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Canadian Immunization Guide

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Part 4
Active Vaccines

Cholera and Enterotoxigenic Escherichia Coli (ETEC) Travellers’ Diarrhea vaccine

Key Information (Refer to text for details)

What

  • Cholera –
    • Is caused by Vibrio cholerae serogroups O1 and O139
    • Is associated with poor sanitation; generally acquired from contaminated water or food
    • If untreated, severe fluid loss can lead to rapid dehydration and hypovolemic shock, which may be life-threatening
  • Enterotoxigenic Escherichia coli (ETEC) –
    • Accounts for 25% to 50% of travellers’ diarrhea
    • Is transmitted by contaminated food and, less often, contaminated water
    • Most episodes are mild and self-limited
  • Cholera and travellers’ diarrhea vaccine (DUKORAL®, Crucell Vaccines Inc.) efficacy is about 86% for epidemic cholera and approximately 25% for overall travellers’ diarrhea. It protects against Vibrio cholera serogroup O1 but does not protect against cholera caused by V. cholerae O139 or other species of Vibrio.
  • Following the primary series, protection against cholera lasts for 2 years in persons 6 years of age and older and 6 months in children 2 to 5 years of age. Protection against ETEC travellers’ diarrhea lasts for 3 months.
  • The most commonly reported adverse events following immunization are abdominal pain, diarrhea, nausea and vomiting.

Who

  • For protection against cholera: Travellers to cholera-endemic countries who will be at significantly increased risk of exposure (e.g., humanitarian workers or health professionals working in endemic countries) may benefit from cholera and travellers’ diarrhea vaccination.
  • For protection against travellers’ diarrhea: Vaccination with cholera and travellers’ diarrhea vaccine is of limited benefit and is not routinely recommended except for high risk travellers 2 years of age and older.

How

  • Cholera prevention –
    • 6 years of age and older: give 2 doses orally, 1 to 6 weeks apart
    • 2 to 5 years of age: 3 doses orally, 1 to 6 weeks apart
  • ETEC travellers’ diarrhea prevention: give 2 doses orally, 1 to 6 weeks apart
  • Booster doses should be administered, if indicated. The interval varies with age and indication.
  • Avoid oral administration of medicinal products or intake of food and/or drink for 1 hour before and 1 hour after vaccine administration.
  • Separate the administration of cholera and travellers’ diarrhea vaccine and oral typhoid vaccine by at least 8 hours.

Why

  • Most travellers following the usual tourist itineraries in countries affected by cholera are at extremely low risk of acquiring cholera infection; travellers’ diarrhea is usually a mild and self-limited illness.
  • Not all recipients of this vaccine will be fully protected against cholera or travellers’ diarrhea.

Since the publication of 2006 Canadian Immunization Guide:

  • New data have been obtained on the epidemiology of cholera.

For additional information, refer to the Committee to Advise on Tropical Medicine and Travel (CATMAT) Statement on new oral cholera and travellers’ diarrhea vaccination.

Epidemiology

Disease description

Infectious agent
Cholera is caused by the toxin-producing bacterium Vibrio cholerae serogroups O1 and O139. V. cholerae serogroup O1 causes the majority of cholera outbreaks and has two biotypes, Classical and El Tor. Each biotype has two serotypes, Inaba and Ogawa.

Enterotoxigenic Escherichia coli (ETEC) is the most common cause of travellers’ diarrhea. Many ETEC strains produce a heat-labile enterotoxin that is similar to cholera toxin.

Reservoir
Humans and water sources are the main reservoirs of V. cholerae. Humans are the reservoir for ETEC.

Transmission
Cholera
Cholera is associated with poor sanitation and is generally acquired from contaminated water or food, particularly undercooked or raw shellfish and fish. The incubation period is 2 hours to 5 days and V. cholerae remain in the feces for 7 to 14 days after infection. Transmission from person to person is rare.

ETEC travellers’ diarrhea
ETEC is transmitted by contaminated food and, less often, contaminated water. The incubation period is usually 24 to 72 hours and excretion of ETEC may be prolonged.

Risk factors
Cholera
Travellers at higher risk of cholera infection include those who drink or eat contaminated water or food, in particular undercooked or raw shellfish and fish. Humanitarian relief workers and those visiting areas of high risk with limited access to safe water and food are also at increased risk. The risk of cholera can increase following disaster situations due to the disruption of water and sanitation systems or the displacement of populations to overcrowded camps. Immunocompromised persons (such as malnourished children or HIV-infected persons) are at greater risk of morbidity if infected.

Travellers’ diarrhea
The most important determinants of risk for travellers’ diarrhea are the travel destination and the type of travel (e.g., five-star accommodations vs. backpacking). Factors associated with a higher probability of acquiring travellers’ diarrhea include gastric hypochlorhydria and the relative lack of gut immunity seen in small children. In addition, specific groups of travellers are at an increased risk of serious consequences of travellers’ diarrhea:

  • persons with chronic illnesses, such as immunodeficiency diseases
  • individuals with chronic renal failure
  • persons with congestive heart failure
  • individuals with insulin-dependent diabetes mellitus
  • persons with inflammatory bowel disease

Spectrum of clinical illness
Cholera
Cholera presents as profuse, watery diarrhea. If left untreated, severe fluid loss can lead to rapid dehydration and occasionally hypovolemic shock, which may be life-threatening. Case fatality ranges from 50% or more without treatment to less than 1% among adequately treated patients. The spectrum of disease is wide, with mild and asymptomatic illness occurring more frequently than severe disease. The ratio of symptomatic to asymptomatic cases varies from strain to strain.

Travellers’ diarrhea
Most episodes of travellers’ diarrhea are mild and self-limited although the illness can be debilitating and particularly difficult to manage in remote or unfamiliar surroundings. Some travellers experiencing more severe acute inflammatory gastroenteritis may develop persistent gastrointestinal symptoms, but long term sequelae resulting from non-inflammatory gastroenteritis such as that caused by ETEC are very uncommon.

Disease distribution
Incidence/prevalence

Global
Cholera: The World Health Organization (WHO) estimates that approximately 3 to 5 million cholera cases occur annually, with up to 120,000 deaths. Cholera is endemic in many countries. A map of the areas reporting cholera outbreaksExternal Link is available from the World Health Organization (WHO).

Travellers’ diarrhea: It is estimated that up to 50% of travellers from developed countries who visit developing countries will have traveller’s diarrhea, depending on the destination. The highest rates are seen in Latin America, Africa and the Indian subcontinent, while intermediate rates of 8% to 15% are seen for travellers to China, Russia, the Middle East and southeastern Asia.

National
In Canada, cholera cases are very uncommon. There have been 19 cases of cholera reported between 2005 and 2008. There are no Canadian data on ETEC and travellers’ diarrhea.

Recent outbreaks
Since the 19th century, cholera pandemics have killed millions of people across all continents. The current cholera pandemic began in South Asia in 1961, reached Africa in 1971 and the Americas in 1991. In recent years there has been multiple cholera outbreaks related to mass population movement, especially at times of strife, such as within refugee camps in resource-poor countries. Recently, two large scale outbreaks included Zimbabwe in 2009 and Haiti in 2010. In Haiti, over a one year period, almost half a million cases were reported, with over 6,200 deaths.

Preparation Available for Use in Canada

Cholera and travellers’ diarrhea vaccine
  • DUKORAL®: inactivated, oral, travellers’ diarrhea and cholera vaccine containing heat inactivated V. cholerae O1 Inaba classic strain, formalin inactivated V. cholerae O1 Inaba El Tor strain, and heat and formalin inactivated V. cholerae O1 Ogawa classic strain with recombinant non-toxic cholera toxin B subunit, Crucell Sweden AB (manufacturer), Crucell Vaccines Inc.(distributor)

For complete prescribing information, consult the product leaflet or information contained within Health Canada’s authorized product monographs available through the Drug Product DatabaseExternal Link. Refer to Table 1 in General Considerations in Part 1 for a list of all vaccines available for use in Canada and their contents.

Efficacy, Effectiveness and Immunogenicity

Efficacy and effectiveness

Cholera
A clinical trial using an early formulation of cholera and travellers’ diarrhea vaccine demonstrated an overall efficacy against V. cholerae O1 El Tor of 64% and complete protection against moderate to severe diarrhea. A large field trial using an early formulation of this vaccine demonstrated efficacy of 85% against V. cholerae O1 El Tor disease for the initial 6 months and 50% for the 3-year follow-up period. A field trial using the current cholera and travellers’ diarrhea vaccine demonstrated an efficacy of 86% against epidemic cholera. Cholera and travellers’ diarrhea vaccine does not protect against cholera caused by V. cholerae O139 or other species of Vibrio.

Protection against cholera can be expected approximately one week after completion of primary immunization and lasts for 2 years in persons 6 years of age and older, and 6 months in children 2 to 5 years of age.

ETEC travellers’ diarrhea
Cholera and travellers’ diarrhea vaccine provides moderate, short-term protection against diarrhea caused by ETEC. Given that less than 50% (range, 25% to 50%) of cases of travellers’ diarrhea are caused by ETEC, the overall protection provided by cholera and travellers’ diarrhea vaccine against travellers’ diarrhea is estimated to be approximately 25%. A large field trial using an early formulation of this vaccine demonstrated 67% protection against ETEC for 3 months, with the number needed to vaccinate to prevent one case of ETEC calculated as over 2,600 from the published data. Another study demonstrated that the vaccine had a protective efficacy of approximately 50% against ETEC diarrhea. A third study showed efficacy against ETEC diarrhea of 52% and an overall protection against travellers’ diarrhea of 23%.

Protection against ETEC travellers’ diarrhea can be expected approximately one week after completion of primary immunization and lasts for 3 months.

Immunogenicity

Immunological correlates of protection against cholera after oral vaccination have not been identified. There is a poor correlation between serum antibody responses and protection. IgA antibodies produced in the intestine probably mediate protective immunity.

Cholera and travellers’ diarrhea vaccine induces intestinal IgA responses in 70% to 100% of vaccinated subjects and serum antibodies have also been detected. A booster dose elicits an anamnestic response indicative of an immune memory. The duration of the immunological memory is estimated to be at least 2 years in adults.

Recommendations for Use

Travellers (2 years of age and older)

Vaccination with cholera and travellers’ diarrhea vaccine is of limited benefit and is not routinely recommended for most travellers. For travellers, prevention of cholera or travellers’ diarrhea relies primarily on care in the choice of food and water supply and in the use of good hygienic measures rather than on immunization. A detailed, travel-related risk assessment should be made to determine which travellers are most likely to benefit from vaccination.

Cholera and travellers’ diarrhea vaccine is not recommended in children less than 2 years of age because efficacy has not been studied in this age group.

Cholera
Travellers to cholera-endemic countries who may be at significantly increased risk of exposure (e.g., humanitarian workers or health professionals working in endemic countries) may benefit from immunization with cholera and travellers’ diarrhea vaccine. Most travellers following the usual tourist itineraries in countries affected by cholera are at extremely low risk of acquiring cholera infection.

Travellers should take all the necessary precautions to avoid contact with or ingestion of potentially contaminated food or water since not all recipients of cholera and travellers’ diarrhea vaccine will be fully protected against cholera. This is particularly true for travellers to areas where the V. cholerae O139 is endemic.

No country or territory requires vaccination against cholera as a condition for entry.

Travellers’ diarrhea
Cholera and travellers’ diarrhea vaccine may be considered for prevention of travellers’ diarrhea in the following short-term travellers, 2 years of age and older:

  • Persons with chronic illnesses (e.g., chronic renal failure, congestive heart failure, insulin-dependent diabetes mellitus, inflammatory bowel disease) for whom there is an increased risk of serious consequences from travellers’ diarrhea
  • Persons at increased risk of acquiring travellers’ diarrhea (e.g., children 2 to 5 years of age; people with gastric hypochlorhydria)
  • Persons who are immunosuppressed because of human immunodeficiency virus (HIV) infection or other immunodeficiency states
  • Persons with a history of repeated severe travellers’ diarrhea

Indications for cholera and travellers’ diarrhea vaccine to prevent travellers’ diarrhea are limited because:

  • Most episodes of travellers’ diarrhea are mild and self-limited.
  • Therapeutic options (oral rehydration, dietary management, anti-motility and antibiotic treatment) are available if prevention fails.
  • The overall protection provided by cholera and travellers’ diarrhea vaccine against travellers’ diarrhea is expected to be approximately 25%.
  • Vaccinated travellers may have a false sense of security and may not be as strict in observing food and water precautions.

Refer to Booster doses and re-immunization and Schedule.

Pregnancy and lactation

Cholera and travellers’ diarrhea vaccine has not been studied in pregnant or lactating women. Administration of this vaccine to pregnant women may be considered in high-risk situations only (e.g., outbreak) after evaluation of the benefits and risks. This vaccine may be given to lactating women. Refer to Immunization in Pregnancy and Lactation in Part 3 for additional general information.

Immunocompromised persons

Immunocompromised persons, included HIV-infected persons, may be immunized with cholera and travellers’ diarrhea vaccine; however, the antibody response may be suboptimal. Refer to Immunization of Immunocompromised Persons in Part 3 for additional general information

Vaccine Administration

Dose, route of administration, and schedule

Dose
Cholera and travellers’ diarrhea vaccine consists of a single-dose vial of vaccine and a sachet of sodium hydrogen carbonate effervescent buffer granules. Prepare the buffer solution and vaccine in accordance with the instructions in the manufacturer’s product leaflet.

Route of administration
Cholera and travellers’ diarrhea vaccine is for oral administration only. It can be self-administered. Refer to Vaccine Administration Practices in Part 1 for additional information.

Schedule

Table 1 summarizes the schedule for cholera or ETEC travellers’ diarrhea immunization, by age.

Table 1: Immunization Schedule for cholera and travellers’ diarrhea and cholera vaccine,
by indication and age
  Cholera ETEC Travellers’ Diarrhea General instructions
2 to 5 years of age 6 years of age and older 2 years of age and older
Primary immunization 3 doses orally, 1-6 weeks apart 2 doses orally, 1-6 weeks apart 2 doses orally, 1-6 weeks apart If more than 6 weeks elapses between doses, re-peat primary series

Give final dose at least 1 week before departure
Booster 1 dose every 6 months 1 dose every 2 years 1 dose every 3 months If more than 5 years have passed since primary immunization or last booster dose, repeat primary series.
Booster doses and re-immunization

Cholera
An optimal booster dose or interval has not been established; however, if indicated based on ongoing risk:

  • For children 2 to 5 years of age - a booster dose is recommended every 6 months
  • For people 6 years of age and older - a booster dose is recommended every 2 years; a complete primary series (2 doses) is recommended if the last dose was received more than 5 years previously.

ETEC travellers' diarrhea
Cholera and travellers’ diarrhea vaccine provides short-term protection (approximately 3 months) against ETEC diarrhea; therefore, if the traveller will be at ongoing risk, booster doses should be considered. An optimal booster dose or interval has not been established; however, if there is an ongoing risk:

  • For people 2 years of age and older - a booster dose is recommended every 3 months.

Serologic Testing

Serologic testing is not recommended before or after receiving cholera and travellers’ diarrhea vaccine.

Storage Requirements

Store cholera and travellers’ diarrhea vaccine in a refrigerator at +2C to +8C. Do not freeze. The vaccine can be stored at room temperature (less than +27C) for up to 2 weeks on one occasion only. The buffer sachet may be stored at room temperature. If the vaccine and buffer mixture is not used immediately, it can be stored at room temperature (less than +27C) for up to 2 hours. Refer to Storage and Handling of Immunizing Agents in Part 1 for additional general information.

Simultaneous Administration with Other Vaccines

The administration of cholera and travellers’ diarrhea vaccine and oral typhoid vaccine capsules should be separated by at least 8 hours. Oral administration of other vaccines should be avoided 1 hour before and 1 hour after vaccination with cholera and travellers’ diarrhea. There are limited data, but there is no known interaction between cholera and travellers’ diarrhea vaccine and other commonly used travel vaccines, such as hepatitis A, hepatitis B, meningococcal and yellow fever vaccines. Refer to Timing of Vaccine Administration in Part 1 for additional general information.

Vaccine Safety and Adverse Events

Refer to Vaccine Safety Part 2 for additional general information.

Common and local adverse events

In a clinical trial, the most commonly reported adverse events following immunization with cholera and travellers’ diarrhea vaccine were: abdominal pain (16%), diarrhea (12%), nausea (4%) and vomiting (3%). These events are most likely due to the bicarbonate buffer used with the vaccine since they occurred with similar frequency when vaccine and buffer or buffer alone were given.

Less common and serious or severe adverse events

Anaphylaxis following vaccination with cholera and travellers’ diarrhea vaccine may occur but is very rare.

Globally over 7 million vaccine doses have been distributed. Events such as paraesthesia, dyspnea, urticaria, pruritus, angioedema, gastroenteritis, lymphadenitis, flu-like syndrome and hypertension have been reported very rarely (less than 1 per 10,000 doses distributed), and no causal relation has been established.

Guidance on reporting Adverse Events Following Immunization (AEFI)

Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event felt to be temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI. Refer to Box 1 in Vaccine Safety in Part 2 and Reporting Adverse Events Following Immunization (AEFI) in Canada for additional information about AEFI reporting.

Contraindications and precautions

Cholera and travellers’ diarrhea vaccine is contraindicated in persons with history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Refer to Table 1 in General Considerations in Part 1 for lists of all vaccines available for use in Canada and their contents.

Administration of Cholera and travellers’ diarrhea vaccine should be postponed in persons with moderate or severe acute illness or acute gastrointestinal illness. Persons with minor acute illness (with or without fever) may be vaccinated.

Refer to General Contraindications and Precautions in Part 2 for additional general information.

Drug-drug and drug-food interactions

Avoid oral administration of medicinal products or intake of food and/or drink for 1 hour before and 1 hour after Cholera and travellers’ diarrhea vaccine administration. Food and/or drink may increase acid production in the stomach and impair the effect of the vaccine.

Selected References

  • American Academy of Pediatrics. In: Pickering LK, Baker CJ, Kimberlin DW, et al. (editors). Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009.
  • Centers for Disease Control and Prevention. Health Information for International Travel 2012. The Yellow Book. Accessed July 2011 at: http://wwwnc.cdc.gov/travel/content/yellowbook/home-2010.aspx
  • Clemens JD, Sack DA, Harris JR et al. Cross-protection by B subunit-whole cell cholera vaccine against diarrhea associated with heat-labile toxin-producing enterotoxigenic Escherichia coli: results of a large-scale field trial. J Infect Dis 1988;158(2):372-77.
  • Clemens JD, Sack DA, Harris JR et al. Field trial of oral cholera vaccines in Bangladesh: results from three-year follow-up. Lancet 1990;335(8684):270-73.
  • Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on new oral cholera and travellers' diarrhea vaccination. Can Comm Dis Rep. 2005;31(ACS7):1-12.
  • Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on travellers' diarrhea. Can Comm Dis Rep. 2001;27(ACS3):1-12.
  • Crucell Vaccines Inc. Product Monograph - DUKORAL®. September 2011.
  • Ericsson CD, DuPont HL. Travelers' diarrhea: approaches to prevention and treatment. Clin Infect Dis 1993;16(5):616-24.
  • Peltola H, Siitonen A, Kyronseppa H et al. Prevention of travellers' diarrhoea by oral B-subunit/whole-cell cholera vaccine. Lancet 1991;338(8778):1285-89.
  • Pitzinger B, Steffen R, Tschopp A. Incidence and clinical features of traveler's diarrhea in infants and children. Pediatr Infect Dis J 1991;10(10):719-23.
  • Sanchez JL, Vasquez B, Begue RE et al. Protective efficacy of oral whole-cell/recombinant-B-subunit cholera vaccine in Peruvian military recruits. Lancet 1994;344(8932):1273-76.
  • Scerpella EG, Sanchez JL, Mathewson III JJ, et al. Safety, immunogenicity, and protective efficacy of the whole-cell/recombinant B subunit (WC/rBS) oral cholera vaccine against travelers' diarrhea. J Travel Med 1995;2(1):22-7.
  • Steffen R. Epidemiologic studies of travelers' diarrhea, severe gastrointestinal infections, and cholera. Rev Infect Dis 1986;8 (Suppl 2):S122-30.
  • World Health Organization. Cholera, 2006. Wkly Epidemiol Rec 2007;82:273–84.
  • World Health Organization. Cholera vaccines. Wkly Epidemiol Rec 2001;76(16):117-24.
  • World Health Organization. International and travel health, 2011. Chapter 6 - Vaccine preventable diseases and vaccines. Accessed June 2011 at: http://www.who.int/ith/chapters/ith2011chap6.pdf

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