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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)*
Statement on New Oral Cholera
and Travellers' Diarrhea
Vaccination
PDF Version
12 Pages - 179 KB
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
(http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/01vol27/27sup/acs3.html)(7).
Oral Cholera Vaccines: Preparations Licensed for
Immunization
Two oral cholera vaccines are available in Canada:
- 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).
- An oral, inactivated cholera vaccine, DukoralTM,
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™ (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, DukoralTM, 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.
TheWorld 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.
Table 1. Summary of schedule and dosage of
BS-WC vaccine |
|
Cholera |
ETEC |
|
|
Adults and children aged > 6 years |
Children aged 2 to 6 years |
Adults and children aged ≥ 2 years |
General instructions |
Primary Immunization |
2 doses at least 1 week but < 6 weeks apart |
3 doses at least 1 week but < 6 weeks apart |
2 doses at least 1 week but < 6 weeks apart |
If > 6 weeks elapse between doses, restart the primary immunization.
Children aged 2 to 6 year: one-half the amount of buffer solution
is discarded, and the remaining part is mixed with the entire
contents of the vaccine vial. |
Booster |
1 dose after 2 years |
1 dose after 6 months |
1 dose tous les 3 mois en cas de risque continu |
If > 5 years have passed since primary immunization or the
last booster dose, restart primary series. |
ETEC = enterotoxigenic Escherichia coli |
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.
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Rendi-Wagner P, Kollaritsch H. Drug
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Black RE, Levine MM, Clements ML et al. Protective
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Clemens JD, Sack DA, Harris JR et al. Field
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Sanchez JL, Vasquez B, Begue RE et al. Protective
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Clemens JD, Sack DA, Harris JR et al. Cross-protection
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Scerpella EG, Sanchez JL, Mathewson IJ et al. Safety,
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Jertborn M, Svennerholm AM, Holmgren J. Evaluation
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Ortigao-de-Sampaio MB, Shattock RJ, Hayes P et al.
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___________________________________
*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.
[Canada Communicable Disease Report]
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