Oral cholera vaccines: use in clinical practice

Review

Oral cholera vaccines: use in clinical practice David R Hill, Lisa Ford, David G Lalloo

Cholera continues to occur globally, particularly in sub-Saharan Africa and Asia. Oral cholera vaccines have been developed and have now been used for several years, primarily in traveller populations. The licensure in the European Union of a killed whole cell cholera vaccine combined with the recombinant B subunit of cholera toxin (rCTB-WC) has stimulated interest in protection against cholera. Because of the similarity between cholera toxin and the heatlabile toxin of Escherichia coli, a cause of travellers’ diarrhoea, it has been proposed that the rCTB-WC vaccine may be used against travellers’ diarrhoea. An analysis of trials of this vaccine against cholera (serotype O1) shows that for 4–6 months it will protect 61–86% of people living in cholera-endemic regions; lower levels of protection continue for 3 years. Protection wanes rapidly in young children. Because the risk of cholera for most travellers is extremely low, vaccination should be considered only for those working in relief or refugee settings or for those who will be travelling in cholera-epidemic areas and who will be unable to obtain prompt medical care. The vaccine can be expected to prevent 7% or less of cases of travellers’ diarrhoea and should not be used for this purpose.

Introduction An oral, whole cell, killed Vibrio cholerae vaccine combined with the recombinant B subunit of cholera toxin (Dukoral) was approved by the European Union (EU) in April 2004. This vaccine is the second licensed oral vaccine for prevention of cholera; an oral liveattenuated vaccine (Orochol or Mutachol) is also licensed in some countries but is not currently being produced. The approval of Dukoral has renewed interest in vaccine prevention of cholera in travellers. Several recent reviews and policy statements have focused on the role of cholera vaccination in both travellers and people living in choleraendemic areas.1–8 In the EU, Dukoral is licensed as a cholera vaccine, but in many other countries it has also been approved for protection against enterotoxigenic Escherichia coli (ETEC; table 1). Here, we focus on the role of the killed oral vaccine in the prevention of cholera in travellers and assess whether it has a role in the prevention of ETEC and travellers’ diarrhoea.

highly likely that cholera is endemic in Pakistan and Bangladesh,15 but these countries have not reported cases in recent years. V cholerae serogroup O1 are the main cause of epidemic cholera. V cholerae O1 can be divided into Country

Date of approval

Indication

Argentina

May 5, 1997

Cholera and ETEC

Aruba

Nov 13, 2002

Cholera and ETEC

Australia

Sept 9, 2003

Cholera

Benin

May 15, 2003

Cholera and ETEC

Brazil

Jan 12, 2004

Cholera and ETEC

Burkina Faso

Dec 5, 2003

Cholera and ETEC

Cameroon

Nov 1, 2004

Cholera and ETEC

Canada

Feb 21, 2003

Cholera and ETEC

Chile

Apr 28, 2004

Cholera and ETEC

Democratic Republic of the Congo

Jun 12, 2003

Cholera and ETEC

Colombia

Mar 10, 2003

Cholera and ETEC

Cote d’Ivoire

Dec 26, 2002

Cholera and ETEC

Curacao

Aug 30, 2005

Cholera and ETEC

Epidemiology and clinical manifestations

European Union

Apr 28, 2004

Cholera

Cholera is caused by the bacterium V cholerae and is endemic throughout many resource-poor regions of the world. Transmission occurs through ingestion of faecally contaminated water and food. Large numbers of bacteria (108–1011) are needed to establish infection in people with normal gastric acidity. Rapid spread is common in communities where there is poor hygiene, lack of sanitation, and poverty. Cholera can be a major problem affecting people in refugee settings.9 In 2004, 101 383 cases of cholera with 2345 deaths were reported to WHO from all continents except Oceania (figure 1).10 African countries accounted for 94% of the global total. Table 2 indicates cumulative cholera cases reported to WHO for the years 2000–04.10–14 The reported figures are likely to be considerable underestimates; routine culture of stool samples for V cholerae is often not done or available in endemic areas, and some affected countries may not report cases because of concerns about the impact on their travel industry. For example, it is

Gabon

Mar 31, 2004

Cholera and ETEC

Kenya

Aug 2001

Cholera and ETEC

Madagascar

Jun 9, 1999

Cholera and ETEC

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Malaysia

Apr 22, 2003

Cholera and ETEC

Mauritius

Jul 25, 2001

Cholera and ETEC

Mexico

Jul 26, 2001

Cholera and ETEC

New Zealand

Feb 28, 2002

Cholera and ETEC

Norway

Nov 4, 1997

Cholera and ETEC

Philippines

Dec 7, 2001

Cholera and ETEC

Senegal

Jan 19, 2004

Cholera and ETEC

Singapore

Feb 6, 2003

Cholera and ETEC

South Africa

Sept 17, 2004

Cholera and ETEC

Thailand

Sept 4, 2002

Cholera and ETEC

Togo

Mar 22, 2005

Cholera and ETEC

Trinidad and Tobago

Apr 8, 2003

Cholera and ETEC

Lancet Infect Dis 2006; 6: 361–73 National Travel Health Network and Centre, London, UK, and London School of Hygiene and Tropical Medicine (Prof D R Hill FRCP, L Ford MBBS); Liverpool School of Tropical Medicine, Liverpool, UK (L Ford, D G Lalloo FRCP) Correspondence to: Professor David R Hill, Director, National Travel Health Network and Centre, Mortimer Market, Capper Street, London WC1E 6AU, UK. Tel +44 (0)845 155 5000 ext 5943; fax +44 (0)20 7380 9486; [email protected]

ETEC=enterotoxigenic Escherichia coli. *Authorisations as of Jan 31, 2006. Data provided by SBL Vaccin AB, Sweden.

Table 1: Worldwide Dukoral marketing authorisations and indications*

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Countries/areas with cholera cases Imported cholera cases

Figure 1: Countries reporting cholera cases in 2004 Reproduced from reference 10, with permission.

classic and El Tor biotypes, and two main serotypes, Ogawa and Inaba. All combinations of serotypes and biotypes may occur. Specific genetic markers are increasingly used to differentiate organisms.6 The El Tor biotype is responsible for the current pandemic that began in 1961 in Celebes (Sulawesi), Indonesia.13,16 This pandemic moved west, reaching the Indian subcontinent, Africa, and eventually South America by 1991.17 A large outbreak of cholera occurred in Bangladesh and India in 1992. On this occasion a new serogroup O139 (synonym Bengal) was isolated. V cholerae O139 has since spread to at least 11 other countries.18 Approximately 15% of laboratory-confirmed cases in endemic countries of Asia are caused by V cholerae O139,14 and 59% of the cholera cases in China in 2004 were caused by the O139 serogroup.10 Cholera is characterised by the sudden onset of profuse, watery stools with occasional vomiting.19 The incubation period is usually 2–5 days but may be only a few hours. In severe disease, which occurs in 5–10% of those infected, dehydration, metabolic acidosis, and circulatory collapse may rapidly develop. If left untreated, over 50% of the most severe cases may die within several hours; with prompt treatment, mortality is less than 1%. In 2004, the global case fatality rate was 2% and as high as 41% in vulnerable populations.10 Mild cases with only moderate diarrhoea also occur and asymptomatic infection is common. In healthy travellers, the infection is often self-limiting and not severe. 362

Treatment of cholera is by rehydration with oral or intravenous fluids. In severe cases, antibiotic treatment can be given to reduce the volume of diarrhoea and duration of excretion of V cholerae.20 There is increasing resistance of V cholerae to doxycycline, the antibiotic of choice, so alternatives such as co-trimoxazole (trimethoprim-sulfamethoxazole), erythromycin, chloramphenicol, ciprofloxacin, and azithromycin can be used where organisms are sensitive.21–24

Pathogenesis and immune responses V cholerae colonise the gut using pili or fimbriae that enable them to attach to receptors on the small bowel epithelium.25 Once attached, the bacterium releases a toxin known as cholera toxin that is made up of two subunits: an A (active) unit and a pentameric B (binding) unit.6 Cholera toxin is structurally and functionally similar to the heatlabile toxin produced by some E coli.26–29 The B subunit binds cholera toxin to GM1 ganglioside receptors on the surface of intestinal epithelial cells. Once the toxin has bound, the A subunit is internalised and activates the enzyme adenylate cyclase. This activation leads to an increase in cyclic adenosine monophosphate in the epithelial cell, causing active secretion of chloride anions, decreased absorption of sodium, and the resultant loss of electrolytes (eg, sodium, chloride, and potassium), bicarbonate, and water into the gut lumen,30 which can led to hypovolemic shock and metabolic acidosis. Following challenge or infection with V cholerae, human beings mount both systemic and mucosal http://infection.thelancet.com Vol 6 June 2006

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immune responses that can produce long-lasting and effective immunity to homologous biotypes.31–38 Although Area/country

Total number

Annual median

Africa Mozambique

84 654

17 647

Democratic Republic of the Congo

87 318

14 995

South Africa

systemic vibriocidal (and anti-toxin) antibodies develop during illness and vibriocidal titres correlate with a decreased risk of subsequent infection, they may just be a marker of infection, since protection against cholera in vaccine trials may occur despite low serum titres.39–41 The mucosal response is thought to have the major role in protection against natural infection, with intestinal antitoxin immunity helping to protect against disease.31,34,42,43

142 490

10 004

Tanzania

28 886

4637

Risk of cholera in travellers and expatriates

Ghana

13 043

3331

Nigeria

15 546

2799

Estimating the risk of cholera in travellers to resourcepoor regions of the world is difficult. An intensive surveillance programme screening for V cholerae in Japanese travellers with diarrhoea on their return to Japan produced estimates of cholera incidence at five cases per 100 000 travellers to all destinations and 13 cases per 100 000 travellers to Bali.44,45 However, general estimates of risk based on cholera cases imported into Europe and North America are in the order of two to three cases per million travellers.44–48 Most cases of cholera in Europe, North America, Australia, New Zealand, and Japan are imported. About 60 imported cases have been reported from these regions annually since 2000 with 45% of them imported to Japan and 18% to the UK.10–14 In England, Wales, and Northern Ireland there were 139 laboratory notifications of cholera between 1990 and 2003 (T Cheasty, Laboratory of Enteric Pathogens, Health Protection Agency Centre for Infections, UK, personal communication). 64% of these cases were imported from the Indian subcontinent, translating into an estimated risk of cholera in UK travellers to the Indian subcontinent of one case per 100 000 travellers. It is likely that some cases of cholera in travellers are treated overseas; however, studies of travellers’ diarrhoea have usually not isolated V cholerae.49,50 Expatriates living in an epidemic country may be at greater risk of cholera. Surveillance of US embassy staff who had diarrhoea and were based in Lima during the Peruvian cholera outbreak in the early 1990s estimated an incidence of 5·3 cases per 1000 population per year of exposure.45,51 Most cases were not severe in this expatriate population.

Malawi

40 815

2395

Zambia

18 929

2283

Uganda

11 873

2274

Liberia

40 068

1115

Cote d’Ivoire

11 239

1034

Zimbabwe

6578

1009

Kenya

3319

870

Burundi

3852

819

Benin

5757

468

Guinea

2492

392

Togo

4755

384

Niger

3111

236

Comoros

5147

226

Cameroon

8660

207

Rwanda

1990

157

Guinea-Bissau

1287

155

Swaziland

6994

141

Mali

4379

67

Chad

10 830

55

Madagascar

36 334

27

Burkina Faso

1095

1

606 173

111 436

Total

Central and South America Peru

1444

16

66

9

Brazil

743

7

Guatemala

627

1

3697

29

India

18 931

3807

China

2441

223

Iraq

1472

187

Cholera vaccines

Philippines

920

174

Parenteral vaccines

Iran

754

105

8873

41

Whole cell, killed parenteral vaccines stimulate the development of short-term immunity to V cholerae O1. Approximately 50–65% of people living in endemic regions were protected for 3–6 months.4,33,52 However, these vaccines are least effective in young children who are at high risk from cholera and its adverse consequences. Protective efficacy in naive people from non-endemic regions is likely to be less. Parenteral vaccines are associated with local reactions in approximately 50% of vaccinees and 10–30% develop more generalised systemic reactions such as fever and malaise.4,33 A parenteral vaccine consisting of phenol-

Ecuador

Total Asia

Afghanistan Malaysia

697

16

Japan

50

8

Singapore

30

8

Hong Kong

44

6

Total World total

35 055

5695

648 748

129 549

Countries are listed that reported cases in at least three of the past 5 years from 2000–04. Imported cases are excluded. Data from WHO reports.10–14

Table 2: Reported indigenous cholera cases, 2000–04

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Vaccine

Composition

Primary course: adult

Dukoral

1 mg rCTB plus 25 x 10⁹ bacteria each of: V cholerae O1 classic Inaba* V cholerae O1 El Tor Inaba† V cholerae O1 classic Ogawa* V cholerae O1 classic Inaba†

Adults and children from Children of 2–6 years: three 6 years: two doses at a 1–6 week doses of vaccine at intervals of interval§ 1–6 weeks§

Primary course: paediatric

Orochol (also known as Mutachol)

Live-attenuated V cholerae O1, classic Inaba, strain CVD 103-HgR. 94% of gene encoding the A subunit of cholera toxin is deleted. Travellers: 2 x 10⁸ cfu Resource-poor regions: 2 x 10⁹ cfu‡

Adults and children 2 years and older: single dose ingested 1 hour before a meal

Booster interval Adults: 2 years Paediatric: 6 months If more than 2 years since last dose, then primary vaccine course should be repeated

Not approved for children under 6 months, although data are the age of 2 years lacking on the appropriate interval

cfu=colony forming units; rCTB=recombinant cholera toxin B subunit. *Heat inactivated. †Formalin inactivated. §Vaccine should be refrigerated at 2–8ºC, but manufacturer information indicates that it may be kept at 25ºC for 14 days without loss of potency. (P Aerkelöf, SB Vaccin AB, Stockholm, Sweden; personal communication). ‡This preparation is called Orochol E Berna.

Table 3: Oral cholera vaccines

inactivated whole cell V cholerae strains Ogawa (usually classic biotype) and Inaba (usually classic biotype) is licensed, but is not being produced. The vaccine’s limited efficacy, lack of utility in control of cholera outbreaks,53 and frequent adverse reactions make this vaccine no longer useful.

Oral vaccines Two oral vaccines have been licensed for commercial use: the killed whole cell V cholerae plus recombinant B subunit of cholera toxin vaccine (rCTB-WC; Dukoral; SBL Vaccin AB, Stockholm, Sweden), and the live attenuated V cholerae O1 strain CVD 103-HgR vaccine (Orochol; Berna Biotech Ltd, Berne, Switzerland; known as Mutachol in Canada). Details of these two vaccines can be found in table 3. Dukoral does not contain the A subunit of cholera toxin and therefore no pathogenic toxin is present. Licensure and marketing are listed in table 1. 94% of the gene encoding the A subunit of cholera toxin has been deleted for Orochol. This vaccine is currently not being produced.

Efficacy studies of oral killed whole cell V cholerae plus cholera toxin B vaccine against cholera Seven studies of the efficacy of whole cell vaccines in combination with either purified cholera toxin B (CTBWC) or recombinant cholera toxin B (rCTB-WC), have been published: one study was in volunteers challenged with V cholerae and six others were in indigenous populations at risk for cholera in Bangladesh, Peru, Vietnam, and Mozambique. These studies are summarised in table 4. The Bangladesh trial compared whole cell vaccine and CTB-WC vaccine against placebo.54–56 At 6 months the CTB-WC vaccine exhibited 85% protective efficacy in all age groups against V cholerae O1; whole cell vaccine alone was 58% protective. At 36 months the cumulative protective efficacy of the CTB-WC vaccine was 50%. Protection against classic cholera was higher than for the El Tor biotype. There was an age association 364

for protection; protective efficacy with CTB-WC for young children rapidly decreased after 6 months, so that at 36 months the cumulative protective efficacy was 26% in children aged 2–5 years, compared with a cumulative protective efficacy of 63% in adults and children over the age of 5 years. Young children did not fully respond until they had received the third dose,63 leading to the current recommendations that children aged 2–6 years receive three doses of vaccine. When all ages were included, two or three doses of vaccine achieved similar levels of protection, but a single dose did not. An important new analysis of the data from this study was recently carried out.64 A herd immunity effect occurred in areas where vaccine coverage achieved levels of more than 50%. Thus, fewer cases of cholera (and perhaps lower levels of vibrio colonisation and excretion65) in vaccinated individuals translated into fewer cases in non-vaccinated people living in proximity to the vaccinated group. This effect has implications for potentially reducing the burden of cholera in endemic areas. The first Peruvian trial used rCTB-WC vaccine and was done shortly after the introduction of cholera into Peru.57 The Peruvian population is considered more susceptible to cholera due to the predominance of blood group O, a recognised factor in determining susceptibility. Two doses were planned, rather than the three doses in the Bangladesh trial. Previous studies of two doses, 2 weeks apart, as well as a sub-analysis of the Bangladesh study suggested that two doses would induce protective antibody responses.66–68 An epidemic of cholera occurred following the first dose and therefore prevented evaluation of protective efficacy after the planned two-dose schedule. A single dose did not confer protection. The second Peruvian trial was done with analysis after two doses and then following a third booster dose at 10 months.58 Initial results following two doses were disappointing; there was no reduction in the number or severity of cholera episodes. After the booster dose was http://infection.thelancet.com Vol 6 June 2006

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given at 10 months, the overall protective efficacy was 61%. Following three doses protection was seen against severe disease as defined by hospitalisation (82% protective efficacy); protective efficacy for children aged 2–5 years was 50%. In an analysis of a small number of patients with El Tor Inaba, the vaccine demostrated most protection against this strain. A third trial in Peru was carried out in military recruits in 1994.59 The protective efficacy against cholera in recipients of two doses of vaccine was 86%. An open efficacy trial in Vietnam of a locally produced whole cell vaccine without cholera toxin B demonstrated 66% protective efficacy following two doses.60 Efficacy was assessed as prevention of hospitalisation for cholera. There was similar efficacy for children age 2–5 years compared with older individuals. The most recently reported field trial used rCTB-WC vaccine in Mozambique before a seasonal cholera outbreak.61 Individuals in a community at risk for cholera were vaccinated with two doses of rCTB-WC vaccine; cases of diarrhoea that occurred in the community were then analysed. There was a high degree of protective efficacy: a protective efficacy of 84% was observed in those who received two doses of vaccine. Some people only received a single dose of vaccine (approximately

20% of the original target population); the protective efficacy in those who received one or two doses was 78%. There was no protection against non-choleric diarrhoea. Of interest, HIV antenatal seroprevalence in this community was estimated to be 20–30%. There is a single study on the protective efficacy of three doses of CTB-WC against cholera in a challenge study with non-immune volunteers.62 The CTB-WC vaccine provided 64% protection against cholera, with cases in vaccine recipients less severe than in controls.

Efficacy studies of oral, live attenuated CVD 103-HgR vaccine against cholera A challenge study using V cholerae El Tor Inaba in 51 US volunteers immunised with a single dose of CVD 103-HgR demonstrated an efficacy of 80% against all diarrhoea and 91% against severe diarrhoea at 3 months.69 An earlier, smaller controlled challenge study demonstrated 62% vaccine efficacy.70 Protection began as early as 8 days following vaccination and persisted for 4–6 months.71 The efficacy of this vaccine in challenge studies was dependent upon the infecting strain, with the best protection achieved when the challenge strain was of the same biotype and serotype (classic Inaba).72

Study site, year,* and trial type

Study population

Predominant V cholerae type

Vaccine

Sample size

Schedule

Protective efficacy (95% CI)

Bangladesh, 1985. Randomised, doubleblinded, placebo controlled trial54–56

Children aged 2–15 years and women over 15 years

El Tor Ogawa

Placebo (E coli K12) WC CTB-WC

Placebo: 21 220 WC: 21 137 CTB-WC: 21 141

Three doses at 6 week intervals

6 months WC: 58% (16–79%) CTB-WC: 85% (62–94%) First year WC: 53% (38% lower boundary) CTB-WC: 62% (50% lower boundary) Second year WC: 57% (42% lower boundary) CTB-WC: 57% (42% lower boundary) Third year WC: 43% (19% lower boundary) CTB-WC: 17% (–15% lower boundary)

Peru, 1992. Randomised, double-blinded, placebo controlled trial57

Adults aged 17–23 years

El Tor Ogawa

Placebo (E coli K12) rCTB-WC

307 people received two doses of either placebo or vaccine

Two doses at a 2 week interval

One dose of vaccine rCTB-WC: 8% developed cholera Placebo: 14% developed cholera

Peru, 1993. Randomised, double-blinded, placebo controlled trial58

Children and adults aged 2–65 years

El Tor Ogawa

Placebo (E coli K12) rCTB-WC

17 799 received two doses of either placebo or vaccine

Two doses at a 2 week interval third dose given after 10 months

Two doses evaluated over 1 year: –3·6% (–88% to 43%) Three doses evaluated over 1 year: 61% (28–79%)

Peru, 1994. Randomised, double-blinded, placebo controlled trial59

Men aged 16–45 years

El Tor Ogawa

Placebo (E coli K12) rCTB-WC

1426 received two doses of either placebo or vaccine

Two doses at 1–2 week interval

18 weeks mean follow-up 86% (37–97%)

Vietnam, 1992. Open comparative trial60

Children and adults aged 1 year and older

El Tor Ogawa

WC†

No vaccine: 67 058 WC: 51 975

Two doses at a 2 week interval

8–10 months 66% (46–79%)

Mozambique, 2003–04. Case control trial61

Children and adults aged 2 years and older

El Tor Ogawa

rCTB-WC

11 070

Two doses at a 15–31 day interval

5 months 84% (43–95%)

USA, 1986. Challenge study62

Adults aged 18–35 years

El Tor Inaba, 2 x 106

WC‡ CTB-WC

No vaccine: 8 and 7 WC: 9 CTB-WC: 11

Three doses at 2 week intervals

4–5 weeks WC: 3/9 vs 6/8 individuals developed cholera CTB-WC: 4/11 vs 7/7 individuals developed cholera

(r)CTB=(recombinant) cholera toxin B subunit; WC=killed whole cell V cholerae. *Year trial was carried out, if stated, otherwise year of publication. †The trial used a locally produced WC only vaccine. The fourth vaccine strain used (formalin-killed V cholerae Inaba, classic biotype) differed from the SBL Vaccin product. ‡The WC vaccine consisted of three strains of V cholerae: 5 x 1010 bacteria each of heat-killed classic Inaba and El Tor Inaba, and 1 x 1011 bacteria of formalin-killed El Tor Inaba.

Table 4: Efficacy trials of (r)CTB-WC vaccines against cholera

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Study population, year,* and trial type

Vaccine used (sample size)

Schedule

ETEC isolates (%) and LT or LT/ST ETEC isolates (%)

Diarrhoea and protective efficacy

Bangladeshi children aged 2–15 years, women >15 years, 1985. Randomised double-blinded placebo controlled trial96†

WC (24 770) CTB-WC (24 842)

Two or three doses at 6 week intervals

ETEC: .. LT or LT/ST ETEC: 19·7%‡

3 months Diarrhoea: .. PE LT ETEC: 67% (30% lower boundary)

Adult Finnish travellers to Morocco, 1989. Randomised double-blinded placebo controlled trial97

Placebo (E coli K12) (307) CTB-WC (308)

Two doses at a 2 week interval

ETEC: 25·9% LT or LT/ST ETEC: 12·7%

Placebo Diarrhoea: 31% CTB-WC§ Diarrhoea: 24% PE all cases: 23% (95% CI 16–30%) PE ETEC: 52% (95% CI 44–59%) PE LT ETEC: 60% (95% CI 52–68%)

Adult US college students in Mexico, 1992. Randomised double-blinded placebo controlled trial98

Placebo (bicarbonate buffer) (252) Two doses at a 10 day interval, rCTB-WC (250) administered in Mexico

ETEC: 29·8% LT or LT/ST ETEC: 19·8%

Placebo Diarrhoea: 49·2% rCTB-WC Diarrhoea: 50·8% PE ETEC <7 days: –11% (95% CI –27% to 21%) PE ETEC ≥ 7 days: 50% (95% CI 14–71%)

Adult and child Austrian travellers to 44 countries, 2000. Randomised double-blinded placebo controlled trial99

Placebo (E coli K12) (66) rCTB-ETEC|| (62) rCTB-WC (56)

ETEC: 63·2% (12/19) LT or LT/ST ETEC: 15·8% (3/19)

Placebo Diarrhoea: 21% rCTB-ETEC Diarrhoea: 24% rCTB-WC Diarrhoea: 27%

Two doses at a 7–21 day interval

..=not reported; (r)CTB=(recombinant) cholera toxin B subunit; ETEC=enterotoxigenic Escherichia coli; LT=heat-labile toxin; PE=protective efficacy; ST=heat-stable toxin; WC=killed whole cell V cholerae. *Year trial was carried out, if stated, otherwise year of publication. †This study was a secondary analysis of an efficacy trial of placebo, WC and CTB-WC vaccines against V cholerae O1. ‡The percentage of LT or LT/ST ETEC that occurred in all diarrhoeal episodes during trial period. §A recalculation of the data yielded: the 95% CI for a 23% PE for all cases of diarrhoea was 1–42% (p=0·059), the 95% CI for the 52% PE against ETEC was 11–74% (p=0·028), and the 95% CI for the 60% PE against LT ETEC was 1–84% (p=0·08). ||ETEC vaccine consisted of 1011 formalin-killed ETEC, with five ETEC strains expressing coli surface antigens 1–6.

Table 5: Efficacy trials of (r)CTB-WC vaccines against ETEC and travellers’ diarrhoea

The efficacy demonstrated in volunteer challenge studies led to licensure of the vaccine. The only large placebocontrolled field trial, which took place in Indonesia, did not detect significant protection at years 1–4, and had too few evaluable cases in the first 6 months to determine whether protection occurred over this period.73 When the vaccine was used as part of several measures to control a cholera outbreak in the Federated States of Micronesia in 2000, there was evidence of protective efficacy.10,74

Travellers’ diarrhoea and enterotoxigenic E coli Diarrhoea is the most frequent health problem experienced by travellers to resource-poor regions of the world and is estimated to occur in 20–60% of travellers.75–78 Many studies have examined the aetiology of travellers’ diarrhoea from different destinations.50,79,80 Although the syndrome is caused by bacterial, viral, and parasitic agents, bacterial aetiologies are responsible for 50–80% of cases,81 and ETEC cause 15% or more of travellers’ diarrhoea.49,50,79 Other common bacteria include other types of E coli (eg, enteroaggregative E coli [EAEC], a recently determined aetiology),82,83 Salmonella spp, Shigella spp, and Campylobacter spp. The most common parasite aetiologies are Giardia intestinalis and Cryptosporidium hominis (with Cyclospora cayetanensis less frequent); common viral organisms are rotavirus and small round structured viruses, including noroviruses. E coli has the capacity to cause diarrhoea via several different pathogenic mechanisms.84,85 Of the E coli in cases of travellers’ diarrhoea, ETEC, EAEC, and mixed infections are most common. 366

In addition to being an important cause of diarrhoea in travellers, ETEC contribute to the burden of diarrhoeal illness in resource-poor regions of the world and particularly in young children.86–89 WHO estimate that of the 1·5 billion episodes of diarrhoea in children under the age of 5 years, ETEC account for 210 million of these cases, and cause 380 000 deaths.90 ETEC may also cause severe illness leading to hospitalisation more frequently than is commonly recognised.86,91 ETEC need to adhere to intestinal epithelial cells and then elaborate an enterotoxin to cause disease. ETEC express colonisation factors (most of which are protein fimbriae) that allow attachment.86,92 There are several classes of these colonisation factors. ETEC of human origin produce two major enterotoxins: heat-stable toxin and heat-labile toxin.84,93 The heat-stable toxin acts by activating guanylate cyclase in the intestinal epithelium, resulting in chloride secretion and/or inhibition of sodium chloride absorption,94 leading to a net intestinal fluid secretion. The toxin is not immunogenic because of its small molecular size. The heat-labile toxin is closely related in structure and function to the enterotoxin (cholera toxin) expressed by V cholerae.26–29 Like cholera toxin, the major mode of action of the heat-labile toxin is to promote secretion of electrolytes and fluid into the gut. The immunological cross reactivity between heat-labile toxin and cholera toxin means that CTB-WC vaccine has the potential to prevent diarrhoea caused by ETEC that express heat-labile toxin. As a result, this vaccine has been evaluated for protection against ETEC and travellers’ diarrhoea.5,86,95 http://infection.thelancet.com Vol 6 June 2006

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Efficacy studies of (r)CTB-WC vaccine against ETEC and travellers’ diarrhoea Support for a role of CTB-WC vaccine in preventing ETEC came from a secondary analysis of the Bangladesh trial showing that the vaccine induced protection against heat-labile toxin-producing ETEC.96 Over the first 3 months, there were 67% fewer episodes of heat-labile toxin ETEC (both heat-labile toxin only and heat-labile toxin plus heat-stable toxin) in those who had received two or three doses of CTB-WC compared with those who took the whole cell vaccine alone (table 5). This effect was limited to the first 3 months and declined to 21% at 12 months follow-up. The benefit was greatest against severe, life-threatening diarrhoea (protective efficacy, 86%). It is not clear how much this protection depended upon previous exposure to ETEC. In addition to the information from the Bangladesh trial, it is known that some natural immunity to ETEC infection develops in people who are repeatedly infected.100–102 This immunity appears to be directed against colonisation factors, other surface antigens, and heat-labile toxin.86,95 Therefore, vaccination against ETEC is an important strategy given the morbidity associated with ETEC infection. Although there have been several studies examining vaccines that combine recombinant cholera toxin B with killed ETEC that express different colonisation factors,95,103–105 the approach to travellers has usually been to use a CTB-WC vaccine, based on the favourable results from the Bangladesh trial.96 Travel destination, year*

Number of stool samples (number positive for pathogens)

Three studies have examined the protective efficacy of CTB-WC or rCTB-WC vaccine against both ETEC and the general syndrome of travellers’ diarrhoea (table 5).97–99 The first study was carried out in Finnish travellers to Morocco.97 There was a relative risk reduction for all cases of diarrhoea in vaccine recipients of 23%. Enteropathogens were isolated in 78 of the 166 (47%) patients with diarrhoea. Heat-labile toxin-producing ETEC (either alone or with heat-stable toxin) were isolated in 21 patients (15 controls and six vaccinees). The number of ETEC isolates producing heat-stable toxin was not different between vaccinated and control groups. There was 52% protection against all ETEC and 60% protection against heat-labile toxin-producing ETEC. A re-analysis of this data suggests wider confidence intervals for protective efficacies than those reported (table 5). The second study was in US students travelling to Mexico; rCTB-WC vaccine was administered after they had arrived in Mexico.98 Serum anti-cholera toxin titres were measured, efficacy against travellers’ diarrhoea was determined, and side-effects were recorded. Anti-cholera toxin seroconversion occurred in 87% of vaccines. There was no difference in the incidence of diarrhoea between controls and vaccinees. There was also no significant difference between the proportion of vaccinees and controls with ETEC (all types) or heat-labile toxinproducing ETEC: 31% of the control group with diarrhoea and 28% of the vaccine group had ETEC diarrhoea, and 9% of vaccinees and 11% of controls had diarrhoea caused by heat-labile toxin-producing ETEC. 33% of ETEC

ETEC isolates (% of all stools)

LT positive isolates (% of ETEC; % of all stools)

ST positive isolates (% of ETEC; % of all stools)

LT and ST positive isolates (% of ETEC; % of all stools)

Jamaica, 1994–97107

332 (118)

87 (26·2%)

34 (39·1%; 10·2%)

22 (25·3%; 6·6%)

31 (35·6%; 9·3%)

Nepal, 1997108

207 (..)

26 (12·5%)

6 (23·1%; 2·9%)

15 (57·7%; 7·2%)

5 (19·2%; 2·4%)

13 (from 11 specimens)

0

10 (76·9%; ..)

3 (23·1%; ..)

Cruise ships, 1997–98109 Mexico 1 (n=30)

11 (..)

Mexico 2 (n=19)

6 (..)

Jamaica (n=197)

10 (..)

7 (from four specimens) 12 (from 8 specimens)

2 (28·6%; ..)

4 (57·1%; ..)

1 (14·3%; ..)

3 (25%; ..)

6 (50%; ..)

3 (25%; ..)

Various, 1996–9850 Montego Bay, Jamaica

322 (102)

38 (11·8%)

22 (57·9%; 6·8%)

10 (26·3%; 3·1%)

6 (15·8%; 1·9%)

Goa, India

293 (161)

73 (24·9%)

18 (24·7%; 6·1%)

22 (30·1%; 7·5%)

33 (45·2%; 11·3%)

Mombasa, Kenya

464 (246)

164 (35·3%)

30 (18·3%; 6·5%)

83 (50·6%; 17·9%)

51 (31·1%; 11·0%)

Asia, Africa, Latin America, southern Europe, 1991110

217 (101)

37 (17·1%)

6 (16·2%; 2·8%)

20 (54·1%; 9·2%)

11 (29·7%; 5·1%)

Swedish travellers admitted to hospital with diarrhoea on return, 1996–97111

750 (417)

62 (8·3%)

28 (45·2%; 3·7%)

12 (19·4%; 1·6%)

2 (35·5%; 2·9%)

Mexico, 1992–97112

928 (404)

195 (21·0%)

144 (73·8%; 15·5%) LT or LT/ST positive

..

..

Nepal, 1992–93113 Expatriates Tourists

69 (44)

15 (21·7%)

2 (13·3%; 2·9%)

8 (53·3%; 11·9%)

5 (33·3%; 7·2%)

120 (100)

34 (28·3%)

7 (20·6%; 5·8%)

19 (55·9%; 15·8%)

8 (23·5%; 6·7%)

Morroco, 1989114

126 (76)

28† (22·2%)

7 (25·0%; 5·6%)

16 (57·1%; 12·7%)

5 (17·9%; 4·0%)

Mexico, 1997115

127 (39)

24 (18·8%)

7 (29·2%; 5·5%)

8 (33·3%; 6·3%)

9 (37·5%; 7·1%)

..=not reported; ETEC=enterotoxigenic E coli; LT=heat-labile toxin; ST=heat-stable toxin. *Year studied was carried out, if stated, otherwise year of publication. †11 of these ETEC were mixed with other organisms.

Table 6: Prevalence of ETEC in studies of travellers’ diarrhoea

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Area of deployment, year*

Number of stool samples (number positive for pathogens)

Saudi Arabia, 1990–91116

181

47 (26·0%)

1 (2·1%; 0·6%)

Indonesia

80

19 (23·8%)

1 (5·3%; 1·3%)

13 (68·4%; 16·3%)

5 (26·3%; 6·3%)

Thailand

191

19 (9·9%)

1 (5·3%; 0·5%)

18 (94·7%; 9·4%)

0 0

ETEC isolates (% of all stools)

LT positive isolates (% of ETEC; % of all stools)

ST positive isolates (% of ETEC; % of all stools)

LT and ST toxin positive isolates (% of ETEC; % of all stools)

34 (72·3%; 18·8%)

12 (25·5%; 6·6%)

Southeast Asia, 1997108

40

4 (10·0%)

1 (25·0%; 2·5%)

3 (75·0%; 7·5%)

Cairo, Egypt, 1987117

Philippines

183

60 (32·8%)

24 (40·0%; 13·1%)

31 (51·7%; 16·9%)

Somalia, 1992–93118

113 (59)

18 (15·9%)

8 (44·4%; 7·0%)

9 (50·0%; 8·0%)

1985–87119

289 (146)

50 (17·3%)

13 (26·0%; 8·9%)

19 (38%; 6·6%)

18 (36%; 6·2%)

242

42 (17·4%)

..

..

..

47

8 (17·0%)

..

..

..

32 (16·9%; 7·4%)

73 (38·6%; 16·9%)

84 (44·4%; 19·4%)

South America West Africa Egypt and Saudi Arabia, 1989–90120

432 (212)

189 (43·8%)

5 (8·3%; 2·7%) 1 (5·6%; 0·9%)

..=not reported; ETEC=enterotoxigenic E coli; LT=heat-labile toxin; ST=heat-stable toxin. *Year studied was carried out, if stated, otherwise year of publication.

Table 7: Prevalence of ETEC in studies of military personnel with travellers’ diarrhoea

isolates produced heat-stable toxin. Because many cases of diarrhoea occurred within 7 days of the second dose of vaccine, a time at which individuals were not likely to be immune, the investigators did a sub-analysis of ETEC diarrhoea that occurred 7 days or more after the second dose. This analysis demonstrated a protective efficacy of 50%. Placebo and vaccine groups had similar frequency of mild side-effects. In the third trial, a rCTB-ETEC vaccine was the main focus of study.99 Non-immune travellers to 44 countries in Africa, Asia, and Latin America were randomised to the ETEC vaccine, the rCTB-WC cholera vaccine, or placebo. There was no statistical difference in the incidence of diarrhoea between the groups. Only 13 stool specimens were provided from the two vaccine groups to test for pathogens. In the rCTB-WC group, six of seven samples contained ETEC (five producing heat-stable toxin only) and five of six samples contained ETEC in the control group (all producing heat-stable toxin only). Side-effect profiles were similar between groups. Taken together, these three studies show a limited efficacy of oral cholera vaccine in preventing the syndrome of travellers’ diarrhoea in general, and ETEC specifically, in non-immune travellers.97–99 In only two of the studies was protection documented;97,98 the third trial was not adequately Pathogen

Incidence of travellers’ diarrhoea (%)*

Percentage of travellers’ diarrhoea caused by pathogen†

Protective Percentage of all efficacy against travellers’ diarrhoea pathogen (%) prevented by vaccine‡

All ETEC

20 60

21·4 21·4

5098 5297

2·1 6·6

LT positive plus LT/ST positive ETEC

20 60

9·9 9·9

6097 6796

1·2 4·0

rCTB-WC=recombinant cholera toxin B subunit with killed whole cell V cholerae; ETEC=enterotoxigenic E coli; LT=heat-labile toxin; ST=heat-stable toxin. *Estimated range of 20–60%. †Median estimates from table 6 and table 7. ‡Calculated as: incidence of travellers’ diarrhoea x percentage of travellers’ diarrhoea caused by pathogen x protective efficacy against pathogen.

Table 8: Calculated percent of travellers’ diarrhoea prevented by a rCTB-WC vaccine

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powered to demonstrate efficacy against ETEC.99 The variable efficacy of the vaccine against travellers’ diarrhoea reflects the multiple aetiologies of this condition. Antiheat-labile toxin immunity induced by the rCTB-WC vaccine is specific and does not protect against ETEC strains producing only heat-stable toxin, non-ETEC E coli, other bacteria, or non-bacterial pathogens.

Efficacy study of CVD-103HgR vaccine against ETEC and travellers’ diarrhoea In a randomised double-blind placebo controlled trial in 134 Dutch travellers, the CVD 103-HgR live-attenuated vaccine did not protect against ETEC (15% ETEC diarrhoea incidence in vaccine recipients vs 11% in placebo) or all cause travellers’ diarrhoea (52% diarrhoea incidence in vaccine recipients vs 46% in placebo).106 The time of onset of ETEC diarrhoea was significantly shorter (p=0·043) in the placebo group compared with the vaccinated group (5 days vs 15 days).

Efficacy estimates of (r)CTB-WC vaccine against travellers’ diarrhoea Table 6 and table 7 list studies published since 1990 that determined the proportion of travellers’ diarrhoea caused by ETEC and the toxins that they produced. The percentage of episodes of travellers’ diarrhoea due to ETEC ranged from 8–35% (median 21%) in studies of travellers (table 6) and 10–44% (median 21%) in studies of military populations (table 7). Heat-labile toxin producing (either heat-labile toxin alone or both heat-labile and heat-stable toxins) strains ranged from 5% to 20% (median 11%) of all isolates in studies of travellers and 1–27% (median 8%) in military studies. These figures are very similar to those found by Leyten and colleagues106 in their study of CVD 103-HgR vaccine in Dutch travellers in whom only 5% experienced an episode of heat-labile toxin or heat-labile/ heat-stable toxin ETEC diarrhoea. http://infection.thelancet.com Vol 6 June 2006

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Using these data and the results of efficacy trials (using trials that demonstrated a protective effect; table 8), it can be estimated that between 1% and 7% of cases of travellers’ diarrhoea would be prevented by the use of the rCTB-WC vaccine.

Adverse events associated with oral cholera vaccines

is too low to be able to carry out an efficacy trial. Efficacy can only be extrapolated from the small numbers enrolled in volunteer challenge studies and from the trials carried out in endemic countries. The contribution that previous exposure to V cholerae makes to vaccine efficacy is not completely defined. However, in field trials the presence of pre-existing serum anti-vibriocidal antibody tends to blunt the systemic immune response following

Adverse events with (r)CTB-WC Placebo controlled field studies of the CTB-WC and rCTBWC vaccines in Bangladesh,54,63 Peru,121,122 and Colombia123 have demonstrated that mild gastrointestinal side-effects are seen with equal frequency between vaccine and placebo control groups. In these studies, diarrhoea, nausea, and/or abdominal pain have occurred in 2–15% of cases. Vomiting has occurred in 3% of cases or less. In volunteer challenge studies in Sweden and the USA, rates of side-effects are similar to those seen in the field studies.124,125 Some side-effects may be attributed to the buffer used to neutralise stomach acid, since volunteers given vaccine with half strength buffer had fewer symptoms. However, in these patients, the immune response to the rCTB-WC vaccine was impaired.125 Over 5 million doses of rCTB-WC vaccine have been supplied worldwide. According to manufacturer information from clinical trials and post-marketing surveillance, mild gastrointestinal symptoms (abdominal pain, cramping, diarrhoea, nausea) are the most commonly reported symptoms, occurring at a frequency of 0·1–1%.126 Serious adverse events—including a flu-like syndrome, rash, arthralgia, and paraesthesias—are rare, occurring in less than 1 in 10 000 doses distributed. Sideeffects approaching significant differences from controls include vomiting, abdominal pain, and cramps.4

Adverse events with CVD 103-HgR Safety and immunogenicity trials and a clinical use study have documented diarrhoea in 0–12% of patients who have received this vaccine,72,127 a rate similar to control groups. The vaccine manufacturer states that diarrhoea occurs in more than 10% of cases; abdominal cramps, headache, nausea, fatigue, skin eruption, discomfort, gurgling gastrointestinal sounds, raised temperature (≤38°C), and loss of appetite occur in 1–10% of cases.128

Discussion The development of cholera vaccines against V cholerae O1 that stimulate intestinal immunity, are well tolerated, and have good efficacy is welcome. Although these products have been primarily used for travellers, their role in prevention of cholera in endemic countries and in decreasing the morbidity and mortality of cholera during epidemics is becoming increasingly defined.10,61,64 Field trial data is stronger in support of the rCTB-WC vaccine compared with the CVD-103 HgR vaccine. The true efficacy of these vaccines in preventing cholera in travellers is not known, since the risk in this population http://infection.thelancet.com Vol 6 June 2006

Panel: Summary and graded recommendations for the role of rCTB-WC in clinical practice Cholera O The oral rCTB-WC is well tolerated. Most side-effects are limited to mild gastrointestinal events (AI). O Both CTB-WC and the rCTB-WC vaccines demonstrate good protective efficacy against V cholerae O1 for 4–6 months in people living in endemic countries (protective efficacy 61–86%) (AI). O In children aged 2–5 years, protection wanes rapidly after 6 months. O The vaccine will not protect against infection with V cholerae O139. O The risk of cholera can be estimated to be 2–3 imported cases per million travellers to 1–4 cases per 10 000 people when enhanced surveillance or expatriate populations are included (BII). O Vaccination against cholera can be considered for the following categories of travellers (in the absence of specific data)132 (CIII): – relief and disaster workers – people with remote itineraries in areas where cholera epidemics are occurring and there is limited access to medical care. O Using available resources to document cholera outbreaks, it is key to make an individual risk assessment based on the traveller’s underlying health, the destination and duration of travel, and planned activities. Travellers’ diarrhoea O The contribution of heat-labile toxin-producing ETEC in travellers’ diarrhoea is variable and often small: a median of 21% of samples are positive for ETEC; the percentage of heat-labile toxin positive ETEC is 6%, and heat-labile and/or heat-labile/heat-stable toxin positive ETEC is 10% (see table 6 and table 7) (AII). O Vaccination with (r)CTB-WC has moderate cross protection (60–67%) against heatlabile toxin-producing E coli over 3 months (BII). O There is evidence in travellers of a low protective efficacy of (r)CTB-WC vaccine against the syndrome of travellers’ diarrhoea (CI). O The live-attenuated vaccine, CVD 103-HgR does not protect against travellers’ diarrhoea (DI). O Based on estimates of the incidence of travellers’ diarrhoea, the prevalence of heatlabile toxin-producing E coli, and the protective efficacy of the vaccine, the rCTB-WC can be expected to protect 7% or less of travellers (BIII). O In general, the rCTB-WC vaccine should not be used for the prevention of travellers’ diarrhoea (DIII). O Vaccination with rCTB-WC vaccine does not preclude exercising care with food and drink selection during travel. Clinical guidelines ranked by the Infectious Diseases Society of America-United States Public Health Service Grading System for ranking recommendations in clinical guidelines.133 Strength of recommendation: A—good evidence to support a recommendation; B—moderate evidence to support a recommendation for use; C—poor evidence to support a recommendation for use; D— moderate evidence to support a recommendation against use; E—good evidence to support a recommendation against use. Quality of evidence: I—evidence from one or more properly randomised, controlled trials; II—evidence from one or more welldesigned clinical trials, without randomisation, from cohort or case-controlled analytic studies (preferably from more than one centre), from multiple time-series, or from dramatic results from uncontrolled experiments; III—evidence from opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.

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Search strategy and selection criteria References for this review were identified by searches of Medline and Pubmed using the search terms “cholera”, “cholera vaccine”, “travellers’ diarrhoea”, “travellers’ diarrhoea vaccine”, “travel vaccines”, “enterotoxigenic Escherichia coli”, “Escherichia coli” “Escherichia coli vaccine”, and “travel health advice”. Additional references were obtained from the author’s personal collections and from the references of the articles identified in the search. Chiron also provided articles on the B subunit cholera toxin, whole cell V cholerae vaccine.

vaccination with rCTB-WC vaccine, whereas responses to cholera toxin as an immunogen do not seem to be as affected by pre-existing anti-toxin antibody.57,121,122 Indeed, in the first Peruvian trial where an outbreak of cholera occurred between doses of rCTB-WC vaccine, the serum anti-toxin responses were boosted by vaccine.57 The issue for cholera vaccination in travel medicine is who should receive the vaccine. Cholera vaccination has not been required as a condition of international travel since 1973.129 Given the extremely low risk of cholera in travellers, this is not a vaccine that should be used routinely. Travellers rarely expose themselves to the extreme conditions of poverty, crowding, and poor sanitation that define many cholera outbreaks. Currently, WHO recommends cholera vaccination for those determined to be at increased risk of the disease, particularly relief and health-care workers in refugee situations.2 Although the specific risk for people working in relief and refugee settings is not known, vaccinating this group seems appropriate given the chance of epidemic cholera in these settings. It is also reasonable to consider vaccination for those travelling to cholera-epidemic areas who would not be able to get prompt medical care in the event of a severe dehydrating diarrhoeal illness. Up-to-date information on cholera outbreaks is necessary for travel health-care professionals to make these assessments. However, maintaining such information is a challenge. For all travellers in whom vaccination is considered, the impact of a potentially severe diarrhoeal illness upon the health of the traveller needs to be considered. The data do not support the role of rCTB-WC vaccine as a vaccine for travellers’ diarrhoea. The vaccine is only effective against ETEC and specifically those that produce heat-labile toxin. The CVD-103HgR vaccine showed no efficacy in this syndrome in a single trial.106 Although the prevalence of ETEC varies throughout the world, information from recent studies in visitors to developing regions places the median prevalence of ETEC at 21% (range 8–44%). This estimate is less than that found in older studies but similar to a recent review documenting ETEC prevalence in childhood diarrhoea.86 In a review of studies from the 1970s and 1980s the median percentage of ETEC in travellers to Mexico was 370

42%, to other areas of Latin America 35%, and to Asia 16%.49 The proportion of episodes that are caused by strains producing heat-labile toxin alone or both heatlabile and heat-stable toxins together is even less (median 10%) because heat-stable toxin is more common in many areas. For example, over 50% of ETEC isolates from Kenya were positive for heat-stable toxin,50 as were ETEC isolates from Swedish travellers to multiple regions of the world;110 heat-stable toxin-producing isolates were also more common in the efficacy study of CVD 103-HgR in Dutch travellers.106 Development of more specific ETEC vaccines5,86,95 has been prompted in part by the limitation of efficacy of rCTB-WC to heatlabile toxin-producing ETEC. There are also alternative approaches to travellers’ diarrhoea that make it less attractive to use a vaccine with coverage against only one aetiology of this syndrome. Prompt treatment with hydration and the selected use of antimotility agents and antibiotics can result in rapid improvement of symptoms.75,130 Given this information on rCTB-WC vaccine and travellers’ diarrhoea, how should the health practitioner counsel an individual traveller regarding its use for this syndrome? The vaccine has low efficacy against a common travel-related illness and one cannot assure the traveller that they will be protected if they take the vaccine. The rCTB-WC vaccine might protect 7% or less of travellers depending upon the incidence of travellers’ diarrhoea and the prevalence of heat-labile toxinproducing ETEC (table 8). Our estimated figure for protection is supported by the study of CTB-WC vaccine in Finnish travellers in whom 7% of cases of travellers’ diarrhoea were prevented.97 Providing the vaccine might also give the traveller a false sense of protection and result in less care with food and drink hygiene. Even if travellers receive rCTB-WC vaccine, they will still need to carry self-treatment medications and continue to exercise care in food and drink selection. Based on our analysis of the data, we do not recommend rCTB-WC vaccine for travellers’ diarrhoea, by contrast with more enthusiastic recommendations recently published.7,131 If it is given to travellers for reasons other than for protection against cholera, the traveller will need to understand and accept that this vaccine will protect against only one cause of travellers’ diarrhoea—heatlabile toxin-producing ETEC—and therefore will only marginally reduce their chances of becoming ill. Recommendations for the role of rCTB-WC in clinical practice, based on current evidence and graded according to the US Public Health Service, Infectious Diseases Society of America grading system are given in the panel. Conflicts of interest We declare that we have no conflicts of interest. Acknowledgments We thank Eric Walker and Sarah O’Brien for helpful reviews of the manuscript.

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