Vaccine 34 (2016) 616–621

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Vaccine
journal homepage: www.elsevier.com/locate/vaccine

Cost-utility analysis of dengue vaccination in a country with

heterogeneous risk of dengue transmission
Pablo Wenceslao Orellano a,b,∗ , Julieta Itati Reynoso c , Hans-Christian Stahl d ,
Oscar Daniel Salomon a,e
a
Consejo Nacional de Investigaciones Cientificas y Tecnicas, Buenos Aires, Argentina
b
Universidad Tecnologica Nacional, Facultad Regional San Nicolas, San Nicolas, Argentina
c
Hospital Interzonal General de Agudos “San Felipe”, San Nicolas, Argentina
d
Institute of Public Health, University Hospital Heidelberg, Heidelberg, Germany
e
Instituto Nacional de Medicina Tropical, Puerto Iguazu, Argentina

a r t i c l e i n f o a b s t r a c t

Article history: Background: Dengue is one of the most important vector-borne diseases worldwide, and annually, nearly
Received 29 July 2015 390 million people are infected and 500,000 patients are hospitalized for severe dengue. Argentina has
Received in revised form great variability in the risk of dengue transmission due to eco-climatic reasons. Currently no vaccines are
17 November 2015
available for dengue even though several vaccines are under development.
Accepted 15 December 2015
Available online 24 December 2015
Objective: The aim of this study was to estimate the cost-effectiveness of a dengue vaccine in a country
with heterogeneous risk of dengue transmission like Argentina.
Methods: The analysis was carried out from a societal perspective using a Markov model that included both
Keywords:
Dengue vaccine and disease parameters. Utility was measured as disability adjusted life years (DALYs) averted,
Dengue vaccines and the incremental cost-effectiveness ratio (ICER) of the vaccination was expressed in 2014 American
Cost-utility analysis dollars (US$) per DALY averted. One-way and probabilistic sensitivity analyses were performed to eval-
Argentina uate uncertainty in model outcomes, and a threshold analysis was conducted to estimate the highest
possible price of the vaccine.
Results: The ICER of the vaccination program was found to be US$ 5714 per DALY averted. This value
is lower than 3 times the per capita GDP of Argentina (US$ 38,619 in 2014); 54.9% of the simulations
were below this value. If a vaccination program would be implemented the maximum vaccine price per
dose has to be US$1.49 for a vaccination at national level or US$28.72 for a targeted vaccination in high
transmission areas.
Conclusions: These results demonstrate that vaccination against dengue would be cost-effective in
Argentina, especially if carried out in predetermined regions at high risk of dengue transmission. How-
ever, these results should be interpreted with caution because the probabilistic sensitivity analysis
showed that there was considerable uncertainty around the ICER value. The influence of variations in
vaccine efficacy, cost and other important parameters are discussed in the text.
© 2015 Elsevier Ltd. All rights reserved.

1. Introduction urbanization and globalization [1]. Annually, about 390 million

people are infected and approximately 500,000 patients, including
Dengue is considered to be one of the most important vector- a high proportion of children, develop severe dengue and require
borne diseases worldwide, and both its incidence and dispersion hospitalization [2]. In Argentina, several outbreaks of dengue,
are rising due to environmental conditions, population growth, occurring mainly in the northern region of the country, have been
reported [3]. The largest outbreak of dengue in Argentina occurred
in 2009 with over 26,000 indigenous cases and 6 deaths spread
over several provinces [4]. Four dengue serotypes are circulating
∗ Corresponding author at: Universidad Tecnologica Nacional, Facultad Regional
in the country, with reports of two or more viral serotypes being
San Nicolas, Colon 332, 2900 San Nicolas, Buenos Aires, Argentina.
present during the same year. However, due to eco-climatic diver-
Tel.: +54 336 4420830; fax: +54 336 4420830.
E-mail addresses: [email protected], [email protected] sity among the provinces, dengue incidence shows wide variability
(P.W. Orellano). between regions and between successive years. Some regions

http://dx.doi.org/10.1016/j.vaccine.2015.12.040
0264-410X/© 2015 Elsevier Ltd. All rights reserved.
 P.W. Orellano et al. / Vaccine 34 (2016) 616–621 617

bordering the endemic areas have indigenous transmission almost Accordingly, five possible health states were considered in the
every year while other regions have either the vector without the model: susceptible, immune by vaccination, immune to one
virus or have neither the virus nor the vector. These factors lead to serotype by natural infection, immune to two serotypes by natural
great variability in the risk of dengue transmission throughout the infection, and dead. The vaccination branch of the Markov model is
country. shown in Supplementary Fig. 1. As both dengue and severe dengue
Currently, no vaccines or specific treatments are available for have a rapid onset and a short course they were incorporated in the
dengue and prevention depends exclusively on vector control model as transitional states. Probabilities describing the likelihood
which has demonstrated limited effectiveness in controlling dis- of transitions among the health states included probability of
ease transmission [5]. Several vaccines are under development, dengue virus infection, proportion of unapparent or subclinical
including three attenuated chimeric tetravalent dengue vaccines, cases, risk of severe dengue during primary and secondary infection
which are the most advanced vaccines being developed [6]. Early and case-fatality rate for severe dengue. In the vaccine branch of the
phase III trials of one of these vaccines in Asia and America pre- Markov model, the probability of being immunized was calculated
dict efficacy values greater than 50% [7,8]. According to a recent as the product of the vaccination coverage and the vaccine efficacy,
review, the pooled rates of efficacy for symptomatic dengue and assuming lifetime protection. Vaccine coverage was defined as
severe dengue were 65.6% and 93.2% respectively for children older the proportion of people who receive the complete vaccination
than 9 years [9]. A vaccine with such an efficacy profile would be of schedule in relation to the people targeted for vaccination.
substantial benefit to public health, and would support large-scale
vaccine administrations [10]. In December 2015, Mexico became 2.2. Model parameters
the first country in the world to approve the use of this vac-
cine for the prevention of dengue. The tetravalent dengue vaccine The model parameters included transition probabilities
will be available to children and adults who live in areas where between health states, variables for estimating costs and for
the disease is endemic. Even though this vaccine may not com- estimating the DALYs associated with dengue and severe dengue
pletely prevent transmission, it should prevent severe disease [11]. (Table 1). These transition probabilities and input data for other
However, it is essential to consider the costs and benefits of the parameters were obtained from published studies that used
dengue vaccine before it is recommended and introduced into the prospective cohort designs and reported on data from Latin Amer-
public market. To date, four studies on the cost-effectiveness of ica and/or Asia (see Supplementary Table 1). The annual incidence
a hypothetical dengue vaccine have been published [12–15] and of dengue was estimated using the values of average and range
all these studies show the vaccine to be cost-effective. However, for annual dengue incidence from 2009 to 2014, as reported to the
these studies were carried out in countries with a high incidence Pan American Health Organization [18]. This pooled incidence was
of dengue, and to the best of our knowledge, no such studies on calculated considering areas showing high and low transmission
the cost-effectiveness of the dengue vaccine have been conducted rates, and other areas in which transmission was not observed, in
in countries with heterogeneous risk of dengue transmission like order to account for the transmission heterogeneity. The risk of
Argentina. This heterogeneity means that the virus transmission is dengue was considered age-dependent, using an equation that con-
restricted to summer months and to specific regions located in the siders the conditional risk of symptomatic dengue by age [19]. The
north of the country. probability of infection was calculated from the dengue incidence
The aim of this study was to estimate the cost-effectiveness of a and the proportion of subclinical cases. Vaccination coverage data
dengue vaccine in Argentina compared to no vaccination by taking were obtained from a study that evaluated the coverage of other
into account the current and known parameters and by performing vaccines in Argentina, considering only those vaccines with at least
a thorough sensitivity analysis to address potential uncertainties. 3 doses [20]. Vaccine efficacy data were obtained from a recent
This analysis was performed considering a vaccination program clinical trial in Latin America that used a vaccination schedule of 0,
that might be implemented by the Argentinean Ministry of Health 6 and 12 months [8]. Model costs included direct medical costs for
at national level, and an alternative scenario in which the vaccina- outpatient visits, laboratory practices, and hospital care in medical
tion program is targeted to high transmission areas. wards and in intensive care units, and were taken according to
2014 public hospital tariffs [21]. Considering the universal health
2. Materials and methods coverage of Argentina, a 100% of patients were assumed to have
access to medical care. Indirect costs included the absenteeism cost
2.1. Model overview due to dengue illness and hospitalization, and the cost of dengue
deaths as a consequence of severe dengue. These costs were
The methods and reporting of this study are conformed to the estimated using the human-capital approach [22], and calculations
Consolidated Health Economic Evaluation Reporting Standards were based on average salaries of Argentina according to statistics
(CHEERS) instrument recommended for cost-effectiveness anal- of the National Ministry of Labor of Argentina. The vaccination
ysis in health [16]. This study was carried out from a societal program included vaccine transport, storage and administration
perspective and included both direct and indirect costs associated for a three dose scheme [7,8,23]. The price of each vaccine dose
with a vaccination program at national level for children of 2 years was approximated using per dose production costs and ranges
of age [17]. In addition, two one-way sensitivity threshold analyses estimated from a study which analyzed vaccine production costs
were performed to estimate the maximum possible price of the of an attenuated chimeric tetravalent dengue vaccine produced
vaccine under two different scenarios: the vaccination program at the Butantan Institute in Brazil [24]. Based on results from two
at national level and a vaccination strategy limited only to high dengue vaccine meta-analysis and two phase 3 efficacy trials, the
transmission areas, as detailed later. Disability adjusted life years vaccine side effects were not considered [7–9,25]. In concurrence
(DALYs) due to dengue and severe dengue was used as the index with other studies on dengue vaccine cost-effectiveness, DALYs
of utility. A Markov simulation model was developed with 1-year were used as the measure of utility with disability weights of
cycles that followed a hypothetical cohort of 100,000 people from 0.197 and 0.545 for dengue and severe dengue, respectively. These
birth to death, considering the life table and life expectancy of values were based on the World Health Organization disability
Argentina (76 years from birth). Due to the low dengue infection weights for diseases and conditions [26]. DALYs per episode of
rates reported in Argentina, the possibility of just one reinfection dengue or severe dengue was estimated by taking into account the
with a different virus serotype was the only possibility considered. duration of symptoms in days. A discount rate of 0.03, with a range
618 P.W. Orellano et al. / Vaccine 34 (2016) 616–621

Table 1
Transition probabilities, effectiveness and costs used in the model; parameter values, ranges and distributions used in the sensitivity analyses.

Model input parameter Value (range) Distribution for probabilistic Source

sensitivity analysis

Dengue incidence (per 100,000 persons-year) 17.66 (0.53–71.06)a Beta (0.86, 4898) Own calculation based on [18]
Age-specific risk of clinical dengue 1 − exp(−0.000259 × age3.991 ) – [19]
Proportion of inapparent 0.77 (0.42–0.93)a Beta (6.28, 1.86) [38]
Proportion of severe dengue (1st infection) 0.036 ()b [39]
Proportion of severe dengue (2nd infection) 0.118 ()b [39]
Death rate from severe dengue in children (per 0.007 Point estimate [40]
1000 cases)
Death rate from severe dengue in adults (per 0.045 Point estimate [40]
1000 cases)
Vaccine efficacy against dengue 0.647 (0.587–0.698)b Beta (143, 78) [8]
Vaccine efficacy against severe dengue 0.955 (0.688–0.999)b Beta (5, 0.24) [8]
Vaccine efficacy against hospitalized dengue 0.803 (0.647–0.895)b Beta (24, 6) [8]
Vaccination coverage 0.73 (0.71–0.76)a Beta (690, 255) [20]
Proportion of hospitalization (dengue cases) 0.247 (0.154–0.340)b Beta (15, 48) [41]
Proportion of hospitalization (severe dengue 0.907 (0.779–0.974)b Beta (24, 2) [41]
cases)
Length of hospital stay in days (dengue cases) 3.8 Point estimate [42]
Length of hospital stay in days (severe dengue 5.0 Point estimate [40]
cases)
Duration of illness in days (dengue cases) 4.36 Point estimate [43]
Duration of illness in days (severe dengue 8.31 Point estimate [43]
cases)
Average number of ambulatory visits (dengue 4.2 Point estimate [42]
cases)
Cost per dengue case (US$ per ambulatory 141.93 (113.54–170.32)c Triangular Own calculation
case)
Cost per dengue case (US$ per hospitalized 830.87 (664.70–997.04)c Triangular Own calculation
case)
c
Cost per severe dengue case (US$ per 225.15 (180.12–270.18) Triangular Own calculation
ambulatory case)
Cost per severe dengue case (US$ per 2139.02 (1711.02–2566.82)c Triangular Own calculation
hospitalized case)
Cost of death from severe dengue (US$ per 12,402.09 Point estimate Own calculation
year)
Vaccine price (US$ per dose) 0.58 (0.51–0.65) Gamma (205, 355) [24]
Vaccination cost (including vaccine transport, 1.89 — Own calculation
storage and administration for a three dose
scheme) (US$ per vaccinated person)
Disability weight for dengue cases 0.197 (0.172–0.211)a Beta (245, 1002) [26]
Disability weight for severe dengue cases 0.545 (0.475–0.583)a Beta (139, 116) [26]
Vaccine price (US$ per dose) (0–100)a First and second threshold Own assumption
analysis
Dengue incidence (per 100,000 persons-year) 280.16 Second threshold analysis Own calculation based on data from
the National Ministry of Health
a
Range: minimum–maximum.
b
Range: 95% confidence interval.
c
Range: value ± 20%.

from 0.00 to 0.05, was considered for both costs and utilities as it 2.4. Sensitivity analysis
is recommended for economic evaluations [27]. The calculations
used to arrive at the values for the various parameters are given in A one-way sensitivity analysis was performed for price, cost,
Supplementary Table 2. probability and utility parameters in the Markov model to deter-
mine the impact of uncertainty on model outcomes. A probabilistic
sensitivity analysis based on 10,000 Monte Carlo simulations was
2.3. Cost-utility analysis also performed to assess the simultaneous effect of uncertainty
on model results. The gamma, beta and triangular distributions
The incremental cost-effectiveness ratio (ICER) was calculated were used for the price, costs, transition probabilities and other
as the ratio of the difference in vaccination and disease costs to parameters, while the outcome variables were assumed to be nor-
the difference in DALYs averted and was expressed in American mally distributed [27]. A cost-effectiveness acceptability curve was
dollars per DALY averted (US$/DALY). Argentina does not have plotted using probability of the vaccination being cost-effective at
a defined willingness-to-pay threshold for health interventions. different threshold values of willingness-to-pay per DALY averted.
Thus, according to a World Health Organization report [28], the A first threshold analysis was performed to determine the max-
intervention was considered “cost-effective” if the cost of one DALY imum price per dose at which the vaccination program at national
averted was less than three times the per capita national gross level could still be deemed cost-effective. The vaccine price per dose
domestic product (GDP). Argentina’s per capita GDP was US$ 12,873 was varied from US$0.1 to US$100. A second threshold analysis
in 2014 [29], therefore the cost-effectiveness threshold was calcu- was carried out to estimate the maximum vaccine price per dose in
lated to be US$ 38,619 per DALY averted. All costs were expressed a scenario in which the vaccination is preceded by a risk stratifica-
in 2014 American dollars (US$). tion system and is limited only to high transmission areas. For this
 P.W. Orellano et al. / Vaccine 34 (2016) 616–621 619

Base case ICER: US$ 5,217

Dengue incidence (per 100,000 persons-year) (0.53–71.06)
Proportion of severe dengue (1st infection) (0.004 - 0.123)
Discount rate (0 - 0.05)
Vaccine price (US$ per dose) (0.51 – 0.65)
Proportion of hospitalization (dengue cases) (0.154 - 0.340)
Cost per dengue case (US$ per hospitalized case) (664 - 997)
Vaccine efficacy against severe dengue (0.688 - 0.999)
Vaccine efficacy against dengue (0.587 - 0.698)

0 10000 20000 30000 40000 50000

ICER (US$ per DALY averted)

Fig. 1. Tornado diagram representing the univariate influence of key parameters in the incremental cost-effectiveness ratio (ICER). The interrupted line represents the base
case ICER.

scenario, the incidence of the San Martin department was the one has a 54.9% probability of being cost effective at a threshold of 3
used. This area is located in the northern region of the country and times per capita GDP of Argentina.
has an average incidence of 280 cases per 100,000 people, a value The first threshold analysis estimated in US$1.49 the highest
greater than 10 times the pooled incidence of Argentina in the last possible vaccine price per dose to still consider the vaccination
5 years. program as cost-effective if the vaccination is implemented at
national level. If the vaccination program is implemented in high
3. Results transmission areas, as evaluated in the second threshold analysis,
the highest vaccine price per dose was estimated in US$28.72.
3.1. Base-case analysis

From a societal perspective, our model estimated that it would 4. Discussion

cost US$ 190,065 to treat dengue infection in the cohort of 100,000
individuals with no vaccination program, while it would cost US$ In the present study, the cost-utility of the currently most
238,815 if the vaccination program is implemented. The ICER for the advanced tetravalent dengue vaccine was estimated using data
vaccination program was US$ 5714 per DALY averted, implying that from the largest phase III clinical trial on vaccine efficacy conducted
vaccination would be cost-effective when based on the WHO cost- in Latin America. Our results indicate that the dengue vaccine,
effectiveness thresholds and the GDP of Argentina. When using which is partially effective and has a satisfactory safety profile [30],
a discount rate of 0% instead of 3%, the vaccination program was would be cost-effective, even though there is a temporally and
dominant compared to no vaccination. geographically limited risk of transmission in Argentina.
Our analysis is based on data from a clinical trial of vaccine
3.2. Sensitivity analysis efficacy in more than 20,000 participants across Latin America.
Although the initial Phase IIb study failed to reach its primary
A tornado diagram indicating the cost variables in descending efficacy endpoint, the next two Phase III studies report efficien-
order of influence is shown in Fig. 1. Parameters that changed cies of over 50% against dengue, 80% against hospitalizations and
the ICER by more than 10% were included in the figure. The pre- 95% against severe forms of the disease [9,31]. It was further
dicted ICER values were most sensitive to changes in the rate of determined that there is no risk in administering the vaccine in
dengue incidence, in the proportion of severe dengue after the first dengue-endemic populations and this safety profile has been con-
infection and in the discount rate. The vaccine price was the forth sistent across the trials [9,25,31]. Therefore, it is likely that there
parameter that had the strongest influence on the ICER. Fig. 2 shows will be no problems in licensing this vaccine, and plans for large-
the sensitivity of the ICER to a range of vaccine prices. scale vaccine production are already underway [11].
The probabilistic sensitivity analysis showed that the Median Regarding the vaccine price for estimating the vaccination costs
ICER was US$27,410 per DALY averted with an inter quartile range of the program, production costs were considered since our model
of US$555–US$140,156 per DALY averted. The cost effectiveness had a societal perspective and because market prices for vaccines
acceptability curve (Fig. 3) showed that the vaccination program can be highly distorted [32]. Importantly, the vaccine production

ICER
Base-case ICER (US$ 5,217)
50000
ICER (US$ per DALY averted)

WTP Threshold (US$38,619)

45000
40000
35000
30000
25000
20000
15000
10000
5000
0
0 0,2 0,4 0,6 0,8 1 1,2 1,4 1,6 1,8 2

Vaccine price per dose (US$)

Fig. 2. Univariate analysis. Incremental cost effectiveness ratio (ICER) as a function of the vaccine price per dose (in US$).
620 P.W. Orellano et al. / Vaccine 34 (2016) 616–621

Vaccination strategy
0.9

0.8 Base-case ICER (US$5,714)

0.7 WTP Threshold (US$38,619)

Probability ICER acceptable 0.6

0.5

0.4

0.3

0.2

0.1

0
0 5000 10000 15000 20000 25000 30000 35000

Willingness to pay (US$ per DALY averted)

Fig. 3. Cost-effectiveness acceptability curve showing the probability that vaccination strategy is cost-effective.

costing used in our model was based on actual data derived from derived from observational studies, and the possibility of bias
a study that examined vaccine production costs at the Butantan could not be completely avoided. Regarding to this, stringent
Institute in Brazil [24]. measures were followed to ensure transparent selection of model
Univariate sensitivity analysis revealed that uncertainties in parameters and sensitivity analyses were carried out to consider
dengue incidence had the greatest potential impact on the ICER. the uncertainty of these parameters. Thirdly, the present model
Other parameters that significantly influenced the ICER were the does not factor in the effect of herd immunity. This is because
probability of severe dengue after the first infection, the proportion according to some studies published to date, vaccine coverage
of hospitalizations between dengue cases, the cost of dengue cases, required to reach herd immunity would be 82% for dengue [15,34]
the discount rate and those parameters inherent to the vaccine while we assumed a lower coverage value (73%) for base-case
itself: vaccine price and efficacy. On the other hand, the prob- analysis. Consequently, and similar to other studies on vaccine cost-
abilistic sensitivity analysis showed that there was considerable effectiveness, it was decided not to consider the effect of herd
uncertainty respecting the optimum strategy, while nearly half of immunity [35,36]. However, it is also true that each vaccinated
simulations indicated that the vaccination program at national level person could have an impact on the R0 and thus decrease the dis-
was not cost-effective. ease transmission independently of a vaccine coverage threshold
The threshold analysis showed that the vaccination program to reach herd immunity. Accordingly, it would be worth includ-
at national level remained cost-effective for a vaccine price below ing the effects of herd immunity in future estimations, especially
US$1.49 per dose. However, even allowing for higher vaccine prices when more data on indirect protection of dengue vaccine would be
the vaccination strategy could be cost-effective if it is carried demonstrated. Fourthly, the use of public hospital tariffs may have
out conforming to a risk stratification system in predetermined masked higher dengue hospitalizations costs incurred in private
high risk regions. Moreover, dengue incidence has been increas- settings. Fifthly, this study did not take into account the impact of
ing steadily over the last two decades, and since 1998, an increase dengue on international tourism [37]. This influence is difficult to
in the number of indigenous cases, the frequency of outbreaks, and measure, but its inclusion in future simulation models would prob-
the spread of the vector in areas previously unaffected by dengue ably improve the cost-effectiveness performance of dengue vacci-
have been observed [33]. Therefore, the vaccination strategy can be nation. Finally, the incidence of dengue, both without vaccination
expected to become increasingly and steadily cost-effective over and after implementation of a vaccination program, was estimated
time. assuming concurrent operation of vector control activity, and the
A literature search revealed that there are only four published reasons for this are twofold. First, the need to continue vector con-
studies on the cost-effectiveness of vaccination against dengue in trol efforts and other prevention strategies even in the presence of
Asia and South America [12–15]. Further, all these studies were a vaccination program is widely recognized [10], and second, the
conducted from a societal perspective and the vaccination strategy effect of vector control activities can be separately assessed only
was proven to be either cost-effective or highly cost-effective. One by using a model that estimates transmission risk starting from the
of these studies used estimates of the same tetravalent dengue vac- vector populations. Such a model would be unlike to the present
cine, while the others used generic parameters of a non-specified model that uses the real time data on dengue incidence.
vaccine. However, all these studies were carried out in highly In conclusion, a dengue vaccine would be cost-effective as a pre-
endemic regions, while our analyses has been performed in the set- vention strategy in a country with heterogeneous risk of dengue
ting of limiting climatic conditions for the transmission of dengue transmission like Argentina, especially when targeting high-risk
and irregular occurrence of outbreaks. areas. However, these results should be interpreted with caution
Although we report that vaccination would be cost-effective, due to the high variability observed in the probabilistic sensitivity
there are several limitations. First, dengue incidence in Argentina analysis. It is expected that in future the incidence of dengue would
is both temporally and geographically highly variable and adds increase as a consequence of climatic changes and risks associated
uncertainty to the results. Secondly and similar to other cost- with globalization. If this trend continues, our results suggest that
effectiveness analysis based on simulation models, the results the vaccination of children will be even more cost-effective over
presented here are highly dependent on the probability values both the medium and long term.
 P.W. Orellano et al. / Vaccine 34 (2016) 616–621 621

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