Vaccines for preventing typhoid fever

  • Review
  • Intervention

Authors


Abstract

Background

Typhoid fever and paratyphoid fever continue to be important causes of illness and death, particularly among children and adolescents in south-central and southeast Asia. Two typhoid vaccines are commercially available, Ty21a (oral) and Vi polysaccharide (parenteral), but neither is used routinely. Other vaccines, such as a new, modified, conjugated Vi vaccine called Vi-rEPA, are in development.

Objectives

To evaluate the efficacy and adverse effects of vaccines used to prevent typhoid fever.

Search methods

In June 2013, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, EMBASE, LILACS, and mRCT. We also searched relevant conference proceedings up to 2013 and scanned the reference lists of all included trials.

Selection criteria

Randomized and quasi-randomized controlled trials (RCTs) comparing typhoid fever vaccines with other typhoid fever vaccines or with an inactive agent (placebo or vaccine for a different disease).

Data collection and analysis

Two review authors independently applied inclusion criteria and extracted data. We computed vaccine efficacy per year of follow-up and cumulative three-year efficacy, stratifying for vaccine type and dose. The outcome addressed was typhoid fever, defined as isolation of Salmonella typhi in blood. We calculated risk ratios (RRs) and efficacy (1-RR as a percentage) with 95% confidence intervals (CIs).

Main results

In total, 18 RCTs were included in this review; 12 evaluated efficacy (Ty21a: five trials; Vi polysaccharide: six trials; Vi-rEPA: one trial), and 11 reported on adverse events.

Ty21a vaccine (oral vaccine, three doses)

A three-dose schedule of Ty21a vaccine prevents around one-third to one-half of typhoid cases in the first two years after vaccination (Year 1: 35%, 95% CI 8% to 54%; Year 2: 58%, 95% CI 40% to 71%; one trial, 20,543 participants; moderate quality evidence; data taken from a single trial conducted in Indonesia in the 1980s). No benefit was detected in the third year after vaccination. Four additional cluster-RCTs have been conducted, but the study authors did not adjust for clustering.

Compared with placebo, this vaccine was not associated with more participants with vomiting, diarrhoea, nausea or abdominal pain (four trials, 2066 participants; moderate quality evidence) headache, or rash (two trials, 1190 participants; moderate quality evidence); however, fever (four trials, 2066 participants; moderate quality evidence) was more common in the vaccine group.

Vi polysaccharide vaccine (injection, one dose)

A single dose of Vi polysaccharide vaccine prevents around two-thirds of typhoid cases in the first year after vaccination (Year 1: 69%, 95% CI 63% to 74%; three trials, 99,979 participants; high quality evidence). In Year 2, the trial results were more variable, with the vaccine preventing between 45% and 69% of typhoid cases (Year 2: 59%, 95% CI 45% to 69%; four trials, 194,969 participants; moderate quality evidence). The three-year cumulative efficacy of the vaccine is around 55% (95% CI 30% to 70%; 11,384 participants, one trial; moderate quality evidence). These data are taken from a single trial in South Africa in the 1980s.

Compared with placebo, this vaccine was not associated with more participants with fever (four trials, 133,038 participants; moderate quality evidence) or erythema (three trials, 132,261 participants; low quality evidence); however, swelling (three trials, 1767 participants; moderate quality evidence) and pain at the injection site (one trial, 667 participants; moderate quality evidence) were more common in the vaccine group.

Vi-rEPA vaccine (two doses)

Administration of two doses of the Vi-rEPA vaccine prevents between 50% and 96% of typhoid cases during the first two years after vaccination (Year 1: 94%, 95% CI 75% to 99%; Year 2: 87%, 95% CI 56% to 96%; one trial, 12,008 participants; moderate quality evidence). These data are taken from a single trial with children 2 to 5 years of age conducted in Vietnam.

Compared with placebo, the first and second doses of this vaccine were not associated with increased risk of adverse events. The first dose of this vaccine was not associated with fever (2 studies, 12,209 participants; low quality evidence), erythema (two trials, 12,209 participants; moderate quality evidence) or swelling at the injection site (two trials, 12,209 participants; moderate quality evidence). The second dose of this vaccine was not associated with fever (two trials, 11,286 participants; low quality evidence), erythema (two trials, 11,286 participants; moderate quality evidence) and swelling at the injection site (two trials, 11,286 participants; moderate quality evidence).

Authors' conclusions

The licensed Ty21a and Vi polysaccharide vaccines are efficacious. The new and unlicensed Vi-rEPA vaccine is as efficacious and may confer longer immunity.

Plain language summary

Ty21a and Vi polysaccharide vaccines are effective in reducing typhoid fever; new vaccines are promising

Typhoid fever is a bacterial infection found mainly among children and adolescents in south and east Asia, Africa, Latin America and the Caribbean. Typhoid fever is spread by food, drink, or contaminated water. It is characterized by fever, abdominal symptoms, headache, loss of appetite, cough, weakness, sore throat, dizziness and muscle pains. The infection also sometimes causes psychosis and confusion. Mortality varies and can reach 10% of cases. Treatment normally consists of antibiotics, but problems with drug-resistant strains have been reported. Improved sanitation and food hygiene are important control measures. However, these are associated with socioeconomic progress that has been slow in most affected areas. Therefore vaccination is an effective way to try to prevent this disease. The review found 18 trials (17 with usable data): Six evaluated vaccine effectiveness only; six evaluated vaccine effectiveness and adverse events; and six provided data only on adverse events. The two major vaccines currently licensed for use, Ty21a and Vi polysaccharide, were effective in reducing typhoid fever; adverse events such as nausea, vomiting and fever were rare. Other vaccines, such as a new, modified, conjugated Vi vaccine called Vi-rEPA, are in development and appear promising. A vaccine that could be given to infants would be helpful as they are probably at increased risk of this infection.

எளியமொழிச் சுருக்கம்

டைபாய்ட் காய்ச்சலை குறைப்பதில் Ty21a மற்றும் Vi பாலிசாக்ரைட் தடுப்பு மருந்துகள் திறன் மிக்கவையாக உள்ளன; புதிய தடுப்பு மருந்துகள் நம்பிக்கையளிக்கின்றன.

டைபாய்ட் காய்ச்சல் என்பது, தெற்கு மற்றும் கிழக்கு ஆசியா, ஆப்பிரிக்கா, லத்தீன் அமெரிக்கா மற்றும் கரீபியன் பகுதிகளிலுள்ள குழந்தைகள் மற்றும் வளர் பருவத்தினரிடையே முக்கியமாக காணப்படும் ஒரு பாக்டீரியா தொற்றாகும். டைபாய்ட் காய்ச்சல் உணவு, பானம் அல்லது மாசுபட்ட குடிநீர் மூலம் பரவும். காய்ச்சல், வயிற்று பிரச்சனை அறிகுறிகள், தலைவலி, பசியின்மை, இருமல், பலவீனம், தொண்டைக் கட்டு, தலைச்சுற்றல் மற்றும் தசை வலிகள் போன்றவற்றை கொண்டிருக்கும். சிலசமயங்களில் இந்த தொற்று, உளநோய் மற்றும் குழப்பத்தை ஏற்படுத்தக் கூடும். 10% வரை இறப்பு ஏற்படக் கூடும், மற்றும் இது வேறுப்படும். பொதுவாக, சிகிச்சையானது தடுப்பு மருந்துகளை கொண்டிருக்கும். ஆனால், மருந்து எதிர்ப்பு பிரச்சனைகள் அறிக்கையிடப்பட்டுள்ளன. மேம்படுத்தப்பட்ட சுகாதாரம் மற்றும் சுத்தமான உணவு இரண்டும் மிக முக்கியமான தடுப்பு முறைகளாகும். எனினும், இவை, டைபாய்ட் மிகவும் பாதித்துள்ள பகுதிகளில் மெதுவாக முன்னேறும் அவற்றின் சமூக-பொருளாதாரத்தோடு தொடர்புடையதாக உள்ளன. ஆதலால் இந்த நோயை தடுப்பதற்கான திறன் மிக்க வழி தடுப்பு மருந்தாகும். இந்த திறனாய்வு 18 சோதனைகளை (பயன்படுத்த தகுந்த தரவுடன் 17 ஆய்வுகள் ) கண்டது. ஆறு ஆய்வுகள் தடுப்பு மருந்தின் திறனை மட்டும் ஆராய்ந்தன; ஆறு ஆய்வுகள் தடுப்பு மருந்தின் திறன் மற்றும் பாதகமான நிகழ்வுகளையும்; மற்றும் ஆறு ஆய்வுகள் பாதகமான நிகழ்வுகளின்மேலான தரவை மட்டும் ஆராய்ந்தன. தற்போது, பயன்பாட்டிற்கு உரிமம் உள்ள இரண்டு முக்கிய தடுப்பு மருந்துகள் Ty21a மற்றும் Vi பாலிசாக்ரைட் ஆகியவை டைபாய்ட் காய்ச்சலை குறைப்பதில் திறன் மிக்கவையாக உள்ளன; குமட்டல், வாந்தி மற்றும் காய்ச்சல் போன்ற பாதகமான விளைவுகள் மிகவும் அரிதாக இருந்தன. Vi-rEPA என்று அழைக்கப்படும் Vi இணைப்பு தடுப்பு மருந்து போன்ற புதிய,மாற்றியமைக்கப்பட்ட பிற தடுப்பு மருந்துகள் உருவாக்கப்பட்டு கொண்டிருக்கின்றன மற்றும் இவை நம்பிக்கை அளிப்பதாக உள்ளன. இந்த தொற்றின் அதிகரித்த அபாயத்தைக் கொண்டிருக்கும் குழந்தைகளுக்கு அளிக்கப்படுவதற்கு ஒரு தடுப்பு மருந்து இருந்தால் உதவியாக இருக்கும்.

மொழிபெயர்ப்பு குறிப்புகள்

மொழிபெயர்ப்பாளர்: சிந்தியா ஸ்வர்ணலதா ஸ்ரீகேசவன்

Summary of findings(Explanation)

Summary of findings for the main comparison. Ty21a vaccine (three doses) compared with control; efficacy for preventing typhoid fever
  1. 1The incidence of typhoid in a medium -risk setting is taken from the control group in a study from china (Yang 2001 CHN).The incidence of typhoid in a high-risk setting is taken from a study in India (Sur 2009 IND). This is consistent with the incidence levels described by a global epidemiological study (Crump 2004).
    2No serious risk of bias detected.
    3No serious inconsistency: The result was consistent across the two trials (I2 = 0).
    4Downgraded by 1 for indirectness: The vaccine has been evaluated only in trials from one endemic setting (Indonesia).
    5No serious imprecision: The result is statistically significant with a narrow 95% confidence interval. The meta-analysis is adequately powered to detect this effect.
    6No serious inconsistency: The result was consistent across the two trials (I2 = 1%).
    7No serious inconsistencies: The results were consistent across the 5 trials (I2 = 0).
    8Downgraded by 1 for serious imprecision: The result is not statistically significant.
    9No serious inconsistency: The results were consistent across the three trials (I2 = 0).
    10No serious inconsistency.
    11Downgraded by 1 for indirectness: The vaccine has been evaluated only in trials from high-incidence settings (Indonesia and Thailand).
    12No serious imprecision: The result is statistically significant with a narrow 95% confidence interval.

Ty21a vaccine (3 doses) compared with control; efficacy for preventing typhoid fever
Patient or population: adults and children aged 5 years of age and older
Settings: any
Intervention: Ty21a vaccine (3 doses)
Comparison: placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Placebo Ty21a vaccine
Incidence of typhoid fever, Year 1 Moderate1 RR 0.65
(0.46 to 0.92)
20,543
(1 study, 2 arms)
⊕⊕⊕⊝
moderate 2,3,4,5
Additional cluster-randomized studies have evaluated this vaccine but did not adjust for the effect of clustering and therefore were not included in the meta-analysis
4 per 10,000 3 per 10,000
(2 to 4)
High1
59 per 10,000 38.4 per 10,000
(27.1 to 54.3)
Incidence of typhoid fever, Year 2 Moderate1 RR 0.42
(0.29 to 0.6)
20,543
(1 study, 2 arms)
⊕⊕⊕⊝
moderate 2,4,5,6
 
4 per 10,000 1.7 per 10,000
(1.2 to 2.4)
High1
59 per 10,000 24.8 per 10,000
(17.1 to 35.4)
Serious adverse eventsSee commentSee commentNot estimable2620
(3 studies, 5 arms)
See commentNo serious adverse events were reported
Fever 17 per 1000 25 per 1000
(14 to 45)
RR 1.53
(0.86 to 2.72)
2066
(2 studies, 4 arms)
⊕⊕⊕⊝
moderate 2,7,8
 
Rash 4 per 1000 8 per 1000
(2 to 28)
RR 1.89
(0.56 to 6.43)
1190
(2 studies, 4 arms)
⊕⊕⊕⊝
moderate 2,8,9
 
Vomiting 25 per 1000 15 per 1000
(7 to 31)
RR 0.61
(0.3 to 1.24)
2066
(1 study, 2 arms)
⊕⊕⊕⊝
moderate 2,8,10
 
Any mild adverse event 70 per 1000 117 per 1000
(72 to 191)
RR 1.67
(1.03 to 2.72)
1360
(2 studies, 3 arms)
⊕⊕⊕⊝
moderate 2,11,12
 
*The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence.
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 2 Vi polysaccharide vaccine (one dose) compared with control; efficacy for preventing typhoid fever

Summary of findings 2. Vi polysaccharide vaccine (one dose) compared with control; efficacy for preventing typhoid fever
  1. 1The incidence of typhoid in a medium-risk setting is taken from the control group in a study from china (Yang 2001 CHN).The incidence of typhoid in a high-risk setting is taken from a study in India (Sur 2009 IND). This is consistent with the incidence levels described by a global epidemiological study (Crump 2004).
    2No serious risk of bias detected.
    3No serious inconsistency: The result was consistent across all three trials (I2 = 0%).
    4No serious indirectness: The vaccine has been evaluated in trials from Nepal, South Africa and China. Of note, none of the trials were conducted in travellers from nonendemic settings, and all three trials excluded children younger than 2 years of age and pregnant women.
    5No serious imprecision: The result is statistically significant with a narrow 95% CI. The meta-analysis is adequately powered to detect this effect.
    6Downgraded by 1 for inconsistency: The magnitude of the protective effect varied between trials from 34% to 69% (I2 = 72%). The reasons for this are not clear; one potential factor may be the different age groups included in the trials, with the trial by (Khan 2012 PAK) suggesting lower protective effect in children < 5 years of age.
    7No serious indirectness: The vaccine has been evaluated in trials from endemic settings (India, Pakistan, China and South Africa).
    8No serious indirectness: The vaccine has been evaluated in trials from endemic settings (China) and in one trial conducted in a nonendemic setting (USA).
    9Downgraded by 1 for serious imprecision: The result is not statistically significant.

    10Downgraded by 1 for inconsistency (I2 = 63%).

Vi polysaccharide vaccine (1 dose) compared with control; efficacy for preventing typhoid fever
Patient or population: adults and children of 2 years of age and older
Settings: any
Intervention: Vi polysaccharide vaccine (1 dose)
Comparison: control; efficacy
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control; efficacy Vi polysaccharide vaccine (1 dose)
Incidence of typhoid feverYear 1
Blood culture
Moderate1 RR 0.31
(0.26 to 0.37)
99,797
(3 studies)
⊕⊕⊕⊕
high 2,3,4,5
 
4 per 10,000 1.2 per 10,000
(1.0 to 1.5)
High1
51 per 10,000 15.8 per 10,000
(13.3 to 18.9)
Incidence of typhoid feverYear 2 Moderate1 RR 0.41
(0.31 to 0.55)
194,969
(4 studies)
⊕⊕⊕⊝
moderate 2,6,7,5
 
4 per 10,000 1.6 per 10,000
(1.2 to 2.2)
High1
51 per 10,000 20.9 per 10,000
(15.8 to 28.1)
Serious adverse eventsSee commentSee commentNot estimable133,240
(4 studies)
See commentNo serious adverse events were reported
Fever 5 per 1000 5 per 1000
(3 to 8)
RR 0.93
(0.57 to 1.53)
133,038
(4 studies)
⊕⊕⊕⊝
moderate 2,3,8,9
 
Erythema 5 per 1000 6 per 1000
(2 to 22)
RR 1.15
(0.33 to 4.03)
132,261
(3 studies)
⊕⊕⊕⊝
low 2, 10, 9
 
*The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Summary of findings 3 Vi-rEPA vaccine (two doses) compared with control; efficacy for preventing typhoid fever

Summary of findings 3. Vi-rEPA vaccine (two doses) compared with control; efficacy for preventing typhoid fever
  1. 1The incidence of typhoid in a medium -risk setting is taken from the control group in a study from china (Yang 2001 CHN).The incidence of typhoid in a high-risk setting is taken from a study in India (Sur 2009 IND). This is consistent with the incidence levels described by a global epidemiological study (Crump 2004).
    2No serious risk of bias detected.
    3Downgraded by 1 for indirectness: The vaccine has been evaluated by only one trial in children 2 to 5 years of age in a high-incidence setting (Vietnam).
    4Downgraded by 1 for serious inconsistency: I2 = 89%.
    5Downgraded by 1 for serious imprecision: The result is not statistically significant.

Vi-rEPA vaccine (2 doses) compared with control; efficacy for preventing typhoid fever
Patient or population: adults and children of 2 years of age and older
Settings: any
Intervention: Vi-rEPA vaccine (2 doses)
Comparison: control; efficacy
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control; efficacy Vi-rEPA vaccine (2 doses)
Incidence of typhoid feverYear 1
Follow-up: 1 year
Moderate1 RR 0.06
(0.01 to 0.25)
12,008
(1 study)
⊕⊕⊕⊝
moderate 2,3
 
4 per 10,000 024 per 10,000
(0.04 to 1)
High1
59 per 10,000 3.5 per 10,000
(0.6 to 14.8)
Incidence of typhoid feverYear 2 Moderate1 RR 0.13
(0.04 to 0.44)
12,008
(1 study)
⊕⊕⊕⊝
moderate 3
 
4 per 10,000 0.52 per 10,000
(0.16 to 1.8)
High1
59 per 10,000 7.7 per 10,000
(2.4 to 26.0)
Serious adverse eventsSee commentSee commentNot estimable12,209
(2 studies)
See commentNo serious adverse events were reported
Fever after Vi-rEPA (dose1) 9 per 1000 14 per 1000
(5 to 39)
RR 1.55
(0.57 to 4.23)
12,209
(2 studies)
⊕⊕⊝⊝
low 4,5
 
Erythema after Vi-rEPA (dose 1) 0 per 1000 0 per 1000
(0 to 5)
RR 3.03
(0.32 to 28.64)
12,209
(2 studies)
⊕⊕⊕⊝
moderate 5
 
Swelling at injection site after Vi-rEPA (dose 1) 0 per 1000 0 per 1000
(0 to 2)
RR 1.01
(0.15 to 7.03)
12,209
(2 studies)
⊕⊕⊕⊝
moderate 5
 
*The basis for the assumed risk (eg, the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio.
GRADE Working Group grades of evidence:
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

Description of the condition

Epidemiology

Typhoid fever remains an important global public health problem. It is estimated that typhoid fever has caused 21.7 million illnesses and 217,000 deaths worldwide (Crump 2004). However, this is likely to be a conservative estimate because availability of diagnostic testing and surveillance is limited, and the burden of typhoid fever is unknown in many developing countries (Crump 2010).

The highest burden of typhoid fever is seen in south-central and south-eastern Asia (Crump 2004). Recent large population-based surveillance studies conducted in five Asian countries (China, India, Indonesia, Pakistan and Vietnam) have confirmed the high incidence of typhoid fever in the region (Ochiai 2008). Typhoid fever incidence in sub-Saharan Africa is poorly described; historically, typhoid fever within the region has been thought to occur in the form of outbreaks rather than as endemic disease. However, a recent population-based surveillance study conducted in Kenya found a high incidence of typhoid fever among children in urban settings, with rates similar to those seen in south-central and south-eastern Asia (Breiman 2012). Typhoid fever is rare in industrialized nations, although travellers to endemic countries are at risk of acquiring the disease (Bennish 1995).

Until recently, the common view was that typhoid fever mainly affects children of school age and adults. However, it is now recognized that typhoid fever is an important cause of morbidity among younger children in areas of high incidence (Ochiai 2008; Sinha 1999; Saha 2001).

Clinical features

Typhoid fever is a systemic infection caused by the Gram-negative bacterium Salmonella enterica serotype typhi (S. typhi). S. typhi is spread by food, drink or water contaminated by faecal or urinary carriers excreting the bacteria. After ingestion, the bacteria spread from the intestine via the blood, where they multiply to the intestinal lymph nodes, liver and spleen. Typhoid fever is characterized by fever and abdominal symptoms. Nonspecific symptoms such as chills, perspiration, diarrhoea or constipation, headache, anorexia, cough, weakness, sore throat, dizziness and muscle pains are frequently present before the onset of fever in typhoid. Neuropsychiatric manifestations, including psychosis and confusion, occur in 5% to 10% of those with typhoid fever. Other symptoms include bradycardia, rose spots, hepatomegaly, and splenomegaly (Mandell 2005).

Complications occur in 10% to 15% of patients, usually in the third and fourth weeks of infection. The most important complications are gastrointestinal bleeding, intestinal perforation and typhoid encephalopathy. Gastrointestinal bleeding is the most common, occurring in up to 10% of patients (Parry 2002). Estimates of case-fatality rates in typhoid fever range from 1% to 4%; fatality rates in children younger than 4 years of age are 10 times higher than in older children. In untreated cases, the fatality rates may rise to 10% to 20% (Bhutta, 1996).

Diagnosis and treatment

Confirmation of typhoid fever requires isolation of S. typhi from blood, bone marrow, stool or duodenal fluid; blood culture is the most common method of diagnosis. The Widal test identifies the agglutinating antibodies against the O (somatic) and H (flagellar) S. typhi antigens, which appear a week to 10 days after disease onset. However, the high numbers of false-positive and false-negative Widal test results limit its clinical usefulness (Bhan 2005).

Typhoid fever is treated with antibiotics. Increased case-fatality rates have been associated with multidrug-resistant strains and delays in antimicrobial therapy. Chloramphenicol was for a long time the preferred treatment for typhoid fever, but owing to substantial relapse rates and the development of bacterial resistance during the 1970s and 1980s, this drug was widely replaced by ampicillin and co-trimoxazole. More recently, increasing resistance to the latter antibiotics has prompted the use of quinolone derivatives and third-generation cephalosporins (WHO 2008).

Potential control measures

As humans are the only source of infection and because of the route of transmission, improved sanitation and food hygiene are important control measures. However, these measures are associated with socioeconomic progress that has been slow in most endemic areas. Furthermore, achieving control of typhoid fever by antimicrobial treatment alone requires well-functioning medical services and is hindered by the increasing problem of antibiotic-resistant S. typhi. Therefore vaccination against typhoid fever is a key control measure in high-risk areas (WHO 2008). In addition to the populations residing in areas in which typhoid fever is endemic, travellers to these regions as well as household contacts of typhoid fever carriers and laboratory workers may benefit from an effective vaccine (Parry 2002).

Description of the intervention

Typhoid vaccines

Vaccination against typhoid fever is a key control measure; however, although they have been evaluated among populations in endemic middle- and low-income countries, typhoid fever vaccines have been used predominantly among travellers from high-income countries. This situation is changing, thanks to the availability of high-quality burden of disease data from endemic countries (Ochiai 2008) and to the experience of typhoid vaccination programs in Thailand, China, Vietnam and India (DeRoeck, 2008), and of vaccine demonstration projects in five Asian countries (Ochiai, 2007). A 2008 World Health Organization (WHO) position paper on the use of typhoid vaccines concluded that given the continued high burden of disease and increasing antibiotic resistance, countries should consider the programmatic use of typhoid vaccines for controlling endemic disease (WHO 2008). Despite this recommendation, very few typhoid endemic countries have implemented a typhoid vaccination programme (Maurice, 2012).

Two typhoid vaccines are currently available internationally: the live oral Ty21a vaccine (an attenuated strain of S. typhi) and the parenteral Vi polysaccharide (based on the purified capsular polysaccharide S. typhi Vi antigen).

Researchers are working to develop a low-cost typhoid vaccine that is effective in children younger than two years, and that can therefore be incorporated into the infant EPI (Expanded Programme on Immunization) schedule. Typhoid vaccine development is currently moving in two main directions: the development of Vi conjugate vaccines, and the development of an improved live oral vaccine (WHO 2008).

Inactivated whole-cell typhoid vaccine

Vaccines of this type were introduced in 1896 (WHO 2005). Their efficacy was established only in 1960 in controlled trials in Yugoslavia, the Soviet Union, Poland and Guyana. The 1998 version of this Cochrane Review demonstrated that two doses of this type of vaccine resulted in 73% efficacy over three years (95% confidence interval 65% to 80%) (Engels 1998a). Different methods of inactivating cells of S. typhi have been used to prepare these vaccines: acetone-inactivated, alcohol-inactivated or heat-inactivated and phenol preserved. In field trials, the vaccine has been associated with fever and systemic reactions in 9% to 34% of recipients, and with short absences from work or school in 2% to 17% of cases (WHO 2000). Therefore, the inactivated whole-cell typhoid vaccine is considered unsuitable for use as a public health vaccine, and, although licensed, it is no longer available for use (Garmory 2002). Consequently, we have not included killed whole-cell vaccines in this update.

Ty2la vaccine

This live oral vaccine is available as an enteric-coated capsule or liquid formulation. It is given in three doses every other day and is approved for use in children at least 5 years of age. It elicits protection that starts 10 to 14 days after the third dose. Travellers should be revaccinated annually, and those living in disease endemic areas every three years. A theoretical question associated with the Ty21a vaccine is whether it reverts to virulence; however, such hypothetical effects have never been documented in any of the multiple large field trials conducted (WHO 2008).

The 2007 version of this Cochrane review found that compared with placebo, the TY21a vaccine provided statistically significant protection over the first three years following vaccination, and that this vaccine was not associated with an increased rate of mild adverse events (Fraser 2007a).

Vi polysaccharide vaccine

The Vi polysaccharide vaccine is given as a single parenteral dose. Protection begins seven days after injection, and maximum protection is reached 28 days after injection, when the highest antibody concentration is attained (Garmory 2002). This vaccine is approved for persons of 2 years of age and older. Revaccination every three years is recommended.

The 2007 version of this Cochrane review found that this vaccine provided protection in Year 1 and in Year 2 but not in Year 3 (Fraser 2007a).

Vi-rEPA vaccine

A new, modified Vi vaccine conjugated to a nontoxic recombinant Pseudomonas aeruginosa exotoxin A (rEPA) has been evaluated in a randomized controlled trial (RCT) among children 2 to 5 years of age. This vaccine (Vi-rEPA) has the potential of being immunogenic in infants younger than age 2 (Parry 2002). However, this prototype vaccine is not yet licensed.

Why it is important to do this review

This update of the 2007 Cochrane Review (Fraser 2007a) provides a more accurate assessment of the efficacy and safety of vaccines to prevent typhoid fever by incorporating data from new trials. We would have included head-on comparisons of vaccines had these been conducted.

Objectives

To evaluate the efficacy and adverse effects of vaccines used to prevent typhoid fever.

Methods

Criteria for considering studies for this review

Types of studies

Randomized and quasi-randomized controlled trials.

Types of participants

Adults and children.

Types of interventions

Intervention
  • Typhoid fever vaccines (live oral vaccine Ty2la or genetic modifications of this strain, Vi polysaccharide vaccine, and Vi conjugate vaccine).

Control
  • Other typhoid fever vaccines or inactive agents (placebo or vaccine for a different disease).

Excluded
  • Trials evaluating killed whole-cell vaccines, because these vaccines are no longer in use. Trials assessing only adverse events but not efficacy (the number of typhoid fever cases prevented) of experimental vaccines that have not yet been evaluated for efficacy. We excluded trials that reported only on adverse events while comparing different brands of the same type of typhoid vaccine.

Types of outcome measures

Primary outcomes
Cases of typhoid fever

Cases of typhoid fever were defined by isolation of S. typhi from a blood culture.

Secondary outcomes
Adverse events

Serious adverse events (leading to death, requiring inpatient hospitalization or prolonged existing hospitalization, life threatening, or resulting in persistent or significant disability or incapacity). Other adverse events (eg fever, erythema at injection site, vomiting, diarrhoea).

Search methods for identification of studies

We attempted to identify all relevant trials regardless of language or publication status (published, unpublished, in press and in progress).

Databases

We searched the following databases using the search terms and strategy described in Appendix 1: Cochrane Infectious Diseases Group Specialized Register (June 2013); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2013); MEDLINE (1966 to June 2013); EMBASE (1974 to June 2013); and LILACS (1982 to June 2013). We also searched the metaRegister of Controlled Trials (mRCT) using 'typhoid' and 'vaccine' as search terms. We searched the Internet for new drug application (NDA) documents of the US Food and Drug Administration, which may include unpublished studies.

Conference proceedings

We searched the following conference proceedings for relevant abstracts: Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC; 1995 to 2013); European Congress of Clinical Microbiology and Infectious Diseases (ECCMID; 2001 to 2013); and the Annual Meeting of the Infectious Diseases Society of America (IDSA; 2001 to 2013).

Reference lists

We checked the reference lists of the included trials.

Data collection and analysis

We used standard methodological procedures as expected by The Cochrane Collaboration.

Selection of studies

We (E Anwar, E Goldberg and M Paul) independently inspected titles and abstracts identified by the literature search to identify potentially relevant publications. Potentially relevant articles, according to at least one review author, were obtained in full-text format. We applied the inclusion criteria for the final decision regarding eligibility. We also checked that trials were independent, that is, we looked for multiple publications of the same trial and made sure that we included each trial only once. We resolved disagreements by discussion and consensus. Reasons for excluding studies from the review were documented. We attempted to contact trial authors for clarification if it was unclear whether a potentially relevant trial was eligible for the review.

Data extraction and management

We (E Anwar and E Goldberg) independently extracted data into a standard form; a third review author (M Paul) extracted the data in cases of disagreement. We discussed data extraction, documented decisions and, when necessary, contacted the trial authors for clarification or additional details. E Anwar entered data into Review Manager 5. We aimed to extract data according to an intention-to-treat analysis. If a discrepancy was noted in the number randomly assigned and the numbers analyzed in each treatment group, we reported this information. We recorded the surveillance method used to assess outcomes in each trial, categorizing it as active (staff entry into the field to identify cases or establishment of additional study clinics), intermediate (reliance on existing clinics and encouragement to evaluate participants for typhoid fever) or passive (no increase in surveillance). We also recorded the unit of randomization and indicated whether trials were adjusted for cluster-randomization in the analysis.

For dichotomous outcome measures, we recorded the number of participants experiencing the event and the number analyzed in each treatment group. For trials randomly assigned using clusters (cluster-RCTs) we extracted cluster-adjusted risk ratios when available; we also recorded the number of clusters in the trial, the average size of clusters and the unit of randomization (eg, household or institution). The statistical methods used to analyze the trial results were documented, along with details describing whether these methods were adjusted for clustering or for other co-variables.

Assessment of risk of bias in included studies

We (E Anwar and E Goldberg) independently assessed the risk of bias in included trials; in cases of disagreement, we consulted a third review author (M Paul). We took an individual component approach to quality assessment by using five variables: generation of allocation sequence; allocation concealment; blinding of participants and investigators; inclusion of all randomly assigned participants in the analysis; and reporting of all stated outcomes. We categorized generation of the allocation sequence and allocation concealment as adequate, unclear, or inadequate by using the approach described in Jüni 2001. We recorded whether trials used single, double or no blinding, and whether all randomly assigned participants were included in the results. We classified inclusion of all randomly assigned participants in the analysis as adequate if at least 90% and as inadequate if less than 90%.

Data synthesis

If a single reference included more than one trial, we labelled the trials separately using a letter (eg, Wang 1997a CHN and Wang 1997b CHN); if a single trial compared several vaccine arms with a control arm, we labelled the arms separately using a roman numeral (eg, Black 1990i CHL and Black 1990ii CHL). To avoid including data for controls more than once in the same comparison, we divided the placebo group into equal parts while assuming equal incidence in these groups.

We combined dichotomous data from trials that randomly assigned individuals by using risk ratios (RRs) and presented them with 95% confidence intervals (CIs). We interpreted the results as efficacy, defined as 1-RR and expressed as a percentage. We pooled cluster-RCT data that had been adjusted for clustering with data from trials that randomly assigned individuals (individual-RCTs) using the generic inverse variance method. When the results of a cluster-RCT had not been adjusted for clustering, we did not pool the data but presented the data in the additional table section.

We explored the following potential sources of heterogeneity in subgroup analyses: number of doses; length of follow-up; and vaccine type (Ty21a vaccine, Vi polysaccharide vaccine or Vi-rEPA) and age (if data were available). We rounded to the nearest year when trials included follow-up for only part of a year.

We calculated cumulative three-year efficacy, defined as efficacy for the entire three-year period, by vaccine type, as above. We also recorded cumulative data on vaccine efficacy for longer than three years of follow-up, if available. We analyzed efficacy per year and cumulative efficacy, as they provide different information. Analyses per year show whether the effect of the vaccine decreases over time, and cumulative efficacy demonstrates efficacy overall, for a given period, regardless of whether changes over time occurred within this period.

We extracted data on adverse events from trials comparing a typhoid fever vaccine with placebo, and from trials comparing a typhoid fever vaccine with a different typhoid fever vaccine. When the occurrence of adverse events was reported after each of several doses, we extracted only the occurrence after the first dose. Similarly, when reports provided estimates of the incidence of adverse events for different time points after vaccination, we presented the data corresponding to 24 hours after vaccination.

We assessed heterogeneity by inspecting the forest plots to detect overlapping confidence intervals and by applying the Chi2 test with a P-value of 0.10 indicating statistical significance and the I2 statistic with a value of 50% used to denote moderate levels of heterogeneity. The random-effects model was used throughout the review.

We calculated number needed to treat for an additional beneficial outcome (NNTB) (1/reduction in risk of typhoid fever attributable to vaccination) for each type of vaccine based on the cumulative 2.5- to 3-year point estimate and the incidence of typhoid fever in control groups of trials assessing the given vaccination.

Quality of evidence

The quality of evidence across each outcome measure was assessed using the GRADE approach. The quality rating across studies has one of four levels: high, moderate, low or very low. Randomized trials are initially categorized as high quality but can be downgraded after assessment of five criteria: risk of bias, consistency, directness, imprecision and publication bias (Guyatt 2008). The main results of the review and the quality assessments are displayed in the 'Summary of findings' tables.

Results

Description of studies

Results of the search

Four hundred forty-two potentially relevant publications were identified, and after screening, 80 publications were retrieved for full-text inspection. See Figure 1 for the study flow diagram. Five trials were identified as currently ongoing (see Characteristics of ongoing studies).

Figure 1.

Study flow diagram.

Included studies

Altogether, 26 publications (18 trials—12 individual-RCTs and six cluster-RCTs) met the inclusion criteria (see details in Characteristics of included studies table).

This review update includes four new trials that were not included in the previous review: three of the new trials evaluated the Vi polysaccharide vaccine, two trials reported on efficacy and adverse events (Khan 2012 PAK; Sur 2009 IND ) and one trial reported adverse events only (Zhou 2007 CHN). One trial evaluated adverse events associated with the Vi-rEPA vaccine (Thiem 2011 VNM). All of the newly included trials were conducted in Asia.

Excluded studies

A total of 50 publications (43 trials) were excluded from the review. For details of excluded trials and reasons for their exclusion, see the Characteristics of excluded studies table.

Outcomes

Data on the primary outcome, cases of typhoid fever, were derived from 12 trials:

Data on the secondary outcome, adverse events, were taken from 11 trials:

One additional trial assessed the Ty21a vaccine and reported on adverse events but did not provide the number of participants per study arm (Cryz 1993 THA); therefore results of this trial were not included in the meta-analysis.

All efficacy trials and all but one adverse event trial (Keitel 1994 USA) were performed in countries in which typhoid fever is endemic; Chile four trials, China three trials, Vietnam two trials, Thailand two trials, Egypt one trial, India one trial, Indonesia one trial, Nepal one trial, Pakistan one trial and South Africa one trial. None of the trials evaluated vaccine efficacy in travellers from developed countries. None of the trials compared the efficacy of different types of typhoid vaccines.

Risk of bias in included studies

See Figure 2 for a summary of the assessment and the 'Characteristics of included studies' for further details on the reasons for review authors' judgements.

Figure 2.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Efficacy trials

Five of the 12 efficacy trials reported adequate randomization procedures (Khan 2012 PAK; Simanjuntak 1991i IDN; Simanjuntak 1991ii IDN; Sur 2009 IND; Wang 1997a CHN; Wang 1997b CHN; Yang 2001 CHN). In the other seven trials, insufficient information was supplied to permit judgement. All but one trial (Klugman 1987 ZAF) used adequate methods to conceal allocation.

Adverse event trials

Six of the 12 trials looking at adverse events reported adequate randomization procedures (Khan 2012 PAK; Simanjuntak 1991i IDN; Simanjuntak 1991ii IDN; Sur 2009 IND; Wang 1997a CHN; Wang 1997b CHN; Yang 2001 CHN; Zhou 2007 CHN). Six of 12 trials used adequate methods to conceal allocation (Khan 2012 PAK; Lin 2001 VNM; Simanjuntak 1991i IDN; Simanjuntak 1991ii IDN; Sur 2009 IND; Wang 1997a CHN; Wang 1997b CHN; Yang 2001 CHN), but in the other trials, insufficient information was supplied to permit judgement.

Blinding

Efficacy trials

All but two trials used double blinding. Two cluster-randomized trials (Khan 2012 PAK; Sur 2009 IND) could not guarantee blinding of researchers or participants, as they used vaccines that were packaged differently and therefore did not look identical. However, both trials tried to minimize this effect by assigning each vaccination team to only one vaccine, identifying the vaccines only by code and not informing local research staff members or participants of the assignment of the code or the vaccine.

Adverse event trials

All but three trials used double blinding. Two trials (Khan 2012 PAK; Sur 2009 IND) used vaccines that did not look identical, as outlined above, and one trial (Thiem 2011 VNM) did not state whether blinding had taken place.

Incomplete outcome data

Efficacy trials

Nine of 12 trials were assessed as adequate in terms of including all randomly assigned participants in the analysis. In three trials (Black 1990i CHL; Black 1990ii CHL; Levine 1987i CHL; Levine 1987ii CHL; Levine 1987iii CHL; Levine 1987iv CHL; Levine 1990i CHL; Levine 1990ii CHL), no reasons for missing data were provided.

Adverse event trials

Ten of 12 trails were assessed as adequate in terms of including all randomly assigned participants in the analysis or providing reasons for missing outcome data. Two trials were unclear on this issue (Cryz 1993 THA; Levine 1986i CHL; Levine 1986ii CHL). One additional trial assessed the Ty21a vaccine and reported on adverse events but did not provide the number of participants per study arm (Cryz 1993 THA); therefore results of this trial were not included in the meta-analysis.

Selective reporting

Efficacy trials

All 12 trials reported on expected outcomes.

Adverse event trials

All 12 trials reported on expected outcomes.

Other potential sources of bias

Efficacy trials

Four of the six cluster-RCTs provided data on the efficacy of the Ty21a vaccine (Black 1990i CHL;; Levine 1987i CHL; Levine 1990i CHL; ; Wahdan 1980a EGY). However, these four cluster-RCTs, all of which randomly assigned by classroom, did not adjust for clustering in their results; therefore we could not include their results in the meta-analyses.

The two remaining cluster-RCTs included within the review provided data on the efficacy of the Vi polysaccharide vaccine (Khan 2012 PAK; Sur 2009 IND). Both of these trials randomly assigned by geographic clusters. Study authors were contacted to gather unpublished cluster-adjusted data for inclusion within the meta-analysis.

Adverse event trials

Two cluster-RCTs provided data on adverse events associated with the Vi polysaccharide vaccine (Khan 2012 PAK; Sur 2009 IND); however, these cluster-RCTs did not adjust for clustering in their results and therefore were not included in the meta-analyses.

Effects of interventions

See: Summary of findings for the main comparison Ty21a vaccine (three doses) compared with control; efficacy for preventing typhoid fever; Summary of findings 2 Vi polysaccharide vaccine (one dose) compared with control; efficacy for preventing typhoid fever; Summary of findings 3 Vi-rEPA vaccine (two doses) compared with control; efficacy for preventing typhoid fever

TY21a vaccine

Efficacy

This vaccine has been evaluated in one three-arm RCT (Simanjuntak 1991i IDN) and in four cluster-RCTs. The cluster-RCTs did not adjust analyses for the effect of clustering; therefore any protective effect is likely overestimated (Black 1990ii CHL; Levine 1987i CHL; Levine 1987ii CHL; Levine 1987iii CHL; Levine 1987iv CHL; Wahdan 1980a EGY, Levine 1990i CHL. Levine 1990ii CHL). We could not include these studies in the meta-analysis.

A three-dose schedule of Ty21a vaccine provided vaccine efficacy of 35% at Year 1 (95% CI 8% to 54%; 20,543 participants; Analysis 1.1), 58% at Year 2 (95% CI 40% to 71%; 20,543 participants; Analysis 1.2) and 46% at Year 3, although this finding was not statistically significant (95% CI -6% to 72%; 20,543 participants; Analysis 1.3). The cumulative efficacy of the Ty21a vaccine over 2.5 to 3 years was 48% (95% CI 34% to 58%; 20,543 participants; Analysis 1.4). A comparison of cumulative efficacy between the liquid formulation and the enteric capsules showed no statistically significant difference (10,215 participants; Simanjuntak 1991ii IDN; Analysis 2.1).

Results of the four unadjusted cluster-RCTs for the three-dose schedule of Ty21a vaccine liquid formulation or enteric capsules were similar to the individual-RCT results and are presented in Table 1. Cumulative efficacy of the three-dose schedule of Ty21a vaccine for over three years is available from two of the unadjusted cluster-RCTs (Levine 1987ii CHL; Levine 1990i CHL). Cumulative efficacy was 79% at five years (95% CI 65% to 87%; Table 2) and 62% at seven years (95% CI 48% to 73%; Table 2).

Table 1. Efficacy of Ty21a vaccine: unadjusted cluster-trial resultsa
  1. aFailure to adjust for the potential effect of a cluster design is likely to lead to overestimation of the treatment effect.
    bRisk ratio with 95% confidence intervals.

TrialYearPreparationNo. dosesRR (95% CI)bEfficacy
Black 1990ii CHL1Enteric capsules10.75 (0.51 to 1.09)25% (-9% to 49%)
20.65 (0.39 to 1.08)35% (-8% to 61%)
30.99 (0.52 to 1.87)1% (-87% to 48%)
41.06 (0.63 to 1.77)-6% (-77% to 37%)
51.10 (0.57 to 2.13)-10% (-113% to 43%)
Black 1990ii CHL1Enteric capsules20.48 (0.31 to 0.74)52% (24% to 69%)
20.29 (0.15 to 0.56)71% (44% to 85%)
30.78 (0.40 to 1.54)22% (-54% to 60%)
40.81 (0.47 to 1.41)19% (-41% to 53%)
50.93 (0.47 to 1.84)7% (-84% to 53%)
Levine 1987ii CHL1Enteric capsules30.29 (0.12 to 0.67)71% (33% to 88%)
20.40 (0.17 to 0.90)60% (10% to 83%)
30.33 (0.15 to 0.73)67% (27% to 85%)
40.22 (0.07 to 0.65)78% (35% to 93%)
50.53 (0.22 to 1.24)47% (124% to 78%)
Wahdan 1980a EGY1Liquid formulation30.06 (0.00 to 1.13)94% (-13% to 100%)
20.06 (0.00 to 0.98)94% (2% to 100%)
30.14 (0.02 to 1.12)86% (-12% to 98%)
Levine 1987i CHLCumulative incidence 2.5 to 3 yearsEnteric capsules30.41 (0.28 to 0.91)59% (9% to 72%)
Levine 1987ii CHLCumulative incidence 2.5 to 3 yearsEnteric capsules30.33 (0.18 to 0.63)67% (82% to 37%)
Levine 1990ii CHLCumulative incidence 2.5 to 3 yearsEnteric capsules30.63 (0.35 to 1.12)37% (-12% to 65%)
Wahdan 1980a EGYCumulative incidence 2.5 to 3 yearsLiquid formulation30.04 (0.01 to 0.33)96% (67% to 99%)
Levine 1990i CHLCumulative incidence 2.5 to 3 yearsLiquid formulation30.24 (0.13 to 0.47)76% (53% to 87%)
Levine 1987iii CHLCumulative incidence 2.5 to 3 yearsGelatin capsules30.69 (0.39 to 1.20)31% (-20% to 61%)
Levine 1987iv CHLCumulative incidence 2.5 to 3 yearsGelatin capsules30.81 (0.47 to 1.39)19% (-39% to 53%)
Levine 1990i CHLCumulative incidence 2.5 to 3 yearsLiquid preparation vs enteric capsules30.35 (0.21, 0.56)65% (44% to 79%)
Table 2. Cumulative efficacy of Ty21a vaccine at > 3 years: vaccine vs control
  1. aConfidence intervals.

TrialVaccine/formulationLength of follow-upVaccine: incidenceControl: incidenceEfficacy (95% CI)a
Black 1990i CHLTy21a: enteric capsules, 2 doses5 years95/27,620164/27,30543% (26% to 55%)
Black 1990ii CHLTy21a: enteric capsules, 1 dose5 years200/27,618164/27,305-21% (-48% to 2%)
Levine 1987ii CHLTy21a: enteric capsules, 3 doses7 years50/22,170131/21,90662% (48% to 73%)
Levine 1990i CHLTy21a: liquid formulation, 3 doses5 years34/36,62343/10,30279% (65% to 87%)

We were unable to conduct subgroup analysis by age, as trials evaluating the efficacy of the Ty21a vaccine did not stratify results by age.

Adverse events

None of the individual- or cluster-randomized trials report any serious adverse events (leading to death, requiring inpatient hospitalization or prolonged existing hospitalization, life threatening or resulting in persistent or significant disability or incapacity).

Compared with placebo, the Ty21a vaccine (both preparations) was not associated with an increased rate of vomiting (two trials/four arms, 2066 participants; Analysis 3.2), diarrhoea (two trials/four arms, 2066 participants; Analysis 3.3), nausea or abdominal pain (two trials/four arms, 2066 participants; Analysis 3.4), headache (one trial/two arms, 1190 participants; Analysis 3.5) or rash (one trial/two arms, 1190 participants; Analysis 3.6) compared with control. However, fever (RR 1.84, 95% CI 1.02 to 3.05; two trials/four arms, 2066 participants) was more common after vaccine delivery. A pooled analysis of two individual-RCTs showed a marginal increase in risk of any mild adverse events (RR 1.67, 95% CI 1.03 to 2.72; two trials/three arms, 1360 participants; Analysis 3.7).

Vi polysaccharide vaccine

Efficacy

The efficacy of this vaccine has been evaluated in four individually randomized RCTs (Acharya 1987 NPL; Klugman 1987 ZAF; Wang 1997a CHN; Yang 2001 CHN) and in two cluster-RCTs (Khan 2012 PAK; Sur 2009 IND). We contacted the cluster-randomized study authors to obtain unpublished cluster-adjusted results for efficacy at Year 2 following vaccination. We were therefore able to pool the results from the individually randomized RCTs and the cluster-adjusted RCTs using the generic inverse variance method.

The efficacy of the Vi polysaccharide vaccine was 69% at Year 1 (95% CI 63% to 74%; three trials, 99,797 participants; Analysis 4.1), 59% at Year 2 (95% CI 45% to 69%; four trials, 194,969 participants; Analysis 4.1) and 50% at Year 3 based on a single trial (95% CI 22% to 68%, 11,384 participants; Analysis 4.1). Cumulative efficacy at 2.5 to 3 years, based on the same single trial (Klugman 1987 ZAF), was 55% (95% CI 30% to 70%; 11,384 participants; Analysis 4.2).

Two of the trials used the Widal test (as well as a positive culture) to detect cases of typhoid fever (Wang 1997a CHN; Yang 2001 CHN). Results of the Widal test were not included in the meta-analysis. Both trials followed participants for six years, and their combined results demonstrated that protection was significant in each of the first two years but not in Years 3 to 6 separately. Three-year cumulative efficacy was 69% (95% CI 50% to 81%), and combined efficacy for Years 4 through 6 was 11% (95% CI -76% to 55%) (analyses not shown).

Three of the trials conducted subgroup analysis by age: one individual-RCT (Yang 2001 CHN) and two cluster-RCTs (Khan 2012 PAK; Sur 2009 IND). However, the individual-RCT (Yang 2001 CHN) included very small numbers in each age group; the two cluster-RCTs (Khan 2012 PAK; Sur 2009 IND) did not adjust for clustering and presented their results in the form of hazard ratios rather than risk ratios (with effectiveness of vaccination estimated as [1-hazard ratio] × 100%). We were therefore unable to conduct subgroup analysis by age. Unadjusted results by age from the two cluster-RCTs are presented in Table 3. The cluster-randomized trial conducted in India (Sur 2009 IND) found that compared with control, the Vi polysaccharide vaccine provided significant protection for children 2 to 5 years of age two years after vaccination (efficacy 59%, 95% CI 18% to 79%). However, contrary to these results, the cluster-randomized trial conducted in Pakistan (Khan 2012 PAK) showed no protection among children between two and five years of age compared with placebo at two years after vaccination (efficacy -30%, 95% CI -183% to 40%).

Table 3. Efficacy of Vi polysaccharide vaccine: unadjusted cluster-trial results by agea
  1. a Failure to adjust for the potential effect of a cluster design is likely to lead to overestimation of the treatment effect.

Trial Year Age at baseline Typhoid episodes: Vi vaccine Typhoid episodes: control Efficacy (95% CI): not adjusted
Khan 2012 PAKCumulative incidence at 2 years2 to < 5 years16/315413/3324-30% (-183% to 40%)
5 to 16 years14/10,08436/10,66959% (9% to 81%)
Sur 2009 INDCumulative incidence at 2 years2 to < 5 years5/109727/109582% (58% to 92%)
5 to < 15 years21/428254/458459% (18% to 79%
≥ 15 years8/13,49015/13,12548% (-44% to 81%)
Adverse events

No trials reported any serious adverse events (leading to death, requiring inpatient hospitalization or prolonged existing hospitalization, life threatening, or resulting in persistent or significant disability or incapacity).

Overall, no statistically significant difference was noted between vaccine and placebo in the incidence rate of fever (four trials, 133,038 participants; Analysis 5.1) or erythema (three trials, 132,261 participants; Analysis 5.2). However, swelling (RR 6.06, 95% CI 1.07 to 34.22; three trials, 1767 participants; Analysis 5.3) and pain at the injection site (RR 7.98, 95% CI 3.69 to 17.24; one trial, 667 participants; Analysis 5.4) were more common after delivery of the Vi polysaccharide vaccine.

Two cluster-RCTs presented data on adverse events for a subgroup of participants. These data were not adjusted for clustering and therefore could not be included within the meta-analysis; results were similar to the individual-RCT results, with erythema and pain at the injection site reported more commonly in the vaccine group (Table 4).

Table 4. Adverse events following ViPS vaccine delivery: unadjusted results from cluster-randomized trialsa
  1. a Failure to adjust for the potential effect of a cluster design is likely to lead to overestimation of the treatment effect.

Trial Adverse event Number of events: ViPS vaccine Number of events: control group Statistical significance
Khan 2012 PAKFever5/1251/117Not significant
Khan 2012 PAKPain at injection site4/1251/117Not significant
Sur 2009 INDErythema24/1105/92P < 0.001
Sur 2009 INDPain at injection site61/11017/92P < 0.001
Sur 2009 INDFever8/1101/92P = 0.04

Vi-rEPA vaccine

Efficacy

The efficacy of this vaccine has been evaluated by one trial in children 2 to 5 years of age conducted in Vietnam (Lin 2001 VNM). The efficacy of the Vi-rEPA vaccine was 94% at Year 1 (95% CI 75% to 99%; 12,008 participants; Analysis 6.1) and 87% at Year 2 (95% CI 56% to 96%; 12,008 participants; Analysis 6.1). The cumulative efficacy of the Vi-rEPA vaccine after 3.8 years was 89% (95% CI 76% to 97%; 12,008 participants).

The efficacy of this vaccine has been evaluated only in children 2 to 5 years of age; we were therefore unable to conduct subgroup analysis by age.

Adverse events

No trials reported any serious adverse events (leading to death, requiring inpatient hospitalization or prolonged existing hospitalization, life threatening or resulting in persistent or significant disability or incapacity).

Two trials evaluated adverse events associated with this vaccine (Lin 2001 VNM; Thiem 2011 VNM). Investigators reported no statistically significant difference between the vaccine and placebo for the incidence of fever after doses 1 and 2 (Analysis 7.1; Analysis 7.2), erythema after doses 1 and 2 (Analysis 7.3; Analysis 7.4) or swelling after doses 1 and 2 (Analysis 7.5; Analysis 7.6).

Heterogeneity

In most comparisons that included several trials, the degree of heterogeneity was not substantial (ie, I2 < 50% and Chi2 test with P value > 0.10). However, because of the limited number of trials included in each comparison, we were unable to conclude why a greater degree of heterogeneity in trial results was apparent in some comparisons.

Sensitivity analyses

We performed sensitivity analyses for trials for which the control arm was split in the main analyses and found that the results were not altered (analyses not shown). As most comparisons included few trials, we could not perform sensitivity analyses by trial methodological quality (risk of bias). No difference was noted in adverse event results from trials that did and did not evaluate efficacy, although no formal testing was undertaken.

Number needed to treat for an additional beneficial outcome (NNTB) to prevent one case of typhoid fever

Ty21a vaccine

Based on the results of one individual-RCT, the liquid formulation of the Ty21a vaccine had a three-year cumulative protective efficacy of 53% (95% CI 34% to 67%; Simanjuntak 1991i IDN; Analysis 1.4). The incidence rate in the control group was 2021/100,000 with a corresponding NNTB of 93 (95% CI 74 to 145). The enteric capsule formulation of the Ty21a vaccine had three-year cumulative protective efficacy of 42% (95% CI 21% to 58%; Simanjuntak 1991ii IDN; Analysis 1.4). The incidence in the control group was 2031/100,000, and the corresponding NNTB was 237 (95% CI 86 to 119)

Vi polysaccharide vaccine

The Vi polysaccharide vaccine has a 2.5- to 3-year cumulative protective efficacy of 55% (95% CI 30% to 70%; Klugman 1987 ZAF; Analysis 3.2) with an incidence rate of 1160/100,000. From these data, we estimated the NNTB to be 192 (95% CI 124 to 288).

Discussion

Summary of main results

Ty21a vaccine (three doses)

A three-dose schedule of Ty21a vaccine probably prevents around one-third to one-half of typhoid cases during the first two years after vaccination (Year 1: 35%, 95% CI 8% to 54%; Year 2: 58%, 95% CI 40% to 71%; one trial, 20,543 participants; moderate quality evidence). These data are taken from a single trial conducted in Indonesia in the 1980s. No statistically significant benefit was seen in the third year after vaccination. Four additional cluster-RCTs have been conducted, but the authors did not adjust for clustering.

Compared with placebo, this vaccine was not associated with more participants with vomiting, diarrhoea, nausea or abdominal pain (four trials, 2066 participants; moderate quality evidence) headache, or rash (two trials, 1190 participants; moderate quality evidence); however, fever (four trials, 2066 participants; moderate quality evidence) was more common in the vaccine group.

Vi polysaccharide vaccine (one dose)

A single dose of Vi polysaccharide vaccine prevents around two-thirds of typhoid cases in the first year after vaccination (Year 1: 69%, 95% CI 63% to 74%; three trials, 99,979 participants; high quality evidence). In Year 2, trial results were more variable, with the vaccine probably preventing between 45% and 69% of typhoid cases (Year 2: 59%, 95% CI 45% to 69%; 4 trials, 194,969 participants; moderate quality evidence). The three-year cumulative efficacy of the vaccine is probably around 55% (95% CI 30% to 70%; 11,384 participants, one trial; moderate quality evidence). These data were taken from a single trial conducted in South Africa in the 1980s.

Compared with placebo, this vaccine was not associated with an increased rate of fever (four trials, 133,038 participants; moderate quality evidence) or erythema (three trials, 132,261 participants; low quality evidence); however, swelling (three trials, 1767 participants; moderate quality evidence) and pain at the injection site (one trial, 667 participants; moderate quality evidence) were more common in the vaccine group.

Vi-rEPA vaccine (two doses)

Administration of two doses of the Vi-rEPA vaccine probably prevents between 50% and 96% of typhoid cases during the first two years after vaccination (Year 1: 94%, 95% CI 75% to 99%; Year 2: 87%, 95% CI 56% to 96%, one trial, 12,008 participants; moderate quality evidence). These data are taken from a single trial with children two to five years of age conducted in Vietnam.

Compared with placebo, the first and second doses of this vaccine were not associated with increased risk of adverse events. The first dose of this vaccine was not associated with fever (two trials, 12,209 participants; low quality evidence), erythema (two trials, 12,209 participants; moderate quality evidence) or swelling at the injection site (two trials, 12,209 participants; moderatequality evidence). The second dose of this vaccine was not associated with fever (two trials, 11,286 participants; low quality evidence),erythema (two trials, 11,286 participants; moderate quality evidence)and swelling at the injection site (two trials, 11,286 participants; moderate quality evidence).

Overall completeness and applicability of evidence

In the absence of trials directly comparing different types of typhoid vaccines, we provide an indirect means of comparing the efficacy of different vaccines. The cumulative efficacy at 2.5 to 3 years for the Ty21a vaccine (3 doses) and the Vi polysaccharide vaccine was 48% (95% CI 34% to 58%) and 55% (95% CI 30% to 70%), respectively. The cumulative efficacy of the Vi-rEPA vaccine at 3.8 years was higher (89%, 95% CI 76% to 97%), but this vaccine is unlicensed. Adverse events were mild in nature and, for the most, were not significantly different between vaccine and placebo groups.

Ty21a vaccine (three doses)

Although the efficacy of the Ty21a vaccine was evaluated in five separate trials, four of these were cluster-RCTs that did not account for this design in the analysis and therefore were not included in the meta-analyses. In general, the cluster-RCTs suggested greater efficacy of the Ty21a vaccine, as would be expected in trials that do not adjust appropriately for the effect of clustering. The data for the efficacy of this vaccine therefore were derived from one three-arm individually randomized RCT conducted in Indonesia in the 1980s. Further evidence from other settings would be valuable in proving the generalizability of these findings.

None of the studies presented subgroup data by age. Therefore, we cannot report on efficacy of this vaccine in different age groups.

Vi polysaccharide vaccine (one dose)

Evidence available from four trials conducted in four different settings (two high-incidence settings: India and Pakistan; and two medium-incidence settings: China and South Africa) demonstrates that the Vi polysaccharide vaccine is efficacious for the first two years after vaccination. One trial from South Africa conducted in the 1980s provided efficacy data at three years.

Two recent cluster-RCTs presented unadjusted efficacy results stratified by age with contrasting results (presented in Table 3). The cluster-RCT conducted in India (Sur 2009 IND) found that compared with control, the ViPS vaccine provided significant protection in children 2 to 5 years of age two years after vaccination. However, contrary to these results, the cluster-RCT conducted in Pakistan (Khan 2012 PAK) did not show any protection among children between two and five years of age compared with placebo. The reasons for the difference in effectiveness by age are unclear. The two trials differed in methodology, with the trial in India taking a mass vaccination approach (vaccinating the entire population) and the trial in Pakistan targeting only children. The trial conducted in India, which took a mass vaccination approach, demonstrated indirect protection (herd immunity) within the population under study; this was not seen in the trial in Pakistan, in which only children were vaccinated. It may be that this indirect protection led to reduced overall transmission within the intervention clusters and a reduced incidence of typhoid fever among young children compared with control clusters observed within the Indian trial.

Vi-rEPA vaccine (two doses)

Evidence of the efficacy of this vaccine is available from a single trial conducted in Vietnam (Lin 2001 VNM). This single study assessed efficacy of the vaccine only in children two to five years of age; therefore vaccine efficacy in different settings and age groups is unknown.

Quality of the evidence

We assessed the quality of evidence provided by the randomized studies using the GRADE approach; these assessments are presented in Summary of findings for the main comparison, Summary of findings 2 and Summary of findings 3.

Ty21a vaccine (three doses)

Evidence obtained for the protective efficacy of the Ty21a vaccine was judged to be of moderate quality. The quality was downgraded for indirectness—this vaccine has been evaluated in only one setting (Indonesia), and studies from elsewhere would be important before this result can be widely generalized.

Vi polysaccharide vaccine (one dose)

Evidence obtained for the protective efficacy of the Vi polysaccharide vaccine was judged to be of high quality at Year 1 and of moderate quality at Year 2. At Year 2, the quality was downgraded for inconsistency—the magnitude of the protective effect varied between trials from 34% to 69% (I2 = 72%). The reason for this may be the different efficacy of the vaccine within different age groups, with one cluster trial (Khan 2012 PAK) finding that compared with control, the vaccine did not provide significant protection to children between 2 and 5 years of age.

Vi-rEPA vaccine (two doses)

Evidence obtained for the protective efficacy of the Vi-rEPA vaccine was judged to be of moderate quality. The quality was downgraded for indirectness—the vaccine has been evaluated only in children 2 to 5 years of age in one high-incidence setting (Vietnam), and studies of participants of different ages conducted elsewhere would be important before this result can be widely generalized.

The quality of the evidence obtained for the adverse event of fever was downgraded for inconsistency (I2 = 89% Year 1; I2 = 85% Year 2). The reason for this heterogeneity is unclear, as both trials were conducted among children younger than 5 years in Vietnam. Further investigation of the potential adverse events of this vaccine is warranted.

Authors' conclusions

Implications for practice

Based on the available evidence, the currently licensed Ty21a and Vi polysaccharide vaccines are efficacious and safe public health measures for preventing typhoid fever. Factors such as costs, availability and convenience of administration may determine which vaccine is chosen for use.

Implications for research

An effective typhoid vaccine is needed for young children. Neither the Vi polysaccharide vaccine nor the Ty21a vaccine is licensed for children younger than 2 years of age. Given the finding that typhoid fever affects infants (Saha 2001; Sinha 1999), development of a vaccine suitable for this age group is required. Future trials should be sufficiently powered to present results stratified by age group. This would mean that vaccine efficacy in different groups could be analyzed and would ensure that vaccine delivery can be targeted appropriately (eg, via a school-based programme or through the expanded programme of vaccination (EPI)).

None of the included trials compared different types of vaccines used to prevent typhoid fever. Such future comparisons may be helpful in allowing direct conclusions regarding the relative efficacy of the vaccines, although such evidence would not necessarily promote the introduction of vaccines against typhoid fever to new settings and would require substantial resources.

Future trials should conduct analyses suited to their design; cluster-randomization should be accounted for in sample size calculations and in analyses of results.

Acknowledgements

We thank the Cochrane Infectious Diseases Group for support and assistance provided. The editorial base for the Cochrane Infectious Diseases Group is funded by the UK Department for International Development (DFID) for the benefit of developing countries.

Data and analyses

Download statistical data

Comparison 1. Ty21a vaccine (three doses) vs control; efficacy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of typhoid fever, Year 1220543Risk Ratio (M-H, Random, 95% CI)0.65 [0.46, 0.92]
1.1 Enteric capsules110331Risk Ratio (M-H, Random, 95% CI)0.72 [0.45, 1.15]
1.2 Liquid formulation110212Risk Ratio (M-H, Random, 95% CI)0.58 [0.35, 0.96]
2 Incidence of typhoid fever, Year 2220543Risk Ratio (M-H, Random, 95% CI)0.42 [0.29, 0.60]
2.1 Enteric capsules110331Risk Ratio (M-H, Random, 95% CI)0.49 [0.30, 0.79]
2.2 Liquid formulation110212Risk Ratio (M-H, Random, 95% CI)0.34 [0.20, 0.59]
3 Incidence of typhoid fever, Year 3220543Risk Ratio (M-H, Random, 95% CI)0.54 [0.28, 1.06]
3.1 Enteric capsules110331Risk Ratio (M-H, Random, 95% CI)0.49 [0.18, 1.31]
3.2 Liquid formulation110212Risk Ratio (M-H, Random, 95% CI)0.59 [0.23, 1.50]
4 Cumulative incidence of typhoid fever at 2.5 to 3 years220543Risk Ratio (M-H, Random, 95% CI)0.52 [0.42, 0.66]
4.1 Enteric capsules110331Risk Ratio (M-H, Random, 95% CI)0.58 [0.42, 0.79]
4.2 Liquid formulation110212Risk Ratio (M-H, Random, 95% CI)0.47 [0.33, 0.66]
Analysis 1.1.

Comparison 1 Ty21a vaccine (three doses) vs control; efficacy, Outcome 1 Incidence of typhoid fever, Year 1.

Analysis 1.2.

Comparison 1 Ty21a vaccine (three doses) vs control; efficacy, Outcome 2 Incidence of typhoid fever, Year 2.

Analysis 1.3.

Comparison 1 Ty21a vaccine (three doses) vs control; efficacy, Outcome 3 Incidence of typhoid fever, Year 3.

Analysis 1.4.

Comparison 1 Ty21a vaccine (three doses) vs control; efficacy, Outcome 4 Cumulative incidence of typhoid fever at 2.5 to 3 years.

Comparison 2. Ty21a vaccine: liquid formulation vs enteric capsules (3 doses)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Cumulative incidence of typhoid fever at 2.5 to 3 years1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 2.1.

Comparison 2 Ty21a vaccine: liquid formulation vs enteric capsules (3 doses), Outcome 1 Cumulative incidence of typhoid fever at 2.5 to 3 years.

Comparison 3. Ty21a vaccine vs control; adverse events
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Fever42066Risk Ratio (M-H, Random, 95% CI)1.84 [1.02, 3.31]
1.1 Enteric capsules21141Risk Ratio (M-H, Random, 95% CI)2.72 [1.06, 6.96]
1.2 Liquid formulation1588Risk Ratio (M-H, Random, 95% CI)1.36 [0.61, 3.03]
1.3 In milk with sodium bicarbonate1337Risk Ratio (M-H, Random, 95% CI)2.08 [0.19, 22.77]
2 Vomiting42066Risk Ratio (M-H, Random, 95% CI)1.15 [0.43, 3.05]
2.1 Enteric capsules21141Risk Ratio (M-H, Random, 95% CI)1.92 [0.13, 27.74]
2.2 Liquid formulation1588Risk Ratio (M-H, Random, 95% CI)1.91 [0.37, 9.79]
2.3 In milk with sodium bicarbonate1337Risk Ratio (M-H, Random, 95% CI)0.66 [0.33, 1.31]
3 Diarrhoea42066Risk Ratio (M-H, Random, 95% CI)0.80 [0.52, 1.24]
3.1 Enteric capsules21141Risk Ratio (M-H, Random, 95% CI)1.21 [0.57, 2.58]
3.2 Liquid formulation1588Risk Ratio (M-H, Random, 95% CI)0.71 [0.34, 1.49]
3.3 In milk with sodium bicarbonate1337Risk Ratio (M-H, Random, 95% CI)0.61 [0.29, 1.30]
4 Nausea or abdominal pain42066Risk Ratio (M-H, Random, 95% CI)1.70 [0.77, 3.75]
4.1 Enteric capsules21141Risk Ratio (M-H, Random, 95% CI)2.92 [1.53, 5.57]
4.2 Liquid formulation1588Risk Ratio (M-H, Random, 95% CI)1.84 [0.90, 3.77]
4.3 In milk with sodium bicarbonate1337Risk Ratio (M-H, Random, 95% CI)0.66 [0.39, 1.13]
5 Headache21190Risk Ratio (M-H, Random, 95% CI)1.31 [0.76, 2.27]
5.1 Enteric capsules1602Risk Ratio (M-H, Random, 95% CI)1.40 [0.64, 3.07]
5.2 Liquid formulation1588Risk Ratio (M-H, Random, 95% CI)1.23 [0.57, 2.65]
6 Rash21190Risk Ratio (M-H, Random, 95% CI)2.94 [0.61, 14.12]
6.1 Enteric capsules1602Risk Ratio (M-H, Random, 95% CI)2.81 [0.29, 26.83]
6.2 Liquid formulation1588Risk Ratio (M-H, Random, 95% CI)3.06 [0.34, 27.24]
7 Any mild adverse event31360Risk Ratio (M-H, Random, 95% CI)1.67 [1.03, 2.72]
7.1 Enteric capsules1602Risk Ratio (M-H, Random, 95% CI)1.78 [1.08, 2.95]
7.2 Liquid formulation2758Risk Ratio (M-H, Random, 95% CI)0.74 [0.06, 8.55]
8 Serious adverse events52236Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
8.1 Enteric capsules21141Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
8.2 Liquid formulation2758Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
8.3 In milk with sodium bicarbonate1337Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 Ty21a vaccine vs control; adverse events, Outcome 1 Fever.

Analysis 3.2.

Comparison 3 Ty21a vaccine vs control; adverse events, Outcome 2 Vomiting.

Analysis 3.3.

Comparison 3 Ty21a vaccine vs control; adverse events, Outcome 3 Diarrhoea.

Analysis 3.4.

Comparison 3 Ty21a vaccine vs control; adverse events, Outcome 4 Nausea or abdominal pain.

Analysis 3.5.

Comparison 3 Ty21a vaccine vs control; adverse events, Outcome 5 Headache.

Analysis 3.6.

Comparison 3 Ty21a vaccine vs control; adverse events, Outcome 6 Rash.

Analysis 3.7.

Comparison 3 Ty21a vaccine vs control; adverse events, Outcome 7 Any mild adverse event.

Analysis 3.8.

Comparison 3 Ty21a vaccine vs control; adverse events, Outcome 8 Serious adverse events.

Comparison 4. Vi polysaccharide vaccine (one dose) vs control; efficacy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of typhoid fever6 Risk Ratio (Random, 95% CI)Subtotals only
1.1 Year 1399797Risk Ratio (Random, 95% CI)0.31 [0.26, 0.37]
1.2 Year 24194969Risk Ratio (Random, 95% CI)0.41 [0.31, 0.55]
1.3 Year 3111384Risk Ratio (Random, 95% CI)0.50 [0.32, 0.78]
2 Cumulative incidence of typhoid fever at 2.5 to 3 years111384Risk Ratio (M-H, Random, 95% CI)0.45 [0.30, 0.70]
Analysis 4.1.

Comparison 4 Vi polysaccharide vaccine (one dose) vs control; efficacy, Outcome 1 Incidence of typhoid fever.

Analysis 4.2.

Comparison 4 Vi polysaccharide vaccine (one dose) vs control; efficacy, Outcome 2 Cumulative incidence of typhoid fever at 2.5 to 3 years.

Comparison 5. Vi polysaccharide vaccine vs control; adverse events
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Fever4133038Risk Ratio (M-H, Random, 95% CI)0.98 [0.85, 1.14]
2 Erythema3132261Risk Ratio (M-H, Random, 95% CI)3.04 [0.45, 20.30]
3 Swelling at injection site31767Risk Ratio (M-H, Random, 95% CI)6.06 [1.07, 34.22]
4 Pain at injection site1667Risk Ratio (M-H, Random, 95% CI)7.98 [3.69, 17.24]
5 Serious adverse events4133038Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 5.1.

Comparison 5 Vi polysaccharide vaccine vs control; adverse events, Outcome 1 Fever.

Analysis 5.2.

Comparison 5 Vi polysaccharide vaccine vs control; adverse events, Outcome 2 Erythema.

Analysis 5.3.

Comparison 5 Vi polysaccharide vaccine vs control; adverse events, Outcome 3 Swelling at injection site.

Analysis 5.4.

Comparison 5 Vi polysaccharide vaccine vs control; adverse events, Outcome 4 Pain at injection site.

Analysis 5.5.

Comparison 5 Vi polysaccharide vaccine vs control; adverse events, Outcome 5 Serious adverse events.

Comparison 6. Vi-rEPA vaccine (two doses) vs control; efficacy
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of typhoid fever1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
1.1 Year 11 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Year 21 Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 6.1.

Comparison 6 Vi-rEPA vaccine (two doses) vs control; efficacy, Outcome 1 Incidence of typhoid fever.

Comparison 7. Vi-rEPA vaccine vs control; adverse events
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Fever after Vi-rEPA (dose1)212209Risk Ratio (M-H, Random, 95% CI)1.55 [0.57, 4.23]
2 Fever after Vi-rEPA (dose 2)211286Risk Ratio (M-H, Random, 95% CI)2.29 [0.56, 9.46]
3 Erythema after Vi-rEPA (dose 1)212209Risk Ratio (M-H, Random, 95% CI)3.03 [0.32, 28.64]
4 Erythema after Vi-rEPA (dose 2)211286Risk Ratio (M-H, Random, 95% CI)2.01 [0.18, 22.21]
5 Swelling at injection site after Vi-rEPA (dose 1)212209Risk Ratio (M-H, Random, 95% CI)1.01 [0.15, 7.03]
6 Swelling at injection site after Vi-rEPA (dose 2)211286Risk Ratio (M-H, Random, 95% CI)5.27 [0.26, 106.74]
7 Serious adverse events212209Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 7.1.

Comparison 7 Vi-rEPA vaccine vs control; adverse events, Outcome 1 Fever after Vi-rEPA (dose1).

Analysis 7.2.

Comparison 7 Vi-rEPA vaccine vs control; adverse events, Outcome 2 Fever after Vi-rEPA (dose 2).

Analysis 7.3.

Comparison 7 Vi-rEPA vaccine vs control; adverse events, Outcome 3 Erythema after Vi-rEPA (dose 1).

Analysis 7.4.

Comparison 7 Vi-rEPA vaccine vs control; adverse events, Outcome 4 Erythema after Vi-rEPA (dose 2).

Analysis 7.5.

Comparison 7 Vi-rEPA vaccine vs control; adverse events, Outcome 5 Swelling at injection site after Vi-rEPA (dose 1).

Analysis 7.6.

Comparison 7 Vi-rEPA vaccine vs control; adverse events, Outcome 6 Swelling at injection site after Vi-rEPA (dose 2).

Analysis 7.7.

Comparison 7 Vi-rEPA vaccine vs control; adverse events, Outcome 7 Serious adverse events.

Appendices

Appendix 1. Search methods: detailed search strategies

Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSb
1typhoid fevertyphoid*typhoid*typhoid$typhoid fever
2vaccine*typhoid-fever*typhoid feverTYPHOID FEVERvaccine*
31 and 2salmonell*TYPHOID FEVERtyphoid fever1 and 2
41 or 2 or 3salmonell*salmonell$typhoid vaccine
5vaccine*1 or 2 or 3 or 41 or 2 or 3 or 4paratyphoid vaccine
64 and 5vaccine*vaccine$3 or 4 or 5
75 and 65 and 6
8TYPHOID-PARATYPHOID VACCINESTYPHOID VACCINE
9TY21 TYPHOID VACCINETYPHOID-PARATYPHOID VACCINE
10VI POLYSACCHARIDE VACCINE, TYPHOID7 or 8 or 9
117 or 8 or 9 or 10Limit 10 to human
12Limit 11 to human

aCochrane Infectious Diseases Group Specialized Register.
bSearch terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2006); upper case: MeSH or EMTREE heading; lower case: free text term.

What's new

DateEventDescription
17 June 2013New search has been performedThis is an update of the review prepared by Fraser et al (Fraser 2007a). This review update includes four new trials, three evaluating the Vi polysaccharide vaccine (two reporting on efficacy and adverse events, one reporting on adverse events only) and one evaluating the Vi-rEPA vaccine (reporting adverse events).
17 June 2013New citation required but conclusions have not changedFour new trials added.

History

Protocol first published: Issue 4, 1998
Review first published: Issue 4, 1998

DateEventDescription
22 August 2008AmendedConverted to new review format with minor editing.
26 April 2007New citation required and conclusions have changed2007, Issue 3: This review is an update of the original version prepared by EA Engels and J Lau (Engels 1998a). This review evaluates the evidence available for a new vaccine (Vi-rEPA) and includes 3 new efficacy trials that were not included in Engels 1998a (1 evaluating the Vi-rEPA and 2 evaluating the Vi polysaccharide vaccine). It would also have included head-on comparisons of the different types of vaccines (not included in Engels 1998a) had these direct comparisons been conducted. Since Engels 1998a was published, killed whole-cell vaccines are no longer in use and therefore are not included in this review.

Contributions of authors

E Anwar: data collection and management, analysis, interpretation of results and review writing. E Goldberg: data collection. M Paul: data extraction and review writing. A Fraser: review writing, CJ Acosta: review writing. L Leibovici: review writing.

Declarations of interest

For all review authors, none known.

Sources of support

Internal sources

  • Liverpool School of Tropical Medicine, UK.

  • University of Liverpool, UK.

External sources

  • Department for International Development (DFID), UK.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Acharya 1987 NPL

Methods

Design: individual-RCT

Active surveillance for efficacy (health workers visited vaccinees every 2 days; in case of a fever lasting longer than 3 days, a blood sample was taken) and adverse events (health workers examined vaccinees on days 1 to 3 post-vaccination)

Participants

Number: 6907

Inclusion criteria: age 5 to 44 years

Exclusion criteria: children age < 2 years; fever or acute illness; pregnancy

Interventions

1. Capsular polysaccharide of S. typhi, Vi: 25 µg Vi in 0.5 mL; 3457 participants
2. Pneumococcal vaccine: 25 µg; 3450 participants

Route and schedule: intramuscular injection; 1 dose

Concomitant medication: not specified

Outcomes1. Typhoid fever cases (S. typhi bacteraemia)
2. Adverse events
Notes

Location: 5 villages near Kathmandu, Nepal

Socioeconomic description: rural, low income

Setting: home

Date: 1986 to 1988

No demographic information

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomized, random arrangement of syringes in packages of 10. Insufficient information about the sequence generation process provided to permit judgement
Allocation concealment (selection bias)Low riskSequentially numbered vaccines of identical appearance
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-blind trial
Incomplete outcome data (attrition bias)
All outcomes
Low riskInclusion of randomized assigned participants in analysis: 100%
Selective reporting (reporting bias)Low riskAll expected outcomes reported on
Other biasLow riskNone

Black 1990i CHL

Methods

Design: cluster (classroom)-RCT

Intermediate surveillance for efficacy: enteric fever and isolation of S. typhi from blood or bone marrow in clinics and local hospital during the study (5-year follow-up)

Participants

Number: 54,925 participants

Number of classrooms: 3655

Inclusion criteria: age 5 to 22 years

Exclusion criteria: no details

Interventions

1. Lyophilized attenuated S. typhi strain Ty21a: enteric-coated capsule containing 2-5 × 109 viable Ty21a; 27,620 participants
2. Placebo: in enteric-coated capsule; 27,305 participants

Route and schedule: oral; 2 doses, 1 week apart

Concomitant medication: not specified

Outcomes1. Typhoid fever cases (S. typhi bacteraemia or in bone marrow)
Notes

Location: northern area of Santiago, Chile

Socioeconomic description: no details

Setting: school

Date: 1982 to 1987

No demographic information

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskGeneration of allocation sequence: unclear
Allocation concealment (selection bias)Low riskAllocation concealment: central (WHO). Sequentially numbered vaccines of identical appearance
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskOf 91,954 participating children, 82,543 received all assigned doses. No reason for missing data provided
Selective reporting (reporting bias)Low riskAll expected outcomes reported on
Other biasUnclear riskUnclear whether data were adjusted for clustering

Black 1990ii CHL

MethodsSee Black 1990i CHL (Black 1990ii CHL is a different arm of the same trial)
ParticipantsDetails as for Black 1990i CHL, except number: 54,923
Interventions

1. Lyophilized attenuated S. typhi strain Ty21a: enteric-coated capsule containing 2-5 × 109 viable Ty21a; 27,618 participants
2. Placebo: in enteric-coated capsule; 27,305 participants

Route and schedule: oral; 1 dose (2nd dose contained placebo in all participants)

Concomitant medication: not specified

OutcomesDetails as for Black 1990i CHL
NotesDetails as for Black 1990i CHL
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDetails as for Black 1990i CHL
Allocation concealment (selection bias)Low riskDetails as for Black 1990i CHL
Blinding (performance bias and detection bias)
All outcomes
Low riskDetails as for Black 1990i CHL
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDetails as for Black 1990i CHL
Selective reporting (reporting bias)Low riskDetails as for Black 1990i CHL
Other biasUnclear riskDetails as for Black 1990i CHL

Cryz 1993 THA

MethodsDesign: individual-RCT
Participants

Number: 634

Inclusion criteria: children 2 to 6 years old with no history of typhoid fever

Exclusion criteria: no details

Interventions

1. Ty21a liquid formulation
2. Placebo

Route and schedule: oral solution; 3 doses

Outcomes1. Adverse events
2. Immunogenicity
Notes

Location: Thailand

Socioeconomic description: no details

Date: no details

No demographic details

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskGeneration of the allocation sequence: unclear
Allocation concealment (selection bias)Low riskSequentially numbered vaccines of identical appearance
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInclusion of randomly assigned participants in analysis: unclear
Selective reporting (reporting bias)Unclear riskInsufficient information to permit judgement
Other biasLow riskNone

Keitel 1994 USA

Methods

Design: individual-RCT

Active surveillance for adverse events: local and systemic symptoms before and at 24 and 48 hours after inoculation; fever and symptoms at 6 to 9 hours, days 1, 2, 7, 14 and 28 after inoculation

Participants

Number: 323

Inclusion criteria: age 8 to 40 years; healthy; no previous typhoid vaccination

Exclusion criteria: no details

Interventions

1. Capsular polysaccharide of S. typhi, Vi vaccine (freeze-dried preparation and liquid preparation): 25 µg Vi in 0.5 mL; 237 participants
2. Placebo: 86 participants

Route and schedule: intramuscular injection; 1 dose

Concomitant medication: not specified

Outcomes1. Adverse events
2. Immunogenicity
Notes

Location: Houston, Texas, USA

Socioeconomic description: urban, high income

Setting: clinic

Date: no information

No demographic information

Results presented jointly for 3 separate trials

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskGeneration of allocation sequence: unclear
Allocation concealment (selection bias)Unclear riskAllocation concealment: unclear
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data. Inclusion of randomly assigned participants in analysis: 100%
Selective reporting (reporting bias)Low riskAll outcomes reported on
Other biasLow risknone

Khan 2012 PAK

Methods

Design: Cluster (geographic clusters)-RCT

Intermediate surveillance for efficacy: Participants were identified through three study health centres during study period (2 years)

Surveillance for adverse events: All participants were visited 30 minutes after vaccination, a subgroup of 240 participants were visited 3 days after vaccination and an adverse event form was completed

Participants

51,965 participants

120 geographic clusters using the Geographic Information System (GIS) imagery (60 clusters in each study arm)

Inclusion criteria: children between the ages of 2 and 16 years

Exclusion criteria: married female children older than 12 years of age were not included to avoid inadvertent immunization of pregnant women. Recent history of fever

Interventions

Single-dose capsular polysaccharide of S. typhi, Vi vaccine (dose 25 mcg) or hepatitis A vaccine (dose 720 IU)

Route and schedule: single intramuscular injection, Vi vaccine or hepatitis A vaccine

Outcomes

1. Typhoid fever cases (S. typhi bacteraemia)

2. Indirect protection from typhoid fever

3. Adverse events

Notes

Location: Karachi, Pakistan

Socioeconomic description: low socioeconomic urban squatter settlements

Date: 2002 and 2007

Setting: vaccination centres and health centres

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA table of random numbers was used
Allocation concealment (selection bias)Low riskVaccine identified by code, code assignment held centrally
Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and investigators blinded— vaccines identified only by code. One vaccine administered per cluster
Incomplete outcome data (attrition bias)
All outcomes
Low riskReason for missing data given (migration, dying from other causes) and balanced across groups
Selective reporting (reporting bias)Low riskStudy protocol not available but published study reports on both primary and secondary outcome
Other biasLow riskNo recruitment bias, no baseline imbalance, no loss of clusters, analysis adjusted for clustering using generalized estimating equation

Klugman 1987 ZAF

Methods

Design: individual-RCT

Active surveillance for efficacy: blood cultures if febrile with no obvious clinical cause

Participants

Number: 11,384

Inclusion criteria: 5 to 15 years

Exclusion criteria: no details

Interventions

1. Capsular polysaccharide of S. typhi, Vi vaccine: 25 µg Vi; 5692 participants
2. Meningococcal vaccine: 25 µg Vi; 5692 participants

Route and schedule: intramuscular injection; 1 dose

Concomitant medication: not specified

Outcomes1. Typhoid fever cases (S. typhi bacteraemia)
2. Immunogenicity
Notes

Location: eastern Transvaal area of South Africa

Socioeconomic description: no details

Setting: school

Date: 1985 to 1988

No demographic information

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomization process unclear
Allocation concealment (selection bias)Low riskSequentially numbered vaccines of identical appearance. Code held by independent observers
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind. Vaccines identical in appearance
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data. Inclusion of randomized assigned participants in analysis: 100%
Selective reporting (reporting bias)Low riskAll expected outcomes reported
Other biasLow riskNone

Levine 1986i CHL

Methods

Design: individual-RCT

Active surveillance for adverse events: no further details

Participants

Number: 539

Inclusion criteria: adults, no details

Exclusion criteria: no details

Interventions

1. Enteric-coated capsules S. typhi Ty21a vaccine: 172 participants
2. Placebo: 367 participants

Route and schedule: oral capsules; 3 doses

Concomitant medication: not specified

Outcomes1. Adverse events
Notes

Location: Chile

Socioeconomic description: no details

Setting: no details

Date: no details

No demographic information

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskGeneration of allocation sequence: unclear
Allocation concealment (selection bias)Unclear riskAllocation concealment: unclear
Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding: double blind (no details)
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInclusion of randomly assigned participants in analysis: unclear
Selective reporting (reporting bias)Low riskAll expected outcomes reported
Other biasLow riskNone

Levine 1986ii CHL

MethodsSee Levine 1986i CHL (Levine 1986ii CHL is a different arm of the same trial with separate placebo group)
Participants

Number: 337

Inclusion criteria: children, no details

Exclusion criteria: no details

Interventions

1. S. typhi Ty21a vaccine in milk with NaHCO3S: 172 participants
2. Placebo: 172 participants

Route and schedule: oral capsules; 3 doses

Concomitant medication: not specified

OutcomesDetails as for Levine 1986i CHL
NotesDetails as for Levine 1986i CHL
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDetails as for Levine 1986i CHL
Allocation concealment (selection bias)Unclear riskDetails as for Levine 1986i CHL
Blinding (performance bias and detection bias)
All outcomes
Low riskDetails as for Levine 1986i CHL
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDetails as for Levine 1986i CHL
Selective reporting (reporting bias)Low riskDetails as for Levine 1986i CHL
Other biasLow riskDetails as for Levine 1986i CHL

Levine 1987i CHL

Methods

Design: cluster (classroom)-RCT

Intermediate surveillance for efficacy: enteric fever and isolation of S. typhi from blood, bone marrow or bile-stained duodenal fluid in the hospital or in clinics during the trial (3 years)

Participants

Number: 27,074

Number of classrooms: 4312

Inclusion criteria: age 6 to 21 years; parental consent; no further details

Exclusion criteria: no details

Interventions

1. Enteric capsules of S. typhi, Ty21a vaccine: 21,598 participants
2. Placebo: 5476 participants (placebo group divided into 4 equal groups for the comparison)

Route and schedule: oral capsules; 3 doses given 21 days apart

Concomitant medication: not specified

Outcomes1. Typhoid fever cases (S. typhi bacteraemia, in bone marrow or in duodenal fluid)
Notes

Location: Chile socioeconomic description: no details

Setting: school

Date: 1983 to 1986

No demographic information

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskGeneration of allocation sequence: unclear
Allocation concealment (selection bias)Low riskSequentially numbered vaccines of identical appearance
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInclusion of randomly assigned participants in analysis: 78% (109,594/141,127) of enrolled children received 3 doses and included in results. No reason for missing data given
Selective reporting (reporting bias)Low riskAll expected outcomes reported
Other biasUnclear riskAnalysis not adjusted for clustering

Levine 1987ii CHL

Methods

See Levine 1987i CHL (Levine 1987ii CHL is a different arm of the same trial)

Details as for Levine 1987i CHL, except blinding: placebo given in a similar regimen, but not mentioned if identical to gelatin or enteric capsules

ParticipantsDetails as for Levine 1987i CHL, except number: 27,647
Interventions

1. Enteric capsules of S. typhi, Ty21a vaccine: 22,170 participants
2. Placebo: 5477 participants (placebo group divided into 4 equal groups for the comparison)

Route and schedule: oral capsules; 3 doses given 2 days apart
Concomitant medication: not specified

OutcomesDetails as for Levine 1987i CHL
NotesDetails as for Levine 1987i CHL
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDetails as for Levine 1987i CHL
Allocation concealment (selection bias)Low riskDetails as for Levine 1987i CHL
Blinding (performance bias and detection bias)
All outcomes
Low riskDetails as for Levine 1987i CHL
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDetails as for Levine 1987i CHL
Selective reporting (reporting bias)Low riskDetails as for Levine 1987i CHL
Other biasUnclear riskDetails as for Levine 1987i CHL

Levine 1987iii CHL

MethodsSee Levine 1987i CHL (Levine 1987iii CHL is a different arm of the same trial)
ParticipantsDetails as for Levine 1987i CHL, except number: 27,017
InterventionsDetails as for Levine 1987i CHL, except:
1. Gelatin capsules of S. typhi, Ty21a vaccine: 21,541
2. Placebo: 5476 (placebo group divided into 4 equal groups for the comparison)
OutcomesDetails as for Levine 1987i CHL
NotesDetails as for Levine 1987i CHL
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDetails as for Levine 1987i CHL
Allocation concealment (selection bias)Low riskDetails as for Levine 1987i CHL
Blinding (performance bias and detection bias)
All outcomes
Low riskDetails as for Levine 1987i CHL
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDetails as for Levine 1987i CHL
Selective reporting (reporting bias)Low riskDetails as for Levine 1987i CHL
Other biasUnclear riskDetails as for Levine 1987i CHL

Levine 1987iv CHL

Methods

See Levine 1987i CHL (Levine 1987iv CHL is a different arm of the same trial)

Details as for Levine 1987i CHL, except blinding: placebo given in a similar regimen, but not mentioned whether identical to gelatin or enteric capsules

ParticipantsDetails as for Levine 1987i CHL, except number: 27,856
Interventions

1. Gelatin capsules of S. typhi, Ty21a vaccine: 22,379 participants
2. Placebo: 5477 participants (placebo group divided into 4 equal groups for the comparison)

Route and schedule: oral capsules; 3 doses given 2 days apart

Concomitant medication: not specified

OutcomesDetails as for Levine 1987i CHL
NotesDetails as for Levine 1987i CHL
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDetails as for Levine 1987i CHL
Allocation concealment (selection bias)Low riskDetails as for Levine 1987i CHL
Blinding (performance bias and detection bias)
All outcomes
Low riskDetails as for Levine 1987i CHL
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDetails as for Levine 1987i CHL
Selective reporting (reporting bias)Low riskDetails as for Levine 1987i CHL
Other biasUnclear riskDetails as for Levine 1987i CHL

Levine 1990i CHL

Methods

Design: cluster (classroom)-RCT

Intermediate surveillance for efficacy: enteric fever and isolation of S. typhi from blood, bone marrow or bile-stained duodenal fluid in the hospital or in clinics during the study (5 years)

Participants

Number: 42,073

Number of classes: 5423

Inclusion criteria: 5 to 19 years old; parental consent; no further details

Exclusion criteria: no details

Interventions

1. Liquid formulation of S. typhi, Ty21a vaccine: 36,623 participants
2. Placebo: 5450 participants

Route and schedule: oral solution; 3 doses given 2 days apart

Concomitant medication: not specified

Outcomes1. Typhoid fever cases (S. typhi bacteraemia, in bone marrow or in duodenal fluid)
Notes

Location: Chile

Socioeconomic description: no details

Setting: school

Date: 1986 to 1991

No demographic information

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskGeneration of allocation sequence: unclear
Allocation concealment (selection bias)Low riskSequentially numbered vaccines of identical appearance. Code kept at WHO
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind. Identical packets and capsules
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskInclusion of randomly assigned participants in analysis: 85% (81,621/95,910 children who received at least 1 dose) received all 3 doses and included in results. No reason for missing data given
Selective reporting (reporting bias)Low riskAll expected outcomes reported
Other biasUnclear riskAnalysis not adjusted for clustering; however, authors state, "analysis of cases by class after three years of follow-up showed no clustering"

Levine 1990ii CHL

Methods

See Levine 1990i CHL (Levine 1990ii CHL is a different arm of the same trial)

Details as for Levine 1990i CHL, except intermediate surveillance for efficacy for 3 years

ParticipantsDetails as for Levine 1990i CHL, except number: 39,548
InterventionsDetails as for Levine 1990i CHL, except:
1. Enteric capsules of S. typhi, Ty21a vaccine: 34,696 participants
2. Placebo: 4852 participants
OutcomesDetails as for Levine 1990i CHL
NotesDetails as for Levine 1990i CHL
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskDetails as for Levine 1990i CHL
Allocation concealment (selection bias)Low riskDetails as for Levine 1990i CHL
Blinding (performance bias and detection bias)
All outcomes
Low riskDetails as for Levine 1990i CHL
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskDetails as for Levine 1990i CHL
Selective reporting (reporting bias)Low riskDetails as for Levine 1990i CHL
Other biasUnclear riskDetails as for Levine 1990i CHL

Lin 2001 VNM

Methods

Design: individual-RCT

Active surveillance for efficacy and adverse events: weekly history; temperature; blood cultures and serology if febrile during the trial (27 months); review of bacteriological records in the provincial hospital

Passive surveillance: 19 additional months

Participants

Number: 12,008

Inclusion criteria: age 2 to 5 years; no further details

Exclusion criteria: illnesses that required ongoing medical care; fever > 37.5 °C at first injection

Interventions

1. Vi-rEPA vaccine; capsular polysaccharide of S. typhi, Vi, bound to a nontoxic recombinant protein that is antigenically identical to Pseudomonas aeruginosa exotoxin A; 22 µg Vi in 0.5 mL; 5991 participants
2. Placebo: 6017 participants

Route and schedule: intramuscular injection; 2 doses, 6 weeks apart

Concomitant medication: not specified

Outcomes

1. Typhoid fever cases (S. typhi bacteraemia)
2. Adverse events
3. Immunogenicity

Subgroups for gender, age and study year

Notes

Location: Dong Thap Province, Mekong Delta, Vietnam

Socioeconomic description: rural; low income

Setting: home

Date: 1998 to 2000

Sex, age at vaccination, household composition and size and interval between the 2 injections similar in both groups

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskIdentical looking vaccine and placebo were randomly numbered 0 to 9 and packaged in packets of 10; however, unclear how randomization sequence generated
Allocation concealment (selection bias)Low riskCode identifying identical-looking vaccine and placebo was kept at the central pharmacy
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind. Vaccine and placebo vials indistinguishable
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data. Inclusion of randomly assigned participants in analysis: 100%
Selective reporting (reporting bias)Low riskAll expected outcomes reported on
Other biasLow riskNone

Olanratmanee 1992 THA

Methods

Design: individual-RCT

Active surveillance for adverse events: 1.5 hours of observation and parental reporting via adverse event report sheet

Participants

Number: 170

Inclusion criteria: age 4 to 6 years; no further details

Exclusion criteria: no details

Interventions

1. Liquid formulation of S. typhi, TY21a: 88 participants
2. Placebo: 82 participants

Route and schedule: oral solution; 3 doses, alternate days

Concomitant medication: not specified

Outcomes1. Adverse events
2. Immunogenicity
Notes

Location: Thailand

Socioeconomic description: no details

Setting: clinic

Date: no details

No demographic information

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskGeneration of allocation sequence: not mentioned
Allocation concealment (selection bias)Unclear riskAllocation concealment: no information
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind. Identical vaccine and placebo packages
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data. Inclusion of randomly assigned participants in analysis: 100%
Selective reporting (reporting bias)Low riskAll expected outcomes reported
Other biasLow riskNone

Simanjuntak 1991i IDN

Methods

Design: individual-RCT

Intermediate surveillance for efficacy: isolation of S. typhi from blood during trial (2.5 years)

Surveillance for adverse events: questionnaires collected from 588 individuals

Participants

Number: 10,212

Inclusion criteria: age 3 to 44 years; no further details

Exclusion criteria: pregnant women; febrile illness

Interventions

1. Liquid formulation of S. typhi, Ty21a: 5066 participants
2. Placebo: 5146 participants

Route and schedule: oral solution; 3 doses, 1 week apart

Concomitant medication: not specified

Note Simanjuntak 1991ii IDN is a different arm of the same trial (see below for further details). Simanjuntak 1991i IDN and Simanjuntak 1991ii IDN had different placebo groups

Outcomes

1. Typhoid fever cases (S. typhi bacteraemia)
2. Adverse events

Subgroups for age and study year

Notes

Location: Plaju and Sungai Gerong, Sumatra, Indonesia

Socioeconomic description: no details

Setting: clinic

Date: 1986 to 1989

Sex, age at vaccination, residence in a compound, history of typhoid vaccination and level of education similar in both groups

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskGeneration of allocation sequence: computer-generated table of random numbers
Allocation concealment (selection bias)Low riskIdentical vaccine and placebo
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind. Identical vaccine and placebo
Incomplete outcome data (attrition bias)
All outcomes
Low risk93% of participants (20,543/22,001) received 3 doses and included in results. Missing outcome data balanced across intervention and control groups
Selective reporting (reporting bias)Low riskAll expected outcomes reported on
Other biasLow riskNone

Simanjuntak 1991ii IDN

Methods

See Simanjuntak 1991i IDN (Simanjuntak 1991ii IDN is a different arm of the same trial)

Details as for Levine 1990i CHL, except surveillance for adverse events: questionnaires collected from 602 individuals

ParticipantsDetails as for Simanjuntak 1991i IDN, except number: 10,331
Interventions

1. Enteric capsules of S. typhi, Ty21a: 5209 participants
2. Placebo: 5122 participants

Route and schedule: oral capsules; 3 doses, 1 week apart
Concomitant medication: not specified

Note Simanjuntak 1991i IDN is a different arm of the same trial (see below for further details). Simanjuntak 1991i IDN and Simanjuntak 1991ii IDN had different placebo groups

OutcomesDetails as for Simanjuntak 1991i IDN
NotesDetails as for Simanjuntak 1991i IDN
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskDetails as for Simanjuntak 1991i IDN
Allocation concealment (selection bias)Low riskDetails as for Simanjuntak 1991i IDN
Blinding (performance bias and detection bias)
All outcomes
Low riskDetails as for Simanjuntak 1991i IDN
Incomplete outcome data (attrition bias)
All outcomes
Low riskDetails as for Simanjuntak 1991i IDN
Selective reporting (reporting bias)Low riskDetails as for Simanjuntak 1991i IDN
Other biasLow riskDetails as for Simanjuntak 1991i IDN

Sur 2009 IND

Methods

Design: cluster (geographic clusters)-RCT

Active surveillance for efficacy: five study clinics were established to conduct surveillance
for febrile illnesses and to refer participants with severe disease for hospital care during study period (2 years)

Surveillance period adverse events: all participants 30 minutes after vaccination, subgroup of 320 participants for 3 consecutive days, passive surveillance for adverse events for 1 month at all study clinics and hospitals

Participants

37,673 participants

80 contiguous geographic clusters (40 clusters in each study group)

Inclusion criteria: 24 months of age and older, no reported fever or had an axillary temperature not greater than 37.5 °C at time of administration

Exclusion criteria: not stated

Interventions

Single-dose capsular polysaccharide of S. typhi, Vi vaccine (dose 25 mcg) or inactivated hepatitis A vaccine (dose 720 IU for children 2 to 18, 1440 IU for adults)

Route and schedule: single intramuscular injection, Vi vaccine or inactivated hepatitis A vaccine

Outcomes

1. Typhoid fever cases (S. typhi bacteraemia)

2. Indirect protection from typhoid fever

3. Adverse events

Notes

Location: Kolkata, India

Socioeconomic description: slum-dwelling residents

The clusters were stratified according to ward and the number of residents who were 18 years of age or younger (< 200 vs ≥ 200 persons) and the number of residents who were older than 18 years (< 500 vs ≥ 500 persons), resulting in eight strata

Date: November 2004 to December 2006

Setting: vaccination centres set up for each cluster and health clinics

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Used a table of random numbers to assign half the 80 clusters to each vaccine"
Allocation concealment (selection bias)Low risk"The vaccines were labelled only with code letters." However, two vaccines were not packaged in an identical fashion. Attempts to minimize this bias unlikely to have affected the findings of the trial
Blinding (performance bias and detection bias)
All outcomes
Low riskParticipants and study personnel blind. Not stated whether outcome assessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for missing data given (migration, dying from other causes) and balanced across groups
Selective reporting (reporting bias)Low riskStudy protocol not available but published study reports on both primary and secondary outcomes
Other biasLow riskNo recruitment bias, no baseline imbalance, no loss of clusters, analysis adjusted for clustering using generalized estimating equation

Thiem 2011 VNM

Methods

Design: individual-RCT

Active surveillance adverse events: Participants were observed at the clinic for 30 minutes after injection. They were visited by the commune health staff 6, 24 and 48 hours after each vaccination for measurement of temperature and inspection of the injection sites

Participants

301 full-term infants

Inclusion criteria: full-term, birth weight > 2500 g

Exclusion criteria: born to mothers with serious medical problems

Interventions

Three arms:

Vi-r EPA and expanded programme on immunization (EPI) versus Hib-TT and EPI versus EPI only

Route and schedule: intramuscular injection, infants vaccinated at 2, 4, 6 and 12 months

Outcomes1. Adverse events
Notes

Location: Thanh Thuy District, Phu Tho Province, Vietnam

Socioeconomic description: rural area

Date: not stated

Setting: community health centre and district hospital

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskInsufficient information to permit judgement
Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement
Blinding (performance bias and detection bias)
All outcomes
Unclear riskInsufficient information to permit judgement
Incomplete outcome data (attrition bias)
All outcomes
Low risk318 infants were randomly assigned. 301 infants received the first injection, 294 the second, 283 the third and 167 the fourth of either Vi-rEPA or Hib-TT. Reasons for missing data given
Selective reporting (reporting bias)Low riskExpected outcomes reported on
Other biasLow riskNone

Wahdan 1980a EGY

Methods

Design: cluster (classroom)-RCT

Intermediate surveillance for efficacy: isolation of S. typhi from blood in the hospital during the study (3 years)

Surveillance for adverse events: no details

Participants

Number: 32,388

Inclusion criteria: age 6 to 7 years; no further details

Exclusion criteria: no details

Interventions

1. Liquid formulation of S. typhi, Ty21a: 16,486 participants
2. Placebo: 15,902 participants

Route and schedule: oral solution; 3 doses, alternate days

Concomitant medication: not specified

Outcomes1. Typhoid fever cases (S. typhi bacteraemia)
2. Adverse events
Notes

Location: Alexandria, Egypt

Socioeconomic description: no details

Setting: school

Date: 1978 to 1981

No demographic information

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskGeneration of allocation sequence: unclear
Allocation concealment (selection bias)Unclear riskVaccine and placebo identical. Allocation concealment unclear
Blinding (performance bias and detection bias)
All outcomes
Low riskVaccine and placebo identical
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data. Inclusion of randomly assigned participants in analysis: 100%
Selective reporting (reporting bias)Low riskAll expected outcomes reported on
Other biasUnclear riskAnalysis not adjustment for clustering

Wahdan 1980b EGY

Methods

Design: cluster (classroom)-RCT

Surveillance for adverse events: no details

Participants

Number: 884

Inclusion criteria: age 6 to 7 years; no further details

Exclusion criteria: no details

Interventions

1. Liquid formulation of S. typhi, Ty21a: 413 participants
2. Placebo: 471 participants

Route and schedule: oral solution; 3 doses, alternate days

Concomitant medication: not specified

Outcomes1. Adverse events
Notes

Location: Alexandria, Egypt

Socioeconomic description: no details

Setting: school

Date: 1978

No demographic information

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskGeneration of allocation sequence: unclear
Allocation concealment (selection bias)Unclear riskVaccine and placebo identical. Allocation concealment unclear
Blinding (performance bias and detection bias)
All outcomes
Low riskVaccine and placebo identical
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data. Inclusion of randomly assigned participants in analysis: 100%
Selective reporting (reporting bias)Unclear riskAll expected outcomes reported on
Other biasUnclear riskAnalysis not adjusted for clustering

Wang 1997a CHN

Methods

Design: individual-RCT

Passive surveillance for efficacy: signs and symptoms of typhoid fever; blood cultures and serum Widal's test (1 year)

Participants

Number: 81,506

Inclusion criteria: age 5 to 55 years; healthy

Exclusion criteria: history of liver, kidney or heart disease; hypertension; acute infection; psychiatric disease; allergic history; prior typhoid infection; pregnancy; prior typhoid vaccination in the last 2 years

Interventions

1. Capsular polysaccharide of S. typhi, Vi vaccine: 30 µg Vi: 41,118 participants
2. Meningococcal vaccine: 40,388 participants

Route and schedule: intramuscular injection; 1 dose

Concomitant medication: not specified

Outcomes

1. Typhoid fever cases (S. typhi bacteraemia)
2. Adverse reactions

Subgroups for age and gender

Notes

Location: Baoying County, Jiangsu Province, China

Socioeconomic description: no details

Setting: no details

Date: 1994 to 1995

No demographic information

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskGeneration of allocation sequence: computer-generated random numbers ?
Allocation concealment (selection bias)Low riskAllocation concealment: code concealed from field workers and study population
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind. Identical vaccine and placebo vials
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data. Inclusion of randomly assigned participants in analysis: 100%
Selective reporting (reporting bias)Low riskAll expected outcomes reported on
Other biasLow riskNone

Wang 1997b CHN

Methods

Design: individual-RCT

Surveillance for adverse events: fever and local symptoms checked before immunization, and 6 to 8, 24 and 48 hours after immunization

Participants

Number: 777

Inclusion criteria: > 6 years old; healthy

Exclusion criteria: no details

Interventions

1. Capsular polysaccharide of S. typhi, Vi vaccine: 30 µg Vi; 384 participants
2. Meningococcal vaccine: 393 participants

Route and schedule: intramuscular injection; 1 dose

Concomitant medication: not specified

Outcomes1. Adverse reactions
Notes

Location: Baoying County, Jiangsu Province, China

Socioeconomic description: no details

Setting: no details

Date: 1994

No demographic information

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskGeneration of allocation sequence: computer-generated random numbers
Allocation concealment (selection bias)Low riskAllocation concealment: code concealed from field workers and study population
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind. Vaccine and placebo identical
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll expected outcomes reported
Other biasLow riskNone

Yang 2001 CHN

Methods

Design: individual-RCT

Passive surveillance for efficacy: clinical symptoms; positive blood cultures and serum Widal's test during trial (1.6 years)

Surveillance for adverse events: parental reporting of adverse effects in 3 schools

Participants

Number: 131,271

Inclusion criteria: healthy children age 3 to 19 years and adults age < 51 years

Exclusion criteria: chronic disease; under medication; pregnancy

Interventions

1. Capsular polysaccharide of S. typhi, Vi vaccine: 30 µg Vi; 65,287 participants
2. Placebo: 65,984 participants

Route and schedule: hypodermically; 1 dose

Concomitant medication: not specified

Outcomes

1. Typhoid fever cases (S. typhi bacteraemia)
2. Adverse events

Subgroups for age, profession and sex

Notes

Location: County of Quan, north-eastern part of Guangxi Zhuang

Autonomous Region, southern China

Socioeconomic description: no details

Setting: clinic

Date: 1995 to 1996

Age, sex and profession similar in both groups

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskGeneration of allocation sequence: unique serial number to each participant; having an even or an odd number determined allocation to vaccine or placebo
Allocation concealment (selection bias)Low riskAllocation concealment: code concealed from field workers and study population
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll expected outcomes reported
Other biasLow riskNone

Zhou 2007 CHN

  1. a

    Cluster-RCT: randomized controlled trial that randomly assigned clusters (eg, classrooms); ELISA: enzyme-linked immunosorbent assay; individual-RCT: randomized controlled trial that randomly assigned individual participants; WHO: World Health Organization.

Methods

Design: individual-RCT

Active surveillance for adverse events: All participants were observed for 2 hours at the vaccination
site after administration of the study agent and were visited by trained clinicians on days 1, 2, 3 and 28

Participants

Number: 667

Inclusion criteria: school children ages 9 to 14 who have previously received a primary dose of Vi vaccine, no signs or symptoms consistent with an infection within the 2 weeks before injection, no history of typhoid fever and axillary temperature of 37.5 °C on the day of the planned injection

Exclusion criteria: no previous primary dose of Vi vaccine, signs or symptoms of infection within the 2 weeks before injection, history of typhoid fever or axillary temperature higher than 37.5 °C on day of planned injection

Interventions

1. Capsular polysaccharide of S. typhi, Vi vaccine to previously vaccinated children (revaccination), 334 participants

2. Placebo (normal saline), 333 participants

Route and schedule: intramuscular injection, one dose

Outcomes1. Adverse events
Notes

Location: Suzhou, Jiangsu, China

Socioecomic description: no details

Setting: school

Date: 2002

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Computer generated random numbers"
Allocation concealment (selection bias)Unclear riskInsufficient information to permit judgement
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind—blinding of participants and study personnel. Vaccine and placebo identical
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskAll expected outcomes reported
Other biasLow riskNone

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    RCT: randomized controlled trial.

Ali 2011No relevant outcome measures
Arya 1997Letter; not an RCT
Ashcroft 1967Evaluated the inactivated whole-cell vaccine, which is no longer in use
Black 1983No relevant outcome measures
Bumann 2001Evaluated experimental live-attenuated oral vaccine candidates; no efficacy trials of this vaccine
Cahn 2004Study arms randomly assigned to receive different doses of same vaccine
Chuttani 1977Evaluated the inactivated whole-cell vaccine, which is no longer in use
Cordero-Yap 2001Compared 2 Vi polysaccharide vaccines made by 2 different companies
Cryz 1995No relevant control group
Cumberland 1992Evaluated Vi vaccine versus inactivated whole-cell vaccine, which is no longer in use
Ferreccio 1989RCT compared different doses of the Ty21a vaccine
Hejfec 1965Two separate randomized trials, described together; none of the chemical subunit vaccines that were studied are in use
Hejfec 1966Evaluated the inactivated whole-cell vaccine, which is no longer in use
Hejfec 1968Evaluated the inactivated whole-cell vaccine, which is no longer in use
Hejfec 1969Evaluated the inactivated whole-cell vaccine, which is no longer in use
Hejfec 1976Evaluated the inactivated whole-cell vaccine, which is no longer in use
Hien 2010Evaluated adverse events of new M01ZH09 vaccine, no efficacy trials of this vaccine
Hohmann 1996aNo random allocation
Hohmann 1996bNo random allocation
Kantele 2013No relevant outcome measures
Keddy 1999No relevant outcome measures
Khan 2007Nonrandomized study
Khoo 1995Evaluated safety of Vi vaccine compared with meningococcal vaccine or combination
Kirkpatrick 2006Evaluated adverse events of new M01ZH09 vaccine; no efficacy trials of this vaccine
Lebacq 2001Evaluated different brands of Vi vaccine
Levin 1975No random allocation; compared Vi with inactivated whole-cell vaccine, which is no longer in use
Lyon 2010Evaluated adverse events of new M01ZH09 vaccine; no efficacy trials of this vaccine
Murphy 1991No random allocation to vaccine and placebo arms
Nisini 1993No random allocation
Panchanathan 2001Compared Vi vaccine with inactivated whole-cell vaccine, which is no longer in use
Polish committee 1966Evaluated the inactivated whole-cell vaccine, which is no longer in use
Sabitha 2004Compared 2 brands of Vi vaccine
Tacket 1992Evaluated experimental live-attenuated oral vaccine candidates; no efficacy trials of these vaccines
Tacket 1997Evaluated experimental live-attenuated oral vaccine candidates; no efficacy trials of these vaccines
Tacket 2000Evaluated experimental live-attenuated oral vaccine candidates; no efficacy trials of these vaccines
Tapa 1975Evaluated the inactivated whole-cell vaccine, which is no longer in use
Thiem 2006No relevant outcome measures
van Damme 2011Evaluated adverse events of new conjugate vaccine (Vi-CRM); no efficacy trials of this vaccine
Wahdan 1975Quasi-RCT evaluating the inactivated whole-cell vaccine, which is no longer in use
Wahid 2011No relevant outcome measures
Yang 2005No relevant outcome measures
Yang 2009Safety only, evaluated different brands of same vaccine
Yug Ty Comm 1962Evaluated the inactivated whole-cell vaccine, which is no longer in use
Yug Ty Comm 1964Evaluated the inactivated whole-cell vaccine, which is no longer in use
Zhou 2008 CHNSafety only; evaluated different brands of same vaccine

Characteristics of ongoing studies [ordered by study ID]

Chinnasami

Trial name or titleA Clinical Trial to Study the Optimal Use of Conjugate Typhoid Vaccine—Single Dose vs Two Doses
Methods 
Participants400 healthy children between 6 months and 5 years of age
Interventions

1. Conjugated typhoid vaccination: two doses at two-month intervals, each dose 0.5 mL

2. Conjugated typhoid vaccination: single dose, dose 0.5 mL

OutcomesSeroconversion rate
Starting dateDecember 2012
Contact information

Dr Bilal Chinnasami

balajictriumphants@gmail.com

NotesLocation: Tamil Nadu, India
Clinical Trials Registry—India: CTRI/2010/091/003031

Darton 2012

Trial name or titleUnderstanding Typhoid Disease After Vaccination: A Single Centre, Randomised, Doubleblind, Placebo Controlled Study to Evaluate M01ZH09 in a Healthy Adult Challenge Model, Using Ty21a Vaccine as a Positive Control.
Methods 
Participants99 adults ages 18 to 60 years and in good health
Interventions

1. M10ZH09 vaccine

2. Ty21a vaccine

3. Vaccine placebo

OutcomesDiagnosis of typhoid fever (2 weeks after typhoid challenge)
Starting dateJuly 2011
Contact information

Thomas Darton

01865857420

Notes

Location: Oxford, United Kingdom

National Clinical Trials identifier: NCT01405521

House 2011

Trial name or titleA Phase II, Single-centre, Randomised, Single-blind Study to Evaluate Vi-CRM197 Against Historical Unvaccinated Controls in a Healthy Adult Challenge Model, With a Vi-PS Vaccine Control Arm—Understanding Immunity After Typhoid Vaccination
Methods 
Participants36 adults ages 18 to 60 years and in good health
Interventions

1. Vi-CRM197 conjugate vaccine

2. Vi-PS control arm

Outcomes

Main objective: Using an established model of human typhoid infection, in which healthy adults are deliberately infected with typhoid-causing bacteria, we will determine how effective a new typhoid vaccine (Vi-CRM197, Novartis Vaccine Institute for Global Health) is in preventing infection

Primary end point(s): the proportion of participants developing typhoid fever after challenge with S. typhi (Quailes strain) given 28 days after vaccination with NVGH Vi-CRM197 vaccine

Starting dateDecember 2011
Contact information

Ms Heather House

heather.house@admin.ox.ac.uk

Notes

Location: Oxford, United Kingdom

EU Clinical Trials Registration identifier: EUCTR2011-003653-26-GB

Mitra 2012

Trial name or titleIncidence of Typhoid Fever as Observed Over 1 Year in Children Aged 6 Months-12 Years After Receiving Conjugated Typhoid Vaccine (Peda Typh TM) Versus a Similar Non-vaccinated Group in the Same Locality in Kolkata
Methods 
Participants2000 healthy children and teenagers of both sexes from 6 months to 12 years of age
Interventions

1. Vi-Tetanus toxoid conjugated typhoid vaccine (Peda Typh TM)

2. Nil

OutcomesIncidence of typhoid fever and paratyphoid fever in the vaccinated and non vaccinated groups
Starting dateJuly 2012
Contact information

Dr Monjori Mitra

monjorim@medclinsearch.com

NotesLocation: Kolkata, India
Clinical Trials Registry—India: CTRI/2012/06/002719

Ancillary