ARCHIVED - Interval Between Administration of Vaccines Against Diphtheria, Tetanus, and Pertussis


Canada Communicable Disease Report
Volume 31 • ACS-9
15 October 2005

An Advisory Committee Statement (ACS)

National Advisory Committee on Immunization (NACI)*?

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24 Pages - 348 KB



The National Advisory Committee on Immunization (NACI) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public health advice relating to immunization. The Public Health Agency of Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and is disseminating this document for information purposes. People administering the vaccines should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s) have sought approval of the vaccine(s) and provided evidence as to its safety and efficacy only when it is used in accordance with the product monographs. NACI members and liaison members conduct themselves within the context of the Public Health Agency of Canada's Policy on Conflict of Interest, including yearly declaration of potential conflict of interest.


This statement provides information regarding the intervals between administration of vaccines against diphtheria, tetanus, and pertussis. It also updates the National Advisory Committee on Immunization (NACI) statement on the Prevention of Pertussis in Adolescents and Adults(1) and its clarification(2).Forinfant vaccination, please refer to the 2002 edition of the Canadian Immunization Guide(3).


NACI recommends the administration of a single dose of the adolescent/adult formulation of the acellular pertussis vaccine to pre-adolescents, adolescents, and adults who have not received a dose of acellular pertussis vaccine. Since there is no monovalent acellular pertussis vaccine currently available in Canada, the only product available for protection against pertussis among pre-adolescents, adolescents, and adults is a combination product, the adolescent/adult formulation of the combined diphtheria-tetanus-acellular pertussis vaccine (dTap). Prior to dTap being approved and recommended for use in Canada, diphtheria-tetanus toxoid (dT) was routinely administered at 14 to 16 years of age. The dT booster is recommended every 10 years, and a 5-year minimum interval has been encouraged(3). This interval creates a problem for persons who require protection only against pertussis and have recently received a dT booster, particularly adolescents who have received the dT booster at 14 to 16 years of age.

In order to minimize the delay in providing protection against pertussis for these individuals, NACI has reviewed the evidence on the risk of adverse events associated with the administration of a diphtheria- and tetanus toxoid- containing vaccine within a 5-year time interval. The published literature, adverse event information, and data from three postmarketing studies undertaken in Canada since the introduction of dTap were reviewed.

Adverse events associated with diphtheria- and tetanus toxoid- containing vaccines administered with an interval of < 5 years

Tetanus vaccination became widely used following World War II after it effectively prevented tetanus in soldiers(4). Case reports of vaccine failure in both the military and the civilian population led to the administration of additional booster doses of tetanus toxoid to increase protection(5). In 1957, Ipsen first reported a high incidence of adverse vaccine reactions in individuals who had received multiple doses of tetanus toxoid(6). Since this time, a number of case series and reports of adverse reactions have been published(7-23). Adverse reactions appear to be correlated with the presence of high tetanus antibody titres and the number of previous doses administered. Three types of adverse event were reported:

  1. Injection site reactions, classified as either immediate (< 20 minutes), intermediate (i.e., Arthus type, 2 to 8 hours after injection(12) ), or delayed (tuberculin type, 48 hours).

  2. Allergic type reaction with edema/urticaria.

  3. Systemic reactions that include fever, headache, myalgia, arthralgia, and malaise.

The most frequently reported adverse event was local reaction at the injection site. In the most severe cases, there was swelling of the entire arm. However, this swelling disappeared within 5 days in the great majority of cases when treated with rest and ice. Levine et al. found that < 10% of vaccinees had reactions of greater than local significance(8). In other reports in which a denominator was given, information about the number of previous booster doses and the interval between doses is lacking.

In summary, it is not possible, from the published literature, to derive a rate of adverse events following the administration of two doses of diphtheria- and tetanus toxoid-containing vaccines within a short time interval; but it is clear that the cases described in the literature were associated with a large number of doses administered within a short period of time, as was recommended practice in the ?50s. No case reports have been published in the last 25 years, despite the large number of doses given to adults for wound management.

The Canadian experience

In Canada, the combined DPT vaccine (diphtheria, whole cell pertussis, tetanus toxoid) became widely used in the general population in 1948. The schedule at that time included three doses of DPT for primary immunization and five booster doses of DTP or DT before the age of 15 years(24). The DPT and DT were fluid vaccines. DPT contained 40 flocculating units (Lf) of diphtheria formol toxoid and 8 Lf of tetanus formol toxoid, whereas DT contained 40 Lf of diphtheria formol toxoid and 10 Lf of tetanus formol toxoid. The schedule was altered slightly in 1959 with the availability of combined DPT-polio or DT-polio vaccines.

In addition to reports of more frequent adverse events with repeated doses of tetanus- or diphtheria- and tetanus toxoid- containing vaccines, other studies have found that antibodies remain at protective levels for very long periods of time(25-29). Given that vaccine-induced immunity after the primary series was effective, and that frequent boosters were of no additional benefit and were associated with adverse events, the schedule was changed in the mid-1960s(30). The number of booster doses administered to children was reduced from five to three. For adults, booster doses were recommended every 10 years, with the provision that a 5-year interval was recommended for wound management. Despite large number of doses being recommended for nearly two decades, NACI is not aware of any reports of death or serious sequelae after a diphtheria- and tetanus toxoid- containing booster in Canada.

In summary, the long experience with diphtheria- and tetanus toxoid-containing vaccines in Canada does not indicate a risk of a severe outcome, even when more frequent dosing was the norm.

Canadian postmarketing data

Within Canada three investigators have evaluated the safety of administering a dose of dTap within 5 years after receiving diphtheria-, tetanus toxoid- and/or pertussis-containing vaccines (DTP, DTaP, or dT). These three studies were reviewed. The first study was conducted in Yukon in the spring of 2004 when dTap was offered to Grade 9 and 12 students(31). In general, the grade 12 students received dTap 3 to 5 years after having received their dT booster, whereas the grade 9 students had not received a diphtheria- or tetanus toxoid-containing vaccine within 5 years. A group of 239 grade 9 and 178 grade 12 students received dTap. There was no significant difference in the severity or duration of symptoms reported by the two groups. None of the respondents reported obtaining medical attention for vaccine-associated adverse events (VAAE), and no medical professionals reported seeing patients with VAAE associated with dTap.

The second study was conducted in the spring of 2004 in Montreal, Quebec (Dr. J.L. Grenier, personal communication, April 18, 2005). All students from Grade 7 to 11 in two secondary schools were offered dTap. Most grade 10 and 11 students had previously received dT in grade 9. As a result, a group of 178 out of 465 respondents had received dT 1 to 5 years previously. The rates of VAAE were the same in this group as among the other students, who had received the vaccine> 5 years earlier, and did not vary with the time interval that had passed since the previous dT immunization.

In Prince Edward Island in the fall of 2004, an open-label, nonrandomized province-wide study of 7001 students aged 7 to 19 years was conducted to assess the rates of adverse events after dTap administration, according to the type and interval from last dose of diphtheria- and tetanus toxoid-containing vaccine  
(Dr. S. Halperin, personal communication, July 12, 2005). Grade 3 to 12 students were offered dTap. Students had received dT (Grade 11 to 12), DTP (Grade 7 to 9), or DTaP (Grade 3 to 6) in the past. The group of Grade 11 to 12 (966) students received dTap at an interval of 2 or 3 years after their dT booster. No severe adverse events related to the vaccine, including Arthus type reactions, were observed during the study. Rates of local reactions were not increased. There was a modest increase in injection site reactions with decreasing interval since previous immunization, but these were well tolerated. Fever was infrequent and not related to the time interval since previous immunization. The study conclusion was that dTap was well tolerated by adolescents who had been immunized after intervals of 2 to 10 years following a diphtheria- and tetanus toxoid-containing vaccine and could be safely administered at intervals of 2 or more years since previous diphtheria-tetanus toxoid vaccine.

Although the number of subjects in these studies is not large enough to exclude rare severe adverse events, collectively the three studies demonstrate that the rate of VAAE among Canadian adolescents does not appear to be increased when the interval between diphtheria- and toxoid-containing vaccines is shorter than 5 years.


Since there is no monovalent acellular pertussis vaccine currently available in Canada, a combination product, dTap, must be used whenever there is a need for a pertussis booster in adolescents and adults who have recently received dT vaccine. After reviewing the data from the published literature and from the three studies described, NACI concluded that there is no evidence of increased risk of severe adverse events for Canadian adolescents after receiving diphtheria- and tetanus toxoid-containing vaccines at intervals of < 5 years. In the context of catch-up programs, because of the vulnerability of this group to pertussis the pertussis booster (dTap) should not be delayed for fear of adverse events related to the diphtheria or tetanus toxoid component, regardless of the elapsed time since the previous diphtheria- and tetanus toxoid-containing vaccine. Since the evidence is still limited, postmarketing studies remain a priority.


1. National Advisory Committee on Immunization (NACI). Prevention of pertussis in adolescents and adults. CCDR 2003; 29(ACS-5):1-9

2. Clarification: prevention of pertussis in adolescents and adults. Can Comm Dis Rep 2004;30:603.

3. Health Canada. Canadian immunization guide 2002.6th ed. Cat. No. H49-8/2002E. Ottawa: 2002.

4. Tetanus toxoid - adverse events following immunization.In: Plotkin SA, Orenstein WA (eds.). Vaccines 4th ed. Philadelphia: Saunders, 2004; 763-5.

5. Edsall G, Elliott MW, Peebles TC, et al. Excessive use of tetanus toxoid boosters. JAMA 1967;202:111-3.

6. Ipsen J. Annual report to commission on immunization. Armed Forces Epidemiological Board, 1957.

7. Sweeney JE. Reactions after infection of tetanus toxoid. JAMA 1959;169:1398.

8. Levine L, Ipsen J Jr, McComb JA. Adult immunization: Preparation and evaluation of combined fluid tetanus and diphtheria toxoids for adult use. Am J Hyg 1961;73:20-35.

9. McComb JA, Levine L. Adult immunization: Dosage reduction as a solution to increasing reactions to tetanus toxoids.NewEnglJ Med 1961;265:1152-3.

10. Brindle MJ, Twyman DG. Allergic reaction to tetanus toxoid.Br Med J 1962;1:1117.

11. Kuhns WJ. The relationship of immediate wheal reactions to the repeated administration of diphtheria and tetanus toxoids.J Immunol 1962;89:652-9.

12. Eisen AH, Cohren JJ, Rose B. Reaction to tetanus toxoids - report of a case with immunologic studies.NEnglJMed 1963;269:1408-11.

13. Trinca JC. Active tetanus immunization: Effect of a reduced reinforcing dose of adsorbed toxoid on the partly immunized reactive patient. Med J Aust 1963;II:389-92.

14. Schneider CH. Reactions to tetanus toxoid: A report of five cases. Med J Aust 1964;22:303-5.

15. Holden JM, Strang DU. Reaction to tetanus toxoid: comparison of fluid and adsorbed toxoids. New Z Med J 1965;64:574-7.

16. Sisk CW, Lewis CE. Reactions to tetanus-diphtheria toxoid (adult). Arch Environ Health 1965;11:34-6.

17. Kittler FJ, Smith P Jr, Hefley BF et al. Reactions to tetanus toxoid. South Med J 1966;59:149-53.

18. Fardon DF. Unusual reactions to tetanus toxoid.JAMA 1967;199:125-6.

19. Relihan M. Reactions to tetanus toxoid. J Ir Med Assoc 1969;62:430-4.

20. Facktor MA, Bernstein RA, Fireman P. Hypersensitivity to tetanus toxoid. J Allergy Clin Immunol 1973;52:1-12.

21. White WG, Barnes GM. Reactions to tetanus toxoids. J Hygiene (London) 1973;71:283-97.

22. Collier LH, Polakoff S, Mortimer J. Reactions and antibody responses to reinforcing doses of adsorbed and plain tetanus vaccines. Lancet 1979;1:1364-8.

23. White WG. Reactions after plain and adsorbed tetanus vaccines. Lancet 1980;1:42.

24. Wilson RJ. Experience with tetanus toxoid in combined vaccines. In: 2nd International Conference on Tetanus, 1966. Bern: Hans Huber Publishers.

25. Gottlieb S, McLaughlin FX, Levine L et al. Long-term immunity to tetanus - a statistical evaluation and its clinical implications. Am J Public Health Nations Health 1964;54:961-71.

26. Gottlieb S, Martin M, McLaughlin FX et al. Long-term immunity to diphtheria and tetanus: A mathematical model. In : 2nd International Conference on Tetanus, 1966. Bern: Hans Huber Publishers.

27. Scheibel I, Bentzon MW, Christensen PE et al. Duration of immunity after tetanus immunization. In: 2nd International Conference on Tetanus, 1966. Bern: Hans Huber Publishers.

28. Peebles TC, Levine L, Eldred MC et al. Tetanus-toxoid emergency boosters: a reappraisal. N Engl J Med 1969;280:575-81.

29. Edsall G. Diphtheria tetanus and pertussis immunization.Arch Environ Health 1967;15:473-7.

30. Recommendation of the public health service advisory committee on immunization practices - diphtheria, tetanus, and pertussis vaccines - tetanus prophylaxis in wound management. MMWR 1966:416-8.

31. David ST, Hemsley C, Pasquali PE et al. Enhanced surveillance for vaccine-associated adverse events: DTap catch-up of high school student in Yukon. CCDR 2005;31:117-26.  

24. Wilson RJ. Experience with tetanus toxoid in combined vaccines. Dans : 2nd International Conference on Tetanus, 1966. Bern: Hans Huber Publishers.


*Members: Dr. M. Naus (Chair), Dr. T. Tam (Executive Secretary), Dr. I. Bowmer, Dr. S. Dobson, Dr. B. Duval, Dr. J. Embree, Ms. A. Hanrahan, Dr. J. Langley, Dr. A. McGeer, Dr. K. Laupland, Dr. M-N Primeau, Dr. B. Tan, Dr. B. Warshawsky.

Liaison Representatives : S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. L. Chapman (CDC), Dr. D. Money (SOGC), A. Honish (CNCI), Dr.B.Larke(CCMOH),Dr.B.Law (ACCA), Dr. M. Salvadori (AMMI Canada), Dr. S. Rechner (CFPC), Dr. J. Salzman (CATMAT), Dr. L. Samson (CPS), Dr. D. Scheifele (CAIRE).

Ex-Officio Representatives: Dr.S.Deeks(CIDPC), Dr. H. Rode (BGTD), Dr.M. Lem (FNIHB), Dr. M. Tepper (DND).

?This statement was prepared by Dr. Bernard Duval, Dr. Gaston De Serres, and Dr. Shelley Deeks. It was approved by NACI and approved by the Public Health Agency of Canada.

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