ARCHIVED - Statement on New Oral Cholera and Travellers' Diarrhea Vaccination

Canada Communicable Disease Report
Volume 31 • ACS-7
1 July 2005

An Advisory Committee Statement (ACS)

Committee to Advise on Tropical Medicine and Travel (CATMAT)*?

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer( s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Introduction

This statement provides usage recommendations on the new oral cholera and enterotoxigenic Escherichia coli (ETEC) travellers' diarrhea vaccine for Canadian travellers.

Cholera

Infection with Vibrio cholerae, a toxin-producing bacteria, presents clinically as profuse watery diarrhea. If left untreated, severe fluid loss can lead to rapid dehydration and hypovolemic shock, which may be life threatening. Mortality ranges from > 50% for those without treatment to < 1% among adequately treated patients. Treatment consists of mainly oral or parenteral rehydration and antibiotics. The spectrum of disease is wide, with mild and asymptomatic cases occurring more frequently than do severe ones.

Cholera infection is associated with poor sanitation and is generally acquired from contaminated water or food, particularly undercooked or raw shellfish and fish. Two serogroups, O1 and O139 (Bengal), have been implicated in human epidemics. Within the serogroup O1 are the classical and the El Tor biotypes.

The seventh cholera pandemic began in 1961, when Vibrio 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, leading to an epidemic in other Amazon and Central American countries.

During the 1990s, a new strain of cholera, serogroup O139 (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, cholera cases are typically uncommon; in fact, only four were reported in 2002, and five were reported in 2003. Of these, all related to travel or immigration. No secondary transmission was noted, which is expected in countries such as Canada with modern sanitation, good hygiene, and clean water supplies.

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

Travellers' Diarrhea

Diarrhea is the most common medical problem affecting those who travel to developing countries and is characterized by the passage of three or more unformed stools in a 24-hour period. 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. Up to 50% of travellers from developed to developing countries can expect to have at least one episode of acute diarrhea during a 2-week stay, with 20% being confined to bed for a day^(1,2).

The risk of travellers' diarrhea varies with geographic region. For example, in the Caribbean and in Eastern and Southern Europe, the risk varies from 15% to 20%, whereas in Africa, Southeast Asia, and Latin America, the risk ranges from 20% to 50%⁽³⁾.

The most important determinants of risk for travellers' diarrhea is the travel destination and the type of travel (five-star accommodations vs. backpacking). The factors that may associate with a higher probability of acquiring travellers' diarrhea include gastric hypochlorhydria(4) and the relative lack of gut immunity seen in small children(5-7). In addition, specific groups of travellers are at an increased risk of serious consequences of travellers' diarrhea; specifically, those with chronic illnesses, such as immunodeficiency diseases, individuals with chronic renal failure, persons with congestive heart failure, individuals with insulin-dependent diabetes mellitus, and those with inflammatory bowel disease.

Contaminated food is the most common cause of travellers' diarrhea, and ETEC is most frequently associated with foodborne transmission; however, outbreaks of ETEC on cruise ships highlight the possibility of waterborne transmission(8). No food group can be regarded as "safe," and the sources of foodborne illness are numerous, including poorly cooked meat, contaminated raw vegetables, or unpasteurized dairy products. Food may stand for several hours at ambient temperatures, allowing for bacterial proliferation, or it may become contaminated by food handlers or the environment before being consumed.

Bacterial pathogens cause > 80% of cases of travellers' diarrhea. The most commonly isolated organisms include Escherichia coli, primarily ETEC strains, Campylobacter jejuni, Salmonella, and Shigella species^(9,10). Even though ETEC is the most commonly isolated bacteria in travellers' diarrhea, the incidence ranges from approximately 25% to 50% of cases overall but varies widely by geographic region^(11,9).

The prevention strategies for travellers' diarrhea include education about the ingestion of safe food and beverages, water purification, chemoprophylaxis with nonantibiotic drugs or antibiotics, and vaccination.

If prevention strategies fail, therapeutic options for travellers' diarrhea may include oral rehydration, dietary management, antimotility agents, and antibiotic treatment.

For more detailed information on epidemiology, etiology, prevention strategies, and therapy options, please visit the CATMAT Statement on Travellers' Diarrhea⁽⁷⁾.

Oral Cholera Vaccines: Preparations Licensed for Immunization

Two oral cholera vaccines are available in Canada:

1. Oral, live attenuated cholera vaccine, CVD 103-HgR (Mutacol^® ), is approved for use in adults and in children aged > 2 years. The 2002 Canadian Immunization Guide provides the information on this vaccine(12).

2. An oral, inactivated cholera vaccine, Dukoral^TM, was approved for use in Canada in 2003, for children aged ≥ 2 years and for adults. This vaccine comprises killed whole cell Vibrio cholerae (WC) and the non-toxic, recombinant cholera toxin B-subunit (BS). Through the BS component, the oral cholera vaccine, Dukoral^TM (BS-WC), has been shown to provide moderate, short-term protection against diarrhea caused by ETEC.

Note: This statement discusses the BS-WC oral cholera vaccine, Dukoral^TM, only.

Efficacy: Protection Against Cholera

A clinical trial conducted in adult volunteers from the U.S. (using an early formulation of the vaccine) demonstrated an overall efficacy of 64% against challenge with Vibrio cholerae O1 El Tor and complete (100%) protection against moderate to severe diarrhea⁽¹³⁾.

In Bangladesh, a large double-blind, placebo-controlled field trial (using an early formulation of the vaccine) demonstrated an efficacy of 85% against El Tor disease for the initial 6 months and 50% for the 3-year follow-up period⁽¹⁴⁾.

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 a cholera epidemic⁽¹⁵⁾. Note, there is no efficacy against the O139 Bengal strain of cholera⁽¹⁶⁾.

Efficacy: Protection Against ETEC Diarrhea

Many ETEC strains produce a heat-labile enterotoxin (LT) that is similar to cholera toxin. As a result, through the B-subunit, the BS-WC cholera vaccine provided moderate, short-term protection against diarrhea caused by ETEC^(17,18).

In the Bangladesh oral cholera vaccine field trial, the BS-WC vaccine demonstrated 67% protection against ETEC for 3 months⁽¹⁸⁾.

A prospective double-blind study of U.S. students in Mexico demonstrated a protective efficacy of approximately 50% against ETEC diarrhea⁽¹⁹⁾. Given the proportion of travellers' diarrhea caused by ETEC, it would be expected that the overall protection against travellers' diarrhea would be about 25%. Another prospective, double-blind study conducted among tourists who visited Morocco from Finland and who used the BS-WC vaccine showed efficacy against ETEC diarrhea of 52% and an overall protection against travellers' diarrhea of 23%⁽²⁰⁾.

Recommended Usage: Cholera

Travellers should take all the necessary precautions to avoid contact with, or ingestion of, potentially contaminated food or water because not all vaccine recipients will be fully protected against cholera. This is particularly true for travellers to areas where the O139 Bengal strain is endemic.

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

However, travellers who may be at a significant 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⁽²¹⁾. A detailed, travel-related risk assessment should be made to determine those travellers most likely to benefit from vaccination.

Recommended Usage: Travellers' Diarrhea

Indications for the oral BS-WC vaccine are limited because of the following: 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) < 50% (range 25% to 50%) of travellers' diarrhea cases are caused by ETEC bacteria; 4) the protection by the vaccine against ETEC diarrhea is approximately 50%; and 5) vaccinated travellers may gain a false sense of security and possibly avoid being as strict in observing food and water precautions.

In summary, vaccination with the BS-WC vaccine as a prevention strategy for travellers' diarrhea is of limited value and cannot be routinely recommended for the majority of travellers.

BS-WC vaccine may be considered for the following selected high-risk, short-term travellers who are aged > 2 years:

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

Conduct a detailed, individual travel-related risk assessment to determine those travellers who may benefit most from BS-WC vaccination as a prevention strategy for travellers' diarrhea.

The BS-WC vaccine provides short-term protection only (approximately 3 months) against ETEC diarrhea, so for the traveller at ongoing risk who has had the vaccine administered, consider the need for booster doses.

Schedule and Dosage

There are two schedules for this vaccine due to the two indications: cholera and ETEC travellers' diarrhea.

Cholera

Primary Immunization

• Adults and children aged > 6 years: 2 doses at intervals of at least 1 week but not greater than 6 weeks.
• Children aged 2 to 6 years: 3 doses at least 1 week apart but not greater than 6 weeks apart.

If > 6 weeks elapse between doses (for both children and adults), restart the primary immunization.

Booster dose(s)

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 aged > 6 years. For children aged 2 to 6 years, a single booster dose after 6 months is recommended.

ETEC Travellers' Diarrhea

Primary Immunization

• Adults and children aged ≥ 2 years: 2 doses at intervals of at least 1 week but not greater than 6 weeks. If > 6 weeks elapse between doses, restart the primary immunization.

Booster dose(s)

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.

The following recommendations apply for both cholera and ETEC indications of the oral BS-WC vaccine:

• If > 5 years have passed since the primary immunization or last booster dose, restarting the primary series is recommended.
• For children aged 2 to 6 years, one-half the amount of the buffer solution is discarded, and the remaining half is mixed with the entire contents of the vaccine solution.
• Protection against cholera and ETEC diarrhea can be expected approximately 1 week after completing the primary immunization⁽²²⁾.

Table 1 provides a summary of the schedule and dosage of BSWC vaccine.

Route of Administration and Storage

The 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. Dissolve the buffer granules in a glass of water (the water should be between 2° C to 27° C). Avoid using milk, juice, or other beverages. Shake the vaccine vial, and add the entire contents to the buffer solution. Avoid food and drink for 1 hour before and 1 hour after vaccine administration. If the vaccine and buffer mixture is not used immediately, store at room temperature (< 27° C) for up to 2 hours.

Refrigerate the vaccine (at a temperature of 2° C to 8° C) until used. The vaccine can be stored at room temperature (< 27° C) for up to 2 weeks on one occasion only. The buffer sachet may be stored at room temperature. (See product monograph for additional details.)

Simultaneous Administration with Other Vaccines

The administration of the oral BS-WC vaccine and oral typhoid capsules should be separated by at least 8 hours. The oral typhoid vaccine available in sachet form does not require separation from the oral BS-WC vaccine; however, the two vaccines should not be mixed in the same glass of water, because the buffer solutions differ(12).

Data are limited; nevertheless, because it is an inactivated vaccine, there is no known interaction between the use of the oral BS-WC vaccine and other commonly used travel vaccines, such as hepatitis A, hepatitis B, meningococcal, and yellow fever(23).

Adverse Reactions

In field trials in Bangladesh and Peru, the side effect profile did not differ significantly between the vaccine group and the placebo group(20,22,24). The most common reported adverse events were abdominal pain (16%), diarrhea (12%), nausea (4%), and vomiting (3%). Other adverse events, including headache, dizziness, and dyspnoea, have been reported rarely (< 1/100,000 doses distributed)(23); however, a causal relationship 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; therefore a history of allergy to raspberry is not a contraindication. Defer vaccination in the presence of any acute febrile illness or acute gastrointestinal illness.

Pediatric Use

BS-WC vaccine has been given to children between age 1 and 2 years in safety and immunogenicity studies; however, the protective efficacy has not been studied in children aged < 2 years, so it is not recommended in this age group.

Use in Pregnant and Nursing Women

Although the inactivated, oral BS-WC vaccine is not 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 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 Hosts

The BS-WC vaccine can be given to immunocompromised hosts, including those with HIV. However, immunocompromised persons may not obtain the expected immune response^(25-27).

Summary

Cholera

The BS-WC vaccine offers protection against serogroup O1 cholera. It does not protect against serogroup O139 (Bengal strain)^{[B 11]}.

The use of the BS-WC vaccine is not routinely recommended for the prevention of cholera for most travellers to endemic areas, and a detailed travel-related risk assessment should be used to detect travellers at increased risk of acquiring cholera (e.g. highrisk ex-patriots, such as relief and aid workers or health professionals working in endemic countries)^[C11].

Travellers' Diarrhea

The prevention strategies for travellers' diarrhea are as follows: 1) education about the ingestion of safe food and beverages[A 11]; 2) water purification[A11]; 3) chemoprophylaxis with nonantibiotic drugs or antibiotics[B11]; and 4) vaccination.

The BS-WC vaccine provides limited short-term protection (approximately 3 months) against diarrhea caused by ETEC^[A1].

Vaccination with BS-WC as a prevention strategy for ETEC travellers' diarrhea is of limited value and cannot be routinely recommended for the majority of travellers, based on the epidemiology, etiology, prevention strategies, and therapeutic options available ^[C111].

A detailed, individual travel-related risk assessment should be made to determine those travellers who may benefit most from BS-WC vaccination as a prevention strategy for travellers' diarrhea ^[C111].

References

1. Rendi-Wagner P, Kollaritsch H. Drug prophylaxis for travelers' diarrhea. Clin Infect Dis 2002;34(5):628-33.

2. Ericsson CD, DuPont HL. Travelers' diarrhea: approaches to prevention and treatment. Clin Infect Dis 1993;16(5):616-24.

3. Kollaritsch H. Traveller's diarrhea among Austrian tourists to warm climate countries: II. Clinical features. Eur J Epidemiol 1989;5(3):355-62.

4. Holt P. Severe salmonella infection in patients with reduced gastric acidity. Practitioner 1985;229(1409):1027-30.

5. 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.

6. Steffen R. Epidemiologic studies of travelers' diarrhea, severe gastrointestinal infections, and cholera. Rev Infect Dis 1986;8 (Suppl 2):S122-30.

7. Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on travellers' diarrhea. CCDR 2001; ACS-3:1-12.

8. Daniels NA, Neimann J, Karpati A et al. Traveler's diarrhea at sea: three outbreaks of waterborne enterotoxigenic Escherichia coli on cruise ships. J Infect Dis 2000;181(4):1491-5.

9. Vargas M, Gascon J, Gallardo F et al. Prevalence of diarrheagenic Escherichia coli strains detected by PCR in patients with travelers' diarrhea. Clin Microbiol Infect 1998;4(12):682-8.

10. Robins-Browne RM, Hartland EL. Escherichia coli as a cause of diarrhea. J Gastroenterol Hepatol 2002;17(4):467-75.

11. Jiang ZD, Lowe B, Verenkar MP et al. Prevalence of enteric pathogens among international travelers with diarrhea acquired in Kenya (Mombasa), India (Goa), or Jamaica (Montego Bay). J Infect Dis 2002;185(4):497-502.

12. National Advisory Committee on Immunization. Canadian Immunization Guide, 6th ed. Ottawa: Health Canada, 2002. Cat No. H49-8/2002E.

13. Black RE, Levine MM, Clements ML et al. Protective efficacy in humans of killed whole-vibrio oral cholera vaccine with and without the B subunit of cholera toxin. Infect Immun 1987;55(5):1116-20.

14. 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):270-3.

15. 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):1273-6.

16. Cholera vaccines. Wkly Epidemiol Rec 2001;76(16):117-24.

17. Svennerholm AM, Holmgren J. Oral vaccines against cholera and enterotoxigenic Escherichia coli diarrhea. Adv Exp Med Biol 1995;371B:1623-8.

18. 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):372-7.

19. Scerpella EG, Sanchez JL, Mathewson IJ 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.

20. Peltola H, Siitonen A, Kyronseppa H et al. Prevention of travellers' diarrhoea by oral B-subunit/whole-cell cholera vaccine. Lancet 1991;338(8778):1285-9.

21. Committee to Advise on Tropical Medicine and Travel (CATMAT) and the National Advisory Committee on Immunization (NACI). Preliminary conjoint statement on oral cholera vaccination. CCDR 1996;22(10):73-5.

22. Jertborn M, Svennerholm AM, Holmgren J. Evaluation of different immunization schedules for oral cholera B subunitwhole cell vaccine in Swedish volunteers. Vaccine 1993;11(10): 1007-12.

23. Dukoral Product Monograph. In; 2003.

24. Begue RE, Castellares G, Ruiz R et al. Community-based assessment of safety and immunogenicity of the whole cell plus recombinant B subunit (WC/rBS) oral cholera vaccine in Peru. Vaccine 1995;13(7):691-4.

25. Ortigao-de-Sampaio MB, Shattock RJ, Hayes P et al. Increase in plasma viral load after oral cholera immunization of HIVinfected subjects. Aids 1998;12(14):F145-50.

26. Lewis DJ, Gilks CF, Ojoo S et al. Immune response following oral administration of cholera toxin B subunit to HIV-1-infected UK and Kenyan subjects. Aids 1994;8(6):779-85.

27. Eriksson K, Kilander A, Hagberg L et al. Intestinal antibody responses to oral vaccination in HIV-infected individuals. Aids 1993;7(8):1087-91.

___________________________________

*Members: Dr. B.Ward (Chairperson), Dr. C. Beallor, M. Bodie-Collins (Executive
Secretary), Dr. K. Gamble, Dr. S. Houston, Dr. S. Kuhn, Dr. A. McCarthy, Dr. K.L. McClean, Dr. J. Plourde, Dr. J.R. Salzman.

Liaison Representatives: Dr. R.J. Birnbaum (CUSO), Dr. G. Dickinson (CAEP), Dr. C. Greenaway (CIDS), Dr. C. Hui (CPS), Dr. R. Saginur (CPHA), Dr. P. Teitelbaum (CSIH).

Ex-Officio Members: Dr. R. Corrin (HC), Dr. B. Dobie (CIC), Dr. N. Gibson (DND), Dr. J. Given (HC), Dr. P. McDonald (HC), Dr. M. Parise (CDC), S. Steele (CDC), Dr. M. Tepper (DND).

Member Emeritus: Dr. C.W.L. Jeanes.

?This statement was prepared by Dr. James Salzman and approved by CATMAT.