Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Cholera Vaccine

Epidemiology Preparations approved for use in Canada Efficacy and immunogenicity Recommended usage Schedule and dosage Route of administration Booster doses and re-immunization

Serologic testing Storage requirements Simultaneous administration with other vaccines Adverse reactions Contraindications and precautions Other considerations Selected references

Cholera is an acute bacterial infection that presents as profuse, watery diarrhea. It is associated with rapid dehydration and occasionally hypovolemic shock, which may be life-threatening. The spectrum of disease is wide, with mild and asymptomatic illness occurring more frequently than severe disease. Cholera is caused by an enterotoxin produced by Vibrio cholerae. Two serogroups, 01 and 0139 (Bengal), have been implicated in human epidemics. Currently, serogroup 01 predominates worldwide. Within serogroup 01 are the classical and El Tor biotypes.

Case fatality ranges from 50% or more without treatment to less than 1% among adequately treated patients. Treatment consists mainly of oral or parenteral rehydration. Cholera infection is associated with poor sanitation and is generally acquired from contaminated water or food, particularly undercooked or raw shellfish and fish.

The ratio of symptomatic to asymptomatic cases varies from strain to strain. In El Tor infections, the ratio of symptomatic to asymptomatic cases (1:50) is much lower than in cholera infection due to the classical biotype (1:5). Humans are the only known natural host.

Changes since the publication of the 2002 Canadian Immunization Guide include 1) changes in preparations approved for use in Canada; 2) additional recommended usage for travellers' diarrhea; 3) new schedule and dosage table for the protection against cholera and enterotoxigenic Escherichia coli (ETEC); 4) changes to booster doses and re-immunization indications; and 5) information on the simultaneous administration with antibiotics or antimalarials.

Epidemiology

The seventh cholera pandemic began in 1961, when V. cholerae of the El Tor biotype spread through Southern Asia, the Middle East, Eastern Europe and, in 1970, Africa. In 1991, the El Tor biotype caused an outbreak in Peru, which led to an extensive epidemic in other Amazonian and Central American countries. In recent years there have been multiple cholera outbreaks related to mass population movement, especially at times of strife, such as within refugee camps in resource-poor countries.

During the 1990s in Asia, beginning in India and Bangladesh around the Bay of Bengal, there was an epidemic caused by a new strain of cholera, serogroup 0139. This epidemic spread to other countries in Asia but not outside the region.

In Canada, cholera cases are very uncommon. There were five cases of cholera 01/0139 reported in 2003 and three cases reported in 2004. All were related to travel or immigration. No secondary transmission was noted. The risk of transmission is low in countries such as Canada that have modern sanitation, good hygiene and clean water supplies.

For travellers, prevention relies primarily on care in the choice of food and water supply and in the use of good hygienic measures rather than on immunization.

Preparations approved for use in Canada

This chapter will deal only with vaccines that are currently marketed in Canada.

• Dukoral^™ (oral, inactivated travellers' diarrhea and cholera, [Chol-Ecol-O]), Sanofi Pasteur Ltd (distributor).

Dukoral^™ was approved for use in Canada in 2003 for children 2 years of age and older, and adults. This vaccine consists of killed V. cholerae and the non-toxic recombinant cholera toxin B-subunit. Through its beta-subunit (BS), Chol-Ecol-O vaccine has been shown to provide moderate, short-term protection against diarrhea caused by ETEC.

For a list of all approved products in Canada, please refer to Table 1 in the General Considerations chapter.

Efficacy and immunogenicity

Protection against cholera

A clinical trial in adult US volunteers (using an early formulation of the vaccine) demonstrated an overall efficacy against challenge with V. cholerae 01 El Tor of 64% but complete (100%) protection against moderate to severe diarrhea. A large, double-blind, placebo-controlled field trial (using an early formulation of the vaccine) was undertaken in Bangladesh, which demonstrated an efficacy of 85% against El Tor disease for the initial 6 months and 50% for the 3 year follow-up period. A double-blind, placebo-controlled field trial in Peru (using the currently licensed recombinant BS component of the vaccine) demonstrated an efficacy of 86% against epidemic cholera.

Of note is the observation that there is no efficacy against the 0139 Bengal strain of cholera.

Protection against ETEC diarrhea

Many ETEC strains produce a heat-labile enterotoxin that is similar to cholera toxin. As a result, through the B-subunit, the Chol-Ecol-O vaccine has been shown to provide moderate, short-term protection against diarrhea caused by ETEC.

In the Bangladesh oral cholera vaccine field trial, the Chol-Ecol-O vaccine demonstrated 67% protection against ETEC for 3 months.

A prospective, double-blind study involving US students in Mexico demonstrated that the vaccine had a protective efficacy of approximately 50% against ETEC diarrhea. Given the proportion of travellers' diarrhea caused by ETEC, the overall protection against this condition would be expected to be approximately 25%. This was demonstrated in another prospective, double-blind study of the Chol-Ecol-O vaccine conducted among tourists who went to Morocco from Finland. The study showed efficacy against ETEC diarrhea of 52% and an overall protection against travellers' diarrhea of 23%.

Recommended usage

Cholera

Travellers should take all the necessary precautions to avoid contact with or ingestion of potentially contaminated food or water since not all recipients of the vaccine will be fully protected against cholera. This is particularly true for travellers to areas where the 0139 Bengal strain is endemic.

The World Health Organization indicates that, since 1992, no country or territory has required a certificate of vaccination against cholera from international travellers. Most travellers following the usual tourist itineraries in countries affected by cholera are at extremely low risk of acquiring cholera infection.

Travellers who may be at significantly increased risk (e.g., high-risk ex-patriots such as relief and aid workers or health professionals working in endemic countries) may benefit from immunization. A detailed, travel-related risk assessment should be made to determine which travellers are most likely to benefit.

Travellers' diarrhea

Indications for the Chol-Ecol-O vaccine to prevent diarrhea are limited because 1) most episodes of travellers' diarrhea are usually mild and self-limited; 2) therapeutic options (oral rehydration, dietary management, antimotility and antibiotic treatment) are available if prevention fails; 3) less than 50% (range 25% to 50%) of travellers' diarrhea cases are caused by ETEC; 4) the protection against ETEC diarrhea is approximately 50%; and 5) vaccinated travellers may gain a false sense of security and may not be as strict in observing food and water precautions.

In summary, vaccination with the Chol-Ecol-O vaccine as a prevention strategy against travellers' diarrhea is of limited value and is not routinely recommended for the majority of travellers.

Chol-Ecol-O vaccine may be considered for selected high-risk, short-term travellers. These individuals would include people 2 years of age and over:

• 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;
• with an increased risk of acquiring travellers' diarrhea (e.g., young children 2 years of age and over, and people with gastric hypochlorhydria);
• who are immunosuppressed because of human immunodeficiency virus (HIV) infection or other immunodeficiency states;
• with a history of repeated severe travellers' diarrhea.

In addition, individuals for whom a brief illness cannot be tolerated (i.e., elite athletes, business or political travellers) may want to consider immunization.

A detailed, individual, travel-related risk assessment should be made to determine which travellers may benefit the most from Dukoral^™ vaccination as a prevention strategy for travellers' diarrhea.

As noted previously, the Chol-Ecol-O vaccine provides only short-term protection (approximately 3 months) against ETEC diarrhea, so for the traveller who has been vaccinated but is at ongoing risk, the need for booster doses should also be considered

Schedule and dosage

The schedule varies by whether protection is sought against cholera or ETEC and by age, as shown in Table 1.

Protection against cholera and ETEC diarrhea can be expected approximately 1 week after completion of the primary immunization.

Table 1. Summary of Schedule and Dosage of Chol-Ecol-O vaccine

Route of administration

Chol-Ecol-O vaccine consists of a whitish suspension in a single-dose glass vial along with a sodium hydrogen carbonate effervescent granule buffer that has a raspberry flavour. The buffer granules should be dissolved in a glass of water that is at a temperature between +2° and +27° C. Do not use milk, juice or other beverages. The vaccine vial should be shaken, and the entire contents should be added to the buffer solution. Food and drink must be avoided for 1 hour before and 1 hour after vaccine administration. If the vaccine and buffer mixture is not used immediately, it can be stored at room temperature (but below + 27° C) for up to 2 hours.

Booster doses and re-immunization

Cholera

An optimal booster dose or interval has not been established. However, if indicated, the manufacturer recommends a single booster after 2 years for adults and children older than 6 years. For children 2 to 6 years of age, a single booster dose after 6 months is recommended.

ETEC travellers' diarrhea

An optimal booster dose or interval has not been established. However, if indicated, the manufacturer recommends a single booster dose every 3 months for those at ongoing risk.

Serologic testing

There is no indication for pre- or post-immunization serology.

Storage requirements

The Chol-Ecol-O vaccine should be kept refrigerated (at a temperature of +2° to +8° C) until used. The vaccine can be stored at room temperature, but below + 27° C, for up to 2 weeks on one occasion only. The buffer sachet may be stored at room temperature.

Simultaneous administration with other vaccines

The administration of the Chol-Ecol-O vaccine and oral typhoid capsules should be separated by at least 8 hours. The administration of oral typhoid vaccine available in sachet form does not need to be separated from Chol-Ecol-O vaccine, but the two vaccines should not be mixed in the same glass of water because they use a different buffer solution.

There are limited data, but the Chol-Ecol-O vaccine is an inactivated vaccine, and there is no known interaction between it and other commonly used travel vaccines, such as hepatitis A, hepatitis B, meningococcal and yellow fever vaccines.

Adverse reactions

In field trials of Chol-Ecol-O vaccine in Bangladesh and Peru, the side effect profile for the vaccine group was similar to that of the placebo group. The most commonly reported adverse events included abdominal pain (16%), diarrhea (12%), nausea (4%) and vomiting (3%). Serious adverse events, such as dizziness and dyspnea, have been reported very rarely (< 1/100,000 doses distributed), and a causal relation has not been established.

Contraindications and precautions

A history of an anaphylactic reaction to a previous dose of the vaccine or hypersensitivity to any component of the vaccine is an absolute contraindication to vaccination. The buffer solution uses an artificial raspberry flavouring, and therefore a history of allergy to raspberry is not a contraindication.

Vaccination should be deferred in the presence of any acute febrile illness or acute gastrointestinal illness.

Pediatric use

Chol-Ecol-O vaccine has been given to children between 1 and 2 years of age in studies of safety and immunogenicity, but because the protective efficacy has not been studied in children less than 2 years of age, it is not recommended in this age group.

Use in pregnant and nursing women

Although the inactivated, Chol-Ecol-O vaccine would not be expected to have any adverse effects, its safety in pregnancy has not been directly studied. Therefore, the benefits of vaccine must be carefully weighed against any potential adverse effects before it is given to pregnant women.

Although there are no data, it is reasonable to assume that this vaccine can be used safely in nursing mothers.

Use in immunocompromised persons

The Chol-Ecol-O vaccine can be given to immunocompromised persons, including those with HIV. However, immunocompromised persons may not obtain the expected immune response.

Other considerations

Simultaneous administration with antibiotics or antimalarials

Since the Chol-Ecol-O vaccine is not a live vaccine there is no anticipated interaction or interference when co-administered with antibiotics or antimalarials.

Selected references

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. Journal of Infectious Diseases 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. Canada Communicable Disease Report 2005;31(ACS7):1-12.

Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on travellers' diarrhea. Canada Communicable Disease Report 2001;27(ACS3):1-12.

Ericsson CD, DuPont HL. Travelers' diarrhea: approaches to prevention and treatment. Clinical Infectious Diseases 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. Pediatric Infectious Disease Journal 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. Journal of Travel Medicine 1995;2(1):22-7.

Steffen R. Epidemiologic studies of travelers' diarrhea, severe gastrointestinal infections, and cholera. Reviews of Infectious Diseases 1986;8 (Suppl 2):S122-30.

World Health Organization. Cholera vaccines. Weekly Epidemiological Record 2001;76(16):117-24.

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