosewhoreceivedahepatitisBvaccine (foranyreason)outsideoftheinfantilenationalprogramwere excludedfromthestudy.

Studysample

Thesamplesizecalculationwasbasedonanestimated inci-denceofHBVinfectionintheIranianpopulationaccordingto thelastCenterofDiseaseControldata.6_Atotalof1129

par-ticipantswereneededineachgroup,given90%poweranda two-sidedsignificancelevelof5%.Therefore,asamplesizeof 2256wasrequiredforthestudy,andconsideringtheattrition rate,weadded10%moreineachgroup.

Immunizationstatus

An individualized investigation was conducted by trained staff.Basicinformation,includingsex,birthdate,risk assess-ment, occupation, medical and immunization history was collected through an interview. Immunization status was recordedfromtheimmunizationcertificateor,ifnotavailable, byreviewoftheimmunizationorhealthrecord.Full vaccina-tionwasdefinedasthereceiptofthreedosesofhepatitisB vaccinewithin12months.Alldatawasrecordedindividually.

Specimencollection

Bloodsamples(4mL)wereobtainedfromeachenrolled per-son.Serumwasseparatedinlocallaboratories,transported, and storedat−20◦_{C,atprovincial laboratoriesbythe cold}

chainservice.

Laboratorytesting

SerumwastestedforHBsAgbyELISAmethod(HBsAg,Dia.Pro DiagnosticBioprobesSrl,Italy),andtheantibodytohepatitisB coreantigen(anti-HBc)wasmeasuredbyCompetitiveEnzyme ImmunoAssay(HBcAb,Dia.ProDiagnosticBioprobesSrl,Italy).

Definitionofevents

Personswereregardedasuninfectediftheywerenegativefor bothHBsAgandanti-HBc.Achroniccarrierwasdefinedasa personpositiveforHBsAgintwodifferenttimesamplings.A breakthroughinfectionwasdefinedasapositivecoreantibody inavaccinatedperson.

Vaccineeffectiveness(VE)wasmeasuredbycalculatingthe riskofdiseaseamongvaccinatedandunvaccinatedpersons anddefiningthepercentagereductioninriskofdiseaseamong vaccinatedpeopleinrelationtotheunvaccinatedgroup.20 Dataanalysis

All data were doubleentered and analyzedwith IBMSPSS StatisticsforWindowsversion20.0(IBMCorp.2011.Armonk, NY:IBMCorp.).Descriptivestatisticswerefirstprovidedat95% confidenceinterval(95%CI).TheChi-squaretestwasrunto comparecategoricalvariables.Ap-valuelessthan 0.05was consideredstatisticallysignificant.

Accordingtotheobtainedincidencerates,theriskratio(RR) and95%CIwerecalculated,aswasthevaccineeffectiveness (VE)usingtheformula:VE=(1-RR)*100andthe95%CIwere estimatedusingtheTaylorseries,

95%CIforRR: exp







The surveywas approved byShiraz Medical Sciences Uni-versity Ethics Committee (Ethics code: IR.SUMS.REC. 1397. 437),andallstudycomponentshavetreatedaccordingtothe nationalethicsregulations.Studyparticipantswereinformed of study purpose, signed a written informed consent and voluntarilyenrolledinthestudy.Theywereassured confiden-tiality.

Results

Characteristicsofthestudypopulation

Inthisstudy,basedontheinclusionand exclusioncriteria, 2720persons(age,17–49years)wereinterviewedandprovided bloodsamples.Themeanagewas26.9years(21.6for vacci-natedand31.6forunvaccinatedpersons),withslightlymore females(56.6%),andover50%hadcollegeeducationorhigher (51.6%).

Table1describesthesocio-demographiccharacteristicsof vaccinatedandunvaccinatedgroups.Vaccinatedand unvac-cinatedpersonsdidnotdifferintermsofahistoryofHBV

1 _{VaccineEffectivenessLowerLimit} 2 _{RelativeriskLowerLimit}

3 _{VaccineEffectivenessUpperLimit} 4 _{RelativeriskUpperLimit}

Table1–Distributionofsocio-demographiccharacteristicsamongvaccinated(N=1273)andunvaccinated(N=1447) cohorts.

Frequency(%)

Variable Vaccinated Unvaccinated p-value

Sex

Male 309(24.3) 872(60.3) <0.001

Female 964(75.7) 575(39.7)

Education

ElementaryorMiddleschool 55(4.3) 134(9.3) <0.001

Highschool 89(7.0) 65(4.5)

Diploma 558(44.0) 409(28.3)

UndergraduateorBachelor 553(43.6) 600(41.6)

MasterofScience(MSc) 8(0.6) 208(14.4)

DoctororPhD 6(0.5) 27(1.9)

Historyofbloodtransfusion

Yes 18(1.4) 42(2.9) 0.002 No 1239(97.7) 1366(95.2) Idon’tremember 11(0.9) 27(1.9) Historyofdialysis Yes 0(0.0) 0(0.0) N/A* No 1267(100.0) 1436(100.0) Historyofjaundice Yes 27(2.1) 40(2.8) 0.036 No 1229(96.6) 1360(94.6) Idon’tremember 17(1.3) 37(2.6)

∗ _{Notapplicable(Nostatisticsarecomputedbecause“Historyofdialysis”isaconstant).}

infection of a family member (p=0.306) and any high-risk behavior(p=0.200).

ImmunizationcoverageofhepatitisBvaccineforthetwo groups

Atotalof1273(46.8%)hadreceivedfullthreedosesofhepatitis Bvaccinationintheinfantileperiod,and1447(53.2%)hadnot receivedhepatitisBvaccineatanyageperiod.

For the vaccinated group, born in 1994 and afterwards, closeto100%receivedthreeconsecutivedosesandatimely birthdoseofhepatitisBvaccineaccordingtoavailablehealth records.

PrevalenceofHBsAgandAnti-HBcamongpeoplebornin 1992andearlier(unvaccinatedgroup)andpeoplebornin 1994andafterwards(vaccinatedgroup)

TheprevalenceofHBsAgamongvaccinatedandunvaccinated cohortswas0.6%and1.1%,respectively.Theratesfor anti-HBcwere5.5%and7.4%amongvaccinatedandunvaccinated cohorts,respectively(Table2).Inourstudy,althoughtherates ofHBsAg+inthetwogroupswerenotsignificantlydifferent (p=0.112),therateofanti-HBc+wassignificantlyloweramong fullyimmunizedpeoplethanamongnon-immunizedpersons (P=0.041).ConsideringeitherHBsAg+oranti-HBc+orbothas markersofinfection,17,21,22_{therateofHBVinfectionamong}

thevaccinatedgroup(5.9%)wassignificantlylowerthanthe 8.3%intheunvaccinatedgroup(p=0.017).

Table3showstherateofHBVinfectionamongpersonswith high-riskbehaviorhistoryandinthosereportingHBV infec-tionamonganyfamilymember.AstheTabledemonstrates, amongunvaccinatedpersonstherewasastrongassociation

betweenHBVinfectionandpresenceofhepatitisBinfection inanyfamilymember(p=0.003).However,inthevaccinated grouptherewasnoassociationbetweenHBVinfection and thesetwoparameters(p=0.738).

Vaccineeffectiveness

Overall,194caseswithmarkersofHBVinfectionwere identi-fiedinthestudy.Ofthese,119casesoccurredinunvaccinated personsand75casesinvaccinatedpersonsyieldingaRRof 0.71(95%CI:0.54–0.94).Theestimatedvaccineeffectiveness againstHepatitis Binfectionwas 29%(95% CI:6%–46%)for thosewhoreceivedthreedosesatbirth,twoandsixmonths withthenationalinfantilevaccinationprogram.Ontheother hand,vaccinationeffectivenessforthepreventionofHBsAg carriagewas51%.

Discussion

Hepatitis B is aserious infectious disease in Iran and our region. Forthat reason,weevaluated theimpactof neona-talhepatitisBvaccinationonHBVinfectionseromarkersin Iranianswhowerefullyvaccinatedatbirthandcomparedit withanunvaccinatedgroup.Basedonthenational serosur-veyin1980,prevalenceofHBsAginIranianpopulationwas about3.5%forallagegroups,includingyoungchildren.23_A

reviewarticlepublishedbyMerat etal.10 _{inthe 1980s}

indi-catedthat3%oftheIranianpopulationwerechronicHBsAg carriers.In1996,inanothernationalstudybyZalietal.,the rateofHBV carriersrangedbetweenzeroand3.9%withan averageof1.7%.24_{Oldermaleslivinginruralareaswithpoor}

sanitation,lowsocioeconomicstatus,andfamilyclose con-tactwerethemainriskfactorsforhepatitisBinfectioninIran

Table2–RatesofhepatitisBmarkersbeforeandafterstartingthehepatitisBvaccinationprograminIran.

Variable Frequency(%) p-value RRand95%CIofHBV

(Vaccinated/Unvaccinated) Vaccinated Unvaccinated Total

HBSAg Positive 7(0.6) 16(1.1) 23(0.9) 0.112 0.49(0.20–1.20) Negative 1255(99.4) 1414(98.9) 2669(99.1) Anti-HBc Positive 69(5.5) 106(7.4) 175(6.5) 0.041 0.74(0.55–0.98) Negative 1193(94.5) 1324(92.6) 2517(93.5) HepatitisB(HBSAg+or Anti-HBc+) Yes 75(5.9) 119(8.3) 194(7.2) 0.017 0.71(0.54–0.94) No 1187(94.1) 1311(91.7) 2498(92.8)

Table3–FactorsaffectingHBVinfectioninvaccinatedandunvaccinatedcohorts.

Variable Vaccinated Unvaccinated

Number(%) P-Value Number(%) P-Value

HBVPositive HBVNegative HBVPositive HBVNegative

Historyofany high-riskbehaviors Yes 54(6.6) 763(93.4) 0.161 84(8.8) 870(91.2) 0.218 No 20(4.6) 411(95.4) 31(6.9) 420(93.1) HistoryofHBVin familymembers Yes 3(6.8) 41(93.2) 0.738* 9(23.1) 30(76.9) 0.003* No 68(5.8) 1112(94.2) 98(7.7) 1178(92.3) ∗ _Fishertest.

atthetimethestudywasconducted.Basedontheresultsof ourstudy,amongunvaccinatedindividuals,HBVinfectionwas associatedwithhistoryofafamilymemberwithhepatitisB infection,butnosuchassociationwasseeninthevaccinated group.Onepossiblereasonforthisfindingisthatvaccination maynotonlyhaveadirecteffectonreducingHBVinfection, butmayalsoreducetheriskhepatitisBinfectioninfamily members.Therefore,itisrecommendedthatinfuturestudies, thisrelationshipbeinvestigatedinmoredetail.

ThefindingsfromourstudyrevealedthatthemeanHBsAg prevalencein the Iranian population is now close to 0.9% withasignificantdeclineinthevaccinatedpopulationwith arateof0.6%.InrespectoftheWHOgoalof1.0%prevalence ofHBsAgby2020,25,26_{itseemsthatIranalreadyachievedit.}

Therefore,auniversalinfantimmunizationprograminIran hadamajorroleinthecontroloftheHBsAgcarriage.These findingsarecompatiblewithotherinternationalstudies.27,28

Aseriesoflong-termfollow-upreportsintheliteraturewith vaccinatedinfantshasshownthattheuniversal immuniza-tionwiththehepatitisBvaccinestartingatbirthhasintensely reducedthesubsequentdevelopmentofchronichepatitisB infection inthe vaccinated population. Moreover,it affects both HBsAg carrier state and subsequent HBV complica-tions such as HCC. These beneficial effects were detected inregionsofbothhighendemicity27–29_{and alow}

endemic-ity of HBV infection.16,25,30–33 _{Also, in an important report}

ofthe WHO Western Pacific Region, in 22 of 36 countries, includingChina,theprevalenceofHBsAgpositivitywas8% ormore beforethe introduction ofhepatitisBvaccination. WithbroadeninghepatitisBvaccinationcoverage,including implementationofinfantilevaccinationprogram,the preva-lenceofHBsAgamongchildrenbornin2012haddecreased to less than 1% in 24 of 36 countries.34 _{Also, in another}

study inMalaysia,HBsAg seroprevalenceamong 7–12-year-old children decreased from 1.6% in 1997 to 0.3% in 2003

afterimplementingauniversalinfantvaccinationprogramin 1990.35

Intheotherpartofourstudy,wedemonstratedasignificant differenceintheprevalenceofHBVinfection(by document-ingHBVseromarkers)betweenvaccinatedandunvaccinated groups.Thesefindingconfirmstheresultsofotherresearchers on theeffectivenessoftheHBV vaccinationasameans to decrease theprevalenceofHBV infectionandits complica-tion suchas cirrhosis and HCC.36–38 _{Also,our findings are}

consistentwiththosefoundinItaly,thepioneerof system-aticvaccinationintheworldin1991inadolescentsaged12 years,39_{wherehepatitisBratesreducedfrom5.1per100,000,}

in1991to1.3in2005.40

Inourstudy,theeffectivenessofhepatitisBvaccination againstchroniccarriageofHBVwas51%25yearsafter immu-nization, and the effectivenessagainst infection was 29%. Thisfigureshowstheeffectivenessoftheuniversalinfancy vaccination programinIran,but these figuresare lower in comparisonwith othersimilar studies carriedout in areas withhighendemicity.Inthoseareas,systematicvaccination has reduced the prevalence of HBsAg by as much as 90% insomereports.21,41_{Forunderstandingthisdiscrepancy,we}

havetwoimportantexplanations.Firstofall,thereissome difference betweenthestatisticalmethodforthe detection ofvaccine effectivenessandmechanicalmodels ofvaccine effects.Inotherwords,dynamicepidemiologicalmodelshave to rely onspatiotemporally determined data, whereas epi-demiologicaldataregularlyactstatic,andthereforearemore responsivetothetoolsofstatistics.42 _{So,wecanfindsome}

differencesbetweentruevaccinationeffectivenessand calcu-latedeffectivenessinstaticstudies.Asasecondexplanation, advancingagehasbeenshowntobeafactorthatadversely affectstheimmuneresponsetohepatitisBvaccinationorto othervaccines.43_{Thus,after25yearsofinfantilevaccination}

affectvaccineeffectiveness.Therefore,thepresentstudyhad alowervaccineeffectivenessthanstudiesconductedshortly aftervaccination.

AccordingtoWHOrecommendation,thisstrategy(global vaccination)shouldbecontinuedandalsoothervaccination strategiessuchasvaccinationinhigh-riskgroupscanbeused incombination.Itshouldbementionedthattheisolated at-riskapproachisnotthemosteffectivestrategyforreducing HBVprevalence,eveninlow-endemicitycountries,asitisvery laborintensiveand moreexpensivetoimplement.44 _Ithas

beenknownthattoreacharapidimpactondiseaseincidence, theidealhepatitisBimmunizationstrategyisimplementation ofuniversalvaccinationinchildrenoradolescents,orboth.45

The present study had some strengths, such as cohort studydesignandevaluationofthelong-termeffectsof hep-atitisBvaccinationamongpeoplewhoweresexuallyactive.

Oneofthelimitationsofourstudywasresistancetobepart ofthestudyasparticipationwasvoluntary.Another proba-blelimitationwasthelackofspecificdataonthevaccination historyinthehealthcardsofthestudyparticipants,butthis wasresolvedbysearchingforinformationfromotheravailable datasources,sotheeffectofthislimitationwasreduced.

Conclusions

Thepresent study showed theimpact ofthe national uni-versal infantile HBV vaccination program in Iran, and we demonstrated for the first time HBV vaccination effective-nessafter 25 years ofprogram implementation.According toourfindings,Iranhassuccessfullyintegratedthe hepati-tis Bvaccineinto routineimmunization programsand has achievedaverysignificanteffectondecreasingtheHBsAg car-rierrateamongthosebornin1994andafterwards.Therate ofhepatitisBsurfaceantigendecreasedgraduallyfrom3.5% beforethevaccinationprogramto0.6%amongthevaccinated groupinrecentyears.TheWHOgoalofreducingHBsAg preva-lenceto1.0%by2020hascertainlybeenreached.Inrespectto bettervaccinationeffectivenessandminimizingthedisease prevalenceinthecountry,catch-up hepatitisBvaccination programs for adolescents before high school entrance can provideimmunityforthepopulation.Atthistime,ourdata suggestthattheadditionofschool-basedprogramsto univer-salhepatitisBimmunizationofinfantsmightbehelpfulfor furtherdecreasingHBVinfectionrateinourcountryandits consecutivecomplications.

Listofabbreviations

HBV HepatitisBvirus

WHO WorldHealthOrganization HCC HepatocellularCarcinoma HBsAg HepatitisBVirusSurfaceAntigen Anti-HBc AntibodytoHepatitisBCoreAntigen VE VaccineEffectiveness

RR RiskRatio

Competing

interests

Wedeclarethattherewerenoconflictsofinterestinthisstudy.

Ethics

approval

and

consent

to

participate

The surveywas approvedbythe Ethics Committeeof Shi-razUniversityofMedicalSciences(Ethicscode:IR.SUMS.REC. 1397.437),andallstudycomponentshavecarriedout accord-ingtothenationalethicsregulations.Studyparticipantswere informedofthepurpose,signedawritteninformedconsent (consent to participate was obtained from the participant themselvesbecausetheiragerangewasbetween17and49 years old)and voluntarilyenrolled inthestudy.They were admittedtoexerciseconfidentiality.

Funding

Thestudyprotocolwasapprovedandfinanciallysupportedby ShirazUniversityofMedicalSciences,Farsprovince,Shiraz, Iranwiththecode95-7704.ShirazUniversityofMedical Sci-encesfundedtheprocessofdatacollection,bloodsampling, preparationofkitsandlaboratorytests.Analysisand interpre-tationofdataandwritingthemanuscriptwereperformedby theauthors.

Disclosures

and

acknowledgments

Wedeclarethattherewerenoconflictsofinterestinthisstudy. Thestudy protocolhasbeen approvedandfinancially sup-portedbyShirazUniversityofMedicalSciences,Farsprovince, Shiraz,Iranunderthecode95-7704.Theauthorsappreciate thecollaborationofresearchandtechnologydeputyofShiraz UniversityofMedicalSciences.

Acknowledgements

Wethankthestaffofthehealthsystemwhichprovidedthe sera and laboratorystaff atthe health department in pro-cessingandtestingthesera.sThisstudyissupportedbyan infrastructuregrantfromtheShirazUniversityofMedical Sci-encesResearchDeputy(ResearchProposalno.95-7704).

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