Typhoid vaccine: Canadian Immunization Guide
Key Information
What
- Typhoid fever is caused by *Salmonella enterica- subspecies enterica serovar Typhi (S. typhi).
- S. typhi is generally transmitted through ingestion of food and water contaminated with the feces of people with the disease or who are chronic S. typhi carriers.
- Clinical course ranges from mild illness with low grade fever to severe systemic disease with abdominal perforation and extra-intestinal infection that, if untreated, may be fatal.
- There are 2 authorized typhoid vaccines: parenteral (Typh-I) and oral (Typh-O). These vaccines provide approximately 50% protection against clinical disease.
- Protection following Typh-I vaccine lasts for 3 years; protection following Typh-O vaccine lasts for about 7 years.
- The most commonly reported adverse events following immunization with Typh-I vaccine are injection site reactions (pain, swelling); the most commonly reported adverse events following receipt of Typh-O vaccine are abdominal pain, nausea, diarrhea, vomiting, fever, headache and rash.
Who
- Typhoid immunization is recommended for most persons, 2 years of age and older, travelling to South Asia including Afghanistan, Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan and Sri Lanka.
- Typhoid immunization is not routinely recommended for travel outside of South Asia; however, it might be considered for travellers to other areas, such as Africa, based on individual-specific risk factors and personal preference.
- Typhoid immunization is recommended for laboratory personnel at risk of exposure to S. typhi and for people in close contact with S. typhi carriers.
How
- A single 0.5 mL dose of Typh-I vaccine should be administered for people 2 years of age and older when indicated.
- One capsule of Typh-O should be taken on alternate days to a total of 4 capsules of vaccine for people 5 years of age and older. Typh-O vaccine should be taken approximately 1 hour before, or 2 hours after a meal.
- Typh-O vaccine is contraindicated in individuals with an acute gastrointestinal condition and in immunocompromised persons, including those with known HIV infection.
- Administration of oral cholera vaccine and Typh-O vaccine should be separated by at least 8 hours.
- Typh-O vaccine may be given concomitantly with or at any time before or after any parenteral vaccine.
- Typh-I vaccine and other travel vaccines may be given concomitantly.
Why
- The World Health Organization (WHO) has estimated that there are 21 million cases of typhoid per year. About 2% to 5% of untreated typhoid cases become chronic carriers.
- The case fatality rate is approximately 10% for untreated cases in low income settings and less than 1% for patients receiving care in high income countries.
This chapter update was conducted in collaboration with the  Recommendations are based on CATMATs .
Epidemiology

# Disease description
Infectious agent
Typhoid fever is caused by a bacterium, *Salmonella enterica- subspecies enterica serovar Typhi (S. typhi). It is a subset of the clinical syndrome known as enteric fever, caused by several *Salmonella- species. The clinical presentation is similar for all of these species; however the vaccine is only active against S.typhi. For additional information about , refer to the Pathogen Safety Datasheet.
Reservoir
Humans
Transmission
S. typhi is generally transmitted through ingestion of food and water contaminated with the feces of people with the disease or those who are chronic S. typhi carriers. The incubation period is usually 8 to 14 days (range, 3 days to more than 60 days). Individuals infected with S. typhi are infectious as long as they are excreting the bacilli, usually from the first week of infection until symptoms have resolved. However, 10% of untreated individuals excrete the bacilli for 3 months or more after initially contracting the disease and 2% to 5% of untreated individuals become asymptomatic chronic carriers.
Risk factors
The overall risk of developing typhoid during travel to typhoid endemic countries is very low (less than 1 case per 100,000 travellers). The strongest and most consistent predictor of typhoid risk in travellers is destination of travel. The estimated risk of developing travel-associated typhoid is about: 1 in 3,000 travellers for travel to South Asia (high risk), 1 in 50,000 to 100,000 travellers for travel to Sub-Saharan Africa, North Africa, the Middle East and South America (intermediate risk), and less than 1 in 300,000 travellers for travel to the Caribbean, Central America and Eastern Mediterranean (low risk).
It is known that people with anatomic or functional asplenia (that is, from sickle cell disease) are at increased risk of severe disease from encapsulated bacteria. Several studies have identified travelling children, longer duration of travel, the presence of achlorhydria or use of acid suppression therapy, and travellers visiting friends or relatives, as factors that increase the risk of travel-associated typhoid. The incremental magnitude of risk that these factors contribute in addition to travel destination is unclear.
Although immunocompromised conditions, such as HIV infection, are recognized to predispose to more severe and complicated infections, in general they do not appear to be associated with an increased risk of S. typhi infection.
In Canada, chronic S. typhi carriers pose the greatest public health risk, particularly when they are working in the food industry.
Spectrum of clinical illness
Typhoid fever is a systemic illness of varying severity. The clinical course ranges from mild illness with low grade fever to severe systemic disease with abdominal perforation and extra-intestinal infection that, if untreated, may be fatal. Symptoms may include fever, headache, abdominal pain, nausea, vomiting, malaise, anorexia, bradycardia, splenomegaly, cough, rose spots on the trunk, and constipation. The case fatality rate is approximately 10% for untreated cases in low income settings and less than 1% for patients receiving care in high income countries. Between 2% and 5% of typhoid cases become chronic carriers, sometimes shedding bacteria in stool for years.

# Disease distribution

## Incidence and prevalence
Global
S. typhi infection continues to be a chief cause of enteric disease and remains a significant public health issue in low and middle income countries, principally among children. The WHO estimates the global incidence of typhoid fever to be 21 million cases per year, with 222,000 associated deaths annually. Globally, it is estimated that more than 90% of typhoid cases and deaths occur in Asian countries, predominantly in South Asia.
The incidence of typhoid fever in high income countries is low at <15 cases per 100,000 persons per year. The majority of cases of typhoid fever in these countries occur among travellers returning from endemic areas in low and middle income countries.
National
In Canada, where most cases of typhoid occur in travellers, there was a mean of 144 cases of typhoid reported annually (2004 to 2013), with a mean incidence rate of 0.43 per 100,000 population. In a recent study in Quebec, more than 90%of typhoid cases reported by international travellers were people who were travelling for the purpose of visiting family members or friends living abroad.
Preparations Authorized for Use in Canada
Typhoid-containing vaccines
- TYPHIM Vi (*Salmonella- typhi Vi capsular polysaccharide vaccine for injection), Sanofi Pasteur SA (manufacturer), Sanofi Pasteur Ltd. (distributor) (Typh-I)
- Vivotif (live, oral, attenuated TY21A typhoid vaccine),PaxVax Berna GmbH. (manufacturer), Crucell Vaccines Inc. (distributor) (Typh-O)
There are no authorized vaccines to protect against S. paratyphi infection (paratyphoid).
For complete prescribing information, consult the product leaflet or information contained within the product monograph available through Health Canadas .
Immunogenicity, Efficacy and Effectiveness

# Immunogenicity
Typh-I vaccine 
Immunity following Typh-I vaccine is thought to last for 3 years. 
Typh-O vaccine
Protective antibodies are detectable for about 7 years following receipt of Typh-O vaccine.

# Efficacy and effectiveness
Efficacy of typhoid vaccine, both oral and intramuscular formulations, in preventing typhoid is approximately 50%. Evidence suggests that oral typhoid vaccine provides some protection against paratyphoid; however, the evidence is insufficient to recommend the off-label use of typhoid vaccine for this indication.
Recommendations for Use

# Travellers

## Children (2 to 17 years of age) and adults (18 years of age and older)
Typh-I vaccine is indicated for persons 2 years of age and older and Typh-O vaccine may be used in people 5 years of age and older who are travelling to endemic areas.
Most Canadian travellers visiting South Asia (including Afghanistan, Bangladesh, Butan, India, Maldives, Maldives, Nepal, Pakistan and Sri Lanka) should be offered typhoid vaccine. The risk of typhoid is highest for persons travelling to India, Pakistan, and Bangladesh. Data suggest that most cases of typhoid occur when travellers stay more than 2 weeks.
The decision of whether to immunize a traveller for destinations other than South Asia (for example, Africa) should be carefully balanced against the presence of other factors that may increase the risk of travel-associated typhoid: travelling children; travellers visiting friends and relatives; longer duration of travel and prolonged exposure to potentially contaminated food and water; anatomic or functional asplenia (including sickle cell anemia), the presence of achlorhydria or the use of acid suppression therapy; and personal preference.
Immunization is only modestly effective against typhoid and provides no protection against other fecal-oral diseases; therefore, all travellers should be advised to adhere to basic sanitation and food and water precautions irrespective of whether they are immunized against typhoid.
Contacts of chronic carriers
Typhoid immunization is recommended for individuals with ongoing or intimate exposure (for example, family member) to a chronic carrier of S. typhi.

# Schedule
Typh-I vaccine
Persons 2 years of age and older for whom the vaccine is indicated should receive a single 0.5 mL dose intramuscularly at least 14 days prior to potential exposure.
Typh-O vaccine
Persons 5 years of age and older for whom the vaccine is indicated should take 1 capsule on alternate days to a total of 4 capsules. All 4 capsules must be taken for optimal protection. Minor variations in dosing schedule are not expected to affect efficacy. However, if it is necessary to repeat the series because of a longer interval between doses (more than 1 week), the administration of an additional full course of vaccine is not harmful. The capsules should be administered in accordance with the instructions in the manufacturers product leaflet. Immunization (i.e. ingestion of all 4 capsules) should be completed at least 7 days prior to potential exposure. 
- Individuals with an acute gastrointestinal condition and in immunocompromised persons.
Based on the Committee to Advise on Tropical Medicine and Travel (CATMAT) Statement on International Travellers and Typhoid. Can Commun Dis Rep 2014;40(4).
Re-immunization should be carried out if a person remains at risk in conditions of repeated or continuous exposure. There is no data on continued protection in travellers.
This recommendation is consistent with the Health Canada's vaccine authorization for re-immunization every 7 years.

# Booster doses and re-immunization
Periodic booster doses in persons at continued risk of typhoid may be expected to increase antibody titres and to maintain protection. Booster doses should be offered when a person remains at risk in conditions of repeated or continuous exposure. For Typh-I vaccine, a booster dose should be administered every 3 years. For Typh-O vaccine, a booster of 4 doses should be administered every 7 years.

## Outbreak control
Typhoid immunization is not routinely recommended for the control or containment of typhoid outbreaks in Canada.
Vaccination of Specific Populations

# Pregnancy and breastfeeding
No information is available on the safety of Typh-I vaccine in pregnancy; however, there is no theoretical reason to suspect an increased risk from inactivated vaccines, such as Typh-I vaccine. Typhoid vaccine should be considered in pregnant women, when indicated for travel to endemic areas, the presence of risk factors, and personal preference. Breastfeeding women may be given inactivated Typh-I vaccine.
Before immunization of pregnant women with Typh-O vaccine, the benefits of administration must be carefully weighed against potential adverse events. Typh-O vaccine should only be used in pregnancy when there is a high risk of infection and Typh-I vaccine is not available. It is not known if the live bacteria or any other component of Typh-O vaccine can pass into breast milk.

# Immunocompromised persons
Typh-I vaccine may be administered to immunocompromised persons if indicated; however, an adequate response may not be achieved. When considering immunization of an immunocompromised person with Typh-I vaccine, consultation with the individual's health care provider may be of assistance. For complex cases, referral to a health care provider with expertise in immunization or immunodeficiency is advised. Typh-O vaccine should not be given to immunocompromised persons, including those with known HIV infection.

## Household contacts
Household contacts of immunocompromised persons may receive Typh-O vaccine; healthy persons vaccinated with Typh-O vaccine do not shed vaccine-strain organisms in their stool and secondary transmission to contacts does not occur.

# Workers
Typhoid vaccine is recommended for laboratory personnel regularly working with S. typhi. Technicians working in routine microbiology laboratories do not need to be vaccinated with typhoid vaccine.
Vaccine Administration Practices

# Dose
Each dose of Typh-I vaccines is 0.5 mL. 
Each dose of Typh-O vaccine is 1 capsule.

# Route of administration
Typh-I vaccine 
 should be administered intramuscularly. Typh-O vaccine should be administered orally; it can be self-administered.

# Interchangeability of vaccines
Although there are no data regarding the interchangeability of typhoid vaccines, it is presumed that boosting can be performed with any of the available formulations, regardless of the vaccine used initially. The boosting interval should correspond to the interval established for the preceding vaccine.

# Concurrent administration with other vaccines
The administration of oral cholera and travellers diarrhea vaccine and Typh-O vaccine capsules should be separated by at least 8 hours; Typh-O vaccine can be given concomitantly with or at any time before or after any parenteral vaccine. There is no known interaction between Typh-I vaccine and other travel vaccines, such as hepatitis A vaccine, yellow fever vaccine and hepatitis B vaccine.

# Serologic testing
Serologic testing is not recommended before or after receiving typhoid vaccine.
Storage and Handling Requirements
Typhoid vaccines should be stored at +2C to +8C and should not be frozen. Typh-O vaccine should be protected from light, moisture and high humidity.
Safety and Adverse Events

# Common and local adverse events
Typh-I vaccine
Common adverse events (1% to 10% of vaccine recipients) include: injection site tenderness, induration, redness or pain, fever, headache, general malaise or myalgia.
Typh-O vaccine
Common adverse events include: abdominal pain, nausea, diarrhea, vomiting, fever, headache and rash. 

## Less common and serious or severe adverse events
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association. Anaphylaxis following vaccination with typhoid vaccine is very rare.

## Guidance on reporting Adverse Events Following Immunization (AEFI)
Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event temporally related to vaccination. An unexpected AEFI is an event that is not listed in available product information but may be due to the immunization, or a change in the frequency of a known AEFI.

# Contraindications and precautions
Typhoid vaccine is contraindicated in people with a history of anaphylaxis after previous administration of the vaccine and in people with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container.
Typh-O vaccine is contraindicated in individuals with an acute gastrointestinal condition and in immunocompromised persons.
Administration of typhoid vaccine should be postponed in persons with severe acute illness. Persons with minor acute illness (with or without fever) may be vaccinated.

## Drug-drug and drug-food interactions
The Typh-O vaccine series should be finished at least 3 days before commencing, or initiated at least 3 days after completing, treatment with sulphonamides or other antibiotics active against S. typhi, or antimalarials. Exceptions include chloroquine, mefloquine and atovaquone/proguanil (MALARONE), as these antimalarials do not affect the immune response to Typh-O vaccine and can be administered at the same time as, or at any interval before or after Typh-O vaccine.
Typh-O vaccine should be taken approximately 1 hour before, or 2 hours after a meal. Alcoholic beverages should not be consumed 1 hour before or 2 hours after taking Typh-O vaccine.
Typh-I or Typh-O vaccines can be given before, concurrently with, or after immunoglobulin or other blood products.