Vaccines for preventing enterotoxigenic <i>Escherichia coli</i> (ETEC) diarrhoea

Tanvir Ahmed; Taufiqur R Bhuiyan; K Zaman; David Sinclair; Firdausi Qadri

doi:10.1002/14651858.CD009029.pub2

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Figure 1

Study flow diagram.

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Figure 2

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

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Analysis 1.1

Comparison 1 Cholera killed whole cell vaccine (Cholera WC‐BS) versus placebo, Outcome 1 ETEC diarrhoea.

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Analysis 1.2

Comparison 1 Cholera killed whole cell vaccine (Cholera WC‐BS) versus placebo, Outcome 2 Severe ETEC diarrhoea.

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Analysis 1.3

Comparison 1 Cholera killed whole cell vaccine (Cholera WC‐BS) versus placebo, Outcome 3 All‐cause diarrhoea.

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Analysis 1.4

Comparison 1 Cholera killed whole cell vaccine (Cholera WC‐BS) versus placebo, Outcome 4 Adverse events.

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Analysis 2.1

Comparison 2 Cholera killed whole cell vaccine with recombinant B‐subunit (Cholera WC‐rCTB) versus placebo, Outcome 1 ETEC diarrhoea.

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Analysis 2.2

Comparison 2 Cholera killed whole cell vaccine with recombinant B‐subunit (Cholera WC‐rCTB) versus placebo, Outcome 2 All‐cause diarrhoea.

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Analysis 2.3

Comparison 2 Cholera killed whole cell vaccine with recombinant B‐subunit (Cholera WC‐rCTB) versus placebo, Outcome 3 ETEC diarrhoea (Scerpella 1995a subgroup analysis excluding cases of ETEC occurring < 7 days after vaccination).

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Analysis 2.4

Comparison 2 Cholera killed whole cell vaccine with recombinant B‐subunit (Cholera WC‐rCTB) versus placebo, Outcome 4 Immunological response: > 4‐fold increase in toxin‐specific IgG antibody responses in serum/plasma.

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Analysis 3.1

Comparison 3 ETEC killed whole cell vaccine with recombinant cholera B‐subunit (ETEC WC‐rCTB) versus placebo, Outcome 1 ETEC diarrhoea.

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Analysis 3.2

Comparison 3 ETEC killed whole cell vaccine with recombinant cholera B‐subunit (ETEC WC‐rCTB) versus placebo, Outcome 2 Severe ETEC diarrhoea.

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Analysis 3.3

Comparison 3 ETEC killed whole cell vaccine with recombinant cholera B‐subunit (ETEC WC‐rCTB) versus placebo, Outcome 3 All‐cause diarrhoea.

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Analysis 3.4

Comparison 3 ETEC killed whole cell vaccine with recombinant cholera B‐subunit (ETEC WC‐rCTB) versus placebo, Outcome 4 Adverse events: ETEC WC‐rCTB versus placebo (after first dose).

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Analysis 3.5

Comparison 3 ETEC killed whole cell vaccine with recombinant cholera B‐subunit (ETEC WC‐rCTB) versus placebo, Outcome 5 Immunological response: > 2‐fold increase in CFA/I‐specific IgA antibody response in serum/plasma.

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Analysis 3.6

Comparison 3 ETEC killed whole cell vaccine with recombinant cholera B‐subunit (ETEC WC‐rCTB) versus placebo, Outcome 6 Immunological response: > 2‐fold increase in toxin‐specific IgA antibody responses in serum/plasma.

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Analysis 4.1

Comparison 4 Live attenuated cholera vaccine (CVD 103‐HgR) versus placebo, Outcome 1 ETEC diarrhoea.

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Analysis 4.2

Comparison 4 Live attenuated cholera vaccine (CVD 103‐HgR) versus placebo, Outcome 2 Moderate to severe ETEC diarrhoea.

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Analysis 4.3

Comparison 4 Live attenuated cholera vaccine (CVD 103‐HgR) versus placebo, Outcome 3 All‐cause diarrhoea.

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Analysis 5.1

Comparison 5 Live attenuated ETEC vaccine (PTL‐003) versus placebo, Outcome 1 ETEC diarrhoea.

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Analysis 5.2

Comparison 5 Live attenuated ETEC vaccine (PTL‐003) versus placebo, Outcome 2 Moderate to severe ETEC diarrhoea.

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Analysis 5.3

Comparison 5 Live attenuated ETEC vaccine (PTL‐003) versus placebo, Outcome 3 Adverse events (after first dose).

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Analysis 5.4

Comparison 5 Live attenuated ETEC vaccine (PTL‐003) versus placebo, Outcome 4 Immunological response: > 2‐fold increase in TSA.

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Analysis 6.1

Comparison 6 Transcutaneous LT patch versus placebo, Outcome 1 ETEC diarrhoea.

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Analysis 6.2

Comparison 6 Transcutaneous LT patch versus placebo, Outcome 2 Moderate to severe ETEC diarrhoea.

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Analysis 6.3

Comparison 6 Transcutaneous LT patch versus placebo, Outcome 3 All‐cause diarrhoea.

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Analysis 6.4

Comparison 6 Transcutaneous LT patch versus placebo, Outcome 4 Adverse events.

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Analysis 6.5

Comparison 6 Transcutaneous LT patch versus placebo, Outcome 5 Immunological response.

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Analysis 7.1

Comparison 7 Hyperimmune anti‐E. coli CFA versus placebo, Outcome 1 All‐cause diarrhoea.

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Analysis 7.2

Comparison 7 Hyperimmune anti‐E. coli CFA versus placebo, Outcome 2 Adverse events.

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Summary of findings for the main comparison. Cholera WC‐rCTB vaccine for preventing enterotoxigenic E. coli (ETEC) diarrhoea

*Cholera killed whole cells plus recombinant B‐subunit vaccine for enterotoxigenic E. coli* (ETEC) diarrhoea**
Patient or population: People travelling from non‐endemic settings Settings: Endemic settings Intervention: Cholera killed whole cells plus recombinant B‐subunit vaccine (WC‐rCTB Cholera)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Vaccine
ETEC diarrhoea	99 per 1000	120 per 1000 (72 to 198)	RR 0.93 (0.61 to 1.41)	502 (1 study)	⊕⊕⊝⊝ low^1,2,3,4
Severe ETEC diarrhoea	‐	‐	‐	(0 studies)	‐
All‐cause diarrhoea	492 per 1000	512 per 1000 (428 to 610)	RR 1.04 (0.87 to 1.24)	502 (1 study)	⊕⊕⊝⊝ low^1,4,5
Adverse events	‐	‐	‐	502 (1 study)	⁶
The basis for the assumed risk* (eg the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ This single study was conducted in adults travelling from the USA to Mexico (Scerpella 1995). Although the paper does not clearly describe the methods used to prevent selection bias, we have not downgraded the evidence as selection bias is probably unlikely in a trial where everyone is healthy at enrolment. ² Two older trials evaluated a prototype of this vaccine which contained purified cholera B‐subunit rather than the recombinant subunit contained in this vaccine. Although both trials found some evidence of benefit, the evidence may no longer be applicable due to changes in both composition and dosing of the vaccine. ³ Downgraded by one for indirectness: in this study the vaccine was provided in two doses 10 days apart after the travellers had arrived in Mexico. Most cases of ETEC diarrhoea occurred between doses or within seven days of administration of the second dose. The authors conducted a subgroup analysis of only those participants who had diarrhoea > 7 days after the second dose, which excluded 75% of cases. We did not find a statistically significant difference in our analysis of this data. ⁴ Downgraded by one for imprecision: this trial was small and underpowered to reliably prove or exclude a clinically important effect with the vaccine. ⁵ Downgraded by one for indirectness: in this study the vaccine was provided in two doses 10 days apart after the travellers had arrived in Mexico. Further studies are required which assess administration prior to travel to a variety of destinations. ⁶Scerpella 1995 reported no differences in the frequency of gastrointestinal symptoms, headaches, or febrile illnesses between vaccinees, or placebo recipients but data were not presented.

Summary of findings for the main comparison. Cholera WC‐rCTB vaccine for preventing enterotoxigenic E. coli (ETEC) diarrhoea

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Table 1. Currently available and experimental ETEC vaccines

Oral inactivated vaccines

Cholera/rCTB – killed whole cell V. cholerae O1 (four strains, Classical and El Tor) with additional purified recombinant cholera toxin B subunit. It is commercially available as Dukoral®, produced by SBL/Crucell, Sweden.

ETEC‐rCTB ‐ killed whole cell ETEC (five strains expressing CFA/I,CS1‐CS5).

Colicin inactivated vaccine.

Inactivated Shigella vector‐ETEC vaccine expressing several ETEC antigens.

Oral live attenuated vaccines

CFA/II toxin mutant formulation.

Attenuated ETEC strains with gene deletion but with CFA/II antigen expression, Hola Vax, Cambridge Biostability Ltd, Cambridge, UK.

Attenuated Shigella vector‐ETEC hybrid vaccine expressing the CFA/I CFs including the non‐toxic mutated derivatives of LT.

Attenuated V. cholerae vector‐ETEC hybrid vaccines based on CVD 103‐HgR or Peru‐15 strains expressing several CFs including the B subunit of CT.

Attenuated S. typhi‐ETEC hybrid vaccine expressing several ETEC antigens.

ETEC vaccine based on attenuated Shigella flexneri hybrid constructs expressing CS3 and LTB/ST fusion toxin.

Other ETEC vaccines under development include

Vaccine based on different ETEC fimbrial antigens.

CF hyperexpression on ETEC strains.

LT patch for transcutaneous immunization route.

LT/CS6 patch for transcutaneous immunization route.

DNA/vectored vaccine.

Toxin conjugate vaccines.

Edible plant derived LTB‐based ETEC vaccine.

WC/rCTB: whole cell/recombinant cholera toxin B subunit; ETEC: enterotoxigenic E. coli; CFA: colonization factor antigen; CS: E. coli surface antigen; LT: heat labile toxin; CT: cholera toxin; LTB/ST: heat labile toxin B subunit/heat stable toxin.

Table 1. Currently available and experimental ETEC vaccines

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Table 2. Detailed Search Strategy

Search set	CIDG SR¹	CENTRAL	MEDLINE²	EMBASE²	LILACS²
1	E.coli	Enterotoxigenic Escherichia coli [MeSH]	Enterotoxigenic Escherichia coli [MeSH]	Enterotoxigenic Escherichia coli [Emtree]	E.coli
2	Enterotoxigenic	ETEC	ETEC ti, ab	ETEC ti, ab	Enterotoxigenic
3	ETEC	Enterotoxigenic E coli	Enterotoxigenic E coli ti, ab	Enterotoxigenic E coli ti, ab	ETEC
4	Travel* diarrh*	Travel* diarrh*	Travel* diarrh* ti, ab	Traveller diarrhea [Emtree]	Travel$ diarrh$
5	1 or 2 or 3 or 4	1 or 2 or 3 or 4	1 or 2 or 3 or 4	1 or 2 or 3 or 4	1 or 2 or 3 or 4
6	Vaccin*	Vaccin*	Vaccin* ti, ab	Vaccin* ti, ab	Vaccin$
7	5 and 6	5 and 6	5 and 6	5 and 6	5 and 6
8		Escherichia coli vaccines [MeSH]	Escherichia coli vaccines [MeSH]	Escherichia coli vaccine [Emtree]
9		7 or 8	7 or 8	7 or 8
10			Limit 9 to humans	Limit 9 to Human
¹Cochrane Infectious Diseases Group Specialized Register. ²Search terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2008).

Table 2. Detailed Search Strategy

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Table 3. Characteristics of trials assessing clinical efficacy

Vaccine details				Study ID	Population details			Challenge
Type	Name	Route	Schedule	Study ID	Age	Group	Country setting	Challenge
Inactivated	Cholera WC‐BS	Oral	Three doses, at 6 week intervals	Clemens 1988	Children aged 2 to 15 years Women aged > 15 years	Endemic	Bangladesh	Natural
	Cholera WC‐BS	Oral	Two doses two weeks apart	Peltola 1991	Adults	Travellers	From Finland to Morocco	Natural
	Cholera WC‐rCTB (Dukoral®)	Oral	Two doses, 10 days apart	Scerpella 1995	Adults	Travellers	From USA to Mexico	Natural
	ETEC WC‐rCTB	Oral	Two doses, 7 to 21 days apart	Sack 2007	Adults	Travellers	From USA to Mexico or Guatemala	Natural
	ETEC WC‐rCTB	Oral	Two doses, 7 to 21 days apart	Wiedermann 2000	All ages	Travellers	From Austria to Latin America, Africa, and Asia.	Natural
Live attenuated	CVD 103‐HgR	Oral	Single dose	Leyten 2005	Adults	Travellers	From Holland to Indonesia, Thailand, India, or West Africa	Natural
Live attenuated	PTL‐003	Oral	2 doses, 10 days apart	McKenzie 2008	Adults	Volunteers	USA	Artificial
Other	Transcutaneous LT‐ETEC patch	Patch	2 to 3 doses, at 2 to 3 week intervals	Frech 2008	Adults	Travellers	From USA to Mexico and Guatemala	Natural
	Transcutaneous LT‐ETEC patch	Patch	2 to 3 doses, at 2 to 3 week intervals	McKenzie 2007	Adults	Volunteers	USA	Artificial
	*Hyper immune Anti‐E coli.* CFA**	Oral	3 times daily for 5 to 7 days	Freedman 1998	Adults	Volunteers	USA	Artificial
	*Hyper immune Anti‐E coli.* CFA**	Oral	3 times daily for 5 to 7 days	Tacket 1999	Adults	Volunteers	USA	Artificial
WC = killed whole cell, BS = cholera toxin B subunit, rCTB = recombinant cholera toxin B subunit.

Table 3. Characteristics of trials assessing clinical efficacy

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Table 4. Outcome definitions for primary and secondary measures of clinical efficacy

Vaccine	Study ID	Trial definitions		Challenge type	Confirmation of ETEC
Vaccine	Study ID	DIarrhoea	Moderate or Severe Diarrhoea	Challenge type	Confirmation of ETEC
Cholera WC‐BS	Clemens 1988	≥ 3 non‐bloody loose stools in 24 hours, or fewer episodes with signs of dehydration	Severe diarrhoea = absent or feeble pulse plus one other sign of dehydration.	Natural	Faecal culture
Cholera WC‐BS	Peltola 1991	Any diarrhoea confirmed by the physician as abnormally loose	Not reported.	Natural	Faecal culture
Cholera WC‐rCTB (Dukoral®)	Scerpella 1995	≥ 4 unformed stools in 24 hours, or ≥3 unformed stools in 8 hours, plus an additional symptom (nausea. pain, fever, urgency, tenesmus)	Not reported.	Natural	Faecal culture
ETEC WC‐rCTB	Sack 2007	≥ 3 loose stools in 24 hours, plus at least one other symptom, such as abdominal pain, cramps or nausea.	Severe diarrhoea = ≥ 5 loose stools in 24 hours, or illness episodes with abdominal cramps, pain, or vomiting that interfered with daily activities.	Natural	Faecal culture
ETEC WC‐rCTB	Wiedermann 2000:	≥ 3 liquid stools	Not reported.	Natural	Faecal culture
CVD 103‐HgR	Leyten 2005	≥ 3 unformed stools in 24 hours, or 2 unformed stools accompanied by vomiting, abdominal cramps or subjective fever,	Moderate diarrhoea = 3 to 6 stools per day Severe diarrhoea = ≥ 6 stools per day	Natural	Faecal culture
PTL‐003	McKenzie 2008	1 loose stool weighing ≥ 300 g, or ≥ 2 loose stools in 48 h with a combined weight of ≥200 g,	Moderate diarrhoea = 4 to 5 loose stools, or 401 to 800 g of loose stool, in 24 hours Severe diarrhoea = ≥ 6 loose stools, or > 800 g of loose stools, in 24 hours Or mild diarrhoea plus one of these symptoms rated as moderate or severe: nausea, vomiting, anorexia, abdominal pain, or cramps.	Artificial	Assumed all
Transcutaneous LT‐ETEC patch	Frech 2008	≥ 3 loose stools in 24 hours	Moderate diarrhoea = 4 to 5 loose stools Severe diarrhoea = 6 or more loose stools	Natural	Faecal culture
Transcutaneous LT‐ETEC patch	McKenzie 2007	1 loose stool weighing ≥ 300 g or ≥ 2 loose stools in 48 hours weighing a total of ≥200 g, within 120 hours after challenge.	Moderate/severe diarrhoea = > 400 g of loose stool in 24 hours, or ≥ 4 loose stools in 24 hours, or ≥ 2 loose stools within a 48 hour period totaling ≥ 200 g, or a single loose stool weighing ≥ 300 g plus one of the following symptoms rated as moderate or severe: nausea, vomiting, abdominal pain, or cramps.	Artificial	Assumed all
*Hyperimmune Anti‐E coli.* CFA**	Freedman 1998	1 liquid stool of ≥ 300 mL or 2 liquid stools totaling > 200 mL during any 48 hour period within 120 hours after challenge.	Not reported.	Artificial	Assumed all
*Hyperimmune Anti‐E coli.* CFA**	Tacket 1999	1 diarrhoeal stool of > 300 mL or 2 diarrhoeal stools totaling > 200 mL passed during a 48 hour period within 96 hours after challenge.	Not reported.	Artificial	Assumed all

Table 4. Outcome definitions for primary and secondary measures of clinical efficacy

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Table 5. Additional immunological data for responses to CFs in the IgA isotype to ETEC WC‐rCTB vaccine

Study ID

Age group

Trial setting

Number of participants with a > 2‐fold increase in immunological response after the second dose of oral ETEC‐rCTB (%)

CFA/I

CS1

CS2

CS3

CS4

Remarks

Savarino 1998

Adults

Egypt

15/16

(94%)

4/16

(25%)

11/16

(69%)

1/16

(6%)

13/16

(81%)

2/16

(13%)

16/16

(100%)

6/16

(38%)

Serum

Cohen 2000 (Study 2)

Adults

Israel

9/35

(26%)

1/40

(3%)

11/35

(31%)

2/40

(5%)

Serum

Jertborn 2001

Adults

Sweden

16/19

(84%)

0/12

(0%)

4/19

(21%)

1/12

(8%)

10/19

(53%)

0/12

(0%)

12/19

(63%)

0/12

(0%)

Serum

Hall 2001 (Study 1)

Adults

Egypt

26/38

(68%)

2/35

(6%)

21/38

(56%)

0/35

(0%)

12/38

(31%)

2/35

(6%)

26/38

(69%)

4/35

(12%)

Serum

Savarino 1999 (Study 1)

Children

6‐12 Y

Egypt

16/16

(100%)

2/16

(13%)

3/8

(38%)

1/9

(11%)

12/13

(92%)

2/12

(17%)

14/15

(93%)

4/16

(25%)

ASC

Hall 2001 (Study 2)

Children

6‐12 Y

Egypt

49/51

(96%)

6/54

(11%)

47/51

(92%)

4/54

(7%)

40/51

(78%)

5/54

(9%)

43/51

(84%)

3/54

(6%)

Serum

Savarino 1999 (Study 2)

Children

2‐5 Y

Egypt

18/19

(95%)

1/10

(10%)

15/18

(83%)

1/10

(10%)

ASC

Hall 2001 (Study 3)

Children

2‐5 Y

Egypt

41/47

(87%)

5/46

(11%)

43/47

(91%)

1/46

(2%)

37/47

(79%)

6/46

(12%)

33/47

(70%)

3/46

(7%)

Serum

Qadri 2003

Children

18‐36 M

Bangladesh

58/79

(73%)

13/79

(16%)

61/79

(77%)

10/79

(13%)

69/79

(87%)

8/79

(10%)

55/79

(70%)

2/79

(3%)

Plasma

Savarino 2002

Children

6‐18 M

Egypt

22/36

(61%)

5/28

(18%)

7/36

(20%)

1/28

(4%)

9/36

(26%)

1/28

(4%)

14/36

(39%)

2/28

(7%)

Serum

Qadri 2006a

Children

6‐17 M

Bangladesh

47/79

(59%)

4/79

(5%)

53/79

(67%)

26/79

(33%)

37/79

(47%)

16/79

(20%)

40/79

(50%)

12/79

(15%)

Plasma

V = vaccine, P = placebo, CS = colonization surface antigen, ND = not done , ASC = antibody secreting cell, CFA = colonization factor antibody

Table 5. Additional immunological data for responses to CFs in the IgA isotype to ETEC WC‐rCTB vaccine

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Table 6. Additional immunological data for IgA response to CFs to live oral attenuated vaccine

Study ID	Number of participants with > 2‐fold increase in immunological response (%)
	CS1		CS2		CS3		CS4		Remarks
	V	P	V	P	V	P	V	P
McKenzie 2008	7/17 (41%)	1/16 (6%)	ND	ND	7/17 (41%)	0/16 (0%)	ND	ND	Serum
V = vaccine, P = placebo, CS = colonization surface antigen, ND = not done

Table 6. Additional immunological data for IgA response to CFs to live oral attenuated vaccine

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Comparison 1. Cholera killed whole cell vaccine (Cholera WC‐BS) versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ETEC diarrhoea Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2 Severe ETEC diarrhoea Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3 All‐cause diarrhoea Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

4.1 Any symptoms	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.2 Gastrointestinal symptoms	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.3 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.4 Respiratory symptoms	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.5 Others	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 1. Cholera killed whole cell vaccine (Cholera WC‐BS) versus placebo

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Comparison 2. Cholera killed whole cell vaccine with recombinant B‐subunit (Cholera WC‐rCTB) versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ETEC diarrhoea Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2 All‐cause diarrhoea Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3 ETEC diarrhoea (Scerpella 1995a subgroup analysis excluding cases of ETEC occurring < 7 days after vaccination) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3.1 Cholera WC‐rCTB versus placebo (all participants included in denominator)	1	502	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.24, 1.47]
3.2 Cholera WC‐rCTB versus placebo (participants who had ETEC diarrhoea before vaccination complete excluded from denominator)	1	457	Risk Ratio (M‐H, Fixed, 95% CI)	0.58 [0.23, 1.44]
4 Immunological response: > 4‐fold increase in toxin‐specific IgG antibody responses in serum/plasma Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 2. Cholera killed whole cell vaccine with recombinant B‐subunit (Cholera WC‐rCTB) versus placebo

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Comparison 3. ETEC killed whole cell vaccine with recombinant cholera B‐subunit (ETEC WC‐rCTB) versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ETEC diarrhoea Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

2 Severe ETEC diarrhoea Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

3 All‐cause diarrhoea Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4 Adverse events: ETEC WC‐rCTB versus placebo (after first dose) Show forest plot	11		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

4.1 Any symptoms	9	926	Risk Ratio (M‐H, Fixed, 95% CI)	1.63 [1.34, 1.97]
4.2 Diarrhoea	9	1528	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.55, 1.40]
4.3 Abdominal pain	7	1275	Risk Ratio (M‐H, Fixed, 95% CI)	1.17 [0.79, 1.73]
4.4 Loss of appetite	7	696	Risk Ratio (M‐H, Fixed, 95% CI)	1.83 [1.03, 3.24]
4.5 Gas/abdominal distension/bloating	1	158	Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4.6 Nausea	4	904	Risk Ratio (M‐H, Fixed, 95% CI)	1.24 [0.73, 2.09]
4.7 Vomiting	9	1528	Risk Ratio (M‐H, Fixed, 95% CI)	2.00 [1.16, 3.45]
4.8 Fever	7	778	Risk Ratio (M‐H, Fixed, 95% CI)	0.87 [0.34, 2.22]
4.9 Headache	2	154	Risk Ratio (M‐H, Fixed, 95% CI)	1.46 [0.88, 2.42]
4.10 Malaise	2	154	Risk Ratio (M‐H, Fixed, 95% CI)	1.77 [0.91, 3.44]
4.11 Spitting with cough	1	158	Risk Ratio (M‐H, Fixed, 95% CI)	1.0 [0.14, 6.92]
4.12 Others	5	1058	Risk Ratio (M‐H, Fixed, 95% CI)	1.37 [0.83, 2.26]
5 Immunological response: > 2‐fold increase in CFA/I‐specific IgA antibody response in serum/plasma Show forest plot	12		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

6 Immunological response: > 2‐fold increase in toxin‐specific IgA antibody responses in serum/plasma Show forest plot	13		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

Comparison 3. ETEC killed whole cell vaccine with recombinant cholera B‐subunit (ETEC WC‐rCTB) versus placebo

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Comparison 4. Live attenuated cholera vaccine (CVD 103‐HgR) versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ETEC diarrhoea Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Moderate to severe ETEC diarrhoea Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 All‐cause diarrhoea Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 4. Live attenuated cholera vaccine (CVD 103‐HgR) versus placebo

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Comparison 5. Live attenuated ETEC vaccine (PTL‐003) versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ETEC diarrhoea Show forest plot	1		Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

2 Moderate to severe ETEC diarrhoea Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3 Adverse events (after first dose) Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

3.1 Abdominal cramps/pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.2 Diarrhoea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.3 Gas/abdominal distension/bloating	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.4 Gurgling/bubbling	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.5 Nausea	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.6 Loss of appetite	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.7 Vomiting	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.8 Fever	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.9 Malaise	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.10 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
3.11 Arthalgias/myalgias	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
4 Immunological response: > 2‐fold increase in TSA Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

Comparison 5. Live attenuated ETEC vaccine (PTL‐003) versus placebo

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Comparison 6. Transcutaneous LT patch versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 ETEC diarrhoea Show forest plot	2	217	Risk Ratio (M‐H, Fixed, 95% CI)	0.83 [0.64, 1.08]

2 Moderate to severe ETEC diarrhoea Show forest plot	2	217	Risk Ratio (M‐H, Fixed, 95% CI)	0.86 [0.59, 1.25]

3 All‐cause diarrhoea Show forest plot	1	170	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.35, 1.42]

4 Adverse events Show forest plot	2	1643	Risk Ratio (M‐H, Fixed, 95% CI)	3.87 [3.10, 4.84]

4.1 Rash	2	260	Risk Ratio (M‐H, Fixed, 95% CI)	5.80 [3.88, 8.67]
4.2 Pruritus	2	260	Risk Ratio (M‐H, Fixed, 95% CI)	4.66 [3.25, 6.68]
4.3 Vesicles	1	59	Risk Ratio (M‐H, Fixed, 95% CI)	10.65 [0.62, 184.25]
4.4 Skin discoloration	2	260	Risk Ratio (M‐H, Fixed, 95% CI)	9.73 [2.87, 32.92]
4.5 Fever	1	201	Risk Ratio (M‐H, Fixed, 95% CI)	2.0 [0.13, 31.48]
4.6 Malaise	1	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.11 [0.39, 3.19]
4.7 Headache	1	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.59, 2.82]
4.8 Diarrhoea	1	201	Risk Ratio (M‐H, Fixed, 95% CI)	1.5 [0.67, 3.38]
5 Immunological response Show forest plot	2		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

5.1 > 4‐fold increase in anti‐LT specific IgA responses in serum/plasma	2	217	Risk Ratio (M‐H, Fixed, 95% CI)	43.00 [12.33, 149.97]

Comparison 6. Transcutaneous LT patch versus placebo

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Comparison 7. Hyperimmune anti‐E. coli CFA versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause diarrhoea Show forest plot	2	45	Risk Ratio (M‐H, Fixed, 95% CI)	0.51 [0.22, 1.15]

2 Adverse events Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected

2.1 Anorexia	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.2 Malaise	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.3 Gas	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.4 Abdominal pain	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
2.5 Headache	1		Risk Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 7. Hyperimmune anti‐E. coli CFA versus placebo

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