1775

An Outbreak of Typhoid Fever, Xing-An County, People’s Republic of China,

1999: Estimation of the Field Effectiveness of Vi Polysaccharide
Typhoid Vaccine
Hong Hui Yang,1 Paul E. Kilgore,4 Ling Hong Yang,2 1
Guangxi Health and Anti-Epidemic Center, 2Xing-An County Middle
Jin-Kyung Park,5 You-Fu Pan,3 Yongdai Kim,5 School, and 3Xing-An County Health and Anti-Epidemic Center,
Guangxi Zhuang Autonomous Region, People’s Republic of China;
Young-Jack Lee,4,6 Zhi-Yi Xu,4 4
International Vaccine Institute, 5Department of Statistics, Hankuk
and John D. Clemens4 University of Foreign Studies, and 6Department of Statistics,

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Hanyang University, Seoul, Republic of Korea

To evaluate the effectiveness of Vi polysaccharide vaccine (Vi vaccine) in preventing typhoid

fever, an analysis was done of an outbreak of typhoid fever among students attending a middle
school in the People’s Republic of China, where Vi vaccine is licensed for use. Vi vaccine
effectiveness was analyzed by using Cox proportional hazards modeling to account for the
time-dependent nature of vaccination and illness status during the outbreak. Among 1260
students who had been immunized before the outbreak, receipt of Vi vaccine was associated
with 73% (95% confidence interval [CI], 32%–89%) protection. Among the additional 441
students immunized during the outbreak, receipt of Vi vaccine was associated with 71% (95%
CI, ⫺9% to 92%) protection. These results provide the first evidence about the effectiveness
of Vi vaccine when deployed routinely in a typhoid-endemic area and support the use of Vi
vaccine as a public health tool to control typhoid fever.

Typhoid fever is responsible for an estimated yearly burden of
∼16,591,000 cases and ∼580,000 deaths worldwide [1–3]. The
greatest burden of illness occurs in Asia, where ∼13,310,000 cases
and ∼440,000 deaths occur annually. In Africa, Asia, Europe,
and the Americas, multidrug-resistant strains of Salmonella typhi
have emerged over the past 2 decades and have been responsible
for numerous outbreaks in typhoid fever–endemic areas [4–7].
Such increases in antimicrobial resistance suggest that treatment
of typhoid fever in many developing countries may be achieved
in the future only through the use of more expensive antibiotics,
such as the quinolones or recent-generation cephalosporins [8–
10]. The persistence of typhoid fever endemicity among large
populations and the global emergence of multidrug-resistant
strains impose greater urgency on the evaluation of existing and
new vaccines to prevent typhoid fever [11–13].
In 1986, Vi polysaccharide typhoid vaccine (Vi vaccine) was
evaluated in a field trial in Nepal. In this setting, Vi vaccine
demonstrated 76% efficacy against typhoid fever after 21
months of follow-up [14]. In a subsequent trial of Vi vaccine
in South Africa, vaccine efficacy against typhoid fever was 61%
during nearly 2 years of follow-up [15]. Based on these favor-
able data, in 1989, investigators at the Lanzhou Institute of
Biological Products in China embarked on the development
and production of Vi vaccine in cooperation with the original
developers of the vaccine at the US National Institutes of
Health. Two large-scale, randomized, placebo-controlled trials
of this locally produced vaccine in China demonstrated ∼70%
protection at 12 and 19 months after vaccination, respectively
[16, 17]. On the basis of these trial results, the locally produced
Vi vaccine was licensed for use in China, although, to date, no
postlicensure evaluations of Vi vaccine have been undertaken
in China or elsewhere.
Guangxi Zhuang Autonomous Region (Guangxi) in China
has used Vi vaccine as a public health tool for school-age chil-
dren since 1995. In 1999, an outbreak of typhoid fever occurred
in a middle school in the region. This outbreak provided a
unique opportunity to evaluate the practical impact of Vi vac-
cination in a public health program.

Received 5 December 2000; revised 5 March 2001; electronically published
17 May 2001.
Informed consent was obtained from participating students and their par-
ents or guardians.
Financial support: Diseases of the Most Impoverished Program, Bill and
Melinda Gates Foundation (coordinated by the International Vaccine
Institute).
Reprints or correspondence: Dr. Paul Kilgore, International Vaccine In-
stitute, Kwanak PO Box 14, Seoul, Republic of Korea (pkilgore@ivi.int).
The Journal of Infectious Diseases 2001; 183:1775–80
䉷 2001 by the Infectious Diseases Society of America. All rights reserved.
0022-1899/2001/18312-0009$02.00
Materials and Methods
Study area and population. Xing-An County is located in
northeastern Guangxi Province and has a population of ∼369,000
[18]. Xing-An County is an area in which typhoid fever is endemic.
In this area, in 1996–1998, typhoid fever incidence rates were 38.8–
102.7 cases per 100,000 residents (Y. F. Pan, personal communi-
cation). Typhoid fever is a seasonal disease in Xing-An, with peaks
from April through October.
In 1995, public health authorities initiated administration of Vi
vaccine among residents in 40 counties of Guangxi. From 1996
1776 Yang et al.
through 1999, in Xing-An County, 61,030 doses of Vi vaccine were
administered in immunization programs (Y. F. Pan, personal com-
munication). In 1998, public health officials and school health
workers introduced Vi vaccine into the school-based immunization
program of Xing-An County.
In Guangxi, government public health agencies investigate all
reported cases of suspected and confirmed typhoid fever. If typhoid
fever cases are confirmed and an outbreak is present or expected,
interventions typically include measures to improve hygienic han-
dling of food, water, and sewage. In addition, when large outbreaks
occur, antibiotic prophylaxis is sometimes provided to persons con-
sidered to be at high risk for typhoid fever. Since Vi typhoid vaccine
became available in Guangxi, this vaccine has also been used as a
tool to control outbreaks among high-risk persons not previously
vaccinated. When vaccine is administered, names of vaccinees and
dates of vaccination are recorded in logbooks.
Xing-An County has 1 middle school (in this setting, middle
schools include all secondary school grades), located in Xing-An. In
1999, this school had 2111 students in 28 classes spanning 7 grade
levels. Because of large distances between home and school, 60% of
students attending the middle school resided in school dormitories
and usually ate in school dining facilities during the academic year.
Typhoid fever outbreak. During 11–13 May 1999, the physician
for the Xing-An County Middle School detected an increase in the
number of students suspected of having typhoid fever. Cases of
suspected typhoid fever were referred to the single hospital serving
Xing-An residents (Xing-An County Hospital) for further evalu-
ation and treatment. On 13 May 1999, public health officials from
the Xing-An Anti-Epidemic Center were alerted to a sharp increase
in the number of reported cases of suspected typhoid fever. On 14
May 1999, school officials implemented active case finding by
screening all students for fever and other signs or symptoms con-
sistent with typhoid fever.
Laboratory evaluations of patients with suspected typhoid fever.
As part of the evaluation of suspected typhoid fever at Xing-An
County Hospital, patients routinely had blood specimens taken at
the time of admission for diagnosis of typhoid fever by use of the
Widal test, and blood cultures were done whenever possible. After
discharge, patients were scheduled for follow-up, to obtain con-
valescent serum samples for Widal testing. By July, most students
had left the school for the summer vacation, and thus the majority
of ill students were unavailable for follow-up blood sampling.
A standardized Widal test was done at the Xing-An County Hos-
pital clinical laboratory (Lanzhou Institute of Biological Products)
[19–21]. Microbiology laboratory staff of Xing-An County Hospital
isolated S. typhi from blood specimens by standard microbiologic
techniques. Technicians inoculated 1 mL of blood into 10 mL of
culture broth, which was incubated for 24 h at 37⬚C. At 24 h after
inoculation, all specimens were routinely subcultured onto Mac-
Conkey and Salmonella-Shigella agar plates (Shanghai Reagent Pro-
vision and Research Center for Diarrheal Control; Beijing Land
Bridge Technology; Guangdong Shan-tou Chemicals). Microbiology
staff did the initial identification and serotyping of bacterial isolates
at the Xing-An County Hospital clinical laboratories (National In-
stitute for Control of Pharmaceutical and Biological Products). Mi-
crobiologists of the Guangxi Anti-Epidemic Center confirmed sero-
typing results of S. typhi isolates by using standard reagents (Chinese
Academy of Preventive Medicine).
JID 2001;183 (15 June)
Typhoid immunization and chemoprophylaxis. In 1998, school
health officials and workers from the Xing-An Anti-Epidemic Cen-
ter began a school-based immunization program in which 1 30-mg
dose of Vi vaccine (Wuhan Institute of Biologic Products, lot
971205) was administered subcutaneously. More than 1200 students
of the Xing-An County Middle School received Vi vaccine as a
part of this program. Because of the ongoing typhoid fever epi-
demic that began in May 1999, Xing-An Anti-Epidemic Center
officials instituted another Vi immunization program designed to
deliver single 30-mg doses of Vi (Lanzhou Institute of Biological
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Products, lot 81008) to students who had not been vaccinated in
1998. To minimize disruption of classroom activities and because
of an intervening weekend (19 and 20 May), school administrators
initiated this immunization program on 17 and 18 May for grades
1, 2, 4, and 5 and administered the last group of immunizations
on 21 May for students in grades 3, 6, and 7. School health workers
recorded the names of all vaccinees in school clinic logbooks during
the Vi immunization program.
In the context of the typhoid outbreak described, public health
workers giving Vi vaccine occasionally did so without careful ref-
erence to immunization records, but relied instead on the memories
of students and their parents about past immunizations. This led
to inadvertent administration of 2 doses to a small number (74) of
students. After receipt of Vi vaccination records from the Anti-
Epidemic Center, school health workers recorded the names of all
vaccinees in school records. Immunization records were later en-
tered into central computer databases for the present analysis. In
response to an increase in the number of suspected typhoid fever
cases, chemoprophylaxis with norfloxacin (400 mg orally 3 times
per day for 4 days; Southwest Pharmaceutical Factory) was pro-
vided on 19 June 1999 to 2097 of the 2111 students (the 14 students
not receiving prophylaxis were hospitalized for treatment of sus-
pected typhoid fever during this time).
Outbreak investigation. During 10–14 September 1999, inves-
tigators from both the Xing-An County and the Guangxi Anti-
Epidemic centers surveyed Xing-An County Middle School stu-
dents to collect demographic information (e.g., age, sex, and school
attendance information; class level; and locations for eating and
sleeping during the school year). Reported vaccination histories
were verified by using student names and classrooms recorded in
school immunization logbooks. During 15–17 September 1999, in-
vestigators working at Xing-An County Hospital retrospectively
reviewed clinical and microbiology laboratory records, to identify
all cases of suspected and confirmed typhoid fever during the out-
break period (1 May–30 June 1999). For purposes of the analysis,
30 June was considered the end of the outbreak: The outbreak had
clearly waned, and no cases had been detected during the prior
week. Also, students went home for summer vacation on 1 July,
making it impossible to conduct systematic surveillance for typhoid
fever after this date among the dispersed student population.
Case definition. Before the conduct of analyses of the outbreak,
we stipulated that, to be classified as having typhoid fever in the
analyses, either a patient must have had S. typhi isolated by blood
culture or, in lieu of blood culture positivity, the patient must have
had (1) body temperature ⭓38.5⬚C (measured orally), with a duration
of reported fever ⭓24 h; and (2) ⭓1 of the following signs or symp-
toms: fatigue, headache, generalized malaise, anorexia, abdominal
pain, or constipation; and (3) a positive Widal test result, as indicated
JID 2001;183 (15 June) Effectiveness of Vi Typhoid Vaccine
by the presence, in acute or convalescent serum samples, of antibody
titers ⭓1:80 to mutant S. typhi cells lacking flagellar antigen, together
with antibody titers to nonmutant S. typhi cells greater than titers
to whole cells of Salmonella group A, B, or C, or a ⭓4-fold increase
in antibody titers to flagella-negative S. typhi cells in convalescent,
versus acute, serum specimens.
Data analysis. The major goal of our analysis was to estimate
the protective impact of receipt of Vi vaccine on typhoid fever
during the outbreak. Because students were not randomly assigned
to receive Vi vaccine, it was necessary first to ascertain nonvaccine
factors that were associated with the risk of typhoid fever during
the outbreak, so that these factors could be analytically controlled
in the subsequent analyses of vaccine impact.
To analyze characteristics of students associated with typhoid
fever during the outbreak, we compared the risk of typhoid fever
in those with versus those without the characteristic and statistically
analyzed these differences by the x2 test. To evaluate whether the
characteristics were independently associated with typhoid fever,
we fitted the characteristics as independent variables in a multiple
logistic regression model with typhoid fever as the dependent var-
iable. Coefficients for these independent variables were exponen-
tiated, to estimate the multivariate odds ratios (mORs) for asso-
ciations between each independent variable and the occurrence of
typhoid fever. We used SEs for the coefficients to estimate P values
and to calculate 95% confidence intervals (CIs) for the mORs.
In unadjusted analyses, we assessed the association between ever
having received Vi vaccine and the subsequent occurrence of ty-
phoid fever. In these crude analyses, a case of typhoid fever was
judged to be related to vaccination if the putative date of infection,
defined as 8 days before the onset of symptoms, was on or after
the date of vaccination. This analytic strategy, which classified a
case of typhoid fever as a vaccine failure even if the putative date
of infection occurred on the day of vaccination, before the vaccine
could elicit a protective immune response, was intentionally con-
servative, since our analysis was intended to address the protective
effect of a decision to vaccinate. In this univariate analysis, we
calculated 95% CIs for the protective efficacy by using the method
of Greenland and Robins [22].
Because receipt of Vi vaccine was a time-varying variable (e.g.,
a student who was unvaccinated at the beginning of the epidemic
in 1999 could have been vaccinated subsequently during the epi-
demic), it was necessary to take time into account in analyses of
vaccine protection. To do this, we fitted Cox proportional hazards
models to the data [23], fitting vaccination status as an independent
time-varying variable, together with additional variables (age, sex,
and dining at school) found to be associated with the risk of typhoid
fever in earlier analyses or judged on substantive grounds to be
potential confounders.
Three models were fitted. In the first, designed to evaluate the
protective effect of receipt of Vi vaccine in 1998 or 1999, we in-
cluded the entire cohort of 2111 children. In the second, formulated
to evaluate the protective effect of receipt of Vi vaccine in 1998,
we compared only children who were vaccinated in 1998 versus
those who were never vaccinated. In the third, designed to assess
the protective effect of vaccination during the outbreak in 1999,
we assessed only children who had not been vaccinated in 1998.
In each model, the 74 children who were vaccinated in both 1998
and 1999 were excluded, since the research question of interest was
1777
the protective effect of a single dose of Vi vaccine. As in the simple
analyses, cases of typhoid fever were attributed to vaccination if
the date of onset of symptoms minus 8 days was on or after the
day of vaccination. To estimate the relative rate (RR) of typhoid
fever in Vi vaccinees versus nonvaccinees in each model, we ex-
ponentiated the coefficient for the vaccination variable in the
model. The expression [1 ⫺ RR] ⫻ 100% denoted the protective ef-
fectiveness (PE) of vaccination. P values and 95% CIs for PE were
computed with use of the SEs of the model coefficients. All sta-
tistical tests were interpreted in a 2-tailed fashion, to estimate P
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values and to calculate CIs.
Results
Epidemiologic investigation. The outbreak of typhoid fever
began on 1 May 1999 (figure 1) and peaked in the second and
third weeks of June 1999. The last case was detected on 24
June 1999. In total, 24 students met the case definition for
typhoid fever during the outbreak (14 male and 10 female stu-
dents). Among the 13 typhoid patients who had never been
immunized, the clinical signs and symptoms included fever
(92%), fatigue (85%), malaise (85%), and anorexia (85%).
Among the 11 students who were immunized and developed
typhoid fever, the most common signs and symptoms were an-
orexia (100%), malaise (100%), headache (91%), fatigue (82%),
and fever (73%). Two students who presented to the school
physician and were referred to Xing-An County Hospital had
blood cultures positive for S. typhi. Of the remaining 22 stu-
dents with typhoid fever, the diagnosis was based on a Widal
test of a single blood specimen in 19 students and on Widal
tests of paired blood specimens in 3 students.
Analyses of typhoid fever in relationship to potential risk
factors revealed that older students (17–21 years old) had a
suggestively greater risk for typhoid fever than did students
aged 12–16 years (mOR p 2.0; 95% CI, 0.8–6.1). The risk for
typhoid fever differed little by sex but was significantly lower
among students who ate most meals in their homes rather than
at school (mOR p 0.1; 95% CI, 0.0–0.5).
Effectiveness of Vi vaccine immunization. Of the 2111 stu-
dents attending the Xing-An County school, 1260 (60%) were
immunized on 15 May 1998 during a routine immunization pro-
gram conducted by the Guangxi Anti-Epidemic Center. During
the 1999 Vi vaccine immunization program at the school, an
additional 441 students, who had not earlier received Vi vaccine,
were immunized. In total, 1701 (81%) students who attended the
school at the outset of the outbreak received Vi vaccine. Passive
surveillance for adverse events reported to teachers after Vi vac-
cine immunization in both 1998 and 1999 did not detect serious
local or systemic reactions among the vaccinees.
The crude analyses of Vi vaccine effectiveness showed an
81% (95% CI, 54%–93%) lower risk of typhoid fever during
the outbreak among 1186 students immunized only in 1998, in
comparison with those never vaccinated (table 1). The protec-
tive effectiveness of Vi vaccine administered in 1999 was 79%
1778 Yang et al. JID 2001;183 (15 June)

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Figure 1. Typhoid fever cases, Xing-An County Middle School, Guangxi Zhuang Autonomous Region, People’s Republic of China, by week of
onset, 1 May through 24 June 1999.

(95% CI, 25%–94%). The protective effectiveness among stu- tective effect of Vi vaccine administered in routine public health
dents vaccinated in both 1998 and 1999 was 57% (95% CI, practice in a population with endemic typhoid fever.
⫺221% to 94%), on the basis of 1 case that occurred among Our results warrant careful interpretation. First, only 2 stu-
74 students who received vaccine in both years. For students dents had typhoid fever confirmed by isolation of organisms
vaccinated in either 1998 or 1999, Vi vaccine was associated in blood culture; the remaining students were diagnosed by
with an 80% (95% CI, 55%–91%) lower risk of typhoid fever. using a combination of clinical signs and symptoms of typhoid
In the multivariate analysis of vaccine protection of Vi deliv- fever in conjunction with Widal test results. It is well recognized
ered in 1998, vaccination was associated with 73% (95% CI, that the Widal test can have problems of nonspecificity in pop-
32%–89%) protection against typhoid fever during the outbreak ulations with endemic typhoid fever [25, 26]. However, this
(table 2). Among 441 students immunized in 1999 after the onset feature is unlikely to have been a problem for the interpretation
of the outbreak, Vi vaccine was associated with a 71% (95% CI, of our findings, since nonspecificity of the Widal test in clas-
⫺9% to 92%) lower rate of typhoid fever among immunized sifying outcomes would have been expected to have lowered
students, compared with unimmunized students. Overall, for the estimates of vaccine protection in our study, making our anal-
1701 students immunized in either 1998 or 1999, vaccination with ysis conservative. Moreover, although a single Widal test has
Vi was associated with 71% (95% CI, 34%–87%) protection limited specificity for diagnosing sporadic cases of typhoid in
against typhoid fever during the outbreak. an endemic area where there are many other etiologies of pro-
longed, febrile, typhoid-like illnesses, in the setting of a closed,
presumptively common source outbreak such as the one de-
Discussion
Table 1. Proportion of students developing typhoid fever and protec-
Overall, receipt of a single dose of Vi vaccine in either 1998 tive effectiveness of the Vi polysaccharide vaccine (Vi vaccine), by year
or 1999 was associated with 71% protection against typhoid of vaccination, during the 1999 outbreak of typhoid fever in Xing-An
fever during the Xing-An County Middle School outbreak of County Middle School, Guangxi Province, People’s Republic of China.
1999. The finding that students who were immunized with Vi Year of receipt Proportion of students Protective effectiveness
a
vaccine in May 1998 experienced 73% protection against ty- of Vi vaccine with typhoid fever (95% CI), %
phoid fever during the typhoid fever epidemic ∼1 year later Never vaccinated 13/410 —
b
suggests that the Chinese-produced Vi vaccine affords protec- 1998 only 7/1186 81 (54–93)
c
1999 only 3/441 79 (25–94)
tion similar to that afforded by other available Vi vaccines [14, 1998 and 1999 1/74 57 (⫺221 to 94)
d

24]. Although our analysis showed that Vi vaccine administered 1998 or 1999 11/1701 80 (55–91)
b

during the typhoid fever outbreak in 1999 was associated with a

Protective effectiveness is calculated as [1 ⫺ (risk ratio of typhoid fever in the
a nearly identical level (71%) of protection, our sample was too cited vaccinated group vs. the never vaccinated group)] ⫻ 100%. CI, confidence
small to estimate with adequate statistical precision the pro- interval.
b
P ! .001.
tective effect of vaccine given during the outbreak. To our c
P p .01.
d
knowledge, this is the first controlled demonstration of the pro- P p .39.
JID 2001;183 (15 June) Effectiveness of Vi Typhoid Vaccine 1779

Table 2. Relative rates (RRs) of typhoid fever associated with receipt could be incriminated. Whatever the source of the epidemic,
of Vi polysaccharide vaccine (Vi vaccine) and other characteristics, by
Vi vaccination had notable protective impact.
year of vaccination, Xing-An County, Guangxi Province, People’s Re-
public of China. Our estimates of the field effectiveness of Vi vaccine are con-
sistent with prelicensure field trials of Vi in Nepal and South
RR (95% CI) of typhoid fever associated with the
a
characteristic in Cox regression models, by year Africa [14, 24]. The South African trial enrolled 11,384 children
Vi vaccine was administered aged 5–15 years and noted 61% protection over a 21-month
Characteristic 1998 1999 1998 or 1999 period. In the Nepalese trial, with a 17-month follow-up and
Age, years 6438 participants aged 5–44 years, vaccine efficacy was 76%.
12–16 Referent Referent Referent Our results also are similar to the ∼70% protection observed

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17–21 1.36 (0.48–3.84) 1.77 (0.49–6.42) 1.78 (0.64–4.82) in 2 earlier prelicensure trials of the Chinese-produced Vi vac-
Sex
Female Referent Referent Referent cine [16, 17, 27]. Moreover, our analysis supports findings from
Male 0.95 (0.38–2.39) 2.08 (0.77–5.67) 1.32 (0.58–3.02) a massive outbreak of typhoid fever in Tajikistan in 1996–1997,
Dining location during which mass immunization with Vi vaccine in the course
School Referent Referent Referent
Home 0.17 (0.04–0.76)
b
0.26 (0.06–1.19) 0.15 (0.03–0.64)
c of an epidemic was associated with a decline in typhoid inci-
Vaccination dence, although concurrently controlled evaluations of Vi vac-
No Referent Referent Referent
c b cine protection were not undertaken in that study [28].
Yes 0.27 (0.11–0.68) 0.29 (0.08–1.09) 0.29 (0.13–0.66)
a
An orally administered, live, attenuated Ty21a typhoid vac-
Point estimates (adjusted rate ratios) and 95% confidence intervals (CIs) were
calculated by using Cox proportional hazards models. In these models, the 74
cine also was protective in randomized clinical trials in Egypt,
students who received Vi vaccine in both 1998 and 1999 were excluded. Vaccine Chile, and Indonesia [29–32]. However, the commercially avail-
protective effectiveness estimates, corresponding to the estimates of RRs, were 73% able Ty21a typhoid vaccine must be given in a 3-dose alter-
(32%–89%), 71% (⫺9% to 92%), and 71% (34%–87%) for Vi vaccine given in 1998,
in 1999, and in 1998 or 1999, respectively (see text for further details).
nating-day immunization schedule, which is impractical for
b
P ! .05. most public health programs in developing countries. More-
c
P ! .01. over, Ty21a is thermally labile and therefore requires a strict
cold chain for storage, which also limits the applicability of
this vaccine to public health programs in developing countries.
scribed, patients presenting with typhoid-like illnesses are very In contrast, Vi vaccine can be delivered as a single dose and is
likely to have typhoid fever. In such a setting, a positive Widal more heat resistant. For these practical reasons, 2 typhoid-
test result in conjunction with consistent signs and symptoms endemic countries, China and Vietnam, have decided to invest
would be expected to provide reasonably specific diagnoses of in the technology for local production of Vi vaccine for use in
typhoid fever. Supporting this argument is the observation that national immunization programs.
results for vaccine protection in this analysis did not change There are some data on the postlicensure effectiveness of
when we used a more conservative 1:160 threshold titer for older-generation typhoid vaccines in public health programs.
interpreting anti–O serum antibody titers (with the more strin- One study suggested that older generation whole cell vaccines
gent criterion, the protective effectiveness of Vi given in either conferred useful levels of protection [33]. In addition, analysis
1998 or 1999 was 76% [95% CI, 32%–92%]). of the secular trend of declining incidence of typhoid fever in
Second, norfloxacin was systematically administered to most Thailand during the 1970s and 1980s suggested that the use of
immunized and unimmunized students during the outbreak. Be- the heat-phenol–inactivated whole cell typhoid vaccine in that
cause of the nonselective manner of administration of this an- country reduced the burden of typhoid fever [34].
tibiotic, we would not expect this intervention to have altered Unfortunately, similar data on the performance of newer-gen-
our estimate of vaccine protection. Moreover, when we restricted eration typhoid vaccines in routine use in public health programs
our analysis to the period before this antibiotic intervention, our in populations with endemic typhoid fever are sparse. Indeed, it
estimates of vaccine protection were virtually unchanged. is anomalous that the Vi vaccine, which seems well suited to use
Third, although the point estimates for vaccine protection as a public health measure in typhoid-endemic countries, is cur-
for Vi vaccine given before versus during the school outbreak rently being used in public sector programs only in China. Doc-
of typhoid fever were remarkably similar, the results for vaccine umentation of the effect of Vi vaccine in China’s public health
administered during the epidemic were not statistically signif- program should prove useful to public health decision makers
icant. Future studies are needed to confirm the usefulness of in other countries with high rates of typhoid fever.
giving Vi vaccine during typhoid fever epidemics. Over the past decade, data from outbreaks and laboratory-
Finally, we presumed, on the basis of analyses of student based surveillance have demonstrated infections due to mul-
dining location, that the outbreak described originated from a tidrug-resistant strains of S. typhi [35–37]. The spread of mul-
food handler in the school dining facilities. Surprisingly, despite tidrug-resistant S. typhi strains in typhoid fever–endemic areas
efforts by Guangxi public health workers to identify a point further highlights the need for considering introduction of
source of the outbreak, no food service worker or food item newer-generation typhoid vaccines such as Vi into public health
1780 Yang et al.
programs of developing countries with significant burdens of
typhoid fever [5, 28, 38–41].
Acknowledgments
We thank Zou Yu-Ping and Wang Xiong-Wen for microbiologic
testing of specimens during this outbreak and Wang Ming Liu and Li
Cui Guangxi for confirmation of culture results (all with the Anti-
Epidemic Center Microbiology Laboratory) and Camilo Acosta, Mos-
hadeqque Hossain, Eunsik Park, and Lorenz Von Seidlein (Interna-
tional Vaccine Institute) for scientific review during manuscript
preparation.
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