Vaccines for preventing typhoid fever

  • Review
  • Intervention

Authors


Abstract

Background

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 vaccines for preventing typhoid fever.

Search methods

In December 2006, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2006, Issue 3), MEDLINE, EMBASE, LILACS, and mRCT. We also searched relevant conference proceedings up to 2004 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 an inactive agent (placebo or vaccine for a different disease).

Data collection and analysis

Two 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. We calculated risk ratios (RR) and efficacy (1-RR as a percentage) with 95% confidence intervals (CI).

Main results

Of the 17 included RCTs, 10 evaluated efficacy (Ty21a: 5 trials; Vi polysaccharide: 4 trials, Vi-rEPA: 1 trial), and 11 reported on adverse events.

Ty21a vaccine (3 doses). According to one trial (20,543 participants), this vaccine provided statistically significant protection in each of the first three years (one: 35%, 95% CI 8% to 54%; two: 58%, 95% CI 40% to 71%; three: 46%, 95% CI -6% to 72%), and the cumulative efficacy for 2.5 to 3 years was 48% (95% CI 34% to 58%). Four cluster-RCTs that did not adjust for clustering were not included in the meta-analyses. Compared with placebo, this vaccine was not associated with an increased rate of fever, vomiting, diarrhoea, nausea or abdominal pain, headache, or rash.

Vi polysaccharide vaccine (1 dose). This vaccine provided protection in year one (68%, 95% CI 50% to 80%; 99,979 participants, 3 trials) and year two (60%, 95% CI 31% to 76%; 142,555 participants, 2 trials), but not in year three (11,384 participants, 1 trial). The three-year cumulative efficacy was 55% (95% CI 30% to 70%; 11,384 participants, 1 trial). Compared with placebo, there was no statistically significant difference in the incidence of fever or erythema, but local swelling was more common with the vaccine.

Vi-rEPA vaccine (2 doses). In one trial of 12,008 participants, this vaccine provided protection in year one (94%, 95% CI 75% to 99%) and year two (87%, 95% CI 56% to 96%). Cumulative efficacy at 46 months (3.8 years) was 89% (95% CI 76% to 97%). No swelling or erythema occurred in the vaccine or placebo group; fever was more frequent in the vaccine group.

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.

摘要

背景

預防傷寒之疫苗

市面上有兩種疫苗, 口服Ty21a及注射Vi多醣體, 而兩者皆未常規使用. 另一種新疫苗, 為結構改造重組結合Vi疫苗稱為VirEPA正在研發中

目標

評估傷寒疫苗的預防效果

搜尋策略

在2006年12月, 我們搜尋the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2006, Issue 3), MEDLINE, EMBASE, LILACS,和mRCT.我們同時也搜尋2004年前相關的會議報告, 並掃瞄所有試驗中所提及的參考文獻

選擇標準

比較傷寒疫苗和其他傷寒疫苗或其他非活化試劑(安慰劑或用於不同疾病之疫苗)的隨機和類隨機對照組控制式試驗

資料收集與分析

兩位獨立的作者檢視依標準納入研究之數據. 我們計算疫苗之年效果和三年之累積效應並依疫苗之種類和劑量分層統計. 我們計算相對危險度(relative risks, RR)與效益(1RR, 以百分比表示)及95%信賴區間.

主要結論

在17個被納入之隨機, 對照組控制試驗中, 10個是評估疫苗效力的研究(5個試驗:Ty21a; 4個試驗:Vi polysaccharide; 1個試驗:VirEPA), 有11篇報告不良事件. Ty21a疫苗(3次劑量): 根據其中1個試驗(20,543位參與者), 顯示這種疫苗在前3年均可提供具統計意義的保護(第1年: 35%, 95%信賴區間 8%到54%; 第2年: 58%, 95%信賴區間 40%到71%; 第3年: 46%, 95%信賴區間 6%到72%),及2.5到3年的累積效力為48%(95%信賴區間, 34%到58%). 有4個未經調整的隨機, 對照組控制試驗群並沒有包括在這些分析結果中. 和安慰劑比較, 這些疫苗沒有增加發燒, 嘔吐, 腹瀉, 噁心或腹痛, 頭痛或皮疹的機率. Vi 多醣體疫苗(1個劑量). 提供第1年(68%, 95%信賴區間 50%到80%;99,979參與者, 3個試驗)和第2年(60%, 95%信賴區間 31%到76%;142,555 參與者, 2個試驗)的保護但無法持續至第3年(11,384 參與者, 1個試驗). 三年的累積效力為55%(95%信賴區間 30%到70%; 11,384 參與者, 1個試驗). 和安慰劑比較, 發燒發生率或皮膚紅疹並沒有統計上的差異, 但在VirEPA疫苗(2個劑量)中, 較常出現局部腫脹. 在1個有12,008參與者的試驗中, 這種疫苗提供第1年(94%, 95%信賴區間 75%到99%)及第2年的保護(87%, 95%信賴區間 56%到96%). 在46個月(3.8年)的累積效力為89%(95% 95%信賴區間 76%到97%). 在疫苗組及安慰劑組中, 並沒有腫脹或發紅的情形發生; 發燒較常發生在疫苗組

作者結論

通過證明的Ty21a和Vi多醣體疫苗是有效. 新型而未被許可的VirEPA疫苗也同樣有效且可提供較長的免疫力

翻譯人

本摘要由三軍總醫院林斈府翻譯。

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

Ty21a和Vi多醣體疫苗可以有效的降低傷寒的發生; 新型的疫苗也是有不錯的結果. 傷寒是種細菌感染, 主要發生在南亞和東亞, 非洲, 拉丁美洲及加勒比地區. 它的特徵有發燒, 腹部症狀, 發冷, 腹瀉或便秘, 頭痛, 喪失食欲, 咳嗽, 虛弱, 喉嚨痛, 暈眩和肌肉痛. 有時也有精神症狀和混亂. 致死率在不同地區有所差異有可能達到10%. 正常的治療需要抗生素但會造成抗藥性菌株的問題. 疫苗是另一種預防這種疾病的方式. 這篇文章發現17個試驗(16個試驗有可用的數據): 4個試驗只評估疫苗效力; 5個試驗評估疫苗效力及不良事件; 7個試驗只提供不良事件的數據. 2個主要的疫苗, Ty21a和Vi多醣體疫苗是目前許可的, 可有效的降低傷寒之發生; 不良反應包括噁心, 嘔吐, 和發燒, 均罕見. 可用於嬰兒的疫苗將十分有益的因為他們感染傷寒的風險較高.

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 in South and East Asia, Africa, Latin America, and the Caribbean. It is characterized by fever, abdominal symptoms, chills, diarrhoea or constipation, 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 is normally with antibiotics, but there are problems with drug-resistant strains. Vaccination is another way of trying to prevent this disease. The review found 17 trials (16 with usable data): four evaluated vaccine efficacy only; five evaluated efficacy and adverse events; and seven provided data only on adverse events. The two major vaccines currently licensed for use, Ty21a and Vi polysaccharide, were both effective in reducing typhoid fever; adverse events such as nausea, vomiting, and fever were rare. A vaccine that could be given to infants would be helpful as they are probably at increased risk of this infection.

Background

Typhoid fever is a major cause of morbidity with an estimated global incidence of 22 million cases and 200,000 deaths per year. It is a substantial public health problem in South and East Asia (> 100 cases per 100,000 people annually), Africa, Latin America, and the Caribbean and Oceania (10 to 100 cases per 100,000 people annually) (Crump 2004). Until recent years, the common view was that typhoid fever affects mainly children of school age and adults. However, it is now recognized that typhoid fever is an important cause of morbidity among younger children as well (Sinha 1999; Saha 2001).

In some developing countries the annual incidence may reach 1% with case-fatality rates as high as 10%, with about 70% of all deaths in Asia (WHO 2000). Typhoid is rare in industrialized nations, though travellers to endemic countries may occasionally acquire the disease (Bennish 1995). In the USA, less than 1% of persons with typhoid fever die (Mandell 2000).

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. Following 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 2000). Complications occur in 10% to 15% of patients, usually in the third and fourth week 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).

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 2000).

As humans are the only source of infection and due to the route of transmission, improved sanitation and food hygiene are important control measures. However these are associated with socioeconomic progress that has been slow to improve in most endemic areas. Furthermore, achieving control of typhoid fever by antimicrobial treatment alone requires well-functioning medical services and is hindered by the development of resistance. Therefore vaccination against typhoid fever remains an important control measure (WHO 2000).

In addition to 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).

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 the 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.

Two typhoid vaccines are currently commercially available: orally administered Ty21a (an attenuated strain of S. Typhi) and parenteral Vi polysaccharide (based on the purified capsular polysaccharide S. Typhi Vi antigen). The cumulative efficacy of these vaccines over a three-year period has been estimated at 51% and 55%, respectively, with fewer adverse effects than the whole-cell vaccines (Engels 1998a; Engels 1998b). However, neither has been adopted as a routine public health tool in any country with endemic typhoid fever.

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 aged at least five years old. It elicits protection starting from 10 to 14 days after the third dose. Travellers should be revaccinated annually, and those living in disease endemic areas every three years. The 1998 version of this Cochrane Review found this vaccine to be associated with more frequent mild adverse events than placebo (Engels 1998a). This vaccine is licensed in 56 countries in Africa, Asia, Europe, South America, and the USA (WHO 2003). A theoretical problem 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.

Vi polysaccharide vaccine

The Vi polysaccharide vaccine is given as a single parenteral dose. Protection begins seven days after injection, with maximum protection reached 28 days after injection when the highest antibody concentration is obtained (Garmory 2002). The vaccine is approved for persons aged over two years. Revaccination is recommended every three years. Mild local adverse reactions occur; for example, 17% of adult vaccinees and 86.7% of child vaccinees experience local pain at the injection site, although these reactions are usually transient and mild (Garmory 2002). The 1998 version of this Cochrane Review included only one trial that assessed adverse events associated with the Vi polysaccharide vaccine; the Vi polysaccharide vaccine was associated with less adverse events than a meningococcal vaccine (Engels 1998b). This vaccine is licensed in Australia and in more than 92 countries in Africa, the Americas, Asia, and Europe (WHO 2003).

Vi-rEPA vaccine

A new modified Vi vaccine conjugated to a nontoxic recombinant Pseudomonas aeruginosa exotoxin A (rEPA) has also been evaluated in a randomized controlled trial (RCT) among children aged two to five years. This vaccine has the potential of being immunogenic in infants under the age of two (Parry 2002).

Research continues to develop more effective typhoid vaccines. It is concentrated on two main efforts. The first is development of new parenteral Vi polysaccharide protein conjugate vaccines, which are expected to produce higher antibody titres following initial and booster immunizations. The second effort is to genetically attenuate strains of S. Typhi to achieve high immunogenicity while at the same time rendering the strain nonpathogenic (Garmory 2002).

This update of the 1998 Cochrane Review incorporates data from new trials. We would have also included head-on comparisons of vaccines had these been conducted.

Objectives

To evaluate vaccines for preventing 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 vaccine or inactive agent (placebo or vaccine for a different disease).

Excluded: Trials evaluating killed whole-cell vaccines since these vaccines are no longer in use. Trials assessing only the safety (ie providing data on adverse events) but not efficacy of experimental vaccines that have not been evaluated for efficacy (ie providing data on the number of cases of typhoid fever).

Types of outcome measures

Primary

Cases of typhoid fever, defined by isolation of S. Typhi.

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, swelling at injection site, vomiting, or 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 (December 2006); Cochrane Central Register of Controlled Trials (CENTRAL), published in The Cochrane Library (2006, Issue 3), MEDLINE (1966 to December 2006); EMBASE (1974 to December 2006); and LILACS (1982 to December 2006). We also searched the metaRegister of Controlled Trials (mRCT) using 'typhoid' and 'vaccine' as search terms. We also 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 2003); European Congress of Clinical Microbiology and Infectious Diseases (ECCMID; 2001 to 2004) and the Annual Meeting of the Infectious Diseases Society of America (IDSA; 2001 to 2004).

Reference lists

We also checked the reference lists of the included trials.

Data collection and analysis

Selection of studies

We (A Fraser and E Goldberg) independently inspected titles and abstracts identified by the literature search to identify potentially relevant publications. Potentially relevant articles, according to at least one 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 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 (A Fraser and E Goldberg) independently extracted data into a standard form; a third author (M Paul) extracted the data where there were disagreements. We discussed the data extraction, documented decisions, and, where necessary, contacted the trial authors for clarification or additional details. A Fraser entered data into Review Manager 5. We aimed to extract data according to an intention-to-treat analysis. If there was a discrepancy in the number randomized and the numbers analysed in each treatment group, we reported this information. We also recorded the surveillance method used to assess outcomes in each trial, categorizing it as active (staff going into the field to identify cases), intermediate (relying on existing clinics and encouragement to evaluate participants for typhoid fever), or passive (no increase of surveillance). We also recorded the unit of randomization and whether trials adjusted for cluster randomization in the analysis.

For dichotomous outcome measures, we recorded the number of participants experiencing the event and the number analysed in each treatment group. For trials randomized using clusters (cluster-RCTs), 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 analyse the trial were documented along with details describing whether these methods adjusted for clustering or other co-variables.

Assessment of risk of bias in included studies

We (A Fraser and E Goldberg) independently assessed the risk of bias in included trials; in case of disagreement, we consulted a third author (M Paul). We used an individual component approach to quality assessment using four variables: generation of allocation sequence; allocation concealment; inclusion of all randomized participants in the analysis; and blinding of participants and investigators. We categorized the generation of the allocation sequence and allocation concealment as adequate, unclear, or inadequate using the approach described in Jüni 2001. We recorded if trials used single, double, or no blinding, and whether all randomized participants were included in the results. We classified inclusion of all randomized participants in the analysis as adequate if it is at least 90% and inadequate if less than 90%.

Data synthesis

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

We combined dichotomous data from trials randomizing individuals using risk ratios (RR) and presented them with 95% confidence intervals (CI). We also interpreted the results as efficacy, defined as 1-RR and expressed as a percentage. When the results of a cluster-RCT had not been adjusted for clustering, we did not pool the data with cluster-RCTs that had correctly accounted for clustering or trials randomizing individuals (individual-RCTs).

This review includes four cluster-RCTs of efficacy that randomized classrooms (Black 1990i; Black 1990ii; Levine 1987i; Levine 1987ii; Levine 1987iii; Levine 1987iv; Levine 1990i; Levine 1990ii; Wahdan 1980a). These trials did not adjust for clustering in their results and therefore were not included in meta-analyses. Results of these trials are presented separately.

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). We rounded to the nearest year when trials included follow up for only part of a year.

We also calculated the cumulative three-year efficacy defined as the 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 analysed 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 the cumulative efficacy demonstrates efficacy overall, for a given period, regardless 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 following vaccination, we present data corresponding to 24 hours after vaccination.

We assessed heterogeneity by inspecting the forest plots to detect overlapping confidence intervals, applying the chi-squared test with a P-value of 0.10 indicating statistical significance, and also with I 2 test with a value of 50% used to denote moderate levels of heterogeneity. The random-effects model was used throughout the review.

We calculated numbers needed to treat (NNT) (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.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of ongoing studies.

Four-hundred and twelve potentially relevant publications were identified, 65 publications were retrieved for full-text inspection, and 35 trials (41 publications) were excluded (see 'Characteristics of excluded studies'). Seventeen RCTs − 13 individual RCTs and four cluster-RCTs − met the inclusion criteria (see details in 'Characteristics of included studies'). We also identified three ongoing studies (Khan 2006; Szu 2006; Tacket 2006; see 'Characteristics of ongoing studies').

Data on the primary outcome was available from 10 trials: five trials of Ty21a (Black 1990i; Black 1990ii; Levine 1987i; Levine 1987ii; Levine 1987iii; Levine 1987iv; Levine 1990i; Levine 1990ii; Simanjuntak 1991i; Simanjuntak 1991ii; Wahdan 1980a); four trials of Vi polysaccharide (Acharya 1987; Klugman 1987; Wang 1997a; Yang 2001); and one Vi-rEPA trial (Lin 2001). Data on adverse events were also available from 10 trials, including five trials of Ty21a. One additional trial assessed the Ty21a and reported on adverse events but did not provide the number of participants per study arm (Cryz 1993); therefore results of this trial were not included in the meta-analysis.

Four of the trials that evaluated efficacy (ie reported the primary outcome: number of typhoid cases) included more than two study arms (Black 1990i; Black 1990ii; Levine 1987i; Levine 1987ii; Levine 1987iii; Levine 1987iv; Levine 1990i; Levine 1990ii; Simanjuntak 1991i; Simanjuntak 1991ii); and four also provided data on adverse events (Wahdan 1980a; Lin 2001; Simanjuntak 1991i; Simanjuntak 1991ii; Yang 2001). Three of the efficacy trials (Wang 1997a; Lin 2001; Yang 2001) were not included in the 1988 Cochrane Review (Engels 1998a). The four cluster-RCTs were efficacy trials that randomized classrooms (Black 1990i; Black 1990ii; Levine 1987i; Levine 1987ii; Levine 1987iii; Levine 1987iv; Levine 1990i; Levine 1990ii; Wahdan 1980a). However, these cluster-RCTs, which all evaluated the Ty21a vaccine, did not adjust for clustering in their results and therefore were not included in meta-analyses.

Of the 11 trials that evaluated adverse events, four were efficacy trials and an additional seven evaluated only adverse events (Cryz 1993; Keitel 1994; Levine 1986i; Levine 1986ii; Levine 1986iii; Olanratmanee 1992; Wahdan 1980b; Wang 1997b).

All efficacy trials and all but three adverse event trials (Cryz 1993; Keitel 1994; Olanratmanee 1992) were performed in countries in which typhoid fever is endemic. None of the trials evaluated vaccine efficacy in travellers from developed countries. Most trials included children aged five years and above; the one trial that evaluated the Vi-rEPA vaccine included children aged two to five years.

None of the trials compared different types of typhoid vaccines.

Risk of bias in included studies

See Appendix 2 for a summary of the assessment and the 'Characteristics of included studies' for details on methods.

Efficacy trials

Three of the 10 trials reported adequate randomization procedures, and all 10 trials used adequate methods to conceal allocation. All but two trials used double blinding. In Lin 2001, the first 27 months of follow up were conducted in a double-blind fashion and an additional 19 months were conducted without blinding. Enteric and gelatin capsules were given two and 21 days apart (3 doses) in one trial (Levine 1987i; Levine 1987ii; Levine 1987iii; Levine 1987iv); therefore double blinding was only possible between arms receiving the different capsules on the same schedule. This was also the only efficacy trial that was inadequate (instead of adequate) in terms of including all randomized participants in the analysis.

Adverse event trials

Only one trial reported adequate methods to generate the allocation sequence and conceal allocation (Wang 1997b). These were unclear in the other trials, and because it was unclear whether classrooms or individuals were randomized in one pilot study (Wahdan 1980b), we did not include this trial's results in meta-analyses. All trials used double blinding. Four trials included all randomized participants in the analysis, and three were unclear on this issue (Cryz 1993; Levine 1986a i; Levine 1986a ii; Levine 1986b).

Effects of interventions

1. Cases of typhoid fever

1.1. Ty21a vaccine (3 doses) versus control

Two arms of one individual-RCT (liquid formulation, Simanjuntak 1991i; enteric capsules, Simanjuntak 1991ii) provided data that could be used in a meta-analysis, while the data from the cluster-RCTs are presented in Appendix 3 (Wahdan 1980a; Levine 1987i; Levine 1987ii; Levine 1987iii; Levine 1987iv; Black 1990ii; Levine 1990i; Levine 1990ii). The individual-RCT (both arms combined with 20,543 total participants) gave a vaccine efficacy of 35% at year one (95% CI 8% to 54%; Analysis 1.1), 58% at year two (95% CI 40% to 71%; Analysis 1.2), and 46% at year three (95% CI -6% to 72%; Analysis 1.3), and a cumulative efficacy at 2.5 to 3 years of 48% efficacy (95% CI 34% to 58%; Analysis 1.4). A comparison of the cumulative efficacy between the liquid formulation and enteric capsules showed no statistically significant difference (10,215 participants, Simanjuntak 1991ii, Analysis 2.1). Results of a cluster-RCT (Levine 1990i) also favoured the liquid formulation (Appendix 3).

Long-term cumulative efficacies (> 3 years of follow up) were available for several comparisons and are presented in Appendix 4.

We had intended to conduct subgroup analyses by age, but we were unable to because randomization was not stratified by age in the three trials that used different cut-off ages to define age groups, that is, these analyses could not be considered analyses of randomized participants (Levine 1987i; Levine 1987ii; Levine 1987iii; Levine 1987iv; Levine 1990i; Levine 1990ii; Simanjuntak 1991i; Simanjuntak 1991ii).

1.2. Vi vaccine versus control
Vi polysaccharide vaccine

The efficacy of this vaccine was 68% at year one (95% CI 50% to 80%; 99,797 participants, 3 trials, Analysis 3.1) and 60% at year two (95% CI 31% to 76%; 142,555 participants, 2 trials, Analysis 3.1). Efficacy in the third year, based on a single trial (Klugman 1987), was not statistically significant (50%, 95% CI 11% to 78%; 11,384 participants, Analysis 3.1). Cumulative efficacy at 2.5 to 3 years, based on the same one trial, was 55% (95% CI 30% to 70%; 11,384 participants, Analysis 3.2).

Two trials diagnosed typhoid fever using Widal test (rather than a positive culture) and followed participants for six years (Wang 1997a; Yang 2001). Their combined results demonstrated that the protection was significant in each of the first two years but not in years three to six separately. The three-year cumulative efficacy was 69% (95% CI 50% to 81%) and the combined efficacy for years four through six was 11% (95% CI -76% to 55%) (analyses not shown).

Vi-rEPA vaccine

One trial, Lin 2001, tested this vaccine and found it to be was efficacious in each of the first two years (up to month 27 after vaccination): 94% at year one (95% CI 75% to 99%) and 87% at year two (95% CI 56% to 96%); both analyses included 12,008 participants (Analysis 4.1). Vi-rEPA continued to be effective for an additional 19 months (82.4%, 95% CI 22.3% to 99.1%) and the cumulative efficacy for 46 months (3.8 years) of follow up was 89% (95% CI 76% to 97%; Appendix 4).

2. Adverse events

To evaluate safety we included trials comparing a typhoid vaccine to placebo. We did not identify any trials comparing one type of typhoid vaccine to another. Four efficacy trials (Wahdan 1980a;; Simanjuntak 1991i; Simanjuntak 1991ii; Lin 2001; Yang 2001) and four pilot studies of efficacy trials (Wahdan 1980b; Levine 1986i; Levine 1986ii; Levine 1986iii; Wang 1997b) reported adverse events as well as two trials evaluating safety and immunological responses (Olanratmanee 1992; Keitel 1994).

2.1. Ty21a vaccine versus placebo

The Ty21a vaccine (all preparations) was not associated with an increased rate of fever (Analysis 5.1), vomiting (Analysis 5.2), diarrhoea (Analysis 5.3), or nausea or abdominal pain (Analysis 5.4) (all 2450 participants, 2 trials/5 arms). Rates of headache (1941 participants, 2 trials/2 arms, Analysis 5.5) and rash (1941 participants, 2 trials/3 arms, Analysis 5.6) were also similar. A pooled analysis of two individual-RCTs (three arms) showed a marginal increase in risk of any mild adverse events (RR 1.67, 95% CI 1.03 to 2.72; 1360 participants, Analysis 5.7).

2.2. Vi vaccine versus placebo
Vi polysaccharide

There was no statistically significant difference between the vaccine and placebo in the incidence rate of fever (133,371 participants, 3 trials, Analysis 6.1) or erythema (131,594 participants, 2 trials, Analysis 6.2). Local swelling was more common among the vaccine recipients (RR 8.13, 95% CI 1.04 to 63.66; 1100 participants, 2 trials, Analysis 6.3).

Vi-rEPA vaccine

One trial evaluated this vaccine and reported no swelling or erythema in either group of the 12,008 participants (Lin 2001). Fever was more frequent in the vaccine group (RR 2.54, 95% CI 1.69 to 3.82; 12,008 participants, Analysis 7.1), but the incidence rate in the vaccine group was only 1.3%. No difference was found for serious adverse events (Analysis 7.2).

3. Heterogeneity

In most comparisons that included several trials, the degree of heterogeneity was not substantial (ie I 2 < 50% and chi-squared test with a P value > 0.10). Due to 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.

4. Sensitivity analyses

We performed sensitivity analyses for trials for which the control arm was split in the main analyses and found that the results did not alter (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 events results from trials that did and did not evaluate efficacy, although no formal test was undertaken.

5. Number needed to treat (NNT) to prevent one case of typhoid fever

5.1. Ty21a vaccine

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

5.2. 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, Analysis 3.2), with an incidence rate of 1160/100,000. From these, we estimated the NNT to be 192 (95% CI 124 to 288).

Discussion

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 were 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 most, not significantly different between vaccine and placebo groups. However, many of the comparisons included only one trial.

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 were therefore not included in the meta-analyses. In general, the cluster-RCTs suggested greater efficacy of the Ty21a vaccine than the one individual-RCT. Therefore, we feel that it is reasonable to conclude that current evidence shows that three doses of the Ty21a vaccine are efficacious for least three years. When we compared the three-year cumulative efficacy of three doses of the Ty21a liquid formulation with the enteric capsules the point estimate favoured the liquid formulation, but the result was not statistically significant.

The Ty21a liquid formulation has an advantage over the enteric capsules as it is licensed for use in children from two years of age while enteric capsules are licensed for use in children from five years of age (WHO 2000). This difference may be of public health importance due to findings that the incidence of typhoid fever is elevated in children under the age of five (Sinha 1999; Saha 2001). Both the liquid formulation and enteric capsules should be kept refrigerated. The first is stable for 48 hours and the latter for seven days if not refrigerated (PHAC 2005).

Evidence available from four trials demonstrates that the Vi polysaccharide vaccine is efficacious for the first two years. The one trial that provided data for year three had 50% efficacy, but the confidence intervals were wide (-11% to 78%).

The new but unlicensed Vi-rEPA vaccine also seems to be a promising candidate. The 3.8-year cumulative efficacy was 89% (95% CI 76% to 97%) in children aged two to five years. This vaccine is now undergoing further evaluation through the World Health Organization Expanded Programme on Immunization (EPI) in infants in Vietnam (Szu 2006).

The optimal vaccine against typhoid fever would be an oral vaccine that is administered in a single dose thermostable, easy to administer to young infants, affordable for those in most need, safe elucidates long-term protection, and has both direct and indirect (herd immunity, ie when protection is conferred to a group even if all members are not immune) protection.

Authors' conclusions

Implications for practice

Based on the available evidence, both the currently licensed Ty21a and Vi polysaccharide vaccines are efficacious 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

Neither the Vi polysaccharide vaccine nor the Ty21a vaccine is licensed for children under two years of age. Given the recent finding that typhoid fever affects infants (Sinha 1999; Saha 2001), development of a vaccine suitable for this age group may be warranted.

None of the included trials compared different types of vaccines to prevent typhoid fever. Such future comparisons may be helpful in drawing 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 their design; cluster randomization should be accounted for in sample size calculations as well as analyses of results.

Acknowledgements

We thank the Cochrane Infectious Diseases Group for their support and assistance. 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 (3 doses) vs control
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 (3 doses) vs control, Outcome 1 Incidence of typhoid fever, year 1.

Analysis 1.2.

Comparison 1 Ty21a vaccine (3 doses) vs control, Outcome 2 Incidence of typhoid fever, year 2.

Analysis 1.3.

Comparison 1 Ty21a vaccine (3 doses) vs control, Outcome 3 Incidence of typhoid fever, year 3.

Analysis 1.4.

Comparison 1 Ty21a vaccine (3 doses) vs control, 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. Vi polysaccharide vaccine (1 dose) vs control
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Incidence of typhoid fever4 Risk Ratio (M-H, Random, 95% CI)Subtotals only
1.1 Year 1399797Risk Ratio (M-H, Random, 95% CI)0.32 [0.20, 0.50]
1.2 Year 22142655Risk Ratio (M-H, Random, 95% CI)0.40 [0.24, 0.69]
1.3 Year 3111384Risk Ratio (M-H, Random, 95% CI)0.50 [0.22, 1.11]
2 Cumulative incidence of typhoid fever at 2.5 to 3 years1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 3.1.

Comparison 3 Vi polysaccharide vaccine (1 dose) vs control, Outcome 1 Incidence of typhoid fever.

Analysis 3.2.

Comparison 3 Vi polysaccharide vaccine (1 dose) vs control, Outcome 2 Cumulative incidence of typhoid fever at 2.5 to 3 years.

Comparison 4. Vi-rEPA vaccine (2 doses) vs control
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)Not estimable
1.2 Year 21 Risk Ratio (M-H, Random, 95% CI)Not estimable
Analysis 4.1.

Comparison 4 Vi-rEPA vaccine (2 doses) vs control, Outcome 1 Incidence of typhoid fever.

Comparison 5. Ty21a vaccine vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Fever52450Risk Ratio (M-H, Random, 95% CI)1.53 [0.86, 2.72]
1.1 Enteric capsules31611Risk Ratio (M-H, Random, 95% CI)1.44 [0.41, 4.98]
1.2 Liquid formulation1588Risk Ratio (M-H, Random, 95% CI)1.36 [0.61, 3.03]
1.3 In milk with sodium bicarbonate1251Risk Ratio (M-H, Random, 95% CI)1.04 [0.10, 11.33]
2 Vomiting52450Risk Ratio (M-H, Random, 95% CI)0.61 [0.30, 1.24]
2.1 Enteric capsules31611Risk Ratio (M-H, Random, 95% CI)0.44 [0.15, 1.28]
2.2 Liquid formulation1588Risk Ratio (M-H, Random, 95% CI)1.91 [0.37, 9.79]
2.3 In milk with sodium bicarbonate1251Risk Ratio (M-H, Random, 95% CI)0.63 [0.28, 1.39]
3 Diarrhoea52450Risk Ratio (M-H, Random, 95% CI)0.72 [0.38, 1.37]
3.1 Enteric capsules31611Risk Ratio (M-H, Random, 95% CI)0.71 [0.18, 2.78]
3.2 Liquid formulation1588Risk Ratio (M-H, Random, 95% CI)0.71 [0.34, 1.49]
3.3 In milk with sodium bicarbonate1251Risk Ratio (M-H, Random, 95% CI)0.58 [0.24, 1.37]
4 Nausea or abdominal pain52450Risk Ratio (M-H, Random, 95% CI)1.21 [0.56, 2.60]
4.1 Enteric capusles31611Risk Ratio (M-H, Random, 95% CI)1.32 [0.34, 5.12]
4.2 Liquid formulation1588Risk Ratio (M-H, Random, 95% CI)1.84 [0.90, 3.77]
4.3 In milk with sodium bicarbonate1251Risk Ratio (M-H, Random, 95% CI)0.66 [0.35, 1.23]
5 Headache31941Risk Ratio (M-H, Random, 95% CI)1.28 [0.83, 1.96]
5.1 Enteric capsules21353Risk Ratio (M-H, Random, 95% CI)1.30 [0.78, 2.18]
5.2 Liquid formulation1588Risk Ratio (M-H, Random, 95% CI)1.23 [0.57, 2.65]
6 Rash31941Risk Ratio (M-H, Random, 95% CI)1.89 [0.56, 6.43]
6.1 Enteric capsules21353Risk Ratio (M-H, Random, 95% CI)1.52 [0.35, 6.65]
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]
Analysis 5.1.

Comparison 5 Ty21a vaccine vs placebo, Outcome 1 Fever.

Analysis 5.2.

Comparison 5 Ty21a vaccine vs placebo, Outcome 2 Vomiting.

Analysis 5.3.

Comparison 5 Ty21a vaccine vs placebo, Outcome 3 Diarrhoea.

Analysis 5.4.

Comparison 5 Ty21a vaccine vs placebo, Outcome 4 Nausea or abdominal pain.

Analysis 5.5.

Comparison 5 Ty21a vaccine vs placebo, Outcome 5 Headache.

Analysis 5.6.

Comparison 5 Ty21a vaccine vs placebo, Outcome 6 Rash.

Analysis 5.7.

Comparison 5 Ty21a vaccine vs placebo, Outcome 7 Any mild adverse event.

Comparison 6. Vi polysaccaharide vaccine vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Fever3132371Risk Ratio (M-H, Random, 95% CI)1.09 [0.58, 2.07]
2 Erythema2131594Risk Ratio (M-H, Random, 95% CI)2.30 [0.22, 24.23]
3 Swelling21100Risk Ratio (M-H, Random, 95% CI)8.13 [1.04, 63.66]
Analysis 6.1.

Comparison 6 Vi polysaccaharide vaccine vs placebo, Outcome 1 Fever.

Analysis 6.2.

Comparison 6 Vi polysaccaharide vaccine vs placebo, Outcome 2 Erythema.

Analysis 6.3.

Comparison 6 Vi polysaccaharide vaccine vs placebo, Outcome 3 Swelling.

Comparison 7. Vi-rEPA vaccine vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Fever1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
2 Serious adverse events1 Risk Ratio (M-H, Random, 95% CI)Subtotals only
Analysis 7.1.

Comparison 7 Vi-rEPA vaccine vs placebo, Outcome 1 Fever.

Analysis 7.2.

Comparison 7 Vi-rEPA vaccine vs placebo, Outcome 2 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.

Appendix 2. Risk of bias assessment

TrialGenerationof allocation sequenceAllocation concealmentBlindingInclusionaRandomization unit
Acharya 1987AdequateAdequateDouble blindYesIndividual
Black 1990iUnclearAdequateDouble blindAdequateCluster (classroom): not accounted for in analysis
Black 1990iiUnclearAdequateDouble blindAdequateCluster (classroom): not accounted for in analysis
Cryz 1993UnclearUnclearDouble blindUnclearIndividual
Keitel 1994UnclearUnclearDouble blindYesIndividual
Klugman 1987AdequateAdequateDouble blindYesIndividual
Levine 1986iUnclearUnclearDouble blindUnclearIndividual
Levine 1986iiUnclearUnclearDouble blindUnclearIndividual
Levine 1986iiiUnclearUnclearDouble blindUnclearIndividual
Levine 1987iUnclearAdequateNoInadequateCluster (classroom): not directly accounted for in analysisb
Levine 1987iiUnclearAdequateUnclearInadequateCluster (classroom): not directly accounted for in analysisb
Levine 1987iiiUnclearAdequateNoInadequateCluster (classroom): not directly accounted for in analysisb
Levine 1987ivUnclearAdequateUnclearInadequateCluster (classroom): not directly accounted for in analysisb
Levine 1990iUnclearAdequateDouble blindAdequateCluster (classroom): not directly accounted for in analysisc
Levine 1990iiUnclearAdequateDouble blindAdequateCluster (classroom): not directly accounted for in analysisc
Lin 2001AdequateAdequateDouble blindYesIndividual
Olanratmanee 1992UnclearUnclearDouble blindYesIndividual
Simanjuntak 1991iAdequateAdequateDouble blindAdequateIndividual
Simanjuntak 1991iiAdequateAdequateDouble blindAdequateIndividual
Wahdan 1980aUnclearAdequateDouble blindYesCluster (classroom): not accounted for in analysis
Wahdan 1980bUnclearUnclearDouble blindYesCluster (classroom): not accounted for in analysis
Wang 1997aAdequateAdequateDouble blindYesIndividual
Wang 1997bAdequateAdequateDouble blindYesIndividual
Yang 2001AdequateAdequate YesIndividual

aInclusion of all randomized participants in the analysis.
b227 cases occurred in 221 classrooms, and in classes with > 1 case these occurred in separate years. Analysing data as proportion of classes with cases of typhoid fever yielded similar results to analysing individual level data.
cOf 5423 participating classrooms, cases occurred in 374 and of these only 18 had > 1 case (17 had 2 cases and 1 had 3 cases). Trial authors reported distribution of cases/classroom did not significantly differ from a Poisson distribution unadjusted for clustering. Results also analysed as proportion of classes with cases of typhoid fever and results were similar to analysing individuals.

Appendix 3. Typhoid fever cases: Ty21a vaccine vs control, cluster-RCTsa

TrialYearPreparationNo. dosesRR (95% CI)bEfficacy
Black 1990ii1Enteric 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 1990ii1Enteric 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 1987ii1Enteric 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 1980a1Liquid 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 1987iCumulative 2.5 to 3Enteric capsules30.41 (0.28 to 0.91)59% (9% to 72%)
Levine 1987iiCumulative 2.5 to 3Enteric capsules30.33 (0.18 to 0.63)67% (82% to 37%)
Levine 1990iiCumulative 2.5 to 3Enteric capsules30.63 (0.35 to 1.12)37% (-12% to 65%)
Wahdan 1980aCumulative 2.5 to 3Liquid formulation30.04 (0.01 to 0.33)96% (67% to 99%)
Levine 1990iCumulative 2.5 to 3Liquid formulation30.24 (0.13 to 0.47)76% (53% to 87%)
Levine 1987iiiCumulative 2.5 to 3Gelatin capsules30.69 (0.39 to 1.20)31% (-20% to 61%)
Levine 1987ivCumulative 2.5 to 3Gelatin capsules30.81 (0.47 to 1.39)19% (-39% to 53%)
Levine 1990iCumulative 2.5 to 3Liquid preparation vs enteric capsules30.35 (0.21, 0.56)65% (44% to 79%)

aCluster-randomized controlled trials that did not account for clustering in the analysis.
bRisk ratio with 95% confidence intervals.

Appendix 4. Typhoid fever cases, cumulative efficacy at > 3 years: vaccine vs control

TrialVaccine/formulationLength of follow upVaccine: incidenceControl: incidenceEfficacy (95% CI)a
Black 1990iTy21a: enteric capsules, 2 doses5 years95/27,620164/27,30543% (26% to 55%)
Black 1990iiTy21a: enteric capsules, 1 dose5 years200/27,618164/27,305-21% (-48% to 2%)
Levine 1987iiTy21a: enteric capsules, 3 doses7 years50/22,170131/21,90662% (48% to 73%)
Levine 1990iTy21a: liquid formulation, 3 doses5 years34/36,62343/10,30279% (65% to 87%)
Lin 2001Vi-rEPA3.8 years8/599117/601789% (76% to 97%)

aConfidence intervals.

What's new

DateEventDescription
22 August 2008AmendedConverted to new review format with minor editing.

History

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

DateEventDescription
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

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

Declarations of interest

CJ Acosta is currently Director of Epidemiology Latin America, Clinical Research, Development & Medical Affairs, Vaccines − N.A. GlaxoSmithKline. Most of his typhoid-related work was done while working for The International Vaccine Institute, Seoul Korea as the DO MI-Typhoid Project Coordinator. For all other authors: none known.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • Department for International Development (DFID), UK.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Acharya 1987

Methods

Design: individual-RCT

Generation of allocation sequence: random arrangement of syringes in packages of 10; method of syringe arrangement is unclear

Allocation concealment: coded syringes

Blinding: vaccine vials were coded (double)

Inclusion of randomized participants in analysis: 100%

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

Immunogenicity assessment: not done

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

Black 1990i

Methods

Design: cluster (classroom) RCT

Generation of allocation sequence: unclear

Allocation concealment: central (WHO)

Blinding: placebo identical in appearance to vaccine (double)

Inclusion of randomized participants in analysis: 90% (82,543/91,954)

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 years)

Immunogenicity assessment: not done

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 x 10^9 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

Black 1990ii

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

1. Lyophilized attenuated S. Typhi strain Ty21a: enteric-coated capsule containing 2-5 x 10^9 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
NotesDetails as for Black 1990i

Cryz 1993

Methods

Design: individual-RCT

Generation of the allocation sequence: unclear

Allocation concealment: vaccine and placebo packages were coded

Blinding: double; passive surveillance for adverse events by parental reporting

Inclusion of randomized participants in analysis: unclear

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

Keitel 1994

Methods

Design: individual-RCT

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: unclear

Inclusion of randomized participants in analysis: 100%

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

Immunogenicity assessment: blood samples taken before, and 7, 14, and 28 days, 11 to 34 months after inoculation; Vi antibodies measured using RIA

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, USA

Socioeconomic description: urban, high income

Setting: clinic

Date: no information

No demographic information

Results presented jointly for 3 separate trials

Klugman 1987

Methods

Design: individual-RCT

Generation of allocation sequence: randomly sorted vaccine number; randomization process unclear

Allocation concealment: code held by independent observers

Blinding: preparations identical in appearance

Inclusion of randomized participants in analysis: 100%

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

Immunogenicity assessment: blood samples taken before, and 6 and 12 months after vaccination from 62 participants; blood samples taken from 96 participants after 3 years; Vi antibodies measured using ELISA, RIA, and PHA

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

Levine 1986i

Methods

Design: individual-RCT

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: double (no details)

Inclusion of randomized participants in analysis: unclear

Active surveillance for adverse events: no further details

Immunogenicity assessment: no details

Participants

Number: 539

Inclusion criteria: children, no details

Exclusion criteria: no details

Interventions

1. Enteric-coated 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

Levine 1986ii

MethodsSee Levine 1986i (Levine 1986ii is a different arm of the same trial)
ParticipantsDetails as for Levine 1986i, except number: 337
InterventionsDetails as for Levine 1986i, except:
1. S. Typhi Ty21a vaccine in milk with NaHCO3: 165 participants
2. Placebo: 172 participants
OutcomesDetails as for Levine 1986i
NotesDetails as for Levine 1986i

Levine 1986iii

MethodsSee Levine 1986i (Levine 1986iii is a different arm of the same trial)
Participants

Details as for Levine 1986i, except:

Number: 751

Inclusion criteria: adults, no details

InterventionsDetails as for Levine 1986i, except:
1. Enteric-coated S. Typhi, Ty21a vaccine: 384 participants
2. Placebo: 367 participants
OutcomesDetails as for Levine 1986i
NotesDetails as for Levine 1986i

Levine 1987i

Methods

Design: cluster (classroom) RCT

Generation of allocation sequence: unclear

Allocation concealment: code kept at Berne and Geneva

Blinding: placebo given in a different regimen

Inclusion of randomized participants in analysis: 78% (109,594/141,127) of enrolled children received 3 doses and included in results

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

Immunogenicity assessment: not done

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 to 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

Levine 1987ii

Methods

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

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

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

1. Enteric capsules of S. Typhi, Ty21a vaccine: 22,170 participants
2. Placebo: 5477 participants (placebo group divided to 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
NotesDetails as for Levine 1987i

Levine 1987iii

MethodsSee Levine 1987i (Levine 1987iii is a different arm of the same trial)
ParticipantsDetails as for Levine 1987i, except number: 27,017
InterventionsDetails as for Levine 1987i, except:
1. Gelatin capsules of S. Typhi, Ty21a vaccine: 21,541
2. Placebo: 5476 (placebo group divided to 4 equal groups for the comparison)
OutcomesDetails as for Levine 1987i
NotesDetails as for Levine 1987i

Levine 1987iv

Methods

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

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

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

1. Gelatin capsules of S. Typhi, Ty21a vaccine: 22,379 participants
2. Placebo: 5477 participants (placebo group divided to 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
NotesDetails as for Levine 1987i

Levine 1990i

Methods

Design: cluster (classroom) RCT

Generation of allocation sequence: unclear

Allocation concealment: code kept at WHO

Blinding: identical packets and capsules

Inclusion of randomized participants in analysis: 85% (81,621/95,910 children who received at least 1 dose) received all 3 doses and included in results

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

Immunogenicity assessment: not done

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

Levine 1990ii

Methods

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

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

ParticipantsDetails as for Levine 1990i, except number: 39,548
InterventionsDetails as for Levine 1990i, except:
1. Enteric capsules of S. Typhi, Ty21a vaccine: 34,696 participants
2. Placebo: 4852 participants
OutcomesDetails as for Levine 1990i
NotesDetails as for Levine 1990i

Lin 2001

Methods

Design: individual-RCT

Generation of allocation sequence: identical looking vaccine and placebo were randomly numbered 0 to 9 and packaged in packets of 10; however unclear how randomization sequence generated

Allocation concealment: code identifying identical-looking vaccine and placebo was kept at the central pharmacy

Blinding: vaccine and placebo vials indistinguishable

Inclusion of randomized participants in analysis: 100%

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

Immunogenicity assessment: paired serum samples from 76 children before the first injection and 4 weeks after the second injection; serum IgG Vi antibodies assayed by ELISA

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 ºC 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

Olanratmanee 1992

Methods

Design: individual-RCT

Generation of allocation sequence: not mentioned

Allocation concealment: no information

Blinding: identical vaccine and placebo packages

Inclusion of randomized participants in analysis: 100%

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

Immunogenicity assessment: paired serum samples from 160 children before the first injection and 21 days after vaccination; serum anti-LPS antibodies assayed by ELISA

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

Simanjuntak 1991i

Methods

Design: individual-RCT

Generation of allocation sequence: computer-generated table of random numbers

Allocation concealment: identical vaccine and placebo

Blinding: identical vaccine and placebo

Inclusion of randomized participants in analysis: 93% (20,543/22,001) received 3 doses and included in results

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

Surveillance for adverse events: questionnaires collected from 588 individuals

Immunogenicity assessment: not done

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

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

Simanjuntak 1991ii

Methods

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

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

ParticipantsDetails as for Simanjuntak 1991i, 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

OutcomesDetails as for Simanjuntak 1991i
NotesDetails as for Simanjuntak 1991i

Wahdan 1980a

Methods

Design: cluster (classroom) RCT

Generation of allocation sequence: unclear

Allocation concealment: central

Blinding: vaccine and placebo indistinguishable

Inclusion of randomized participants in analysis: 100%

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

Surveillance for adverse events: no details

Immunogenicity assessment: not done

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

Wahdan 1980b

Methods

Design: cluster (classroom) RCT

Generation of allocation sequence: unclear

Allocation concealment: unclear

Blinding: vaccine and placebo indistinguishable

Inclusion of randomized participants in analysis: 100%

Surveillance for adverse events: no details

Immunogenicity assessment: not done

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

Wang 1997a

Methods

Design: individual-RCT

Generation of allocation sequence: computer-generated random numbers

Allocation concealment: code concealed from field workers and study population

Blinding: identical vaccine and placebo vials

Inclusion of randomized participants in analysis: 100%

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

Wang 1997b

Methods

Design: individual-RCT

Generation of allocation sequence: computer-generated random numbers

Allocation concealment: code concealed from field workers and study population

Blinding: identical vaccine and placebo vials

Inclusion of randomized participants in analysis: 100%

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

Yang 2001

  1. a

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

Methods

Design: individual-RCT

Generation of allocation sequence: unique serial number to each participant; having an even or odd number determined allocation to vaccine or placebo

Allocation concealment: code concealed from field workers and study population

Blinding: double blinded

Inclusion of randomized participants in analysis: 100%

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

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    RCT: randomized controlled trial

Anonymous 1966Evaluated the inactivated whole cell vaccine, which is no longer in use
Arya 1997Letter; not a 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 randomized 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 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
Hohmann 1996aNo random allocation
Hohmann 1996bNo random allocation
Keddy 1999No relevant outcome measures
Khoo 1995Evaluated safety of Vi vaccine compared to meningococcal vaccine or combination
Lebacq 2001Evaluated different brands of Vi vaccine
Levin 1975No random allocation; compared Vi with inactivated whole cell vaccine, which is no longer in use
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
Sabitha 2004Compared 2 brands of Vi vaccine
Tacket 1992Evaluated experimental live-attenuated oral vaccines candidates; no efficacy trials of these vaccines
Tacket 1997Evaluated experimental live-attenuated oral vaccines 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
Wahdan 1975Quasi-RCT evaluating the inactivated whole cell vaccine, which is no longer in use
Yang 2005No relevant outcomes
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

Characteristics of ongoing studies [ordered by study ID]

Khan 2006

Trial name or titleLessons and implications from a mass immunization campaign in squatter settlements of Karachi, Pakistan: an experience from a cluster-randomized double-blinded vaccine trial [NCT00125047]
Methods
ParticipantsChildren aged 2 to 16 years
Interventions1. Vi polysaccharide vaccine
2. Hepatitis A vaccine
Outcomes1. Efficacy
2. Adverse events
Starting dateVaccination given during August and September 2003
Contact informationZulfiqar A Bhutta
zulfiqar.bhutta@aku.edu
Notes

Location: Karachi, Pakistan

ClinicalTrials.gov identifier: NCT00125047

Szu 2006

Trial name or titleEvaluation of the safety, immunogenicity and compatibility with DTP of an investigational Vi-rEPA(2) conjugate vaccine for typhoid fever when administered to infants in Vietnam concurrently with DTP
Methods 
Participants300 healthy newborns
Interventions1. Vi-rEPA + DTP
2. Hib-TT + DTP
3. DTP
Outcomes

Blood samples will be assayed for Vi, Hib, diphtheria, tetanus and pertussis antibodies

The levels of serum IgG anti-Vi elicited by Vi-rEPA administered to infants by the schedule will be compared to those elicited by this vaccine in 2 to 5 year-olds in the efficacy trial conducted in Dong Thap (Lin 2001)

Starting date1999
Contact informationShousun C Szu
szus@mail.nih.gov
Notes

Location: Vietnam

ClinicalTrials.gov identifier: NCT00342628

Tacket 2006

Trial name or titleCVD 909 Vi prime boost study
Methods 
ParticipantsAdults volunteers aged 18 to 40 years
Interventions1. Vi polysaccharide vaccine after priming by live-attenuated oral Vi+ Salmonella Typhi strain CVD 909
2. Vi polysaccharide vaccine
Outcomes1. Seroconversion rate and titre of serum IgG anti-Vi antibodies
2. Timing of development and longevity of serum anti-Vi antibodies
3. Subclasses and avidity of antibodies developed
4. Memory B and T cell responses elicited
Starting date2006
Contact informationCarol Tacket
ctaket@medicine.umaryland.edu
Notes

Location: USA

ClinicalTrials.gov identifier: NCT00326443

Ancillary