Analysis of the universal immunization programme and introduction of a rotavirus vaccine in India with IndiaSim

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Megiddo, Itamar and Colson, Abigail R. and Nandi, Arindam and

Chatterjee, Susmita and Prinja, Shankar and Khera, Ajay and

Laxminarayan, Ramanan (2014) Analysis of the universal immunization

programme and introduction of a rotavirus vaccine in India with

IndiaSim. Vaccine, 32 (Supple). A151-A161. ISSN 0264-410X ,

http://dx.doi.org/10.1016/j.vaccine.2014.04.080

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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

Analysis

of

the

Universal

Immunization

Programme

and

introduction

of

a

rotavirus

vaccine

in

India

with

IndiaSim

Itamar

Megiddo

,

Abigail

R.

Colson

,

Arindam

Nandi

,

Susmita

Chatterjee

,

Shankar

Prinja

,

Ajay

Khera

,

Ramanan

Laxminarayan

a_{CenterforDiseaseDynamics,Economics&Policy,Washington,DC,USA} b_{PrincetonEnvironmentalInstitute,PrincetonUniversity,Princeton,NJ,USA} c_{PublicHealthFoundationofIndia,NewDelhi,India}

d_{SchoolofPublicHealth,PostgraduateInstituteofMedicalEducationandResearch,Chandigarh,India} e_{MinistryofHealthandFamilyWelfare,GovernmentofIndia,NewDelhi,India}

a

b

s

t

r

a

c

t

Backgroundandobjectives:Indiahasthehighestunder-fivedeathtollglobally,approximately20%ofwhichisattributedtovaccine-preventablediseases. India’sUniversalImmunizationProgramme(UIP)isworkingbothtoincreaseimmunizationcoverageandtointroducenewvaccines.Here,weanalyze thediseaseandfinancialburdenalleviatedacrossIndia’spopulation(bywealthquintile,ruralorurbanarea,andstate)throughincreasingvaccination ratesandintroducingarotavirusvaccine.

Methods:WeuseIndiaSim,asimulatedagent-basedmodel(ABM)oftheIndianpopulation(includingsocio-economiccharacteristicsandimmunization status)andthehealthsystemtomodelthreeinterventions.Inthefirstintervention,arotavirusvaccineisintroducedatthecurrentDPT3immunization coveragelevelinIndia.Inthesecondintervention,coverageofthreedosesofrotavirusandDPTandonedoseofthemeaslesvaccineareincreasedto 90%randomlyacrossthepopulation.Inthethird,weevaluateanincreaseinimmunizationcoverageto90%throughtargetedincreasesinruraland urbanregions(acrossallstates)thatarebelowthatlevelatbaseline.Foreachintervention,weevaluatethediseaseandfinancialburdenalleviated,costs incurred,andthecostperdisability-adjustedlife-year(DALY)averted.

Results:Baselineimmunizationcoverageislowandhasalargevarianceacrosspopulationsegmentsandregions.Targetingspecificregionscan approx-imatelyequatetheruralandurbanimmunizationrates.IntroducingarotavirusvaccineatthecurrentDPT3level(interventionone)averts34.7(95% uncertaintyrange[UR],31.7–37.7)deathsand$215,569(95%UR,$207,846–$223,292)out-of-pocket(OOP)expenditureper100,000under-fivechildren. Increasingallimmunizationratesto90%(interventiontwo)avertsanadditional22.1(95%UR,18.6–25.7)deathsand$45,914(95%UR,$37,909–$53,920) OOPexpenditure.Scalingupimmunizationbytargetingregionswithlowcoverage(interventionthree)avertsaslightlyhighernumberofdeathsandOOP expenditure.Thereducedburdenofrotavirusdiarrheaistheprimarydriveroftheestimatedhealthandeconomicbenefitsinallinterventionscenarios. Allthreeinterventionsarecostsaving.

Conclusion:ImprovingimmunizationcoverageandtheintroductionofarotavirusvaccinesignificantlyalleviatesdiseaseandfinancialburdeninIndian households.Populationsubgroupsorregionswithlowexistingimmunizationcoveragebenefitthemostfromtheintervention.Increasingcoverageby targetingthosesubgroupsalleviatestheburdenmorethansimplyincreasingcoverageinthepopulationatlarge.

©2014PublishedbyElsevierLtd.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/3.0/).

1. Introduction

Indiahasthelargestnumberofunder-fivedeathsintheworld

[1].Vaccine-preventablediseasesareamajorcontributortothe burden,causingapproximately20%ofunder-fivedeathsin South-eastAsia[2].In1985IndialauncheditsUniversalImmunization Programme (UIP), which provides free vaccines for measles, poliomyelitis, tuberculosis (BCG), hepatitis B, and diphtheria,

∗ _{Correspondingauthorat:CenterforDiseaseDynamics,Economics&Policy,}

Washington,DC,USA.

E-mailaddress:ramanan@cddep.org(R.Laxminarayan).

pertussis,tetanus(DPT).Despitetheseefforts,eachyearmorethan 50,000childrenundertheageoffivediefrommeaslesinIndia(44% ofglobalunder-fivemeaslesdeaths)[3].Indiaaccountsfor56% (2525)ofglobaldiphtheriacases,18%(44,154)ofpertussiscases, and23%(2404)oftetanuscases[4].TheUIPhasyettoincorporate existing vaccines against mumps, pneumococcal disease and rotavirus.

In theGlobalImmunizationVisionand Strategy (GIVS)from 2005, the World Health Organization (WHO) and the United NationsChildren’s Fund(UNICEF)seta goalfor allcountriesto achieve 90%nationalvaccinationcoverage and80% coveragein everydistrictby2010[5].TheUIPhasfallenshortofthesetargets.In 2007only53.5%ofchildrenwerefullyvaccinated,andvaccination http://dx.doi.org/10.1016/j.vaccine.2014.04.080

coveragevariedconsiderablyacrossthecountry[6].Immunization coverageispredictedtohaveimprovedinrecent years,butfull coverageremainsbelow70%inurbanareasandbelow60%inrural areas[7].

Rotavirus vaccines were first introduced in national immu-nization programs in 2006 as a key intervention to address the burden of diarrheal disease. By January 2014, 53 coun-trieshadintroducedrotavirusvaccines[8].Thesevaccines have the potential to significantly alleviate the disease and finan-cial burden in India, where each year approximately 113,000 under-fives die from rotavirus (39% of diarrhea cases). Indi-ans spend between $37.4 million and $66.8 million annually on direct medical costs of rotavirus diarrhea hospitalizations in children under five (457,000–884,000) and outpatient treat-ment(2millionvisits)[9].In2014Indianregulatorslicensedthe Indian-madevaccine 116E following a successful Phase 3 trial

[10,11].

In this paper we evaluate the health and financial effects of interventions introducing a rotavirus vaccine to the immu-nizationprogram and increasingtheimmunization coverage of the DPT3 and measles vaccines. We build on IndiaSim [12], a simulated agent-based model (ABM) of the Indian population and health system, and use household-level data on immu-nizationdecisions.Wesimulatethreeinterventionscenarios:(i) the introduction of the rotavirus vaccine at the current DPT3 level; (ii) an increase in DPT3, measles, and rotavirus vac-cination coverage to 90% (the GIVS target) randomly across Indianhouseholds;and(iii),targetedstate-levelandrural–urban implementation that increases coverage in sub-regions that are below 90% immunization coverage in the baseline sce-nario.

Our analysis does not include the benefits of poliomyelitis immunization.Indiaispolio-freeandanychangesinthecoverage levelofthepoliomyelitisvaccinewillnotyieldadditionalhealthor economicbenefits.WealsoomittheBCGvaccinefromtheanalysis: theburdenofmiliarytuberculosisislow[13],andBCGcoverageis highinIndia[14].

2. Methods

2.1. Populationsample

IndiaSimispopulatedwithdatafromtheDistrictLevel House-hold Survey (DLHS-3, conducted during 2007–08) of India [6]. DLHS data are representative at the district level and cover morethan720,000households and3.8millionindividualsfrom 601 districts. The survey data include indicators on demo-graphics,householdsocioeconomicstatus,householdvaccination choices of UIP vaccines, and other indicators of health-seeking behavior.Thesimulationsarebasedonarandomlyselected sub-set of 128,000 households comprising approximately 750,000 individuals.

2.2. Disease,vaccination,andtreatmentdata

Table1presentstheinputdataontheepidemiology,treatment, andpreventionofDPT,measles,androtavirus.DPTandmeasles incidencesare calibratedusingthecase-fatalityrates (CFR)and theGBD2010mortalityrates[15].Rotavirusincidence[16]is dis-tributedacrosswealthquintilesaccordingtoRheingansetal.[17], andCFRiscalibratedtothatincidenceandthemortalityrate[18]. Wedonotincludecomorbidityofdiseasesbecauseofapaucityof data.

Intheabsenceofdatatoparameterizeademandfunctionfor treatmentofvaccine-preventablediseases,weassumethat every-onewhocontractsavaccine-preventablediseaseseekstreatment. Wedonotmodeltheeffectoftreatmentondiseasetransmission. Weassumethatthebaselineleveloftreatmentutilizationresults intherealizedbaselineincidenceandmortalityratesinthe pop-ulation.Inaddition,weassume thatthedemandandsupply of treatmentforindividualswithdiseaseisequivalentacrossall simu-lationscenarios.TreatmentcostsforDPTandmeaslesareestimated fromtheNationalSampleSurvey(NSS) 60throundschedule25

[19],andtreatmentcostsforrotavirusarefromTateetal.[9].All costsinthemodelarein2013USdollars.

Totalroutineimmunizationcostis thesumof costsfor vac-cines,personnel,vehiclesandtransportation,coldchainequipment andmaintenance,andprogramandotherrecurrentcosts, includ-ingplanning,supervision,monitoring,andsurveillance.Thedata werecollectedfromtheMinistryofHealthand FamilyWelfare (MoHFW) by personal communication. We usethe WHO com-prehensivemulti-yearplanning(cMYP)forimmunizationtoolto analyzethedataandassumethatinterventionsareintroducedin 2016.Costsincludeprogramaswellasvaccinecostsandarenot separablebyvaccinetype.

Baselinevaccinationcoveragerates arefrom2011estimates

[14].

2.3. Incomedata

Thegrossdomesticproduct(GDP)percapitaforIndiaisfromthe WorldBank[20].Thedistributionacrosswealthquintilesisfrom NSSexpendituredata.Thestate-levelGDPpercapitaisfromthe Indiangovernment’sPressInformationBureau[21].

2.4. Model

IndiaSimisaniterative,stochasticABM.Themodelcomprises67 regions,representingtheurbanandruralareasof34Indianstates anddistricts.Nagalandisnotincludedinthemodelbecauseitis omittedfromDLHS-3,andtheurbanareaofAndamanandNicobar isdroppedbecauseofalownumberofobservations.Eachregion comprisesasetofrepresentativehouseholds.Asetof character-isticsdescribeseachhousehold(socioeconomicindicators)andits individuals(ageandsex).Aniterationofasimulationrepresentsa day(thetimestepofthemodel).

Individualsinthemodelareinoneofseveraldiseasestates: theyarehealthyortheysufferfromdiphtheria,pertussis,tetanus, measles, and/or rotavirus. They contract diseases based on a stochasticfunctionoftheircharacteristics(age,sex,and wealth quintile)andtheirimmunizationhistory.Thosesufferingfrom dis-easeseek treatmentatpublicor privatefacilities basedonthe averagetreatment-seekingratesbyincomequintileinthe DLHS-3data.Birthsinthemodelarebasedonahousehold-levelprobit regressionmodelthatisboundedtothestate-levelfertilityrates

[12].Deathsnotrelatedtothefivediseasesinthemodelare deter-minedonthebasisofWHOlifetables[22].

Weassumethathouseholdsthatimmunizedpreviouslyborn childreninthebaselineDLHS-3datawillimmunizeanychildren bornduringthesimulationwiththosevaccines. Toincreasethe urbanandruralsub-regionrates to2011estimates,weselecta randomsetofhouseholdstoalsovaccinate.Intheintervention sce-narios,toscaleupthecoveragerates,themodelmakesadditional householdsvaccinationcompliant.Themethodofselectingthese extrahouseholdsvariesacrossscenarios(e.g.,randomortargeted bystateandregion).

Table1

Diseaseandinterventionparameters.

Variable Base-caseestimate Sensitivityrange Source

Diphtheria

Incidence(per100,000) Basedon[15]andCFR

<1year 42.2 29.5–54.8

1–5years 18.3 12.8–23.8

CFR 0.012 0.008–0.016 [37]

Costofseekingtreatment

Publicfacilities $0.35 $0.25–$0.46 [19]

Privatefacilities $0.37 $0.26–$0.49 Treatmentcost

Publicfacilities $3.51 $2.45–$4.56 [19]

Privatefacilities $4.59 $3.21–$5.97

DPT3vaccinationrelativeriskreduction 0.955 0.921–0.989 [38]

Pertussis

Incidence(per100,000) Basedon[15]andCFR <1year 2123.2 1486.3–2760.2

1–5years 313.4 219.4–407.5

CFR [39]

<1year 0.037 0.026–0.048

1–4.9years 0.010 0.007–0.013

Costofseekingtreatment [19]

Publicfacilities $0.72 $0.50–$0.93 Privatefacilities $0.77 $0.54–$1.00

Treatmentcost [19]

Publicfacilities $5.83 $4.08–$7.58 Privatefacilities $7.63 $5.34–$9.92

DPT3vaccinationrelativeriskreduction 0.840 0.680–1.00 [40]

Tetanus

Incidence(per100,000) Basedon[15]andCFR

<1year 637.1 446.0–828.2

1–5years 3.2 2.2–4.1

CFR [41]

<1months 0.864 0.648–1.000 1month–5years 0.328 0.230–0.427

Costofseekingtreatment [19]

Publicfacilities $0.55 $0.38–$0.71 Privatefacilities $0.58 $0.41–$0.76

Treatmentcost [19]

Publicfacilities $3.54 $2.48–$4.60 Privatefacilities $4.63 $3.24–$6.02

DPT3vaccinationrelativeriskreduction 1.000 .990–1.00 [42]

DPT3vaccinationbaselinecoverage 76.8% Basedon[6,14]

Measles

Incidence(per100,000) Basedon[15]andCFR <1year 4776.9 3343.9–6210.0

1–5years 2723.3 1906.3–3540.3

CFR 0.015 0.011–0.020 [45]

Costofseekingtreatment

Publicfacilities $1.24 $0.87–$1.61 [19]

Privatefacilities $1.32 $0.92–$1.72 Treatmentcost $5.92 $4.14–$7.69

Vaccinationrelativeriskreduction 0.840 0.83–0.87 [43]

Vaccinationbaselinecoverage 82.2% Basedon[6,14]

Rotavirus

Incidence(perchild-year) Basedon[9,16,17]

<6monthsquintileI 1.38 0.96–1.79

QuintileII 1.17 0.89–1.52

QuintileIII 0.97 0.68–1.25

QuintileIV 0.76 0.53–0.98

QuintileV 0.50 0.35–0.65

6months–1yearquintileI 2.08 1.46–2.70

QuintileII 1.81 1.27–2.35 QuintileIII 1.53 1.07–1.99 QuintileIV 1.15 0.80–1.49 QuintileV 0.76 0.53–0.98 1–2yearsquintileI 1.74 1.22–2.26 QuintileII 1.44 1.00–1.87 QuintileIII 1.24 0.87–1.61 QuintileIV 0.94 0.66–1.22 QuintileV 0.59 0.42–0.77 2–5yearsquintileI 1.11 0.78–1.44 QuintileII 0.94 0.66–1.23 QuintileIII 0.78 0.55–1.01 QuintileIV 0.59 0.42–0.77 QuintileV 0.38 0.27–0.50

Table1(Continued)

Variable Base-caseestimate Sensitivityrange Source

CFR 0.0009 0.00063–0.00117 Basedonincidenceand[18]

Outpatientcostofseekingtreatment $0.36 $0.25–$0.46

Outpatienttreatmentcost $3.12 $2.18–$4.05 [9]

Inpatientcostofseekingtreatment $3.70 $2.59–$4.81 Inpatienttreatmentcost $74.26 $51.99–$96.54

Vaccinationrelativeriskreduction 0.56 0.420–0.700 [44]

Vaccinationbaselinecoverage 0.00%

UIPcostperDPT3child BasedoncMYPandpersonal communicationwithMoFWH

Baseline $22.50 $15.75–$29.25

Interventionone $27.00 $18.90–$35.10 Interventiontwo/three $23.50 $16.45–$30.55

2.5. Analysis

2.5.1. SimulatedresultsfromoneyearareanalyzedinR

Analysisvariablesfallintofourcategories,whichconsiderthe intervention’sassociated effect ondisease burden, intervention costs,cost-effectiveness,andfinancialimpact.Theeffecton dis-easeburdenincludesbothdeathsanddisability-adjustedlifeyears (DALYs)averted(wediscountat3%anduseuniformage-weights thatvalueanyextrayearoflifeequally).Cost-effectivenessis mea-suredby dollars per DALY averted incremental tothe baseline scenario.ThefinancialimpactmeasuresfollowVerguetetal.[23]

andincludetheout-of-pocket(OOP)expenditureavertedfromthe baselinescenario,whichmeasuresthesavingsofthepopulation thatresultfromtheintervention,andthemoney-metricvalueof insurance,whichmeasuresthevalueofprotectionfrom expendi-tureondiseasetreatment(includingthecostsofseekingcare).The money-metricvalueofinsuranceherediffersslightlyfrom Ver-guetetal.’sanalysis.Ouranalysisperiodisoneyearaswestudya cross-sectionoftheunder-fivepopulation,whiletheystudyabirth cohort,whichissusceptibletodiseaseoverthefirstfiveyearsof life.Giventhis,weincludeonlyoneyearofdisposableincomein thecalculationasopposed tofiveyears.Additionally,we evalu-atethevalueofinsuranceofaninterventionwithrespecttothe baselinebysubtractingonefromtheother.Weanalyzehealthand financialburdenalleviatedacrossIndiabywealthquintile,state, andruralversusurbanareas.

2.6. Sensitivityanalysis

Toquantifytheuncertaintyofthemodel,weconducta 100-simulation Latin hypercube sampling (LHS) sensitivity analysis overaplausiblerangeoftheinputparameters(Table1).Foreach disease,theparametersanalyzedincludetheincidence,CFR, vac-cineefficacy,vaccinecost,andtreatmentcost.Ninety-fivepercent uncertaintyrangesforourmeanestimatedoutcomesarecalculated onthebasisofthissensitivityanalysisandreportedinparentheses.

3. Results

Inthebaseline, immunizationcoverageis77%forDPT3,82% formeasles,and thereisnocoverageforrotavirus.From DLHS-3 data,we find that baseline coverage increases bywealth for DPT3andmeasles.Therural-to-urbanimmunizationcoverageratio is 1.09 for DPT3 and 1.05 for measles(Fig.1,row 1).Baseline DPT3coverageislowestinArunachalPradeshandUttarPradesh where53%and55%ofunder-fivesarevaccinated(Fig.2,column 1). Another nine states vaccinate less than 80% of their chil-dren;allof them arerelatively poorstates,withthe exception ofGujarat(77%coverage).EightstateshaveDPT3coverageabove 90%.Measlesvaccinationcoverageinsixstatesislessthan80%;

aswithDPT3,coverageislowestinArunachalPradesh(58%)and UttarPradesh (60%). Twelve states areabove 90% coverage for measles,and HimachalPradeshand Maharashtraareabove95% coverage.

Our interventions decrease the coverage disparity between wealthquintiles,ruralandurbanpopulations,andstates. Interven-tiontworeducestheurban-to-ruralvaccinecoverageratioforall threevaccines to1.03 (Fig.1,row1),thoughatotalof 9states donotachieve90%coverageforallvaccines,andmeasles cover-ageremainsbelow80%inArunachalPradeshandUttarPradesh (Fig.2).Interventionthreeequatesurbanandruralcoverage(i.e., theurban-to-ruralvaccinecoverageratioisapproximately1)and makescoverageineach stateatorabove90% forallthree vac-cines.

Inthebaselinescenario,Indiaatlargehas88.7(95%uncertainty range[UR],85.1–92.4)rotavirusdeathsper100,000under-fives; therateismorethan60%higherinruralareasthaninurbanareas (96.6versus59.8).Interventiononeaverts34.7(95%UR,31.7–37.7) deathsand995(95%UR,910–1081)DALYsper100,000under-fives peryear,roughly44,500deathsand1.28millionDALYsthroughout thecountry.Thenumberofdeathsavertedper100,000under-fives is25.2(95%UR,19.9–30.5)inurbanpopulationsand 37.3(95% UR, 33.8–40.8)in ruralpopulations(Fig.1,row2).Intervention twoavertsanother22.1deaths(95%UR,18.6–25.7)per100,000 under-fivesand 630(95%UR, 522–737) DALYsper100,000 for alloftherelateddiseases.Interventionthreeavertsslightlymore deathsandDALYsthaninterventiontwo.Typically,thereduced burdenishighestforthepoorandinruralareas(Fig.1,row2);this trendismorepronouncedininterventionthreethanin interven-tiontwo.

Fig.3(totaldeathsavertedfromthebaselineacrossall under-fives)andthefirstrowofFig.4(DALYsavertedacrossallunder-fives inoneyear)mapthediseaseburdenalleviatedinallinterventions. Inallstateswithsufficientdata,introducingtherotavirusvaccine (interventionone)avertsmorethan15rotavirusdeathsand450 DALYsper100,000under-fives,thoughthestandarddeviationsare high.Theinterventionavertsmorethan45deathsper100,000in Karnataka,Uttarakhand,AndhraPradesh,HimachalPradesh,West Bengal,JammuandKashmirandBiharandmorethan1500DALYs per100,000inJammuandKashmir,KarnatakaandAndhraPradesh. Interventiononecostsalmost$93millionperyearforallofIndia. ThetotalinterventioncostsaremappedinFig.4,row2.In interven-tionone,thecostper100,000under-fivesrangesfrom$26,127(95% UR,$16,996–$35,257)inArunachalPradeshto$212,878(95%UR, $185,763–$239,994)inDelhi;thecostper100,000under-fivesin UttarPradeshislowrelativetootherstates(approximately48,500), butthestatehasthehighestoverallcosts(approximately$14.1 million),takingintoaccounttheentireunder-fivepopulation.The urban-to-ruralcostratiois1.17(95%UR,1.09–1.27)per100,000 underfives.

Fig.1. Analysisbyruralandurbanpopulationsper100,000under-fivesineach.

Resultsarefor100simulations.Confidenceintervalsaroundthemeanarefromthesensitivityanalysis.OOP=out-of-pocket.

Ininterventionstwo(randomlyincreasingallthreevaccinesto 90%coverage)andthree(increasingallthreevaccinestoatleast 90%coverageineach region),stateswithlow coverageratesin interventiononeachievethegreatestadditionalreductionsin bur-den (Figs. 3 and 4,row 1).For example,UttarPradeshhasthe secondlowestcoverageininterventionone,anditavertsan addi-tional427(95%UR,275–580)rotavirus-relatedDALYsper100,000 under-fivesperyearininterventiontwoand548(95%UR,372–724) per100,000ininterventionthree.Approximately665,000DALYs areavertedforallfivediseasesinUttarPradeshinintervention three.

The intervention costs incremental tothe baseline in inter-vention two for all five diseases are $137,926 (95% UR, $120,787–$155,065) per 100,000 under-fives in Uttar Pradesh ($41 million for its entire population) and above $30,000 in

all other states. In intervention three, the cost incremental to the baseline is above $100,000 in nine states, includ-ing Uttar Pradesh, where the cost is $186,454 (95% UR, $167,960–$204,948)per 100,000;thecost forallunder-fivesin UttarPradeshis approximately$53million (Fig. 4,row2).The urban-to-rural cost ratio is 0.88 (95% UR, 0.54–1.41) in inter-ventiontwoand 0.75(95%UR, 0.47–1.17)in interventionthree (Fig.2).

MostoftheOOPexpenditureavertedresultsfromthereduced rotavirus burden (Figs. 2 and 5, row 3): $232,354 (95% UR, $224,029–$240,678)avertedper100,000under-fivesin interven-tionone,withanadditional$49,489(95%UR,$40,861–$58,118) and$56,295(95%UR,$47,599–$64,991)avertedininterventions two and three, respectively.The OOPaverted for DPT (approx-imately 1800) and measles(approximately 5500) is highest in

Fig.2.Under-fiveimmunizationcoverage.

Resultsarefor100simulations.Rotavirusimmunizationisnotavailableinthebaselinescenario,andthereforethemapisgreyedout.Additionally,stateswithalowsample populationaregreyedout.

intervention three (Fig. 4, row 3?). The urban-to-rural ratio of OOPexpenditureaverteddecreasesfrominterventiononethrough interventionthree(Fig.1,row4;e.g.,therotavirusratiodecreases from0.70to0.48).

Theinterventionsarecostsavinginallstatesthathavesufficient data.IfweexcludeOOPexpenditureavertedand onlyconsider theinterventioncosts,theincrementaldollarsperDALYaverted inintervention one is $70.89 (95%UR, 95% UR, $61.51–$80.28) withrespect to the baseline. For interventions two and three, theincremental dollars per DALY averted are $30.47 (95%UR, −$4.36–$65.28)and$36.97(95%UR, $7.96–$65.97)withrespect tointerventionone.ExcludingOOPexpenditureaverted,the dol-larsperDALYavertedarebelow$110inallstates(withsufficient samplesize)inallinterventions.

The value of intervening is highest for rotavirus. In inter-ventionone,themoney-metric valueofinsurance forrotavirus rangesfrom$521(95%UR, $280–$761)per100,000under-fives inDelhi to$6756 (95%UR,$6318–$7196) inBihar (Fig.5).It is highestininterventionthreeinBihar(approximately$7500per 100,000under-fives)andUttarPradesh(approximately$5400per 100,000).ThevaluesforDPTandmeaslesareatorbelow$250per 100,000under-fivesinallstatesinallinterventions.Inall inter-ventions,themoney-metricvalueofinsurancedecreasesaswealth increases.

4. Discussion

In this paperwe present an ABM analysisfor introducing a rotavirusvaccinetotheUIPandincreasingUIPcoveragetothe90% goalsetintheGIVS.Weanalyzetheeffectsacrossthewealth dis-tribution,theruralandurbanpopulationdistribution,andstates. Theresultsdonotpresenttheexactbenefitsandcoststhatwould berealizedbyimplementingtheinterventionscenarios,butthey highlightthevariationacrosspopulationsegments.Themodelisa usefultooltounderstandwhichstrategyandpopulationstotarget whenallocatingscarceresources.

Immunizationisoneofthemostcost-effectiveinterventionsfor improvinghealthoutcomes[24].Eveninahigh-qualityhealth sys-tem,immunizationpolicyaddressesanimportantmarketfailure: individualstendtounder-vaccinate,andgovernmentintervention isneededtofixthatfailure.ThoughIndiahassucceededin elim-inatingpolio,ithasachievedlessthroughroutineimmunization. Targetedimmunizationcampaignsmaybesimplertoimplement thanroutineimmunization.Forexample,thepulsepoliocampaign involvedasingle-doseimmunization.Routinevaccinations, how-ever,mayrequireamorecompleximmunizationdeliveryschedule ifseveraldosesarerequired.

UIPcoverageremainslowinIndia,especiallyincertainsectors ofthepopulation.Targetingexpansioninthesesubpopulationsin

Fig.3. Totalunder-fivedeathsavertedfrombaseline.

Resultsarefor100simulations.DPT3andmeaslesvaccinationcoveragedoesnotchangeininterventionone,andthereforethemapisgreyedout.Statesinwhichimmunization coverageis90%oraboveinthebaselinearegreyedoutininterventionthree.Additionally,stateswithalowsamplepopulationorahighstandarddeviationaregreyedout.

interventionthreeavertsagreaterburdenthantherandom vac-cinationdistributionininterventiontwo.Thisispartiallybecause coverageisslightlyhigherthan90%ininterventionthree(afew stateshavehigher-than-90%coverageinthebaselineandmaintain thatcoveragerateininterventionthree).However,thesimulation resultsalsoshowthatoftentheareasthatsufferthehighest dis-easeburdenandthathavethegreatestpotentialmarginalgainsto vaccinationaretheareasthatcurrentlyunder-vaccinatethemost. Althoughruralareashave lowerrotavirusimmunization cover-agethanurbanareasininterventionone,ruralareasavertmore rotavirusdeathsinthatscenario.Moreover,interventionstendto haveagreaterfinancialbenefitforthosesegmentsofthe popula-tion.PoorandruralareasavertmoredeathsandOOPexpenditure thanurbanareas.

Demandandsupplybothcontributetolowimmunizationrates. Lackofeducationcontributestolowimmunizationdemand.Ina

UNICEFsurveyofvaccinationcoverageinIndia,themost-cited rea-sonsfornon-immunizationincluded“didnotfeeltheneed,”“not knowingaboutvaccines,”and“notknowingwheretogofor immu-nization”[7].Additionally,ruralareashavepooraccesstohealth carefacilities.Wherefacilitiesareavailable,theyoftensufferfrom staffingissuesandpoorqualityofservice,whichalsodecreases healthcaredemand[25].

TheIndianimmunizationdeliverysystemreliesheavilyon com-munity health workers (CHWs) to mobilize and vaccinate the ruralpopulation[26].StrengtheningCHWprogramscanincrease immunization coverage [26,27] and encourage age-appropriate immunization[28].Researchsuggeststhatprovidingincentivesto familiescanalsoimprovevaccinationrates[29].However,effects ofthesestrategieshavebeenlittlestudied.

AlthoughIndiaisnotcurrentlyreachingitstargetimmunization coveragewiththeUIP,itrecognizesthepotentialofnewvaccines.

Fig.4.Healthandfinancialimpact(totalsbystate).

Resultsarefor100simulations.Stateswithalowsamplepopulationorahighstandarddeviationaregreyedout.Valuesareinmillions.OOPexpenditureavertedassumes 100%demandfortreatment.Allinterventionsremaincost-effectiveifOOPexpenditureavertedisexcluded.DALYs=disability-adjustedlifeyears;OOP=out-of-pocket.

Ithasintroducedanewpentavalentvaccineinafewstates[30]and planstorollitoutacrossthecountryin2014–15.Giventheresource constraints,research into which vaccines alleviatethe greatest burdenisimportant.Arotavirusvaccineisacompellingchoice. RotavirusputsaheavyburdenontheIndianpopulation,especially onunder-twoyearolds,anddoesnotsignificantlydecreasewith improvementsinhygieneandsanitation[31].

Ouranalysisofarotavirusvaccineshowsthatitsintroduction cansignificantlyreducerotavirusburden.Wepredictthat introduc-ingthevaccineattheDPT3levelwillavertapproximately44,500 under-fiverotavirusdeathsperyearinIndia.Increasingrotavirus immunizationcoverageto90%inourmodelavertsapproximately another8500and 9500 deathsin interventions two and three, respectively;allthreeinterventionsarecost saving.Ourresults forinterventiononearesimilartoothercost-effectiveness mod-els[32,33]. Our DPT3coverage,which is estimatedfor 2011,is

higherthanthatofEspositoetal.[33].Thesimilarresultdespite thedisparityinvaccinationcoverageisbecauseofdifferentmodel assumptions.Ourdeathrateislowerandourvaccineefficacyis slightlyhigher.ArecentreportbytheInternationalVaccineAccess Center(IVAC)atJohnsHopkinsBloombergSchoolofPublicHealth

[34] usesa baselinedeathratemuch lowerthan ours (approx-imately 54,000 versus 113,000) and estimates approximately 22,000rotavirusdeathsavertedat72%vaccinationcoverage.Their costaverteddifferssignificantlyfromourOOPaverted,thoughin additiontodifferentmodelparameterstheyincludecomponents wedonot(e.g.lostproductivity).Verguetetal.[23]estimate(with DLH-3vaccinationrates)theOOPexpenditureavertedfora1 mil-lionbirthcohortandthemoney-metricvalueofinsurancefor1 millionhouseholds.Theircohortaverts$1.8millionOOP expendi-tureoverthefirstfiveyearsoflifeandthemoney-metricvalueof insuranceis$16,000for1millionhouseholds.Weestimatethat

Fig.5. Money-metricvalueofinsuranceper100,000under-fives.

Resultsarefor100simulations.DPT3andmeaslesvaccinationcoveragedoesnotchangeininterventionone,andthereforethemapisgreyedout.Statesinwhichimmunization coverageis90%oraboveinthebaselinearegreyedoutininterventionthree.Additionally,stateswithalowsamplepopulationorahighstandarddeviationaregreyed out.Money-metricvalueofinsurance=thevalueofprotectionfromtheriskofexpenditureondiseasetreatment(includingthecostsofseekingcare).Itistheamountthe populationiswillingtopaytoavoidthatrisk.

approximately$2.3millionOOPisaverted and amoney-metric valueofinsuranceof$23,500summedoverthewealthquintilesin across-section1millionpopulationofunder-fives.Wesumover wealthquintilesforcomparabilitywiththeirstudy,thoughwealth quintilesdonotincludeanequalnumberofunder-fiveyearolds. Ourresultsaresimilar,butthecomparisonisnotexactduetothe differingmodelpopulationsandassumptions.Themostsignificant differenceinmodelassumptions ofthetwo analysesis theage distributionoftheunder-fivepopulation.

Thecost-effectiveness results hereare moreoptimistic than otheranalyses[32,33]becauseofourassumptionof100% treat-mentdemand.IfwedonotconsiderOOPaverted,wehavealower boundestimateofcost-effectiveness,andtheinterventionsremain verycost-effectivebyWHO’scost-effectivenesscriteria[35]:the costperDALYavertedislessthanIndia’spercapitaGDP.

Theregionaldetailinthemodelisanadditionalreasonforthe differencesbetweenourfindingsandpastanalyses.Asdiscussed, themarginalgainsfromimmunizationareoftenhighestinareas thatcurrentlyvaccinatetheleast.Introducingrotavirusaccording toDPT3vaccinationcoverage(thesamehouseholds)maintainsthat trend.

Amajorchallengetorealizingthepotentialbenefitsdescribed here is the low investment in routine immunization [36]. In 2011–12theMoHFWspentapproximately$233milliononroutine immunization.ContinuingtheUIPatcurrentcoveragerateswould costapproximately$438millionintheinterventionyear(cMYP andpersonalcommunicationwithMoHFW).Theestimatedcostfor thepoliocampaignduringtheinterventionyearisapproximately $108million.Underthemodelassumptions,introducingarotavirus vaccineatDPT3levelscostsanotherapproximately$93million,or

roughlya17%increaseontopofthetotalcostsoftheexisting rou-tineimmunizationandthepoliocampaign.Interventionthreewill costapproximately$129millionmorethanwouldbespentinthe baseline($53millionofwhichwouldbespentforUttarPradesh). Asignificantincreaseinimmunizationprogramfundingisneeded bothtointroducethenewvaccinesandtoincreaseimmunization coverageinIndia.

Thestudyislimitedbytheparametersweuse.Thoughour anal-ysisfocusesonthedistributionacrosspopulationsubgroups,the parametersdonotcaptureallthecovariatesaffectingthesegroups. Forexample,wedonotcapturethestatefixedeffectsinmanyofour variables.Weusethepopulationdistributions(byage,wealth,and sex)toextrapolatethevaluesforspecificsubgroups.Additionally, weassumethattheper-childUIPcostsaredistributeduniformly acrossstates.Despitenotfullycapturingallthefactorsaffectingthe diseaseandexpendituredistributionsacrossthesubpopulations, wefeelthatthisresearchisastepintherightdirection. Addition-ally,wedonotmodeltheinfectiousdiseasedynamics,whichmeans wedonotconsideranyadditionalbenefitsfromherdimmunity.

5. Conclusion

IntroducingarotavirusvaccinetoUIPandincreasingUIP cov-eragearecost-effectiveinterventionsthatwouldgreatlyalleviate thediseaseandfinancialburdenofvaccine-preventablediseases inIndia.Theresultspresentedhereareusefulforpolicyanalysis, giventhepaucityofdataontheinterventions’effectsizeacross dif-ferentsubsetsofthepopulation:atthestatelevel,intheruraland urbanpopulations,andacrossthewealthdistribution.Additional researchisneededtointroduceaninfectiousdiseasemodelinto theABMusedhereandtotakeintoaccountthestatefixedeffects.

Acknowledgments

WethankAshvinAshokforhisresearchassistance.

Conflictsof interest: None declared. Funding: This work was fundedbytheBillandMelindaGatesFoundationthroughthe Dis-ease ControlPriorities projectat the University of Washington (grantno.720165),GrandChallengesCanadathroughtheSaving Brainsproject,andJohnsHopkinsUniversity(purchaseorderno. 2002067649)throughthecost-effectivenessofrotavirus vaccina-tioninIndiagrant.Thefundershadnoroleinstudydesign,writing thereport,thedecisiontosubmit,ordatacollection,analysis,and interpretation.

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