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Vaccine 29 (2011) 6686– 6694

Contents lists available at ScienceDirect

Vaccine

j ourna l ho me pag e: www.elsev ier .com/ locate /vacc ine

ost-effectiveness of conjugate pneumococcal vaccination in Singapore:omparing estimates for 7-valent, 10-valent, and 13-valent vaccines

aren Richards Tyoa, Melissa M. Rosena, Wu Zenga, Mabel Yapb, Keng Ho Pweeb,i Wei Angb, Donald S. Sheparda,∗

Schneider Institutes for Health Policy, Heller School, Brandeis University, 415 South Street, PO Box 549110, MS035 Waltham, MA 02454-9110, USASingapore Ministry of Health, College of Medicine Building, 16 College Road, Singapore 169854, Singapore

r t i c l e i n f o

rticle history:eceived 18 March 2011eceived in revised form 20 June 2011ccepted 24 June 2011vailable online 13 July 2011

eywords:neumococcal conjugate vaccineingaporeublic health impactaccine costaccine efficacyerd immunity effecterotype replacementost-effectiveness

a b s t r a c t

Introduction: Although multiple studies of cost-effectiveness of pneumococcal conjugate vaccines havebeen conducted, no such study has examined Singapore’s situation nor compared the licensed conjugatevaccines in an Asian population. This paper estimates the costs and public health impacts of pneumococcalconjugate vaccine programs, varying estimates of serotype replacement and herd immunity effects as keyparameters in the analysis. Based in part on a 2008 analysis also presented here, Singapore has approvedthe PCV-7, PHiD-10, and PCV-13 pneumococcal conjugate vaccines as part of its National ChildhoodImmunisation Programme.Methods: An economic evaluation was performed using a Markov simulation model populated withSingapore-specific population parameters, vaccine costs, treatment costs, and disease incidence data.The vaccinated infant and child cohort of 226,000 was 6% of the Singapore resident population of 3.8million. Vaccine efficacy estimates were constructed for PCV-7, PHiD-10, and PCV-13 vaccines based ontheir serotype coverage in Singapore and compared to ‘no vaccination’. The model estimated impactsover a five-year time horizon with 3% per year discounting of costs and health effects. Costs were pre-sented in 2010 U.S. dollars (USD) and Singapore dollars (SGD). Sensitivity analyses included varying herdimmunity, serotype replacement rates, vaccine cost, and efficacy against acute otitis media.Results: Under base case assumptions for the revised analysis (i.e., herd effects in the unvaccinated pop-ulation equivalent to 20% of direct effects) PCV-13 prevented 834 cases and 7 deaths due to pneumonia,meningitis, and bacteremia in the vaccinated population, and 952 cases and 191 deaths in the unvac-cinated population over the 5-year time horizon. Including herd effects, the cost-effectiveness ratio forPCV-13 was USD $37,644 (SGD $51,854) per QALY. Without herd effects, however, the ratio was USD$204,535 (SGD $281,743) per QALY. The PCV-7 cost per QALY including herd effects was USD $43,275(SGD $59,610) and for PHiD-10 the ratios were USD $45,100 (SGD $62,125). The original 2008 analysis,which had higher estimates of pneumonia prevention due to herd immunity and lower estimates of costper dose, had found a cost-effectiveness ratio of USD $5562 (SGD $7661) per QALY for PCV-7.Conclusions: When compared to cost-effectiveness thresholds recommended by the World Health Orga-nization (WHO), our 2008 analysis found that vaccination of infants in Singapore with PCV-7 wasvery cost-effective if herd immunity effects were present. However, knowledge on herd immunity

and serotype replacement that emerged subsequent to this analysis changed our expectations aboutindirect effects. Given these changed inputs, our current estimates of infant vaccination against pneu-mococcal disease in Singapore find such programs to be moderately cost-effective compared to WHOthresholds. The different findings from the 2008 and 2011 analyses suggest that the dynamic issue ofserotype replacement should be monitored post-licensure and, as changes occur, vaccine effectiveness

alyse

and cost-effectiveness an

∗ Corresponding author. Tel.: +1 781 736 3975; fax: +1 888 429 2672.E-mail addresses: karentyo@brandeis.edu (K.R. Tyo), mrosen@brandeis.edu

M.M. Rosen), wuzengcn@brandeis.edu (W. Zeng), Mabel YAP@moh.gov.sg (M.ap), PWEE Keng Ho@moh.gov.sg (K.H. Pwee), ANG Li Wei@moh.gov.sg (L.W. Ang),hepard@brandeis.edu (D.S. Shepard).

264-410X/$ – see front matter © 2011 Elsevier Ltd. All rights reserved.oi:10.1016/j.vaccine.2011.06.091

s should be re-evaluated.© 2011 Elsevier Ltd. All rights reserved.

1. Introduction

Given the constant advance of health technologies and

constraints on health care spending, economic modeling of inter-ventions such as vaccination can provide an important input topolicy decisions. This practice has been especially true for the pneu-mococcal conjugate vaccines, which impact several pneumococcal

ine 29

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K.R. Tyo et al. / Vacc

iseases across a broad age range [1,2], and which appear to haveeen priced well above the break-even level when including onlyirect vaccine effects [3,4].

Pneumococcal conjugate vaccines (PCVs) containing polysac-haride antigens connected to carrier proteins have been found toe effective in developing an immune response and in reducingasopharyngeal carriage of vaccine-type pneumococcus in infantsnd children [5–10]. The first conjugate vaccine, called PCV-7 forhe seven serotypes targeted (4, 6B, 9V, 14, 18C, 19F and 23F), waspproved for use in the United States in 2000 and subsequentlydopted in many developed countries [7–9]. In 2009, a 10-valentaccine (covering serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and3F) conjugated to Hemophilus influenzae protein-D (PHiD-10) waspproved in Europe [11], and in 2010, a 13-valent conjugate vac-ine covering serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A,9F and 23F (PCV-13) was licensed in the United States [11,12].pprovals for PCV-13 and PHiD-10 were made based on immuno-enicity trials [7,13,14]; and no studies of efficacy against invasiveneumococcal disease have been conducted for these neweraccines.

Despite multiple studies of cost-effectiveness of conjugateneumococcal vaccines in children, no such study has examinedingapore’s situation nor compared all three vaccines in an Asianopulation. The aim of this study is to quantitatively model the costnd public health impact of adding various pneumococcal vacci-ation strategies to Singapore’s National Childhood Immunisationrogramme (NCIP). This cost-effectiveness analysis extends otherost-effectiveness studies by incorporating the following factors:overage of vaccines using Singapore-specific serotype distribu-ions, adjustments to cost and effectiveness due to a 2 + 1 dosing

chedule, cost of pneumococcal illness in Singapore consideringhe country’s efficient health system, and Singapore’s statistics forneumococcal disease. We present the findings from an analysis ofost-effectiveness of PCV-7 performed jointly by researchers from

ig. 1. Portion of TreeAge model showing branches for children aged 0–5 years. Circles

he final outcomes. The model loops 5 times, so children enter at the left based on their s

(2011) 6686– 6694 6687

the Ministry of Health (MOH) of Singapore and Brandeis Universityin 2008, and our 2011 revisions to the analysis.

Based in part on the 2008 joint analysis, the MOH, Singaporerecommended pneumococcal vaccination of infants, and approvedPCV-7 in 2009 and PHiD-10 and PCV-13 in 2010. The MOH approvedthe use of parents’ Medisave (a personal medical savings accountfor Singapore residents) to pay for the pneumococcal vaccination,and provides vaccination with public subsidy through polyclinics.

Since 2008, new information related to herd immunity andserotype replacement has emerged and been incorporated into ouranalysis, and new vaccines have been licensed. We present the 2008and 2011 results for PCV-7 so that readers can see how chang-ing information has impacted these cost-effectiveness ratios overtime.

2. Methods

2.1. Model structure

The cost-effectiveness of pneumococcal vaccination inSingapore was estimated using a Markov simulation modeldeveloped with TreeAge Pro 2009 Suite (Release 1.0.2, TreeAgeSoftware Inc., Williamstown, MA). A Markov model was designedto take a cross section of the Singapore resident population througha 5-year simulation of costs and benefits due to immunization.The model analyzed the impact of the vaccine studied againstinvasive pneumococcal disease (meningitis, bacteremia), all-causeacute otitis media (AOM), and all-cause pneumonia in the vaccinetargeted population (age 0–5) and incorporated herd effectsagainst all-cause pneumonia and pneumococcal bacteremia for

non-vaccinated older age groups. The non-vaccinated population(those over age 5) was divided into three age groups (6–19, 20–59,and 60 plus years) to estimate age-specific herd effects. The branchof the TreeAge model for ages 0–5 is shown in Fig. 1.

denote chance nodes, branches the possible intermediate outcomes, and trianglestatus (alive or dead) at the end of the previous year.

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.2. Disease data

Data for the model were obtained through a systematic reviewf the literature, an expert panel, and MOH’s databases. An exam-nation of the literature was conducted using library databasesnd resulted in the review of 72 studies of the cost-effectivenessf vaccination. Information collected from the literature includedncidence of disease in the population, herd immunity effects, prob-bility of disability or other sequelae and quality-adjusted life yearQALY) losses due to disease. In addition, data specific to Singaporehat were not available in the literature or country databases wereollected using the Delphi process. MOH identified nine expertsn Singapore’s medical and research communities and asked themo respond to a written questionnaire on pneumococcal disease iningapore. The expert panel contained two specialists in pediatrics,wo in family medicine, and one physician specializing in each ofhe following areas: microbiology, otorhinolaryngology, infectiousiseases, respiratory and critical care medicine, and respiratoryedicine. The questionnaire was administered twice. In the first

ound, the experts were asked to estimate key statistics on otitisedia infections, cost of ambulatory care, and quality losses for sev-

ral disease conditions. During the second round, MOH researchersave respondents the results compiled from the first round, andffered them a chance to refine their estimates and answer ini-ially omitted questions. Means were computed for quantitativeesponses for analysis in the model.

The probability of transitioning to a disease state was derived,here possible, from Singapore data and Singapore-based litera-

ure; where this was not possible, a value from the internationaliterature was used. The incidence of all-cause pneumonia wasalculated from 2002 to 2006 MOH hospitalization statistics onneumonia. These statistics incorporated effects of the long estab-

ished adult pneumonia vaccine, PPV23. An ambulatory cohort ofases was created by multiplying the hospitalized cohort by a factoruggested by the Delphi panel. Death rates for all-cause pneumo-ia and for deaths due to causes outside the model were calculated

rom Singapore MOH mortality statistics from 2002 to 2006.The incidence of acute otitis media in Singapore in the 0–5 age

roup is an important factor in the cost-effectiveness estimate.iterature reports of annual incidence of acute otitis media varyubstantially, from 1.2% in an Asian population in 1991 [15] to 64%n a Finnish population [16]. As these data were not available for

ingapore, this study used the estimate provided by the Delphianel (38%) as its central value.

Once in a disease state, the probability of transitioning to a par-icular complication or outcome was determined based on values

able 1ncidence, rates of complications, and death probabilities for diseases in model.

Morbidity or mortality item Ages 0–5

Annual incidence per 100,000 populationMeningitis 2.2

Bacteremia 2.3

All-cause pneumonia 1120

Acute otitis media (AOM) 38,000

Death due to other causes 41

Conditional probability for those with specified diseaseTympanostomy after AOM 0.0046

Deafness after meningitis 0.3

Disability after meningitis 0.16

Complicated bacteremia after bacteremia 0.12

Complicated pneumonia after all-cause pneumonia 0.51

Case fatality ratesMeningitis 8.6%

Bacteremia 1.0%

All-cause pneumonia 0.6%

ote: MOH denotes health statistics provided by Singapore Ministry of Health.

(2011) 6686– 6694

gathered from literature review. Table 1 shows key disease ratesand their data sources.

The age groups 6–19, 20–59, and 60 plus were included inthe model for calculation of herd immunity effects. Several cost-effectiveness studies [20–24] incorporated herd immunity effectsinto their analyses of the conjugate vaccines. This herd immu-nity effect was based on the theory that nasopharyngeal carriageof vaccine serotypes was diminished by vaccination, thus reduc-ing spread of disease in the population. The model evaluates herdimmunity reductions in two health conditions: all-cause pneumo-nia and bacteremia.

The value for herd immunity protection against bacteremia andpneumonia was set at 20% of the efficacy of the vaccine in the vac-cinated population. The U.S. experience with herd immunity wasapproximately 30% of the direct effect, with all-cause pneumoniareductions approaching 80% of the direct effect [23]. Our reduc-tion to 20% was made due to the serotype replacement impact onherd effects observed in Europe; it is hypothesized that serotypereplacement has a disproportionate effect on herd immunity dueto the differing serotype distributions in the pediatric and adultpopulations [3].

2.3. Cost data

In calculating the costs associated with treatment of an illness,the health sector perspective was employed; therefore, the studysought to estimate costs, rather than household expenditures orinsurance payments. All costs in this paper were calculated inmid-2010 Singapore dollars (SGD) and converted to 2010 U.S. dol-lars (USD). As of July 1, 2010, SGD $1.00 equaled USD $0.716 andUSD $1.00 equaled SGD $1.397 (http://www.x-rates.com, accessed04.11.10). However, for the 2008 joint analysis, 2007 SGD wereused.

For bacteremia and meningitis, the costs of these illnesses werecalculated from MOH hospitalization claims data in 2006, assumingall cases were hospitalized, plus a small increment (USD $52, SGD$72) based on Delphi panel estimates for ambulatory follow-up.Pneumonia patients were divided into ambulatory and hospitalizedcases. Most of the costs for hospitalized patients were obtainedfrom MOH data, with a small increment for ambulatory care follow-up care added based on Delphi panel input. In addition, costs forthe care of ambulatory-only pneumonia patients were determined

from Delphi panel input.

Table 2 shows costs associated with each illness or condition.Meningitis is an invasive pneumococcal disease that can havesevere and long-lasting sequelae. Deafness and neurologic impair-

Ages 6–19 Ages 20–59 Ages 60+ Source

– – – [17]1 4 25 [17]149 135 1939 MOH– – – [18]17 152 2448 MOH

– – – [19]– – – [19]– – – [19]0.12 0.12 0.12 MOH0.51 0.51 0.51 [19]

– – – [19]– 20.8% 33.1% [18]1.0% 7.0% 26.0% MOH

K.R. Tyo et al. / Vaccine 29 (2011) 6686– 6694 6689

Table 2Direct medical costs included in model (2010 USD).

Item Ages 0–5 Ages 6–19 Ages 20–59 Ages 60+

Vaccine administration, per dosea $15 –c –c –c

Bacteremia treatment, per episodea $3779 $4513 $7185 $14,757Meningitis treatment, per episodea $14,152 –c –c –c

Pneumonia treatment, per episodea $1432 $1616 $3349 $2928AOM treatment, per episodea $89 –c –c –c

Pneumonia complications, per episodea $8141 $8141 $8141 $8141Tympanostomy, per surgerya $3751 –c –c –c

Disability costs, lifetime, discounted at 3%b $334,400 $321,116 $236,780 $109,174

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ent are especially common after meningitis. These impairmentsere modeled as a sequence of recurring costs for ongoing treat-ent or for residential-level care, if living in the community was

o longer possible. The yearly costs for these conditions were takenrom an Australian study of meningitis sequelae [19]. Costs wereiscounted at 3% per year over the future lifetime of affected indi-iduals to yield a total present value. In addition, a conversion factor0.49) based on the relative expenditures on health as a percentagef GDP for Singapore and Australia was used to adjust for variationn health care efficiencies between these countries.

Vaccine cost was obtained through MOH. The cost of a dose ofCV-7 vaccine was USD $116 (SGD $161), while PHiD-10 and PCV-3 prices were USD $123 (SGD $170) and USD $123 (SGD $169)espectively. The unit cost of vaccine administration per dose (USD15; SGD $20) was also estimated in consultation with MOH.

.4. Vaccination schedule and effectiveness

In 2009, the Expert Committee on Immunization of MOH recom-ended a 2 + 1 vaccination schedule for conjugate pneumococcal

accines, with primary doses at 3 and 5 months, and a boosterose between 12 and 24 months [25]. From a cost standpoint,he model expects that 98% of the child cohort would receiveome vaccinations, with 95%, 2% and 1% of the cohort receiving

doses, 2 doses and 1 dose, respectively. This rate of complianceas consistent with the compliance rates of other immunizations

n Singapore [26]. For example, 95–97% of children completed thenfant Diphtheria-Pertussis-Tetanus series, and 94–96% of childrenompleted the 3-dose Hepatitis B series [27]. With this very highompliance, herd immunity for the 0–5 age group was assumed,ith full protection for the entire age group modeled in all analy-

es. The comparison case for the Markov model was no vaccination.

o catch-up immunization strategy was evaluated.

While PCV-7 had undergone randomized controlled efficacyrials, PHiD-10 and PCV-13 were approved based on immuno-enicity rather than efficacy trials. Therefore, efficacy for the

able 3eduction in disease due to programs with alternative vaccines.

Disease state PCV-13 (%)

Vaccinated population (children 0–5)Invasive pneumococcal diseasea 89.4

All-cause pneumoniab 6.5

All-cause acute otitis mediaa 6.9

Non-vaccinated population (age 6 and above, protected through herd immunity)Invasive pneumococcal diseasec 17.9

All-cause pneumoniad 1.3

ev denotes 2011 revised analysis; orig denotes 2008 original analysis.a Source: [29].b Source: [30].c Source: Delphi panel estimate.d Source: [19].

newer vaccines was estimated from what had been known aboutthe immunogenicity and performance of PCV-7. Table 3 outlinesefficacy estimates, which have been constructed to reflect the dis-tribution of serotypes measured in Singapore [17,28].

Vaccine efficacy parameters from randomized controlled trialsof the vaccine against invasive pneumococcal disease, pneumonia,and acute otitis media were used as a starting point to calculateeffectiveness of the vaccines in Singapore [29–31]. As clinical trialsfor 2 + 1 dosing demonstrated reduced antibody titers for serotypes6B and 23F [32–35], a 10% reduction in efficacy against theseserotypes was factored into the estimate. For invasive pneumo-coccal disease in the vaccinated population, efficacy was estimatedas the percent coverage against Singapore serotypes, modified byreduction in efficacy for the reduced dose regimen, and decreasedslightly by assuming 97.4% efficacy against covered serotypes [36].To evaluate the effectiveness against all-cause pneumonia andacute otitis media, as well as herd immunity protection, basecase values from population studies of PCV-7 effectiveness weremodified by a factor comparing serotype coverage to the 83%serotype coverage of PCV-7 in the U.S. [37,38]. The efficacy of PHiD-10 against acute otitis media (AOM) caused by non-typeable H.influenza is controversial [39,40]. The European Medicines Agencyfound that the “claim for protection against AOM caused by non-typeable H. influenzae at this stage is not supported by clinicaldata” [41]. Therefore in our model for PHiD-10, the base case forprotection against otitis media does not include efficacy againstH. influenzae.

Vaccine efficacy was examined against two key parameters:quality adjusted life years (QALYs) gained and deaths averted.QALYs lost due to death were calculated by finding the remaininglife expectancy for the average individual in the age cohort [42],and converting these years to QALYs using the World Health Orga-

nization Healthy Average Life Expectancy values for Singapore anddiscounting at 3% yearly. QALY losses per disease episode weretaken from literature [19] and Delphi panel estimates of utilitylosses. For sequelae with long lasting implications such as deaf-

PHiD-10 (%) PCV-7rev (%) PCV-7orig (%)

78.1 77.0 83.85.6 5.6 5.66.0 5.9 6.0

15.6 15.4 21.61.1 1.1 4.7

6690 K.R. Tyo et al. / Vaccine 29 (2011) 6686– 6694

Table 4QALY loss per death, disabling condition, or case of illness.

Item Ages 0–5 Ages 6–19 Ages 20–59 Ages 60+

Total lifetime QALYs lost due to death or disability (discounted at 3%)Death loss, per persona 30.0 28.7 23.5 5.9Deafness loss, per personb 11.9 11.3 9.3 2.3Disability loss, per personb 20.3 19.4 15.9 4.0QALY loss per person due to short-term morbidity, per caseMeningitisc 0.015 – – –Bacteremiac 0.011 0.011 0.011 0.011Pneumoniac 0.0057 0.0057 0.0057 0.0057Acute otitis mediac 0.0016 – – –Tympanostomyc 0.0041 – – –Severe or complicated bacteremiac 0.043 0.043 0.043 0.043

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ess and disability, a net present value of losses was obtained byumming and discounting utilities taken from a survey focusedn specific sequelae after meningitis [43,44]. Table 4 shows utilityosses and their data sources.

.5. Differences between the 2008 and 2011 analyses

Updates to the assumptions in the 2008 joint cost-effectivenessnalysis were based on developments in pneumococcal vaccina-ion observed in the past two years. In 2009 and 2010, Singapore’sCIP recommended a 2 + 1 dosing schedule for PCV-7, PHiD-10 andCV-13. The 2008 model assumed a 3 + 1 rather than a 2 + 1 series,nd estimated a price per dose (USD $82) considerably lower thanhe actual market price established for PCV-7 in Singapore (USD119). After implementation of nationwide vaccination programsn France, Spain, the Netherlands, and England, analyses of epidemi-logical statistics there showed significant serotype replacementnd little evidence of a herd effect [45–49]. Therefore, the assump-ion that Singapore would experience a robust herd effect–similaro that seen after implementation of PCV-7 vaccination in the.S.–was modified. In the revised analysis, we did not use estimatesf herd effect strength based on the U.S. experience but instead

odeled it as a percentage (20%) of the direct effect. The estimated

eduction in pneumonia in those over age 60 was most affected byhis change, going from a 4.7% decrease in pneumonia cases in thisge group to a 1.1% reduction (see Table 5).

able 5omparison of methodology in 2008 MOH report and 2011 revised analysis.

Item 2008 MOH report

Economic differencesVaccines studied PCV-7

Currency 2007 SGD

Price per dose $111 SGD (2007)

PCV-7 $82 USD (2010)

Number of doses 4 total doses recommended

Average 3.3 doses per child

Efficacy differencesPCV-7 efficacy Equivalent to efficacy in U.S. Kaiser Pe

trial, adjusted for serotype coverage i(83.8% reduction in IPD in covered po

Herd immunity Herd immunity equivalent to that seeclinical trial, modified by serotype covSingapore (about 30% of direct effect)

Sensitivity analysis differencesCost of vaccine Varied from 50% of base cost to 200%

Serotype replacement Serotype replacement varied from 0%case) to 50% impact on efficacy

Herd immunity Herd immunity protection for pneumfrom 1% to 7% (4.7% is base case)

Acute otitis media protection for PHiD-10 Not applicable

2.6. Sensitivity analyses

One-way sensitivity analyses were undertaken for individualvariables considered most significant in affecting the cost-effectiveness ratio. The three most critical sensitivity analysesfocused on serotype replacement, strength of the herd immunityeffect, and reduction in acute otitis media by PHiD-10.

Epidemiological monitoring in the U.S. after PCV-7 vaccina-tion observed significant and sustained reduction in pneumococcaldisease in the non-vaccinated population [23,50]. However, compa-rable studies in Europe have not observed such reductions [45–49].Rapid replacement of disease caused by non-vaccine serotypes isa possible explanation for this finding [50]. Serotype replacementwas modeled in two ways: first, by variation in herd immunity fromno herd immunity to full herd immunity (with the non-vaccinatedpopulation enjoying protection equal to that observed in the vac-cinated population); and second, by reducing the effectiveness ofthe vaccine in the vaccinated and non-vaccinated populations bya percentage that was compounded yearly over the 5-year timehorizon.

The carrier lipoprotein in PHiD-10 is derived from non-typeableH. influenzae, an organism that is one of the major causes of acute

otitis media. Efficacy of this vaccine against all-cause acute otitismedia may be higher than for PCV-7 or PCV-13 vaccines. A clini-cal trial of a PHiD-type vaccine demonstrated a 33.6% reduction inacute otitis media cases compared to no vaccination [51]. In this

2011 revised analysis

PCV-7, PHiD-10, PCV-132010 USD and 2010 SGD$161 SGD (2007)$116 USD (2010)3 total doses recommendedAverage 2.9 doses per child

rmanenten Singaporepulation)

Equivalent to efficacy in U.S. Kaiser Permanente trial,adjusted for serotype coverage in Singapore and for 3-doserather than 4-dose schedule (73.8% reduction in IPD incovered population)

n in U.S.erage in

Herd immunity set to 20% of direct effect due to lowerrates of indirect effects in Europe. Sensitivity analysisconsidered various herd immunity effects.

of base cost Varied from 75% of base cost to 125% of base cost impact (base Serotype replacement rate varied from 0% (base case) to

30%, compounded yearlyonia varied Herd immunity for pneumonia and bacteremia varied from

none to 40% of direct effect protectionCase of 33.6% reduction in acute otitis media modeled

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rial, the vaccine was an 11-valent formulation administered in 4-dose series, and the definition of a case of otitis media wasestricted. Therefore, this reduction effect is likely to be strongerhan the result achieved by a 10-valent vaccine administered in a-dose series outside of a clinical trial. The best-case scenario of a3.6% reduction in acute otitis media by PHiD-10 was examined in

sensitivity analysis.In a final sensitivity analysis, vaccine cost per dose for the three

accines was decreased by 25% and increased by 25% to examinehe impact this factor had on cost-effectiveness ratios [23].

. Results

.1. Reduction in disease

Prior to vaccination, the 0–5 year old population of 226,000ncurred about 86,000 cases of all-cause acute otitis media, 2535ases of all-cause pneumonia, and 10 cases of meningitis and bac-eremia yearly. In the non-vaccinated population aged 6 and older,2,382 cases of all-cause pneumonia and 209 cases of bacteremiaere predicted over the same 1-year period. Prior to a vaccinationrogram using a conjugate vaccine, pneumonia was estimated toause 15 deaths in the age group of 0–5 years and 2319 deaths in thelder child and adult population annually. The estimate of deathsue to meningitis and bacteremia in the age group of 0–5 years was.5 per year, while 54 deaths due to bacteremia were expected inhe older population.

The results of base case analysis in Table 6 show that a PCV-7accination program would reduce the number of all-cause acutetitis media cases by approximately 4900 cases yearly. PHiD-10as a slightly larger reduction, nearing 5000 cases avoided. PCV-3 has the strongest effect against acute otitis media, averting anstimated 5700 acute otitis media cases. The reduction of all-causeneumonia cases in the vaccinated population varies from 135 to58 cases, with PCV-13 providing the greatest benefit. A similar

umber of cases would be avoided in the non-vaccinated popula-ion, reflecting a lower herd immunity effect and low pneumoniancidence in ages 6–60. PCV-7 and PHiD-10 would prevent 7.6 casesf meningitis and bacteremia in the vaccinated population, while

able 6ase case analysis: yearly totals for impact of pneumococcal vaccination program on Sing

Indicator or vaccine Direct effects Totaleffec

AOM Pneumonia Meningitis + bacteremia

Baseline: number before vaccinationCases 85,995 2535 10.2 88,54Deaths – 15 0.47 15

Cases avertedPCV-7orig 5179 143 8.6 5331PCV-7rev 4894 135 7.6 5036PHiD-10 4967 137 7.6 5111PCV-13 5716 158 8.8 5883Deaths avertedPCV-7orig – 0.83 0.40 1.2

PCV-7rev – 0.79 0.35 1.1

PHiD-10 – 0.80 0.36 1.2

PCV-13 – 0.92 0.41 1.3

QALYs gained (years)PCV-7orig 8.6 26 39 74

PCV-7rev 8.2 24 34 67

PHiD-10 8.2 25 35 68

PCV-13 9.6 29 40 78

Direct savings, excluding vaccination costs (2010 USD$, thousands)PCV-7orig $823 $806 $331 $196PCV-7rev $775 $762 $279 $181PHiD-10 $789 $772 $283 $184PCV-13 $904 $890 $325 $211

ote: orig denotes 2008 original analysis; rev denotes 2011 revised analysis; AOM denotes

(2011) 6686– 6694 6691

PCV-13 would avert 8.8 cases. The number of bacteremia casesavoided in the non-vaccinated group ranges from 31 for PCV-7 to36 for PCV-13.

The model estimated that 1 death would be avoided yearly frompneumonia, bacteremia or meningitis in the vaccinated population.In the non-vaccinated population, 34 deaths due to pneumoniaor bacteremia would be prevented yearly by a vaccination pro-gram using PCV-7 or PHiD-10, with 40 deaths avoided due to herdimmunity using PCV-13.

3.2. QALYs gained

A vaccination program with PCV-7 would add 67 QALYs inthe vaccinated population and 269 QALYs through herd effects.Vaccination with PHiD-10 would augment PCV-7 results by oneadditional QALY in direct effects and 8 QALYs from herd effects.PCV-13, with the highest number of pneumonia cases averted, con-tributes to the largest yield in QALYs compared to no vaccination:78 QALYs gained through direct effects and 397 QALYs gained inthe unvaccinated population. In the 0–5 years age group, the largestproportion of QALYs gained were from avoidance of meningitis, anda significant percentage of these utility gains were a result of theprevention of long-term neurologic effects of meningitis.

3.3. Savings and cost-effectiveness

Table 6 also shows that vaccination with PCV-7 or PHiD-10would result in yearly medical savings in the vaccinated popula-tion of USD $1.8 million (M) (SGD $2.5 M). Savings would increase toUSD $2.1 M (SGD $2.9 M) for PCV-13. Projected savings due to herdimmunity would total USD $1.5 M, $1.5 M, and $1.7 M (SGD $2.0 M,$2.1 M, and $2.4 M) for PCV-7, PHiD-10, and PCV-13, respectively.Savings could be compared to the cost to vaccinate a single-yearbirth cohort (37,700 infants) of USD $37.1 M (SGD $51.1 M) for PCV-7, $39.1 M (SGD $53.9 M) for PHiD-10, and $38.9 M (SGD $53.6 M)

for PCV-13.

When herd immunity effects were included, all pneumococcalconjugate vaccination programs were projected to be moderatelycost-effective in Singapore, as shown in Table 7. Compared with

apore resident population.

directts

Herd immunity effects Total directand HI effects

Pneumonia Bacteremia Total HI effects

0 12,382 209 12,591 101,1312319 54 2373 2388

3173 45 3218 8549 132 31 163 5199

134 31 165 5277 154 36 190 6073

630 11.7 642 64325 8.0 33 3425 8.1 33 3429 9.3 38 40

1156 163 1319 1393177 92 269 336184 92 277 344213 106 319 397

0 $4926 $566 $5492 $74527 $1138 $338 $1476 $32933 $1153 $343 $1496 $33409 $1328 $395 $1723 $3843

acute otitis media; HI denotes herd immunity.

6692 K.R. Tyo et al. / Vaccine 29 (2011) 6686– 6694

Table 7Incremental cost-effectiveness ratios by vaccine in the base case and in one-way sensitivity analyses (2010 USD per QALY).

Scenario PCV-7orig PCV-7rev PHiD-10 PCV-13

Base casea $5562b $43,275 $45,100 $37,644Efficacy

No decrease in efficacy for 3-dose schedule n.a. $41,067 $42,849 $35,944PHiD efficacy against acute otitis media: 33.6% n.a. n.a. $33,776 n.a.

Herd immunity effectsHerd immunity effect: 40% of direct effects n.a. $21,704 $22,721 $18,566No herd immunity effects $176,208c $231,971 $240,869 $204,535

Serotype replacement10% reduction in efficacy per year n.a. $54,868 $57,090 $48,00730% reduction in efficacy per year n.a. $85,235 $88,499 $75,15550% total reduction in efficacy $15,347d n.a. n.a. n.a.

Vaccine cost25% decrease in vaccine cost per dose $4260 $31,521 $32,795 $27,01525% increase in vaccine cost per dose $6881 $55,029 $57,405 $48,273

Note: orig denotes 2008 original analysis; rev denotes 2011 revised analysis, n.a., not applicablea Base case assumes herd immunity effect equals 20% of direct vaccine effect; 0% yearly serotype replacement; efficacy against invasive pneumococcal disease of 97.4% of

coverage against vaccine serotypes; reduction in efficacy of 3.3% for 3-dose schedule vs. 4-dose schedule.b Reported as 2007 SGD$7362.

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c Reported as 2007 SGD$233,254.d Reported as 2007 SGD$20,316.

o vaccination, the estimated incremental cost-effectiveness ratioICER) for PCV-7 was USD $43,275 (SGD $59,610) per QALY gained.CER estimates (compared to no vaccination) for PHiD-10 and PCV-3 were USD $45,100 (SGD $62,125) and $37,644 (SGD $51,854)er QALY respectively. If herd effects were not included, none of thehree vaccines considered would be cost-effective, with estimatedCERs of more than USD $200,000 (SGD $280,000) per QALY.

.4. Scenario and sensitivity analyses

While decreases in immunogenicity have been observed for + 1 dosing schedules [32–35], there is evidence that the reduced-ose schedule may not result in a reduction in efficacy [52]. Theemoval of this model assumption, which increased vaccine effica-ies slightly, resulted in a small decrease in ICER for each vaccinequal to about 5% of the cost per QALY.

Varying the reduction in disease due to herd immunity fromone to 100% of the efficacy in the vaccinated population showshat inclusion of even a small herd immunity effect – such as 5% ofhe direct effect – created a large decrease in the cost-effectiveness

atios. However, due in part to the high cost of the vaccine, assum-ng herd immunity protection equivalent to direct effects did notesult in cost savings due to vaccination. Fig. 2 shows the impact ofarying herd immunity on ICER.

ig. 2. Effect on cost-effectiveness ratios of varying the herd immunity effect.

4. Discussion

This study originated with joint work between the MOH ofSingapore and Brandeis University researchers. Based on the cost-effectiveness thresholds recommended by WHO, this joint 2008analysis indicated that PCV-7 was very cost-effective, primarilydue to inclusion of a robust herd immunity effect. Based in parton the 2008 joint report, MOH of Singapore recommended thatpneumococcal vaccination be incorporated in the country’s NCIP. InNovember 2009, it authorized use of Medisave (Singapore’s med-ical savings) accounts to pay for this vaccination. In our revised2011 analysis, PCV-7, PHiD-10, and PCV-13 were estimated as beingmoderately cost-effective interventions, with ICER values roughlycomparable to per capita GDP in Singapore. PCV-13 had the mostfavorable cost per QALY. If PHiD-10 had enhanced abilities to reduceacute otitis media cases due to immunogenicity induced by its car-rier protein, it would have the most favorable cost-effectivenessprofile.

The most important factor impacting cost-effectiveness was thestrength of herd immunity effects. Without such effects, none of thevaccines studied were cost-effective. However, inclusion of even asmall herd immunity effect reduced ICERs substantially. Given thatnegligible herd immunity effects had been seen in recent Europeaninvestigations [3,45,47,48], there would be no guarantee of reduc-tions in pneumococcal disease in the unvaccinated population inSingapore.

Previous studies of the cost-effectiveness of PCV-7 largely hadfound the intervention to be cost-effective, but such results weredependent on inclusion of herd immunity effects. In Asian cost-effectiveness studies, PCV-7 was found to be cost-effective whenincluding herd effects in Hong Kong, but not cost effective whenherd effects were excluded in that study [53]. In a Korean studythat excluded consideration of herd effects, PCV-7 was also notestimated to be cost effective [4]. In studies of PCV-13, the newervaccine had been estimated to be highly cost-effective in the UnitedStates if herd immunity was included [38], but it was not deemedcost-effective in the Netherlands without such effects [3,36]. PHiD-10 was found to be cost-effective when including herd effects andenhanced protection against acute otitis media [40].

This was the first estimate for cost-effectiveness of pneu-mococcal vaccination in Singapore, and the first analysis ofcost-effectiveness of newer vaccines (PHiD-10 and PCV-13) in anAsian population. The study made extensive use of Singapore-

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pecific morbidity and mortality data and the MOH of Singapore’slaims data for hospitalized cost analysis. The use of a Singaporeelphi panel was a novel component that improved the accuracyf estimates for ambulatory care costs and quality losses.

In the absence of country-specific data, the model madessumptions about herd immunity that were intermediateetween the favorable findings from the U.S. and more pessimisticesults from Europe. Given the dependence of model outcomes onerd immunity effects, the absence of herd immunity data in thisopulation created considerable uncertainty about results. Our sen-itivity analyses showed that herd effects were critical parameters.

Estimates of the efficacy of PCV-13 and PHiD-10 were con-tructed using the immunogenicity clinical trial results. Whenfficacy studies and post-licensure disease reporting data becomevailable, it will be possible to verify the accuracy of thesemmunogenicity-based estimates.

The novel carrier protein employed in PHiD-10 offers the pos-ibility of reduction in disease incidence caused by non-typeable. influenzae [54]. This protection would be especially helpful inhielding children against recurrent or severe disease, but immuno-enicity trials suggest that children with recurrent disease mount aower immune response to this protein [55]. There is also the pos-ibility that the efficacy of PHiD-10 against pneumococcal diseases not equivalent to PCV-type vaccines [39]. While a single studyf efficacy of a PHiD-type vaccine against acute otitis media haseen published [51], additional efficacy trials examining the impacthat PHiD-10 vaccination has on pneumococcal and non-typeablenfluenza disease rates would provide more information.

The rate of increase in pneumococcal replacement disease aftermplementation of an immunization program is a critical issue, ast determines the effectiveness of the vaccine over time. Dynamicompartmental disease models have shown that several factors,uch as assortive mixing patterns, vaccine competition parameters,asopharyngeal co-carriage rates, and degree of vaccine protec-ion, are important in predicting the rate of serotype replacement56,57]. However, little is known about how and why these param-ters appear to vary between groups [50]. Further research intohe dynamics of serotype replacement might explain the disparateesults achieved by vaccination programs in the U.S. and Europe,nd whether policy guidelines and programs that support rapid oromplete immunization play a role in minimizing serotype replace-ent.

cknowledgments

This work was supported by the Ministry of Health of Singaporend the Heller School at Brandeis. We wish to acknowledge theembers of the MOH Pneumococcal Vaccination Workgroup for

heir input: Ong Siew Chin, Lee Heow Yong, Lee Wei Yann, Lim Engok, and Rajni Gupta. The authors are grateful for the participa-

ion of the following experts in our Delphi panel: Chong Chia Yin,im Poh Lian, Loke Kah Yin, Lynne Lim Hsueh Yee, Pang Weng Sun,hilip Eng Cher Tiew, Phua Mei Fang, Roland Jureen, Shiau Ee Lengnd Sonny Wang Yee. The authors wish to thank researchers andlinicians who contributed hospital data: Chong Chia Yin, Nancyee Wen Sim, Prabha Unny Krishnan, Raymond Lin Tzer Pin, Rolandureen, Tan Ai Ling, Tan Puay Hoon, and Tan Thean Yen. We thankeo Cherng Yeu of Pfizer for vaccine price information. We alsoppreciate Clare Hurley’s assistance in formatting the manuscriptnd Petra van Enckevort of GlaxoSmithKline contributions to theroject in her former capacity at MOH of Singapore, and thankeviewers for their comments.

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