## Abstract

Background. Two currently licensed typhoid vaccines have been evaluated in Asia, yet few Asian countries have considered including typhoid vaccines in their vaccination programs. The Diseases of the Most Impoverished (DOMI) Program was initiated to provide evidence to decide on the introduction of typhoid vaccines in Asian countries.

Methods. The centerpiece of the program is a multidisciplinary demonstration project with Vi vaccine in 5 Asian countries. The project includes epidemiologic, economic, sociobehavioral, and policy studies.

Results. Policy makers want evidence on which to base their vaccine-related decisions. The DOMI Program has provided updated information on the typhoid fever burden at several Asian sites. Cost-of-illness studies found high costs to governments and individuals. Sociobehavioral studies indicated a positive attitude toward typhoid vaccines. The results of the demonstration projects indicate that mass-immunization campaigns are feasible and acceptable.

Conclusions. The DOMI Program has begun to provide momentum for the evidence-based, rational introduction of typhoid vaccines into the public health programs of several Asian countries.

Typhoid fever is controlled in most industrialized countries, but the disease still causes considerable morbidity and mortality in developing countries, accounting for >200,000 deaths annually. More than 90% of the 22 million typhoid fever episodes that occur each year are thought to occur in Asia [1]. Immunization with older-generation, parenterally administered, killed whole-cell typhoid vaccines was shown to control the disease in Thailand, but these vaccines have been abandoned as public health tools because of their unacceptable adverse effects [2].

Two newer-generation typhoid vaccines are safe, protective, and internationally licensed. One, Vi vaccine, is injected as a single dose. Vi vaccine has been found to be 64%–72% protective at 21 and 17 months of follow-up in Nepal and South Africa, respectively [3, 4]. The efficacy in the South Africa trial over 3 years of follow-up was 55%. Similarly, a Vi vaccine produced in China conferred 70% protection at 1 year of follow-up in randomized controlled trials [5, 6]. The second vaccine, Ty21a, a live oral vaccine, is given orally in 3 doses administered every other day. Its current liquid formulation was found to be 53% and 77% protective at 3 years of follow-up in Indonesia and Chile, respectively [7,8–9]. Neither vaccine is currently registered for administration to children <2 years of age. The World Health Organization has recommended both vaccines as disease-control tools in school-based programs in high-risk areas [10].

Despite this recommendation, however, both vaccines are currently used primarily for travelers to high-risk countries rather than as tools for populations experiencing endemic typhoid fever. The Diseases of the Most Impoverished (DOMI) Program was initiated in 2000, with funding from the Bill and Melinda Gates Foundation and under the coordination of the International Vaccine Institute in Seoul, Korea, to rationally introduce the vaccines for the individuals who need them most.

One of the goals of the DOMI Program was to provide updated evidence for decision making about the use of modern typhoid vaccines in developing countries. Early on in the program, a decision was made to focus on Vi vaccine, for several reasons. First, in contrast to Ty21a, which must be given in at least 3 doses at precise every-other-day intervals, Vi is given in a single dose; this was considered to be an important advantage because of the difficulties in ensuring precisely timed administration of multidose vaccine regimens in developing countries. Second, Vi is putatively more thermostable than Ty21a, which is an advantage in developing countries with imperfect cold chains for storage of vaccines. Third, there was already evidence that the production technology for Vi vaccine could be successfully transferred to producers in typhoid-endemic countries. In the present article, we provide a status report on the evidence accrued thus far in the DOMI typhoid program.

## Interviews With Policy Makers In Asia

One of the first activities of the DOMI Program was face-to-face, semistructured interviews of almost 200 policy makers and vaccine opinion leaders in the 7 DOMI partner countries: Bangladesh, China, India, Indonesia, Pakistan, Thailand, and Vietnam [11]. The interviews were designed to determine perceptions about the current importance of typhoid fever as a public health problem, the adequacy of current control measures, and the need for introducing a typhoid vaccine as a control measure. The interviews also queried the policy makers about the data needed to make decisions about introducing typhoid vaccine into their countries, the acceptable cost of a typhoid vaccine, and the importance of local production of typhoid vaccines for vaccine introduction.

The survey found that policy makers, with the exception of those in Thailand, generally regarded typhoid fever as a significant problem in their countries. In several countries, concern was expressed that rising antibiotic resistance rates were likely to exacerbate the seriousness of typhoid fever as a public health problem. It was acknowledged that inadequacies in routine diagnoses, which are generally made without culture confirmation, made current statistics somewhat uncertain, highlighting the need for prospective studies of the typhoid fever burden. Although improved water and sanitation was deemed as the ultimate solution to control typhoid fever, it was generally acknowledged that such improvements were distant goals and that the use of a safe and protective vaccine would be a desirable addition to the public health armamentarium. The results of this survey were instrumental in adapting the DOMI research programs to provide appropriate evidence for the introduction of Vi vaccine in a manner that was responsive to the needs of policy makers.

## Prospective Studies Of Disease Burden

To provide more accurate updated data on the typhoid fever burden in Asia, and as part of multidisciplinary demonstration projects involving Vi vaccine (see below), surveillance for typhoid fever was instituted at sites in 5 Asian countries: Hechi, China; Kolkata, India; North Jakarta, Indonesia; Karachi, Pakistan; and Hue, Vietnam. The sizes of the target populations at these sites ranged from 41,845 in Karachi to 160,261 in Jakarta. All sites employed standardized clinical, microbiological, and surveillance methods to allow comparison of the data. Study sites and age groups under surveillance varied by site, but the age group thought to be at the highest risk, children 5–15 years of age, was included at each site. Study sites were chosen in consultation with local officials on the basis of a high perceived burden of typhoid fever, absence of control programs against the disease, and willingness of the community to participate. The age groups selected were thought to be the most likely targets for typhoid vaccination.

The typhoid fever incidence among children 5–15 years of age at the study sites appeared to be highest in South Asia (400–500 cases per 100,000 persons per year), intermediate in Southeast Asia (100–200 cases per 100,000 persons per year), and lowest in Northeast Asia (<100 cases per 100,000 persons per year). Similar high typhoid fever incidence rates have recently been reported from Bangladesh [12]. These data, together with the data from Nepal [3, 13], seem to suggest that the subcontinental nations, including India, Bangladesh, Pakistan, and Nepal, are at very high risk for typhoid fever. These data are consistent with the observations by Crump et al. [1] that Pakistan, India, and Indonesia are high-incidence areas and that Vietnam and China are lower-incidence areas. The estimated rates of typhoid fever are likely to be underestimates, because the findings are based on blood culture results, which are only 32%–70% sensitive [14,15,16–17]. The study sites were selected on the basis of local public health experts' impressions that there was a high incidence of typhoid fever. Because of this means of selection, caution should be used when considering generalization of the findings to the whole countries and regions in which the sites were located.

## Cost Of Illness and Estimations Of Maximally Acceptable Vaccination Costs

The costs of typhoid illness were estimated in an urban slum of Delhi, India [18]. This site had been shown to have a very high incidence of blood culture–proven typhoid fever (9.7 cases per 1000 general population) [19]. The estimates were based on data collected through weekly interviews conducted for 3 months after diagnosis of 98 culture-positive cases. An average case of blood culture–confirmed typhoid fever costs 3597 Indian rupees (approximately US $101 in 1996). Approximately half of this cost was paid out of pocket by the patient's family, a financially deleterious consequence for families living in the slum, whose average monthly income was approximately US$50.

On the basis of a cost-benefit analysis in which disease incidence, disease costs, and the anticipated performance of Vi vaccine (55% protective for 3 years) were taken into account, typhoid vaccination programs will make sense economically if public health officials adopt a societal perspective [20]. This is especially true when public health decision makers recognize that (1) the incidence of typhoid fever is underestimated when only blood culture–positive cases are considered and (2) the avoided costs of illness represent a significant underestimate of the actual economic benefits of vaccination for individuals.

## Perceptions

An understanding of the factors influencing the acceptance of vaccines is needed to plan typhoid vaccine programs. A cross-sectional study was conducted among randomly sampled households from a site in Lingchuan County in Guangxi, China, experiencing high rates of typhoid and paratyphoid fever [21]. Data on enteric fever were collected through face-to-face interviews with 624 people (51% of whom were female). Vaccine acceptability was measured by an expressed need for vaccination and a willingness to pay. Nearly all respondents considered enteric fever to be prevalent in the community. Importantly, a perceived need for a typhoid vaccine was associated with willingness to pay for the vaccine. The results of this survey suggest a high level of demand for typhoid vaccine at this site and the possibility that the government may be able to recover some of its expenditures on typhoid vaccines for public sector programs by charging users' fees.

In Hue, Vietnam, the site of a large-scale, school-based demonstration project involving immunization with Vi vaccine, surveys were conducted to assess perceptions of typhoid fever, desirability for the Vi vaccine, and reasons for participation and nonparticipation in the trial [22]. Participation was associated with the past use of health care facilities and with knowledge about vaccines and causes of typhoid fever. Satisfaction with the prevaccination information and consent procedures also had an influence on participation. Children and adolescents were active decision makers, because vaccination was performed at school. Only 2% of respondents stated that they would not consider using the Vi vaccine in the future for their children. These findings provide useful ideas to increase coverage in future school-based typhoid immunization programs.

## Effectiveness Studies In 5 Asian Countries

The effectiveness of Vi vaccine administered in public health programs has been assessed in several ways. An outbreak of typhoid fever in a middle school in Guangxi, China, in 1999 provided a unique opportunity to evaluate the practical impact of Vi vaccination in a public health program, because the Guangxi province has used Vi vaccine as a public health tool for school-age children since 1995 [23]. Seventy-three percent protection against typhoid fever was conferred among students who had been immunized with Vi vaccine before the outbreak. For students immunized with Vi vaccine during the outbreak, protection was 71%. A retrospective analysis of the occurrence of typhoid fever, diagnosed by use of clinical and serologic criteria, was conducted to investigate the long-term protection conferred by Vi vaccine in China [24]. The findings suggested that Vi vaccine protects for at least 2 years after vaccination, and there was suggestive protection during the third year. These results support the applicability and value of Vi vaccine in outbreak control and in routine immunization programs in areas in which typhoid fever is endemic.

A major focus of the DOMI Program has been the multicountry Vi vaccine demonstration project. In North Jakarta, Indonesia, a program of school-based mass immunizations was undertaken to assess the feasibility, acceptability, and costs of such a program. At other sites—Hechi, China; Hue, Vietnam; Kolkata, India; and Karachi, Pakistan—controlled, cluster-randomized Vi vaccine trials are being conducted in realistic public health settings to determine the practical protective impact of large-scale Vi vaccine administration [25] (table 1). All of these trials were approved by the institutional review boards at the study sites and at the International Vaccine Institute. In the cluster-randomized trials, targeted age groups residing in designated clusters (geographic areas for Hechi, Kolkata, and Karachi; schools for Hue) received either Vi vaccine or an active control vaccine. Written, informed consent was obtained from each participant (or guardian) before immunization. The cluster-randomized design of the trial is designed to permit analysis not only of protection of vaccine recipients but also of indirect (herd) protection of nonrecipients. Economic studies of the cost of typhoid illness and of Vi vaccine delivery have been nested in the trials. These analyses, in conjunction with the assessment of protection against typhoid, will allow evaluation of vaccine cost-effectiveness.

Table 1

Vi vaccine demonstration projects in the DOMI Program.

Table 1

Vi vaccine demonstration projects in the DOMI Program.

At the 5 sites, mass immunization was conducted in 2003 and 2004. Overall, 194,493 people received Vi vaccine or a control vaccine. The program proved that very large mass-immunization campaigns are programmatically feasible and acceptable, in both community and school settings. The participation rate in the target population varied between 58% and 91%. The highest coverage was achieved in a school-based program in North Jakarta, Indonesia, perhaps partly reflecting the fact that this was the only demonstration project that was not conducted as a randomized, controlled trial.

## Discussion

Despite a continuing high burden of typhoid fever in Asia and the availability of safe and protective modern typhoid vaccines, vaccination is still not being used routinely to control typhoid fever in populations in areas in which the disease is endemic. There are many likely reasons for this lack of routine use, including residual bias against vaccination, as a result of the reactogenicity of older-generation typhoid vaccines. The cost of vaccines has also undoubtedly contributed to hesitation about introducing them into public health programs, although the uptake of Vi vaccine production by several manufacturers in developing countries has begun to yield vaccine at affordable prices.

Ministries of Health in developing countries are faced with many competing demands on already-limited health care budgets. There is, therefore, an increasing demand for evidence to justify the introduction of new interventions, such as vaccines. The DOMI Program was designed to fill those gaps to enable rational decision making about introducing typhoid vaccine into public health programs.

Several key lessons have already been learned. The DOMI Program has provided updated information on disease burden at several Asian sites, which showed very high typhoid fever incidence rates in South Asia (India and Pakistan), an intermediate rate in Indonesia, and relatively low rates in China and Vietnam. Economic analyses are providing information for decision makers regarding the costs and benefits of vaccine programs. Sociobehavioral studies have indicated an overwhelmingly positive attitude toward typhoid vaccines in the study populations. Although the centerpiece of the program, a series of randomized effectiveness trials of Vi, are still in progress, these demonstration projects have already shown that both community-based and school-based mass-immunization campaigns are programmatically feasible and acceptable to communities and health care workers.

It is hoped that the DOMI Program will provide momentum for the rational introduction of typhoid vaccines into programs for the poor in several Asian countries. However, as important as generating this evidence will be the communication of the evidence to decision makers. At the same time, there is a need for the development of new, improved vaccines that can be administered to infants in the routine Expanded Program on Immunization schedule of immunizations, as well as to older persons, and provide extended protection. One such vaccine, Vi conjugate vaccine, holds the potential to meet these requirements but has yet to be licensed by any pharmaceutical company [26]. Single-dose oral vaccines are also being tested [27, 28]. With this promising pipeline of new vaccine candidates, as well as the 2 safe and protective vaccines that are already internationally licensed, the control of typhoid fever with vaccines in Asia may not be a distant goal.

## Acknowledgments

We thank the Bill and Melinda Gates Foundation, GlaxoSmithKline, and the Governments of the Republic of Korea, Sweden, and Kuwait, for supporting the Diseases of the Most Impoverished Program coordinated by the International Vaccine Institute.

Supplement sponsorship. This article was published as part of a supplement entitled “Tribute to Ted Woodward,” sponsored by an unrestricted grant from Cubist Pharmaceuticals and a donation from John G. McCormick of McCormick & Company, Hunt Valley, Maryland.

Potential conflicts of interest. Vaccines for the demonstration projects, except those for the project conducted in China, were donated by GlaxoSmithKline. C.J.A. and C.M.G. currently work for GlaxoSmithKline; the work presented in this article was conducted while they were employed by the International Vaccine Institute. All other authors: no conflicts.

## References

1
Crump
JA
Luby
SP
Mintz
ED
The global burden of typhoid fever
Bull World Health Organ
,
2004
, vol.
82
(pg.
346
-
53
)
2
Bodhidatta
L
Taylor
DN
Thisyakorn
U
Echeverria
P
Control of typhoid fever in Bangkok, Thailand, by annual immunization of schoolchildren with parenteral typhoid vaccine
Rev Infect Dis
,
1987
, vol.
9
(pg.
841
-
5
)
3
Acharya
IL
Lowe
CU
Thapa
R
, et al.  .
Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi: a preliminary report
N Engl J Med
,
1987
, vol.
317
(pg.
1101
-
4
)
4
Klugman
KP
Koornhof
HJ
Robbins
JB
Le Cam
NN
Immunogenicity, efficacy and serological correlate of protection of Salmonella typhi Vi capsular polysaccharide vaccine three years after immunization
Vaccine
,
1996
, vol.
14
(pg.
435
-
8
)
5
Wang
ZG
Zhou
WZ
Shi
J
Efficacy and side effects following immunization with Salmonella typhi Vi capsular polysaccharide vaccine [in Chinese]
Zhonghua Liu Xing Bing Xue Za Zhi
,
1997
, vol.
18
(pg.
26
-
9
)
6
Yang
HH
Wu
CG
Xie
GZ
, et al.  .
Efficacy trial of Vi polysaccharide vaccine against typhoid fever in south-western China
Bull World Health Organ
,
2001
, vol.
79
(pg.
625
-
31
)
7
Simanjuntak
CH
Paleologo
FP
Punjabi
NH
, et al.  .
Oral immunisation against typhoid fever in Indonesia with Ty21a vaccine
Lancet
,
1991
, vol.
338
(pg.
1055
-
9
)
8
Levine
MM
Ferreccio
C
Black
RE
Germanier
R
Large-scale field trial of Ty21a live oral typhoid vaccine in enteric-coated capsule formulation
Lancet
,
1987
, vol.
1
(pg.
1049
-
52
)
9
Levine
MM
Ferreccio
C
Cryz
S
Ortiz
E
Comparison of enteric-coated capsules and liquid formulation of Ty21a typhoid vaccine in randomised controlled field trial
Lancet
,
1990
, vol.
336
(pg.
891
-
4
)
10
World Health Organization
Background document: the diagnosis, treatment and prevention of typhoid fever
,
2003
Geneva
World Health Organization
11
DeRoeck
D
Clemens
JD
Nyamete
A
Mahoney
RT
Policymakers' views regarding the introduction of new-generation vaccines against typhoid fever, shigellosis and cholera in Asia
Vaccine
,
2005
, vol.
23
(pg.
2762
-
74
)
12
Brooks
WA
Hossain
A
Goswami
D
, et al.  .
Bacteremic typhoid fever in children in an urban slum, Bangladesh
Emerg Infect Dis
,
2005
, vol.
11
(pg.
326
-
9
)
13
Malla
S
Kansakar
P
Serichantalergs
O
Rahman
M
Basnet
S
Epidemiology of typhoid and paratyphoid fever in Kathmandu: two years study and trends of antimicrobial resistance
JNMA J Nepal Med Assoc
,
2005
, vol.
44
(pg.
18
-
22
)
14
Farooqui
BJ
Khurshid
M
Ashfaq
MK
Khan
MA
Comparative yield of Salmonella typhi from blood and bone marrow cultures in patients with fever of unknown origin
J Clin Pathol
,
1991
, vol.
44
(pg.
258
-
9
)
15
Gilman
RH
Terminel
M
Levine
MM
Hernandez-Mendoza
P
Hornick
RB
Relative efficacy of blood, urine, rectal swab, bone-marrow, and rose-spot cultures for recovery of Salmonella typhi in typhoid fever
Lancet
,
1975
, vol.
1
(pg.
1211
-
3
)
16
Hoffman
SL
Edman
DC
Punjabi
NH
, et al.  .
Bone marrow aspirate culture superior to streptokinase clot culture and 8 ml 1 : 10 blood-to-broth ratio blood culture for diagnosis of typhoid fever
Am J Trop Med Hyg
,
1986
, vol.
35
(pg.
836
-
9
)
17
Wain
J
Pham
VB
Ha
V
, et al.  .
Quantitation of bacteria in bone marrow from patients with typhoid fever: relationship between counts and clinical features
J Clin Microbiol
,
2001
, vol.
39
(pg.
1571
-
6
)
18
Bahl
R
Sinha
A
Poulos
C
, et al.  .
Costs of illness due to typhoid fever in an Indian urban slum community: implications for vaccination policy
J Health Popul Nutr
,
2004
, vol.
22
(pg.
304
-
10
)
19
Sinha
A
Sazawal
S
Kumar
R
, et al.  .
Typhoid fever in children aged less than 5 years
Lancet
,
1999
, vol.
354
(pg.
734
-
7
)
20
Poulos
C
Bahl
R
Whittington
D
Bhan
MK
Clemens
JD
Acosta
CJ
A cost-benefit analysis of typhoid fever immunization programmes in an Indian urban slum community
J Health Popul Nutr
,
2004
, vol.
22
(pg.
311
-
21
)
21
Chen
X
Stanton
B
Wang
X
, et al.  .
Differences in perception of dysentery and enteric fever and willingness to receive vaccines among rural residents in China
Vaccine
,
2006
, vol.
24
(pg.
561
-
71
)
22
Kaljee
LM
Pack
R
Pach
A
Nyamete
A
Stanton
BF
Sociobehavioural research methods for the introduction of vaccines in the Diseases of the Most Impoverished Programme
J Health Popul Nutr
,
2004
, vol.
22
(pg.
293
-
303
)
23
Yang
HH
Kilgore
PE
Yang
LH
, et al.  .
An outbreak of typhoid fever, Xing-An County, People's Republic of China, 1999: estimation of the field effectiveness of Vi polysaccharide typhoid vaccine
J Infect Dis
,
2001
, vol.
183
(pg.
1775
-
80
)
24
Acosta
CJ
Hong-Hui
Y
Ning
W
, et al.  .
Efficacy of a locally produced, Chinese Vi polysaccharide typhoid fever vaccine during six years of follow-up
Vaccine
,
2005
, vol.
23
(pg.
5618
-
23
)
25
Acosta
CJ
Galindo
CM
Ali
M
, et al.  .
A multi-country cluster randomized controlled effectiveness evaluation to accelerate the introduction of Vi polysaccharide typhoid vaccine in developing countries in Asia: rationale and design
Trop Med Int Health
,
2005
, vol.
10
(pg.
1219
-
28
)
26
Lin
FY
Ho
VA
Khiem
HB
, et al.  .
The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five-year-old children
N Engl J Med
,
2001
, vol.
344
(pg.
1263
-
9
)
27
Kirkpatrick
BD
McKenzie
R
O'Neill
JP
, et al.  .
Evaluation of Salmonella enterica serovar Typhi (Ty2 aroC-ssaV-) M01ZH09, with a defined mutation in the Salmonella pathogenicity island 2, as a live, oral typhoid vaccine in human volunteers
Vaccine
,
2006
, vol.
24
(pg.
116
-
23
)
28
Kirkpatrick
BD
Tenney
KM
CJ
, et al.  .
The novel oral typhoid vaccine M01ZH09 is well tolerated and highly immunogenic in 2 vaccine presentations
J Infect Dis
,
2005
, vol.
192
(pg.
360
-
6
)