Mechanism of Action

Protection against disease attributable to C tetani 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. ^{(8) (9)} A level ≥ 0.1 to 0.2 IU/mL has been considered as protective. ⁽¹⁰⁾ Protection against disease attributable to C diphtheriae is due to the development of neutralizing antibodies to diphtheria toxin. A serum 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. ⁽⁹⁾ Levels of 1.0 IU/mL have been associated with long term protection. ⁽⁸⁾ The mechanism of protection from B pertussis disease is not well understood. However, the pertussis components in ADACEL vaccine have been shown to prevent pertussis in infants in clinical trials with DAPTACEL vaccine. (See Clinical Studies.)

Clinical Studies

The efficacy of the tetanus toxoid and diphtheria toxoid used in ADACEL vaccine was based on the immune response to these antigens compared to a US licensed Tetanus and Diphtheria Toxoids Adsorbed For Adult Use (Td) vaccine manufactured by Aventis Pasteur Inc., Swiftwater, PA. The primary measures of immunogenicity were (a) the percentage of subjects attaining an antibody level of at least 0.1 IU/mL and (b) the percentage of subjects achieving a rise in antibody concentration after vaccination (booster response). The demonstration of a booster response depended on the antibody concentration to each antigen prior to immunization. Threshold or †cut-off† values for antibody concentrations to each antigen were established based on the 95th percentile of the pre-vaccination antibody concentrations observed in previous clinical trials. A booster response was defined as a four-fold rise in antibody concentration if the pre-vaccination concentration was below the cut-off value and a two-fold rise in antibody concentration if the pre-vaccination concentration was above the cut-off value.

The efficacy of the pertussis antigens used in ADACEL vaccine was inferred based on a comparison of pertussis antibody levels achieved in recipients of a single booster dose of ADACEL vaccine with those obtained in infants after three doses of DAPTACEL vaccine. In the Sweden I Efficacy Trial, three doses of DAPTACEL vaccine was shown to confer a protective efficacy of 84.9% (95% CI: 80.1%, 88.6%) against WHO defined pertussis (21 days of paroxysmal cough with laboratory-confirmed B pertussis infection or epidemiological link to a confirmed case). The protective efficacy against mild pertussis (defined as at least one day of cough with laboratory-confirmed B pertussis infection) was 77.9% (95% CI: 72.6%, 82.2%). ^{(11) (12)} In addition, the ability of ADACEL vaccine to elicit a booster response to the pertussis antigens following vaccination was evaluated. The acellular pertussis formulations for ADACEL and DAPTACEL vaccines differ only in the amount of detoxified PT (2.5 µg in ADACEL vaccine versus 10 µg in DAPTACEL vaccine).

The principal immunogenicity study was a comparative, multi-center, randomized, observer blind, controlled trial that enrolled male and female adolescents and adults, 11-64 years of age inclusive, who had not received tetanus or diphtheria toxoid-containing vaccines within 5 years. Participants were vaccinated with either a dose of ADACEL vaccine (N = 1,268) or Td vaccine (N = 1,023). (Blinding procedures for safety assessments are described in the ADVERSE REACTIONS section.) Participants were randomized between groups. The study also included age stratification to ensure adequate representation across the entire age range of 11-64. Sera were obtained before and approximately 35 days after vaccination.

For subjects enrolled in this comparative trial, demographic characteristics were similar between the vaccine groups. The immunogenicity profiles for tetanus and diphtheria toxoids between ADACEL and Td vaccines were comparable. (See Table 1 and Table 2.) ADACEL vaccine induced pertussis antibodies that exceeded those after three doses of DAPTACEL vaccine. (See Table 3.) Acceptable booster responses to each of the pertussis antigens were also demonstrated, ie, the percentage of subjects with a booster response exceeded the pre-defined lower limit. ⁽¹²⁾ (See Table 4.)

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