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Simultaneous immunization of infants and children against diphtheria, tetanus, and pertussis has been a routine practice in the US since the late 1940s, and has played a major role in markedly reducing disease and deaths from these infections.3
Corynebacterium diphtheriae may cause both localized and generalized disease. The systemic intoxication is caused by diphtheria exotoxin, an extracellular protein metabolite of toxigenic strains of C diphtheriae.
Prior to the widespread use of diphtheria toxoid in the late 1940s, diphtheria disease was common in the US. More than 200, 000 cases, primarily among children, were reported in 1921. Approximately 5% to 10% of cases were fatal; the highest case-fatality rates were in the very young and the elderly. More recently, reported cases of diphtheria of all types declined from 306 in 1975 to 59 in 1979; most were cutaneous diphtheria reported from a single state. After 1979, cutaneous diphtheria was no longer reportable.3 From 1980 through 2000, 51 cases of diphtheria were reported in the US. During the period 1980-1996, six fatal cases of diphtheria were reported. One case of diphtheria was reported each year in 1998-2000 with no fatalities.4 Of 49 reported cases with known age since 1980, twenty-seven (55%) cases were in persons ≥ 20 years of age. Most cases have occurred in unimmunized or inadequately immunized persons. Although diphtheria disease is rare in the US, it appears that C diphtheriae continues to circulate in areas of the country with previously endemic diphtheria.5
Diphtheria continues to occur in other parts of the world. A major epidemic of diphtheria occurred in the Newly Independent States (NIS) of the former Soviet Union beginning in 1990. In 1994-1995, the peak of the epidemic, > 98, 000 cases and 3, 400 deaths were reported in the NIS.6 This outbreak was believed to be due to several factors, including a lack of routine immunization of adults in these countries.7
Complete immunization significantly reduces the risk of developing diphtheria, and immunized persons who develop disease have milder illness. Following adequate immunization with diphtheria toxoid, protection is thought to last for at least 10 years. Protection against disease is due to the development of neutralizing antibodies to diphtheria toxin. A serum diphtheria antitoxin level of 0.01 IU/mL is the lowest level giving some degree of protection. Antitoxin levels of at least 0.1 IU/mL are generally regarded as protective.8 Immunization does not, however, eliminate carriage of C diphtheriae in the pharynx, nose, or on the skin.3
Following routine use of tetanus toxoid in the US, the occurrence of tetanus disease decreased dramatically from 560 reported cases in 1947, to an average of 50-100 cases reported annually from the mid 1970s through the late 1990s, to 35 cases in 2000.4 The case-fatality rate has declined from 30% to approximately 10% in recent years. During the years 1982-1998, 52% of reported cases were among persons 60 years of age or older. In the mid to late 1990s, the age distribution of reported cases shifted to a younger age group, in part due to an increased number of cases among injection drug users in California. Persons < 40 years increased from 28% of cases during 1991-1995 to 42% of cases during 1996-2000. In the US, tetanus occurs almost exclusively among unvaccinated or inadequately vaccinated persons.5
Spores of C tetani are ubiquitous. Serological tests indicate that naturally acquired immunity to tetanus toxin does not occur in the US. Thus, universal primary immunization, with subsequent maintenance of adequate antitoxin levels by means of appropriately timed boosters, is necessary to protect all age groups. Following adequate immunization with tetanus toxoid, it is thought that protection persists for at least 10 years.3 Protection against disease is due to the development of neutralizing antibodies to tetanus toxin. A serum tetanus antitoxin level of at least 0.01 IU/mL, measured by neutralization assays, is considered the minimum protective level.9,10 More recently, a level ≥0.1 to 0.2 IU/mL has been considered as protective.11
Pertussis (whooping cough) is a disease of the respiratory tract caused by Bordetella pertussis. This gram-negative coccobacillus produces a variety of biologically active components. The role of the different components produced by B pertussis in either the pathogenesis of, or immunity to, pertussis is not well understood.12
Pertussis is highly communicable (with attack rates of up to 100% in susceptible individuals with intense exposure13) and can cause severe disease, particularly among young infants. Since pertussis became a nationally reportable disease in the US in 1922, the highest number of pertussis cases (approximately 260, 000) was reported in 1934. Following introduction and widespread use of the whole-cell pertussis DTP vaccines (Diphtheria and Tetanus Toxoids and Pertussis Vaccine Adsorbed For Pediatric Use) among infants and children in the mid to late 1940s, pertussis incidence gradually declined, reaching a historical low of 1, 010 cases in 1976.14
Concerns about the safety of whole-cell pertussis DTP vaccines prompted the development of less reactogenic DTaP vaccines that contain purified antigens of B pertussis. DTaP vaccines were first available for use in infants in the US in 1996 and have been routinely recommended for all doses of the vaccination series for infants and children 6 weeks to < 7 years of age since 1997.15
The incidence of pertussis among children aged 6 months to 4 years has remained stable throughout the 1990s, suggesting that protection offered by vaccination has continued with the introduction of DTaP vaccines.14,16 Conversely, an increase in pertussis among infants too young to receive 3 doses of pertussis-containing vaccine suggests a true increase in pertussis circulation.14 Atypical infection, including nonspecific symptoms of bronchitis or upper respiratory tract infection, may occur at any age but more commonly in older children and adults, including some who were previously immunized. In these cases, pertussis may not be diagnosed because classic signs, particularly the inspiratory whoop, may be absent.17 Surveillance data from the 1990s indicates an increase in the pertussis rate among adolescents and adults who may also play a role in transmission to infants.5,14
During 1997 to 2000, a total of 29, 134 cases were reported, for an estimated average annual incidence rate of 2.7 per 100, 000 population.14 Among 29, 048 cases for whom age was known, 29% were aged < 1 year, 12% were aged 1 to 4 years, 10% were aged 5 to 9 years, 29% were aged 10 to 19 years and 20% were ≥ 20 years of age.14 Average annual incidence rates during 1997 to 2000 were highest among infants aged < 1 year (55.5 cases per 100, 000 population) and lower in children aged 1 to 4 years (5.5), children aged 5 to 9 years (3.6), persons aged 10 to 19 years (5.5) and persons aged ≥ 20 years (0.8).14
The severity of pertussis remains highest in infants. Of 7, 203 infants < 6 months of age reported as having pertussis during the period 1997-2000, 63% were hospitalized, 12% had pneumonia, 1.4% had one or more seizures, 0.2% had encephalopathy and 0.8% died.14
Efficacy of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine)
Two clinical studies were conducted to assess the protective efficacy of the acellular pertussis component of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine. A randomized, controlled clinical trial in Sweden assessed efficacy after two doses of the pertussis component in children 5-11 months of age.18 A second study was conducted in Germany using a three-dose schedule to evaluate the protective efficacy of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine in younger infants.19
In 1986-1987, a double-blind, randomized, placebo-controlled efficacy trial of two BIKEN acellular pertussis vaccines was conducted in Sweden. One of the vaccines was a two-component vaccine comparable to the acellular pertussis components contained in Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine. This prospective trial used a standardized case definition and active case ascertainment. In this trial, 1, 389 children, 5-11 months of age (median 8.5 months), received two doses of the acellular pertussis vaccine 7-13 weeks apart and 954 received a placebo control. During the 15 months of follow-up from 30 days after the second dose, culture-confirmed whooping cough (cough of any duration and a positive culture of B pertussis) occurred in 40 placebo and 18 acellular pertussis vaccine recipients. The point estimate of protective efficacy for two doses of vaccine was 69% (95% CI; 47% to 82%) for all cases of culture-confirmed pertussis with any cough 1 day or longer and 79% (95% CI; 57% to 90%) using a secondary case definition of culture-confirmed cases with cough of over 30 days duration.18 In a reanalysis of the Swedish data, efficacy estimates increased with duration of coughing spasms and when the case definition included whoops and whoops plus at least nine coughing spasms a day.20 Using a case definition of 21 days or more of coughing spasms, confirmed by positive culture, resulted in an efficacy estimate of 81% (95% CI; 61% to 90%).20
Using a passive reporting system, three-year unblinded follow-up of vaccine and placebo recipients from the above Swedish study has shown a post-trial efficacy of 77% (95% CI; 65% to 85%) for all culture-proven cases of pertussis, and an efficacy of 92% (95% CI; 84% to 96%) for culture-proven cases with a cough of over 30 days duration.21
A case-control study to evaluate the efficacy of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine was conducted in Germany.19 The study population consisted of patients in 63 pediatric practices who had no contraindications to pertussis immunization and were enrolled in the study between the ages of 6 and 17 weeks (actual range of age at first visit was up to 20 weeks for the Diphtheria and Tetanus Toxoids Adsorbed (DT) for Pediatric Use group). By parental choice, infants received Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine or whole-cell pertussis DTP vaccine (manufactured by Chiron Behring, Germany [formerly Behringwerke]) at approximately 3, 5, and 7 months of age, or DT, or no vaccine. Cases of pertussis were identified by obtaining cultures for B pertussis from all patients between the ages of 2 and 24 months who presented to the physician's office with 7 or more days of cough. Identification of presumptive cases of pertussis was made by primary care physicians who were not blinded to the vaccine status of subjects. Cases were confirmed by positive culture in the subject or positive culture in a subject's household contact. Duration of cough in study subjects was determined at an office visit, by telephone, or by home visit 21-24 days after the onset of cough.
Four age-matched controls were selected for each case from the same pediatric practice. Selection of controls was done without knowledge of vaccination status. The vaccine (or no vaccine) and number of doses which each case and control subject received subsequently was determined from medical records.
In order to adjust for potentially confounding variables, information on sex, race, day-care attendance, well-baby visits, sick-child visits, pertussis vaccination status of siblings, age of siblings, number of siblings, day-care attendance of siblings, and parental employment status was obtained through interview of parents. Information on erythromycin use was not obtained for the study population.
A total of 16, 780 infants were enrolled in the study, of whom 74.6% received Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine and 10.9%, 12.5%, and 2.1% received whole-cell pertussis DTP vaccine, DT vaccine, or no vaccine, respectively, by non-random parental choice. A total of 11, 017 cultures for B pertussis was obtained and 140 cases were identified using a primary case definition of cough ≥21 days, plus positive culture for B pertussis or household contact with a person with culture-positive pertussis. Of the 140 cases, 130 cases were diagnosed on the basis of a positive culture and 10 on the basis of household contact with a culture-positive case. For the 140 cases, 543 controls were selected. Of the 140 cases, 29 (20.7%) received three doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine, 5 (3.6%) received two doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine, 44 (31.4%) received two or three doses of DT vaccine, 44 (31.4%) received one dose of either Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine, whole-cell pertussis DTP vaccine or DT vaccine, and 18 (13%) received no vaccine. Of the 543 controls, 175 (32.2%) received three doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine, 67 (12.3%) received two doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine, 45 (8.3%) received two or three doses of whole-cell pertussis DTP vaccine, 73 (13.4%) received DT vaccine, 153 (28.2%) received one dose of either DT vaccine, whole-cell pertussis DTP vaccine, or Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine, and 30 (5.5%) received no vaccine. Adjusting for sibling age, sibling pertussis immunization by age group, siblings in day care, number of siblings in day care, and father's employment status, the vaccine efficacy of three doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine compared to two or three doses of DT vaccine was 80% (95% CI; 59% to 90%).2
In a clinical study conducted in 65 US and 89 German infants, a single lot of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine was administered at 2, 4, and 6 months of age for the purpose of comparing immune responses to PT and FHA. This study showed that US and German infants, who received three doses of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine, expressed similar levels of antibodies to these antigens. The percentage of infants demonstrating a four-fold or greater antibody response, was also similar for PT and FHA in both groups.2
Efficacy of diphtheria toxoid used in Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine was determined on the basis of immunogenicity studies, with a comparison to a serological correlate of protection (0.01 antitoxin units/mL) established by the Panel on Review of Bacterial Vaccines & Toxoids.10
Efficacy of tetanus toxoid used in Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine was determined on the basis of immunogenicity studies, with a comparison to a serological correlate of protection (0.01 antitoxin units/mL) established by the Panel on Review of Bacterial Vaccines & Toxoids.10
Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) Vaccine Combined With ActHIB Vaccine (TriHIBit vaccine) By Reconstitution
Clinical studies examined the immune response in 15- to 20-month-old children when Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine was used to reconstitute one lyophilized single dose vial of ActHIB vaccine (TriHIBit vaccine). All children received three doses of Haemophilus b Conjugate Vaccine [ActHIB vaccine or HibTITER(Haemophilus b Conjugate Vaccine Diphtheria CRM197 Protein Conjugate manufactured by Lederle Laboratories)] and three doses of whole-cell pertussis DTP vaccine at approximately 2, 4, and 6 months of age. Table 1 shows the pertussis responses when Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine was used to reconstitute ActHIB vaccine (TriHIBit vaccine) compared to the two vaccines given concomitantly but at different sites. In children who received the vaccines separately or combined, 100% had an antibody response to the PRP component ≥1.0 mg/mL.2 Responses to both diphtheria and tetanus toxoids were similar for children in the two groups.2
TABLE 12 IMMUNE RESPONSES IN 15- TO 20-MONTH-OLD CHILDREN WHEN TRIPEDIA (diphtheria and tetanus toxoids and acellular pertussis vaccine) VACCINE IS COMBINED WITH ActHIB VACCINEBY RECONSTITUTION (TriHIBitVACCINE) COMPARED TO THE VACCINES ADMINISTERED SEPARATELY
GMT (ELISA units/mL)
% 4-Fold Rise
% 4-Fold Rise
GMT (ELISA units/mL)
% 4-Fold Rise
* N = Number of Children
**The clinical significance of the difference in 4-fold rise of anti-FHA is unknown at present.
Concomitantly Administered Vaccines
In a clinical study, US infants received Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine, ActHIB vaccine, and hepatitis B vaccine (Recombinant), manufactured by Merck & Co. , Inc. , concomitantly at separate sites, and OPV vaccine (poliovirus vaccine live oral trivalent), manufactured by Lederle Laboratories. In one of the study groups, Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine, ActHIB vaccine and OPV vaccine were administered at 2, 4, and 6 months of age and hepatitis B vaccine was given at 2 and 4 months of age. One hundred percent of the 69 children who received Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine concomitantly with ActHIB vaccine demonstrated anti-PRP antibodies ≥1.0 mg/mL. Sera from a subset of 12 infants who received hepatitis B vaccine concomitantly at 2 and 4 months of age showed that 93% had anti-HBs titers of ≥ 10 mIU/mL. Sera from a subset of 20 infants who received OPV vaccine concomitantly at 2, 4, and 6 months of age showed that 100% had protective neutralizing antibody responses to all three polio virus types.
In clinical studies evaluating concomitant administration of TriHIBit vaccine (ActHIB vaccine reconstituted with Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine) with measles, mumps and rubella (MMR) vaccine, manufactured by Merck & Co. , to 15- to 20-month-old children, the data suggest that the combination vaccine does not interfere with the immunogenicity of the MMR vaccine. Overall seroconversion rates in children who received TriHIBit vaccine were 98% (46/47), 98% (42/43) and 96% (43/45) for measles, mumps and rubella, respectively.
Data on the concomitant administration of Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine or TriHIBit vaccine (ActHIB vaccine reconstituted with Tripedia (diphtheria and tetanus toxoids and acellular pertussis vaccine) vaccine) with varicella vaccine, inactivated poliovirus vaccine (IPV) or pneumococcal conjugate vaccine are not available.
3. Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Committee on Immunization Practices (ACIP). Diphtheria, tetanus, and pertussis: recommendations for vaccine use and other preventive measures. MMWR 1991;40: (RR-10): 1-28.
4. CDC. Notice to readers: final 2000 reports of notifiable diseases. MMWR 2001;50(33): 712.
5. CDC. Epidemiology and prevention of vaccine-preventable diseases, Atkinson, W et al, eds. 7th ed. Atlanta, GA, 2003;Chapters 4, 5, 6.
6. Golaz A, et al. Epidemic diphtheria in the newly Independent States of the former Soviet Union: implications for diphtheria control in the United States. J Infect Dis 2000;181(Suppl 1): S237-S243.
7. Hardy IRB, et al. Current situation and control strategies for resurgence of diphtheria in newly independent states of the former Soviet Union. Lancet 1996;347: 1739-1744.
8. Mortimer EA, et al. Diphtheria Toxoid. In: Plotkin SA and Orenstein WA, eds. Vaccines. 3rd ed. Philadelphia, PA: WB Saunders Company 1999:140-157.
9. Wassilak SGF, et al. Tetanus Toxoid. In: Plotkin SA and Orenstein WA, eds. Vaccines. 3rd ed. Philadelphia, PA: WB Saunders Company 1999: 441-474.
10. Department of Health and Human Services, Food and Drug Administration. Biological products; Bacterial vaccines and toxoids; Implementation of efficacy review: Proposed rule. Federal Register December 13, 1985;50(240): 51002-51117.
11. CDC. General recommendations on immunization: Recommendations of the ACIP and the American Academy of Family Physicians (AAFP). MMWR 2002;51(RR-2): 1-35.
12. Edwards KM, et al. Pertussis Vaccine. In: Plotkin SA and Orenstein WA, eds. Vaccines. 3rd ed. Philadelphia, PA: WB Saunders Company 1999; 293-344.
13. Nelson Textbook of Pediatrics. - 16th ed. [edited by] Behrman RE, Kliegman RM, Jenson HB. WB Saunders Company 2000;838-842.
14. CDC. Pertussis - United States, 1997-2000. MMWR 2002;51(04): 73-76.
15. CDC. Pertussis vaccination: use of acellular pertussis vaccines among infants and young children. Recommendations of the ACIP. MMWR 1997;46(RR-7): 1-25.
16. Güris D, et al. Changing epidemiology of pertussis in the United States: increasing reported incidence among adolescents and adults, 1990-1996. Clin Infect Dis 1999;28: 1230-1237.
17. Training and Education Branch, National Immunization Program, CDC. Pertussis. In: Atkinson W, et al, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 6th ed. Atlanta, GA: Public Health Foundation 2000: 67-83.
18. Kallings LO, et al. Placebo-controlled trial of two acellular pertussis vaccines in Sweden protective efficacy and adverse events. The Lancet 1988;955-960.
19. Liese, JG, et al. Efficacy of a two-component acellular pertussis vaccine in infants. Pediatr Infect Dis J 1997;16: 1038-1044.
20. Blackwelder WC, et al. Acellular pertussis vaccines. Efficacy and evaluation of clinical case definitions. Am J Dis Child 1991;145(11): 1285-1289.
21. Olin P, et al. Relative efficacy of two acellular pertussis vaccines during three years of passive surveillance. Vaccine 1992;10:142-144.
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This monograph has been modified to include the generic and brand name in many instances.
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