Since the publication of the 2006 Canadian Immunization Guide:
For additional information, refer to the National Advisory Committee on Immunization (NACI) Statement on the recommended use of pentavalent and hexavalent vaccines.
Diphtheria is caused by exotoxin-producing strains of the bacterium Corynebacterium diphtheriae.
Diphtheria is transmitted by person-to-person spread from the respiratory tract or, rarely, by contact with articles soiled with excretions of infected persons. The incubation period is about 2 to 5 days (range, 1 to 10 days). The infectious period in untreated persons is usually 2 weeks or less and, rarely, more than 4 weeks. Chronic carriers are asymptomatically colonized with C. diphtheriae on the skin or in the nasopharynx and may shed organisms for 6 months or more.
Inadequately or unimmunized travellers to areas with endemic diphtheria are at higher risk of acquiring disease. A list of countries where diphtheria is endemic is available from the United States Centers for Disease Control and Prevention (CDC) or the current version of the CDC’s Health Information for International Travel Yellow Book.
Diphtheria occurs most frequently in winter and spring months in temperate climates.
Spectrum of clinical illness
Respiratory diphtheria affects the mucous membrane of the upper respiratory tract. Symptoms include a mild fever, sore throat, difficulty swallowing, malaise and loss of appetite. It can progress to acute respiratory distress, upper airway obstruction and asphyxia in young children. An adherent, asymmetrical, grayish white membrane visible on the tonsils and oropharynx typically appears within 2 to 3 days of illness. Dissemination of diphtheria toxin can result in systemic complications such as myocarditis and central nervous system effects. The case-fatality rate is about 5% to 10%; the highest rates occur among the unvaccinated very young, and elderly, and in non-endemic countries because diagnosis is often late. Localized infection of the skin (cutaneous diphtheria) may occur but is rarely associated with systemic complications.
Diphtheria occurs worldwide and is endemic in many developing countries as well as in Albania, Russia and other countries of the former Soviet Union. In other countries, occasional cases of imported diphtheria are identified. Resurgence of diphtheria has been reported in countries with low vaccine coverage. A total of 4,187 cases of diphtheria were reported to the World Health Organization (WHO) in 2010.
Routine infant and childhood diphtheria immunization has resulted in a dramatic decline in reported cases of diphtheria (refer to Figure 1). A small number of toxigenic strains of diphtheria bacilli are detected each year (0 to 5 isolates), although classic diphtheria is rare. Serosurveys of healthy adult populations in Canada indicate that approximately 20% (higher in some age groups) do not have protective concentrations of antibody to diphtheria; adult booster doses are required.
Population data sources:
Statistics Canada, Population by Sex and Age, 1921-1971, revised annual
estimates of population, Canada and the provinces, (Catalogue 91-512)
Statistics Canada, Population estimates 0-90+ July Canada - Provinces 1971-2008.xls
The potential for re-emergence of diphtheria if immunization levels decline was demonstrated during the 1990s in the Commonwealth of Independent States (former Soviet Union) when over 140,000 cases and 4,000 deaths were reported.
Diphtheria toxoid is only available as a combination vaccine. The amount of diphtheria toxoid present varies by product. Preparations containing higher concentrations of diphtheria toxoid (designated as “D”) are administered for primary immunization of infants and young children less than 7 years of age (pediatric formulation). Preparations containing a lower concentration (designated as “d” and referred to as “reduced”) may be administered as a booster dose to children 4 years to less than 7 years of age and are the recommended product for older children, adolescents and adults (adolescent/adult formulation).
For complete prescribing information, consult the product leaflet or information contained within Health Canada’s authorized product monographs available through the Drug Product Database. Refer to Table 1 and Table 2 in General Considerations in Part 1 for lists of all vaccines and passive immunizing agents available for use in Canada and their contents.
Diphtheria toxoid protects against the systemic effects of diphtheria toxin but does not directly protect against infection. Carriage of C. diphtheriae can occur in immunized individuals, but the rate of carriage is lower in immunized populations. After a complete primary series, more than 97% of vaccinees develop antibody concentrations that are protective against diphtheria toxin. In studies assessing booster response, 100% of vaccinees had a protective antibody titre one month after the booster dose. Antitoxin is believed to persist at protective concentrations for 10 years or more.
Diphtheria toxoid-containing vaccine is recommended for routine infant immunization beginning at 2 months of age. DTaP-IPV (with or without Hib) vaccine is authorized for use in children less than 7 years of age. DTaP-HB-IPV-Hib vaccine is authorized for use in children 6 weeks to 23 months of age and may be given to children aged 24 months to less than 7 years, if necessary. DTaP-IPV or Tdap-IPV vaccine should be used as the booster dose for children at 4 to 6 years of age. Children 7 years of age and older should receive the adolescent/adult formulation of diphtheria-tetanus-pertussis-containing vaccine with or without polio (Tdap or Tdap-IPV) as it contains less diphtheria toxoid than preparations given to younger children and is less likely to cause reactions in older children. Tdap vaccine should be administered to adolescents at 14 to 16 years of age as the first 10-year booster dose; Tdap-IPV vaccine should be used if IPV vaccine is also indicated.
Adults who have not previously received a primary series (at least 3 doses) of diphtheria toxoid-containing vaccine should receive one dose of Tdap-IPV vaccine followed by two doses of Td-IPV vaccine. There is new evidence that a booster dose of Td vaccine may not be required every 10 years. Pending review, a booster dose of Td vaccine is recommended every 10 years.
Refer to Schedule and Booster doses and re-immunization. Refer to Tetanus Toxoid, Pertussis Vaccine, Poliomyelitis Vaccine, Haemophilus influenzae type b Vaccine and Hepatitis B Vaccine in Part 4 for additional information.
Children and adults lacking adequate documentation of immunization should be considered unimmunized and started on an immunization schedule appropriate for their age and risk factors. When available, serologic testing for diphtheria and tetanus antitoxin concentrations may guide the need for continued immunization. Refer to Immunization of Children and Adults with Inadequate Immunization Records in Part 3 for additional general information.
Susceptible pregnant women may receive Td vaccine if indicated. There is no evidence to suggest a risk to the fetus or to the pregnancy from maternal immunization with Td vaccine. The use of Tdap vaccine during pregnancy is currently under review. Refer to Pertussis Vaccine in Part 4 for additional information. Refer to Immunization in Pregnancy and Breastfeeding in Part 3 for additional general information.
Premature infants in stable clinical condition should be immunized with a diphtheria toxoid-containing vaccine at the same chronological age and according to the same schedule as full-term infants. Infants born prematurely (especially those weighing less than 1,500 grams at birth) are at higher risk of apnea and bradycardia following vaccination. Hospitalized premature infants should have continuous cardiac and respiratory monitoring for 48 hours after their first immunization. Refer to Immunization of Infants Born Prematurely in Part 3 for additional general information.
Residents of long-term care facilities should receive all routine immunizations appropriate for their age and risk factors, including diphtheria toxoid-containing vaccine. Refer to Immunization of Patients in Health Care Institutions in Part 3 for additional general information.
Diphtheria-tetanus-pertussis-polio-Hib-containing vaccines may be administered to immunocompromised persons. When considering immunization of an immunocompromised person, consultation with the individual’s attending physician may be of assistance in addition to the guidance provided below. For complex cases, referral to a physician with expertise in immunization and/or immunodeficiency is advised.
Individuals with congenital immunodeficiencies involving any part of the immune system, including persons with partial T-lymphocyte defects (e.g., DiGeorge syndrome, Wiskott-Aldrich syndrome, ataxia-telangiectasia), may receive diphtheria-tetanus-pertussis-polio-Hib -containing vaccine if indicated.
Hematopoietic stem cell transplantation (HSCT- autologous or allogeneic)
Solid organ transplantation
Vaccination status for diphtheria, tetanus, pertussis, polio, and Hib should be reviewed for immunocompetent persons who might be anticipating initiation of immunosuppressive treatments or who have diseases that might lead to immunodeficiency. Although diphtheria-tetanus-pertussis-polio-Hib-containing vaccine can safely be given at any time before, during or after immunosuppression, all attempts should be made to time vaccination so that optimal immunogenicity is achieved.
If indicated, diphtheria-tetanus-pertussis-polio-Hib-containing vaccines as appropriate for age should be administered at least 14 days before the initiation of immunosuppressive therapy (e.g., high-dose systemic corticosteroids [2 mg/kg per day or 20 mg/day or more of prednisone or its equivalent] for 14 days or more; chemotherapy; radiation therapy; azathioprine; cyclosporine; cyclophosphamide; infliximab). If this cannot be done, a period of at least 3 months should elapse after immunosuppressive drugs (except high-dose systemic corticosteroids) have been stopped before administration of diphtheria-tetanus-pertussis-polio-Hib-containing vaccines to ensure immunogenicity. A period of at least 4 weeks should elapse between discontinuation of high-dose systemic steroids and administration of diphtheria-tetanus-pertussis-polio-Hib-containing vaccines. The interval between discontinuation of immunosuppressive drugs and diphtheria-tetanus-pertussis-polio-Hib-containing preparations may vary with the intensity of the immunosuppressive therapy, underlying disease and other factors.
If immunosuppressive therapy cannot be stopped or reduced, diphtheria-tetanus-pertussis-polio-Hib-containing vaccine should be given when the person is least immunosuppressed, unless it is urgently needed (such as based on exposure risk to circulating diseases or for a tetanus booster post-exposure).
People with neurological disorders with onset preceding immunization should receive all routinely recommended immunizations. Refer to Tetanus Toxoid and Pertussis Vaccine in Part 4 for information regarding other components in diphtheria toxoid-containing combination vaccines. Refer to Immunization of Persons with Chronic Diseases in Part 3 for additional general information.
Unimmunized or incompletely immunized travellers should receive diphtheria-tetanus-pertussis-polio-Hib-containing vaccine as appropriate for age. For infants embarking on travel, the first dose of DTaP-IPV-Hib or DTaP-HB-IPV-Hib vaccine can be given at 6 weeks of age (refer to Schedule). Previously immunized adult travellers should receive a booster dose of a tetanus-diphtheria toxoid-containing preparation every 10 years. For adults who have not previously received a dose of acellular pertussis vaccine in adulthood, it is recommended that the Td vaccine booster dose be replaced by Tdap vaccine. Some travellers may also need a polio booster. Refer to Poliomyelitis Vaccine in Part 4 for additional information. Refer to Immunization of Travellers in Part 3 for additional general information.
Health care providers who see people newly arrived in Canada should review the immunization status and update immunization for these individuals. Refer to Immunization of Persons New to Canada in Part 3 for additional general information.
All health care workers should be immune to diphtheria and receive a booster dose of Td vaccine every 10 years as recommended for all adults. All health care and child care workers, regardless of age, should receive a single dose of Tdap vaccine for pertussis protection if not previously received in adulthood, even if not due for a tetanus and diphtheria booster. Refer to Immunization of Workers in Part 3 for additional general information.
Close contacts (e.g., household, classroom) of a diphtheria case should receive a dose of a diphtheria toxoid-containing vaccine as appropriate for age unless the contact is known to have been fully immunized and the last dose of diphtheria toxoid-containing vaccine was given within 10 years. The diphtheria toxoid-containing vaccine series should be completed for previously unimmunized or incompletely immunized contacts.
Prophylaxis of diphtheria
Diphtheria antitoxin is not recommended for prophylaxis of immunized or unimmunized close contacts of diphtheria cases, given the substantial risk of allergic reaction to equine serum and lack of evidence of additional benefit of antitoxin for contacts who have received antimicrobial prophylaxis.
Treatment of diphtheria
Diphtheria antitoxin for treatment of diphtheria disease is available on an emergency basis through local public health officials. Antitoxin should be administered when there is clinical suspicion of diphtheria, before bacteriologic confirmation. The method of testing for sensitivity to equine serum, as well as the dose and route of administration, are indicated in the manufacturer’s product leaflet. If sensitivity tests are positive, desensitization must be undertaken according to the manufacturer’s recommendations. Intramuscular administration usually suffices, but intravenous administration may be necessary in some cases.
Persons who have recovered from diphtheria should receive diphtheria toxoid-containing vaccine as recommended for people who have not had the disease. Because symptoms of diphtheria are largely mediated through toxins produced by the diphtheria bacterium and not the bacterium itself, recovery from diphtheria disease does not necessarily confer immunity.
Refer to Vaccine and Antitoxin Safety and Adverse Events for safety information.
For complete prescribing information, consult the product leaflet or information contained within Health Canada’s authorized product monographs available through the Drug Product Database.
Refer to Passive Immunizing Agents Part 5 for additional general information.
Each dose of diphtheria toxoid-containing vaccine is 0.5 mL.
Diphtheria toxoid-containing vaccines must be administered intramuscularly. Refer to Vaccine Administration Practices in Part 1 for additional information.
Infants and children (2 months to 6 years of age)
Routine diphtheria immunization of infants: DTaP-IPV-Hib vaccine should be given at 2, 4, 6 and 12 to 23 months of age (generally given at 18 months of age).
If infant immunization for hepatitis B is undertaken, DTaP-HB-IPV-Hib vaccine may be used as an alternative to separately administered hepatitis B and DTaP-IPV-Hib vaccines. DTaP-HB-IPV-Hib vaccine is authorized for use in children 6 weeks to 23 months of age and may be given to children aged 24 months to less than 7 years, if necessary. DTaP-HB-IPV-Hib vaccine may be given at 2, 4, 6 and 12 to 23 months of age but the fourth dose is unlikely to provide significant additional hepatitis B protection and will increase cost. Alternative schedules may be used as follow:
If rapid protection is required for an infant, the first dose of DTaP-IPV-Hib or DTaP-HB-IPV-Hib vaccine can be given at 6 weeks of age. The first three doses may be administered at intervals of 4 weeks and, optimally, the fourth dose given 12 months after the third dose. The fourth dose may be given at a minimum interval of 6 months after the third dose in certain situations (e.g., travel) but must be administered at or after 12 months of age for sustained immunity.
Children less than 7 years of age not immunized in infancy: should receive three doses of DTaP-IPV (with or without Hib) vaccine with an interval of 8 weeks between doses, followed by a dose of DTaP-IPV vaccine 6 to 12 months after the third dose. A booster dose of either DTaP-IPV or Tdap-IPV vaccine should be administered at 4 to 6 years of age (school entry). The booster dose at 4 to 6 years of age is not required if the fourth dose of tetanus-toxoid containing vaccine was administered after the fourth birthday.
If rapid protection is required for a child less than 7 years of age not immunized in infancy, the first three doses of vaccine may be administered at intervals of 4 weeks and, optimally, the fourth dose given 12 months after the third dose. The fourth dose may be given at a minimum interval of 6 months after the third dose in certain situations (e.g., travel).
Children who received a primary series of a diphtheria toxoid-containing vaccine and a booster dose 6-12 months later as outlined above should receive a booster dose of either DTaP-IPV or Tdap-IPV vaccine at 4 to 6 years of age (school entry); and, 10 years later, a booster dose of Tdap vaccine at 14 to 16 years of age. The booster dose at 4 to 6 years of age is not required if the fourth dose of diphtheria toxoid-containing vaccine was administered after the fourth birthday.
Children and adolescents (7 years to 17 years of age)
Children 7 years of age and older not previously immunized should receive three doses of Tdap-IPV vaccine with an interval of 8 weeks between the first two doses followed by a third dose administered 6 to 12 months after the second dose. A booster dose of Tdap vaccine should be administered 10 years after the last dose.
Adults (18 years of age and older)
Adults who have not previously received a primary series (at least 3 doses) of diphtheria toxoid-containing vaccine should receive one dose of Tdap-IPV vaccine and two doses of Td-IPV vaccine. The dose of Tdap-IPV vaccine should be given first, followed 8 weeks later by a dose of Td-IPV vaccine. The second dose of Td-IPV vaccine should be given 6 to 12 months after the previous dose of Td-IPV vaccine.
There is new evidence that booster doses of Td vaccine may not be required every 10 years. Pending review, booster doses of Td vaccine are recommended every 10 years. Adults who have not received an adult dose of pertussis-containing vaccine should receive one dose of Tdap vaccine which can be administered regardless of the interval since the last dose of tetanus and diphtheria toxoid-containing vaccine. Refer to Schedule.
Serologic testing is not recommended before or after receiving diphtheria toxoid-containing vaccine.
Store diphtheria toxoid-containing preparations in a refrigerator at +2ºC to +8ºC and do not freeze. Refer to Storage and Handling of Immunizing Agents in Part 1 for additional general information.
Diphtheria toxoid-containing vaccines may be administered concomitantly with routine vaccines at different injection sites using separate needles and syringes. Refer to Timing of Vaccine Administration in Part 1 for additional general information.
Refer to Vaccine Safety Part 2 for additional general information. Refer to Tetanus Toxoid, Pertussis Vaccine, Poliomyelitis Vaccine, Haemophilus influenzae type b Vaccine and Hepatitis B Vaccine in Part 4 for additional information regarding other components in diphtheria toxoid-containing combination vaccines.
Redness, swelling and pain at the injection site are the most common adverse reactions to childhood diphtheria toxoid-containing combination vaccines. A nodule may be palpable at the injection site and persist for several weeks. Abscess at the injection site has been reported.
In clinical trials, injection site adverse reactions, including tenderness, erythema, and/or swelling were reported in 10% to 40% of children after each of the first 3 doses of diphtheria-toxoid containing vaccine. Mild systemic reactions such as fever, irritability and/or fussiness were commonly reported (8% to 29%), as well as drowsiness (40% to 52%).
In two clinical studies, swelling (greater than 5 cm) and erythema were reported in 15% to 20% of vaccinees after the fourth or fifth doses of DTaP vaccines. Extensive limb swelling (greater than 10 cm in diameter) possibly involving the entire proximal limb may occur in 2% to 6% of children. While these injection site reactions produce significant swelling, pain is generally limited. There is some evidence that children with extensive limb swelling following the fourth dose of a DTaP vaccine are at increased risk of such an event following the fifth dose. The presence of a large injection site reaction to a previous dose is not a contraindication to continuing the recommended schedule.
Among adults given a booster dose of Tdap vaccine, very common reactions include pain, redness and swelling at the injection site, headache, and fatigue. Fever and chills are common reactions. Adverse reactions following Td vaccine are similar. Overall, adverse reactions are less common in adults than adolescents. The interval between the childhood DTaP vaccine series or a dose of Td vaccine, and a dose of Tdap vaccine does not affect the rate of injection site or systemic adverse events.
Diphtheria antitoxin may trigger allergic reactions of varying severity. The most commonly reported reactions are: skin pruritus/pain/swelling/redness; urticaria; dry cough/hoarseness; nausea/vomiting; or asthma-like crisis. The frequency varies and the reactions occur within the first 24 hours after administration of DAtx. Persons previously treated with serum of equine origin may have a higher risk of reaction.
Serious adverse events are rare following immunization with diphtheria toxoid-containing vaccines and, in most cases, data are insufficient to determine a causal association. Severe systemic reactions such as generalized urticaria, anaphylaxis, or neurologic complications have been reported rarely.
Severe (arthus-type) injection site reactions are occasionally reported following receipt of diphtheria toxoid or tetanus toxoid-containing vaccines. There may be extensive painful swelling around the injection site, often involving the arm from shoulder to elbow and generally beginning 2 to 8 hours after injection. Such reactions are most often reported in adults, particularly those who have received frequent doses of diphtheria and/or tetanus toxoid. Persons experiencing severe injection site reactions usually have very high serum antitoxin concentrations and should not receive further routine booster doses of Td vaccine for at least 10 years.
Severe reactions are uncommon. Fatal anaphylactic shock has been reported in 1:50,000 persons receiving DAtx. Serum sickness (fever, urticaria, arthralgia, adenomegaly and, more rarely, neurological or renal compromise) may occur between 5 and 24 days after the administration DAtx in approximately 8%.
Cases of Guillain-Barre Syndrome (GBS) or polyneuritis have been reported following receipt of diphtheria toxoid-containing vaccine. While the evidence favours a causal relationship between tetanus toxoid and GBS, there is little evidence to support an independent association between receipt of diphtheria toxoid and GBS.
Vaccine providers are asked to report, through local public health officials, any serious or unexpected adverse event felt to be 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. Refer to Reporting Adverse Events Following Immunization (AEFI) in Canada in Vaccine Safety Part 2 for additional information about AEFI reporting.
Diphtheria toxoid-containing vaccines are contraindicated in persons with a history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Refer to Table 1 and Table 2 in General Considerations in Part 1 for lists of all vaccines and passive immunizing agents available for use in Canada and their contents. For the diphtheria toxoid-containing vaccines, potential allergens include:
There are no currently known potential allergens in ADACEL® or Td ADSORBED vaccines.
Hypersensitivity to yeast is very rare and a personal history of yeast allergy is not generally reliable. In situations of suspected hypersensitivity or non-anaphylactic allergy to vaccine components, investigation is indicated which may involve immunization in a controlled setting. Consultation with an allergist is advised.
Administration of diphtheria toxoid-containing vaccine should be postponed in persons with moderate or severe acute illness. Persons with minor acute illness (with or without fever) may be vaccinated.
It is prudent to not administer further doses of tetanus-toxoid containing vaccine to persons who develop GBS within 6 weeks of receiving such vaccine. Those who develop GBS outside the 6 week interval may receive subsequent doses of tetanus toxoid-containing vaccine. If there is a history of both Campylobacter infection (which has been associated with GBS) and receipt of a tetanus and diphtheria toxoid-containing vaccine within the 6 weeks before the onset of GBS, consultation with an infectious disease specialist is advised.
People who experience a severe injection site reaction following a dose of tetanus toxoid-containing vaccine should not be given another dose for at least 10 years.
Refer to General Contraindications and Precautions in Part 2 and Passive Immunization Part 5 for additional general information.
The primary series of three doses of diphtheria toxoid-containing vaccine should be completed with an appropriate vaccine from the same manufacturer whenever possible. However, if the original vaccine is unknown or unavailable, an alternative combination vaccine from a different manufacturer may be used to complete the primary series. On the basis of expert opinion, an appropriate product from any manufacturer can be used for all booster doses. Refer to Principles of Vaccine Interchangeability in Part 1 for additional general information.