Canada Communicable Disease Report
Vol. 24 (ACS-5)
1 December 1998

An Advisory Committee Statement (ACS)
Committee to Advise on Tropical Medicine and Travel (CATMAT)*

STATEMENT ON ORAL CHOLERA VACCINATION

Introduction

Infection with Vibrio cholerae, a toxin-producing bacteria, presents clinically as profuse watery diarrhea. If untreated, severe fluid loss can lead to rapid dehydration, cardiovascular system collapse, and kidney failure. The spectrum of illness is wide, with both mild and asymptomatic cases occurring more frequently than severe disease. Two serogroups, O1 and O139 (Bengal) have been implicated in human epidemics. Within the serogroup O1 are the classical and El Tor biotypes.

Cholera infection is associated with poor sanitation, often due to inadequate sewage and water treatment facilities in non-industrial countries. Infection is generally acquired from contaminated water or food, particularly undercooked or raw shellfish and fish.

In 1997, no cases of cholera were reported in Canada. In 1996, four cases were reported. These were all related to foreign travel and did not result in any secondary spread.

For the traveller, emphasis must be placed on personal hygiene, and food and water precautions; these measures appear to be the most effective protection against cholera.

Cholera Vaccine

The World Health Organization indicates that, since 1992, no country or territory has required a certificate of vaccination against cholera from international travellers.

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

Oral Cholera Vaccine

Oral live attenuated cholera vaccine, CVD 103-HgR (Mutachol^®) has recently been licenced in Canada. Cloned strains of V. cholerae are used to prepare the live attenuated vaccine. 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 given 1 hour before food or drink. It is approved for adults and children > 2  years of age.

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.

Safety

Randomized controlled studies have been carried out in several thousand subjects in a number of cholera-endemic and non-endemic areas, and have demonstrated good safety of the vaccine^(1-5).

Immunogenicity

Several studies have shown a good immune response with seroconversion rates > 90% following a single oral dose of the vaccine^(1-7). Seroconversion occurred as early as 8 days after administration of the vaccine and lasted for 6 months.  

Protective efficacy of the vaccine was tested in volunteers challenged with pathogenic V. cholerae of both biotypes and serotypes. Complete protection against the classical biotype was demonstrated in 82% to 100% of subjects, and in 62% to 67% of subjects exposed to the El Tor biotype. However, even when the vaccine did not provide complete protection, no volunteer lost > 1 L diarrheal fluid/24 hours.

No cholera vaccine currently available has been shown to be protective against the O139 Bengal strain that emerged in south Asia starting in 1992.

Adverse reactions

The side-effect profile for the vaccine group was similar to the control (placebo) group. Adverse reactions were mild in nature and of short duration. They included nausea, abdominal cramps, and diarrhea^(1-5).

Booster dose

An optimal booster dose or interval has not yet been established⁽⁷⁾. However, the manufacturer recommends that a repeat dose be given every 6 months if indicated.

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).

The vaccine should not be given during an acute febrile illness or to any person with acute gastrointestinal disease.

Since it is a live vaccine, it should be used with caution in immunocompromised or immunosupppressed individuals, pregnant women, or nursing mothers. A risk/benefit analysis should be used to determine if an individual in these groups should be immunized. It is not known whether the vaccine is excreted in human milk.

The safety and efficacy of the vaccine has not been established in children < 2 years of age and therefore it is not recommended for use in this age group.

Antibiotics may interfere with the effectiveness of the vaccine. It is recommended that individuals on antibiotic therapy 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.

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

The concomitant administration of oral polio vaccine or yellow fever vaccine does not interfere with the immune response to oral cholera vaccine.

Oral Cholera Vaccination in the Prevention of Travellers' Diarrhea

The oral cholera vaccine (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. However, an experimental vaccine containing B-subunit/whole-cell oral cholera vaccine, which is not currently licenced in Canada, may offer some protection against ETEC-associated diarrhea⁽⁸⁾.

Cholera Disease Risk Assessment

Most travellers visiting an area where cholera occurs are at very low risk of acquiring infection. The estimated risk of cholera disease in European or North American travellers to endemic areas is one to two cases per million trips⁽⁹⁾. Travellers who may be at increased risk for acquiring cholera (e.g. health professionals working in endemic areas or aid workers in refugee camps) may benefit from vaccination. A detailed, individual risk assessment should be made in order to determine which travellers may benefit from vaccination.

Recommendations

Table 1 below presents evidence-based medicine categories for the strength and quality of the evidence for each of the recommendations that follow.

1. Parenteral, inactivated cholera vaccine offers short limited effectiveness and is not recommended for the prevention of cholera in travellers to endemic areas (D II).

2. The use of oral cholera vaccine is not recommended for the prevention of cholera in the majority of travellers to endemic areas (C II).

3. A detailed, individual risk assessment should be used to detect a traveller at increased risk for acquiring cholera (e.g. aid workers or health professionals working in endemic areas) who may benefit from vaccination (C II).

4. Oral cholera vaccine (CVD 103-HgR) has not been shown to offer protection against ETEC-associated travellers' diarrhea (D II).

5. Travellers are advised to follow the CATMAT recommendations for the prevention and treatment of travellers' diarrhea⁽¹¹⁾ (B I).

Table 1 Strength and quality of evidence summary sheet⁽¹⁰⁾

References

1. Cryz 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 103-HgR in Swiss adults. Vaccine 1990;8:577-80.

2. 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.

3. Levine MM, Herrington D, Losonsky G et al. Safety, immunogenicity, and efficacy of  recombinant live oral vaccines, CVD 103 and CVD 103-HgR. Lancet 1988;2:467-70.

4. Su-Arehawaratana P, Singharaj P, Taylor DN et al. Safety and immunogenicity of different immunization regimens of CVD 103-HgR live oral cholera vaccine in soldiers and civilians in Thailand. J Infect Dis 1992;165:1042-48.

5. Suharyono, Simanjuntak C, Witham N et al. Safety and immunogenicity of single-dose live oral cholera vaccine CVD 103-HgR in 5 to 9 year old Indonesian children. Lancet 1992;340:689-94.

6. Kaper JB, Morris JG, Levine MM. Cholera. Clin Microbiology Rev 1995;8:48-86.

7. Tacket CO, Losonky G, Nataro JP et al. Onset and duration of pro- tective immunity in challenged volunteers after vaccination with live oral cholera vaccine CVD 103-HgR. J Infect Dis 1992;166:837-41.

8. 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.

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

10. MacPherson DW. Evidence-based medicine. CCDR 1994;20:145-47.

11. Committee to Advise on Tropical Medicine and Travel. Statement on travellers' diarrhea. CCDR 1994;20:149-55.

* Members: Dr. K. Kain (Chairman); H. Birk; M. Bodie-Collins (Executive Secretary); Dr. S.E. Boraston; Dr. H.O. Davies; Dr. K. Gamble; Dr. L. Green; Dr. J.S. Keystone; Dr. K.S. MacDonald; Dr. J.R. Salzman; Dr. D. Tessier.

Ex-Officio Members: Dr. E. Callary (HC); R. Dewart (CDC); Dr. E. Gadd (HC); Dr. C.W.L. Jeanes; Dr. H. Lobel (CDC); Dr. A. McCarthy (DND).

Liaison Representatives: Dr. R. Birnbaum (CSIH); S. Kalma (CUSO); Dr. V. Marchessault (CPS); Dr. H. Onyette (CIDS); Dr. R. Saginur (CPHA); Dr. F. Stratton (ACE); Dr. B. Ward (NACI).

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