Vaccines for preventing cholera: killed whole cell or other subunit vaccines (injected)

  • Review
  • Intervention

Authors


Abstract

Background

Injected cholera vaccines are rarely used today, although they may have some benefit. It is valuable to summarize the evidence for effectiveness of injected cholera vaccines for comparison with newer oral vaccines (subject of a separate Cochrane Review).

Objectives

To evaluate killed whole cell (KWC) cholera vaccines and other inactive subunit vaccines (administered by injection) for preventing cholera and death, and to evaluate the adverse effects.

Search methods

In September 2008, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2008, Issue 3), EMBASE, and LILACS. We also searched reference lists and handsearched the journal Vaccine up to 1997.

Selection criteria

Randomized and quasi-randomized controlled trials comparing injected cholera vaccines (KWC or other inactive subunit) with placebo, control vaccines, or no intervention in adults and children irrespective of immune status or special risk category.

Data collection and analysis

Two authors extracted data and assessed trial methodological quality independently. Dichotomous data were reported using the risk ratio (RR) with 95% confidence intervals (CI). Vaccine efficacies were also calculated (% vaccine efficacy = (1-RR) x 100%).

Main results

Sixteen trials, involving over one million adults, children and infants, fulfilled the inclusion criteria. Twenty-four comparisons reported on vaccine efficacy (cholera cases and/or deaths) and 11 comparisons considered adverse effects (nine reported on both). Compared to placebo, vaccinees had a reduced risk of death from cholera (RR 0.49, 95% CI 0.25 to 0.93; 837,442 participants) and a reduced risk of contracting cholera at 12 months (RR 0.52, 95% CI 0.42 to 0.65, random-effects model; 1,512,573 participants). This translates to an efficacy of 48%, 95% confidence interval 35% to 58%. Significant protection lasted for two years, even after only a single dose, and for three years with an annual booster. Children over five years and adults were protected for up to three years, while children under five years were protected for up to a year. Injected cholera vaccines were associated with more systemic and local adverse effects compared to placebo, but these were not severe or life-threatening.

Authors' conclusions

Injected cholera vaccines appear to be safe and relatively more effective than usually realized. Protection against cholera persists for up to two years following a single dose of vaccine, and for three years with an annual booster. However, they have been superseded by oral vaccines.

Résumé scientifique

Vaccins pour prévenir le choléra : vaccins à germes entiers inactivés ou autres vaccins sous-unitaires (injectés)

Contexte

Les vaccins anticholériques injectés sont rarement utilisés de nos jours, mais ils pourraient conférer certains bénéfices. Il est utile de résumer les preuves d'efficacité des vaccins anticholériques injectés afin de pouvoir les comparer aux vaccins oraux plus récents (qui font l'objet d'une revue Cochrane séparée).

Objectifs

Évaluer les vaccins anticholériques à germes entiers inactivés (GEI) et d'autres vaccins sous-unitaires inactivés (administrés par injection) dans la prévention du choléra et des décès, et examiner leurs effets indésirables.

Stratégie de recherche documentaire

En septembre 2008, nous avons consulté le registre spécialisé du groupe Cochrane sur les maladies infectieuses, CENTRAL (Bibliothèque Cochrane 2008, numéro 3), EMBASE et LILACS. Nous avons également examiné les références bibliographiques et effectué une recherche manuelle dans la revue Vaccine jusqu'en 1997.

Critères de sélection

Les essais contrôlés randomisés et quasi-randomisés comparant des vaccins anticholériques injectés (GEI ou autre sous-unité inactivée) à un placebo, des vaccins de contrôle ou une absence d'intervention chez des adultes et des enfants, indépendamment de l'état immunitaire ou de la catégorie de risque spécifique.

Recueil et analyse des données

Deux auteurs ont extrait les données et évalué la qualité méthodologique des essais de manière indépendante. Les données dichotomiques ont été rapportées sous forme de risque relatif (RR) avec des intervalles de confiance (IC) à 95 %. L'efficacité des vaccins a également été calculée (% d'efficacité du vaccin = (1 - RR) x 100 %).

Résultats principaux

Seize essais portant sur plus d'un million d'adultes, enfants et nourrissons remplissaient les critères d'inclusion. Vingt-quatre comparaisons documentaient l'efficacité des vaccins (cas de choléra et/ou décès) et 11 comparaisons examinaient les effets indésirables (neuf comparaisons documentaient ces deux critères de jugement). Par rapport au placebo, le risque de décès dû au choléra diminuait chez les personnes vaccinées (RR de 0,49, IC à 95 %, entre 0,25 et 0,93 ; 837 442 participants), de même que le risque de contracter le choléra à 12 mois (RR de 0,52, IC à 95 %, entre 0,42 et 0,65, modèle à effets aléatoires ; 1 512 573 participants). Cela se traduit par une efficacité de 48 %, intervalle de confiance à 95 %, entre 35 et 58 %. Une protection significative était conférée pendant deux ans, même après une dose unique, et pendant trois ans avec un rappel annuel. Les enfants âgés de plus de cinq ans et les adultes étaient protégés au cours d'une période allant jusqu'à trois ans, tandis que les enfants de moins de cinq ans étaient protégés au cours d'une période allant jusqu'à un an. Les vaccins anticholériques injectés étaient associés à davantage d'effets indésirables systémiques et locaux par rapport au placebo, mais ces effets n'étaient pas graves et n'engageaient pas le pronostic vital.

Conclusions des auteurs

Les vaccins anticholériques injectés semblent sûrs et sont relativement plus efficaces que ce que l'on pense généralement. La protection anticholérique dure jusqu'à deux ans après l'administration d'une dose unique de vaccin, et jusqu'à trois ans avec un rappel annuel. Néanmoins, ils ont été supplantés par les vaccins oraux.

Plain language summary

Killed whole cell or other inactive subunit vaccines (injected) for preventing cholera

Cholera is an acute gastroenteritis caused by Vibrio cholerae. Infection causes profuse watery diarrhoea, and up to 40% of patients die if untreated. Cholera was a major cause of death in many countries in the past; epidemics are now less common, but cholera remains an important cause of death in developing countries, especially in Africa.

Vaccination against cholera was first tested in the nineteenth century and may play a role in controlling epidemics. Injected (parenteral) whole cell vaccines were used in the 1960s and 1970s, but they went out of favour as their efficacy was thought to be low and short-lived, and associated with a high rate of adverse effects. This review summarizes the evidence for effectiveness of injected cholera vaccines. A separate Cochrane Review describes trials with oral cholera vaccines, which were introduced more recently and are used currently.

Sixteen trials, involving over one million adults, children, and infants, were included. Injected cholera vaccines reduced the risk of death from cholera and the risk of contracting cholera at 12 months. Significant protection lasted for two years. Injected cholera vaccines had more systemic and local adverse effects than placebo, but these adverse effects were relatively well tolerated and were not severe or life-threatening.

The authors conclude that injected cholera vaccines appear to be relatively safe and more effective than usually realized. However, they are not currently available and therefore cannot be recommended for use. This review provides a solid background of evidence for the effects of cholera injected vaccines, against which to compare the effects of oral vaccines.

Résumé simplifié

Vaccins à germes entiers inactivés ou autres vaccins sous-unitaires inactivés (injectés) pour prévenir le choléra

Le choléra est une gastroentérite aiguë causée par Vibrio cholerae. L'infection entraîne une abondante diarrhée aqueuse et jusqu'à 40 % des patients meurent en l'absence de traitement. Par le passé, le choléra était une cause majeure de mortalité dans de nombreux pays ; les épidémies sont aujourd'hui moins courantes, mais le choléra demeure une cause importante de mortalité dans les pays en voie de développement, en particulier en Afrique.

La vaccination contre le choléra a été testée pour la première fois au dix-neuvième siècle, et pourrait avoir un rôle à jouer dans le contrôle des épidémies. Les vaccins à germes entiers injectés (voie parentérale) étaient utilisés dans les années 1960 et 1970, mais ils ont été abandonnés en raison de leur efficacité considérée insuffisante et de courte durée, et des taux élevés d'effets indésirables. Cette revue résume les preuves d'efficacité des vaccins anticholériques injectés. Une revue Cochrane séparée décrit les essais portant sur des vaccins anticholériques oraux, qui ont été introduits plus récemment et sont actuellement utilisés.

Seize essais portant sur plus d'un million d'adultes, enfants et nourrissons ont été inclus. Les vaccins anticholériques injectés réduisaient le risque de décès dû au choléra et le risque de contracter le choléra à 12 mois. Une protection significative était conférée pendant deux ans. Les vaccins anticholériques injectés présentaient davantage d'effets indésirables systémiques et locaux que le placebo, mais ces effets indésirables étaient relativement bien tolérés, n'étaient pas sévères et n'engageaient pas le pronostic vital.

Les auteurs en concluent que les vaccins anticholériques injectés semblent relativement sûrs, et plus efficaces que ce que l'on pense généralement. Néanmoins, ils ne sont pas disponibles à l'heure actuelle et leur usage ne peut donc pas être recommandé. Cette revue fournit une base factuelle solide permettant de comparer les effets des vaccins anticholériques injectés par rapport aux vaccins oraux.

Notes de traduction

Traduit par: French Cochrane Centre 1st April, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Background

Cholera is an acute infection that causes sudden onset of profuse watery diarrhoea, and up to 40% of patients die if untreated. Cholera was a major cause of death in many countries in the past, although epidemics are now less common. Nevertheless, cholera remains an important cause of death in developing countries. In 2005, there were a total of 131,943 reported cases of cholera throughout the world, including 2272 deaths (WHO 2006a), and it is known that there were many more cases that were not reported. Ninety-five per cent of reported cases were in Africa. Cholera can lead to serious outbreaks: in 2005, the World Health Organization (WHO) confirmed 49 different outbreaks in 36 countries (WHO 2006a).

Cholera is caused by the Gram-negative bacillus Vibrio cholerae. There are over a hundred serological groups of V. cholerae, each with varying potential to cause disease. Until recently only one of these (V. cholerae 01) caused epidemic cholera. In 1992 to 1993, an epidemic of cholera originating in the Indian subcontinent was found to be caused by V. cholerae 0139, also called 0139 Bengal. Cholera strains are also classified by their biotype (Classical or El Tor), and within the biotype, the serotype (Ogawa or Inaba). Serotype differences are based on differences in structure of the lipopolysaccharide membrane. The various serological groups are important as each vaccine component tends to be specific to particular groups of V. cholerae.

Transmission of V. cholerae occurs predominantly when people ingest faecal contaminated water or food. The disease spreads rapidly where there is poverty, poor hygiene, and lack of sanitation. Waterborne spread can be responsible for devastating epidemics such as that which occurred due to El Tor cholera in the refugee camps of Goma, Zaire in July 1994. This resulted in 70,000 cases and 12,000 deaths (Sánchez 1997).

V. cholerae colonize the gut using small hair like structures ("pili") that attach to the small bowel. High stomach pH and blood group O appear to make colonization more likely. The attached bacteria then release a soluble toxin, which results in the symptoms of the disease. This toxin is composed of two subunits, A and B. The A subunit stimulates cellular mechanisms in the bowel cells that disrupt sodium transport. The net result is a high sodium chloride (salt) concentration in the gut lumen, which holds on to water by osmotic forces, leading to profuse watery diarrhoea, severe dehydration, and eventually death. The B subunit of cholera toxin does not cause toxic effects but does stimulate an immune response from the host. Colonization can be inhibited by specific antibodies which are generated after infection with V. cholerae.

Intravenous rehydration therapy can be very effective in treatment of cholera. However, health services in cholera endemic or epidemic areas often do not have sufficient capabilities for such treatment. Improving hygienic practices in areas of poverty and limited water supply can also be problematic. This has led to attempts to prevent cholera by vaccination. The first vaccine effectively used against cholera was probably that of Ferran, who in 1884 apparently successfully controlled an epidemic in Spain. A vaccine was also produced by the Pasteur Institute in the 1920s.

Widespread use of cholera vaccines began in the 1960s when there was a series of large trials in what was then known as East Pakistan (now Bangladesh), India, and the Philippines. Most of the vaccines used in these trials were composed of whole V. cholerae serogroup 01 cells, usually a mixture of biotypes and serotypes, which were killed by either formalin, phenol, or heat. There were also trials of cholera toxoid vaccines in the 1970s. The killed whole cell vaccines, which were subsequently licensed, are injected and usually given in one or two doses.

Injected (parenteral) whole cell vaccines grew in popularity until the 1970s when they went out of favour (Bhadra 1994) on the grounds that efficacy was thought to be low and short-lived, high titres of serum vibriocidal antibodies were thought not to provide sufficient intestinal immunity to prevent infection, and they were said to have a high rate of adverse effects. The advent of oral rehydration therapy, considered a highly effective treatment, was a major advance in reducing cholera morbidity, and led to a shift in interest away from injected vaccines. Even when injected cholera vaccines were in relatively widespread use in the early 1970s, it was never determined whether an individual's protection was likely to interrupt transmission to others in the community, or how important enteral or parenteral immunity is in bacterial shedding.

Recent cholera epidemics have shown that there still a requirement for an effective vaccine against this major disease (Sánchez 1997; Calain 2004; WHO 2006b). Oral vaccines have been under development since the 1980s, stimulated by the increasing recognition of the importance of stimulating local intestinal immunity in the prevention of the disease. Both killed and live oral vaccines are now licensed, but the injected vaccine is no longer used.

The original version of this review included both injected and oral cholera vaccines (Graves 2001), but this is now superseded and withdrawn. The current review assesses the results of trials with killed parenteral (injected) vaccines only. A separate Cochrane Review describes trials with oral cholera vaccines (Abba (in progress)).

Objectives

To evaluate killed whole cell cholera vaccines and other inactive subunit vaccines (administered by injection) for preventing cases of cholera and preventing death, and to evaluate the adverse effects associated with the vaccination.

Methods

Criteria for considering studies for this review

Types of studies

Randomized or quasi-randomized controlled trials.

Exception: Phase 1 trials, reporting only adverse effects, for vaccines that never reached efficacy trials.

Types of participants

Well adults or children irrespective of immune status or special risk category.

Types of interventions

Intervention

Killed whole cell cholera vaccines or other inactive subunit vaccines administered by injection

Control

Placebo, control vaccines, or no intervention.

Types of outcome measures

Primary
  • Cholera cases, as defined by each trial (usually diarrhoea more than three times in 24 hours with bacteriological confirmation of V. cholerae).

  • All-cause deaths.

  • Cholera deaths.

Adverse effects
  • Number and seriousness of adverse effects (classified as local and systemic).

    • Systemic adverse effects include cases of malaise, nausea, fever, arthralgias, rash, headache and more generalized and serious signs.

    • Local adverse effects include induration, soreness, and redness at the site of inoculation.

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).

We searched the following databases using the search terms and strategy described in Appendix 1: Cochrane Infectious Diseases Group Specialized Register (1 September 2008); Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, Issue 3); MEDLINE (1966 to 1 September 2008); EMBASE (1974 to 1 September 2008); and LILACS (1982 to 1 September 2008).

We searched the bibliographies of included studies. Additionally, we handsearched the journal Vaccine from its first issue to the end of 1997 (Jefferson 1996; Jefferson 1998).

Data collection and analysis

Selection of studies

Four authors (VD, TJ, PG, and JD) read all trials retrieved in the search and applied the inclusion criteria to determine eligibility.

Data extraction and management

PG and JD independently extracted and double-checked the following data: characteristics of participants (number, age, gender, ethnic group, risk category, and previous immunization status, if known); characteristics of interventions (vaccine type, placebo type, dose, immunization schedule, and length of follow up (in months); outcome measures; and trial date, location, sponsor, and publication status. All disagreements in the data extraction were resolved by discussion.

Adverse effect data were extracted individually for each adverse effect where possible. For trials where adverse effects were reported for more than one dose, the average of the number of people reporting each adverse effect for each dose was recorded. Where trials reported the occurrence of adverse effects over time following a single dose, the effects occurring in the first time period (typically 24 hours) were recorded if the total number of people reporting each effect in the complete follow-up period was not given.

We extracted incidence of cholera cases and death over particular time periods of follow up (eg first year following vaccination, second year etc) to determine the duration of protection.

Assessment of risk of bias in included studies

PG and JD independently assessed each trial's method of treatment allocation (random, quasi-random, sequential, not stated), blinding (double, single, or not blind), completeness (percentage of randomized participants completing the immunization schedule and the follow-up period), and the surveillance procedure used to detect cases.

Data synthesis

The overall risk ratio (RR) was used to report the relative rates of cholera cases in vaccinated and placebo groups. This figure was converted to vaccine efficacy using the formula: % vaccine efficacy = (1-RR) x 100%.

Overall risk ratio was also used for adverse effect rates and other outcomes.

We anticipated between-trial variation in estimates of vaccine efficacy as there are several sources of heterogeneity which cannot be standardized. For example, the studies included in this review have been undertaken in a range of countries, each of which has a different pattern of exposure to the cholera pathogens. There are also major differences in the formulation of the vaccines.

To account for these differences in the analysis where significant heterogeneity (P < 0.1) was encountered between the study results, we have incorporated it into the analysis by reporting the results of the analysis using the random-effects model, presented in the results section as a letter R following a result. Elsewhere we have reported the results of analyses using the fixed-effect model.

It was defined a priori that subgroup analyses would be done for different age groups (under and over five years), and over time.

We split trials that included several active arms receiving separate vaccines into individual references (denoted as i, ii, iii, etc). As each active arm is compared to the same placebo group it is important that the analysis does not count the participants and cases in the placebo group more than once. This was prevented by dividing the placebo cases and participants as evenly as possible between the arms. The validity of this approach was confirmed in a second analysis in which the active arms within each trial were added together before the trials were pooled. This gave identical results in analyses using a fixed-effect model, and very similar, but slightly less conservative, results when using a random-effects model.

Results

Description of studies

Search results

Sixteen trials fulfilled the inclusion criteria, although 26 comparisons are included in the review since some trials had more than one arm and we reported on these separately ('Characteristics of included studies'). To avoid counting the control group more than once in these trials, the control cases and participants were divided as evenly as possible between the arms. Fifteen trials were excluded ('Characteristics of excluded studies').

Vaccines

All the included trials tested injected vaccines of which there were two kinds: killed whole cell (KWC) or purified antigen. Various serotypes and formulations of KWC vaccines or purified antigen fractions were tested. All compared the vaccine with placebo (active or inactive).

Trial sites

The trials were conducted starting in 1963 and continuing until the late 1970s. Most were large and required massive programs to undertake the logistics of vaccination and surveillance. Several series of large trials (a total of several hundred thousand people in each site) were conducted in four sites in endemic areas: the Matlab study area of East Pakistan (later Bangladesh); Calcutta, India; Negros Occidental province, Philippines; and Surabaya, Indonesia. One smaller trial (998 participants) was conducted in the former USSR (Burgasov 1976).

Outcome measures

Some of these trials (usually the first one in each series) investigated safety and immunogenicity. Most trials included clinical outcomes detected during massive population surveillance operations. All trials observed incidence of natural infection by cholera. The trial conducted in the former USSR investigated only safety and immunogenicity (Burgasov 1976). In terms of this review's outcome measures, 24 comparisons reported on vaccine efficacy (cholera cases and/or deaths) and 11 comparisons considered adverse effects. Nine reported on both types of outcome. Benenson 1968a and Burgasov 1976 provided data on adverse effects only.

Individual trial descriptions by location

East Pakistan (later Bangladesh)

Six quasi-randomized controlled trials were conducted in this region, but nine comparisons were included since two trials had several arms (denoted as i, ii, and iii), and we reported on these separately; see Benenson 1968b-i and Benenson 1968b-ii; and Mosley 1970-i, Mosley 1970-ii, and Mosley 1970-iii. One trial reported on adverse events only (Benenson 1968a). The comparisons differed in the participant age groups: four included all ages (Benenson 1968a; Oseasohn 1965; Benenson 1968b-i; Benenson 1968b-ii); four included children aged up to 14 years (McCormack 1969; Mosley 1970-i; Mosley 1970-ii; Mosley 1970-iii); and one included females of all ages and males up to age 15 years (Curlin 1975).

The trials compared types of cholera vaccine with active placebos or various schedules of vaccine against active placebos (shown in order of date started):

  • Benenson 1968a: several types of injected KWC with one or two doses versus two active placebos (typhoid/paratyphoid A/paratyphoid B (TAB) and tetanus toxoid).

  • Oseasohn 1965: injected, single-dose KWC versus active placebo (TAB).

  • McCormack 1969: various schedules (one or two initial doses plus two annual boosters; two initial doses without boosters) of injected KWC versus two active placebos (tetanus and diphtheria toxoids).

  • Curlin 1975: two doses of lypohilized cholera toxoid (glutaraldehyde treated) versus active placebo (diptheria-tetanus toxoid).

India (Calcutta)

Four randomized controlled trials were conducted in this region, but five comparisons are included. Two trials were reported in one publication (denoted as a and b), and one of these trials had two arms (denoted as i and ii): das Gupta 1965a; and das Gupta 1965b-i and das Gupta 1965b-ii. All age groups were included in the trials.

All four randomized controlled trials compared one dose of an injected KWC vaccine with an active placebo (shown in order of date started):

  • Taneja 1965: one-dose injected KWC versus active placebo (TAB).

  • Pal 1980: one-dose injected Classical KWC with alum adjuvant versus active placebo (tetanus toxoid).

Indonesia (Surabaya)

One randomized controlled trial was conducted in this region, although it had two arms (Saroso 1978i; Saroso 1978ii). The trial compared one-dose injected KWC vaccine with an active placebo (tetanus toxoid) in all age groups. Saroso 1978i used a non-aluminium-hydroxide adsorbed KWC vaccine, while Saroso 1978ii used an aluminium hydroxide-adsorbed KWC vaccine.

Philippines (Negros Occidental province)

Four randomized controlled trials were conducted in this region, but nine comparisons are included since two trials had several arms (denoted as i, ii, etc) and we reported on these separately. The trials were conducted in all age groups. All trials compared a KWC vaccine with active placebo (shown in order of date started):

  • PCC 1968: one or two doses (at three-week intervals) of El Tor KWC vaccines versus active placebo (typhoid vaccine).

  • PCC 1973b: single-dose Classical KWC injected subcutaneously or intradermally versus active placebo (typhoid vaccine).

Former USSR

One randomized controlled trial was conducted in this region (Burgasov 1976). This trial compared three types of one-dose injected Classical KWC and a partially purified cholera toxoid with inert placebo (sterile physiological solution). Only adults (both sexes) were included.

Risk of bias in included studies

The details for each trial are given under 'Method' in the 'Characteristics of included studies'. We assessed the efficacy and adverse effect trials separately.

Efficacy trials: 14 trials with 24 comparisons

The methodological quality of the efficacy trials was relatively high, considering their age.

Method of treatment allocation

Nine trials with 16 comparisons stated that the allocation method was randomization although only one trial mentioned a particular method (Latin Square (Azurin 1965i; Azurin 1965ii; Azurin 1965iii)). The other five trials (eight comparisons) used a sequential method such as alternate census number (Curlin 1975, all East Pakistan trials). These trials have therefore been classified as quasi-randomized controlled trials rather than randomized controlled trials, and allocation concealment is regarded as inadequate. All of the other trials mentioned some kind of coding system or identical preparation of placebo and are thus classified as adequate for allocation concealment.

Blinding

All efficacy trials were stated to be double blind with the exception of Curlin 1975 (single, possibly double).

Completeness

The major flaw in the reporting of the efficacy trials is the lack of information on the completeness (ie the percentage of randomized participants completing the immunization schedule and the follow-up period). In many trials there was a large difference between the number randomized and the number who actually participated. Some trials reported on the number completing the vaccination schedule (71% for Curlin 1975). Most trial reports provided little information on the percentage of participants who completed even the initial period of follow up. The India, Indonesia, and Philippines trials gave no information on this aspect of the trials. The little information on follow up that can be gleaned from some of the other trials suggests that dropout was not a serious problem – for example, dropout appears to have been less than 5% by two years in McCormack 1969, about 5% by one year in Mosley 1970-i, Mosley 1970-ii, and Mosley 1970-iii, and about 10% in Oseasohn 1965. It is easy to appreciate that keeping track of participants in trials with many thousands of people per arm would be a problem. However, since differential dropout is a serious potential source of bias in vaccine trials, and more information on this topic (perhaps by sampling a proportion of participants) would have been reassuring.

Surveillance procedure used to detect cases

Of the 14 efficacy trials, five used only active surveillance for cases, six used only passive, and three used both (details in Appendix 2). In all but one of the five East Pakistan/Bangladesh efficacy trials, it was claimed that daily or twice-weekly surveillance was carried out at home. In India, all four trials used passive surveillance, whereby cases were not detected unless they presented for treatment or sent a postal or telephone message. The Indonesia trial also used passive surveillance. In the Philippines, one trial used active surveillance only and the other three used a combination of passive surveillance and house to house visits, although the frequency and duration of this activity is not stated.

Adverse effect trials: 7 trials with 11 comparisons

Method of treatment allocation

Allocation method in the adverse effect trials was stated to be randomization in all trials except Benenson 1968a (sequential by census), which was classified as a quasi-randomized controlled trial. Allocation concealment was classed as inadequate in this trial; all other trials were classed as adequate for allocation concealment.

Blinding

Blinding was only single (possibly double, but not clear) in one of the adverse effect trials (Burgasov 1976). All other trials were stated to be double blind.

Completeness

In the adverse effect trials, follow up was usually short and dropouts minimal. Completion of follow up (ie the percentage of randomized participants completing the immunization schedule and the follow-up period) was 100% in two of the trials (Benenson 1968a; Burgasov 1976) but not stated in the others.

Surveillance procedure used to detect cases

The seven trials reporting on adverse effects were very poor in reporting the methods of surveillance (details in Appendix 2). However, since most reported on adverse events within 24 hours of vaccination, it is likely that individuals were actively assessed during that time period. In Burgasov 1976, home follow up continued for 30 days, although the frequency was not stated. In one trial in the Philippines where adverse effects were assessed (Azurin 1965iii), passive surveillance occurred in addition to active follow up because numerous participants reported to health facilities with adverse events.

Effects of interventions

Outcomes considered were cholera cases assessed after different lengths of follow up (up to seven months, up to one year, during year two, three, four, and five after follow up) for which data were available. During the first year of follow up, data from trials may appear in either 'up to seven months follow up' or 'up to one year follow up' depending on the duration of surveillance. Trial results appear in both categories only if the trials reported additional data for the second half of the first year of follow up. It should be noted that only three trials continued follow up for more than two years.

Injected cholera vaccine vs placebo (no booster)

The vaccination schedule for the trials considered here was either a single dose (all trials except McCormack 1969 and PCC 1968) or a 'short schedule'. In McCormack 1969, half of the participants had one dose and the other half had a short schedule of two doses given up to 35 days apart. For this analysis, participants who had booster doses at one year in McCormack 1969 were only included before one year of follow up. In PCC 1968 the data were combined from groups given either one dose or two doses at three-week intervals. Trials with booster doses at one year (Mosley 1970-i; Mosley 1970-ii) were excluded from this comparison after one year's follow up.

1. Cholera cases

Injected cholera vaccines were more effective than placebo at reducing risk of cholera cases for up to two years after immunization (Analysis 1.1): up to seven months (RR 0.44, 95% CI 0.37 to 0.53; 2,098,146 participants, random-effects model); up to one year (RR 0.52, 95% CI 0.42 to 0.65, random-effects model; 1,512,573 participants); and year two (RR 0.58, 95% CI 0.45 to 0.75; 718,579 participants). Considering all age groups together, the vaccines were not significantly efficacious in years three (33,028 participants), four (18,969 participants), and five (18,969 participants); see Analysis 1.1. The corresponding estimates for vaccine efficacy for all vaccines combined are 56% (95% CI 47% to 63%) for up to seven months, 48% (95% CI 35% to 58%) for up to one year, and 41% (95% CI 24% to 55%) for year two.

2. Death

Analysis 1.2 examines deaths (all-cause and cholera) in the first year of follow up. With the vaccine there was no reduction in all-cause deaths (RR 0.99, 95% CI 0.72 to 1.34; 26,743 participants), but there was a significant reduction in cholera deaths (RR 0.49, 95% CI 0.25 to 0.93; 837,442 participants). Note that this comparison included the Philippines trial arm of Azurin 1965iii that tested the cholera oil adjuvant vaccine, which had serious adverse effects.

Injected cholera vaccine vs placebo (stratified analyses)

3.1. Cholera cases by age group

This comparison includes only those trials that reported age-specific outcomes. A single dose or short schedule without booster was used by all trials except two trials that had one booster dose at one year after the first dose (Mosley 1970-i; Mosley 1970-ii). At each time point, we stratified the participants by those aged up to five years and those aged over five years: up to seven months' follow up (Analysis 2.1); up to one year follow up (Analysis 2.2); year two follow up (Analysis 2.3); year three follow up (Analysis 2.4); year four follow up (Analysis 2.5); and year five follow up (Analysis 2.6).

In the first year of follow up, there is little age-related difference in the reduction in risk of cholera cases between the vaccine and placebo when stratified by age group (Analysis 2.2): up to five years (RR 0.45, 95% 0.35 to 0.59; 250,941 participants); and greater than five years (RR 0.51, 95% CI 0.42 to 0.63; 815,791 participants). These translate to efficacies of 55% (95% CI 41% to 65%) and 49% (95% CI 37% to 58%), respectively. There were two trials in which the efficacy at one year was notably better in the younger age group: Pal 1980 (89% versus 56%); and Saroso 1978ii (71% versus 43%). Both trials used alum-absorbed vaccine, suggesting that this adjuvant may increase efficacy in young children. This effect was not observed in Saroso 1978i, which used the same vaccine as Saroso 1978ii without alum (efficacy 43% and 44% in participants aged up to five years and over five years, respectively).

In the second year of follow up, the vaccines were not significantly efficacious in children aged up to five years (RR 0.83, 95% CI 0.52 to 1.31; 42,039 participants) whereas they were in older participants (RR 0.36, 95% CI 0.23 to 0.57; 241,578 participants); see Analysis 2.3. These translate to efficacies of 17% (95% CI -31% to 48%) and 64% (95% CI 476% to 7686%), respectively. This difference was similar also at year three when the vaccines had little effect in children aged up to five years (RR 0.64, 95% CI 0.39 to 1.09; 24,866 participants), but they were still protective in the older participants (RR 0.24, 95% CI 0.11 to 0.54; 41,852 participants); see Analysis 2.4. The equivalent efficacies are 36% (95% CI -10% to 63%) and 76% (95% CI 45% to 90%), respectively.

3.2. Cholera cases by vaccine schedule

This comparison specifically examined the question of whether booster doses of injected vaccines improve the duration of protection. Two trials (one with two sub-trials) included booster schedules: McCormack 1969 and Mosley 1970-i and Mosley 1970-ii. The McCormack 1969 trial included both non-booster and booster arms: the non-booster arm had two doses on a short schedule, while the booster arm had either one or two initial doses followed by additional doses after one and two years. Mosley 1970-i and Mosley 1970-ii tested Classical monovalent Ogawa (Mosley 1970-i) or Inaba (Mosley 1970-ii) vaccines with a single initial dose followed by one booster shot at one year. In both trials the non-booster and/or placebo groups received placebo shots instead of booster doses to maintain blinding. For up to one year of follow up before the booster was given, no difference would be expected between short schedule and booster subgroups: RR 0.55 (95% CI 0.45 to 0.68, random-effects model; 1,442,164 participants) for the single-dose schedule; and RR 0.35 (95% CI 0.13 to 0.98, random-effects model; 64,208 participants for the booster subgroups respectively; see Analysis 3.1. There was no difference between subgroups during year two either (Analysis 3.2). In the third year, significant protection was observed in the booster schedule group: RR 0.34 (95% CI 0.15 to 0.77, random-effects model; 60,941 participants), but not in the other groups (Analysis 3.3). Similar trends were seen in year four (Analysis 3.4) and year five (Analysis 3.5).

3.3. Cholera cases by vaccine type

This comparison examines the efficacy of different biotypes and serotypes of cholera vaccine (including purified antigens) up to one year after immunization. Overall, all types of vaccine except a toxoid (Curlin 1975) demonstrated protective efficacy which ranged from 38% (10% to 57%) (R) for El Tor 01 Ogawa plus Inaba KWC injected, to 86% (25% to 97%) (R) for Classical 01 Inaba KWC injected (Analysis 4.1).

4. Adverse effects

4.1. Versus inert placebo

Only one trial used an inert placebo (Burgasov 1976). As shown in Analysis 5.1, the vaccine used in this trial caused malaise in 11% of recipients (RR 4.36, 95% CI 1.79 to 10.60), tenderness in 38% of recipients (RR 9.56, 95% CI 4.82 to 18.95), erythema in 28% of recipients (RR 2.82, 95% CI 1.83 to 4.34), and local infiltration in 14% of recipients (RR 14.04, 95% CI 3.50 to 56.33). All other adverse effects had no higher frequency in the vaccinated versus placebo groups.

4.2. Versus active placebo

When compared to active placebo (Analysis 5.2), the vaccines caused vomiting in 1.5% of recipients (RR 10.43, 95% CI 1.34 to 81.22) and tenderness in 26% of recipients (RR 1.26, 95% CI 1.04 to 1.53). There were between-trial differences in the risk ratios for other adverse effects, with one trial (Pal 1980) showing large (RR > 1.5) increases in headache, fever, erythema, and swelling, although the averages across all trials were not statistically significant. In Benenson 1968a, the adverse effects were not classified beyond systemic or local;13% of participants had systemic effects (RR 2.30, 95% CI 1.10 to 4.80) and 40% had local effects (RR 3.48, 95% CI 2.14 to 5.63). One trial in the Philippines with three arms reported on trials with Classical vaccine (Azurin 1965i), El Tor vaccine (Azurin 1965ii), and Classical vaccine with oil adjuvant (Azurin 1965iii). There were serious adverse events observed in this trial when participants presented to health facilities (abscesses, ulcers, or hard masses at the site of vaccination), and it is reported that 96% of these occurred in the group who received the oil adjuvant vaccine (Azurin 1965iii). It was also reported that erythema, swelling, pain, induration, fever, and a feeling of weakness were experienced by participants. Overall the percentage of persons experiencing adverse events of any type was 0.8% in those receiving Classical vaccine (Azurin 1965i), 1.7% in those with El Tor vaccine (Azurin 1965ii), 96.1% in the Classical/oil adjuvant vaccine Azurin 1965iii, and 1.4% in the placebo group. However, no breakdown of specific symptom by vaccine group was given, except for the severe events mentioned above. Therefore we cannot include these results in the Analysis 5.2.

Discussion

We included trials of injected cholera vaccines that had clinical outcomes (cholera cases, deaths, and adverse effects). We excluded trials with only immunological outcomes because our main questions were the efficacy and safety of injected cholera killed or subunit vaccines. The number of cases of cholera at different time periods after vaccination was our major outcome measure. We also assessed deaths (both all-cause and cholera specific) by year one of follow up, although this was investigated in few trials. Adverse effects were assessed by relatively few trials with a high variability in definition and measurement which made synthesis across different studies difficult.

The results of our review show that injected cholera vaccines are relatively efficacious in the first seven months. There was no evidence for a marked decline in efficacy in the second half of the first year or in year two, even without a booster dose.

Efficacy estimates stratified by age group (under or over five years) showed little difference in the first year. In year two, the vaccines were significantly less efficacious in children under five years than in older individuals. This difference persisted at year three when the vaccines had little effect in children aged less than five years (efficacy 20%, 95% CI -14% to 43%) but were still strongly protective in persons over five years (efficacy 57%, 95% CI 38 to 71%). By years four and five, neither age group was protected.

Both short vaccination schedules (single dose or two doses up to one month apart) and schedules with annual booster doses induced equivalent protection for two years in recipients. After year two, the booster schedule appeared to provide superior protection: efficacy was 9% for short schedules and 66% for booster schedules in year three and in year four the respective estimates were 7% and 39%. Our assessment of short versus booster schedules is based on a limited number of trials which included boosters (McCormack 1969; Mosley 1970-i; Mosley 1970-ii), only one of which continued beyond three years.

Injected cholera vaccines reduced cholera deaths by half, but they were of marginal efficacy in preventing all-cause death.

Injected cholera vaccines appear to be reasonably safe and were relatively well tolerated. Injected cholera vaccines did not cause significant increase in most individual systemic adverse effects (fever, malaise, headache) compared to active placebo, although they did cause increased malaise compared to inert placebo, and increased vomiting and unspecified systemic reactions compared to active placebo.

Injected cholera vaccines caused an increased number of local adverse effects including erythema, tenderness, and infiltration compared to inert placebo, and unspecified local reactions when compared to active placebo.

Our decision not to include serological outcomes in this review is based partly on the uncertainty of the relationship between protection afforded by the vaccine and a rise in antibody titre following immunization. Previously, the mouse protection index was considered the best correlate measure (Joo 1974), but since then most studies have quantified immunogenicity in terms of serum anti-toxin antibodies and/or vibriocidal antibodies, often in assays which are serotype specific (Inaba and Ogawa). Anti-toxin antibodies may protect by neutralizing cholera toxin, while vibriocidal antibodies may protect against colonization. Currently the critical protective immunity is thought to be antibacterial (vibriocidal) rather than antitoxic (Davis 1995). However, elevated serum vibriocidal antibodies, which may exist in persons in endemic areas, are often not further boosted by either vaccination or exposure to cholera, so rates of seroconversion may not correlate well with vaccine efficacy in these areas. Moreover, studies with serological outcomes reported results in a variety of assays using different definitions of seroconversion, making it very difficult to sum-up in a homogeneous way. Trials with clinical outcomes are the definitive method of assessing protection.

Historically six criticisms have been levelled at injected cholera vaccines. Firstly the protection from these vaccines is frequently stated to be below 30% at four to six months after vaccination (Sánchez 1997), or "modest and short lived" (Clemens 1994), or 50% to 70% with a short duration of three to six months (Feeley 1978), or not exceeding 50% to 60% (Joo 1974). We concur with the estimates of the latter two authors of overall protective efficacy, since our estimate is 57% (50% to 64%) after seven months. But we do not confirm the short duration of efficacy, since our estimate is 51% (4%1 to 59%) efficacy in the first year and 47% (36% to 56%) in the second year.

Secondly, injected cholera vaccines were stated to give "incidence of significant local reactions in up to 30% of vaccinees" (Sánchez 1997) and "immunization is generally accompanied by mild fever, malaise and headache" (Joo 1974). We found some basis for the former statement, but not for the latter since only up to 13% of vaccinees had systemic adverse effects. In general, injected cholera vaccines were well tolerated and the nature of the relatively minor adverse effects must be weighed against the possible severity and catastrophic impact of cholera.

Thirdly, protective efficacy in children aged less than five years was stated to be "below 30%" (Sánchez 1997) or "poor" in the same age group (Joo 1974). Again the letter of these statements is not borne out by the results of our meta-analysis, as in the first year the level of protection is equivalent in under- and over-five year olds (51% and 55% in the two groups). However, protection certainly persists longer in persons aged over five years, in whom efficacy was 57% in the third year after immunization.

Fourthly, it was suggested that injected cholera vaccines do not reduce carriage of V. cholerae 01 (Clemens 1994; Sánchez 1997). We are not able to comment on this statement as the trials reviewed to date have not addressed this issue specifically. Moreover Clemens 1994 noted that the role of asymptomatic excretion of V. cholerae in epidemics is unclear, and consequently the public health importance of interrupting 'carrier' status is not known. Cvjetanović 1978a and Cvjetanović 1978b suggested that lifelong healthy carriers epidemiologically play a negligible role.

Fifthly, Sommer 1973b thought that injected KWC vaccines have no role in controlling an epidemic, assuming an efficacy of around 50%. Although the included trials have not addressed this issue, it certainly appears likely that seeking out and vaccinating household contacts of cases (as considered by Sommer 1973b) would be too late to prevent infection of such secondary cases, and this is supported by one excluded trial (Sommer 1973a). However we believe that this does not discount the potential indirect effect that vaccinating a community would have on controlling or preventing an epidemic (Clemens 1996). Vaccine trials to date have involved individual, rather than community, randomization. The efficacy (or rather effectiveness) of a vaccine is likely to be much greater if given to a whole community rather than to dispersed individuals, if the vaccines reduced excretion of bacteria or if herd immunity was attained. This would have to be tested in trials of different design than the ones reviewed here.

Finally, it is asserted that injected cholera vaccines necessitate more than one inoculation to be effective. We did not find this to be the case for parenterally administered vaccines. Most of trials in our analysis used only one dose. For example, eight of the 10 trials (16 of 18 subtrials) of injected cholera vaccine analysed at seven months' follow up used a single dose, with a summary estimate of 54% efficacy. At two years, our summary estimate for these injected cholera vaccines was 39% (21% to 52%) protective efficacy in the second year of follow up; this was derived from six trials, in five of which only one dose was given. Booster doses do not provide enhanced protection until years three and four.

We conclude that injected cholera vaccines are generally safe and relatively effective, with a combined estimate of 57% efficacy at one year and 47% at two years. Injected cholera vaccines achieve this level of efficacy after one injection or a short schedule of two doses; extending this level of protective efficacy for up to four years requires an annual booster. Vaccines were of equivalent efficacy in children under five years as in older age groups in the first year, but protection persisted longer (up to three years) in older children and adults.

These data provide the background information against which to compare the efficacy of oral cholera vaccines, which are the subject of a separate Cochrane Review (Abba (in progress)).

Disaggregation of study results for this review caused a considerable conceptual and logistic burden. Study reports frequently discussed more than one separate trial in the same published report, and there were multiple publications from single trials. Repetition of study results is to a certain extent inevitable in such large studies of long duration, which lend themselves to multiple publications of progress reports or partial reports of different outcomes. However, we feel that unnecessarily complicated trials, combined with multiple reporting, may have contributed to the underestimation of the extent and longevity of protection induced by injected cholera vaccines. Nevertheless it is not clear how the myth of requirement for six-monthly boosters for this type of vaccine originated, since no trial tested such a schedule, and the few trials comparing annual booster and non-booster schedules showed no advantage of booster until the third year of follow up.

Over one million people, including infants and children, have taken part in large, good quality efficacy trials of injected cholera vaccines over the last 35 years. The overwhelming majority of these participants have been poor residents of cholera-endemic areas. Also hundreds of researchers have devoted years of their careers to these trials. Their contributions deserve to be better recognized by thorough examination of the results of these trials. It appears that the adverse effects have been overestimated and relatively effective injected cholera vaccines have been underestimated.

Authors' conclusions

Implications for practice

Injected cholera vaccines are not currently available and therefore not recommended for either residents of endemic areas or travellers. The accepted wisdom is that they provide weak, partial protection of very short duration and require multiple doses. However, this meta-analysis demonstrated significant protection for populations living in endemic areas for up to two years following a single dose, and for three to four years with annual booster. Risk of death from cholera was also reduced by 50% in the first year after vaccination.

Implications for research

All cholera vaccine trials to date have been individually rather than group randomized. Research is needed on whether cholera vaccines can control epidemics if given on a population basis.

Results of two trials showing that alum adjuvant KWC injected vaccines were more effective in young children than older persons suggest that modern adjuvants could possibly increase the efficacy of injected KWC vaccines in this age group.

This review provides a solid background of evidence for effects of cholera injected vaccines against which to compare the effects of oral vaccines.

Acknowledgements

The authors would like to thank Drs Daniela Rivetti, Franco Bottasso, Ron Behrens, and Alaistair MacMillan who applied quality criteria, and Professor Myron Levine and Mrs Carol Hobbs for assistance. We are very grateful to Mark Pratt who conducted literature searches and initial screening, and developed the trial register.

Data and analyses

Download statistical data

Comparison 1. Injected cholera vaccine vs placebo (no booster)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Cholera cases, by period of follow up214.400266E6Risk Ratio (M-H, Fixed, 95% CI)0.53 [0.49, 0.57]
1.1 Up to 7 months172.098148E6Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.41, 0.52]
1.2 Up to 1 year141.512573E6Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.48, 0.62]
1.3 Year 26718579Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.45, 0.75]
1.4 Year 3233028Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.54, 1.51]
1.5 Year 4118969Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.57, 1.54]
1.6 Year 5118969Risk Ratio (M-H, Fixed, 95% CI)0.92 [0.52, 1.61]
2 Death7864185Odds Ratio (M-H, Fixed, 95% CI)0.88 [0.66, 1.16]
2.1 All cause (year 1)226743Odds Ratio (M-H, Fixed, 95% CI)0.99 [0.72, 1.34]
2.2 Cholera (year 1)5837442Odds Ratio (M-H, Fixed, 95% CI)0.49 [0.25, 0.93]
Analysis 1.1.

Comparison 1 Injected cholera vaccine vs placebo (no booster), Outcome 1 Cholera cases, by period of follow up.

Analysis 1.2.

Comparison 1 Injected cholera vaccine vs placebo (no booster), Outcome 2 Death.

Comparison 2. Injected cholera vaccine vs placebo: by age group
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Cholera cases, up to 7 months' follow up131.874543E6Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.41, 0.54]
1.1 Age < 5 years13250941Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.42, 0.65]
1.2 Age > 5 years131.623602E6Risk Ratio (M-H, Fixed, 95% CI)0.44 [0.38, 0.52]
2 Cholera cases, up to 1 year follow up11926474Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.42, 0.58]
2.1 Age < 5 years11110683Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.35, 0.59]
2.2 Age > 5 years11815791Risk Ratio (M-H, Fixed, 95% CI)0.51 [0.42, 0.63]
3 Cholera cases, year 2 follow up5283617Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.39, 0.74]
3.1 Age < 5 years542039Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.52, 1.31]
3.2 Age > 5 years5241578Risk Ratio (M-H, Fixed, 95% CI)0.36 [0.23, 0.57]
4 Cholera cases, year 3 follow up366718Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.32, 0.75]
4.1 Age < 5 years324866Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.39, 1.09]
4.2 Age > 5 years341852Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.11, 0.54]
5 Cholera cases, year 4 follow up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5.1 Age < 5 years1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 Age > 5 years1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
6 Cholera cases, year 5 follow up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
6.1 Age up to 5 years1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
6.2 Age over 5 years1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 2.1.

Comparison 2 Injected cholera vaccine vs placebo: by age group, Outcome 1 Cholera cases, up to 7 months' follow up.

Analysis 2.2.

Comparison 2 Injected cholera vaccine vs placebo: by age group, Outcome 2 Cholera cases, up to 1 year follow up.

Analysis 2.3.

Comparison 2 Injected cholera vaccine vs placebo: by age group, Outcome 3 Cholera cases, year 2 follow up.

Analysis 2.4.

Comparison 2 Injected cholera vaccine vs placebo: by age group, Outcome 4 Cholera cases, year 3 follow up.

Analysis 2.5.

Comparison 2 Injected cholera vaccine vs placebo: by age group, Outcome 5 Cholera cases, year 4 follow up.

Analysis 2.6.

Comparison 2 Injected cholera vaccine vs placebo: by age group, Outcome 6 Cholera cases, year 5 follow up.

Comparison 3. Injected cholera vaccine vs placebo: by vaccine schedule
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Cholera cases, up to 1 year follow up14 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Single dose111.442164E6Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.49, 0.64]
1.2 Short schedule119933Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.18, 0.65]
1.3 Booster364208Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.33, 0.64]
2 Cholera cases, year 2 follow up8 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Single dose6718480Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.45, 0.74]
2.2 Short schedule119311Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.27, 1.83]
2.3 Booster361480Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.42, 1.19]
3 Cholera cases, year 3 follow up4 Risk Ratio (M-H, Random, 95% CI)Subtotals only
3.1 Single dose114059Risk Ratio (M-H, Random, 95% CI)0.61 [0.22, 1.68]
3.2 Short schedule118969Risk Ratio (M-H, Random, 95% CI)1.04 [0.57, 1.90]
3.3 Booster360941Risk Ratio (M-H, Random, 95% CI)0.34 [0.15, 0.77]
4 Cholera cases, year 4 follow up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
4.1 Single dose0 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.2 Short schedule1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
4.3 Booster1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5 Cholera cases, year 5 follow up1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
5.1 Single dose0 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5.2 Short schedule1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
5.3 Booster1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 Injected cholera vaccine vs placebo: by vaccine schedule, Outcome 1 Cholera cases, up to 1 year follow up.

Analysis 3.2.

Comparison 3 Injected cholera vaccine vs placebo: by vaccine schedule, Outcome 2 Cholera cases, year 2 follow up.

Analysis 3.3.

Comparison 3 Injected cholera vaccine vs placebo: by vaccine schedule, Outcome 3 Cholera cases, year 3 follow up.

Analysis 3.4.

Comparison 3 Injected cholera vaccine vs placebo: by vaccine schedule, Outcome 4 Cholera cases, year 4 follow up.

Analysis 3.5.

Comparison 3 Injected cholera vaccine vs placebo: by vaccine schedule, Outcome 5 Cholera cases, year 5 follow up.

Comparison 4. Injected cholera vaccine vs placebo: by vaccine type
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Cholera cases, up to 1 year follow up24 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Classical 01 Ogawa + Inaba KWC vaccine, injected8861397Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.53, 0.70]
1.2 Classical 01 Ogawa KWC vaccine, injected3234414Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.37, 0.57]
1.3 Classical 01 Inaba KWC vaccine, injected2111765Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.15, 0.33]
1.4 Classical 01 Ogawa + Inaba KWC vaccine plus Al adjuvant, injected2516226Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.30, 0.59]
1.5 Classical 01 Ogawa + Inaba KWC vaccine plus oil adjuvant, injected1290400Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.36, 0.62]
1.6 El Tor 01 Ogawa + Inaba KWC vaccine, injected3707596Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.51, 0.75]
1.7 El Tor 01 Ogawa KWC vaccine, injected189950Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.24, 0.53]
1.8 El Tor 01 Inaba KWC vaccine, injected188700Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.29, 0.61]
1.9 Purified antigen vaccines, injected239755Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.27, 0.60]
1.10 Toxoid vaccine, injected192838Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.75, 1.08]
Analysis 4.1.

Comparison 4 Injected cholera vaccine vs placebo: by vaccine type, Outcome 1 Cholera cases, up to 1 year follow up.

Comparison 5. Injected vaccine vs placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Adverse events vs inert placebo1 Risk Ratio (M-H, Fixed, 95% CI)Totals not selected
1.1 Diarrhoea1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.2 Vomiting1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.3 Abdominal pain/cramp1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.4 Nausea1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.5 Headache1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.6 Fever1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.7 Malaise1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.8 Tenderness1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.9 Adenopathy1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.10 Erythema1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
1.11 Infiltration1 Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]
2 Adverse events vs active placebo523718Odds Ratio (M-H, Fixed, 95% CI)1.27 [1.17, 1.36]
2.1 Vomiting11393Odds Ratio (M-H, Fixed, 95% CI)10.57 [1.35, 82.76]
2.2 Headache43542Odds Ratio (M-H, Fixed, 95% CI)0.90 [0.73, 1.10]
2.3 Fever43542Odds Ratio (M-H, Fixed, 95% CI)1.31 [1.10, 1.56]
2.4 Pain43542Odds Ratio (M-H, Fixed, 95% CI)1.23 [1.03, 1.46]
2.5 Pain43542Odds Ratio (M-H, Fixed, 95% CI)1.23 [1.03, 1.46]
2.6 Erythema32384Odds Ratio (M-H, Fixed, 95% CI)1.23 [0.88, 1.71]
2.7 Tenderness11393Odds Ratio (M-H, Fixed, 95% CI)1.36 [1.06, 1.74]
2.8 Swelling43542Odds Ratio (M-H, Fixed, 95% CI)1.29 [1.05, 1.59]
2.9 Systemic reactions (not otherwise included)1419Odds Ratio (M-H, Fixed, 95% CI)2.49 [1.13, 5.51]
2.10 Local reactions (not otherwise included)1419Odds Ratio (M-H, Fixed, 95% CI)5.13 [2.89, 9.09]
Analysis 5.1.

Comparison 5 Injected vaccine vs placebo, Outcome 1 Adverse events vs inert placebo.

Analysis 5.2.

Comparison 5 Injected vaccine vs placebo, Outcome 2 Adverse events vs active placebo.

Appendices

Appendix 1. Detailed search strategies

Search setCIDG SRaCENTRALMEDLINEbEMBASEbLILACSb
1choleracholeracholeracholeracholera
2vaccin*vaccin*vaccin*vaccin*vaccin*
31 or 21 or 21 or 21 or 21 or 2
4CHOLERA VACCINESCHOLERA VACCINESCHOLERA-VACCINE
53 or 43 or 43 or 4
6Limit 5 to humanLimit 5 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 (Lefebvre 2008); upper case: MeSH or EMTREE heading; lower case: free text term.

Appendix 2. Summary of trials, comparisons, outcomes, and surveillance methods

LocationTrial nameEfficacy outcomesSurveillance method (efficacy)Adverse effects outcomesSurveillance method (adverse effects)
East Pakistan (now Bangladesh)Benenson 1968a a —YesActive (daily clinical assessments at home)
Oseasohn 1965 bYes (cases, deaths)Active (twice weekly at home)
Benenson 1968b-i bYes (cases, deaths)Active (twice weekly at home)
Benenson 1968b-ii b
McCormack 1969 bYes (cases, deaths)Active (daily at home)
Mosley 1970-i bYes (cases)Active (daily at home)
Mosley 1970-ii b
Mosley 1970-iii b
Curlin 1975 bYes (cases)Passive (cases present to health facility)
IndiaTaneja 1965 cYes (cases)Passive (cases make postal, telephone, or clinic notification)YesUnclear; probably active (for 24 hours)
das Gupta 1965a bYes (cases)Passive (cases make postal, telephone, or clinic notification)
das Gupta 1965b-i cYes (cases)Passive (cases make postal, telephone, or clinic notification)YesUnclear; probably active (for 24 hours)
das Gupta 1965b-ii c
Pal 1980 cYes (cases)Passive (attendance at hospital)YesUnclear; probably active (for 24 hours)
IndonesiaSaroso 1978i cYes (cases)Passive (attendance at hospital or clinic)YesUnclear
Saroso 1978ii c
PhilippinesAzurin 1965i cYes (cases, deaths)Active and passive (use of health facilities and house to house enquiry)YesActive and passive
Azurin 1965ii c
Azurin 1965iii c
PCC 1968 bYes (cases)Active (“kept under observation”) — —
PCC 1973a-i bYes (cases, deaths)Active and passive (“kept under observation” and “house to house visits”; frequency not specified) — —
PCC 1973a-ii b
PCC 1973a-iii b
PCC 1973a-iv b
PCC 1973b bYes (cases)Active and passive (“kept under observation” and “house to house visits”; frequency not specified) — —
Former USSRBurgasov 1976 a — —YesActive (medical surveillance for 30 days)

Total trials: 16 (efficacy 14, adverse effects 7); comparisons: 26 (efficacy 24, adverse effects 11).
aAdverse effects only 2 trials, 2 comparisons.
bEfficacy only 9 trials, 15 comparisons.
cBoth efficacy and adverse effects 5 trials, 9 comparisons.

What's new

DateEventDescription
3 August 2010Review declared as stableThis review will no longer be updated because injected cholera vaccines are not available and no longer recommended for use.

History

Protocol first published: Issue 1, 1998
Review first published: Issue 3, 1998

DateEventDescription
7 July 2010New search has been performedThis review is an update of the Cochrane Review of all cholera vaccines (Graves 2001). This update includes only injected vaccines. Oral vaccines are being covered in a new review (Abba (in progress)).
6 July 2010New citation required but conclusions have not changed

A literature search (1 September 2008) did not identify any new trials that were not in Graves 2001. In this update, the authors have restructured the review.

Mark Pratt stepped down as co-author.

Contributions of authors

Vittorio Demicheli, Tom Jefferson, Patricia Graves and Jon Deeks read all trials or trial abstracts and determined eligibility. Patricia Graves and Jon Deeks extracted trial data and assessed quality with the assistance of persons named in the Acknowledgments. Patricia Graves. Jon Deeks and Tom Jefferson conducted analyses with input from all authors on the results. All authors commented on the draft review.

Declarations of interest

None known.

Sources of support

Internal sources

  • Ministry of Defence, UK.

External sources

  • Department for International Development, UK.

  • European Commission (Directorate General XII), Belgium.

Differences between protocol and review

The following phrase was added to 'Types of Interventions – Intervention': "Exception: Phase 1 trials, reporting only adverse effects, for vaccines that never reached efficacy trials."

The following phrase was deleted from "Types of Interventions – Control": "(trials) comparing types, doses or schedules of injected cholera vaccines". No such comparisons were made in the review.

Characteristics of studies

Characteristics of included studies [author-defined order]

Azurin 1965i

Methods

Randomized controlled trial

Generation of allocation sequence: randomized according to a Latin Square

Blinding: double blind

Completeness: not assessable

Surveillance: use of medical facilities and house-to-house enquiry

Participants

Number: 584,026 (1000 for adverse events)

Inhabitants (all ages) of Negros Occidental province, The Philippines, an area endemic for El Tor cholera (incidence estimated as 0.5/1000)

80% of the population (based on 1% sample) had been previously vaccinated against cholera

Interventions

Injected cholera vaccines:

  • Classical bivalent (Ogawa 41 + Inaba 35A3) killed whole cell, Manila

  • El Tor bivalent (Ogawa 1418 + Inaba 6973) lyophilized killed whole cell, Manila

  • Classical bivalent (Ogawa 41 + Inaba 35A3) killed whole cell with oil adjuvant, Japan

Placebo: active placebo (monovalent typhoid vaccine (Manila))

All vaccines contained 8 x 109 organisms/dose

Route: injected subcutaneously
Dose: 1 dose

  • Classical bivalent (Manila) and El Tor vaccines: 0 to 4 years received 0.25 mL; 5 to 9 years received 0.5 mL; ≥10 years received 1 mL

  • Classical bivalent (Japan): 0 to 4 years received 0.05 mL; 5 to 9 years received 0.1 mL; ≥10 years received 0.2 mL

Outcomes
  1. Cholera cases

  2. Cholera deaths

  3. Aymptomatic carrier rate

  4. Carrier rates in household contacts

  5. Adverse effects

LocationPhilippines
Notes

Length of follow up: 18 months

Data for 'up to seven months' (210 days) and 'up to one year follow-up' are reported from Azurin 1967 (see references listed under Azurin 1965i). Cases by age-group are reported only for the first 6-month period from Philippines Cholera Committee 1965 (see references listed under Azurin 1965i)

The denominators in each group were calculated from a 1% sample of the total vaccinated population

This trial Azurin 1965i reports the results of the Classical vaccine versus placebo (vaccine 1). Results for El Tor (vaccine 2) are reported in Azurin 1965ii. Results for the Classical oil adjuvant (vaccine 3) are reported in Azurin 1965iii

Adverse effect data from these trials have not been entered due lack of information on outcomes by vaccine type, but gross reactions occurred in Azurin 1965iii (oil adjuvant vaccine).

Azurin 1965ii

MethodsRandomized controlled trial
ParticipantsSame as Azurin 1965i
Interventions

Injected cholera vaccine: El Tor bivalent (Ogawa 1418 + Inaba 6973) lyophilized killed whole cell, Manila

Placebo: monovalent typhoid vaccine

Route: injected
Dose: 1 dose as Azurin 1965i

OutcomesSame as Azurin 1965i
LocationPhilippines
NotesThis trial reports the results of the El Tor vaccine (vaccine 2) in Azurin 1965i; see Azurin 1965i for additional information

Azurin 1965iii

MethodsRandomized controlled trial
ParticipantsSame as Azurin 1965i
Interventions

Injected cholera vaccine: Classical bivalent (Ogawa 41 + Inaba 35A3) killed whole cell with oil adjuvant, Japan

Placebo: monovalent typhoid vaccine

Route: injected
Dose: 1 dose as in Azurin 1965i

OutcomesSame as Azurin 1965i
LocationPhilippines
Notes

This trial reports the results for the Classical vaccine with oil adjuvant (vaccine 3 in the Azurin (Philippines) trials). See Azurin 1965i for further details

This vaccine and adjuvant combination had serious adverse effects

Benenson 1968a

Methods

Quasi-randomized controlled trial

Generation of allocation sequence: sequential allocation

Blinding: double blind

Completeness: 100% with adverse effect data

Surveillance: by daily clinical assessments at home

Participants

Number: 2801 residents (all ages, both sexes)

87 staff of a military hospital (who had previously been vaccinated many times) and 419 residents of Kadamtali village, Matlab

Interventions

Injected cholera vaccines:

  • CRL: Classical bivalent phenol-killed whole cell

  • 13: Classical bivalent phenol killed whole cell

  • T: lipopolysaccharide (El Tor Ogawa)

Placebos:

  • TAB

  • Tetanus toxoid

  • Saline

Route: injected
Dose: 1 or 2 doses

Outcomes
  1. Geometric mean agglutinin titre and vibriocidal titre to Ogawa antigen

  2. Adverse effects in 24 hours

LocationEast Pakistan: Bandar refugee colony, Mudafa (a rural area), and Kaliganj (a semi-urban area)
NotesOnly the military hospital and Kadamtali village have adverse effect data. Data from the military hospital is excluded as it is not possible to match the 164 vaccinations to the 87 subjects (each participant vaccinated twice, often with different vaccines). Data for Kadamtali (for vaccines 1 and 3 combined) have been estimated from a Figure. The placebo was tetanus toxoid

Benenson 1968b-i

Methods

Quasi-randomized controlled trial

Generation of allocation sequence: allocation according to odd and even census number

Blinding: double blind

Completeness: not ascertained

Surveillance: twice weekly assessments at home

Participants

Number: 25,267

All ages, comprising 78% of the residents of 35 villages in Matlab Thana, Comilla District, East Pakistan. These villages were adjacent to the 23 villages participating in the Oseasohn 1965. Previous immunization status or history of cholera not stated

Interventions

Injected cholera vaccines: Classical bivalent (Ogawa 41, Inaba 35A3) phenol-killed whole cell

Placebo: Tetanus toxoid

Route: injected
Dose: 1 dose

Outcomes
  1. Cholera cases

  2. Deaths (all-cause and cholera)

  3. Cases in household contacts

LocationEast Pakistan
Notes

Length of follow up: 2 years

Vaccination occurred in September to November 1964

Follow up was divided into first cholera season (7 to 9 months after vaccination, up to June 1965) and second cholera season (July 1965 to June 1966)

Cases from first season have been put in 'up to one year follow-up' and cases from second season have been put in 'year 2 of follow-up'. Age breakdown by cholera season is for 0 to 9 and ≥ 10 years. Breakdown by 0 to 4 and 5 to 9 years given only for first cholera season

This trial reports results for Classical bivalent KWC vaccine. Benenson 1968b-ii reports results of the purified Ogawa antigen vaccine

Benenson 1968b-ii

MethodsQuasi-randomized controlled trial
ParticipantsSame as Benenson 1968b-i
Interventions

Injected cholera vaccine: purified freeze-dried Ogawa antigen

Placebo: tetanus toxoid

OutcomesSame as Benenson 1968b-i
LocationEast Pakistan
NotesThis trial reports results results for the purified Ogawa antigen vaccine. Benenson 1968b-i reports results for Classical bivalent KWC vaccine

Burgasov 1976

Methods

Randomized controlled trial

Generation of allocation sequence: random allocation

Blinding: single blind, possibly double blind

Completeness: 100%

Surveillance: medical surveillance for 30 days; frequency not stated

Participants

Number: 998

Adults of both sexes aged over 17 years, not previously vaccinated against or contracted cholera

Interventions

Injected cholera vaccines:

  • Classical bivalent (Ogawa and Inaba) heat-killed whole cell

  • Classical bivalent (Ogawa and Inaba) formalin-killed whole cell

  • El Tor bivalent (Oawa and Inaba) heat-killed whole cell

  • Partially purified cholera toxoid of strain 569B

Placebo: sterile physiological solution

Route: injected (syringe or injector)
Dose: 1 dose of 8 x 109 organisms or 0.8 mg of toxoid

Outcomes
  1. Vibriocidal antibodies (Inaba/Ogawa)

  2. Antitoxin titre

  3. Adverse effects in 30 days

LocationUSSR
Notes

Curlin 1975

Methods

Quasi-randomized controlled trial

Generation of allocation sequence: alternate allocation by census number

Blinding: at least single blind

Completeness: 71% received 2 doses

Surveillance: cases presenting to health facility

ParticipantsNumber: 92,838 participants (females all ages > 1 year; males aged 1 to 15 years)
Interventions

Injected cholera vaccine: Lyophilized cholera toxoid derived from Inaba 569B

Placebo: Diphtheria-tetanus toxoid vaccine

Route: injected (jet injector)
Dose: 2 doses of 0.5 mL containing 100 μg toxoid, 42 days apart

OutcomesCholera cases occurring > 2 weeks after first injection
LocationBangladesh
NotesLength of follow up: 1 year

das Gupta 1965a

Methods

Randomized controlled trial

Generation of allocation sequence: not stated

Blinding: double blind

Completeness: not assessable

Surveillance: through participant making a postal, telephone, or clinic notification

Participants

Number: 79,340

Persons of all ages resident in 5 wards of north-eastern Calcutta (Beliaghata, Maniktola and Ultadanga areas)

Cholera incidence was > 4/1000 in previous years

Previous vaccination status not stated explicitly, but it was alluded to in text as a possible factor leading to lower than expected cholera incidence during the trial

Interventions

Injected cholera vaccines:

  • Classical bivalent (Ogawa + Inaba) phenol killed whole cell (CRI) - as in Taneja 1965

  • Classical bivalent (Ogawa + Inaba) phenol killed whole cell (Haffkine) - same as Taneja 1965

Both vaccines had 8 x 109 organisms/mL

Placebo: TAB (CRI)

Route: injected subcutaneously
Dose: 1 dose; 2 to 4 years received 0.3 mL, 5 to 10 years received 0.5 mL, and ≥ 11 years received 1 mL; dose for infants not given, although from the tables it appears some were vaccinated

OutcomesCholera cases
LocationIndia
Notes

Length of follow up (for both phases): was until 31 December 1965 (ie 6 to 10 months)

This trial is part 1 of the 1965 trials in India reported in one publication by Das Gupta et al 1967 (see references listed under Taneja 1965 for details). In this first part, vaccination started on 2 February 1965 and finished on 22 March 1965. In the second part (see das Gupta 1965b-i and das Gupta 1965b-ii), 25,051 more people from the same Calcutta districts were vaccinated as were an additional 54,606 persons from an adjacent area of the city (total in part II: 79,657) during 2 April to 22 May 1965

The 2 vaccines used in das Gupta 1965a (both classical bivalent killed whole cell) were combined for this analysis

das Gupta 1965b-i

Methods

Randomized controlled trial

Generation of allocation sequence: not stated

Blinding: double blind

Completeness: not assessable

Surveillance: through participant making a postal, telephone, or clinic notification

ParticipantsNumber: 79,657 persons of all ages resident in Calcutta; 25,051 from 5 wards in NE of city (same area as das Gupta 1965a; 54,606 from 5 wards in an adjacent area where the incidence of cholera was > 2/1000 in previous years
Interventions

Injected cholera vaccine:

  • Classical bivalent (Ogawa + Inaba) formol-killed freeze dried whole cell (WRAIR)

  • El Tor bivalent (Ogawa + Inaba) heat killed whole cell (Philippines)

All vaccines has 8 x 109 organisms/mL

Placebo: TAB (CRI)

Route: injected subcutaneously
Dose: 1 dose; age 2 to 4 years received 0.3 mL, age 5 to 10 years received 0.5 mL, and age ≥ 11 years received 1 mL

Outcomes
  1. Cholera cases

  2. Adverse effects within 24 hours

LocationIndia
Notes

Length of follow up: 7 to 8 months

This trial reports on 1 arm of part II of the 1965 India trials reported in das Gupta 1965b-i, which reports the results of 1 of the Classical biotype killed whole cell vaccines (WRAIR) vs placebo

das Gupta 1965b-ii

MethodsRandomized controlled trial
ParticipantsSame as das Gupta 1965b-i
Interventions

Injected cholera vaccine: El Tor bivalent (Ogawa + Inaba) heat-killed whole cell (Philippines) 8 x 109 organisms/mL

Placebo: TAB (CRI)

Route: injected
Dose: 1 dose as in das Gupta 1965b-i

OutcomesSame as das Gupta 1965b-i
LocationIndia
Notes

Length of follow up: 7 to 8 months

This trial reports 1 arm of part II of the 1965 India trials reported by das Gupta 1965b-i, which reports the results of the El Tor biotype killed whole cell vaccine versus placebo

McCormack 1969

Methods

Quasi-randomized controlled trial

Generation of allocation sequence: alternate allocation according to census number

Blinding: double blind

Completeness: 97% at 1 year; 95% at 2 years

Surveillance: daily clinical assessments at home

Participants

Number: 39,862 children included from 53,868 considered

Included: children aged 3 months to 14 years, resident in 132 villages in Matlab, Comilla Distirct, East Pakistan; about 50% of children > 5 years showed immunological evidence of previous exposure to cholera

Interventions

Injected cholera vaccine: Classical bivalent (Ogawa NIH4, Inaba NIH 35A3) phenol killed whole cell, 4000 x106 organisms/dose

Placebo: tetanus + diptheria toxoids

Route: injected
Dose: 0.5 mL/dose; 1 or 2 doses with 25 to 35 days between injections (September to November 1966)

Initially there were 3 groups: OO (2 placebo doses); XO (1 vaccine, 1 placebo); and XX (2 vaccine). Later the trial was extended to 5 years, and third and fourth inoculations were given 1 and 2 years after the first, respectively (in September/October 1967 and September/October 1968). The third XX group was divided into 2. There were then 4 groups: 0000 (4 placebo); X0XX (1 vaccine, 1 placebo, 2 vaccine); XX00 (initially 2 vaccine then 2 placebo); and XXXX (4 vaccine)

Outcomes
  1. Geomentric mean vibriocidal titre (immunological)

  2. Cholera case

  3. Deaths

LocationEast Pakistan
Notes

Length of follow up: initially 7 months after first 2 doses; later extended to 5 years

The XXXX, XXOO, XOXX groups are combined in the principal analyses. The XXXX and XOXX are combined as booster schedules, whilst the XXOO is analysed as a short schedule. Denominators for years 4 and 5 are assumed to be the same as year 3 (no others are given)

Mosley 1970-i

Methods

Quasi-randomized controlled trial

Generation of allocation sequence: alternate allocation by census number

Blinding: double blind

Completeness: 95% at one year

Surveillance: daily clinical assessments at home

Participants

Number: 45,711 children

Aged 0 to 14 years resident in 101 villages in Comilla District, adjacent to Matlab previous trials, East Pakistan; stratified by age (0 to 4, 5 to 9, and 10 to 14 years)

Interventions

Injected cholera vaccines:

  • 1. Classical monovalent (Ogawa NIH 41) formalin killed whole cell, 8 x 109/mL

  • 2. Classical monovalent (Inaba NIH 35A3) formalin killed whole cell, 8 x 109/mL

  • 3. El Tor monovalent (Inaba V86) antigen, 200 μg/mL

Placebo: Tetanus/diptheria toxoids

Route: injected
Dose: 2 doses of 0.5 mL; first dose in October/November 1968; second dose 1 year later in October 1969 (whole cell vaccines only)

Outcomes
  1. Geometric mean vibriocidal titre, Inaba and Ogawa antigen, by age (immunological)

  2. Cholera cases

(Note: most cases (78/83) were due to Inaba serotypes. The paper restricts its analysis mainly to Inaba cases (Ogawa cases are given but not by age of participant))

LocationEast Pakistan
Notes

Length of follow up: 3 years from first dose

This trial had a booster dose at 1 year. Therefore results for 1 year are after 1 dose, results for years 2 and 3 are after 2 doses

This trial reports the results of the comparison Classical Ogawa versus placebo. Mosley 1970-ii reports the results from the Classical Inaba vaccine versus placebo, while Mosley 1970-iii reports results for the purified Inaba antigen

Mosley 1970-ii

MethodsQuasi-randomized controlled trial
ParticipantsSame as Mosley 1970-i
Interventions

Injected cholera vaccine: Classical monovalent (Inaba NIH 35A3) formalin killed whole cell, 8 x 109/mL

Placebo: Tetanus/diphtheria toxoids

Route: injected
Dose: 2 doses of 0.5 mL, 12 months apart

OutcomesSame as Mosley 1970-i
LocationEast Pakistan
NotesSee trial Mosley 1970-i. This trial reports the results of the Classical Inaba vaccine versus placebo

Mosley 1970-iii

MethodsQuasi-randomized controlled trial
ParticipantsSame as Mosley 1970-i
Interventions

Injected cholera vaccine: El Tor monovalent (Inaba V86) antigen 200 μg/mL

Placebo: Tetanus/diphtheria toxoids

Route: injected
Dose: 1 dose

OutcomesSame as Mosley 1970-i
LocationEast Pakistan
NotesSee Mosley 1970-i. This trial reports the results of the Inaba purified antigen versus placebo. This group received 1 dose of the antigen followed by 1 dose of the placebo at 12 months

Oseasohn 1965

Methods

Quasi-randomized controlled trial

Generation of allocation sequence: alternate allocation according to census number

Blinding: double blind

Completeness: estimate 10% emigration in 2 years

Surveillance: twice weekly assessments at home

Participants

Number: 14,059 residents (all ages)

78% had history of prior cholera immunization; 6% had history of previous cholera

Interventions

Injected cholera vaccine: classical bivalent (Inaba 35A3, Ogawa 41) phenol-killed whole cell; 8 x 109 organisms/mL

Placebo: TAB (typhoid - paratyphoid A - paratyphoid B)

Route: injected
Dose: 1, 0.5 mL (reduced to 0.4 mL about half way through trial) for ages > 12 years; 0.25 mL for ages 2 to 12 years; 0.1 mL for ages < 2 years

Outcomes
  1. Cholera cases

  2. Deaths (all causes)

  3. Cases in household contacts

LocationEast Pakistan: 23 villages in Matlab Thana
Notes

Length of follow up: 3 years; data reported separately for first year (Oseasohn et al 1965) and for each of 3 cholera 'seasons' (Benenson et al 1968), which were Season 1 (7 months after vaccination in November 1963 (December 1963 to June 1964), Season 2 (July 1964 to June 1965, and Season 3 (July 1965 to June 1966)

Cases for season 1 have been entered in outcomes for 'up to 7 months' follow up', while cases for season 2 and 3 have been entered in outcomes for year 2 and 3 respectively (most cases in second and third cholera season fell in years 2 and 3 respectively)

Pal 1980

Methods

Randomized controlled trial

Generation of allocation sequence: not stated

Blinding: double blind

Completeness: not assessable

Surveillance: through attendance at hospital with diarrhoea

Participants

Number: 203,170

Persons aged > 1 year living in 17 municipal wards of Calcutta and 2 adjacent wards of South Dum Dum, India

Average annual incidence of hospitalized cases 5/1000

Interventions

Injected cholera vaccine: Classical bivalent (Ogawa + Inaba) killed whole cell, adsorbed onto aluminium phosphate, (CRI Kasauli), 8 x 109 organisms/0.5 mL dose

Placebo: tetanus toxoid (CRI Kasauli)

Route: injected intramuscularly
Dose: 1 dose; 1 to 5 years received 0.25 mL, and > 5 years received 0.5 mL

Outcomes
  1. Cholera cases

  2. Adverse effects during first 24 hours

LocationIndia
NotesLength of follow up: 2 years

PCC 1968

Methods

Randomized controlled trial

Generation of allocation sequence: randomized

Blinding: double blind

Completeness: not assessable

Surveillance: vaccinees were kept under observation by the field team; method and frequency not stated

Participants

Number: 359,600 residents (all ages) of Negros Occidental Province, The Philippines

An estimated 80% had previously been immunized against cholera

Interventions

Injected cholera vaccine: El Tor bivalent (Ogawa 1418, Inaba 6973) killed whole cell

Placebo: active placebo (typhoid vaccine)

Route: injected
Dose: 2 doses at 3 week-intervals, as follows:

  • Group A: 1 dose typhoid and 1 dose cholera, 8 x 109 organisms/mL; 1 mL dose for adults; 0.5 mL dose for children < 10 years

  • Group B: 2 doses cholera at 8 x 109 organisms/mL (children half dose)

  • Group C: 1 dose typhoid and 1 dose cholera at 16 x 109 organisms/mL; children half dose

  • Group D: 2 doses typhoid

OutcomesCholera cases
LocationPhilippines
Notes

Length of follow up: 6 months

Numbers in each group calculated from a 2% sample of the vaccinated population

Results for vaccinated groups A, B, and C have been combined in this analysis

PCC 1973a-i

Methods

Randomized controlled trial

Generation of allocation sequence: randomized

Blinding: double blind

Completeness: not stated

Surveillance: vaccinees kept under observation by field team; method and frequency not stated

Participants

Number: 223,566

Persons of all ages in coastal communities in Negros Occidental province, Philippines

Trial in the same area as the Azurin trials and PCC 1968

Interventions

Injected cholera vaccines:

  • El Tor monovalent (Inaba 8273 and 6973) whole cell (Bureau of Research and Labs, Manila)

  • El Tor monovalent (Ogawa 299 and 1418) whole cell (BRL Manila)

  • Classical monovalent (Ogawa NIH 41) freeze-dried formalin killed whole cell (NIAID, USA)

  • Classical monovalent (Inaba NIH 35A3) freeze-dried formalin killed whole cell (NIAID, USA)

All vaccines contained 8 x 109 organisms/mL

Placebo: active placebo (monovalent typhoid vaccine (BRL Manila)), 1 x 109 organisms/mL

Route: injected subcutaneously
Dose: 1 dose of 0.5 mL

Outcomes
  1. Cholera cases

  2. Cholera deaths

LocationPhilippines
Notes

Length of follow up: 7 months

Denominators in each group estimated from a 2% sample

Vaccines 3 and 4 are the same as those used in Mosley 1970-i and Mosley 1970-ii

Cases not reported by age group, although it is stated in the text that protection was better in age groups > 5 years than for age 0 to 4 years

All cases observed during follow up were El Tor Ogawa

This trial reports the results of the El Tor Inaba vaccine (vaccine 1). See trials PCC 1973a-ii, PCC 1973a-iii, and PCC 1973a-ivfor the other vaccines

PCC 1973a-ii

MethodsRandomized controlled trial
ParticipantsSame as PCC 1973a-i
Interventions

Injected cholera vaccine: El Tor monovalent (Ogawa 299 and 1418) whole cell

Placebo: monovalent typhoid

Route: injected
Dose: 1 dose as PCC 1973a-i

OutcomesSame as PCC 1973a-i
LocationPhilippines
NotesThis trial reports the results of the El Tor Ogawa vaccine; see Philippines PCC 1973a-i for more details

PCC 1973a-iii

MethodsRandomized controlled trial
ParticipantsSame as PCC 1973a-i
Interventions

Injected cholera vaccine: Classical monovalent (Ogawa NIH 41) freeze-dried formalin killed whole cell

Placebo: monovalent typhoid

Route: injected
Dose: 1 dose, see PCC 1973a-i

OutcomesSame as PCC 1973a-i
LocationPhilippines
NotesThis trial reports results of the Classical Ogawa vaccine; see PCC 1973a-i for more details

PCC 1973a-iv

MethodsRandomized controlled trial
ParticipantsSame as PCC 1973a-i
Interventions

Injected cholera vaccine: Classical monovalent (Inaba NIH 42A3) freeze-dried formalin killed whole cell

Placebo: monovalent typhoid vaccine

Route: injected
Dose: 1 dose, see PCC 1973a-i

OutcomesSame as PCC 1973a-i
LocationPhilippines
NotesThis trial reports the results of the Classical Inaba vaccine; see PCC 1973a-i for more details

PCC 1973b

Methods

Randomized controlled trial

Generation of allocation sequence: random allocation

Blinding: double blind

Completeness: not assessable

Surveillance: vaccinees kept under observation by field team; method and frequency not stated

Participants

Number: 120,840

Persons of all ages resident in Negros Occidental province, Philippines

Interventions

Injected cholera vaccines:

  • Classical monovalent (Ogawa NIH 41) formalin killed whole cell, intradermal (NIAID, USA)

  • Same vaccine, subcutaneous

Both vaccines contained 8 x 109 organisms/mL

Placebo: active placebo (typhoid vaccine (BRL Manila)), 1 x 109 organisms/mL

Route and dose: injected subcutaneously (1 x 5 mL dose) or intradermally (1 x 0.2 mL dose) for all ages

OutcomesCholera cases
LocationPhilippines
Notes

Length of follow up: 6.5 months

Numbers in each group estimated from a 5% sample

The vaccine used (monovalent Ogawa) was chosen on the basis of its efficacy in the PCC 1973 trials against the predominant El Tor Ogawa endemic strains (however it does not appear to have been the most efficacious vaccine in that trial)

This trial compared both intradermal and subcutaneous administration with placebo (subcutaneous). The 2 routes have been combined for this review

The age groups given are 1 to 5 years and 5 to 14 years. It is unclear which group includes the children aged 5 years

Saroso 1978i

Methods

Randomized controlled trial

Generation of allocation sequence: allocation method not stated

Blinding: double blind

Completeness: not assessable

Surveillance: through attendance at hospital or clinic with diarrhoea

Participants

Number: 470,000

Persons of all ages resident in Surabaya, Indonesia

Incidence in 1970 to 1972 was 23 to 74 per 100,000, with 15% of cases in the 1 to 4 years age group

Interventions

Injected cholera vaccines:

  • Bivalent killed whole cell vaccine (Human institute, Budapest)

  • Same preparation aluminium hydroxide adsorbed, 1.6 mg Al(OH)3/mL

Both contained 16 x 109 organisms/mL

Placebo: Tetanus toxoid adsorbed to aluminium phosphate

Route: injected subcutaneously
Dose: 1 dose of 0.5 mL to all ages

Outcomes
  1. Cholera cases

  2. Adverse effects

LocationIndonesia
Notes

Length of follow up: 2 years, divided into 4 x 6-month periods; cases reported by age group only up to 14 months

No adverse effect data reported for the placebo group

Numbers in each group calculated from a 1% sample of the vaccinated population

This trial (Saroso 1978i) reports the results of the 'Plain' vaccine (vaccine 1). Saroso 1978ii reports the results of the classical Al(OH)3 adsorbed vaccine (vaccine 2)

The vaccine biotype is not explicitly stated. The predominant cholera during follow-up was El Tor, serotype Inaba

Saroso 1978ii

MethodsRandomized controlled trial
ParticipantsSame as Saroso 1978i
Interventions

Injected cholera vaccine: Bivalent killed whole cell aluminium hydroxide adsorbed vaccine

Placebo: tetanus toxoid adsorbed to aluminium phosphate

Route: injected
Dose: 1 dose same as Saroso 1978i

OutcomesSame as Saroso 1978i
LocationIndonesia
NotesThis trial reports the results of the Al(OH)3 adsorbed vaccine. Saroso 1978i reports the results of the 'plain vaccine' in the same trial. See Saroso 1978i for more details

Taneja 1965

  1. a

    Al(OH)3: aluminium hydroxide (alum).

Methods

Randomized controlled trial

Generation of allocation sequence: not stated

Blinding: double blind

Completeness: not assessable

Surveillance: through participant making a postal, telephone, or clinic notification

Participants

Number: 51,135 persons of all ages and both sexes

Previous vaccination status not explicitly given, but it is stated that "previous anti-cholera vaccination, as usually practiced in an endemic zone" might have influenced the results

Interventions

Injected cholera vaccine: Classical bivalent (Ogawa + Inaba)

  • Phenol-killed whole cell (Vaccine Lab, W Bengal)

  • Phenol-killed whole cell (India)

  • Formol-killed freeze-dried whole cell (Walter Reed)

  • Formol-killed whole cell (Haffkine Inst, Bombay)

Vaccines made in India contained 8 x 109/dose

Placebo: TAB (CRI)

Route: injected
Dose: 1 dose; 0.2 mL for ages 2 to 4 years; 0.4 mL for ages 5 to 8 years; 0.6 mL for ages 9 to 12 years; 0.8 mL for ages 13 to 15 years; 1 mL for ages > 15 years

Outcomes
  1. Cholera cases

  2. Adverse effects within 24 hours

LocationIndia: Calcutta
Notes

Length of follow up: 6 months after the last vaccination (vaccination occurred during 12 March to 30 June 1964)

WRAIR vaccine (No 3) supply ran short; this group had only 7975 participants compared to 10,784-10,789 in the other groups

Results from all 4 vaccine groups (all of which are Classical bivalent killed whole cell) have been combined at present

Rates of adverse effects are very different in the 2 publications

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Beran 1964Observational study
Beran 1965Nonrandomized study
Black 1979Nonrandomized study
Cabrera 2005Not a trial – preparation of vaccine.
Chandra Sekar 1947Observational study (note 'block' unit of observation)
Clasener 1968Immunological outcomes only
Ganguly 1975Immunological outcomes only
Gateff 1975Immunological outcomes only
Gupta 1998No placebo group; immunological and adverse outcomes only. Phase 1 trial comparing 2 polysaccharide cholera toxin conjugate vaccines and polysaccharide alone with licensed killed whole cell vaccine. None of the tested vaccines progressed to efficacy trials
McBean 1972Immunological outcomes only
Mosley 1968Seroprevalence study
Nimbkar 1975Immunological outcomes only
Peltola 1977Nonrandomized study
Russell 1927Nonrandomized study
Sommer 1973aRandomized controlled trial, but vaccine given after exposure to cholera in family members

Ancillary