THE NATIONAL MEDICAL JOURNAL OF INDIAVOL. 23, NO. 2, 2010
Should Vi typhoid vaccine be a part of the
National Immunization Programme in India?
Sur D, Ochiai RL, Bhattacharya SK, Ganguly NK, Ali M, Manna
B, Dutta S, Donner A, Kanungo S, Park JK, Puri MK, Kim DR,
Dutta D, Bhaduri B, Acosta CJ, Clemens JD. (National Institute
of Cholera and Enteric Diseases, Kolkata, India; International
Vaccine Institute, Seoul, South Korea; Indian Council of Medical
Research, Delhi, India; University of Western Ontario, London,
Ontario, Canada.) A cluster-randomized effectiveness trial of Vi
typhoid vaccine in India. N Engl J Med 2009;361:335–44.
A cluster-randomized phase 4 effectiveness trial was conducted to
determine the effectiveness of the Vi typhoid vaccine among the
residents of an urban slum in Kolkata who were >2 years of age.
Eighty geographical clusters were randomized into intervention and
control groups after stratifying the clusters by three characteristics,
i.e. ward, number of individuals <18 years of age (<200 or more) and
number of individuals >18 years of age (<500 or more). The exclusion
criteria were age <2 years, axillary temperature >37.5 oC, and
pregnant and lactating women.
The intervention group received Vi polysaccharide typhoid vaccine
(25 µg/0.5 ml) which was provided in single-dose syringes. The
control group received standard doses of inactivated hepatitis A
vaccine which is available in single-dose vials. The vaccines were
administered by 20 teams at special vaccination centres and the
participants were followed up for 2 years.
Surveillance for adverse events was done by observing the
participants for 30 minutes after the vaccination and 320 participants
were randomly selected for a 3-day home follow up. However, only
63% of these gave consent to participate in the home follow up. All
the participants were monitored for adverse events passively for
The primary and secondary outcomes of the trial were typhoid
fever proven by blood culture and paratyphoid fever, respectively.
Surveillance for enteric fever was done by 5 study clinics. All patients
who reported to the clinic with fever for >3 days were investigated
and a blood culture and sensitivity test was done. Patients were
treated according to the WHO guidelines. Private practitioners were
encouraged to refer all cases with fever to the study clinics. Monitoring
was also done in 2 hospitals near the study area. Survey for serological
response was done in 320 subjects.
At baseline, there were 62 756 residents in the 80 trial clusters, of
whom 61 280 were eligible, according to the age criteria for
participation in the trial. A total of 37 673 subjects were vaccinated:
18 869 (Vi vaccine) and 18 804 (hepatitis A vaccine). The two study
groups at baseline were comparable with respect to age, sex, education,
socioeconomic status, sanitary conditions, etc. The mean rate of
vaccine coverage of the Vi vaccine group (61%) was similar to the
hepatitis A vaccine group (60%). Typhoid fever was diagnosed in 34
participants in the Vi vaccine group compared with 96 participants in
the hepatitis A vaccine group. Therefore, the protective effectiveness
for the Vi vaccine was 61% (95% CI: 41%–75%; p<0.001). Age-wise
analysis showed the rate of protective effectiveness for the Vi vaccine
to be 80% (95% CI: 53%–91%) in children <5 years of age, 56%
(95% CI: 18%–77%) in children 5–14 years and 46% (95% CI: 43%–
79%) in subjects >14 years of age. In an adjusted model, protective
effectiveness against typhoid fever among unvaccinated residents in
the Vi vaccine clusters was 44% (95% CI: 2%–69%; p=0.04). Para-
typhoid fever was diagnosed in 54 participants in the Vi vaccine
group compared with 49 in the hepatitis A vaccine group.
The mean (SD) baseline titre of serum IgG Vi antibody in the Vi
vaccine group was 118.2 (2.2). The titres were significantly raised in
the Vi vaccine group at 6 weeks (2505.3 [4.2]) and 2 years (842.6
[4.3]) after vaccination. However, meaningful analysis of samples
from young children was not possible due to only a few participants
<5 years of age who had blood testing after vaccination. No serious
adverse events were found in either of the groups. The authors
concluded that the potential for combined direct and indirect protection
by Vi vaccine should be considered in future deliberations about
introducing this vaccine in areas where typhoid fever is endemic.
Conservative estimates by WHO give the annual global incidence
of typhoid fever as 21 million cases of which 1%–4% end fatally.
An estimated 90% of these deaths occur in Asia. The annual
incidence of typhoid fever in India in 2003 was 214.2 per
100 000.1 The old, heat-inactivated, whole-cell vaccine showed
protective efficacy rates, which, in controlled studies, ranged
between 51% and 67%. However, the vaccine was associated with
frequent adverse reactions. 2 Currently, 2 new-generation typhoid
vaccines have replaced the older vaccines. In view of the continued
high burden of typhoid fever1,3 and increasing antibiotic resistance,4
and given the safety, efficacy, feasibility and affordability of the
2 licensed vaccines (Vi and Ty21a), countries should consider the
programmatic use of typhoid vaccines for controlling endemic
disease.2 This study addressed a pertinent issue about the
effectiveness of typhoid vaccines in a programmatic mode.
The main strength of this study was that it was conducted in a
large urban slum population where the incidence of typhoid fever
is high because of poor hygienic conditions and this is a likely
target population for such a vaccination programme. Thus, it was
a good, pragmatic trial.
However, critical analysis of the study revealed certain
methodological issues. In this trial, to ascertain the primary
outcome variable, i.e. typhoid fever, passive surveillance was
done to capture individuals with fever for >3 days. Previous
similar studies in Nepal5 and South Africa6 conducted active fever
surveys which is a more appropriate method. Besides, the
methodology was not explicit. It was mentioned that private
practitioners in the study area were encouraged to refer cases of
fever and monitoring was also done in 2 hospitals. However, there
is no information about the cases referred by private practitioners
and other hospitals in the area so as to assure readers that all the
cases of fever could be captured through the system. In that case
the ascertainment of the primary outcome variable is doubtful.
Another limitation is the non-identical package of Vi-typhoid
vaccine and hepatitis A vaccine. Despite efforts made to blind
vaccinators, this could have biased the study results. The amount
of blood collected for culture and sensitivity was not mentioned.
Coffee and progression of liver disease
Freedman ND, Everhart JE, Lindsay KL, Ghany MG, Curto TM,
Shiffman ML, Lee WM, Lok AS, Di Bisceglie AM, Bonkovosky
HL, Hoefs JC, Dienstag JL, Morishima C, Abnet CC, Sinha R and
the HALT-C trial group. (Nutritional Epidemiology Branch,
Division of Cancer Epidemiology and Genetics, National Cancer
Institute, National Institutes of Health, Department of Health and
Human Services, Rockville, Maryland; Division of Digestive
Diseases and Nutrition, National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of Health, Department
of Health and Human Services, Bethesda, Maryland; Division of
Gastrointestinal and Liver Diseases, Keck School of Medicine,
University of Southern California, Los Angeles; Liver Diseases
Branch, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, Department of Health and
Human Services, Bethesda, Maryland; New England Research
Institutes, Watertown, Massachusetts; Hepatology Section,
Virginia Commonwealth University Medical Center, Richmond,
Virginia; Division of Digestive and Liver Diseases, University of
Texas Southwestern Medical Center, Dallas, Texas; Division of
Gastroenterology, University of Michigan Medical Center, Ann
Arbor, Michigan; Division of Gastroenterology and Hepatology,
St Louis University School of Medicine, St Louis, Missouri;
Departments of Medicine and Molecular and Structural Biology
and The Liver–Biliary–Pancreatic Center, University of
Connecticut Health Center, Farmington, Connecticut; Division of
Gastroenterology, University of California—Irvine, Irvine,
California; Gastrointestinal Unit (Medical Services),
Massachusetts General Hospital and the Department of Medicine,
Harvard Medical School, Boston, Massachusetts; Virology
Division, Department of Laboratory Medicine, University of
Washington, Seattle, Washington, USA.) Coffee intake is
associated with lower rates of liver disease progression in chronic
hepatitis C. Hepatology 2009;50:1360–9.
Hepatitis C virus (HCV) is a major cause of chronic liver disease and
hepatocellular carcinoma. The prevalence of HCV infection in India
has been reported to be around 0.8% in the rural general population1
and 0.7%–1.8% among blood donors.2 HCV is the aetiological agent
in 14%–26% of patients with cirrhosis and 14%–20% of liver cancers
This is important because the sensitivity of blood culture depends
on the volume of blood injected into the culture medium. For
schoolchildren and adults the recommended volume is 10–15 ml
and it is 2–4 ml for toddlers and preschool children.7,8 If the
vaccinators knew which group the participants belonged to, this
could have introduced a bias during follow up. The vaccine
manufacturers did the serological tests for the study participants
and it remains unclear whether the assessment was blinded or not.
Finally, it was concluded that Vi typhoid vaccine may contribute
to herd immunity. Even though the vaccine protectiveness among
the unvaccinated group was 44% (2%–69%), the confidence
interval is very wide and it is closer to the null value.
Besides these limitations, there are other factors that should be
considered before introducing a new vaccine into a National
Immunization Programme.9 According to WHO, first, the disease
should be a public health problem. Is typhoid fever a high priority
public health problem in India where the leading causes of under-
5 mortality are diarrhoea (20%) and respiratory infection (19%)?10
Moreover, the introduction of this vaccine would mean an
additional visit after 2 years of age, since no vaccines are given at
that age under the Universal Immunization Programme (UIP).
Currently, immunization coverage in India is still dismal and has
high dropout rates. According to the National Family Health
Survey-3 (NFHS-3), only 43.5% of children are fully immunized.11
What would be the impact of the addition of another vaccine on
the immunization programme?
Is the typhoid vaccine a good investment? In addition to
feasibility studies, a cost-effectiveness analysis would be needed
in view of multiple health issues competing for scarce resources
1 Ochiai RL, Acosta CJ, Danovaro-Holliday MC, Baiqing D, Bhattacharya SK, Agtini
MD, et al.; Domi Typhoid Study Group. A study of typhoid fever in five Asian
countries: Disease burden and implications for controls. Bull World Health Organ
2 Typhoid vaccines. Wkly Epidemiol Rec 2000;75:257–64.
3 National Health Profile 2008. Government of India. Available at http://cbhidghs.nic.in/
writereaddata/mainlinkFile/Health%20Status%20Indicators.pdf (accessed on 10
4 Bhan MK, Bahl R, Bhatnagar S. Typhoid and paratyphoid fever. Lancet 2005;366:
5 Acharya IL, Lowe CU, Thapa R, Gurubacharya VL, Shrestha MB, Cadoz M, et al.
Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of
Salmonella typhi. A preliminary report. N Engl J Med 1987;317:1101–4.
6 Klugman KP, Gilbertson IT, Koornhof HJ, Robbins JB, Schneerson R, Schulz D, et
al. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever.
7 Wain J, Diep TS, Ho VA, Walsh AM, Nguyen TT, Parry CM, et al. Quantitation of
bacteria in blood of typhoid fever patients and relationship between counts and
clinical features, transmissibility, and antibiotic resistance. J Clin Microbiol
8 Gasem MH, Dolmans WM, Isbandrio BB, Wahyono H, Keuter M, Djokomoeljanto
R. Culture of Salmonella typhi and Salmonella paratyphi from blood and bone
marrow in suspected typhoid fever. Trop Geogr Med 1995;47:164–7.
9 Assessing new vaccines for national immunization programmes: A framework to
assist decision makers. Immunization Focus. World Health Organization. Regional
Office for the Western Pacific Manila. Available at http://www.wpro.who.int/
vaccines.pdf (accessed on 16 January 2010).
10 Mortality country fact sheet 2006. World Health Organization. Available at http://
www.who.int/whosis/mort/profiles/mort_searo_ind_india.pdf (accessed on 13
11 International Institute for Population Sciences (IIPS) and Macro International. 2007.
National Family Health Survey (NFHS-3), 2005–06: India. Mumbai:IIPS. Available
at http://www.nfhsindia.org/pdf/IN.pdf (accessed on 13 November 2009).
Centre for Community Medicine
All India Institute of Medical Sciences