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Mechanism Of Action
Diphtheria is an acute toxin-mediated disease caused by toxigenic strains of C diphtheriae. 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.5 Levels of 1.0 IU/mL have been associated with long-term protection.6
Tetanus is an acute disease caused by an extremely potent neurotoxin produced by C tetani. 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 assay is considered the minimum protective level.5,7 A tetanus antitoxin level ≥ 0.1 IU/mL as measured by the ELISA used in clinical studies of DAPTACEL vaccine is considered protective.
Pertussis (whooping cough) is a respiratory disease caused by Bpertussis. This Gram-negative coccobacillus produces a variety of biologically active components, though their role in either the pathogenesis of, or immunity to, pertussis has not been clearly defined.
In a US study in which children received 4 doses of DAPTACEL vaccine at 2, 4, 6 and 1517 months of age, after the third dose, 100% (N = 1,099) achieved diphtheria antitoxin levels of ≥ 0.01 IU/mL and 98.5% achieved diphtheria antitoxin levels of ≥ 0.10 IU/mL. Among a random subset of children who received the fourth dose of DAPTACEL vaccine at 15-16 months of age, 96.5% (N = 659) achieved diphtheria antitoxin levels of ≥ 1.0 IU/mL after the fourth dose.
In a US study in which children received 4 doses of DAPTACEL vaccine at 2, 4, 6 and 15-17 months of age, after the third dose, 100% (N = 1,037) achieved tetanus antitoxin levels of ≥ 0.10 IU/mL. Among a random subset of children who received the fourth dose of DAPTACEL vaccine at 15-16 months of age, 98.8% (N = 681) achieved tetanus antitoxin levels of ≥ 1.0 IU/mL after the fourth dose.
A randomized, double-blinded, placebo-controlled efficacy and safety study was conducted in Sweden during 1992-1995 (Sweden I Efficacy Trial) under the sponsorship of the National Institute of Allergy and Infectious Diseases. A total of 9,829 infants received 1 of 4 vaccines: DAPTACEL vaccine (N = 2,587); another investigational acellular pertussis vaccine (N = 2,566); whole-cell pertussis DTP vaccine (N = 2,102); or DT vaccine as placebo (Swedish National Bacteriological Laboratory, N = 2,574). Infants were immunized at 2, 4 and 6 months of age. The mean length of follow-up was 2 years after the third dose of vaccine. The protective efficacy of DAPTACEL vaccine against pertussis after 3 doses using the World Health Organization (WHO) case definition ( ≥ 21 consecutive days of paroxysmal cough with culture or serologic confirmation or epidemiologic link to a confirmed case) was 84.9% (95% confidence interval [CI] 80.1 to 88.6). The protective efficacy of DAPTACEL vaccine against mild pertussis ( ≥ 1 day of cough with laboratory confirmation) was 77.9% (95% CI 72.6 to 82.2). Protection against pertussis by DAPTACEL vaccine was sustained for the 2-year follow-up period.
In order to assess the antibody response to the pertussis antigens of DAPTACEL vaccine in the US population, 2 lots of DAPTACEL vaccine, including the lot used in the Sweden I Efficacy Trial, were administered to US infants in the US Bridging Study. In this study, antibody responses following 3 doses of DAPTACEL vaccine given to US children at 2, 4 and 6 months of age were compared to those from a subset of the infants enrolled in the Sweden I Efficacy Trial. Assays were performed in parallel on the available sera from the US and Swedish infants. Antibody responses to all the antigens were similar except for those to the PRN component. For both lots of DAPTACEL vaccine, the geometric mean concentration (GMC) and percent response to PRN in US infants (Lot 006, N = 107; Lot 009, N = 108) were significantly lower after 3 doses of vaccine than in Swedish infants (N = 83). In separate US and Canadian studies in which children received DAPTACEL vaccine at 2, 4 and 6 months of age, with a fourth dose at either 17-20 months (Canadian study) or 15-16 months (random subset from US study) of age, antibody responses to each pertussis antigen following the fourth dose (Canadian study N = 275; US study N = 237-347) were at least as high as those seen in the Swedish infants after 3 doses. While a serologic correlate of protection for pertussis has not been established, the antibody response to all antigens in North American infants after 4 doses of DAPTACEL vaccine at 2, 4, 6 and 15-20 months of age was comparable to that achieved in Swedish infants in whom efficacy was demonstrated after 3 doses of DAPTACEL vaccine at 2, 4 and 6 months of age.
Concomitantly Administered Vaccines
In the US Bridging study, DAPTACEL vaccine was given concomitantly with Hib conjugate vaccine (Sanofi Pasteur SA) according to local practices. Anti-PRP immune response was evaluated in 261 infants who received 3 doses of Hib conjugate vaccine. One month after the third dose, 96.9% achieved anti-PRP antibody levels of at least 0.15 mcg/mL and 82.7% achieved antibody levels of at least 1.0 mcg/mL.
In the US study in which infants received DAPTACEL vaccine concomitantly with Hib conjugate (tetanus toxoid conjugate) vaccine, IPV, 7-valent pneumococcal conjugate vaccine, and hepatitis B vaccine [see ADVERSE REACTIONS], at 7 months of age, 100.0% of subjects (N = 1,0501,097) had protective neutralizing antibody levels ( ≥ 1:8 1/dil) for poliovirus types 1, 2 and 3; and 92.4% (N = 998) achieved anti-hepatitis B surface antigen levels ≥ 10.0 mlU/mL. Although there is no established serologic correlate of protection for any of the pneumococcal serotypes, at 7 months of age 91.3%-98.9% (N = 1,027-1,029) achieved anti-pneumococcal polysaccharide levels ≥ 0.5 mcg/mL for serotypes 4, 9V, 14, 18C, 19F and 23F and 80.7% (N = 1,027) achieved an anti-pneumococcal polysaccharide level ≥ 0.5 mcg/mL for serotype 6B. The mumps seroresponse rate was lower when DAPTACEL vaccine was administered concomitantly (86.6%; N = 307) vs. non-concomitantly (90.1%; N = 312) with the first dose of MMR vaccine [upper limit of 90% confidence interval for difference in rates (non-concomitant minus concomitant) > 5%]. There was no evidence for interference in the immune response to the measles, rubella, and varicella antigens or to the fourth dose of the 7-valent pneumococcal conjugate vaccine with concomitant administration of DAPTACEL vaccine.
1 Stratton KR, et al. editors. Adverse events associated with childhood vaccines; evidence bearing on causality. Washington D.C.: National Academy Press. 1994. p. 67-117.
2 Stainer DW, Scholte MJ. A simple chemically defined medium for the production of phase I Bordetella pertussis. J Gen Microbiol 1970;63:211-20.
3 Stainer DW. Production of diphtheria toxin. In: Manclark CR, editor. Proceedings of an informal consultation on the World Health Organization requirements for diphtheria, tetanus, pertussis and combined vaccines. United States Public Health Service, Bethesda, MD. DHHS 91-1174. 1991. p. 7-11.
4 Mueller JH, Miller PA. Variable factors influencing the production of tetanus toxin. J Bacteriol 1954;67(3):271-7.
5 Department of Health and Human Services, Food and Drug Administration. Biological products; bacterial vaccines and toxoids; implementation of efficacy review; proposed rule. Federal Register 1985;50(240):51002-117.
6 Wharton M, et al. Diphtheria Toxoid. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia, PA: W. B. Saunders 2004 p. 211-28.
7 Wassilak SGF, et al. Tetanus Toxoid. In: Plotkin SA, Orenstein WA, editors. Vaccines. 4th ed. Philadelphia, PA: W. B. Saunders 2004 p. 745-81.
Last reviewed on RxList: 8/18/2014
This monograph has been modified to include the generic and brand name in many instances.
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