Dengue Dynamics and Vaccine Cost-Effectiveness Analysis in the Philippines

Transcription

1 Am. J. Top. Med. Hyg., 95(5), 2016, pp doi: /ajtmh Copyight 2016 by The Ameican Society of Topical Medicine and Hygiene Dengue Dynamics and Vaccine Cost-Effectiveness Analysis in the Philippines Eunha Shim 1 * 1 Depatment of Mathematics, Soongsil Univesity, Seoul, Republic of Koea Abstact. Dengue is one of the most poblematic vecto-bone diseases in the Philippines, with an estimated 842,867 cases esulting in medical costs of $345 million U.S. dollas annually. In Decembe 2015, the fist dengue vaccine, known as chimeic yellow feve vius dengue vius tetavalent dengue vaccine, was appoved fo use in the Philippines and is given to childen 9 yeas of age. To estimate the cost-effectiveness of dengue vaccination in the Philippines, we developed an age-stuctued model of dengue tansmission and vaccination. Using ou model, we compaed two vaccination scenaios entailing outine vaccination pogams both with and without catch-up vaccination. Ou esults indicate that the highe the cost of vaccination, the less cost-effective the dengue vaccination pogam. With the cuent dengue vaccination pogam that vaccinates childen 9 yeas of age, dengue vaccination is cost-effective fo vaccination costs up to $70 fom a health-cae pespective and up to $75 fom a societal pespective. Unde a favoable scenaio consisting of 1 yea of catch-up vaccinations that taget childen 9 15 yeas of age, followed by egula vaccination of 9-yea-old childen, vaccination is cost-effective at costs up to $72 fom a health-cae pespective and up to $78 fom a societal pespective. In geneal, dengue vaccination is expected to educe the incidence of both dengue feve and dengue hemohagic feve /dengue shock syndome. Ou esults demonstate that even at elatively low vaccine efficacies, age-tageted vaccination may still be cost-effective povided the vaccination cost is sufficiently low. INTRODUCTION Dengue is the leading cause of vecto-bone vial disease in humans, esulting in 390 million infections and 96 million symptomatic cases annually woldwide. 1 Dengue infection poses a heavy economic buden to the health system in a society. The egion with the highest dengue incidence is southeast Asia (SEA), whee cycles of epidemics occu evey 3 5 yeas. 2 The SEA and the Westen Pacific epesent about 75% of the cuent global buden of dengue, and the Philippines is among the most affected. 2 In the Philippines, the fist epidemic of sevee dengue was documented in Manila in 1953, and since then, dengue has been hypeendemic in most aeas of the county with an inceasing numbe of dengue cases ove time. 1 With an adjustment fo undeepoted dengue cases, a ecent study estimated an annual aveage of 842,867 clinically diagnosed cases of dengue in the Philippines, with diect medical costs of $345 million U.S. dollas. 3 Denguefeve(DF)iscausedbyoneofthefoudistinct seotypes of dengue vius (DENV), DENV 1 4. Infection with one seotype povides life-long immunity against einfection with that paticula seotype, but not against the othes. The fist infection is nomally asymptomatic o pesents only mild symptoms. Howeve, sevee diseases, including dengue hemohagic feve (DHF) and dengue shock syndome (DSS), mostly occu among individuals who have aleady ecoveed fom the fist infection and ae expeiencing a seconday infection with a diffeent seotype. 4 Vaccination is consideed one of the most cost-effective pevention stategies to lowe the buden of dengue, paticulaly in childen, in both developing and developed counties. 5 The Wold Health Oganization (WHO) has called fo the development of a dengue vaccine as an essential pat of the integated dengue pevention effot needed to lowe the dengue buden and dengue-elated fatalities globally befoe On Decembe 23, 2015, the Philippines became the fist county in Asia to license the wold s fist dengue vaccine, a live ecombinant chimeic yellow feve vius DENV tetavalent dengue vaccine (CYD-TDV) called Dengvaxia. 6 This vaccine has been appoved in Mexico and Bazil 6,7 fo use in individuals 9 45 yeas of age living in endemic aeas. It will be administated in thee doses with a 6-month inteval between each dose. Results fom the phase III andomized, contolled vaccine tials of CYD-TDV epoted a elatively low vaccine efficacy of 57% against viologically confimed dengue. 8 In the Philippines, the Depatment of Health launched the dengue school-based immunization pogam to give the dengue vaccines to Gade 4 public school students 9 yeas of age. Howeve, to date, few published studies have examined the economic and disease buden of dengue in the Philippines. 2,3 Although pio cost-effectiveness analyses of dengue vaccination povided valuable esults, a substantial amount of additional infomation has emeged ecently, including vaccine safety, efficacy, and taget ages. Thus, pio cost-effectiveness analyses have not assessed the new school-based pogam of dengue vaccination tageting individuals 9 yeas of age. Ou study is the fist to assess cost-effectiveness of dengue vaccination in the Philippines. We estimated the economic and epidemiological impact of dengue vaccination in the Philippines and calculated its cost-effectiveness at vaious vaccine costs with and without a catch-up dengue vaccination pogam. Specifically, we developed an age-stuctued, dynamic dengue tansmission model and used it to estimate the costeffectiveness of the dengue vaccine in the Philippines, which allowed us to identify a theshold vaccine cost at which the dengue vaccine becomes cost-effective. *Addess coespondence to Eunha Shim, Depatment of Mathematics, Soongsil Univesity, 369 Sangdo-o, Dongjak-gu, Seoul 06978, Republic of Koea. alicia@ssu.ac.k 1137 METHODS Mathematical model of dengue tansmission and vaccination. We constucted a deteministic, age-stuctued, compatmental model that captues key featues of dengue

2 1138 SHIM FIGURE 1. Model diagam. The population is divided into dengue-elated age-dependent epidemiological classes. The subscipt k indicates the age goups (k =1,..., 15). tansmission: clinical coss-immunity among the multiple seotypes of dengue, population age stuctue, and age-specific levels of tansmission (Figue 1). Ou model includes pimay, seconday, and tetiay infections. Two pio dengue infections ae known to povide potective immunity against sevee dengue disease accompanying infection with a thid dengue infection. 9,10 Theefoe, thid infections fom dengue ae likely to be asymptomatic, consistent with ou model assumptions. 9,11 13 We account fo antibody-dependent enhancement by assuming that the pobability of developing DHF and DSS afte a seconday infection is geate than that afte a pimay infection. 14,15 In ou model, the population contains 15 distinct age classes, which epesent individuals 0 4, 5 8, 9, 10 14, 15 19, 20 25,..., 60 64, and 65 yeas of age. Tansition ates among these age classes ae independent of infection status and occu though aging at ate p k (k =1,...,15),wheep 15 =0. Hee, the subscipt k efes to the age goup k. Within each age class, we incopoate susceptible unvaccinated individuals (S k ), pimaily infected unvaccinated individuals (I k ), unvaccinated individuals ecoveing fom pimay infections who ae tempoaily potected against clinical disease (C k ), unvaccinated individuals susceptible to seconday infections (R k ), unvaccinated individuals with seconday infections (Y k ), unvaccinated individuals ecoveing fom seconday infections (W k ), unvaccinated individuals ecoveing fom seconday infections who ae tempoaily potected against clinical disease (P k ), unvaccinated individuals with tetiay infections (J k ), unvaccinated individuals ecoveing fom tetiay infections (Z k ), patially susceptible vaccinated individuals (V k ), pimaily infected vaccinated individuals (VI k ), vaccinated individuals ecoveing fom pimay infections and tempoaily potected against clinical disease (VC k ), vaccinated individuals susceptible to seconday infections (VR k ), vaccinated individuals with seconday infections (VY k ), and vaccinated individuals ecoveing fom seconday infections (VW k ) (Figue 1). The popotion, g, of infected individuals is assumed to be symptomatic. Unvaccinated individuals who ecove fom thid infections (Z k ) o vaccinated individuals who ecove fom seconday infections (VW k ) ae assumed to be immune to all stains. The ates of bith and death ae denoted by b and μ k, espectively. To captue the pattens of age-dependent incidence ates in the Philippines, ou model consides age-dependent infection ates. Specifically, we define β k as the age-dependent tansmission ate among age goup k. Ou model combines the undelying pocess of vecto contact with humans, and the dynamics of infection in the vecto and subsequent tansmission to othe humans into one aggegate ate Such an aggegate ate, denoted by β k in ou model, epesents the mean vecto-mediated ate at which humans infect othe humans. Theefoe, instead of consideing sepaate contact ates fo tansmission fom humans to vectos and vice vesa, ou model consides the ate of infection of susceptibles in age goup k (i.e., the foce of infection, λ k ) whee X 15 β k ði k þ Y k þ J k þ VI k þ VY k Þ λ k ¼. That is, the foce of N infection (λ k ) is assumed to be egulated by the numbe of infectious individuals and the tansmission coefficient (β k ). Infected individuals ae assumed to ecove fom pimay infections at ate γ and gain clinical coss-potection, which pevents clinical illness but allows seoconvesion. The aveage duation of clinical coss-potection is assumed to be 1/γ C (Table 1). Ou vaccination stategy is implemented by vaccinating individuals 9 yeas of age, consistent with cuent ecommendations fo the administation of the dengue vaccine in the Philippines. Specifically, fo age goup k = 3, individuals except those who ae symptomatically infected ae vaccinated at the ate of ϕ k (Figues 2 and 3). To evaluate the potential impact of catch-up vaccination, we also consideed vaccinating individuals 9 15 yeas of age when incopoating the catch-up vaccination pogam in addition to the egula vaccination of 9-yea-old individuals. The estimated efficacy fom dengue vaccine tials has been expessed in tems of eduction of clinically appaent infection, which is distinct fom vaccine efficacy against infection. 36 Theefoe, we assumed the vaccine efficacy against disease afte infection, athe than the efficacy against infection, by incopoating the vaccine tials data into the model. Also, we assumed that the vaccine efficacy is dependent on the seveity of infection and seological status, consistent with the vaccine tials data. 8,9 Specifically, in ou model, vaccine efficacy against both asymptomatic and symptomatic infection is denoted by ε and δ among individuals 9 yeas of age who had neve been exposed to DENV (efeed to as seonegative individuals) and individuals 9 yeas of age who had peviously been exposed to DENV (efeed to as seopositive individuals), espectively (ε < δ). The dengue vaccine tials data ae only based on symptomatic infection, and thus, we assumed that the dengue vaccine efficacy against asymptomatic is the same as the vaccine efficacy against symptomatic

3 COST-EFFECTIVENESS OF DENGUE VACCINATION IN THE PHILIPPINES 1139 TABLE 1 Epidemiological paametes Symbol Paamete Value Distibution Refeences f k Fetility ate in age goup k f 1 = f 2 = f 3 = f 4 = f 15 =0, f 5 = f 6 = f 7 = f 8 = f 9 = f 10 = , f 11 = f 12 = f 13 = f 14 = Point estimate N k Relative size of age goup k N 1 = , Point estimate 29 N 2 = , N 3 = , N 4 = , N 5 = N 6 = N 7 = N 8 = N 9 = N 10 = , N 11 = N 12 = N 13 = N 14 = , N 15 = B Bith ate in Philippines, b ¼ X11 f k N k Point estimate p k Rate of aging out of age goup p 3 = , Point estimate k ( p k =1/a k, whee a k is the age inteval in age goup k) p k = fo k 3 μ k Death ate in age goup k μ 1 = b/n 1 p 1 μ k Point estimate = p k 1 N k 1 =N k p k (k 1) β k Tansmission ate among age goup k β 1 = , Point estimate Data fitting β 2 = , β 3 = , β 4 = , β 5 = β 6 = β 7 = β 8 = β 9 = β 10 = , β 11 = β 12 = β 13 = β 14 = , β 15 = σ n Relative pobability of being susceptible (5 n)/4 Point estimate 30 to nth infection ϕ k Vaccination ate in age goup k φ 3 = and φ k =0 Point estimate Autho s assumption fo k 3 fo Stategy A φ 3 = φ 4 = and φ k = 0 fo k 3 o 4 fo Stategy B ε Vaccine efficacy against infection among Point estimate 31 the seonegative 9 yeas of age δ Vaccine efficacy against infection among Point estimate 31 the seopositive 9 yeas of age δ D Vaccine efficacy against DHF among the Point estimate 31 seopositive 9 yeas of age g Popotion of dengue infections that 0.23 Beta (7, 23) 32,33 ae symptomatic γ Rate of ecovey fom infection 0.146/day Point estimate 15 γ C Rate of loss of coss-immunity /day Beta (37.3, 6,790) 16,34 h 1 Pobability of developing DHF/DSS Beta (5, 2,037) afte pimay symptomatic infection among the unvaccinated h 2,k Pobability of developing DHF/DSS fo k = 1, 2 Point estimate 9 afte pimay symptomatic infection fo k = 3,...,15 among those vaccinated who wee seonegative when vaccinated q 1 Pobability of developing DHF/DSS Beta (50, 1,066) afte seconday symptomatic infection among the unvaccinated χ Risk of death fom DHF/DSS 0.01 Beta (2,198) 30,35 DHF = dengue hemohagic feve; DSS = dengue shock syndome. Paamete values wee used in the analysis unless indicated othewise. 29 infection. 8,9 In addition, δ D is defined as the vaccine efficacy against DHF among seopositive individuals 9 yeas of age. Ou model incopoates both vaccine-induced potection and vaccine-enhanced dengue disease among vaccine ecipients, as obseved in the CYD-TDV tials. 9,9 Results of phase III efficacy tials of CYD-TDV conducted in Asia and Latin Ameica demonstated that an individual s age and DENV seostatus befoe vaccination affect vaccine efficacy. 37 Specifically, vaccine efficacy was geate in seopositive individuals compaed with seonegative individuals (ε < δ). 37,38 Futhemoe, pio exposue to DENV had an impotant ole in the longe-tem (hospital) safety obsevations. 37 Specifically, vaccination may pesent immunological similaities to an attenuated subclinical pimay infection, and thus vaccination of seonegative individuals potentially inceases the isk of DHF duing a subsequent wild-type infection. 37 Thus, in ou model, the pobability of developing DHF/DSS afte pimay symptomatic infection among unvaccinated individuals was assumed to be lowe than individuals who wee seonegative when vaccinated (h 1 < h 2,k ). Hee, h 1 and h 2, k ae defined as the pobability of developing DHF among symptomatically infected individuals in I k and VI k, espectively (Table 1). Using these notations and

4 1140 SHIM assumptions, the age-stuctued model of dengue tansmission and vaccination is given by: ds k ¼ b k þ p k 1S k 1 ðϕ k þ σ 1 λ k þ μ k þ p k ÞS k ; di k ¼ p k 1I k 1 þ σ 1 λ k S k ½γ þ ð1 gþϕ k þ μ k þ p k ŠI k ; dc k dr k dy k dw k dp k ¼ p k 1 C k 1 þ γi k ðγ C þ ϕ k þ μ k þ p k ÞC k ; ¼ p k 1 R k 1 þ γ C C k ðσ 2 λ k þ ϕ k þ μ k þ p k ÞR k ; ¼ p k 1 Y k 1 þ σ 2 λ k R k ½γ þ ð1 gþϕ k þ μ k þ p k ŠY k ; ¼ p k 1 W k 1 þ γy k ðγ C þ ϕ k þ μ k þ p k ÞW k ; ¼ p k 1 P k 1 þ γ C W k ðσ 3 λ k þ ϕ k þ μ k þ p k ÞP k ; dj k ¼ p k 1 J k 1 þ σ 3 λ k W k ðγ þ ϕ k þ μ k þ p k ÞJ k ; dz k dvs k dvi k dvc k dvr k dvy k dvw k ¼ p k 1 Z k 1 þ γj k ðϕ k þ μ k þ p k ÞZ k ; ¼ p k 1 VS k 1 þ ϕ k S k σ 1 λ k ð1 ε Þð1 gþ þ ð1 εþgð1 h 1 Þþgh 2;k ÞgVS k ðμ k þ p k ÞVS k ; ¼ p k 1 VI k 1 þ ð1 gþϕ k I k þ σ 1 λ k ð1 εþð1 gþ þ ð1 εþgð1 h 1 Þþgh 2;k ÞgVS k ðγ þ μ k þ p k ÞVI k ; ¼ p k 1 VC k 1 þ ϕ k C k þ γvi k ðγ C þ μ k þ p k ÞVC k ; ¼ p k 1 VR k 1 þ ϕ k R k þ γ C VC k σ 2 λ k ð1 δþð1 gþþð1 δþg ð 1 q1 Þ þ ð1 δ D Þgq 1 Þ VR k ðμ k þ p k ÞVR k ; ¼ p k 1 VY k 1 þ ð1 gþϕ k Y k þ σ 2 λ k ð1 δ þ ð1 δþgð1 q 1 Þþð1 δ D Þgq 1 Þ VR k ðγ þ μ k þ p k ÞVY k ; ¼ p k 1 VW k 1 þ ϕ k ðw k þ J k þ Z k ÞþγVY k ðμ k þ p k ÞVW k Þð1 gþ X 6 β k ði k þ Y k þ J k þ VI k þ VY k Þ whee b ¼ X6 f k N k, λ k ¼ N and σ n =(5 n)/4. Hee, σ n is defined as a elative pobability of being susceptible to nth infection. We complete the fomulation by giving appopiate initial conditions: S k (0) = S k,0, I k (0) = I k,0, C k (0) = C k,0, R k (0) = R k,0, Y k (0) = Y k,0, W k (0) = W k,0, P k (0) = P k,0, J k (0) = J k,0, Z k (0) = Z k,0,andvs k (0) = VI k (0) = VC k (0) = VR k (0) = VY k (0) = VW k (0) = 0. Hee, the initial conditions of the compatments within each age class diffe due to immunity in olde age goups. The elative size of kth age goup is denoted by N k,wheen k = S k + I k + C k + R k + Y k + W k + P k + J k + Z k + vesus k + VI k + VC k + VR k + VY k + VW k, N 1 ¼ b 1 ; N k ¼ p k 1 N k 1 fo k =2,...,14, μ 1 þ p 1 μ k þ p k and N 15 ¼ p 14 N 14. μ 15 Calibation. Cases of dengue in the Philippines ae known to be substantially undeepoted. 3 The adjustment facto was estimated to be 7.2, meaning that fo each epoted case, thee ae 7.2 actual cases of dengue. 3 Thus, we an the model using baseline paametes and calibated ou model to an adjusted annual symptomatic dengue incidence of 0.84%, which incopoates undeepoted cases. 3,39 This is compaable with the estimates of disease buden associated with dengue in othe south Asian counties. Fo instance, in Thailand, its annual symptomatic dengue incidence, although undeepoted, anges fom 0.58% to 0.69%. 39,34 In addition, 23% of pimay and seconday dengue infections ae assumed to be symptomatic. 32,33 To geneate county-specific dengue pofiles fo each age goup, we allowed the tansmission ates to be age dependent. These ates wee chosen to captue the pattens of empiical dengue incidence in the Philippines (Figue 4). 40 Age-specific incidence pofiles wee obtained using β 1 = , β 2 =0.5536,β 3 = , β 4 =0.7058,β 5 = β 6 = β 7 = β 8 = β 9 = β 10 = , β 11 = β 12 = β 13 = β 14 = , and β 15 = When incopoating adjustments to account fo undeepoting, the annual incidences of DHF in the Philippines is estimated to be 0.016%. 3 These pobabilities wee vaied fo sensitivity analysis when we examined cost-effectiveness. Vaccination stategies. Vaccination scenaios that model the impact of two diffeent vaccination pogams ae pesented (Figues 2 and 3). The fist, called Stategy A, assumed that the ollout of the vaccine consisted of outine vaccination of 9-yea-old individuals. Vaccination ates in outine pogams wee constant ove time and set so that vaccination coveage would each 1 million childen afte 1 yea. 41,42 These vaccination ates wee chosen to oughly coespond with the ate of vaccination aimed fo in the Philippines using a outine immunization campaign. 42 Stategy B consisted of 1 yea of catch-up tageting childen 9 15 yeas of age, followed by egula vaccination of 9-yea-old childen. Fo Stategy B, the same vaccination ates in Stategy A wee used in catch-up and outine pogams. 43 Diect and indiect unit costs. Ou cost-effectiveness analysis was pefomed fom both the health-cae pespective (diect costs only) and the societal pespective (diect and indiect costs). In ou analysis, all health and economic outcomes wee discounted at a unifom ate of 3% pe yea, and all costs wee standadized to 2016 U.S. dollas using the consume pice index. 44 Diect medical costs of a teated hospitalized case aveaged $869 in pivate hospitals and $437 in public hospitals, which esults in a combined cost of $636 (Tables 2 and 3). 3 Fo cases of dengue teated only in an ambulatoy setting, the associated cost was $89 in the public secto and $189 in the pivate secto, which amounts to a combined cost of $ Combining these cost estimates with the distibution of cases, we deived an aveage cost estimate pe DF and DHF infection (i.e., C DF, diect and C DHF, diect, espectively) (Table 3). The estimates of the indiect costs of hospitalized and ambulatoy cases wee obtained fom pio

5 COST-EFFECTIVENESS OF DENGUE VACCINATION IN THE PHILIPPINES 1141 FIGURE 2. Vaccination coveage levels based on Stategy A. Fo Stategy A, vaccines ae given to individuals 9 yeas of age. (A) The numbe of cumulative numbe of vaccinated individuals is pesented. (B) The vaccination coveage level based on Stategy A is pesented. studies based on bivaiate egession. 2 In this bivaiate egession, Shepad and othes extapolated ln(indiect cost) as dependent vaiables, using ln(goss domestic poduct [GDP] pe capita) as one of the independent vaiables. 2 Specifically, indiect costs associated with hospitalized cases and ambulatoy cases ae estimated at $42 and $20 pe individual, espectively. In addition, indiect costs in the Philippines associated with dengue-elated deaths ae estimated at $87,418 pe death fo childen (< 15 yeas of age) and $56,822 pe death fo adults ( 15 yeas of age). 41 We used the human capital appoach to estimate the indiect cost of dengue deaths, by using the aveage ages of death and the aveage discounted life expectancy fo childen and adults based on WHO life tables. 41,53 We estimated the discounted yeas of life lost fo adults and childen by fist multiplying the numbe of fatal dengue episodes in each age goup by the discounted yeas of life lost fo that age goup. The poduct was summed accoding to the age goups (i.e., child o adult), and we then computed the weighted aveage of the discounted yeas of life lost fo each age goup. The economic cost of each yea of discounted life expectancy was valued at the GDP pe capita in the Philippines. Finally, to estimate the indiect cost of fatal cases in childen and in adults, the numbe of dengue fatal cases fo childen (o adults) was multiplied by the Philippines GDP pe capita and the coesponding discounted yeas of life lost. Calculation of quality-adjusted life yeas and costs associated with dengue. We measued the effectiveness of each stategy in quality-adjusted life yeas (QALYs) to account fo both time and quality of life. Specifically, we calculated the timediscounted QALYs lost to DF, DHF/DSS, and dengue-elated deaths. A disability weight of one was used fo pematue death. FIGURE 3. Vaccination coveage levels based on Stategy B. Stategy B consists of 1 yea of catch-up tageting childen 9 15 yeas of age, followed by egula vaccination of 9-yea-old individuals. (A) The numbe of cumulative numbe of vaccinated individuals is pesented. (B) The vaccination coveage level based on Stategy B is pesented.

6 1142 SHIM esidual expected lifespan of an individual in the age goup k in the absence of dengue infection, is the social discount ate of 3%, and Q DF and Q DHF ae the quality of life lost pe episode of DF and DHF (Table 2). To calculate the health effects, the quality-adjusted life expectancy (QALE) was fist calculated in the case of a lethal dengue infection as: Discounted QALE, at age a with disease status, 1 e D ¼ Q D L ð a;d Þ ; FIGURE 4. Annual numbe of symptomatic cases of dengue pe 100,000 in age goup in the pevaccine ea. Repoduced fom Bavo and othes. 40 The ate of new DF cases, DHF cases, and dengue-elated deaths (Death k ) in age goup k wascalculatedasfollows: ddf k ðþ t ddhf k ðþ t ddeath k ðþ t ¼ gð1 h 1 Þλ k S k þ gð1 q 1 Þλ k R k þ ð1 εþgð1 h 1 Þλ k VS k þ ð1 δþgð1 q 1 Þλ k VR k ¼ gh 1 λ k S k þ gq 1 λ k R k þ gh 2;k λ k VS k þ ð1 δ D Þgq 1 λ k VR k ¼ χ ddhfk ðþ t Using the equations above as well as the following equation, we calculated the numbe of dengue episodes and QALYs lost in each case : Z T f 0 e tx15 2 ddf k ðþ t ddhf k ðþ t DQ DF þ DQ DH F ddeath 3 kðþ t 6 þ Q 7 4 no disease L k;no disease 1 e ð Þ ddeathk ðþ t 5 Hee, Q no disease is the quality of life in the absence of dengue infection (assumed to be one), L(k, no disease) is the whee Q D is the quality of life associated with a disease state (D) and L is the esidual life expectancy fo an individual consideing the life expectancy in the Philippines is 70 yeas. 53,55 Theefoe, the discounted QALY loss at age a, associated with dengue-elated deaths, can be calculated as: 1 e DQ D L ð a;d Þ ¼ Q no disease 1 e Q Death 1 e ¼ Q no disease 1 e L ð a;no disease Þ L ð a;death Þ L ð a;no disease Þ Fo the associated nonlethal infections, the QALY loss fo DF and DHF is Q DF and Q DHF, espectively. In addition, the total costs accued due to medical teatment, vaccination, and lost poductivity is estimated by the following: Costs ¼ costs of vaccination þ costs associated with dengue infection ðdh and DHFÞ ¼ Z T f 0 8 X 15 C V;k ϕ k Sk þ ð1 gþi k þ C k þ R k >< >= þ ð1 gþy k þ W k þ J k þ P k þ Z k e t þ X15 ddf k ðþ t ddhf k ðþ t >: C DF;k þ C DH F;k >; Fo the cost-effectiveness analysis fom the health-cae pespective, only diect costs wee consideed in the above 9 TABLE 2 Cost-effectiveness paametes Symbol Paamete Value Distibution Refeences Social discount ate fo QALYs calculations 0.03 Point estimate D Death Disability weight fo death 1 Point estimate D DF Disability weight fo DF Beta (19.7, 80.3) D DHF Disability weight fo DHF/DSS Beta (54.5, 45.5) L DF Time lost due to DF (yeas) Beta (5.7, 294.3) L DHF Time lost due to DHF/DSS (yeas) Beta (13, 387) L Death,k Yeas of life lost due to death fo age goup k 67.5 fo k =1, Point estimate 63 fo k =2, 61 fo k =3, (k 4) fo k =4,...,15 a k Aveage age of dengue exposue in age class k 2.5 fo k =1, Point estimate 7 fo k =2, 9 fo k =3, 5(k 4) fo k =4,...,15 DF = dengue feve; DHF = dengue hemohagic feve; DSS = dengue shock syndome; QALY = quality-adjusted life yea. 45,46 45,46 30,47 30,47 43,30,48,49 43,30

7 COST-EFFECTIVENESS OF DENGUE VACCINATION IN THE PHILIPPINES 1143 TABLE 3 Pobabilities and costs of dengue infection Pobability Relative pobability Diect medical costs ($) Indiect costs ($) Refeences Any pimay dengue infection 1.00 Asymptomatic 0.75 (= 1 g) Symptomatic 0.25 (= g) (= 1 k 1 ) DF = 0.36 (1 k 1 ) Ambulatoy = 0.64 (1 k 1 ) NA 87,418 fo childen 2,3,50 (< 15 yeas of age) 56,822 fo adults ( 15 yeas of age) Hospitalized (= k 1 ) 2,3,50 Sevee (DHF) = (1 χ) k 1 Hospitalized = χ k 1 2,3,30,35 Death 30,35,51,52 Any seconday dengue infection 1.00 Asymptomatic 0.75 (= 1 g) Symptomatic 0.25 (= g) (= 1 k 2 ) DF = 0.36 (1 k 2 ) Ambulatoy = 0.64 (1 k 2 ) NA 197,622 2,3,50 Hospitalized (= k 2 ) 2,3,50 Sevee (DHF) = (1 χ) k 1 Hospitalized = χ k 1 2,3,30,35 Death 30,35,51,52 DF = dengue feve; DHF = dengue hemohagic feve; NA = not applicable. All values ae epoted in 2016 U.S. dollas. equation, wheeas both diect and indiect costs wee consideed fom the societal pespective. Cost-effectiveness of dengue vaccination. To analyze the cost-effectiveness of a vaccination pogam, we consideed the balance between the cost of vaccination and the esulting incemental health effects. Fo ou analysis, incemental effects wee the diffeences between the incidence of dengue infection with and without the vaccination pogam. As customay in analyses of cost-effectiveness, the esults ae pesented in units of cost pe QALY gained by vaccination (compaed with no vaccination) to expess the cost of puchasing a yea of good health. The discounted costs and benefits of a dengue vaccination pogam wee summed ove a time hoizon of 20 yeas. To calculate the cost-effectiveness of the vaccine, we used the fomula of the incemental costeffectiveness atio (ICER), that is, the cost pe QALY gained by vaccination. The fomula fo ICER is as follows: ICER ¼ Cost vaccine Cost no vaccine QALYs vaccine QALYs no vaccine Consistent with the WHO citeia, vaccination is consideed to be vey cost-effective when ICER is less than the GDP pe capita, is cost-effective when ICER is 1 3 times the GDP pe capita, and is not effective when ICER exceeded thee times the GDP pe capita. 56 RESULTS Disease buden of dengue in the Philippines. We fist calculated the annual dengue infection incidence in the absence of vaccination by simulating ou model with ou baseline paamete values. Ou model was then fitted to the dengue incidence data pesented in Figue 4, so that the estimated annual dengue infection incidence in the Philippines, including both asymptomatic and symptomatic infections, was 4.3%. 3 Due to uncetainty in the asymptomatic ates in each age goup, we multiplied the pimay and seconday incidence fo all age goups by a constant symptomatic ate of 23% (g = 0.23) to get symptomatic dengue incidence. On the basis of this assumption, the annual symptomatic dengue incidence was estimated to be 0.84%, which includes the annual DHF incidence of 0.016%. The expected annual numbe of symptomatic cases of dengue pe age goup in the pevaccine ea is pesented in Figue 5A, which is compaable to the empiical data (Figue 4). 3 In ou simulation esults, the highest incidence (1,720 1,810 pe 100,000) occued among individuals unde 14 yeas of age, consistent with the obseved patten. 3 Acoss all age goups, the annual incidence of symptomatic dengue pe 100,000 individuals is estimated to be 860 cases in the pevaccine ea. Epidemiological impact of dengue vaccination. With vaccination stategies A and B, the aveage annual symptomatic incidence of dengue is expected to be 690 and 678 cases pe 100,000 individuals, espectively (Figue 5). In addition, dengue vaccination affected the incidence of DHF. Specifically, above 20 yeas, vaccination stategies A and B educed the incidence of DHF by 5% and 6% in all ages, espectively (Table 4). Howeve, the incidence of DHF is expected to incease by 1% and 0.5% among 9-yea-old individuals with vaccination stategies A and B, espectively. This is because vaccination of seonegative individuals potentially inceases the isk of DHF duing a subsequent wild-type infection. Futhemoe, dengue vaccination had geate effects in the ealy stages of a vaccination pogam than late stages. Specifically, at 5 and 10 yeas afte implementing vaccine Stategy A, the incidence of DF would be educed by 13% and 17%, espectively, compaed with pevaccine ea. Similaly, at 5 and 10 yeas afte adopting vaccine Stategy B, the incidence of DF would be educed by 14% and 18%, espectively, and the incidence of DHF would be educed by 5% and 7%, espectively. Lastly, ou simulation esults indicate that by yea 20, the vaccination stategies A and B would educe the incidence of DF and DHF by at least 20% and 9%, espectively, compaed with pevaccine ea. Vaccine cost-effectiveness. Fom a health-cae pespective, ou model estimated that it would cost $7,687,887 U.S. dollas to teat dengue infections in a population of

8 1144 SHIM FIGURE 5. Expected annual numbe of symptomatic cases of dengue pe 100,000 in espective age goups. (A) Expected annual incidence of symptomatic dengue in the pevaccine ea. (B) Expected annual incidence of symptomatic dengue with vaccine Stategy A. (C) Expected annual incidence of symptomatic dengue with vaccine Stategy B. 100,000 individuals with no vaccination pogam. Howeve, it would cost $6,615,860 o $6,521,900 to teat dengue infections if a vaccination pogam using Stategy A o B is implemented, espectively. Fom a societal pespective, Stategy A would educe the cost of teating dengue infections in a population of 100,000 individuals fom $8,494,586 to $7,332,538 and Stategy B would educe the costs associated with teating dengue infections to $7,229,170. To calculate cost-effectiveness atios, we consideed a ange of vaccine pices because the eventual pice of the vaccine in the Philippines is cuently uncetain. Theefoe, instead of assuming that a single pice would be detemined, we estimated a theshold pice below which a vaccination pogam would be (vey) cost-effective. The cost theshold pe peson below which the vaccine stated to be cost-effective inceased fom $70 fo Stategy A to $72 fo Stategy B, fom a healthcae pespective (Figue 6A). Consevatively, the dengue vaccination pogam is vey cost-effective fom a health-cae pespective when the cost of vaccination pe peson is unde $66 and $68 with Stategy A and B, espectively. Fom a societal pespective, this cost theshold inceases to $72 and to $74, espectively (Figue 6A and B). The theshold costs fo a vaccine pogam to be cost-effective fom a societal pespective incease to $75 with Stategy A and to $78 with Stategy B. Cost-effectiveness acceptability cuve. To depict the likelihood that a chosen vaccination stategy is cost-effective ove a ange of acceptability thesholds, we caied out pobabilistic sensitivity analysis by vaying key paametes ove distibutions. Using this analysis with ove 5,000 model iteations, we detemined a cost-effectiveness acceptability cuve. As an example, we chose the cuent vaccination pogam adopted in the Philippines shown in Stategy A, as well as a vaccination cost of $75 pe individual (Figue 7). This analysis evealed that fom a health-cae pespective, dengue vaccination is likely to be cost-effective at a willingness-to-pay value $2,765 (GDP pe capita in the Philippines) pe QALY in 69% of the model iteations. This likelihood of cost-effectiveness inceased to 74% at an acceptability theshold of $8,295 (thee times the GDP pe capita in TABLE 4 Annual dengue cases with and without a vaccination pogam Pevaccine ea Vaccination Stategy C Vaccination Stategy B Vaccination Stategy A Symptomatic infection (%) Pimay infection (%) Seconday infection (%) No. of DHF cases pe million DHF = dengue hemohagic feve.

9 COST-EFFECTIVENESS OF DENGUE VACCINATION IN THE PHILIPPINES 1145 FIGURE 6. Cost-effectiveness of dengue vaccines. Cost-effectiveness atios of dengue vaccination pe quality-adjusted life yea gained ae pesented (A) using Stategy A, and (B) using Stategy B. The solid lines indicate the cost-effectiveness atios fom health-cae pespective, wheeas the dashed lines indicate the cost-effectiveness atios fom societal pespective. the Philippines) pe QALY. Fom a societal pespective, the likelihood of cost-effectiveness is 68% and 74% at an acceptability theshold of $2,765 (GDP pe capita) pe QALY and $8,295 (thee times the GDP pe capita) pe QALY, espectively. FIGURE 7. Cost-effectiveness acceptability cuves. The cuves show that dengue vaccination in the Philippines is cost-effective at diffeent cost-effectiveness theshold values. The cost-effectiveness acceptability cuves fom health-cae and societal pespectives ae shown fo assumed vaccine coveage levels shown with Stategy A, and if the cost of vaccination is fixed at $75 pe individual. DISCUSSION Ou analysis of the cost-effectiveness of the fist dengue vaccination pogam with the CYD-TDV in the Philippines suggests that the vaccine would be cost-effective fo a wide ange of vaccine costs. Specifically, ou model pedicts that when 9-yea-old individuals ae consistently vaccinated (i.e., Stategy A) the vaccine will be cost-effective at costs as high as $75 fom a societal pespective. These data ae consistent with pio studies based on the data fom the Ameicas. 45,50 58 The fact that ou findings ae consistent with pevious studies is meaningful because age pattens of dengue incidence ae makedly diffeent between SEA and the Ameicas. In the Ameicas, the pedominant clinical expession of DF occus in adults, wheeas in SEA, sevee dengue illnesses have been obseved pimaily in infants and childen. 59 On the basis of ou esults and those of pio studies, dengue vaccination has the potential to be cost-effective with caefully chosen taget goups and sufficiently high vaccine uptake levels. Even with potential vaccine-induced inceases in the isk of DHF, ou study suggests that the dengue vaccine could emain cost-effective in the Philippines as long as the cost is less than $66 pe peson. Unde the cuent vaccination egimen adopted in the Philippines (i.e., Stategy A), when the cost of vaccination is less than $64 pe peson vaccines incu a net savings pe QALY. In othe wods, the avoided costs of teating dengue infection wee geate than the costs of vaccination. Nevetheless, ou study is limited by seveal factos. Fist, thee is uncetainty in existing dengue studies, mainly due to undeepoting of symptomatic dengue infections and limited data on the type of teatment of episodes. 60 In the Philippines,

10 1146 SHIM dengue suveillance depends mainly on disease epoting units and the cuent suveillance system focuses only on hospitalized cases. Thus, symptomatic dengue infections ae undeepoted. 60 Although we used an oveall adjustment facto fo dengue cases in the Philippines, 3 futue studies obtaining moe accuate and compaable measues of the actual disease buden of dengue will geatly impove the estimates on the cost-effectiveness of dengue vaccination. Second, the mechanism of vaccine action in ou model is only one possibility, wheeas othe possibilities have been mentioned in the liteatue, including age-dependent vaccine efficacy and waning vaccine immunity. 43,61 Specifically, the cost-effectiveness of dengue vaccination would decease when vaccine waning is consideed. Thid, ou study did not account fo boade impacts of dengue vaccination, such as educed spending on outbeak contol and aveted losses in touism. 62 Although such factos wee ignoed in ou analysis, we expect that incopoation of these boade benefits would esult in geate economic value of dengue vaccination, thus impoving its cost-effectiveness. In addition, although model inputs wee dawn fom an extensive eview of the liteatue, the souces may vay in quality, and the model paametes may not hold unde all conditions. Lastly, ou model does not explicitly conside the vecto biting pocess. Thus, ou model combines the dynamics of infection in the vecto and subsequent tansmission to othe humans into one aggegate ate, instead of consideing sepaate contact ates fo tansmission fom humans to vectos and vice vesa. Yet many dengue studies, including evaluating the impact of vaccination, have been easonably modeled without explicitly accounting fo vecto population dynamics. 16,17 As a esult, in existing mathematical models of dengue tansmission, the vecto population dynamics ae often omitted, 14,15,18 28 and aely modeled explicitly. 16,17 Nevetheless, fo some modeling objectives including the evaluation of the impact of vecto contol effots, inclusion of vecto population dynamics would be helpful in poviding moe ealistic model outcomes. The goal of the global dengue stategy set foth by WHO aims to educe dengue motality by at least 50% by 2020, and to educe dengue mobidity by at least 25% by Howeve, the incidence of dengue is expected to incease due to vaious factos, including global waming, inceases in population density, and the migation and intenational tavel of infected people. 62 Ou analysis of the ecently appoved dengue vaccination pogam in the Philippines eveals that with appopiate vaccine picing and uptake levels, dengue vaccination holds significant potential to confe excellent value and educe the oveall buden of dengue in the Philippines. Received Mach 10, Accepted fo publication August 1, Published online Septembe 6, Financial suppot: This eseach was suppoted by the Basic Science Reseach Pogam though the National Reseach Foundation of Koea (NRF) funded by the Ministy of Education (2015R1D1A1A ). Autho s addess: Eunha Shim, Depatment of Mathematics, Soongsil Univesity, Seoul, Republic of Koea, alicia@ssu.ac.k. This is an open-access aticle distibuted unde the tems of the Ceative Commons Attibution License, which pemits unesticted use, distibution, and epoduction in any medium, povided the oiginal autho and souce ae cedited. REFERENCES 1. Alea MT, Sikiatkhachon A, Velasco JM, Tac-An IA, Lago CB, Clapham HE, Fenandez S, Levy JW, Thaisomboonsuk B, Klungthong C, Macaeo LR, Nisalak A, Hemann L, Villa D, Yoon IK, Incidence of dengue vius infection in adults and childen in a pospective longitudinal cohot in the Philippines. PLoS Negl Top Dis 10: e Shepad DS, Unduaga EA, Halasa YA, Economic and disease buden of dengue in southeast Asia. PLoS Negl Top Dis 7: e Edillo FE, Halasa YA, Lago FM, Easmo JN, Amoin NB, Alea MT, Yoon IK, Alcantaa AC, Shepad DS, Economic cost and buden of dengue in the Philippines. Am J Top Med Hyg 92: Muell S, Wu SC, Butle M, Review of dengue vius and the development of a vaccine. Biotechnol Adv 29: Tozan Y, Cuent issues in the economics of vaccination against dengue. Expet Rev Vaccines 15: Sanofi Pasteu, Sanofi Pasteu s Dengue Vaccine Appoved in the Philippines. Lyon, Fance: Sanofi Pasteu. Available at: Mexico dengue vaccine fist. Nat Biotechnol 34: Capeding MR, Tan NH, Hadinegoo SR, Ismail HI, Chotpitayasunondh T, Chua MN, Luong CQ, Rusmil K, Wiawan DN, Nallusamy R, Pitisuttithum P, Thisyakon U, Yoon IK, van de Vliet D, Langevin E, Laot T, Hutagalung Y, Fago C, Boaz M, Watel TA, Toniepoth NG, Saville M, Bouckenooghe A, Goup CYDS, Clinical efficacy and safety of a novel tetavalent dengue vaccine in healthy childen in Asia: a phase 3, andomised, obseve-masked, placebo-contolled tial. Lancet 384: Halstead SB, Russell PK, Potective and immunological behavio of chimeic yellow feve dengue vaccine. Vaccine 34: Gibbons RV, Kalanaooj S, Jaman RG, Nisalak A, Vaughn DW, Endy TP, Mammen MP J, Sikiatkhachon A, Analysis of epeat hospital admissions fo dengue to estimate the fequency of thid o fouth dengue infections esulting in admissions and dengue hemohagic feve, and seotype sequences. Am J Top Med Hyg 77: Olkowski S, Foshey BM, Moison AC, Rocha C, Vilcaomeo S, Halsey ES, Kochel TJ, Scott TW, Stoddad ST, Reduced isk of disease duing postseconday dengue vius infections. J Infect Dis 208: Pandey A, Medlock J, The intoduction of dengue vaccine may tempoaily cause lage spikes in pevalence. Epidemiol Infect 143: Halstead SB, Neutalization and antibody-dependent enhancement of dengue viuses. Adv Vius Res 60: Nagao Y, Koelle K, Deceases in dengue tansmission may act to incease the incidence of dengue hemohagic feve. Poc Natl Acad Sci USA 105: Adams B, Boots M, Modelling the elationship between antibody-dependent enhancement and immunological distance with application to dengue. J Theo Biol 242: Johansson MA, Hombach J, Cummings DA, Models of the impact of dengue vaccines: a eview of cuent eseach and potential appoaches. Vaccine 29: Focks DA, Daniels E, Haile DG, Keesling JE, A simulation model of the epidemiology of uban dengue feve: liteatue analysis, model development, peliminay validation, and samples of simulation esults. Am J Top Med Hyg 53: Weaing HJ, Rohani P, Ecological and immunological deteminants of dengue epidemics. Poc Natl Acad Sci USA 103: Coutinho FA, Buattini MN, Lopez LF, Massad E, Theshold conditions fo a non-autonomous epidemic system descibing the population dynamics of dengue. Bull Math Biol 68: Feguson N, Andeson R, Gupta S, The effect of antibodydependent enhancement on the tansmission dynamics and pesistence of multiple-stain pathogens. Poc Natl Acad Sci USA 96: Feguson NM, Donnelly CA, Andeson RM, Tansmission dynamics and epidemiology of dengue: insights fom age-statified

11 COST-EFFECTIVENESS OF DENGUE VACCINATION IN THE PHILIPPINES 1147 seo-pevalence suveys. Philos Tans R Soc Lond B Biol Sci 354: Billings L, Schwatz IB, Shaw LB, McCay M, Buke DS, Cummings DA, Instabilities in multiseotype disease models with antibody-dependent enhancement. J Theo Biol 246: Bianco S, Shaw LB, Schwatz IB, Epidemics with multistain inteactions: the inteplay between coss immunity and antibody-dependent enhancement. Chaos 19: Cummings DA, Schwatz IB, Billings L, Shaw LB, Buke DS, Dynamic effects of antibody-dependent enhancement on the fitness of viuses. Poc Natl Acad Sci USA 102: Recke M, Blyuss KB, Simmons CP, Hien TT, Wills B, Faa J, Gupta S, Immunological seotype inteactions and thei effect on the epidemiological patten of dengue. Poc Biol Sci 276: Schwatz IB, Shaw LB, Cummings DA, Billings L, McCay M, Buke DS, Chaotic desynchonization of multistain diseases. Phys Rev E Stat Nonlin Soft Matte Phys 72: Wikamaatna PS, Simmons CP, Gupta S, Recke M, The effects of tetiay and quatenay infections on the epidemiology of dengue. PLoS One 5: e Billings L, Fioillo A, Schwatz IB, Vaccinations in disease models with antibody-dependent enhancement. Math Biosci 211: U.S. Depatment of Commece, Population Tends Philippines. U.S. Depatment of Commece, 1 4. Available at: Duham DP, Ndeffo Mbah ML, Medlock J, Luz PM, Meyes LA, Paltiel AD, Galvani AP, Dengue dynamics and vaccine cost-effectiveness in Bazil. Vaccine 31: Hadinegoo SR, Aedondo-Gacia JL, Capeding MR, Deseda C, Chotpitayasunondh T, Dietze R, Muhammad Ismail HI, Reynales H, Limkittikul K, Rivea-Medina DM, Tan HN, Bouckenooghe A, Chansinghakul D, Cotes M, Fanouillee K, Foat R, Fago C, Gailhadou S, Jackson N, Noiega F, Plennevaux E, Watel TA, Zambano B, Saville M, The CYD- TDV Dengue Vaccine Woking Goup, Efficacy and longtem safety of a dengue vaccine in egions of endemic disease. N Engl J Med 373: Bhatt S, Gething PW, Bady OJ, Messina JP, Falow AW, Moyes CL, Dake JM, Bownstein JS, Hoen AG, Sankoh O, Myes MF, Geoge DB, Jaenisch T, Wint GR, Simmons CP, Scott TW, Faa JJ, Hay SI, The global distibution and buden of dengue. Natue 496: Honoio NA, Nogueia RM, Codeco CT, Cavalho MS, Cuz OG, Magalhaes Mde A, de Aaujo JM, de Aaujo ES, Gomes MQ, Pinheio LS, da Silva Pinel C, Louenco-de-Oliveia R, Spatial evaluation and modeling of dengue seopevalence and vecto density in Rio de Janeio, Bazil. PLoS Negl Top Dis 3: e Ndeffo Mbah ML, Duham DP, Medlock J, Galvani AP, County- and age-specific optimal allocation of dengue vaccines. J Theo Biol 342: Guble DJ, Dengue and dengue hemohagic feve. Clin Micobiol Rev 11: Rodiguez-Baaque I, Mie-y-Tean-Romeo L, Buke DS, Cummings DA, Challenges in the intepetation of dengue vaccine tial esults. PLoS Negl Top Dis 7: e Guy B, Jackson N, Dengue vaccine: hypotheses to undestand CYD-TDV-induced potection. Nat Rev Micobiol 14: Coudeville L, Bauin N, Vegu E, Estimation of paametes elated to vaccine efficacy and dengue tansmission fom two lage phase III studies. Vaccine j.vaccine Shepad DS, Unduaga EA, Halasa YA, Stanaway JD, The global economic buden of dengue: a systematic analysis. Lancet Infect Dis 16: Bavo L, Roque VG, Bett J, Dizon R, L Azou M, Epidemiology of dengue disease in the Philippines ( ): a systematic liteatue eview. PLoS Negl Top Dis 8: e Ceojano T, Philippines Launches Wold s Fist Mass Dengue Vaccination. Available at: 3ad36f9ba b829e d562/philippines-launches-woldsfist-mass-dengue-vaccination. Accessed August 27, Sandoval E, Fist Mass Dengue Vaccination in the Wold Launched in PHL. MIMS. Alexanda Technopak. Singapoe Rodiguez-Baaque I, Mie-y-Tean-Romeo L, Schwatz IB, Buke DS, Cummings DA, Potential oppotunities and peils of impefect dengue vaccines. Vaccine 32: U.S. Bueau of Labo Statistics, The Consume Pice Indexes (CPI): All Uban Consumes. Available at: Accessed Novembe 26, Caasco LR, Lee LK, Lee VJ, Ooi EE, Shepad DS, Thein TL, Gan V, Cook AR, Lye D, Ng LC, Leo YS, Economic impact of dengue illness and the cost-effectiveness of futue vaccination pogams in Singapoe. PLoS Negl Top Dis 5: e Muay CJ, Quantifying the buden of disease: the technical basis fo disability-adjusted life yeas. Bull Wold Health Ogan 72: Dantes HG, Fafan-Ale JA, Sati E, Epidemiological tends of dengue disease in Mexico ( ): a systematic liteatue seach and analysis. PLoS Negl Top Dis 8: e Chao DL, Halstead SB, Halloan ME, Longini IM J, Contolling dengue with vaccines in Thailand. PLoS Negl Top Dis 6: e Andeson KB, Chunsuttiwat S, Nisalak A, Mammen MP, Libaty DH, Rothman AL, Geen S, Vaughn DW, Ennis FA, Endy TP, Buden of symptomatic dengue infection in childen at pimay school in Thailand: a pospective study. Lancet 369: Shepad DS, Suaya JA, Halstead SB, Nathan MB, Guble DJ, Mahoney RT, Wang DN, Meltze MI, Cost-effectiveness of a pediatic dengue vaccine. Vaccine 22: Unduaga EA, Betancout-Cavioto M, Ramos-Castaneda J, Matinez-Vega R, Mendez-Galvan J, Guble DJ, Guzman MG, Halstead SB, Hais E, Kui-Moales P, Tapia-Conye R, Shepad DS, Economic and disease buden of dengue in Mexico. PLoS Negl Top Dis 9: e Peabody JW, Shimkhada R, Tan C J, Luck J, The buden of disease, economic costs and clinical consequences of tubeculosis in the Philippines. Health Policy Plan 20: Unduaga EA, Halasa YA, Shepad DS, Use of expansion factos to estimate the buden of dengue in southeast Asia: a systematic analysis. PLoS Negl Top Dis 7: e Shim E, Galvani AP, Impact of tansmission dynamics on the cost-effectiveness of otavius vaccination. Vaccine 27: Atkins KE, Shim E, Caoll S, Quilici S, Galvani AP, The cost-effectiveness of pentavalent otavius vaccination in England and Wales. Vaccine 30: Wold Health Oganization, The Wold Health Repot 2002: Reducing Risks, Pomoting Healthy Life. Geneva, Switzeland: Wold Health Oganization. 57. Lee BY, Conno DL, Kitchen SB, Bacon KM, Shah M, Bown ST, Bailey RR, Laosiitawon Y, Buke DS, Cummings DA, Economic value of dengue vaccine in Thailand. Am J Top Med Hyg 84: Oellano PW, Reynoso JI, Stahl HC, Salomon OD, Costutility analysis of dengue vaccination in a county with heteogeneous isk of dengue tansmission. Vaccine 34: Halstead SB, Dengue in the Ameicas and southeast Asia: do they diffe? Rev Panam Salud Publica 20: Shepad DS, Unduaga EA, Betancout-Cavioto M, Guzman MG, Halstead SB, Hais E, Mudin RN, Muay KO, Tapia- Conye R, Guble DJ, Appoaches to efining estimates of global buden and economics of dengue. PLoS Negl Top Dis 8: e WHO-VMI Dengue Vaccine Modeling Goup, Beatty M, Boni MF, Bown S, Buathong R, Buke D, Coudeville L, Cummings DA, Edelman R, Faa J, Focks DA, Gomes MG, Guignad A, Halstead S, Hombach J, Knee G, Koelle K, Lam FC, Lang J, Longini I, Medlock J, Namgyal P, Powell M, Recke M, Rohani P, Standaet B, Stuchine C, Teyssou R, Weaing H, Assessing the potential of a candidate dengue vaccine with mathematical modeling. PLoS Negl Top Dis 6: e Banighausen T, Bloom DE, Cafieo ET, O Bien JC, Valuing the boade benefits of dengue vaccination, with a peliminay application to Bazil. Semin Immunol 25: Muay NE, Quam MB, Wilde-Smith A, Epidemiology of dengue: past, pesent and futue pospects. Clin Epidemiol 5: