Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Diphtheria Toxoid

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 Selected references

Diphtheria is an acute, communicable disease caused by exotoxin-producing strains of the bacterium Corynebacterium diphtheriae. Symptoms result from local infection of the respiratory tract, which may lead to breathing difficulties, or infection of the skin or mucosal surfaces, or from dissemination of diphtheria toxin, which damages the heart and central nervous system. The case-fatality rate remains at about 5% to 10%, the highest death rates occurring among the very young and the elderly. About 3%-5% of healthy persons may be asymptomatically colonized on the skin or in the nasopharynx with C. diphtheriae, making eradication of the disease difficult.

Since the publication of the 2002 Canadian Immunization Guide changes include 1) a recommendation for adolescents aged 14-16 years of age to be vaccinated with tetanus toxoid, diphtheria toxoid and acellular pertussis (Tdap); and 2) a new recommendation about subsequent vaccinations of persons known to have developed Guillain-Barré Syndrome (GBS) within 8 weeks of a previous tetanus vaccine dose.

Epidemiology

Routine immunization against diphtheria in infancy and childhood has been widely practised in Canada since 1930. In 1924, there were 9,000 cases reported, the highest annual number ever recorded in Canada (see Figure 2). At the same time diphtheria was one of the most common causes of death in children from 1 to 5 years of age. By the mid-1950s, routine immunization had resulted in a remarkable decline in the morbidity and mortality of the disease. Toxigenic strains of diphtheria bacilli are detected each year, although classic diphtheria is rare. In Canada, there are 0 to 5 isolates reported each year. In developed countries occasional cases of imported diphtheria are identified.

Serosurveys of healthy adult populations in Canada indicate that approximately 20% of those surveyed (higher in some age groups) do not have protective levels of antibody to diphtheria. The potential for disease re-emergence if immunization levels are allowed to fall was demonstrated during the 1990s in the Commonwealth of Independent States (former Soviet Union), where over 140,000 cases and 4,000 deaths were reported.

Preparations approved for use in Canada

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

• Adacel^® (tetanus and diphtheria toxoids adsorbed combined with component pertussis vaccine, [Tdap]), Sanofi Pasteur Ltd.
• DT Polio Adsorbed (diphtheria and tetanus toxoids adsorbed and inactivated poliomyelitis vaccine), Sanofi Pasteur Ltd.
• Pentacel^® (Act-HIB^® [Haemophilus b conjugate vaccine (tetanus protein conjugate)] reconstituted with Quadracel^®, [DTaP-IPV-Hib]), Sanofi Pasteur Ltd.
• Quadracel^® (component pertussis vaccine and diphtheria and tetanus toxoids adsorbed combined with inactivated poliomyelitis vaccine, [DTaP-IPV]), Sanofi Pasteur Ltd.
• Td Adsorbed (tetanus and diphtheria toxoids [adult]), Sanofi Pasteur Ltd.
• Td Polio Adsorbed (tetanus and diphtheria toxoids and inactivated poliomyelitis vaccine adsorbed [adult]), Sanofi Pasteur Ltd.
• Tripacel^® (component pertussis vaccine combined with diphtheria and tetanus toxoids adsorbed, [DTaP]), Sanofi Pasteur Ltd.

Diphtheria toxoid is a cell-free preparation of diphtheria toxin detoxified with formaldehyde. It is available as a preparation adsorbed with aluminum phosphate and combined with other toxoids or vaccines (e.g., tetanus [T], poliomyelitis [IPV], acellular pertussis [aP], Haemophilus influenzae type b [Hib]). The amount of toxoid present is measured in flocculating units (Lf). The amount of diphtheria toxoid varies with the specific product and manufacturer. Preparations containing from 15 to 25 Lf per 0.5 mL dose (commonly designated as "D") are intended for use in children < 7 years of age (pediatric formulation). Preparations containing 2 Lf per 0.5 mL dose (commonly designated as "d") are intended for use in persons ≥ 7 years of age (adolescent/adult formulation). This reduced amount is less likely to cause reactions in persons who have previously received the vaccine. Polysaccharide vaccines that are conjugated with the CRM (cross-reacting material) diphtheria protein do not provide immunity to diphtheria.

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

Efficacy and immunogenicity

The immunity conferred by diphtheria vaccine is antitoxic, not antibacterial. Vaccination thus protects against the potentially lethal systemic effects of diphtheria toxin but not directly against local infection. After the primary series over 99% of persons develop antibody levels that are considered protective against disease (antitoxin titres of > 0.1 IU/mL). The antitoxin is believed to persist at protective levels for 10 years or more. Titres decline slowly with time but are boosted by additional doses. Carriage of C. diphtheriae can occur in immunized individuals, but the rate has been observed to be lower in immunized populations.

Recommended usage

Routine immunization against diphtheria is recommended for everyone, regardless of the age at which immunization is begun.

Primary immunization of children < 7 years of age

The primary immunizing course of diphtheria toxoid consists of three doses of a combination vaccine beginning at 2 months of age, followed by a booster dose administered approximately 1 year after the third dose. Diphtheria toxoid is most conveniently given as part of the recommended routine immunization schedule. Please refer to the Recommended Immunization Schedules chapter. It is preferable to use products in which diphtheria toxoid is combined with acellular pertussis vaccine and tetanus toxoid (DTaP), with or without inactivated poliomyelitis vaccine (DTaP-IPV) and Hib conjugate vaccine (DTaP-IPV-Hib).

Primary immunization of persons ≥ 7 years of age

The recommended agent is a combined adsorbed tetanus, diphtheria and pertussis preparation (Tdap) containing less diphtheria toxoid than preparations given to younger children.

Schedule and dosage

Children < 7 years of age should be immunized with 0.5 mL of the pediatric formulation of diphtheria toxoid-containing vaccine, DTaP-IPV-Hib, at 2, 4, 6 and 18 months of age. If for any reason this schedule is delayed, three doses of 0.5 mL should be administered with an interval of 4 to 8 weeks between doses, followed by a fourth dose of 0.5 mL administered approximately 1 year after the third dose.

A booster dose of 0.5 mL of DTaP-IPV should be administered between 4 and 6 years of age (school entry). This booster dose is unnecessary if the fourth primary immunizing dose has been administered after the fourth birthday.

A booster dose with the adolescent/adult formulation of tetanus, diphtheria toxoid and acellular pertussis (Tdap) should be administered at 14-16 years of age.

The schedule for routine immunization of persons ≥ 7 years of age is a three-dose series of adolescent/adult formulation of diphtheria toxoid-containing vaccine, as noted in the Recommended Immunization Schedules chapter. The second dose is given 2 months after the first, with a third dose 6 to 12 months later to complete the course.

Please refer to the Immunization of Immunocompromised Persons chapter for recommendations on hematopoietic stem cell and solid organ transplant recipients.

Route of administration

Diphtheria vaccines are prepared as adsorbed products. It is important to ensure that adsorbed vaccines are given intramuscularly because subcutaneous injection of adsorbed products produces a much higher rate of local reactions.

Booster doses and re-immunization

To maintain immunity to diphtheria it is recommended that all Canadians receive a primary immunizing course of diphtheria vacccine (combined with other vaccines), as already described, followed by booster doses at 18 months, 4 to 6 years of age, at 14-16 years of age and then every 10 years.

Additional indications include the following:

• Persons travelling to areas where they are likely to be exposed to diphtheria should be offered a booster dose of Td or Tdap if > 10 years has elapsed since their most recent booster.
• If a case of diphtheria occurs, close contacts (household, classroom or similar) should be given a dose of a toxoid preparation appropriate for their age unless they are known to have been fully immunized and the last dose was given in the previous 10 years. The remaining doses required to provide full immunization should be given to any contacts who were previously unimmunized or incompletely immunized. Patients convalescent from diphtheria should be given a complete primary course of diphtheria toxoid using an appropriate product for their age and immunization history, unless serologic testing indicates protective levels of antitoxin, since diphtheria infection does not always confer immunity.

Persons requiring a booster dose of tetanus toxoid for wound management should receive Td or Tdap as a convenient means of reinforcing their diphtheria protection. The current National Advisory Committee on Immunization recommendation for Tdap in adults is one dose (please refer to the Pertussis Vaccine chapter).

Serologic testing

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

Storage requirements

The package insert should be consulted for the storage requirements for the appropriate combination product being used.

Simultaneous administration with other vaccines

Diphtheria vaccine should always be administered in a combined formulation appropriate to age and prior immunization history (e.g., pertussis, polio, tetanus, Hib). Other vaccines may be given at the same time at a different site (e.g., pneumococcal conjugate vaccine).

For details of usage and precautions to be taken with individual vaccines, see relevant sections of the Guide.

Adverse reactions

Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association. The most common adverse reaction following administration of combination vaccines containing diphtheria toxoid that are given in childhood are redness, swelling and pain at the injection site. Systemic reactions such as fever and irritability are less common. Redness and swelling of > 3.5 cm diameter, with minimal pain, are more common in children receiving the fifth consecutive dose of vaccine at 4 to 6 years of age and have been reported in up to 16% of children. In older persons receiving the Td booster, injection site reactions are reported by about 10% of recipients.

Contraindications and precautions

Individuals ≥ 7 years of age should be given only those preparations formulated for older children and adults (Td or Tdap). Before any combined vaccine is given, it is very important to ensure that there are no contraindications to the administration of any of the other components.

As diphtheria vaccine is given in combination with tetanus vaccine, withholding tetanus (e.g. in persons who develop GBS within 8 weeks of a previous tetanus vaccine dose - see Tetanus Vaccine chapter) would necessitate withholding the diphtheria component as well.

Selected references

David ST, Hemsley C, Pasquali PE et al. Enhanced surveillance for vaccine-associated adverse events: dTap catch-up of high school students in Yukon. Canada Communicable Disease Report 2005;31(11):117-26.

Dittmann S, Wharton M, Vitek C et al. Successful control of epidemic diphtheria in the states of the former Union of Soviet Socialist Republics: lessons learned. Journal of Infectious Diseases 2000;181(Suppl 1):S10-22.

Galazka AM, Robertson SE. Immunization against diphtheria with special emphasis on immunization of adults. Vaccine 1996;14(9):845-57.

Halperin SA, Sweet L, Baxendale D et al. How soon after a prior tetanus-diphtheria vaccination can one give adult formulation tetanus-diphtheria-acellular pertussis vaccine? Pediatric Infectious Disease Journal 2006;25(3):195-200.

National Advisory Committee on Immunization. Interval between administration of vaccines against diphtheria, tetanus, and pertussis. Canada Communicable Disease Report 2005;31(ACS-9).

Plotkin SA, Orenstein WA. Vaccines, 4^th edition. Philadelphia: W.B Saunders Company, 2003: 211-228.

Varughese P. Diphtheria in Canada - surveillance summary. Canada Diseases Weekly Report 1978;4:65-8.

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