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

  1. Patricia M Graves1,*,
  2. Jonathan J Deeks2,
  3. Vittorio Demicheli3,
  4. Tom Jefferson4

Editorial Group: Cochrane Infectious Diseases Group

Published Online: 7 AUG 2010

Assessed as up-to-date: 22 FEB 2009

DOI: 10.1002/14651858.CD000974.pub2


How to Cite

Graves PM, Deeks JJ, Demicheli V, Jefferson T. Vaccines for preventing cholera: killed whole cell or other subunit vaccines (injected). Cochrane Database of Systematic Reviews 2010, Issue 8. Art. No.: CD000974. DOI: 10.1002/14651858.CD000974.pub2.

Author Information

  1. 1

    The Carter Center, Atlanta, Georgia, USA

  2. 2

    University of Birmingham, Public Health, Epidemiology and Biostatistics, Birmingham, UK

  3. 3

    Regione Piemonte - Azienda Sanitaria Locale ASL AL, Health Councillorship - Servizio Regionale di Riferimento per l'Epidemiologia, SSEpi-SeREMI - Cochrane Vaccines Field, Torino, Piemonte, Italy

  4. 4

    The Cochrane Collaboration, Vaccines Field, Roma, Italy

*Patricia M Graves, The Carter Center, 453 Freedom Parkway, Atlanta, Georgia, GA 30307, USA. patricia.graves@emory.edu. pgraves.work@gmail.com.

Publication History

  1. Publication Status: Stable (no update expected for reasons given in 'What's new')
  2. Published Online: 7 AUG 2010

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Characteristics of included studies [author-defined order]
Azurin 1965i

MethodsRandomized 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


ParticipantsNumber: 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


InterventionsInjected 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


NotesLength 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


InterventionsInjected 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


InterventionsInjected 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


NotesThis 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

MethodsQuasi-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


ParticipantsNumber: 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


InterventionsInjected 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

MethodsQuasi-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


ParticipantsNumber: 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


InterventionsInjected 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


NotesLength 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


InterventionsInjected 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

MethodsRandomized 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


ParticipantsNumber: 998

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


InterventionsInjected 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

MethodsQuasi-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)


InterventionsInjected 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

MethodsRandomized 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: 79,340

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


InterventionsInjected 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


NotesLength 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

MethodsRandomized 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


InterventionsInjected 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


NotesLength 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


InterventionsInjected 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


NotesLength 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

MethodsQuasi-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


ParticipantsNumber: 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


InterventionsInjected 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


NotesLength 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

MethodsQuasi-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


ParticipantsNumber: 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)


InterventionsInjected 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


NotesLength 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


InterventionsInjected 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


InterventionsInjected 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

MethodsQuasi-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


ParticipantsNumber: 14,059 residents (all ages)

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


InterventionsInjected 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


NotesLength 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

MethodsRandomized controlled trial

Generation of allocation sequence: not stated

Blinding: double blind

Completeness: not assessable

Surveillance: through attendance at hospital with diarrhoea


ParticipantsNumber: 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


InterventionsInjected 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

MethodsRandomized 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


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

An estimated 80% had previously been immunized against cholera


InterventionsInjected 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


NotesLength 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

MethodsRandomized 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


ParticipantsNumber: 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


InterventionsInjected 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


NotesLength 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


InterventionsInjected 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


InterventionsInjected 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


InterventionsInjected 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

MethodsRandomized 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


ParticipantsNumber: 120,840

Persons of all ages resident in Negros Occidental province, Philippines


InterventionsInjected 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


NotesLength 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

MethodsRandomized 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


ParticipantsNumber: 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


InterventionsInjected 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


NotesLength 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


InterventionsInjected 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

MethodsRandomized 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: 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


InterventionsInjected 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


NotesLength 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

 
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 months
172.098148E6Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.41, 0.52]

    1.2 Up to 1 year
141.512573E6Risk Ratio (M-H, Fixed, 95% CI)0.54 [0.48, 0.62]

    1.3 Year 2
6718579Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.45, 0.75]

    1.4 Year 3
233028Risk Ratio (M-H, Fixed, 95% CI)0.91 [0.54, 1.51]

    1.5 Year 4
118969Risk Ratio (M-H, Fixed, 95% CI)0.93 [0.57, 1.54]

    1.6 Year 5
118969Risk 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]

 
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 years
13250941Risk Ratio (M-H, Fixed, 95% CI)0.52 [0.42, 0.65]

    1.2 Age > 5 years
131.623602E6Risk 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 years
11110683Risk Ratio (M-H, Fixed, 95% CI)0.45 [0.35, 0.59]

    2.2 Age > 5 years
11815791Risk 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 years
542039Risk Ratio (M-H, Fixed, 95% CI)0.83 [0.52, 1.31]

    3.2 Age > 5 years
5241578Risk 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 years
324866Risk Ratio (M-H, Fixed, 95% CI)0.65 [0.39, 1.09]

    4.2 Age > 5 years
341852Risk Ratio (M-H, Fixed, 95% CI)0.24 [0.11, 0.54]

 5 Cholera cases, year 4 follow up1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    5.1 Age < 5 years
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 Age > 5 years
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 6 Cholera cases, year 5 follow up1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    6.1 Age up to 5 years
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    6.2 Age over 5 years
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
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 up14Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Single dose
111.442164E6Risk Ratio (M-H, Fixed, 95% CI)0.56 [0.49, 0.64]

    1.2 Short schedule
119933Risk Ratio (M-H, Fixed, 95% CI)0.34 [0.18, 0.65]

    1.3 Booster
364208Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.33, 0.64]

 2 Cholera cases, year 2 follow up8Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    2.1 Single dose
6718480Risk Ratio (M-H, Fixed, 95% CI)0.58 [0.45, 0.74]

    2.2 Short schedule
119311Risk Ratio (M-H, Fixed, 95% CI)0.70 [0.27, 1.83]

    2.3 Booster
361480Risk Ratio (M-H, Fixed, 95% CI)0.71 [0.42, 1.19]

 3 Cholera cases, year 3 follow up4Risk Ratio (M-H, Random, 95% CI)Subtotals only

    3.1 Single dose
114059Risk Ratio (M-H, Random, 95% CI)0.61 [0.22, 1.68]

    3.2 Short schedule
118969Risk Ratio (M-H, Random, 95% CI)1.04 [0.57, 1.90]

    3.3 Booster
360941Risk Ratio (M-H, Random, 95% CI)0.34 [0.15, 0.77]

 4 Cholera cases, year 4 follow up1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

   4.1 Single dose
0Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.2 Short schedule
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    4.3 Booster
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 5 Cholera cases, year 5 follow up1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

   5.1 Single dose
0Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.2 Short schedule
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    5.3 Booster
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

 
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 up24Risk Ratio (M-H, Fixed, 95% CI)Subtotals only

    1.1 Classical 01 Ogawa + Inaba KWC vaccine, injected
8861397Risk Ratio (M-H, Fixed, 95% CI)0.61 [0.53, 0.70]

    1.2 Classical 01 Ogawa KWC vaccine, injected
3234414Risk Ratio (M-H, Fixed, 95% CI)0.46 [0.37, 0.57]

    1.3 Classical 01 Inaba KWC vaccine, injected
2111765Risk Ratio (M-H, Fixed, 95% CI)0.22 [0.15, 0.33]

    1.4 Classical 01 Ogawa + Inaba KWC vaccine plus Al adjuvant, injected
2516226Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.30, 0.59]

    1.5 Classical 01 Ogawa + Inaba KWC vaccine plus oil adjuvant, injected
1290400Risk Ratio (M-H, Fixed, 95% CI)0.47 [0.36, 0.62]

    1.6 El Tor 01 Ogawa + Inaba KWC vaccine, injected
3707596Risk Ratio (M-H, Fixed, 95% CI)0.62 [0.51, 0.75]

    1.7 El Tor 01 Ogawa KWC vaccine, injected
189950Risk Ratio (M-H, Fixed, 95% CI)0.35 [0.24, 0.53]

    1.8 El Tor 01 Inaba KWC vaccine, injected
188700Risk Ratio (M-H, Fixed, 95% CI)0.42 [0.29, 0.61]

    1.9 Purified antigen vaccines, injected
239755Risk Ratio (M-H, Fixed, 95% CI)0.40 [0.27, 0.60]

    1.10 Toxoid vaccine, injected
192838Risk Ratio (M-H, Fixed, 95% CI)0.90 [0.75, 1.08]

 
Comparison 5. Injected vaccine vs placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Adverse events vs inert placebo1Risk Ratio (M-H, Fixed, 95% CI)Totals not selected

    1.1 Diarrhoea
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.2 Vomiting
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.3 Abdominal pain/cramp
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.4 Nausea
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.5 Headache
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.6 Fever
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.7 Malaise
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.8 Tenderness
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.9 Adenopathy
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.10 Erythema
1Risk Ratio (M-H, Fixed, 95% CI)0.0 [0.0, 0.0]

    1.11 Infiltration
1Risk 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 Vomiting
11393Odds Ratio (M-H, Fixed, 95% CI)10.57 [1.35, 82.76]

    2.2 Headache
43542Odds Ratio (M-H, Fixed, 95% CI)0.90 [0.73, 1.10]

    2.3 Fever
43542Odds Ratio (M-H, Fixed, 95% CI)1.31 [1.10, 1.56]

    2.4 Pain
43542Odds Ratio (M-H, Fixed, 95% CI)1.23 [1.03, 1.46]

    2.5 Pain
43542Odds Ratio (M-H, Fixed, 95% CI)1.23 [1.03, 1.46]

    2.6 Erythema
32384Odds Ratio (M-H, Fixed, 95% CI)1.23 [0.88, 1.71]

    2.7 Tenderness
11393Odds Ratio (M-H, Fixed, 95% CI)1.36 [1.06, 1.74]

    2.8 Swelling
43542Odds 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]