Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Typhoid Vaccine

Epidemiology Preparations approved for use in Canada Efficacy and immunogenicity Recommended usage Schedule and dosage Route of administration Booster doses and re-immunization

Serologic testing Storage requirements Simultaneous administration with other vaccines Adverse reactions Contraindications and precautions Other considerations Selected references

Typhoid fever is caused by Salmonella typhi, which differs from most other Salmonella species in that it infects only humans and frequently causes severe systemic illness. The organism is generally transmitted through food contaminated with the feces or urine of people with the disease or those who are S. typhi carriers. The fatality rate is approximately 16% for untreated cases and 1% for those given appropriate antibiotic therapy. Between 2% and 5% of typhoid cases become chronic carriers, sometimes shedding bacteria in stool for years. The risk of severe illness is increased in people with depressed immunity (e.g., due to HIV) or decreased gastric acid levels.

There are no key changes in the recommendations for typhoid immunization since the publication of the 2002 Canadian Immunization Guide. A second Salmonella typhi Vi (virulence) capsular polysaccharide vaccine is now available in Canada. A combined Vi capsular polysaccharide typhoid vaccine and inactivated hepatitis A vaccine became available in September 2005. Increasingly, strains of S. typhi are found to be resistant to one or more of the antibiotics routinely used in treatment, particularly for infections acquired in the Indian subcontinent.

Epidemiology

In endemic areas (such as Africa [with the exception of South Africa], Asia [except for Singapore and Japan], the Middle East [except Israel and Kuwait], Central and South America, the Dominican Republic and Haiti in the Caribbean) typhoid fever has long been considered a disease that has its greatest impact in individuals 5 to 19 years of age. Age-specific incidence rates vary from one country to another, however, and significant illness and numbers of deaths have been reported in children < 5 years of age in some settings. Several factors may contribute to an apparently lower risk in very young children, including age-specific changes in the immune response, atypical or milder disease in this population and under-reporting. Whatever the cause(s), the observation is important in light of our incomplete knowledge of vaccine immunogenicity and efficacy in this age group.

The incidence of typhoid fever is very low in the industrialized world. An average of 70 cases have been reported annually in Canada over the past 5 years. The low incidence rate in industrialized countries is attributable to overall good living conditions, in particular the high quality of drinking water and sewage treatment. The rates were achieved without vaccines, and vaccination has no ongoing role in disease control.

The greatest risk of typhoid infection for Canadians occurs while they are travelling in countries where sanitation is likely to be poor. However, not all travellers in these countries are at markedly increased risk. Indeed, the risk of suffering from typhoid fever in many settings in developing countries is minimal (e.g., business-class hotels, conference centres and resort hotels). The greatest risk appears to be associated with exposures to food and water in uncontrolled settings (e.g., market stalls, street vendors, home restaurants and family settings). Even relatively short visits with friends and family can put Canadian travellers (the so-called "visiting friends and relatives" or VFR group) at substantial risk of typhoid in some areas.

Regardless of the setting, typhoid immunization is not a substitute for careful selection and handling of food and water. The available vaccines provide only 50% to 55% protection and do not prevent disease in those who ingest a large number of organisms. However, immunization may reasonably be expected to reduce the risk of typhoid fever among otherwise healthy travellers in areas where this disease is either endemic or epidemic.

Preparations approved for use in Canada

This chapter will deal only with vaccines that are currently marketed in Canada

Three types of typhoid vaccine are currently available for protection against typhoid fever.

Parenteral, capsular polysaccharide vaccines (Typh-I)

• Typhim Vi^®, produced by Sanofi Pasteur Ltd. Each 0.5 mL dose of vaccine contains 25 µg of purified polysaccharide.
• Typherix^®, produced by GlaxoSmithKline Inc. Available as a single dose of 0.5 mL containing 25 µg of the Vi polysaccharide of Salmonella typhi.

Each is an injectable solution of Vi antigen prepared from the capsular polysaccharide of S. typhi strain TY2.

Combined vaccine

• ViVaxim™, produced by Sanofi Pasteur Ltd, combines purified Vi polysaccharide typhoid vaccine in solution (25 µg of the Vi polysaccharide typhoid vaccine) and inactivated hepatitis A vaccine in suspension (160 antigen units) in a single-dose, dual chamber syringe.

Oral, live attenuated vaccines (Typh-O)

• Vivotil^®, produced by Berna Biotech. Enteric-coated capsules (four doses containing lyophilized bacteria).
• Vivotif L^®, produced by Berna Biotech. Foil sachets (three doses of lyophilized bacteria).

Both oral formulations contain buffer to enhance passage of the attenuated bacteria through the gastric acid barrier. The vaccines contain the attenuated strain S. typhi Ty21a, which was produced by chemical mutagenesis. This bacterium has lost some virulence factors and replicates for only a limited period of time in human hosts.

For a list of all approved products in Canada, please refer to Table 1 in the General Considerations chapter.

Efficacy and immunogenicity

Typh-I Vaccines

The parenteral vaccine stimulates a specific antibody response (i.e., ≥ 4-fold rise in antibody titre) in about 93% of healthy adults. Controlled trials have demonstrated that the serologic response to vaccine is correlated with protective efficacy. Two randomized, double-blind, controlled field trials of Typh-I in disease-endemic areas have demonstrated protective efficacy rates of 55% (95% confidence interval [CI] 30%-71%). The efficacy of immunization with Typh-I has not been systematically studied in people from industrialized countries who travel to disease-endemic regions or in children < 5 years of age. Typh-I has not been tested among children < 1 year of age. Its protective efficacy in people previously immunized with earlier parenteral formulations or the oral vaccine is unknown. Although antibody titres fall with time after vaccination, immunity following Typh-I is thought to last for 2 to 3 years.

In some regions of the world, virulent but Vi-negative strains of S. typhi have been reported. Typh-I would not be expected to protect against these rare isolates.

Typh-O Vaccines

Live, attenuated Typh-O vaccines stimulate a cell-mediated immune response, as well as inducing both secretory and humoral antibody. Healthy subjects do not shed vaccine-strain organisms in their stool. As a result, secondary transmission to contacts does not occur. Despite the limited capacity of the vaccine-strain organism to replicate, individuals who are immunocompromised should not receive Typh-O vaccines. In studies delivering at least three doses of the enteric-coated capsular form of the vaccine in typhoid endemic regions, a protective efficacy of 51% (95% CI 35%-63%) can be expected. Although less information is available from field trials about the oral formulation supplied in sachets, the available data suggest that three doses of this formulation are at least as effective as four doses of the capsular form. The oral vaccines appear to be less effective for disease prevention in children 5 to 9 years of age (17%-19%) than in older children and adults (54%-72% among 10- to 19-year-olds). Protective antibodies after the administration of three doses of vaccine are detectable for 3 to 4 years and may persist for longer periods in some individuals.

There are no data on the efficacy or duration of protection in travellers from industrialized countries, or in children < 5 years (capsular formulation) or < 3 years of age (liquid formulation). Neither are there reports regarding the protective efficacy of the oral formulations in people previously immunized with parenteral vaccines. The activity of the Typh-O vaccines against the rare Vi-negative isolates is unknown.

Recommended usage

Routine typhoid immunization is not recommended in Canada. However, selective immunization should be considered in the following groups:

• Travellers who will have prolonged (> 4 weeks) exposure to potentially contaminated food and water, especially those travelling to or working in small cities, villages or rural areas in countries with a high incidence of disease. Individuals billeted with or visiting families in such areas may be at particularly high risk. Immunization is not routinely recommended for business travel or short-term (< 4 weeks) holidays in resort hotels in such countries.
• Travellers with reduced or absent gastric acid secretion.
• People with ongoing household or intimate exposure to an S. typhi carrier.
• Laboratory workers who frequently handle cultures of S. typhi. Technicians working in routine microbiology laboratories do not need to receive this vaccine.

Typhoid immunization is not routinely recommended for workers in sewage plants, for controlling common-source outbreaks, for people attending rural summer or work camps or for people in non-endemic areas experiencing natural disasters such as floods. It is not recommended for the control or containment of typhoid outbreaks in Canada. Typhoid vaccine does not confer complete protection against disease, and immunity may be overwhelmed by a large inoculum of S. typhi. Therefore, it is necessary to warn travellers that immunization is only an additional preventive measure against typhoid fever in high-risk situations and that care in the selection of food and water remains of primary importance.

Schedule and dosage

Table 14. Comparison of Typh-O, Typh-I and Combined Vi and Hepatitis A Vaccines

Route of administration

Typhoid vaccine is available in two formats. The live vaccine is taken orally in a series of doses. The Vi capsular polysaccharide vaccine is administered as a single 0.5 mL intramuscular injection.

Typh-I vaccines

Adults and children ≥ 2 years of age should receive a single dose of 0.5 mL (25 µg) intramuscularly.

Combined purified VI polysaccharide typhoid and inactivated hepatitis A vaccine

Persons ≥ 16 years of age should receive a single dose of 1.0 mL of the mixed vaccine administered intramuscularly.

Typh-O vaccine, capsular formulation

For adults and children > 5 years of age, one enteric-coated capsule (Vivotil^®, Berna vaccine) should be taken on alternate days to a total of four capsules. Each capsule should be taken on an empty stomach with a liquid no warmer than 37° C. All four capsules must be taken for optimal protection.

Typh-O vaccine suspension, supplied in double-chambered foil sachets

The suspension packaged in a double-chambered foil sachet (Vivotif L^®, Berna vaccine) is approved for use in adults and children ≥ 3 years of age. Each package contains three double-chambered foil sachets with lyophilized vaccine in one half and buffer in the other half. The contents of both halves of one sachet must be mixed with liquid no warmer than 37º C; it must not be mixed in milk, juice or in a carbonated beverage.

The sachet contents should be re-suspended by gently mixing for 5 to10 seconds and then should be swallowed as soon after mixing as possible. The diluted vaccine-buffer mix should be taken on an empty stomach (e.g., 1 hour before a meal). This procedure is repeated on alternate days for a total of three doses. All three doses must be taken for optimal protection.

Comments applicable to both oral formulations

Antibiotics with activity against S. typhi or other Salmonella (e.g., broad-spectrum penicillins or cephalosporins, fluoroquinolones, trimethoprim-sulfamethoxazole) may interfere with replication of the vaccine-strain bacterium. For people receiving therapy with such antibiotics, immunization must be deferred until at least 48 hours after the antibiotic course has been completed. Typh-O is killed in vitro by mefloquine at levels achievable in the gut and to a lesser extent by chloroquine and proguanil. Ideally, typhoid immunization should be completed before anti-malarial prophylaxis is initiated. If immunization must occur while one or another of these antimalarials is being taken, at least 8 hours should separate the administration of oral vaccine and the antimalarial.

Booster doses and re-immunization

Relatively few data are available to guide recommendations for either the frequency or timing of booster doses in Canadians residing abroad and in travellers. Nonetheless, periodic booster doses in those at continued risk is reasonable and may be expected to increase antibody titres and protection. Administer every 2-3 years for the parenteral formulation and every 7 years for the oral formulations. 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.

Minor variations in dosing schedule are not expected to affect the efficacy of either of the oral typhoid formulations. However, if it is deemed necessary to repeat the series because of long intervals between doses (> 4 days), the administration of an additional full course of vaccine would not be harmful. Although compliance can be an issue with these products because they are self-administered, recent evidence suggests that most travellers take the vaccines competently if properly instructed.

Serologic testing

There is no indication for pre- or post-immunization serology.

Storage requirements

All typhoid vaccines should be maintained at a temperature of +2 C to +8 C until used.

Simultaneous administration with other vaccines

Although all possible combinations have not been specifically studied, there is no known interaction between the Typh-I vaccines and a number of other relevant travel vaccines, such as hepatitis A vaccine, yellow fever vaccine and hepatitis B vaccine. The concomitant administration of yellow fever vaccine does not suppress the immune response elicited by Typh-O vaccines.

Adverse reactions

The Typh-I vaccines are far less reactogenic than the previous parenteral (whole bacterium) product. A meta-analysis suggests that local reactions (e.g., pain, redness, swelling) can be expected in approximately 4% of vaccinees (95% CI 1.3%-10%), whereas only about 1% report systemic effects such as fever (95% CI 0.1%-12.3%). Virtually all of the available data regarding adverse events following immunization with the Vi polysaccharide vaccine have been acquired in studies of children and young adults (age < 25 years).

The reported adverse events following oral immunization are also relatively rare and mild. Local reactions, such as vomiting (2.1%: 95% CI 0.6%-7.8%) and diarrhea (5.1%: 95% CI 1.7%-14.5%) seldom prevent completion of the course of immunization. Low-grade fever can be expected in approximately 2% of vaccinees (95% CI 0.7%-5.3%). Recent case reports raise the possibility that the Ty21a vaccines may, very rarely, predispose vaccinees to reactive arthritis.

Contraindications and precautions

Contraindications

The only contraindication to administration of the Typh-I vaccines is a history of a severe local or systemic reaction to a previous dose of the vaccine. Similarly, the Typh-O vaccines are contraindicated in individuals with hypersensitivity to any component of the vaccine or the enteric-coated capsule. The oral vaccines should not be given to anyone with an acute gastrointestinal condition or inflammatory bowel disease. Typh-O vaccines should also not be administered to persons with phagocytic function disorders, including chronic granulomatous disease, leukocyte adhesion defect and myeloperoxidase deficiency.

Precautions

• Pediatric use: The Typh-I vaccines can be used in children ≥ 2 years. The combined (Vi polysaccharide typhoid and inactivated hepatitis A vaccine) may be administered to those ≥ 16 years. The Typh-O vaccine in capsular format can be administered to children > 5 years of age, and the Typh-O vaccine in sachet (suspension) format may be administered to children aged ≥ 3 years.
• Immunization in pregnant women and nursing mothers: Although the Typh-I vaccines would not be expected to have any adverse effects, their safety in pregnancy has not been directly studied. Therefore, the benefits of vaccine must be carefully weighed against any potential adverse effects before Typh-I injectable vaccine is given to pregnant women. The Typh-O live attenuated vaccines should not be given to pregnant women. Although there are no data, it is reasonable to assume that either vaccine could be used safely in nursing mothers.
• Immunization of immunocompromised persons: The Typh-O vaccines should not be given to immunocompromised or immunosuppressed people, including those with known HIV infection. Note that these concerns for immunocompromised persons are purely theoretical, and no case of disseminated infection with the attenuated bacterium has been reported. The limited capacity of the attenuated strain to replicate in the human host is primarily due to the degree of its attenuation rather than the host's immune status.

Other considerations

• Individuals with decreased gastric acid barriers (e.g., due to achlorhydria, medications that reduce gastric acidity, antacid abuse) who travel to typhoid endemic regions should be offered either parenteral or oral immunization.
• Typhoid immunization may also be considered in a control program to limit a typhoid fever epidemic (e.g., in closed communities, refugee settings).
• Typhoid immunization in non-travelling Canadians is ONLY recommended for individuals regularly working with this organism in clinical or research laboratories and in family members and close contacts of a chronic carrier of S. typhi.

Selected references

Acharya IL, Lowe CU, Thapa R et al. Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi. New England Journal of Medicine 1987;317(18):1101-4.

Barnett ED, Chen R. Children and international travel: immunizations. Pediatric Infectious Disease Journal 1995;14(11):982-92.

Beeching NJ, Clarke PD, Kitchin NR et al. Comparison of two combined vaccines against typhoid fever and hepatitis A in healthy adults. Vaccine 2004;23(1):29-35.

Begier EM, Burwen DR, Haber P, Ball R, the Vaccine Adverse Event Reporting System Working Group. Postmarketing safety surveillance for typhoid fever vaccines from the Vaccine Adverse Event Reporting System, July 1990 through June 2002. Clinical Infectious Diseases 2004;38(6):771-79.

Cambell JD, Levine MM. Typhoid and cholera vaccines. In: Jong EC, Zuckerman JN, eds. Travelers' vaccines. Hamilton, Ontario: Decker Inc, 2004:162-84.

Centers for Disease Control and Prevention. Health information for international travel. U.S. Department of Health and Human Services, 2005:291-307.

Committee to Advise on Tropical Medicine and Travel (CATMAT). Statement on overseas travellers and typhoid. Canada Communicable Disease Report 1994;20(8):61-2. URL: <http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/94pdf/cdr2008.pdf>.

Cryz SJ Jr. Post-marketing experience with live oral Ty21a vaccine. Lancet 1993;341(8836):49-50.

Cryz SJ Jr. Patient compliance in the use of Vivitif Berna™ vaccine, typhoid vaccine, live oral Ty21a. Journal of Travel Medicine 1998;5(1):14-7.

Engels EA, Falagas ME, Lau J et al. Typhoid fever vaccines: a meta-analysis of studies on efficacy and toxicity. British Medical Journal 1998;316(7125):110-16.

Engels EA, Lau J. Vaccines for preventing typhoid fever. Cochrane Database of Systematic Reviews 2000;2:CD001261.

Horowitz H, Carbonaro CA. Inhibition of the Salmonella typhi oral vaccine strain, TY21a, by mefloquine and chloroquine. Journal of Infectious Diseases 1992;166(6):1462-64.

Ivanoff B, Levine MM, Lambert PH. Vaccination against typhoid fever: present status. Bulletin of the World Health Organization 1994;72(6):957-71.

Keitel WA, Bond NL, Zahradnik JM et al. Clinical and serological responses following primary and booster immunization with Salmonella typhi Vi capsular polysaccharide vaccines. Vaccine 1994;12(3):155-59.

Keystone JS, Kozarsky PE, Freedman DO et al. Travel medicine. Elsevier, 2004.

Klugman KP, Gilbertson IT, Koornhof HJ et al. Protective activity of Vi capsular polysaccharide vaccine against typhoid fever. Lancet 1987;2(8569):1165-69.

Levine MM, Ferreccio C, Abrego P et al. Duration of efficacy of Ty21a, attenuated Salmonella typhi live oral vaccine. Vaccine 1999;17(Suppl 2):S22-27.

Levine MM, Ferreccio C, Black RE et al. Large scale field trial of Ty21a live oral typhoid vaccine in enteric-coated capsule formulation. Lancet 1987;1(8541):1049-52.

Levine MM, Ferreccio C, Cryz S et al. Comparison of enteric-coated capsules and liquid formulation of Ty21a typhoid vaccine in randomized controlled field trial. Lancet 1990;336(8720):891-94.

Levine MM, Taylor DN, Ferreccio C. Typhoid vaccines come of age. Pediatric Infectious Disease Journal 1989;8(6):374-81.

Lin FY, Ho VA, Khiem HB et al. The efficacy of a Salmonella typhi Vi conjugate vaccine in two-to-five year old children. New England Journal of Medicine 2001;344(17):1263-69.

Loebermann M, Kollaritsch H, Ziegler T. A randomized, open-label study of the immunogenicity and reactogenicity of three lots of a combined typhoid fever/hepatitis A vaccine in healthy adults. Clinical Therapeutics 2004;26(7):1084-91.

Mahle WT, Levine MM. Salmonella typhi infection in children younger than 5 years of age. Pediatric Infectious Disease Journal 1993;12(8):627-31.

Parry CM, Hien TT, Dougan G et al. Typhoid fever. New England Journal of Medicine 2002;347(22):1770-82.

Sinha A, Sazawal S, Kumar R et al. Typhoid fever in children aged less than 5 years. Lancet 1999;354(9180):734-37.

Steinberg EB, Bishop R, Haber P et al. Typhoid fever in travelers: Who should be targeted for prevention? Clinical Infectious Diseases 2004;39(2):186-91.

Taylor DN, Levine MM, Kuppens L et al. Why are typhoid vaccines not recommended for epidemic typhoid fever? Journal of Infectious Diseases 1999;180(6):2089-90.

World Health Organization. Immunizations, vaccines and biologicals - typhoid vaccine. URL: <http://www.who.int/vaccines/en/typhoid.shtml>.

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