Vaccine-Preventable Diseases

Cholera

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 disease is caused by an enterotoxin produced by Vibrio cholerae. Two serogroups, 01 and 0139 (Bengal), have been implicated in human epidemics. Within the serogroup 01 are the classical and El Tor biotypes.

Mortality ranges from 50% or more without treatment to < 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 spectrum of disease is wide, with mild and asymptomatic cases occurring more frequently than severe ones. The ratio of symptomatic to asymptomatic cases varies from strain to strain. In El Tor infections, this ratio (1:50) is much lower than in cholera infection due to the classical biotype (1:5). Humans are the only known natural host.

Cholera is a quarantinable disease subject to international health regulations. It must be reported to the World Health Organization (WHO) within 24 hours through Health Canada's Division of Quarantine, Travel and Migration Health. The Division must be contacted immediately in the event of a suspected case, at 613-957-3236 (after hours, telephone the medical officer on call at 613-545-7661).

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.

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

In Canada, three cholera cases were reported in 1998; preliminary surveillance data indicate that there were none in 1999 and five (unconfirmed) in 2000. Between 1993 and 1997 there were 23 reported cases of the biotype El Tor or Ogawa. Although travel history was not given for all cases, the reported destinations included El Salvador, Mexico, the Dominican Republic, India and Pakistan. Many of these people had travelled to private homes. No secondary transmission was noted, which is as expected in countries such as Canada that have modern sanitation, good hygiene and clean water supplies, and a low risk of transmission.

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 Licensed for Immunization

Oral, live attenuated cholera vaccine, CVD 103-HgR (Mutacol^®), is licensed in Canada for use in adults and children > 2 years. Cloned strains of V. cholerae are used in its preparation. The vaccine also contains aspartame (a phenylalanine derivative), which is added as a sweetener. The buffer solution contains sodium bicarbonate, ascorbic acid and lactose, which serve to neutralize gastric acid.

There is no cholera vaccine currently available that has been shown to protect against the 0139 Bengal strain in South Asia.

CVD 103-HgR has not been shown to offer protection against enterotoxigenic Escherichia coli (ETEC)-associated diarrhea, which is a common cause of diarrhea in travellers. An experimental oral vaccine containing cholera toxin B-subunit and whole inactivated cholera bacteria (BS-WC), which is not currently licensed in Canada, may offer some protection against ETEC-associated diarrhea as well as against cholera.

A combined, live attenuated oral cholera/typhoid vaccine (Colertif Berna^®) is licensed but not currently distributed in Canada.

Parenteral, inactivated cholera vaccine offers short, limited effectiveness and is not recommended for Canadians travelling to endemic areas.

Note: This chapter will deal only with the oral cholera CVD 103-HgR vaccine.

Efficacy and Immunogenicity

Seroconversion rates over 90% have been reported after a single, oral dose of the vaccine, occurring as early as 8 days after administration and lasting for 6 months. Efficacy studies have been carried out in volunteers challenged with pathogenic V. cholerae of both biotypes and serotypes. Protection against the classic biotype was demonstrated among 82% to 100% of subjects, and protection against the El Tor biotype among 62% to 67% of subjects exposed. However, even when the vaccine did not provide complete protection, no volunteer lost > 1 litre of diarrheal fluid in 24 hours.

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

Recommended Usage

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 0139, for which there is no vaccine, is endemic.

The WHO indicates that since 1992 no country or territory has required a certificate of immunization against cholera. Cholera immunization is no longer required or recommended for the vast majority of Canadian travellers. People following the usual tourist itineraries in countries affected by cholera are at virtually no risk of acquiring infection.

Travellers who may be at increased risk (e.g., health professionals working in endemic areas or workers in refugee camps) may benefit from immunization. A detailed, individual risk assessment should be made in order to determine likely candidates.

Route of Administration

The oral cholera vaccine is administered as a single dose with the provided buffer solution, mixed as a drink in cold or lukewarm water. It should be taken 1 hour before food or drink.

Booster Doses and Re-Immunization

An optimal booster dose or interval has not yet been established. The manufacturer recommends a repeat dose every 6 months, if indicated.

Serologic Testing

There is no indication for pre- or post-immunization serologic testing.

Storage Requirements

CVD 103-HgR should be stored at a temperature between 2° and 8° C in a dry place and be protected from light; it should not be frozen. The reconstituted vaccine should be ingested as soon after mixing as possible.

Simultaneous Administration with Other Vaccines

The administration of oral typhoid vaccine (Ty21a) capsules and oral cholera vaccine should be separated by at least 8 hours. The newer form of the same oral typhoid vaccine available in a sachet form does not need to be separated from the oral cholera vaccine, and the two can be given together, mixed with a single sachet of buffer.

There is no problem anticipated with the concomitant administration of oral cholera vaccine with killed vaccines. The concomitant administration of oral polio vaccine (no longer used in Canada) or yellow fever vaccine does not interfere with the immune response to oral cholera vaccine.

Adverse Reactions

Randomized controlled trials involving several thousand subjects have been carried out in a number of cholera-endemic and non-endemic areas, and have demonstrated good safety of the CVD 103-HgR (Mutachol^®) vaccine. The side effect profile was similar in the placebo and vaccine groups and included nausea, abdominal cramps and diarrhea, all of which were mild in nature and of short duration.

Contraindications and Precautions

Hypersensitivity to the vaccine or the buffer components is a contraindication to further doses. Patients with phenylketonuria must be aware that the vaccine contains aspartame (a phenylalanine derivative), at 17 mg of phenylalanine per double-chamber sachet. The vaccine should not be given during an acute febrile illness or to any person with acute gastrointestinal disease.

Excretion of vaccine organisms is minimal, and spread to contacts of vaccinees is unlikely.

Pediatric use: Because the safety of the oral cholera vaccine has not been established in children < 2 years of age, the product is not recommended for this age group.

Use in pregnant women and nursing mothers: There are no data on the safety of the vaccine in pregnancy. Since it is a live vaccine, it should be used with caution in pregnant and nursing women. A risk/ benefit analysis should be carried out to determine whether an individual in these groups should be immunized. It is not known if the vaccine is excreted in human milk.

Use in immunocompromised hosts: There are no data on the safety of the vaccine in such groups, and the vaccine should be used with caution in the immunocompromised or immunosuppressed. An individual risk assessment should be carried out to determine the indications for immunization.

Other Considerations

Simultaneous administration with antibiotics or antimalarials: Antibiotics may interfere with the effectiveness of the vaccine. People receiving therapy with antibiotics should wait 7 days after the completion of therapy before taking the oral cholera vaccine.

Antimalarial prophylaxis, specifically chloroquine and doxycycline, may interfere with the effectiveness of the vaccine, and therefore antimalarial prophylaxis with these medications should start no sooner than 7 days after administration of the oral cholera vaccine.

Antimalarial prophylaxis with mefloquine or proguanil does not interfere with the effectiveness of the oral cholera vaccine and therefore can be administered simultaneously.

Summary of Recommendations

1. Oral cholera vaccine (CVD 103 HgR) offers protection against serogroup 01. It does not protect against serogroup 0139 (Bengal strain).

2. The use of CVD 103 HgR is not routinely recommended for the prevention of cholera in the majority of travellers to endemic areas, and a detailed, individual risk assessment should be used to detect a traveller at increased risk of acquiring cholera (e.g., aid workers or health care professionals working in endemic areas).

3. CVD 103 HgR has not been shown to offer protection against ETEC-associated travellers' diarrhea.

4. Travellers are advised to follow the CATMAT recommendations for the prevention and treatment of travellers' diarrhea.

Selected References

Committee to Advise on Tropical Medicine and Travel and the National Advisory Committee on Immunization. Statement on oral cholera vaccination. CCDR 1998;24(ACS-5).

Committee to Advise on Tropical Medicine and Travel. Statement on traveller's diarrhea. CCDR 2001;27(ACS-3).

Cyrz SJ, Levine MM, Kaper JB et al. Randomized, double-blind, placebo-controlled trial to evaluate the safety and immunogenicity of the live cholera vaccine strain CVD-HgR in Swiss adults. Vaccine 1990;8:577-80.

Drug monograph. Mutachol Berna^® vaccine - cholera vaccine live oral attenuated CVD 103-HgR manufactured by Swiss Serum and Vaccine Institute Berne. Distributed by Berna Products Corporation, March 1, 2000.

Kotloff KL, Wasserman SS, O'Donnell S et al. Safety and immunogenicity in North Americans of a single dose of live oral cholera vaccine CVD 103-HgR: results of a placebo-controlled, double-blind crossover trial. Infect Immun 1992;60:4430-32.

MacPherson DW, Tonkin M. Cholera vaccination: a decision analysis. Can Med Assoc J 1992;146:1947-52.

Peltola H, Siitonen A, Kyronseppa H et al. Prevention of traveller's diarrhea by oral B-subunit/ whole-cell cholera vaccine. Lancet 1991;338:1285-89.

Sack DA, Cadoz M. Cholera vaccines. In Plotkin SA, Orestein WA. Vaccine. 3^rd edition. Philadelphia: W.B. Saunders, 1999:639-49.