Page 3: Canadian Immunization Guide: Part 4 - Active Vaccines

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

Last complete chapter revision (see Table of Updates): April 2017

Key Information (refer to text for details)

What

  • Cholera:
    • is most often 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 (TD)
    • is transmitted by contaminated food and, less often, contaminated water
    • most episodes are mild and self-limited
  • Vaccine efficacy against all cause diarrhea is about 6%. 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 years to less than 6 years of age. Protection against ETEC travellers' diarrhea may last 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 may be at significantly increased risk of exposure (for example, humanitarian workers or health care providers 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.

How

  • Cholera prevention –
    • 6 years of age and older: 2 doses orally, 1 to 6 weeks apart
    • 2 to less than 6 years of age: 3 doses orally, 1 to 6 weeks apart
  • ETEC travellers' diarrhea prevention: 2 doses orally, 1 to 6 weeks apart
  • Booster doses may be administered, if indicated. The interval varies with age and indication.
  • Oral administration of medicinal products or intake of food or drink should be avoided for 1 hour before and 1 hour after vaccine administration.
  • Administration of cholera and travellers' diarrhea vaccine and oral typhoid vaccine should be separated 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.  Therefore, this vaccine is reserved for those who are the highest risk of infection only.
  • Not all recipients of this vaccine will be fully protected against cholera or travellers' diarrhea.

This chapter update was conducted in collaboration with the Committee to Advise on Tropical Medicine and Travel (CATMAT). Recommendations are based on CATMAT's Statement on Travellers' Diarrhea.

Significant revisions included in this chapter are highlighted in the Table of Updates to the Canadian Immunization Guide.

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. For additional information about Vibrio cholerae refer to the Pathogen Safety Data Sheet.

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. For additional information about Escherichia coli refer to the Pathogen Safety Data Sheet.

Reservoir

Humans and contaminated 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 natural or man-made disasters 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 (for example, 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 who are immunosuppressed
  • 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. The case fatality rate 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 and 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. Refer to the WHO map of areas reporting cholera outbreaks for additional information.

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 30 imported cases of cholera reported between 2008 and 2014. 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. 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. Since 2010, Haiti and the Dominican Republic have been experiencing a cholera epidemic. Since January 2016 outbreaks have increased in East and Southern Africa. For more information, refer to the Travel Health Notices for Cholera.

Preparations Authorized for Use in Canada

Cholera and travellers' diarrhea vaccine

  • DUKORAL® (inactivated, oral, travellers' diarrhea and cholera vaccine containing whole cell 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), Valneva Sweden AB (manufacturer) (Chol-Ecol-O).

For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canada's Drug Product Database.

Refer to Contents of Immunizing Agents Available for Use in Canada in Part 1 for a list of vaccines available for use in Canada and their contents.

Immunogenicity, Efficacy and Effectiveness

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.

Efficacy and effectiveness

Protection against cholera can be expected approximately 1 week after completion of primary immunization. For cholera, duration of protection is estimated to last for 2 years in persons 6 years of age and older, and 6 months in children 2 years to less than 6 years of age.

Protection against ETEC, if any, can be expected approximately 1 week after completion of primary immunization and may last as long as 3 months.

The pooled results from randomized controlled trials found a pooled RR of 0.94 and no increased benefit for preventing an episode of travellers' diarrhea during travel when comparing immunized individuals to those vaccinated with a placebo. Additionally, these studies found no difference in effect for prevention of travellers' diarrhea related to ETEC when compared to placebo.

Recommendations for Use

Travellers

Children (2 to 17 years of age) and adults (18 years of age and older)

Vaccination with cholera and travellers' diarrhea vaccine is of limited benefit and is not routinely recommended for most travellers. However, short-term travellers at high risk for health complications or serious inconvenience from travellers' diarrhea may find that the potential benefits of the vaccine based on their personal values and preferences, coupled with a low likelihood of adverse events may outweigh the burden of their risk. These include individuals:

  • for whom a brief illness cannot be tolerated (i.e., elite athletes, some business or political travellers);
  • with increased susceptibility to TD (e.g., due to achlorhydia, gastrectomy, history of repeated severe TD, young children > 2 years);
  • who are immunosuppressed due to HIV infection with depressed CD4 count or other immunodeficiency states;
  • with chronic illnesses for whom there is an increased risk of serious consequences from TD (e.g., chronic renal failure, congestive heart failure, insulin dependent diabetes mellitus, inflammatory bowel disease).

For travellers, prevention of cholera or travellers' diarrhea relies primarily on taking meticulous 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.

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

  • The overall protection provided by cholera and travellers' diarrhea vaccine against travellers' diarrhea is expected to be approximately 6%.
  • 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.
  • Vaccinated travellers may have a false sense of security and may not be as strict in observing food and water precautions.

Schedule

Table 1 summarizes the schedule for cholera and ETEC travellers' diarrhea immunization, by age.

Table 1: Immunization schedule for cholera and travellers' diarrhea vaccine, by indication and age
Immunization Cholera ETEC Travellers' Diarrhea General instructions
2 years to less than 6 years of age 6 years of age and older 2 years of age and older

Primary

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, repeat 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.

Refer to additional information contained within the product monograph available through Health Canada's Drug Product Database.

Booster doses and re-immunization

Table 1 summarizes the schedule for booster doses of cholera and travellers' diarrhea vaccine, by age.

Cholera

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

  • For children 2 years to less than 6 years of age: a booster dose may be offered every 6 months.
  • For people 6 years of age and older: a booster dose may be offered every 2 years; a complete primary series (2 doses) may be offered if the last dose was received more than 5 years previously.
ETEC travellers' diarrhea

Cholera and travellers' diarrhea vaccine may provide short-term protection (approximately 3 months) against ETEC diarrhea; therefore, if the traveller will be at ongoing risk, booster doses may 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 may be offered every 3 months.

Vaccination of Specific Populations

Pregnancy and breastfeeding

Cholera and travellers' diarrhea vaccine has not been studied in pregnant or breastfeeding women. Administration of this vaccine to pregnant women may be considered in high-risk situations only, such as an outbreak, after evaluation of the benefits and risks. This vaccine may be given to breastfeeding women.

Refer to Immunization in Pregnancy and Breastfeeding in Part 3 for additional information about vaccination of women who are pregnant or breastfeeding.

Persons with chronic diseases

Cholera and travellers' diarrhea vaccine may be considered for prevention of travellers' diarrhea in persons with chronic illnesses such as, chronic renal failure, congestive heart failure, insulin-dependent diabetes mellitus, and inflammatory bowel disease, for whom there is an increased risk of serious consequences from travellers' diarrhea.  However, vaccine benefits have not been studied in these specific groups.

Refer to Immunization of Persons with Chronic Diseases in Part 3 for additional information about vaccination of people with chronic diseases.

Immunocompromised persons

Cholera and travellers' diarrhea vaccine has not been studied in immunocompromised persons. Immunocompromised persons, including HIV-infected persons, may be immunized with cholera and travellers' diarrhea vaccine; however, the antibody response may be suboptimal. When considering immunization of an immunocompromised person with cholera and travellers' diarrhea vaccine, consultation with the individual's attending physician may be of assistance. For complex cases, referral to a physician with expertise in immunization or immunodeficiency is advised.

Refer to Immunization of Immunocompromised Persons in Part 3 for additional information about vaccination of people who are immunocompromised.

Vaccine Administration Practices

Dose

Cholera and travellers' diarrhea vaccine consists of a single dose vial of vaccine and a sachet of sodium hydrogen carbonate effervescent buffer granules.

Vaccine reconstitution

Cholera and travellers' diarrhea vaccine and buffer solution should be prepared according to the manufacturers' guidelines.

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 about pre-vaccination and post-vaccination counselling, vaccine preparation and administration technique, and infection prevention and control.

Concurrent administration of vaccines

The administration of cholera and travellers' diarrhea vaccine and oral typhoid vaccine capsules should be separated by at least 8 hours. 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, although data are limited.

Refer to Timing of Vaccine Administration in Part 1 for additional information about concurrent administration of vaccines.

Serologic testing

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

Storage and Handling Requirements

Cholera and travellers' diarrhea vaccine should be stored at +2°C to +8°C and should not be frozen. The vaccine can be stored at room temperature (less than +25°C) for up to 2 weeks on one occasion only, before opening. 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 +25°C) for up to 2 hours.

Refer to Storage and Handling of Immunizing Agents in Part 1 for additional information and recommendations.

Safety and Adverse Events

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, influenza-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 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 Reporting Adverse Events Following Immunization (AEFI) in Canada and Vaccine Safety in Part 2 for additional information about AEFI reporting.

Contraindications and precautions

Cholera and travellers' diarrhea vaccine is contraindicated in people with a history of anaphylaxis after previous administration of the vaccine, or proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Refer to Contents of Immunizing Agents Available for Use in Canada in Part 1 for a list of 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 Contraindications, Precautions and Concerns in Part 2 for additional information.

Drug-drug and drug-food interactions

Oral administration of medicinal products or intake of food or drink should be avoided for 1 hour before and 1 hour after cholera and travellers' diarrhea vaccine administration. Food or drink may increase acid production in the stomach and impair the effect of the vaccine.

Selected References

  • Ahmed T, Bhuiyan TR, Zaman K, Qadri F. Vaccines for preventing enterotoxigenic Escherichia coli (ETEC) diarrhoea. The Cochrane Library. 2011.
  • 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 2016. The Yellow Book. Accessed January 2017. Available from: https://wwwnc.cdc.gov/travel/page/yellowbook-home-2014
  • Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on travellers' diarrhea 2015. Accessed March 2016. Available from: http://www.phac-aspc.gc.ca/tmp-pmv/catmat-ccmtmv/diarrhea-diarrhee-eng.php#a11   
  • Valneva Sweden AB. Product Monograph - DUKORAL®. December 2015.
  • Public Health Agency of Canada. 2014. Notifiable Diseases On-Line. Accessed January 2017. Available from: http://diseases.canada.ca/notifiable/charts?c=yl
  • 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.
  • 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. International and travel health, 2015. Chapter 6 - Vaccine preventable diseases and vaccines. Accessed July 2015. Available from: http://www.who.int/ith/ITH_chapter_6.pdf?ua=1
  • World Health Organization. Cholera, 2006. Wkly Epidemiol Rec 2007;82:273–84.
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