Clinical Infectious Diseases

SUPPLEMENT ARTICLE

A Review of the Economic Evidence of Typhoid Fever and

Typhoid Vaccines
K. Luthra,1,a,b E. Watts,1 F. Debellut,2 C. Pecenka,3 N. Bar-Zeev,1 and D. Constenla1,b
1
International Vaccine Access Center, Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland; 2Center for Vaccine Innovation and Access,
PATH, Geneva, Switzerland; 3Center for Vaccine Innovation and Access, PATH, Seattle, Washington

Typhoid places a substantial economic burden on low- and middle-income countries. We performed a literature review and critical
overview of typhoid-related economic issues to inform vaccine introduction. We searched 4 literature databases, covering 2000–
2017, to identify typhoid-related cost-of-illness (COI) studies, cost-of-delivery studies, cost-effectiveness analyses (CEAs), and
demand forecast studies. Manual bibliographic searches of reviews revealed studies in the gray literature. Planned studies were iden-
tified in conference proceedings and through partner organization outreach. We identified 29 published, unpublished, and planned
studies. Published COI studies revealed a substantial burden in Asia, with hospitalization costs alone ranging from $159 to $636
(in 2016 US$) in India, but there was less evidence for the burden in Africa. Cost-of-delivery studies are largely unpublished, but 1
study found that $671 000 in government investments would avert $60 000 in public treatment costs. CEA evidence was limited, but
generally found targeted vaccination programs to be cost-effective. This review revealed insufficient economic evidence for vaccine
introduction. Countries considering vaccine introduction should have access to relevant economic evidence to aid in decision-mak-
ing and planning. Planned studies will fill many of the existing gaps in the literature.
Keywords.  typhoid fever; vaccination; cost of illness; cost of vaccine delivery; cost-effectiveness analysis.

Typhoid fever is a common and preventable disease in low- and Gavi, the Vaccine Alliance, paved the way for Gavi-eligible
middle-income countries (LMICs). Varying burden estimates countries to introduce TCVs in their countries with their
from different sources exist, using different modeling methods November 2017 announcement to provide US$85 million in
and ranging from 12 to 293 cases per 100 000 person-years due support [5]. By December 2017, the WHO prequalified the first
to mortality [1, 2] in regions impacted by the disease. Caused typhoid conjugate vaccine, Typbar-TCV, developed by Indian
by the bacteria Salmonella Typhi, typhoid fever is endemic to pharmaceutical company Bharat Biotech, giving way for coun-
countries in South and Southeast Asia and, more recently, in tries to purchase this vaccine through United Nations procure-
Africa, with multidrug-resistant types. Transmission is primar- ment agencies [6].
ily through the ingestion of contaminated food or water [3]. While understanding of the disease burden of typhoid in
Preventive measures include vaccination, in addition to LMICs is growing, the economic burden of typhoid and the
providing access to safe water and improving hygiene and economic benefits of vaccination are not well understood. There
sanitation practices. Typhoid conjugate vaccines (TCVs) have is little consensus on which guidelines to adopt to estimate the
recently been licensed for use in Nepal, India, and China as a costs of typhoid fever. The recent licensure of TCVs, the WHO’s
single, intramuscular dose, and are indicated for use in infants SAGE recommendation, the WHO prequalification, and fund-
at least 6 months of age [4]. ing support for the introduction of TCVs into LMICs by Gavi
The World Health Organization (WHO) Strategic Advisory has catalyzed renewed interest in the economic burden of
Group of Experts (SAGE) on Immunization recommended typhoid and the potential cost-effectiveness (CE) of introduc-
the use of TCVs in the routine immunization programs of ing TCVs into routine immunization, along with catch-up cam-
typhoid-endemic countries in October 2017. A  month later, paigns for children up to 15 years of age in endemic settings.
In this paper, we explore the existing and planned economic
studies related to typhoid fever and vaccination in typhoid-en-
 

a
Present affiliation: Gavi, the Vaccine Alliance, Geneva, Switzerland.
b
K. L. and D. C. contributed equally to this work. demic countries, identify gaps and limitations in the existing
Correspondence: D.  Constenla, International Vaccine Access Center, Department of
International Health, Johns Hopkins Bloomberg School of Public Health, 415 N Washington St.,
literature, and summarize research methodology recommenda-
5th Floor, Baltimore, MD 21231 (dconste1@jhu.edu). tions that may enable future studies to fill these gaps.
Clinical Infectious Diseases®  2019;68(S2):S83–95
© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society
METHODS
of America. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted
reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
We adopted a systematic approach to identify published,
DOI: 10.1093/cid/ciy1122 unpublished, and planned studies covering a 17-year period

Economics of Typhoid Fever and Typhoid Vaccines  •  CID 2019:68 (Suppl 2) • S83

(2000–2017). Key articles representing the evidence around cohorts ranged from all ages in COI studies to selected at-risk
the cost of illness (COI) of typhoid fever, the cost of typhoid groups targeted for vaccination. Table 1 provides a summary of
vaccine delivery, the economic benefits of typhoid vaccines, all available economic evidence.
and forecasting demand for typhoid vaccines were consid-
ered. We used 4 major electronic databases (the US National Cost-of-illness Studies
Library of Medicine and the National Institutes of Health COI studies measure the burden of a disease to society in mone-
Medical [PubMed], Excerpta Medica Database [EMBASE], tary terms. We identified 11 COI studies, which included 5 pub-
Elsevier’s Scopus, and The American Economic Association’s lished studies (Table 2), 1 unpublished study (Table 3), and 5
electronic bibliography [EconLit]) to locate published stud- planned studies (Table 4). Studies adopted either a societal per-
ies using variations of the following 3 terms: “typhoid” AND spective or a government or public system perspective, and most
“paratyphoid” AND “econom*”. Manual bibliographic searches included both inpatient and outpatient costs. Data collection
from relevant review papers and the WHO website, and via included both retrospective and prospective methods. Existing
Google and relevant partner organizations’ websites, revealed evidence was primarily from high-incidence Asian countries,
more articles. Additional studies were identified from abstracts while more geographic diversity was found in planned studies.
and presentations in the 10th International Conference on Most studies required blood culture–positive typhoid fever for
Typhoid and Other Invasive Salmonelloses in Uganda (April inclusion in the study, although blood culture–positive paraty-
2017), and through outreach to partner organizations (eg, The phoid and clinical typhoid were also included in 1 study [8].
Coalition against Typhoid, the Typhoid Vaccine Acceleration Due to the nonspecific nature of clinical typhoid, cost estimates
Consortium, the Severe Typhoid in Africa project, and the of blood culture–negative typhoid fever are difficult to inter-
Surveillance for Enteric Fever in Asia Project) and leading pret, but these figures were presented separately.
researchers in the field. Our primary focus was typhoid-en- Among the studies reviewed, there was considerable
demic countries. intra-country variation reported in the literature, and costs var-
We removed duplicate citations and screened separately ied depending on the study perspective. Hospitalization costs
for eligibility using the title and abstract. Papers meeting the were the most common cost assessed across all studies, and
basic inclusion criteria—original studies published in English, inpatient costs were considerably higher than outpatient costs,
published or conducted from 2000 onward, and that reported regardless of the study perspective. Costs per outpatient case
economic evidence of typhoid and paratyphoid fever and all ranged from $16 to $74 in India [8, 10] and were $39 in Nepal
typhoid vaccines from LMICs—were included in the review. [9]. Inpatient costs ranged from $159 to $636 in India [8, 10].
For the selected papers, we retrieved and read full-length ver- A  study in Nepal with a smaller sample size found the aver-
sions. An independent reviewer extracted the following infor- age cost per hospitalized case to be $233 [9]. Limited numer-
mation from the selected papers: methodological approach (eg, ical data were available for African countries, but 1 study in
perspective, time horizon); key findings of the study by year, Tanzania found the average cost per case (both inpatient and
country, and vaccine analyzed; and types of data used in the outpatient) to be $171 [11].
analysis. Selected papers were not reviewed for quality; how- There were 4 studies that took a societal approach to esti-
ever, their strengths and limitations were assessed. Articles that mating the cost of illness, each using the human capital method
used multiple methodologies were included in more than 1 cat- to calculate indirect costs. Of these, 3 found that indirect costs
egory. References were managed in Endnote [7]. All monetary accounted for the majority of the total cost of illness. Variations
values presented in this review are adjusted to the same cur- in estimates primarily stem from the value assigned to absen-
rency and year (2016 US$) for comparison, unless otherwise teeism from work and to whether caregiver or child produc-
specified. tivity loss were included. In 1 study that modeled the global
cost of typhoid fever, a percentage of gross domestic product
(GDP) per capita was used to value the time lost by caregivers
RESULTS
and patients. The study estimated that the cost of typhoid fever
Literature Search in LMICs exceeded $1.3 billion, with 89% of costs comprised of
The literature search yielded a total of 548 articles, of which indirect costs (V. Mogasale, B. Maskery, R. L. Ochiai, J. S. Lee,
only 31 met the inclusion criteria on the basis of the title and & T. F. Wierzba, manuscript in preparation, unreferenced, see
abstract. These articles were either published, unpublished, or Acknowledgments). A  study in Tanzania estimated the total
planned studies, including 11 COI studies, 5 cost-of-delivery cost per episode at $172. When using the average wage to value
studies, 11 cost-effectiveness analyses (CEA), and 4 demand the lost productivity of patients and caregivers, indirect costs
forecast (DF) studies (Figure 1). Nearly half of the identified accounted for nearly 80% of these costs [11]. Indirect costs were
evidence (n  =  14) came from unpublished studies. Evidence not as substantial in Nepal at the household level, where they
came from 14 countries: 7 in Asia and 7 in Africa. Target represented only a quarter of household costs in hospitalized

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Figure 1.  Typhoid fever economic evidence Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flow diagram. aOutreach to partner organiza-
tions resulted in 2 additional studies: 1 cost-of-illness and 1 cost-effectiveness study. This resulted in 31 studies included in the literature review.

cases and less than 15% of total household costs in outpatient surveyed both public and private health facilities, and 2 more
cases [9]. [8, 13] used modeled costs to estimate the public costs.
The evidence was mixed as to whether child or adult cases
resulted in higher costs, with both outcomes observed across Immunization Delivery Cost Studies
different settings [8, 12]. From 1995–1997, 1 study [8] col- Immunization delivery costs are defined as all costs required
lected data in an urban slum in Delhi. The authors in this study to deliver vaccines to the target population, excluding the costs
included public and private costs (direct medical costs, direct of vaccines and injection supplies. These include health worker
nonmedical costs, and indirect costs). Productivity losses for time and transport expenses to administer vaccines, among
children were valued at one-quarter the average daily wage for other costs. Of the 5 immunization delivery cost studies iden-
5–12 years and one-half the average daily wage for 12–19 years, tified, only 1 was published (Table 5). The study by Lauria et al
which could contribute to the higher than expected COI among [14] adopted a governmental (public health system) perspec-
young adults. In contrast, in the study by Sur and colleagues tive that included direct medical costs and the program costs
[12], hospitalized pediatric patients incurred higher costs than assumed by the public sector to estimate the delivery costs for
hospitalized adult patients. However, 93% of the patients in the a Vi polysaccharide typhoid vaccine (ViPS). This study mod-
sample were children. This study was conducted from the pub- elled the cost of delivery in a hypothetical population of 1 mil-
lic health-care provider perspective and included 2 hospitals in lion (300 000 children, 700 000 adults), and evaluated 3 mass
Kolkata, where 32.5% of population lives in slums with poor vaccination strategies (charging adults and children different
sanitation. [optimal] prices, charging uniform prices, and providing free
Some studies primarily considered treatment costs in the vaccinations). In all of these scenarios, the median cost per
public sector, and private sector treatment rates and costs were vaccination was $1.74. The study found that $671 000 in gov-
under-represented [10]. Only 2 studies [11, 12] exclusively ernment investment would avert $60 000 in public treatment
looked at public health facilities. An additional 2 studies [9, 10] costs [14].

Economics of Typhoid Fever and Typhoid Vaccines  •  CID 2019:68 (Suppl 2) • S85

Table 1.  Summary of Available Economic Evidence

Type of Countries Studied Target Age Groups Represented Vaccines ICER Calculated
Study No. of Studies (No. of Studies)a (No. of Studies)b Assessed (No. of Studies)c

Cost-of-­ 5 studies published; China (1), India (3), Indonesia (1), Nepal All ages (2); 0–40 years (1); >2 months N/A N/A
illness 1 study unpublished; (1), Pakistan (1), Tanzania (1), Vietnam (1); 2–15 years (1); 5–18 years
5 studies planned (1), Bangladesh (1), Burkina Faso (1); 5–60 years (1); <18 years (1);
(1), Ethiopia (1), Ghana (1), India (2), ≥18 years (1); >9 months (1); not
Madagascar (1), Malawi (1), Nepal (2), specified (5)
Pakistan (1)
Cost-of-­ 1 study published; Not specified (1), Malawi (1), Nepal (2) <18 years (2); ≥18 years (1); not specified ViPS, TCV N/A
delivery 1 study unpublished; (3)
3 studies planned
Cost-effec- 6 studies published; India (4), Indonesia (1), Kenya (1), Pakistan 9 months (3); 9 months–5 years ViPS, TCV 7 studies meas-
tiveness 1 study unpublished; (1), Vietnam (2), LMICs (1), India (1), (3); 9 months–15 years (2); ured cost per
and 4 studies planned Malawi (1), Nepal (1), LMICs (1) 9 months–25 years (2); ≥9 months (2); DALY averted as
cost-ben- ≥2 years (4); 2–5 years (1); 2–15 years an outcome; 2
efit anal- (2) studies meas-
ysis 5–14.9 years (4); 6–19 years (1); ured cost per
≥15 years (1); not specified (4) case averted as
an outcome
Demand 1 study published; LMICs (3); LMICs (1) 9 months (3); 15 months (1); 18 months ViPS, Ty21a, N/A
forecast 2 studies unpub- (1); 1–15 years (3); 2–15 years (1); TCV
lished 5–15 years (1)
1 study planned
Total 13 studies published; China (1), Bangladesh (1), Burkina Faso All ages (2); 0–40 years (1); >2 months ViPS, Ty21a, 7 studies meas-
5 studies unpub- (1), Ethiopia (1), Ghana (1), India (12), (1); 9 months (6); 9 months–5 years TCV ured cost per
lished; Indonesia (3), Kenya (1), Madagascar (1), (3); 9 months–15 years (2) DALY averted as
13 studies planned Malawi (3), Nepal (4), Pakistan (2), Tan- 9 months–25 years (2); ≥9 months an outcome;
zania (1), Vietnam (2), LMICs (4) (2); 15 months (1); 18 months (1); 2 studies meas-
1–15 years (3); ≥2 years (4); 2–5 years ured cost per
(1); 2–15 years (4); 5–18 years (1); case averted as
5–14.9 years (5); 5–60 years (1); an outcome
6–19 years (1); <18 years (3); ≥15 years
(1); ≥18 years (2)

The text in italics indicates studies planned, to differentiate where evidence exists and where it is forthcoming.
Abbreviations: DALY, disability-adjusted life-years; ICER, incremental cost-effectiveness ratio; LMICs, low- and middle-income countries; N/A, not applicable; TCV, typhoid conjugate vaccine;
Ty21a, live, attenuated oral typhoid vaccine; ViPS, Vi polysaccharide typhoid vaccine.
a
Studies included data from multiple countries, as well as both studies focusing on selected LMICs (eg, Gavi eligible) and all LMICs.
b
The age groups were counted separately if the study included multiple target age groups.
c
Studies can include both ICER categories.

The cost of delivery is largely driven by the vaccination system perspective was the most common perspective adopted
strategy utilized, which varies by the target population and among the published literature, although 2 studies utilized a
vaccination setting. Apart from delivery costs, a leading societal perspective [15, 16]. The majority of existing evidence
driver of vaccine program costs (and hence of CE) is vaccine is from India and South Asia. The most common outcome mea-
price. Unpublished data from a school-based vaccination sure (incremental cost-effectiveness ratio) evaluated was cost
campaign in Nepal, which included a donated supply of ViPS, per disability-adjusted life-years (DALYs) averted and cost per
found the greatest cost components of vaccine delivery to be case averted.
advocacy and social mobilization. Beyond the cost of deliv- In India, 2 studies performed cost-benefit analyses and found
ery, the issues of affordability and sustainability of typhoid public vaccination programs using ViPSs to be a good value for
vaccines are not raised in the literature. This evidence will money, from a public health system perspective, across a vari-
be especially important for countries transitioning away from ety of age-segregated target cohorts [16, 19]. The earlier study
Gavi support. (2004) found that mass vaccination or school-based vaccina-
tion would produce net benefits when the vaccine price is low.
Cost-effectiveness and Cost-benefit Analyses A  preschool vaccination program would produce net benefits
A CEA is an example of a comparative analysis that looks at at all vaccine price points modeled (between $0.95 and $3.81)
the technical efficiency between 2 or more alternatives and that [19]. The second study found ViPSs would produce net bene-
includes the effects and the costs of those alternatives. A CEA is fits if user fees or the social value of life were included in the
distinct from a cost-benefit analysis, which assigns a monetary analysis. The same study found their results to be very CE from
value to the measure of effect. We identified 11 CEAs, including a societal perspective, using 1 times the GDP per capita per
5 published studies (Table 6). The government or public health DALY averted as a threshold [16].

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 Table 2.  Summary of Cost-of-illness Studies Published

Reference Countries Disease Definition Study ­Participants Study ­Perspective Costs Included Cost Sources Results (Expressed in 2016 US$)

[8] India Blood culture– 0–40 years Societal Direct medical, Prospective participant - Mean total cost per episode: $126;
positive typhoid or nonmedical, and interviews - Mean total cost per case hospitalized: $636;
paratyphoid; blood indirect costs - Mean total cost per outpatient case: $74;
culture–negative with - Private and public costs are similar ($61 and $65);
clinical typhoid - Costs are highest for children (2–5 years)
[9] Nepal Blood culture– positive All ages Societal Direct medical, Qualitative interviews - Mean direct costs per household: $92;
typhoid fever nonmedical, and - Mean indirect costs per household: $32;
Economics of Typhoid Fever and Typhoid Vaccines  •  CID 2019:68 (Suppl 2) • S87

indirect costs - Mean loss of income: $37;

- Money borrowed: $23–284;
- Total direct cost per hospitalized case: $166; - Total
indirect cost per hospitalized case: $67;
- Total direct cost per nonhospitalized case: $39;
- Total indirect cost per nonhospitalized case: $5
[10] China, Indonesia, Blood culture– positive Vietnam: 5–18; Governmental; Direct medical, Patient surveys and hos- - Cost per case hospitalized: $159 (India), $531 (Indonesia);
India, Pakistan, typhoid fever China: 5–60; household nonmedical, and pital records -C ost per nonhospitalized case: $16 (India); $82 (China);
Vietnam India: all ages; indirect costs -H ospitalized case cost: up to 15% of annual household
Pakistan: 2–15. income in some settings
[11] Tanzania Blood culture– >2 months Societal Direct costs and Patient records and - Mean cost per episode: $171;
positive typhoid fever indirect costs interviews - Mean cost for treatment: $24;
- Mean lost wages: $142
[12] India Widal-positive and/ <18 years or Provider Direct medical costs Hospital records - Average cost of treatment: children $23, adults $58, and all $26;
or blood culture– ≥18 years. - Hospitalized child patients incurred higher costs than hospitalized
positive typhoid fever adult patients
Table 3.  Summary of Demand Forecast Studies Published

Costs Cost Results (Expressed

Reference Countries Vaccines Study Participants Included Sources in 2016 US$)
[13] Typhoid endemic TCV - High-risk population and general population; N/A N/A TCV demand ranges
low and LMIC - RI (9 mo.) + catch up 1–15 years; from 40–160 mil-
- RI (9 & 15 mo.) + catch up 1–15 years lion doses/year

Abbreviations: LMIC, low- and middle-income countries; N/A, not applicable; RI, routine immunization; TCV, typhoid conjugate vaccine.

The parameters that most influenced CE include disease outcome was found in a recent study in the same 3 countries
incidence, vaccine costs, and the economic benefits of disease [17]. Another unpublished study found the vaccination of high-
risk reduction [10]. Across delivery platforms (campaign deliv- risk populations in LMICs to be CE, and vaccination in selected
ery in Uganda and a school-based delivery program in India, high-burden countries in South, Southeast, and Central Asia to
Indonesia, Pakistan, and Vietnam), these programs were very be cost-saving (2017 workshop presentation by V. Mogasale &
CE (using a threshold of 1 times the GDP per capita, per DALY J. S. Lee, unreferenced, see Acknowledgments).
averted) in all countries except Vietnam, which had a low In a global study that compared delivery strategies, routine
typhoid incidence in the population studied [15, 18]. immunization alone was likely to be CE in moderate disease
ViPSs are the most common vaccines evaluated, although 1 burden settings (50 cases per 100 000 annually), while adding
published study and several unpublished studies evaluate the a school-based catch-up campaign was likely to be very CE in
new TCVs. Models using ViPSs accounted for herd protection moderate disease burden settings, with larger reductions in the
in selected sensitivity analyses. A  recent TCV model found number of cases and the disease burden, as compared to routine
that accounting for herd immunity impacts CE estimates [17]. immunization alone [20].
However, there was no evidence from this study or any other
study reviewed about the effects of TCVs on intestinal infection, Demand Forecast Studies
transmission, or short- or long-term carriage. In recent years, Accelerated Development and Introduction Plans
The evidence for TCV CE is limited, but generally, studies have used DF studies to shape markets for the purpose of acceler-
have found vaccination of targeted populations to be CE. There ating access to new vaccines in countries where they are needed
was 1 study that found VIPSs are not CE in low-incidence set- most. We identified 3 completed DF studies, of which 1 is pub-
tings [15], but results are subject to assumptions surrounding lished (Table 3) and 2 are internal analyses by international orga-
typhoid incidence and mortality [20]. An evaluation of TCV nizations (Table 7). A 2008 forecast released by Gavi estimated
use in infant routine immunization settings in India, Kenya, the total market for all typhoid vaccines in Gavi-eligible countries
and Vietnam found this vaccine to be CE in most settings over the period of 2011 to 2020 to range from 178 million doses
and cost-saving in endemic settings [17]. (Cost-effectiveness to 497 million, depending on the target cohort and delivery plat-
and cost savings are calculated in the same way. To calculate form utilized (2008 presentation produced by Gavi, the Vaccine
the cost-effectiveness and cost savings of TCVs, it is necessary Alliance, unreferenced, see Acknowledgments). An unpublished
to know the total cost of the vaccine and its administration, study by the Clinton Health Access Initiative estimated the total
as well as the total health consequences and economic costs global market size from 2018 to 2030 will be at 743 million doses
averted through vaccination. Calculating the total costs averted (2017 conference presentation by V.  Vishwanarayan, unrefer-
requires information on direct medical, direct nonmedical, and enced, see Acknowledgments), while a recent paper by Mogasale
indirect costs of care. These costs depend on the proportion of and colleagues projected demand for TCVs to range from 40–160
subjects seeking each of various levels of care and the costs of million doses per year, depending on the target population, deliv-
each level of care. The estimation of total costs also requires ery strategy, and year of introduction for a given country [13].
knowledge of the cost, efficacy, and effectiveness of the vaccine This paper focused on the public sector and estimated demand
and its administration. To estimate the health consequences across LMICs. Target populations included routine immuniza-
averted requires the estimation of the typhoid fever mortality tion of infants and various target groups for catch-up campaigns.
rate. All calculations depend on the size of the target popula- Introduction timing and the scope of catch-up campaigns are the
tion [those potentially affected by typhoid fever].) However, the primary drivers of demand.
additional benefits gained by 1-time catch-up campaigns would
be economically justified. TCVs that result in reduced treat-
DISCUSSION
ment costs are referred to as cost-saving vaccines. If the net ben-
efits of vaccination are sufficiently large compared to the change At the global level, our understanding of the economic burden
in costs, the vaccine is referred to as cost-effective. This same of typhoid fever is largely informed by evidence from a selected

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 Table 4.  Summary of Upcoming Studies by Study Type

Group of Implementers Countries Vaccine Disease Definition Proposed Methods

Cost-of-illness studies
V. Mogasale, D. Song, & S. Pallas India N/A Not specified Hospital-based surveillance 2017–2018 at: (1) Mumbai (urban slum served by the Grant Med-
ical College, a tertiary-care government hospital), and (2) Pune (the King Edward Memorial
[KEM] Hospital rural surveillance site, Vadu)
V. Mogasale & E. Ramani Burkina Faso, N/A Blood culture–positive typhoid/ - Analytical horizon from illness onset through 12 months post-enrollment;
Ethiopia, para- typhoid, iNTS, and - Facility cost estimation: cost to charge ratio;
Ghana, Mad- culture-negative with clinical -P atient cost estimation: in-person interviews throughout duration of illness (at 1 week, 2
agascar diagnosis weeks, 1 month, 3 months, 6 months, 9 months, 12 months) using data cards to track costs
between interviews
S. Pallas, N. M. Gonzalez, & T. Abimbola Bangladesh, N/A Blood culture–positive typhoid - Analytical horizon from illness onset through 12 months post-enrollment;
India, Nepal, fever, paratyphoid fever, and -F  acility cost estimation: ingredients-based micro-costing;
Pakistan iNTS - Patient cost estimation: phone interviews when blood culture confirmed or following patient
discharge (6 weeks and 12 months for cases with complications at 6 weeks), in person
N. Bar-Zeev, C. Pecenka, & F. Debellut Malawi N/A Blood culture–positive typhoid - Analytical horizon from illness onset through 12 months post-enrollment;
fever, paratyphoid fever, and - Facility cost estimation: ingredients-based micro-costing;
iNTS - Patient cost estimation: in-person interviews (at 1 week, 2 weeks, 1 month, 3 months, 6 months,
9 months, 12 months) using data cards to track out-of-pocket expenditures between interviews
D. Constenla, C. Garcia, & E. Watts Nepal N/A Blood culture–positive typhoid - Analytical horizon: from illness onset through 12 months post-enrollment;
fever, paratyphoid fever, and - Facility cost estimation: ingredients-based micro-costing;
iNTS -P atient cost estimation: in-person interviews throughout duration of illness (at days 7, 14,
30, and 90) using caregiver surveys and daily expenditure booklets to track out-of-pocket
Economics of Typhoid Fever and Typhoid Vaccines  •  CID 2019:68 (Suppl 2) • S89

expenditures between interviews

Cost-of-delivery studies
V. Mogasale, D. Song, & S. Pallas India TCV N/A Hospital-based surveillance 2017–2018 at: (1) Mumbai (urban slum served by the Grant
Medical College, a tertiary-care government hospital), and (2) Pune (the KEM hospital rural
surveillance site, Vadu)
C. Pecenka & F. Debellut Malawi TCV N/A -M
 ix of primary data collection during TyVAC impact studies associated with discussions with
country Expanded Program on Immunization (EPI) teams;
-M
 icro-costing approach: costs will be presented per activity, separated between capital and
recurrent costs
D. Constenla, C. Garcia, & E. Watts Nepal TCV N/A -M
 ix of primary data collection during TyVAC impact studies associated with discussions with
country EPI teams;
-M
 icro-costing approach: costs will be presented per activity, separated between capital and
recurrent costs
Cost-effectiveness studies
J. Bilcke, M. Antillon, Z. Pieters, E. Kuylen, Gavi-eligible TCV N/A Model-based approach
L. Abboud, K., M. Neuzil, A. J. Pollard, countries
A. D. Paltiel, & V. E. Pitzer
V. Mogasale, D. Song, & S. Pallas India TCV N/A Hospital-based surveillance 2017–2018 at: (1) Mumbai (urban slum served by the Grant
Medical College, a tertiary-care government hospital), and (2) Pune (the KEM hospital rural
surveillance site, Vadu)
V. Pitzer, C. Pecenka, N. Bar-Zeev, & F. Debellut Malawi TCV N/A Model-based approach
V. Pitzer, D. Constenla, C. Garcia, & E. Watts Nepal TCV N/A Model-based approach
Demand forecast studies
F. Debellut, N. Hendrix, V. Pitzer, D. Con- All low- and TCV N/A -E
 xcel-based flexible-demand forecasting model, allowing for different delivery strategies (rou-
stenla, & C. Pecenka middle-in- tine and campaigns) targeting age ranges;
come coun- -U
 ser-friendly interface, allowing for easy changes of input values around delivery, dosage,
tries coverage proxy, and introduction dates;
-S
 cenario-building through assumptions and engagement within TyVAC and externally

Abbreviations: iNTS, invasive nontyphoid salmonellosis; N/A, not applicable; TCV, typhoid conjugate vaccine; TyVAC,  The Typhoid Vaccine Acceleration Consortium.
Table 5.  Summary of Cost-of-delivery Studies Published

Disease Study Study Costs Cost

Reference Countries Vaccines ­Definition ­Participants ­Perspective ­Included Sources Results (Expressed in 2016 US$)
[14] LMIC pop- ViPS Blood culture– Children, Government Direct Published - Median public cost per case: ~$35
ulation positive ty- adults and public medical litera- ($0–116);
phoid fever (ages un- health costs ture - In a population of 1 million (300 000
(adjusted specified) and children, 700 000 adults) in an LMIC
incidence direct setting;
rate) program - Annual public expenditure for treating
costs typhoid is $61 000;
- Cost of public vaccination program per
1 million people: $670 000

Abbreviations: LMIC, low- and middle-income countries; ViPS, Vi polysaccharide typhoid vaccine.

number of endemic countries, primarily in South and Southeast to have a better understanding of the burden of typhoid fever
Asia and, more recently, in Africa. Moreover, a significant por- at the household level.
tion of the existing evidence comes from unpublished studies, The existing cost-of-delivery evidence was limited to 2 studies:
which makes it difficult to access the full economic evidence 1 school-based pilot program in Lalitpur, Nepal (2012 summary
on disease burden and vaccination. Several planned studies, results by V.  Mogasale, unreferenced, see Acknowledgments)
however, intend to evaluate the costs of typhoid fever and the and a model generalized to LMIC contexts [14]. An import-
economic benefits of TCVs, which will help fill this void. ant limitation of the evidence generated by the pilot program
The COI papers reviewed present a wide variation of cost is that it did not account for shipping and wastage costs, as
estimates for typhoid fever, due to differences in case defini- these were provided by donation, limiting the direct validity
tions, sample populations, data sources, discount rates, and of the results to real-world settings (2012 summary results by
other factors. A  common limitation noted across the COI V. Mogasale, unreferenced, see Acknowledgments). In addition,
evidence was the limited sample size included in each study, neither study included the possible impact or extent of indirect
potentially reducing the generalizability of results and lack of herd protection, which may influence the total number of cases
precision of the estimates, which may account for the substan- and, therefore, public treatment costs avoided [14]. Upcoming
tial inter-study variance [9, 11, 12]. The narrow timeframe of studies may address some of these gaps by accounting for (1)
the studies also limits the generalizability of results, as season- a greater scope of programmatic and delivery costs across a
ality and year-to-year fluctuations of typhoid fever are gener- variety of delivery settings and countries, and (2) TCV speci-
ally not captured in the studies. This limitation extends to the fications in terms of dosing schedules, target populations, and
costs associated with hospitalization rates that were observed delivery strategies.
during the study periods [12]. Available evidence suggests vaccination is highly CE, or CE
Several cost categories (direct medical, direct nonmedi- in moderate- to high-burden settings, but this evidence primar-
cal, and indirect costs) are not included in the literature. For ily evaluated older ViPSs and vaccinations in high-burden set-
example, real drug prices and the prices of capital assets were tings, which might be misleading in a broader context. More
not available in some of the papers [12]. Opportunity costs, evidence is needed on the CE of new TCVs. In addition, as most
such as a typhoid patient utilizing a hospital bed that could studies adopted a narrow (governmental) perspective, several
be allocated to a sicker patient, are not currently included cost differences were not addressed in the CE literature, includ-
[8]. Household costs and indirect costs also comprise a major ing transportation costs, lost productivity, and out-of-pocket
economic component of the cost of illness, yet were largely expenditures, which are potentially catastrophic in certain
excluded from existing studies. In studies that included settings [18]. When the costs of waiting for vaccinations were
household costs, the “cost of costs”—such as transaction costs included, these were not informed by data [15].
or interest payments incurred by households to afford treat- The assumed burden of disease used in published CEA mod-
ment costs—was not considered [10]. Other indirect costs els may be lower than in real-world settings, as studies focused
borne by patients and households, such as behavior change on blood culture–positive cases and assumed only hospitalized
requirements to address or prevent the illness, were not con- cases died [17, 19]. In addition, differences may exist in dis-
sidered [8]. In addition, data on households’ willingness to ease burdens or disease risks between those populations able
pay for the prevention or treatment of typhoid are largely not to access treatment and those who lack access [15]. Such differ-
included [8]. Some of these limitations are addressed directly ences would not be accounted for if cost inputs are used from
in planned studies. For example, we identified several studies COI studies that exclusively recruit participants within treat-
that are considering the inclusion of out-of-pocket payments ment settings. These limitations likely resulted in conservative,

S90 • CID 2019:68 (Suppl 2) •  Luthra et al

 Table 6.  Summary of Cost-effectiveness and Cost-benefit Studies Published

Refer- Vac- Study

ence Countries cines Disease ­Definition Study ­Participants ­Perspective Costs ­Included Cost Sources ICER Results (Expressed in 2016 US$)

[17] India, TCV Blood culture– 5 strategies: (1) RI Payer Direct medical costs Published literature Cost per DALY - At $1/dose, RI (1 dose) alone compared to no vaccination
Kenya, positive typhoid at 9 mos and and vaccine costs and government averted was predicted as cost-saving (Delhi, India; Vietnam), very
Vietnam fever (adjusted RI at 9 mos + planning records CE (Kolkata, India: $854/DALY; Kenya: $1082/DALY), or CE
incidence rate) catch-up; (2) 9 (Kenya: $3138/DALY);
mo–5 yrs; (3) 9 - At $1/dose, RI + campaign was more CE than RI
mo–15 yrs; (4) 9
mo–25 yrs; (5)
≥9 mos
[18] Uganda ViPS Typhoid fever ≥2 yrs of age Government Direct medical costs Published and list Cost per DALY and - Cost/DALY averted: $491;
prices case averted - Cost/case averted: $346
[15] Indonesia, ViPS Blood culture– 5–14.9 years; Societal; Direct medical/ Published literature, Cost per DALY -N et social costs for community vaccination program
Economics of Typhoid Fever and Typhoid Vaccines  •  CID 2019:68 (Suppl 2) • S91

India, positive typhoid 2–15 years; Govern- nonmedical and indi- survey, hospital avoided are very CE: $185/DALY averted (India) and $635/DALY
Pakistan, fever ≥2 years. ment rect costs records, and ex- averted (Indonesia);
Vietnam pert input - School-aged vaccination (Vietnam): $4366/DALY averted
[16] India ViPS Blood culture– 5–14.9 years; Societal Program costs, Published literature Cost per DALY - Cost per DALY avoided: (1) school-based strategy (5–14
positive typhoid 2–15 years; direct nonmedical avoided yrs), $170; (2), school-based strategy (< 15 yrs), $19; (3)
fever (adjusted ≥2 years. costs, and indi- community-based campaign (all ages), $526;
incidence rate) rect costs - Mean private cost/case: $14;
- Mean public cost/case: $5;
- Total vaccine cost: $1.28/dose;
- All 3 strategies are very CE
[19] India ViPS Culture–positive 2–5 years; Government Direct medical Published literature, Cost per case - At a per-unit vaccine cost of $1.53, the public cost/case
typhoid/ paraty- 6–19 years; costs, nonmedical surveys, and averted avoided: $77 (mass vaccination), $63 (school-based vacci-
phoid, culture– ≥2 years. costs, and indi- unpublished liter- nation), $21 (targeted vaccination program for pre-school
negative w/ rect costs ature children)
clinical typhoid
[20] Global TCV Not specified (1) RI (<1 years); Societal Direct program Not specified Cost per DALY - RI may be high CE in moderate-incidence settings;
(2) RI (<1 years) costs and vaccine avoided - RI with school catch-up campaign highly CE in high-inci-
+ campaign costs dence settings
(5–14 years)

Abbreviations: CE, cost-effectiveness; DALY, disability-adjusted life-years; ICER, incremental cost-effectiveness ratio; RI, routine immunization; TCV, typhoid conjugate vaccine; ViPS, Vi polysaccharide typhoid vaccine.
incremental, cost-effectiveness ratio estimates. Including non– of these limitations, as the study accounts for updated WHO
blood culture–confirmed cases in CEA models would cause recommendations regarding the use of typhoid vaccines [21].
typhoid vaccines to appear more cost-effective. In addition, Moving forward, DF studies for new TCVs will need to consider
disease transmission models were limited by intra-country new product information, WHO recommendations, Gavi eligi-
and inter-country differences in disease burden, and a limited bility and transition scenarios, and competing vaccination and
understanding of age-specific disease incidences [20]. Disease other health priorities for countries. Models should be flexible
incidence is a leading determinant of CE, and increased under- and easy to adapt, to account for uncertainty and the evolving
standing of local disease burdens can help inform future CE landscape around key input variables.
studies. Unlike other, more common diseases that result in Key conditions need to be determined and met in order to
death, like pneumonia or diarrhea, typhoid fever has only a make vaccine introduction decisions. The public health ben-
moderate mortality impact. The economic considerations of efit of the vaccine (does the vaccine reduce disease events or
TCV introduction are, thus, more relevant. deaths?) is key, as is the safety of the vaccine, both individu-
CE is typically underestimated, due to the uncertainty of ally and on the population level. Ideally, countries should esti-
the inputs. Typhoid vaccines will remain cost-effective so long mate their own typhoid burden and the costs of typhoid fever
as disease incidence is high. The only instance when vaccines and typhoid vaccination, as both disease burden and costs are
are not cost-effective is when the incidence is found to be low. context-specific. However, this is not always possible. Once the
A cost-effectiveness analysis measures health gain by the num- public health benefit of the vaccine and the safety profile is estab-
ber of averted deaths or events. The higher the incidence or lished, an economic argument can be made about the vaccine’s
mortality in a population, as found in high-risk populations, the cost-effectiveness. Generally, there are 3 potentially advanta-
more disease cases will be prevented. To set a minimum level of geous types of economic profiles for vaccines, based on the rel-
typhoid incidence for any given area that results in cost-effec- ative comparison of costs and health or economic benefits. The
tiveness, a threshold analysis could be performed. A threshold strongest profile would be a vaccine that results in medical cost
analysis is a benchmark that can be used to set a minimum level savings that exceed the costs of the product (cost-saving). In a
of typhoid incidence for any given area that results in cost-ef- second scenario, the net medical costs (vaccine cost - medical
fectiveness. This becomes important when incidence data is cost savings) may generate an acceptable health benefit (often
uncertain. expressed in DALYs; cost-effectiveness). Third, in a cost-benefit
Another major limitation in CE is the lack of accounting for analysis, the cost of a vaccine may exceed the resulting med-
herd protection, waning vaccine efficacy, and natural immuni- ical cost savings, but the combination of productivity gains
ties within communities in many disease transmission models (or other cost savings) and medical cost savings may be suf-
[16, 18]. The limited timeframes adopted in several studies (eg, ficient to cover its costs (net benefit). In order to estimate the
3 years) prevented analyses of incorporating the need for revac- true cost-effectiveness, and facilitate generalizations to other
cination into CE estimates in studies that modeled vaccination settings, key variables influencing the cost-effectiveness ratio
with ViPSs, where protection is assumed to last for only 3 years. need to be identified, including the immunization coverage,
There was also limited information about antimicrobial resis- vaccine efficacy, target population, availability of infrastructure,
tance and its associated costs. Future CE studies may address and disease burden. Incorporation of these key variables into an
some of these gaps through longer study durations, the inclu- economic model can facilitate an evaluation of the cost-effec-
sion of vaccine program costs, and a better understanding of tiveness of the typhoid vaccine in different settings.
vaccine effectiveness and herd protection associated with the In summary, greater understanding of the disease burden
new TCVs. and economic costs of typhoid fever can help decision-mak-
DF studies focused on older typhoid vaccines (Typbar, ers determine the public health priority of devoting additional
licensed in India; 2008 presentation produced by Gavi, the resources to prevention and treatment in endemic countries.
Vaccine Alliance, unreferenced, see Acknowledgments), and Evidence about the economic benefits of TCVs can assist pol-
only 1 published study estimated the demand for new TCVs icymakers in making informed introduction decisions. DF
[21]. Uncertainties in DF parameters are not well reported in studies can assist donors and vaccine manufacturers with sup-
existing models. For example, the optimal number of doses ply decisions and market-shaping strategies. A few suggestions
and boosters needed and targeting strategies are all subject to for ways to improve research methodology for future economic
change and could render current demand estimates quickly studies are presented in Table 8.
outdated. In addition, models do not account for factors that
influence demand at the country level, such as reduced disease
CONCLUSIONS
transmission through economic growth, improved infrastruc-
ture, and better hygiene and sanitation practices [13]. The DF The findings of this study underscore the importance of
study concurrently published in this volume addresses some typhoid fever as a global public health problem. With typhoid

S92 • CID 2019:68 (Suppl 2) •  Luthra et al

 Table 7.  Summary of Unpublished Data by Study Type

Disease ICER Uti-

Referencea Countries Vaccines ­Definition Study ­Participants Perspective Costs Included Cost Sources lized Results (2016 US$)

Cost-of-illness studies
V. Mogasale, B. Mas- LMICs N/A Typhoid fever All ages Societal Direct medical Published litera- N/A - Total annual treatment costs estimated to be
kery, R. L. Ochiai, adjusted costs and ture, open ac- $141 million in direct costs and 1.2 billion in
J. S. Lee, & T. F. for low productivity cess databases, productivity loss;
Wierzba, manu- sensitivity of losses and unpublished -H  igh-risk areas, (eg, southern Africa, Eastern
script in prepara- diagnostics data Asia, and Southeastern Asia contributed
tion, unreferenced disproportionately to treatment costs);
- Average cost per episode was $114; average
cost per outpatient episode was $92; av-
erage cost per inpatient episode was $421
Cost-of-delivery studies
2012 summary Nepal ViPS Not specified School children (ages Provider Direct medical Unpublished data N/A - Cost per dose delivered: $7.78
results by V. Moga- not specified) and program
sale, unreferenced costs
Economics of Typhoid Fever and Typhoid Vaccines  •  CID 2019:68 (Suppl 2) • S93

Cost-effectiveness studies
2017 workshop LMICs TCV Blood culture– - 0–4 years; Government Program costs Published literature Cost/ DALY - Vaccinating high risk: very CE; for countries
presentation by confirmed - 5–14 years; and wastage and unpublished averted in SE Asia, South Asia, and Central Asia,
V. Mogasale & J. S. typhoid fever - ≥15 years data vaccinating population cost saving; - RI +
Lee; unreferenced (adjusted inci- booster dose strategies are less CE than
dence rate) single-dose RI strategies
Demand forecast studies
2008 presentation Gavi-el- ViPS, live oral N/A (1) Mass campaign: N/A Direct pro- WHO, published N/A - Total market (2011–2020); - Campaign
produced by Gavi, igible typhoid vac- 2–15 years; gram costs literature, other 2–15 years: 497 million doses;
the Vaccine Alli- coun- cine; TCV and 5–15 years; and direct sources (un- - Campaign 5–15 years: 453 million doses;
ance, unreferenced tries other typhoid (2) RI (<1 years) and nonprogram specified) - Routine vaccination: 178 million doses
vaccines under catch-up campaign costs
development (1–15 years);
(3) RI (<1 years)
V. Vishwanarayan, Gavi/LMIC TCV N/A - RI (9 months, Government N/A N/A N/A - Total market size 2020–2030: 734 million
unpublished obser- 18 months); doses;
vations catch-up campaign - Peak demand in 2023 with 102 million doses
(1–15 years)

Abbreviations: DALY, disability-adjusted life-years; ICER, incremental cost-effectiveness ratio; LMIC, low- and middle-income countries; N/A, not applicable; RI, routine immunization; SE, southeast; TCV, typhoid conjugate vaccine; ViPS, Vi polysaccharide
typhoid vaccine; WHO, World Health Organization.
a
Unpublished studies are referenced in Acknowledgments.
S94 • CID 2019:68 (Suppl 2) •  Luthra et al

Table 8.  Research Considerations by Study Type

Cost-of-illness Studies Cost-of-delivery Studies Cost-effectiveness Studies

Cost considerations Disease considerations Cost considerations Disease considerations Cost considerations Disease considerations Demand Forecasting Studies
- Adopt a societal perspec- - Include laboratory-con- - Include vaccine supply and - Include herd protection - Adopt a societal perspec- - Incorporate flexibility into - Model expected introduc-
tive; firmed typhoid fever procurement costs in all when accounting for public tive to capture the full eco- models to account for dif- tion process at country
- Improve the generaliza- cases, as misdiagnoses studies, even if vaccine program costs and cost nomic value of vaccination; ferent risk levels and out- level as closely as possible,
bility of results through could reduce costs or in- product is donated; savings - Include geographically break scenarios (eg, when particularly in countries that
selection of participants crease costs; -U  se the WHO/International representative cost data to vaccination occurs within typically implement phased
and costs (eg, use national - Increase follow-up time to Vaccine Institute (IVI) cost increase generalizability; an outbreak context); introductions;
averages for wage rates); capture long-term impact of delivery tool to ensure - Indirect costs to house- - Include potential impact of - Models should incorporate
- Account for different costs of typhoid fever; consistency of cost data holds should also include antimicrobial resistance; ability to adjust parameters
related to treatment-sen- -E  xcluding non–blood reported; data-based travel and - Include geographically based on multiple scenarios
sitive and treatment-resis- culture–confirmed cases -C  onsider issues of afford- waiting-time costs for vac- representative epidemi- and evolving information,
tant cases; may miss a large segment ability and sustainability cination and treatment; ological data to increase including multiple products,
- Transaction costs should of the burden of typhoid of TCV through budget -P  rogram delivery costs generalizability of results; multiple delivery platforms,
be included in costs to fever impact analysis should reflect the delivery - Adjust models to account and multiple supply sce-
households; platform (eg, school-based for increased aware- narios;
- Utilize actual costs of delivery vs. communi- ness and potential for - Account for anticipated
drugs and capital assets, ty-based delivery); early treatment –seeking country-level transitions
rather than list prices, -C  E comparators can be behavior among study from Gavi funding support
when available; expanded beyond no vac- participants to self-financing, as this may
- Include treatment costs cination or different vacci- shift the demand curve
from outpatient and inpa- nation strategies to include
tient care; other typhoid prevention
- Incorporate household will- and reduction measures,
ingness-to-pay estimates as well as other priority
disease areas;
- Account for different
households’ willingness to
pay thresholds in different
settings

Abbreviations: CE, cost-effectiveness; TCV, typhoid conjugate vaccine; WHO, World Health Organization.
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Economics of Typhoid Fever and Typhoid Vaccines  •  CID 2019:68 (Suppl 2) • S95